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2015v1.0
Davidson’s
Principles and Practice of
Medicine
Sir Stanley Davidson (1894-1981)
This famous textbook was the brainchild of one of the great
Professors of Medicine of the 20th century. Stanley Davidson
was born in Sri Lanka and began his medical undergraduate
training at Trinity College, Cambridge; this was interrupted by
World War I and later resumed in Edinburgh. He was seriously
wounded in battle, and the carnage and shocking waste of young
life that he encountered at that time had a profound effect on
his subsequent attitudes and values.
In 1930 Stanley Davidson was appointed Professor of Medicine
at the University of Aberdeen, one of the first full-time Chairs of
Medicine anywhere and the first in Scotland. In 1938 he took
up the Chair of Medicine at Edinburgh and was to remain in this
post until retirement in 1959. He was a renowned educator and
a particularly gifted teacher at the bedside, where he taught that
everything had to be questioned and explained. He himself gave
most of the systematic lectures in Medicine, which were made
available as typewritten notes that emphasised the essentials
and far surpassed any textbook available at the time.
Principles and Practice of Medicine was conceived in the
late 1940s with its origins in those lecture notes. The first
edition, published in 1952, was a masterpiece of clarity and
uniformity of style. It was of modest size and price, but sufficiently
comprehensive and up to date to provide students with the
main elements of sound medical practice. Although the format
and presentation have seen many changes in 22 subsequent
editions, Sir Stanley’s original vision and objectives remain. More
than half a century after its first publication, his book continues to
inform and educate students, doctors and health professionals
all over the world.
Principles and Practice of
23rd Edition
Edited by
Stuart H Ralston
MD, FRCP, FMedSci, FRSE, FFPM(Hon)
Arthritis Research UK Professor of Rheumatology,
University of Edinburgh; Honorary Consultant Rheumatologist,
Western General Hospital, Edinburgh, UK
Ian D Penman
BSc(Hons), MD, FRCPE
Consultant Gastroenterologist,
Royal Infirmary of Edinburgh;
Honorary Senior Lecturer, University of Edinburgh, UK
Mark WJ Strachan
BSc(Hons), MD, FRCPE
Consultant Endocrinologist,
Metabolic Unit, Western General Hospital, Edinburgh;
Honorary Professor, University of Edinburgh, UK
Richard P Hobson
LLM, PhD, MRCP(UK), FRCPath
Consultant Microbiologist,
Harrogate and District NHS Foundation Trust;
Honorary Senior Lecturer, University of Leeds, UK
Illustrations by Robert Britton
ELSEVIER Edinburgh London New York Oxford Philadelphia St Louis Sydney 2018
ELSEVIER
© 2018 Elsevier Ltd. All rights reserved.
Illustrations and boxes in Chapter 8 © Julian White.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording, or any information storage and retrieval system, without permission in writing from
the publisher. Details on how to seek permission, further information about the publisher’s permissions policies and
our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency,
can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the publisher (other than
as may be noted herein).
First edition 1 952
Second edition 1954
Third edition 1956
Fourth edition 1958
Fifth edition 1960
Sixth edition 1 962
Seventh edition 1964
Eighth edition 1966
ISBN 978-0-7020-7028-0
International ISBN 978-0-7020-7027-3
Notices
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds or experiments described herein. Because of rapid advances in the medical
sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent
of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to
persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any
methods, products, instructions, or ideas contained in the material herein.
Ninth edition 1968
Tenth edition 1971
Eleventh edition 1 974
Twelfth edition 1977
Thirteenth edition 1981
Fourteenth edition 1 984
Fifteenth edition 1 987
Sixteenth edition 1991
Seventeenth edition 1 995
Eighteenth edition 1 999
Nineteenth edition 2002
Twentieth edition 2006
Twenty-first edition 2010
Twenty-second edition 2014
Twenty-third edition 2018
your source for books,
journals and multimedia
in the health sciences
www.elsevierhealth.com
ELSEVIER
ELSEVIER
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to grow libraries in
developing countries
www.elsevier.com • www.bookaid.org
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Printed in China
Last digit is the print number: 98765432
Content Strategist: Laurence Hunter
Content Development Specialist: Wendy Lee
Content Coordinator: Susan Jansons
Project Manager: Louisa Talbott
1 Designer: Miles Hitchen
Contents
Preface
ix
Contributors
xi
International Advisory Board
XV
Acknowledgements
xvii
Introduction
xix
PART 1 FUNDAMENTALS OF MEDICINE
i.
Clinical decision-making
N Cooper, AL Cracknell
1
2.
Clinical therapeutics and good prescribing
SRJ Maxwell
13
3.
Clinical genetics
K Tatton-Brown, DR FitzPatrick
37
4.
Clinical immunology
SE Marshall, SL Johnston
61
5.
Population health and epidemiology
H Campbell, DA McAllister
91
6.
Principles of infectious disease
JAT Sandoe, DH Dockrell
99
EMERGENCY AND CRITICAL CARE MEDICINE
131
7.
Poisoning
SHL Thomas
131
8.
Envenomation
J White
151
9.
Environmental medicine
M Byers
163
10.
Acute medicine and critical illness
173
VR Tallentire, MJ MacMahon
vi • CONTENTS
PART 3 CLINICAL MEDICINE 215
11.
Infectious disease
DH Dockrell, S Sundar, BJ Angus
215
12.
HIV infection and AIDS
G Maartens
305
13.
Sexually transmitted infections
GR Scott
329
14.
Clinical biochemistry and metabolic medicine
A Mather, L Burnett, DR Sullivan, P Stewart
345
15.
Nephrology and urology
B Conway, PJ Phelan, GD Stewart
381
16.
Cardiology
DE Newby, NR Grubb
441
17.
Respiratory medicine
PT Reid, JA Innes
545
18.
Endocrinology
MWJ Strachan, JDC Newell-Price
629
19.
Nutritional factors in disease
AG Shand, JPH Wilding
691
20.
Diabetes mellitus
ER Pearson, RJ McCrimmon
719
21.
Gastroenterology
E El-Omar, MH McLean
763
22.
Hepatology
QM Anstee, DEJ Jones
845
23.
Haematology and transfusion medicine
HG Watson, DJ Culligan, LM Manson
911
24.
Rheumatology and bone disease
GPR Clunie, SH Ralston
981
25.
Neurology
JP Leach, RJ Davenport
1061
26.
Stroke medicine
P Langhorne
1147
27.
Medical ophthalmology
J Olson
1163
28.
Medical psychiatry
RM Steel, SM Lawrie
1179
29.
Dermatology
SH Ibbotson
1209
30.
Maternal medicine
L Mackillop, FEM Neuberger
1269
CONTENTS • vii
31.
Adolescent and transition medicine
R Mann
1287
32.
Ageing and disease
MD Witham
1301
33.
Oncology
GG Dark
1313
34.
Pain and palliative care
IA Colvin, M Fallon
1337
35.
Laboratory reference ranges
SJ Jenks
1357
Index
1365
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Preface
Well over two million copies of Davidson’s Principles and Practice
of Medicine have been sold since it was first published in 1952.
Now in its 23rd Edition, Davidson’s is regarded as a ‘must-have’
textbook for thousands of medical students, doctors and health
professionals across the world, describing the pathophysiology
and clinical features of the most important conditions encountered
in the major specialties of adult medicine and explaining how to
investigate, diagnose and manage them. The book is the winner
of numerous prizes and awards and has been translated into
many languages. Taking its origins from Sir Stanley Davidson’s
much-admired lecture notes, the book has endured because it
continues to keep pace with how modern medicine is taught and
to provide a wealth of information in an easy-to-read, concise
and beautifully illustrated format.
Davidson’s strives to ensure that readers can not only recognise
the clinical features of a disease but also understand the underlying
causes. To achieve this, each chapter begins with a summary
of the relevant pre-clinical science, linking pathophysiology with
clinical presentation and treatment so that students can use the
book from the outset of their medical studies right through to
their final examinations and beyond.
The regular introduction of new authors and editors is important
for maintaining freshness. On this occasion, Professor Mark
Strachan and Dr Richard Hobson have come on board as editors,
and 26 new authors have joined our existing contributors to make
up an outstanding team of authorities in their respective fields.
As well as recruiting authors from around the globe, particularly
for topics such as infectious diseases, HIV and envenomation,
we welcome members from 1 7 countries on to our International
Advisory Board. These leading experts provide detailed comments
that are crucial to our revision of each new edition. A particularly
important aspect in planning the revision is for the editors to
meet students and faculty in medical schools in those countries
where the book is most widely read, so that we can respond to
the feedback of our global readership and their tutors. We use
this feedback, along with the information we gather via detailed
student reviews and surveys, to craft each edition. The authors,
editors and publishing team aim to ensure that readers all over the
world are best served by a book that integrates medical science
with clinical medicine to convey key knowledge and practical
advice in an accessible and readable format. The amount of detail
is tailored to the needs of medical students working towards their
final examinations, as well as candidates preparing for Membership
of the Royal Colleges of Physicians (MRCP) or its equivalent.
With this new edition we have introduced several changes in
both structure and content. The opening six chapters provide
an account of the principles of genetics, immunology, infectious
diseases and population health, along with a discussion of
the core principles behind clinical decision-making and good
prescribing. Subsequent chapters discuss medical emergencies
in poisoning, envenomation and environmental medicine, while a
new chapter explores common presentations in acute medicine,
as well as the recognition and management of the critically
ill. The disease-specific chapters that follow cover the major
medical specialties, each one thoroughly revised and updated to
ensure that readers have access to the ‘cutting edge’ of medical
knowledge and practice. Two new chapters on maternal and
adolescent/transition medicine now complement the one on
ageing and disease, addressing particular problems encountered
at key stages of patients’ lives. Medical ophthalmology is also
now included as a direct response to readers’ requests.
The innovations introduced in recent editions have been
maintained and, in many cases, developed. The highly popular
‘Clinical Examination’ overviews have been extended to the
biochemistry, nutrition and dermatology chapters. The ‘Presenting
Problems’ sections continue to provide an invaluable overview
of the most common presentations in each disease area. The
‘Emergency’ and ‘Practice Point’ boxes have been retained along
with the ‘In Old Age’, ‘In Pregnancy’ and ‘In Adolescence’ boxes,
which emphasise key practical points in the presentation and
management of the elderly, women with medical disorders who
are pregnant or planning pregnancy, and teenagers transitioning
between paediatric and adult services.
Education is achieved by assimilating information from many
sources and readers of this book can enhance their learning
experience by using several complementary resources. We are
delighted to have a new self-testing companion book entitled
Davidson’s Assessment in Medicine, containing over 1250
multiple choice questions specifically tailored to the contents of
Davidson’s. The long-standing association of Davidson’s with
its sister books, Macleod’s Clinical Examination (now in its 1 4th
Edition) and Principles and Practice of Surgery (7th Edition), still
holds good. Our ‘family’ has also expanded with the publication of
Davidson’s Essentials of Medicine, a long-requested pocket-sized
version of the main text; Davidson’s 100 Clinical Cases, which
contains scenarios directly based on our ‘Presenting Problems’;
and Macleod’s Clinical Diagnosis, which describes a systematic
approach to the differential diagnosis of symptoms and signs. We
congratulate the editors and authors of these books for continuing
the tradition of easily digested and expertly illustrated texts.
We all take immense pride in continuing the great tradition
first established by Sir Stanley Davidson and in producing an
outstanding book for the next generation of doctors.
SHR, IDP, MWJS, RPH
Edinburgh 2018
This page intentionally left blank
Contributors
Brian J Angus BSc(Hons), DTM&H, FRCP, MD,
FFTM(Glas)
Associate Professor, Nuffield Department of Medicine,
University of Oxford, UK
Quentin M Anstee BSc(Hons), PhD, FRCP
Professor of Experimental Hepatology, Institute of Cellular
Medicine, Newcastle University, Newcastle upon Tyne;
Honorary Consultant Hepatologist, Freeman Hospital,
Newcastle upon Tyne, UK
Leslie Burnett MBBS, PhD, FRCPA, FHGSA
Chief Medical Officer, Genome. One, Garvan Institute of
Medical Research, Sydney; Conjoint Professor, St Vincent’s
Clinical School, UNSW; Honorary Professor in Pathology and
Genetic Medicine, Sydney Medical School, University of
Sydney, Australia
Mark Byers OBE, FRCGP, FFSEM, FIMC, MRCEM
Consultant in Pre-Hospital Emergency Medicine, Institute of
Pre-Hospital Care, London, UK
Harry Campbell MD, FRCPE, FFPH, FRSE
Professor of Genetic Epidemiology and Public Health, Centre
for Global Health Research, Usher Institute of Population
Health Sciences and Informatics, University of Edinburgh, UK
Gavin PR Clunie BSc, MD, FRCP
Consultant Rheumatologist and Metabolic Bone Physician,
Cambridge University Hospitals NHS Foundation Trust,
Addenbrooke’s Hospital, Cambridge, UK
Lesley A Colvin BSc, FRCA, PhD, FRCPE, FFPMRCA
Consultant, Department of Anaesthesia, Critical Care and
Pain Medicine, Western General Hospital, Edinburgh;
Honorary Professor in Anaesthesia and Pain Medicine,
University of Edinburgh, UK
Bryan Conway MB, MRCP, PhD
Senior Lecturer, Centre for Cardiovascular Science,
University of Edinburgh; Honorary Consultant Nephrologist,
Royal Infirmary of Edinburgh, UK
Nicola Cooper FAcadMEd, FRCPE, FRACP
Consultant Physician, Derby Teaching Hospitals NHS
Foundation Trust, Derby; Honorary Clinical Associate
Professor, Division of Medical Sciences and Graduate Entry
Medicine, University of Nottingham, UK
Alison L Cracknell FRCP
Consultant, Medicine for Older People, Leeds Teaching
Hospitals NHS Trust, Leeds; Honorary Clinical Associate
Professor, University of Leeds, UK
Dominic J Culligan BSc, MD, FRCP, FRCPath
Consultant Haematologist, Aberdeen Royal Infirmary;
Honorary Senior Lecturer, University of Aberdeen, UK
Graham G Dark FRCP, FHEA
Senior Lecturer in Medical Oncology and Cancer Education,
Newcastle University, Newcastle upon Tyne, UK
Richard J Davenport DM, FRCPE, BMedSci
Consultant Neurologist, Royal Infirmary of Edinburgh and
Western General Hospital, Edinburgh; Honorary Senior
Lecturer, University of Edinburgh, UK
David H Dockrell MD, FRCPI, FRCPG, FACP
Professor of Infection Medicine, Medical Research Council/
University of Edinburgh Centre for Inflammation Research,
University of Edinburgh, UK
Emad El-Omar BSc(Hons), MD(Hons), FRCPE, FRSE,
FRACP
Professor of Medicine, St George and Sutherland Clinical
School, University of New South Wales, Sydney, Australia
Marie Fallon MD, FRCP
St Columba’s Hospice Chair of Palliative Medicine, University
of Edinburgh, UK
David R FitzPatrick MD, FMedSci
Professor, Medical Research Council Human Genetics Unit,
Institute of Genetics and Molecular Medicine, University of
Edinburgh, UK
Neil R Grubb MD, FRCP
Consultant in Cardiology, Royal Infirmary of Edinburgh;
Honorary Senior Lecturer in Cardiovascular Sciences,
University of Edinburgh, UK
Sally H Ibbotson BSc(Hons), MD, FRCPE
Professor of Photodermatology, University of Dundee;
Honorary Consultant Dermatologist and Head of Photobiology
Unit, Ninewells Hospital and Medical School, Dundee, UK
xii • CONTRIBUTORS
J Alastair Innes BSc, PhD, FRCPE
Consultant, Respiratory Unit, Western General Hospital,
Edinburgh; Honorary Reader in Respiratory Medicine,
University of Edinburgh, UK
Sara J Jenks BSc(Hons), MRCP, FRCPath
Consultant in Metabolic Medicine, Department of Clinical
Biochemistry, Royal Infirmary of Edinburgh, UK
Sarah L Johnston FCRP, FRCPath
Consultant Immunologist, Department of Immunology and
Immunogenetics, North Bristol NHS Trust, Bristol, UK
David EJ Jones MA, BM, PhD, FRCP
Professor of Liver Immunology, Institute of Cellular Medicine,
Newcastle University, Newcastle upon Tyne; Consultant
Hepatologist, Freeman Hospital, Newcastle upon Tyne, UK
Peter Langhorne PhD, FRCPG, FRCPI
Professor of Stroke Care, Institute of Cardiovascular and
Medical Sciences, University of Glasgow, UK
Stephen M Lawrie MD(Hons), FRCPsych, FRCPE(Hon)
Professor of Psychiatry, University of Edinburgh, UK
John Paul Leach MD, FRCPG, FRCPE
Consultant Neurologist, Institute of Neuroscience, Queen
Elizabeth University Hospital, Glasgow; Head of
Undergraduate Medicine and Honorary Associate Clinical
Professor, University of Glasgow, UK
Gary Maartens MBChB, FCP(SA), MMed
Professor of Clinical Pharmacology, University of Cape Town,
South Africa
Lucy Mackillop MA(Oxon), FRCP
Consultant Obstetric Physician, Oxford University Hospitals
NHS Foundation Trust, Oxford; Honorary Senior Clinical
Lecturer, Nuffield Department of Obstetrics and Gynaecology,
University of Oxford, UK
Michael J MacMahon FRCA, FICM, EDIC
Consultant in Anaesthesia and Intensive Care, Victoria
Hospital, Kirkcaldy, UK
Rebecca Mann BMedSci, MRCP, FRCPCh
Consultant Paediatrician, Taunton and Somerset NHS
Foundation Trust, Taunton, UK
Lynn M Manson MD, FRCPE, FRCPath
Consultant Haematologist, Scottish National Blood
Transfusion Service, Department of Transfusion Medicine,
Royal Infirmary of Edinburgh, UK
Sara E Marshall FRCP, FRCPath, PhD
Professor of Clinical Immunology, Medical Research Institute,
University of Dundee, UK
Amanda Mather MBBS, FRACP, PhD
Consultant Nephrologist, Department of Renal Medicine,
Royal North Shore Hospital, Sydney; Conjoint Senior Lecturer,
Faculty of Medicine, University of Sydney, Australia
Simon RJ Maxwell BSc, MD, PhD, FRCP, FRCPE,
FBPhS, FHEA
Professor of Student Learning - Clinical Pharmacology and
Prescribing, and Medical Director, UK Prescribing Safety
Assessment, Clinical Pharmacology Unit, University of
Edinburgh, UK
David A McAllister MSc, MD, MRCP, MFPH
Wellcome Trust Intermediate Clinical Fellow and Beit Fellow,
Senior Clinical Lecturer in Epidemiology, and Honorary
Consultant in Public Health Medicine, University of
Glasgow, UK
Rory J McCrimmon MD, FRCPE
Professor of Experimental Diabetes and Metabolism,
University of Dundee, UK
Mairi H McLean BSc(Hons), MRCP, PhD
Senior Clinical Lecturer in Gastroenterology, School of
Medicine, Medical Sciences and Nutrition, University of
Aberdeen; Honorary Consultant Gastroenterologist, Aberdeen
Royal Infirmary, UK
Francesca EM Neuberger MRCP(UK)
Consultant Physician in Acute Medicine and Obstetric
Medicine, Southmead Hospital, Bristol, UK
David E Newby BA, BSc(Hons), PhD, BM DM DSc,
FMedSci, FRSE, FESC, FACC
British Heart Foundation John Wheatley Professor of
Cardiology, British Heart Foundation Centre for Cardiovascular
Science, University of Edinburgh, UK
John DC Newell-Price MA, PhD, FRCP
Professor of Endocrinology and Consultant Endocrinologist,
Department of Oncology and Metabolism, University of
Sheffield, UK
John Olson MD, FRPCE, FRCOphth
Consultant Ophthalmic Physician, Aberdeen Royal Infirmary;
Honorary Reader, University of Aberdeen, UK
Ewan R Pearson MA, PhD, FRCPE
Professor of Diabetic Medicine, University of Dundee, UK
Paul J Phelan MD, FRCPE
Consultant Nephrologist and Renal Transplant Physician,
Royal Infirmary of Edinburgh; Honorary Senior Lecturer,
University of Edinburgh, UK
Stuart H Ralston MD, FRCP, FMedSci, FRSE,
FFPM(Hon)
Arthritis Research UK Professor of Rheumatology, University
of Edinburgh; Honorary Consultant Rheumatologist, Western
General Hospital, Edinburgh, UK
Peter T Reid MD, FRCPE
Consultant Physician, Respiratory Medicine, Lothian University
Hospitals, Edinburgh, UK
Jonathan AT Sandoe PhD, FRCPath
Associate Clinical Professor, University of Leeds; Consultant
Microbiologist, Leeds Teaching Hospitals NHS Trust, UK
CONTRIBUTORS • xiii
Gordon R Scott BSc, FRCP
Consultant in Genitourinary Medicine, Chalmers Sexual Health
Centre, Edinburgh, UK
Alan G Shand MD, FRCPE
Consultant Gastroenterologist, Western General Hospital,
Edinburgh, UK
Robby M Steel MA, MD, FRCPsych
Consultant Liaison Psychiatrist, Department of Psychological
Medicine, Royal Infirmary of Edinburgh; Honorary (Clinical)
Senior Lecturer, Department of Psychiatry, University of
Edinburgh, UK
Grant D Stewart BSc(Hons), FRCSEd(Urol), PhD
University Lecturer in Urological Surgery, Academic Urology
Group, University of Cambridge; Honorary Consultant
Urological Surgeon, Department of Urology, Addenbrooke’s
Hospital, Cambridge; Honorary Senior Clinical Lecturer,
University of Edinburgh, UK
Peter Stewart MBBS, FRACP, FRCPA, MBA
Associate Professor in Chemical Pathology, University of
Sydney; Area Director of Clinical Biochemistry and Head of
the Biochemistry Department, Royal Prince Alfred and
Liverpool Hospitals, Sydney, Australia
Mark WJ Strachan BSc(Hons), MD, FRCPE
Consultant Endocrinologist, Metabolic Unit, Western General
Hospital, Edinburgh; Honorary Professor, University of
Edinburgh, UK
David R Sullivan MBBS, FRACP, FRCPA, FCSANZ
Clinical Associate Professor, Faculty of Medicine, University of
Sydney; Physician and Chemical Pathologist, Department of
Chemical Pathology, Royal Prince Alfred Hospital, Sydney,
Australia
Shyam Sundar MD, FRCP(London), FAMS, FNASc,
FASc, FNA
Professor of Medicine, Institute of Medical Sciences, Banaras
Hindu University, Varanasi, India
Victoria R Tallentire BSc(Hons), MD, FRCPE
Consultant Physician, Western General Hospital, Edinburgh;
Honorary Clinical Senior Lecturer, University of Edinburgh, UK
Katrina Tatton-Brown BA, MD, FRCP
Consultant in Clinical Genetics, South West Thames Regional
Genetics Service, St George’s Universities NHS Foundation
Trust, London; Reader in Clinical Genetics and Genomic
Education, St George’s University, London, UK
Simon HL Thomas MD, FRCP, FRCPE
Professor of Clinical Pharmacology and Therapeutics, Medical
Toxicology Centre, Newcastle University, Newcastle upon
Tyne, UK
Henry G Watson MD, FRCPE, FRCPath
Consultant Haematologist, Aberdeen Royal Infirmary;
Honorary Professor of Medicine, University of Aberdeen, UK
Julian White MB, BS, MD, FACTM
Head of Toxinology, Women’s and Children’s Hospital, North
Adelaide; Professor, University of Adelaide, Australia
John PH Wilding DM, FRCP
Professor of Medicine, Obesity and Endocrinology, University
of Liverpool, UK
Miles D Witham PhD, FRCPE
Clinical Reader in Ageing and Health, University of Dundee, UK
This page intentionally left blank
International Advisory Board
Amitesh Aggarwal
Associate Professor, Department of Medicine, University
College of Medical Sciences and GTB Hospital, Delhi, India
Ragavendra Bhat
Professor of Internal Medicine, Ras Al Khaimah Medical and
Health Sciences University, Ras Al Khaimah, United Arab
Emirates
Matthew A Brown
Professor and Director of Genomics, Queensland University of
Technology, Brisbane, Australia
Khalid I Bzeizi
Senior Consultant and Head of Hepatology, Prince Sultan
Military Medical City, Riyadh, Saudi Arabia
Arnold Cohen
Clinical Professor of Medicine, Elson S. Floyd College of
Medicine at Washington State University, Spokane,
Washington; Associate Clinical Professor, University of
Washington School of Medicine; Gastroenterologist, Spokane
Digestive Disease Center, Washington, USA
MK Daga
Director Professor of Medicine, and In-Charge Intensive Care
Unit and Center for Occupational and Environment Medicine,
Maulana Azad Medical College, New Delhi, India
D Dalus
Professor and Head, Department of Internal Medicine,
Medical College and Hospital, Trivandrum, India
Sydney C D’Souza
Professor of Medicine, AJ Institute of Medical Science,
Mangalore; Former Head, Department of Medicine, Kasturba
Medical College Mangalore, Manipal University, India
Tarun Kumar Dutta
Professor of Medicine and Clinical Hematology, Mahatma
Gandhi Medical College and Research Institute, Puducherry,
India
M Abul Faiz
Professor of Medicine (Retired), Sir Salimullah Medical
College, Mitford, Dhaka, Bangladesh
AG Frauman
Professor of Clinical Pharmacology and Therapeutics,
University of Melbourne, Australia
Sujoy Ghosh
Associate Professor, Department of Endocrinology, Institute of
Post Graduate Medical Education and Research, Kolkata,
India
Hadi A Goubran
Haematologist, Saskatoon Cancer Centre and Adjunct
Professor, College of Medicine, University of Saskatchewan,
Canada; Professor of Medicine and Haematology (Sabbatical),
Cairo University, Egypt
Rajiva Gupta
Director and Head, Rheumatology and Clinical Immunology,
Medanta - The Medicity, Gurgaon, India
Saroj Jayasinghe
Chair Professor of Medicine, Faculty of Medicine, University of
Colombo; Honorary Consultant Physician, National Hospital of
Sri Lanka, Colombo, Sri Lanka
AL Kakrani
Professor and Head, Department of Medicine, Dr DY Patil
Medical College, Hospital and Research Centre; Dean, Faculty
of Medicine, Dr DY Patil Vidyapeeth Deemed University,
Pimpri, Pune, India
Vasantha Kamath
Senior Professor, Department of Internal Medicine, MVJ
Medical College and Research Hospital, Bengaluru,
Karnataka, India
Piotr Kuna
Professor of Medicine; Chairman, 2nd Department of
Medicine; Head of Division of Internal Medicine, Asthma and
Allergy, Medical University of Lodz, Poland
Pravin Manga
Emeritus Professor of Medicine, Department of Internal
Medicine, University of Witwatersrand, Johannesburg,
South Africa
xvi • INTERNATIONAL ADVISORY BOARD
Ammar F Mubaidin
Professor of Neurology, Jordan University Hospital, Khalidi
Medical Center, Amman, Jordan
Milind Nadkar
Professor of Medicine and Chief of Rheumatology and
Emergency Medicine, Seth GS Medical College and KEM
Hospital, Mumbai, India
Matthew Ng
Honorary Clinical Professor, University of Hong Kong,
Tung Wah Hospital, Hong Kong
Moffat Nyirenda
Professor of Medicine (Global Non-Communicable Diseases),
London School of Hygiene and Tropical Medicine, UK;
Honorary Professor of Research, College of Medicine,
University of Malawi
Tommy Olsson
Professor of Medicine, Department of Medicine, Umea
University Hospital, Sweden
Ami Prakashvir Parikh
Consultant Physician, Sheth VS General Hospital, Ellisbridge,
Ahmedabad; Professor of Medicine and Head of Department
of Medicine, NHL Municipal Medical College, Ahmedabad,
India
Medha Y Rao
Professor of Internal Medicine, Principal and Dean, MS
Ramaiah Medical College, Bangalore, India
NR Rau
Consultant Physician, Anugraha Medical Centre and Adarsha
Hospital, Udupi, Karnataka; Former Professor and Head,
Department of Medicine, Kasturba Medical College, Manipal
University, Karnataka, India
Nirmalendu Sarkar
Professor and Head (Retired), Department of Medicine,
Institute of Post Graduate Medical Education and Research
and SSKM Hospital, Kolkata, India
KR Sethuraman
Vice-Chancellor, Sri Balaji Vidyapeeth University, Pondicherry,
India
Surendra K Sharma
Adjunct Professor, Department of Molecular Medicine, Jamia
Hamdard Institute of Molecular Medicine, Hamdard University,
Delhi; Director of Research and Adjunct Professor,
Departments of General Medicine and Pulmonary Medicine,
JNMC, Datta Meghe Institute of Medical Sciences,
Sawangi (M), Wardha Maharashtra, India
Ibrahim Sherif
Emeritus Professor of Medicine, Tripoli University; Consultant
Endocrinologist, Alafia Clinic, Tripoli, Libya
Ian J Simpson
Emeritus Professor of Medicine, Faculty of Medical and Health
Sciences, University of Auckland, New Zealand
SG Siva Chidambaram
Professor of Medicine, Dean/SPL Officer, Perambalur
Government Medical College and GHQ, Perambalur, India
Arvind K Vaish
Professor and Head, Department of Medicine, Hind Institute
of Medical Sciences, Lucknow; Ex-Professor and Head of
Medicine, KG Medical University, Lucknow, India
Josanne Vassallo
Professor of Medicine, Faculty of Medicine and Surgery,
University of Malta; Consultant Endocrinologist, Division of
Endocrinology, Mater Dei Hospital, Msida, Malta
Acknowledgements
Following the publication of the 22nd edition of Davidson’s,
Professor Brian Walker and Dr Nicki Colledge retired as editors. We
would like to express our gratitude for the immense contribution
they both made to the continuing success of this textbook.
The current editors would like to acknowledge and offer grateful
thanks for the input of all previous editions’ contributors, without
whom this new edition would not have been possible. In particular
we are indebted to those former authors who step down with the
arrival of this new edition. They include Assistant Professor Albiruni
Ryan Abdul-Razak, Professor Andrew Bradbury, Dr Jenny Craig,
Professor Allan Cumming, Dr Robert Dawe, Emeritus Professor
Michael Field, Dr Jane Goddard, Professor Philip Hanlon, Dr
Charlie Lees, Dr Helen Macdonald, Professor lain Mclnnes, Dr
Graham Nimmo, Dr Simon Noble, Dr David Oxenham, Professor
Jonathan Seckl, Professor Michael Sharpe, Professor Neil Turner,
Dr Simon Walker and Professor Timothy Walsh.
We are grateful to members of the International Advisory
Board, all of whom provided detailed suggestions that have
improved the book. Several members have now retired from
the Board and we are grateful for their support during the
preparation of previous editions. They include Professor OC
Abraham, Professor Tofayel Ahmed, Professor Samar Banerjee,
Professor Tapas Das, Professor Tsuguya Fukui, Professor Saman
Gunatilake, Professor Wasim Jafri, Professor Saraladevi Naicker,
Professor Nardeep Naithani, Professor Prem Pais, Professor A
Ramachandran, the late Professor (Mrs) Harsha R Salkar and
Professor Subhash Varma.
Detailed chapter reviews were commissioned to help plan
this new edition and we are grateful to all those who assisted,
including Professor Rustam Al-Shahi, Dr David Enoch, Dr Colin
Forfar, Dr Richard Herriot and Dr Robert Lindsay.
The Editors and Publisher would like to thank all those who
have provided valuable feedback on this textbook and whose
comments have helped shape this new edition. We would
particularly like to extend our thanks to the many readers who
contact us with suggestions for improvements. This input has
been invaluable and is much appreciated; we regret the names
are too numerous to mention individually.
As part of the Publisher’s review, 360 readers from over
200 universities and colleges around the world supplied many
innovative ideas on how to enhance the book. We are deeply
indebted to the following for their enthusiastic support and we
trust we have listed all those who contributed; we apologise if
any names have been accidentally omitted. Rabab Hasan Abbasi,
Ayesha Abdul Aziz, Ahmed Al Abdullah, Osama Abuzagaia,
Humaira Achakzai, Sajan Acharya, Anurag Adhikari, Esha Agarwal,
Avin Aggarwal, Dorothy Agrapidis, Sakir Ahmed, Iman Akhtar,
Muhammad Faizan Ali, Syeda A Rfa Ali, M Amogh, Ramprasath
Anbazhagan, Anju George C, Vamseedhar Annam, Muhammad
Ehtisham Ansar, David C Antoney, Hina Arif, Sriharsha Athota,
Muhammed Ali Azher, Bilal Al Azzawi, Janak Bahirwani, Devyani
Bahl, Mohammed Naseem Baig, Deepak Kumar Bandari, Sagnik
Banerjee, Tapastanu Banerjee, Kieran Bannerman, Emily Bart,
Suranjana Basak, Saravana Bavan, Mark Beeston, Andrew
Beverstock, Jeetendra Bhandari, Navin Bhatt, Soumyadeep
Bhaumik, Rajrsh Bhawani, Kriti Bhayana, Praveen Bhugra,
Amit Bisht, Rahul Bisht, Rudradeep Biswas, Tamoghna Biswas,
Moira Bradfield, S Charles Bronson, Rosie Jane Campbell,
Anup Chalise, Subhankar Chatterjee, Chiranjivi Chaudhari, Lok
Bandhu Chaudhary, Muhammad Hamid Chaudhary, Umar
Iftikhar Chaudhry, Himshree Gaurang Chhaya, Smitha Chirayil,
Alexandra Choa, Rahul Choudhary, Guy Conlon, Gabriel Metcalf-
Cuenca, Jack Cuningham, Gopal Dabade, Saraswata Das, Rahul
Dev, Muinul Islam Dewan, Sree Divya, Muhammad Dizayee,
Lucy Drummond, Simon Dryden, Fiona Drysdale, Kaitlin Duell,
Gemma Dwyer, Md Khader Faheem N, Mahedi Hasan Faisal,
Ali Mokhtari Farivar, Mohammed Omar Farooq, Ten Fu Fatt,
Muhammad Zubair Fazal, Rebecca Ferris, Rebecca Fisher,
Kartik Nimish Gandhi, Vibhav Gandhi, James Gao, Ella Gardner,
Ankit Kumar Garg, Vibhuti Garg, Vishal Garg, Rakesh Garlapati,
Partha Sarathi Ghosh, Prattay Ghosh, Muhammad Umer Gill,
Madelaine Gimzewska, Nikolaos D Giotis, Evan Goh, lain Gow,
Bharatiram Guduri, Aantriksha Gupta, Shiwam Kumar Gupta,
Michael Hagarty, Md Rashid Haider, Iqra Haq, Abdalla A Hassan,
Fatima Hemani, Bianca Honnekeri, Prerana Huddar, Sandip Hulke,
Mohammed Laique Hussain, Syahir Ibrahim, Victor llubaera,
Sushrut Ingawale, Aroobah Iqbal, Tooba Irshad, Nagib Ul-lslam,
Sehra Jabeen, Jeevan Jacob, Samreen Jaffar, Ankita Jain, Anukriti
Jain, Ghazfa Jamil, Karan Jatwani, Surani Dilhani Jayawickrema,
Per-Kristian Jensen, Love Kapil, Ishwor Karki, Ewan D Kennedy,
Amit Keshri, Haider Ali Khalid, Ali Khaliq, Hina Khan, Md Taha
Ali Khan, Raazia Khan, Priya Khetarpal, Robert Kimmitt, Navneet
Kishore, Narendranath Reddy Konda, Kirsten Kramers, Ajay
Kumar, Gaurav Kumar, Karun Kumar, Mudit Kumar, Sathish
Kumar A, Sonu Kumar, Ramasamy Shakthi Kumaran, Joachim
Langhans, Keith Leung, Ang Li, Lai Nai Lim (Jeremiah), Marlene
Da Vitoria Lobo, Bo Lofgren, Sham Kumar Lulla, Apurva Lunia,
Arslan Luqman, Faizan Luqman, Mithilesh Chandra Malviya,
Sudhir Mane, Sachin Mangal, G. Manju, Adupa Manupranay,
Ussama Maqbool, Zahid Marwat, Ronny John Mathew, Ross
Mclaren, Lucy Mcnally, Varshil Mehta, Kamran Younis Memon,
Nisha Menon, Varun Menon P, Jessica Mills, Asim Abid Minhas,
xviii • ACKNOWLEDGEMENTS
Mohd Nasir Mohiuddin, Matshidiso Mokgwathi, Kristin Monk,
Joseph Raja Mony, Sudeb Mukherjee, Sadat Nadeem, Huda
Naim, B Abhilash Nair, Ramya Narasimhan, Rahul Navani,
Ayesha Nazir, Prakhar Nigam, Sripriya Nopany, Prakash Raj
Oli, Chieh Yin Ooi, Muhammad Osama, Kate O’Sullivan, Hajer
Oun, Ashwin Pachat, Akshay Pachyala, Kannan Padma, Gregory
Page, Vishal Krishna Pai, Dhiman Pal, Vidit Panchal, Madhav
Pandey, Ambikapathi Panneerselvam, Rakesh Singh Panwar,
Prakash Parida, Ashwin Singh Parihar, Kunal Parwani, Riya Patel,
Himanshu Pathak, Prathamesh Pathrikar, Samanvith Patlori, Gary
Paul, Harris Penman, Lydia B Peters, Kausthubha Puttalingaiah,
Muneeb Qureshi, Sidra Qureshi, Varun Venkat Raghavan MS,
Raghavendra MS, Abdur Rahaman, Ajmal Rahman Km, SM Tajdit
Rahman, Ankit Raj, Solai Raj, Namita Raja, Revathi Rajagopal,
Aswathy Raju B, Nagarajan Raju, Al-Amin Hossain Rakib, Abhiraj
Ramchandani, Varun Ramchandani, Viviktha Ramesh, Jai Ranjan,
Ganga Raghava Rao, Gomathi Ravula, Aneeqa Abdul Rehman,
Neeha Abdul Rehman, Varun Bhaktarahalli Renukappa, Rosalind
Revans, Madina Riaz, Lachlan Rodd, Jan Ross, Pritam Roy,
Jazeel Sa, Iqra Saeed, Israel Safiriyu, Partha Saha, Mohammed
Sulaiman Sait J, Ribha Salman, Souvik Samaddar, Juliane Rf
Sanner, Abhinav Sathe, Smarter Sawant, Jeff Schwartz, Somanshi
Sehgal, Arbind Shah, Basit Shah, Rakesh Kumar Shah, Mohith
Shamdas, Abhishek Sharma, Anmol Sharma, Deepak Sharma,
Pawan Kumar Sharma, Nisha Sharoff, Alsba Sheikh, Haris
Sheikh, Nujood Al Shirawi, William Shomali, Pratima Shrestha,
Suhana Shrestha, Ajay Shukla, Prithiv Siddharth, Arpit Sikri,
Ankita Singh, Avinash Singh, Deepali Singh, Jeevika Singh,
Prince Singh, Rajshree Singh, Shruti Singh, Vikas Singh, Yogita
Singh, Ayush Keshav Singhal, Dattatreya Sitaram, Brooke Smith,
Yeshwanth Sonnathi, Soundarya Soundararajan, Nicola Stuber,
Maleeha Subhan, Udayasree Sagar Surampally, Monika Surana,
Jason Suresh, Salman Ali Syed, Mohammad Hasnain Tahir,
Syeda Sara Tamkanath, Areeba Tariq, Saipriya Tatineni, Ghias
Un Nabi Tayyab, Arul Qubert Thaya, Jolley Thomas, Stephanie
Tristram, Neelanchal Trivedi, Vaibhav Trivedi, Kriti Upadhyay,
Sanjaya Kumar Upadhyaya, Rukhsar Vankani, Rajkumar Krishnan
Vasanthi, D Vijayaraju, R Vinayak, Neelakantan Viswanathan,
Joarder Wakil, Syed Hamza Bin Waqar, Waiz A Wasey, William
Wasif, Kiran Wasti, Donald Waters, Katherine Weir, Clinton
White, Aalok Yadav, Loong Yee Yew, Shahwar Yousuf, Amal
Yusof and Hassam Zulfiqar.
The authors of Chapter 20 would like to thank Dr Drew
Henderson, who reviewed the ‘Diabetic nephropathy’ section.
Two short sections in Chapter 3 on array comparative genomic
hybridisation and single-molecule sequencing are adapted from Dr
KTatton-Brown’s Massive Open Online Course for FutureLearn.
We would like to thank the Open University and St George’s,
University of London, for permission to use this material.
We are especially grateful to all those working for Elsevier,
in particular Laurence Hunter, Wendy Lee and Robert Britton,
for their endless support and expertise in the shaping, collation
and illustration of this edition.
SHR, IDP, MWJS, RPH
Edinburgh 2018
Introduction
The opening six chapters of the book, making up Part 1 on
‘Fundamentals of Medicine’, provide an account of the principles
of genetics, immunology, infectious diseases and population
health, along with a discussion of the core principles behind
clinical decision-making and good prescribing. Subsequent
chapters in Part 2, ‘Emergency and Critical Care Medicine’,
discuss medical emergencies in poisoning, envenomation and
environmental medicine, while a new chapter explores common
presentations in acute medicine, as well as the recognition and
management of the critically ill. The third part, ‘Clinical Medicine’,
is devoted to the major medical specialties. Each chapter has
been written by experts in the field to provide the level of detail
expected of trainees in their discipline. To maintain the book’s
virtue of being concise, care has been taken to avoid unnecessary
duplication between chapters.
The system-based chapters in Part 3 follow a standard
format, beginning with an overview of the relevant aspects
of clinical examination, followed by an account of functional
anatomy, physiology and investigations, then the common
presentations of disease, and details of the individual diseases
and treatments relevant to that system. In chapters that describe
the immunological, cellular and molecular basis of disease, this
problem-based approach brings the close links between modern
medical science and clinical practice into sharp focus.
The methods used to present information are described below.
Clinical examination overviews
The value of good clinical skills is highlighted by a two-page
overview of the important elements of the clinical examination
at the beginning of most chapters. The left-hand page includes
a mannikin to illustrate key steps in examination of the relevant
system, beginning with simple observations and progressing
in a logical sequence around the body. The right-hand page
expands on selected themes and includes tips on examination
technique and interpretation of physical signs. These overviews
are intended to act as an aide-memoire and not as a replacement
for a detailed text on clinical examination, as provided in our
sister title, Macleod’s Clinical Examination.
Presenting problems
Medical students and junior doctors must not only assimilate
a great many facts about various disorders but also develop
an analytical approach to formulating a differential diagnosis
and a plan of investigation for patients who present with
particular symptoms or signs. In Davidson’s this is addressed
by incorporating a ‘Presenting Problems’ section into all
relevant chapters. Nearly 250 presentations are included,
which represent the most common reasons for referral to each
medical specialty.
Boxes
Boxes are a popular way of presenting information and are
particularly useful for revision. They are classified by the type of
information they contain, using specific symbols.
General Information
These include causes, clinical features, investigations, treatments
and other useful information.
Practice Point
There are many practical skills that students and doctors must
master. These vary from inserting a nasogastric tube to reading
an ECG or X-ray, or interpreting investigations such as arterial
blood gases or thyroid function tests. ‘Practice Point’ boxes
provide straightforward guidance on how these and many other
skills can be acquired and applied.
*
Emergency
These boxes describe the management of many of the most
common emergencies in medicine.
in Old Age
In many countries, older people comprise 20% of the population
and are the chief users of health care. While they contract the
same diseases as those who are younger, there are often
important differences in the way they present and how they are
best managed. Chapter 32, ‘Ageing and disease’, concentrates
on the principles of managing the frailest group who suffer from
multiple comorbidity and disability, and who tend to present
with non-specific problems such as falls or delirium. Many
older people, though, also suffer from specific single-organ
pathology. ‘In Old Age’ boxes are thus included in each chapter
and describe common presentations, implications of physiological
changes of ageing, effects of age on investigations, problems of
XX • INTRODUCTION
treatment in old age, and the benefits and risks of intervention
in older people.
In Pregnancy
Many conditions are different in the context of pregnancy, while
some arise only during or shortly after pregnancy. Particular
care must be taken with investigations (for example, to avoid
radiation exposure to the fetus) and treatment (to avoid the use
of drugs that harm the fetus). These issues are highlighted by
‘In Pregnancy’ boxes distributed throughout the book, which
complement the new chapter on maternal medicine.
In Adolescence
Although paediatric medicine is not covered in Davidson’s, many
chronic disorders begin in childhood and adult physicians often
contribute to multidisciplinary teams that manage young patients
‘in transition’ between paediatric and adult health-care services.
This group of patients often presents a particular challenge,
due to the physiological and psychological changes that occur
in adolescence and which can have a major impact on the
disease and its management. Adolescents can be encouraged
to take over responsibility from their parents/carers in managing
their disease, but are naturally rebellious and often struggle to
adhere to the impositions of chronic treatment. To highlight these
issues, we have introduced a new chapter on adolescent and
transition medicine to accompany the ‘In Adolescence’ boxes
that appear in relevant chapters.
Terminology
The recommended International Non-proprietary Names (INNs)
are used for all drugs, with the exception of adrenaline and
noradrenaline. British spellings have been retained for drug classes
and groups (e.g. amphetamines not amfetamines).
Units of measurement
The International System of Units (SI units) is the recommended
means of presentation for laboratory data and has been used
throughout Davidson’s. We recognise, though, that many
laboratories around the world continue to provide data in non-SI
units, so these have been included in the text for the commonly
measured analytes. Both SI and non-SI units are also given
in Chapter 35, which describes the reference ranges used in
Edinburgh’s laboratories. It is important to appreciate that these
reference ranges may vary from those used in other laboratories.
Finding what you are looking for
A contents list is given on the opening page of each chapter. In
addition, the book contains numerous cross-references to help
readers find their way around, along with an extensive index.
A list of up-to-date reviews and useful websites with links to
management guidelines appears at the end of each chapter.
Giving us your feedback
The Editors and Publisher hope that you will find this edition of
Davidson’s informative and easy to use. We would be delighted to hear
from you if you have any comments or suggestions to make for future
editions of the book. Please contact us by e-mail at: davidson.
feedback@elsevier.com. All comments received will be much
appreciated and will be considered by the editorial team.
N Cooper
AL Cracknell
Clinical decision-making
Introduction 2
Cognitive biases 6
The problem of diagnostic error 2
Type 1 and type 2 thinking 7
Common cognitive biases in medicine 7
Clinical reasoning: definitions 2
Human factors 9
Clinical skills and decision-making 3
Reducing errors in clinical decision-making 9
Use and interpretation of diagnostic tests 3
Cognitive debiasing strategies 9
Normal values 3
Using clinical prediction rules and other decision aids 1 0
Factors other than disease that influence test results 4
Effective team communication 1 0
Operating characteristics 4
Patient-centred evidence-based medicine and shared
Sensitivity and specificity 4
decision-making 10
Prevalence of disease 5
Clinical decision-making: putting it all together 10
Dealing with uncertainty 5
Answers to problems 2
2 • CLINICAL DECISION-MAKING
Introduction
A great deal of knowledge and skill is required to practise
as a doctor. Physicians in the 21st century need to have a
comprehensive knowledge of basic and clinical sciences, have
good communication skills, be able to perform procedures, work
effectively in a team and demonstrate professional and ethical
behaviour. But how doctors think, reason and make decisions
is arguably their most critical skill. Knowledge is necessary, but
not sufficient on its own for good performance and safe care.
This chapter describes the principles of clinical decision-making,
or clinical reasoning.
The problem of diagnostic error
It is estimated that diagnosis is wrong 1 0-1 5% of the time in
specialties such as emergency medicine, internal medicine and
general practice. Diagnostic error is associated with greater
morbidity than other types of medical error, and the majority is
considered to be preventable. For every diagnostic error there are
a number of root causes. Studies of misdiagnosis assign three
main categories, shown in Box 1.1; however, errors in clinical
reasoning play a significant role in the majority of diagnostic
adverse events.
1 .1 Root causes of diagnostic error in studies
Error category
Examples
No fault
Unusual presentation of a disease
Missing information
System error
Inadequate diagnostic support
Results not available
Error-prone processes
Poor supervision of inexperienced staff
Poor team communication
Human cognitive error
Inadequate data-gathering
Errors in reasoning
Adapted from Grader M, Gordon R, Franklin N. Reducing diagnostic errors in
medicine: what’s the goal? Acad Med 2002; 77:981-992.
1.2 Reasons for errors in clinical reasoning
Source of error
Examples
Knowledge gaps
Telling a patient she cannot have biliary
colic because she has had her gallbladder
removed - gallstones can form in the bile
ducts in patients who have had a
cholecystectomy
Misinterpretation of
diagnostic tests
Deciding a patient has not had a stroke
because his brain scan is normal -
computed tomography and even magnetic
resonance imaging, especially when
performed early, may not identify an infarct
Cognitive biases
Accepting a diagnosis handed over to you
without question (the ‘framing effect’)
instead of asking yourself ‘What is the
evidence that supports this diagnosis?’
Diagnostic error has been defined as ‘a situation in which the
clinician has all the information necessary to make the diagnosis
but then makes the wrong diagnosis’. Why does this happen?
Studies reveal three main reasons:
• knowledge gaps
• misinterpretation of diagnostic tests
• cognitive biases.
Examples of errors in these three categories are shown in
Box 1.2.
Clearly, clinical knowledge is required for sound clinical
reasoning, and an incomplete knowledge base or inadequate
experience can lead to diagnostic error. However, this chapter
focuses on other elements of clinical reasoning: namely, the
interpretation of diagnostic tests, cognitive biases and human
factors.
Clinical reasoning: definitions
‘Clinical reasoning’ describes the thinking and decision-making
processes associated with clinical practice. It is a clinician’s
ability to make decisions (often with others) based on all the
available clinical information, starting with the history and physical
examination. Our understanding of clinical reasoning derives
from the fields of education, cognitive psychology and studies
of expertise.
Figure 1.1 shows the different elements involved in clinical
reasoning. Good clinical skills are fundamental, followed by
understanding how to use and interpret diagnostic tests. Other
essential elements include an understanding of cognitive biases
and human factors, and the ability to think about one’s own
thinking (which is explained in more detail later). Other key
elements of clinical reasoning include patient-centred evidence-
based medicine (EBM) and shared decision-making with patients
and/or carers.
Fig. 1.1 Elements of clinical reasoning. (EBM = evidence-based
medicine)
Use and interpretation of diagnostic tests • 3
Clinical skills and decision-making
Even with major advances in medical technology, the history
remains the most important part of the clinical decision-making
process. Studies show that physicians make a diagnosis in
70-90% of cases from the history alone. It is important to
remember that a good history is gathered not only from the
patient but also, if necessary (and with consent if required),
from all available sources: for example, paramedic and
emergency department notes, eye-witnesses, relatives
and/or carers.
Clinicians need to be aware of the diagnostic usefulness of
clinical features in the history and examination. For example,
students are taught that meningitis presents with the following
features:
• headache
• fever
• meningism (photophobia, nuchal rigidity).
However, the frequency with which patients present with certain
features and the diagnostic weight of each feature are important
in clinical reasoning. For example, many patients with meningitis
do not have classical signs of meningeal irritation (Kernig’s sign,
Brudzinski’s sign and nuchal rigidity). In one prospective study,
they had likelihood ratios of around 1 , meaning they carried little
diagnostic weight (Fig. 1.2).
Likelihood ratios (LR) are clinical diagnostic weights. An LR of
greater than 1 increases the probability of disease (the higher the
Infinity
LR-
Increase
probability
No change
Kernig’s sign
Brudzinski’s sign
Nuchal rigidity
Decrease
probability
10
5
2
1
0.5
0.2
0.1
Zero
Change in
probability
of disease
+ 45%
+ 30%
+ 15%
No change
-15%
- 30%
- 45%
Fig. 1.2 Likelihood ratio (LR) of Kernig’s sign, Brudzinski’s sign and
nuchal rigidity in the clinical diagnosis of meningitis.
_ probability of finding in patients with disease
probability of finding in patients without disease
LRs are also used for diagnostic tests; here a physical examination finding
can be considered a diagnostic test. Data from Thomas KE, Hasbun R,
Jekel J, Quagliarello VJ. The diagnostic accuracy of Kernig’s sign,
Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis.
Clin Infect Dis 2002; 35:46-52.
value, the greater the probability). Similarly, an LR of less than 1
decreases the probability of disease. LRs are developed against
a diagnostic standard (e.g. in the case of meningitis, lumbar
puncture results), so do not exist for all clinical findings. LRs
illustrate how an individual clinical finding changes the probability
of a disease. For example, in a person presenting with headache
and fever, the clinical finding of nuchal rigidity (neck stiffness)
may carry little weight in deciding whether to perform a lumbar
puncture because LRs do not determine the prior probability of
disease; they reflect only how a single clinical finding changes
it. Clinicians have to take all the available information from the
history and physical examination into account. If the overall
clinical probability is high to begin with, a clinical finding with
an LR of around 1 does not change this.
‘Evidence-based history and examination’ is a term used
to describe how clinicians incorporate knowledge about the
prevalence and diagnostic weight of clinical findings into their
history and physical examination. This is important because an
estimate of clinical probability is vital in decision-making and the
interpretation of diagnostic tests.
Use and interpretation of
diagnostic tests
There is no such thing as a perfect diagnostic test. Test results
give us test probabilities, not real probabilities. Test results have
to be interpreted because they are affected by the following:
• how ‘normal’ is defined
• factors other than disease
• operating characteristics
• sensitivity and specificity
• prevalence of disease in the population.
Normal values
Most tests provide quantitative results (i.e. a value on a continuous
numerical scale). In order to classify quantitative results as normal
or abnormal, it is necessary to define a cut-off point. Many
quantitative measurements in populations have a Gaussian or
‘normal’ distribution. By convention, the normal range is defined
as those values that encompass 95% of the population, or 2
standard deviations above and below the mean. This means
that 2.5% of the normal population will have values above, and
2.5% will have values below the normal range. For this reason,
it is more appropriate to talk about the ‘reference range’ rather
than the ‘normal range’ (Fig. 1 .3).
Test results in abnormal populations also have a Gaussian
distribution, with a different mean and standard deviation.
In some diseases there is no overlap between results from
the abnormal and normal population. However, in many
diseases there is overlap; in these circumstances, the greater
the difference between the test result and the limits of the
reference range, the higher the chance that the person has a
disease.
However, there are also situations in medicine when ‘normal’
is abnormal and ‘abnormal’ is normal. For example, a normal
PaC02 in the context of a severe asthma attack is abnormal and
means the patient has life-threatening asthma. A low ferritin in a
young menstruating woman is not considered to be a disease
at all. Normal, to some extent, is therefore arbitrary.
4 • CLINICAL DECISION-MAKING
Normal
‘Reference range’
Fig. 1.3 Normal distribution and reference range. For many tests,
the frequency distribution of results in the normal healthy population
(red line) is a symmetrical bell-shaped curve. The mean ±2 standard
deviations (SD) encompasses 95% of the normal population and usually
defines the ‘reference range’; 2.5% of the normal population have values
above, and 2.5% below, this range (shaded areas). For some diseases
(blue line), test results overlap with the normal population or even with the
reference range. For other diseases (green line), tests may be more
reliable because there is no overlap between the normal and abnormal
population.
Factors other than disease that influence
test results
A number of factors other than disease influence test results:
• age
• ethnicity
• pregnancy
• sex
• spurious (in vitro) results.
Box 1 .3 gives some examples.
Operating characteristics
Tests are also subject to operating characteristics. This refers
to the way the test is performed. Patients need to be able to
comply fully with some tests, such as spirometry (p. 569), and if
they cannot, then the test result will be affected. Some tests are
very dependent on the skill of the operator and are also affected
by the patient’s body habitus and clinical state; ultrasound of
the heart and abdomen are examples. A common mistake is
when doctors refer to a test result as ‘no abnormality detected’
when, in fact, the report describes a technically difficult and
incomplete scan that should more accurately be described as
‘non-diagnostic’.
Some conditions are paroxysmal. For example, around
half of patients with epilepsy have a normal standard
electroencephalogram (EEG). A normal EEG therefore does not
exclude epilepsy. On the other hand, around 10% of patients
who do not have epilepsy have epileptiform discharges on their
EEG. This is referred to as an ‘incidental finding’. Incidental
findings are common in medicine, and are increasing in incidence
with the greater availability of more sensitive tests. Test results
should always be interpreted in the light of the patient’s history
and physical examination.
1 .3 Examples of factors other than disease that
influence test results
Factor
Examples
Age
Creatinine is lower in old age (due to relatively
lower muscle mass) - an older person can have a
significantly reduced eGFR rate with a ‘normal’
creatinine
Ethnicity
Healthy people of African ancestry have lower white
cell counts
Pregnancy
Several tests are affected by late pregnancy, due to
the effects of a growing fetus, including:
Reduced urea and creatinine (haemodilution)
Iron deficiency anaemia (increased demand)
Increased alkaline phosphatase (produced by the
placenta)
Raised D-dimer (physiological changes in the
coagulation system)
Mild respiratory alkalosis (physiological maternal
hyperventilation)
ECG changes (tachycardia, left axis deviation)
Sex
Males and females have different reference ranges
for many tests, e.g. haemoglobin
Spurious (in
vitro) results
A spurious high potassium is seen in haemolysis
and in thrombocytosis (‘pseudohyperkalaemia’)
(ECG = electrocardiogram; eGFR = estimated glomerular filtration rate, a better
estimate of renal function than creatinine)
Sensitivity and specificity
Diagnostic tests have characteristics termed ‘sensitivity’ and
‘specificity’. Sensitivity is the ability to detect true positives;
specificity is the ability to detect true negatives. Even a very
good test, with 95% sensitivity, will miss 1 in 20 people with
the disease. Every test therefore has ‘false positives’ and ‘false
negatives’ (Box 1.4).
A very sensitive test will detect most disease but generate
abnormal findings in healthy people. A negative result will therefore
reliably exclude disease but a positive result does not mean
the disease is present - it means further evaluation is required.
On the other hand, a very specific test may miss significant
pathology but is likely to establish the diagnosis beyond doubt
when the result is positive. All tests differ in their sensitivity and
specificity, and clinicians require a working knowledge of the
tests they use in this respect.
In choosing how a test is used to guide decision-making there
is a trade-off between sensitivity versus specificity. For example,
defining an exercise electrocardiogram (p. 449) as abnormal if
there is at least 0.5 mm of ST depression would ensure that
very few cases of coronary artery disease are missed but
would generate many false-positive results (high sensitivity, low
specificity). On the other hand, a cut-off point of 2.0 mm of
ST depression would detect most cases of important coronary
artery disease with far fewer false positives. This trade-off is
illustrated by the receiver operating characteristic curve of the
test (Fig. 1 .4).
An extremely important concept is this: the probability that a
person has a disease depends on the pre-test probability, and
the sensitivity and specificity of the test. For example, imagine that
an elderly lady has fallen and hurt her left hip. On examination,
Dealing with uncertainty • 5
1 1.4 Sensitivity and specificity
Disease
No disease
Positive test
A
B
(True positive)
(False positive)
Negative test
C
D
(False negative)
(True negative)
Sensitivity = A/(A+C) x 1 00
Specificity = D/(D+B) x 1 00
Specificity
Fig. 1.4 Receiver operating characteristic graph illustrating the
trade-off between sensitivity and specificity for a given test. The
curve is generated by ‘adjusting’ the cut-off values defining normal and
abnormal results, calculating the effect on sensitivity and specificity and
then plotting these against each other. The closer the curve lies to the top
left-hand corner, the more useful the test. The red line illustrates a test
with useful discriminant value and the green line illustrates a less useful,
poorly discriminant test.
the hip is extremely painful to move and she cannot stand.
However, her hip X-rays are normal. Does she have a fracture?
The sensitivity of plain X-rays of the hip performed in the
emergency department for suspected hip fracture is around
95%. A small percentage of fractures are therefore missed. If
our patient has (or is at risk of) osteoporosis, has severe pain
on hip movement and cannot bear weight on the affected side,
then the clinical probability of hip fracture is high. If, on the other
hand, she is unlikely to have osteoporosis, has no pain on hip
movement and is able to bear weight, then the clinical probability
of hip fracture is low.
Doctors are continually making judgements about whether
something is true, given that something else is true. This is known
as ‘conditional probability’. Bayes’ Theorem (named after English
clergyman Thomas Bayes, 1702-1761) is a mathematical way
to describe the post-test probability of a disease by combining
pre-test probability, sensitivity and specificity. In clinical practice,
doctors are not able to make complex mathematical calculations
for every decision they make. In practical terms, the answer to the
question of whether there is a fracture is that in a high-probability
patient a normal test result does not exclude the condition, but
in a low- probability patient it makes it very unlikely. This principle
is illustrated in Figure 1 .5.
Sox and colleagues (see ‘Further information’) state a
fundamental assertion, which they describe as a profound
and subtle principle of clinical medicine: the interpretation of
new information depends on what you believed beforehand. In
other words, the interpretation of a test result depends on the
probability of disease before the test.
Prevalence of disease
Consider this problem that was posed to a group of Harvard
doctors: if a test to detect a disease whose prevalence is 1 : 1 000
has a false-positive rate of 5%, what is the chance that a person
found to have a positive result actually has the disease, assuming
you know nothing about the person’s symptoms and signs? Take
a moment to work this out. In this problem, we have removed
clinical probability and are only considering prevalence. The
answer is at the end of the chapter.
Predictive values combine sensitivity, specificity and prevalence.
Sensitivity and specificity are characteristics of the test; the
population does not change this. However, as doctors, we
are interested in the question, ‘What is the probability that a
person with a positive test actually has the disease?’ This is
illustrated in Box 1 .5.
Post-test probability and predictive values are different. Post¬
test probability is the probability of a disease after taking into
account new information from a test result. Bayes’ Theorem can
be used to calculate post-test probability for a patient in any
population. The pre-test probability of disease is decided by the
doctor; it is a judgement based on information gathered prior to
ordering the test. Predictive value is the proportion of patients
with a test result who have the disease (or no disease) and is
calculated from a table of results in a specific population (see
Box 1 .5). It is not possible to transfer this value to a different
population. This is important to realise because published
information about the performance of diagnostic tests may not
apply to different populations.
In deciding the pre-test probability of disease, clinicians often
neglect to take prevalence into account and this distorts their
estimate of probability. To estimate the probability of disease
in a patient more accurately, clinicians should anchor on the
prevalence of disease in the subgroup to which the patient
belongs and then adjust to take the individual factors into account.
1 .5 Predictive values: ‘What is the probability that a
person with a positive test actually has the disease?’
Disease No disease
Positive test A B
(True positive) (False positive)
Negative test C D
(False negative) (True negative)
Positive predictive value = A/(A+B) x 100
Negative predictive value = D/(D+C) x 1 00
Dealing with uncertainty
Clinical findings are imperfect and diagnostic tests are imperfect.
It is important to recognise that clinicians frequently deal with
uncertainty. By expressing uncertainty as probability, new
information from diagnostic tests can be incorporated more
accurately. However, subjective estimates of probability can
sometimes be unreliable. As the section on cognitive biases
will demonstrate (see below), intuition can be a source
of error.
6 • CLINICAL DECISION-MAKING
% probability of having the disease
0 10 20 30 40 50 60 70 80 90 100
Fig. 1.5 The interpretation of a test result depends on the probability of the disease before the test is carried out. In the example shown, the test
being carried out has a sensitivity of 95% and a specificity of 85%. Patient A has very characteristic clinical findings, which make the pre-test probability of
the condition for which the test is being used very high - estimated as 90%. Patient B has more equivocal findings, such that the pre-test probability is
estimated as only 50%. If the result in Patient A is negative, there is still a significant chance that he has the condition for which he is being tested; in
Patient B, however, a negative result makes the diagnosis very unlikely.
Knowing the patient’s true state is often unnecessary in clinical
decision-making. Sox and colleagues (see ‘Further information’)
argue that there is a difference between knowing that a disease
is present and acting as if it were present. The requirement for
diagnostic certainty depends on the penalty for being wrong.
Different situations require different levels of certainty before
starting treatment. How we communicate uncertainty to patients
will be discussed later in this chapter (p. 10).
The treatment threshold combines factors such as the risks of
the test, and the risks versus benefits of treatment. The point at
which the factors are all evenly weighed is the threshold. If a test
or treatment for a disease is effective and low-risk (e.g. giving
antibiotics for a suspected urinary tract infection), then there is a
lower threshold for going ahead. On the other hand, if a test or
treatment is less effective or high-risk (e.g. starting chemotherapy
for a malignant brain tumour), then greater confidence is required
in the clinical diagnosis and potential benefits of treatment first.
In principle, if a diagnostic test will not change the management
of the patient, then careful consideration should be given to
whether it is necessary to do the test at all.
In summary, test results shift our thinking, but rarely give a
‘yes’ or a ‘no’ answer in terms of a diagnosis. Sometimes tests
shift the probability of disease by less than we realise. Pre-test
probability is key, and this is derived from the history and physical
examination, combined with a sound knowledge of medicine and
an understanding of the prevalence of disease in the particular
care setting or the population to which the patient belongs.
Cognitive biases
Advances in cognitive psychology in recent decades have
demonstrated that human thinking and decision-making are
prone to error. Cognitive biases are subconscious errors that lead
to inaccurate judgement and illogical interpretation of information.
They are prevalent in everyday life; as the famous saying goes,
‘to err is human.’
Take a few moments to look at this simple puzzle. Do not try
to solve it mathematically but listen to your intuition:
A bat and ball cost £1 .10.
The bat costs £1 more than the ball.
How much does the ball cost?
The answer is at the end of the chapter. Most people get
the answer to this puzzle wrong. Two things are going on: one
is that humans have two distinct types of processes when it
comes to thinking and decision-making - termed ‘type 1 ’ and
‘type 2’ thinking. The other is that the human brain is wired
to jump to conclusions sometimes or to miss things that are
obvious. British psychologist and patient safety pioneer James
Cognitive biases • 7
Experience
Context
Ambient conditions
Education
Training
Logical competence
Fig. 1.6 The interplay between type 1 and
type 2 thinking in the diagnostic process.
Adapted from Croskerry P. A universal model of
diagnostic reasoning. Acad Med 2009;
84:1022-1028.
Reason said that, ‘Our propensity for certain types of error is
the price we pay for the brain’s remarkable ability to think and
act intuitively - to sift quickly through the sensory information
that constantly bombards us without wasting time trying to work
through every situation anew.’ This property of human thinking
is highly relevant to clinical decision-making.
Type 1 and type 2 thinking
Studies of cognitive psychology and functional magnetic
resonance imaging demonstrate two distinct types of processes
when it comes to decision-making: intuitive (type 1) and analytical
(type 2). This has been termed ‘dual process theory’. Box 1.6
explains this in more detail.
Psychologists estimate that we spend 95% of our daily lives
engaged in type 1 thinking - the intuitive, fast, subconscious
mode of decision-making. Imagine driving a car, for example; it
would be impossible to function efficiently if every decision and
movement were as deliberate, conscious, slow and effortful as
in our first driving lesson. With experience, complex procedures
become automatic, fast and effortless. The same applies to
medical practice. There is evidence that expert decision-making
is well served by intuitive thinking. The problem is that although
intuitive processing is highly efficient in many circumstances, in
others it is prone to error.
Clinicians use both type 1 and type 2 thinking, and both types
are important in clinical decision-making. When encountering a
problem that is familiar, clinicians employ pattern recognition
and reach a working diagnosis or differential diagnosis quickly
(type 1 thinking). When encountering a problem that is more
complicated, they use a slower, systematic approach (type 2
thinking). Both types of thinking interplay - they are not mutually
exclusive in the diagnostic process. Figure 1 .6 illustrates the
interplay between type 1 and type 2 thinking in clinical practice.
Errors can occur in both type 1 and type 2 thinking; for
example, people can apply the wrong rules or make errors in
their application while using type 2 thinking. However, it has been
argued that the common cognitive biases encountered in medicine
tend to occur when clinicians are engaged in type 1 thinking.
For example, imagine being asked to see a young woman who
is drowsy. She is handed over to you as a ‘probable overdose’
because she has a history of depression and a packet of painkillers
1.6 Type 1 and type 2 thinking
Type 1
Type 2
Intuitive, heuristic (pattern recognition)
Analytical, systematic
Automatic, subconscious
Deliberate, conscious
Fast, effortless
Slow, effortful
Low/variable reliability
High/consistent reliability
Vulnerable to error
Less prone to error
Highly affected by context
Less affected by context
High emotional involvement
Low emotional involvement
Low scientific rigour
High scientific rigour
was found beside her at home. Her observations show she has
a Glasgow Coma Scale score of 10/15, heart rate 100 beats/
min, blood pressure 100/60 mmHg, respiratory rate 14 breaths/
min, oxygen saturations 98% on air and temperature 37.5°C.
Already your mind has reached a working diagnosis. It fits a
pattern (type 1 thinking). You think she has taken an overdose.
At this point you can stop to think about your thinking (rational
override in Fig. 1 .6): ‘What is the evidence for this diagnosis?
What else could it be?’
On the other hand, imagine being asked to assess a patient
who has been admitted with syncope. There are several different
causes of syncope and a systematic approach is required to reach
a diagnosis (type 2 thinking). However, you recently heard about a
case of syncope due to a leaking abdominal aortic aneurysm. At
the end of your assessment, following evidence-based guidelines,
it is clear the patient can be discharged. Despite this, you decide
to observe the patient overnight ‘just in case’ (irrational override
in Fig. 1.6). In this example, your intuition is actually availability
bias (when things are at the forefront of your mind), which has
significantly distorted your estimate of probability.
Common cognitive biases in medicine
Figure 1 .7 illustrates the common cognitive biases prevalent in
medical practice. Biases often work together; for example, in
8 • CLINICAL DECISION-MAKING
Anchoring
The common human tendency
to rely too heavily on the first piece
of information offered (the
‘anchor’) when making decisions
Ascertainment bias
We sometimes see what we
expect to see (‘self-fulfilling
prophecy’). For example, a
frequent self-harmer attends the
emergency department with
drowsiness; everyone assumes he
has taken another overdose and
misses a brain injury
Availability bias
Things may be at the forefront of
your mind because you have seen
several cases recently or have
been studying that condition in
particular. For example, when one
of the authors worked in an
epilepsy clinic, all blackouts were
possible seizures
Base rate neglect
The tendency to ignore the
prevalence of a disease, which
then distorts Bayesian reasoning.
In some cases, clinicians do this
deliberately in order to rule out an
unlikely but worst-case scenario
Commission bias
The tendency towards action
rather than inaction, on the
assumption that good can come
only from doing something
(rather than ‘watching and
waiting’)
Confirmation bias
The tendency to look for
confirming evidence to support a
theory rather than looking for
disconfirming evidence to refute
it, even if the latter is clearly
present. Confirmation bias is
common when a patient has been
seen first by another doctor
Diagnostic momentum
Once a diagnostic label has been
attached to a patient (by the patient
or other health-care professionals),
it can gather momentum with each
review, leading others to exclude
other possibilities in their thinking
Framing effect
How a case is presented - for
example, in handover - can
generate bias in the listener. This
can be mitigated by always having
‘healthy scepticism’ about other
people’s diagnoses
Hindsight bias
Knowing the outcome may
profoundly influence the perception
of past events and decision-making,
preventing a realistic appraisal of
what actually occurred - a major
problem in learning from
diagnostic error
Omission bias
The tendency towards inaction,
rooted in the principle of ‘first do
no harm.’ Events that occur through
natural progression of disease are
more acceptable than those that
may be attributed directly to the
action of the health-care team
Overconfidence bias
The tendency to believe we know
more than we actually do, placing
too much faith in opinion instead of
gathered evidence
Posterior probability
Our estimate of the likelihood of
disease may be unduly influenced
by what has gone on before for a
particular patient. For example, a
patient who has been extensively
investigated for headaches
presents with a severe headache,
and serious causes are discounted
Premature closure
The tendency to close the decision¬
making process prematurely and
accept a diagnosis before it, and
other possibilities, have been fully
explored
Psych-out error
Psychiatric patients who present
with medical problems are under¬
assessed, under-examined and
under-investigated because
problems are presumed to be due
to, or exacerbated by, their
psychiatric condition
Search satisficing
We may stop searching because we
have found something that fits or is
convenient, instead of
systematically looking for the best
alternative, which involves more
effort
Triage-cueing
Triage ensures patients are sent to
the right department. However, this
leads to ‘geography is destiny’. For
example, a diabetic ketoacidosis
patient with abdominal pain and
vomiting is sent to surgery. The
wrong location (surgical ward)
stops people thinking about
medical causes of abdominal pain
and vomiting
Unpacking principle
Failure to ‘unpack’ all the available
information may mean things are
missed. For example, if a thorough
history is not obtained from either
the patient or carers (a common
problem in geriatric medicine),
diagnostic possibilities may be
discounted
Visceral bias
The influence of either negative or
positive feelings towards patients,
which can affect our decision¬
making
Fig. 1.7 Common cognitive biases in medicine. Adapted from Croskerry P. Achieving quality in clinical decision-making: cognitive strategies and
detection of bias. Acad Emerg Med 2002; 9:1184-1204.
Reducing errors in clinical decision-making • 9
overconfidence bias (the tendency to believe we know more than
we actually do), too much faith is placed in opinion instead of
gathered evidence. This bias can be augmented by the availability
bias and finally by commission bias (the tendency towards action
rather than inaction) - sometimes with disastrous results.
The mark of a well -calibrated thinker is the ability to recognise
what mode of thinking is being employed and to anticipate and
recognise situations in which cognitive biases and errors are
more likely to occur.
Human factors
‘Human factors’ is the science of the limitations of human
performance, and how technology, the work environment and
team communication can adapt for this to reduce diagnostic
and other types of error. Analysis of serious adverse events
in clinical practice shows that human factors and poor team
communication play a significant role when things go wrong.
Research shows that many errors are beyond an individual’s
conscious control and are precipitated by many factors. The
discipline of human factors seeks to understand interactions
between:
• people and tasks or technology
• people and their work environment
• people in a team.
An understanding of these interactions makes it easier for
health-care professionals, who are committed to ‘first do no harm,’
to work in the safest way possible. For example, performance is
adversely affected by factors such as poorly designed processes
and equipment, frequent interruptions and fatigue. The areas of
the brain required for type 2 processing are most affected by
things like fatigue and cognitive overload, and the brain reverts
to type 1 processing to conserve cognitive energy. Figure 1 .8
illustrates some of the internal and external factors that affect
human judgement and decision-making.
Various experiments demonstrate that we focus our attention
to filter out distractions. This is advantageous in many situations,
but in focusing on what we are trying to see we may not notice
the unexpected. In a team context, what is obvious to one person
may be completely missed by someone else. Safe and effective
team communication therefore requires us never to assume,
and to verbalise things, even though they may seem obvious.
Reducing errors in clinical
decision-making
Knowledge and experience do not eliminate errors. Instead, there
are a number of ways in which we can act to reduce errors in
clinical decision-making. Examples are:
• adopting ‘cognitive debiasing strategies’
• using clinical prediction rules and other decision aids
• engaging in effective team communication.
Cognitive debiasing strategies
There are some simple and established techniques that
can be used to avoid cognitive biases and errors in clinical
decision-making.
History and physical examination
Taking a history and performing a physical examination may
seem obvious, but these are sometimes carried out inadequately.
This is the ‘unpacking principle’: failure to unpack all the
available information means things can be missed and lead
to error.
Problem lists and differential diagnosis
Once all the available data from history, physical examination
and (sometimes) initial test results are available, these need
to be synthesised into a problem list. The ability to identify
key clinical data and create a problem list is a key step in
clinical reasoning. Some problems (e.g. low serum potassium)
require action but not necessarily a differential diagnosis.
Other problems (e.g. vomiting) require a differential diagnosis.
The process of generating a problem list ensures nothing is
missed. The process of generating a differential diagnosis
works against anchoring on a particular diagnosis too early,
thereby avoiding search satisficing and premature closure
(see Fig. 1.7).
| Mnemonics and checklists
These are used frequently in medicine in order to reduce
reliance on fallible human memory. ABODE (airway, breathing,
circulation, disability, exposure/examination) is probably the most
successful checklist in medicine, used during the assessment
and treatment of critically ill patients (ABODE is sometimes
prefixed with ‘C’ for ‘control of any obvious problem’; see p. 188).
Checklists ensure that important issues have been considered
and completed, especially under conditions of complexity, stress
or fatigue.
I Red flags and ROWS (‘rule out worst
case scenario’)
These are strategies that force doctors to consider serious
diseases that can present with common symptoms. Red flags
in back pain are listed in Box 24.19 (p. 996). Considering and
investigating for possible pulmonary embolism in patients who
Internal factors
Knowledge
Training
Beliefs and values
Emotions
Sleep/fatigue
Stress
Physical illness
Personality type
Type 1 thinking/
conservation of
cognitive effort
Cognitive and
affective biases
External factors
Interruptions
Cognitive overload
Time pressure
Ambient conditions
Insufficient data
Team factors
Patient factors
Poor feedback
Fig. 1.8 Factors that affect our judgement and
decision-making. Type 1 thinking = fast, intuitive,
subconscious, low-effort.
10 • CLINICAL DECISION-MAKING
present with pleuritic chest pain and breathlessness is a common
example of ruling out a worst-case scenario, as pulmonary
embolism can be fatal if missed. Red flags and ROWS help to
avoid cognitive biases such as the ‘framing effect’ and ‘premature
closure’.
Newer strategies to avoid cognitive biases and errors in decision¬
making are emerging. These involve explicit training in clinical
reasoning and human factors. In theory, if doctors are aware
of the science of human thinking and decision-making, then
they are more able to think about their thinking, understand
situations in which their decision-making may be affected, and
take steps to mitigate this.
Using clinical prediction rules and other
decision aids
A clinical prediction rule is a statistical model of the diagnostic
process. When clinical prediction rules are matched against the
opinion of experts, the model usually outperforms the experts,
because it is applied consistently in each case. However, it is
important that clinical prediction rules are used correctly - that
is, applied to the patient population that was used to create the
rule. Clinical prediction rules force a scientific assessment of the
patient’s symptoms, signs and other data to develop a numerical
probability of a disease or an outcome. They help clinicians to
estimate probability more accurately.
A good example of a clinical prediction rule to estimate pre-test
probability is the Wells score in suspected deep vein thrombosis
(see Box 10.15, p. 187). Other commonly used clinical prediction
rules predict outcomes and therefore guide the management plan.
These include the GRACE score in acute coronary syndromes
(see Fig. 16.62, p. 494) and the CURB-65 score in community-
acquired pneumonia (see Fig. 17.32, p. 583).
Effective team communication
Effective team communication and proper handovers are vital for
safe clinical care. The SBAR system of communication has been
recommended by the UK’s Patient Safety First campaign. It is
a structured way to communicate about a patient with another
health-care professional (e.g. during handover or when making
a referral) and increases the amount of relevant information
being communicated in a shorter time. It is illustrated in Box 1 .7.
In increasingly complex health-care systems, patients are
looked after by a wide variety of professionals, each of whom
has access to important information required to make clinical
decisions. Strict hierarchies are hazardous to patient safety if
certain members of the team are not able to speak up.
Patient-centred evidence-based
medicine and shared decision-making
‘Patient-centred evidence-based medicine’ refers to the
application of best-available research evidence while taking
individual patient factors into account; these include both clinical
and non-clinical factors (e.g. the patient’s social circumstances,
values and wishes). For example, a 95-year-old man with dementia
and a recent gastrointestinal bleed is admitted with an inferior
myocardial infarction. He is clinically well. Should he be treated
1 1 .7 The SBAR system of communicating
SBAR
Example (a telephone call to the Intensive
Care team)
Situation
1 am [name] calling from [place] about a patient
with a NEWS of 10.
Background
[Patient’s name], 30-year-old woman, no past
medical history, was admitted last night with
community-acquired pneumonia. Since then her
oxygen requirements have been steadily
increasing.
Assessment
Her vital signs are: blood pressure 1 1 5/60 mmHg,
heart rate 120 beats/min, temperature 38°C,
respiratory rate 32 breaths/min, oxygen
saturations 89% on 15 L via reservoir bag mask.
An arterial blood gas shows pH 7.3 (H+
50 nmol/L), PaC02 4.0 kPa (30 mmHg), Pa02
1 kPa (52.5 mmHg), standard bicarbonate
14 mmol/L.
Chest X-ray shows extensive right lower zone
consolidation.
Recommendation
Please can you come and see her as soon as
possible? 1 think she needs admission to Intensive
Care.
(NEWS = National Early Warning Score; a patient with normal vital signs
scores 0)
From Royal College of Physicians of London. National Early Warning Score:
standardising the assessment of illness severity in the NHS. Report of a working
party RCP, July 2012; www.rcplondon.ac.uk/projects/outputs/national-early-
warning-score-news (accessed March 2016).
with dual antiplatelet therapy and low-molecular-weight heparin
as recommended in clinical guidelines?
As this chapter has described, clinicians frequently deal with
uncertainty/probability. Clinicians need to be able to explain risks
and benefits of treatment in an accurate and understandable
way. Providing the relevant statistics is seldom sufficient to guide
decision-making because a patient’s perception of risk may
be influenced by irrational factors as well as individual values.
Research evidence provides statistics but these can be
confusing. Terms such as ‘common’ and ‘rare’ are nebulous.
Whenever possible, clinicians should quote numerical information
using consistent denominators (e.g. ‘90 out of 100 patients
who have this operation feel much better, 1 will die during the
operation and 2 will suffer a stroke’). Visual aids can be used to
present complex statistical information (Fig. 1 .9).
How uncertainty is conveyed to patients is important. Many
studies demonstrate a correlation between effective clinician-
patient communication and improved health outcomes. If patients
feel they have been listened to and understand the problem and
proposed treatment plan, they are more likely to follow the plan
and less likely to re-attend.
Clinical decision-making: putting
it all together
The following is a practical example that brings together many
of the concepts outlined in this chapter:
A 25-year-old woman presents with right-sided pleuritic chest
pain and breathlessness. She reports that she had an upper
Clinical decision-making: putting it all together • 11
Fig. 1.9 Visual portrayal of benefits and risks. The image refers to an
operation that is expected to relieve symptoms in 90% of patients, but
cause stroke in 2% and death in 1%. From Edwards A, Elwyn G, MulleyA.
Explaining risks: turning numerical data into meaningful pictures. BMJ
2002; 324:827-830, reproduced with permission from the BMJ Publishing
Group.
respiratory tract infection a week ago and was almost back to
normal when the symptoms started. The patient has no past
medical history and no family history, and her only medication
is the combined oral contraceptive pill. On examination, her
vital signs are normal (respiratory rate 19 breaths/min, oxygen
saturations 98% on air, blood pressure 115/60 mmHg, heart rate
90 beats/min, temperature 37.5°C) and the physical examination
is also normal. You have been asked to assess her for the
possibility of a pulmonary embolism.
(More information on pulmonary embolism can be found on
page 619.)
Evidence-based history and examination
Information from the history and physical examination is vital in
deciding whether this could be a pulmonary embolism. Pleurisy
and breathlessness are common presenting features of this
disease but are also common presenting features in other
diseases. There is nothing in the history to suggest an alternative
diagnosis (e.g. high fever, productive cough, recent chest trauma).
The patient’s vital signs are normal, as is the physical examination.
However, the only feature in the history and examination that has
a negative likelihood ratio in the diagnosis of pulmonary embolism
is a heart rate of less than 90 beats/min. In other words, the
normal physical examination findings (including normal oxygen
saturations) carry very little diagnostic weight.
|Deciding pre-test probability
The prevalence of pulmonary embolism in 25-year-old women
is low. We anchor on this prevalence and then adjust for
individual patient factors. This patient has no major risk factors
for pulmonary embolism. To assist our estimate of pre-test
probability, we could use a clinical prediction rule: in this case,
the modified Wells score for pulmonary embolism, which would
give a score of 3 (low probability - answering yes only to the
criterion ‘PE is the number one diagnosis, an alternative is
less likely’).
Interpreting test results
Imagine the patient went on to have a normal chest X-ray
and blood results, apart from a raised D-dimer of 900 (normal
<500 ng/mL). A normal chest X-ray is a common finding in
pulmonary embolism. Several studies have shown that the
D-dimer assay has at least 95% sensitivity in acute pulmonary
embolism but it has a low specificity. A very sensitive test will
detect most disease but generate abnormal findings in healthy
people. On the other hand, a negative result virtually, but not
completely, excludes the disease. It is important at this point to
realise that a raised D-dimer result does not mean this patient
has a pulmonary embolism; it just means that we have not been
able to exclude it. Since pulmonary embolism is a potentially fatal
condition we need to rule out the worst-case scenario (ROWS),
and the next step is therefore to arrange further imaging. What
kind of imaging depends on individual patient characteristics
and what is available.
| Treatment threshold
The treatment threshold combines factors such as the risks of the
test, and the risks versus benefits of treatment. A CT pulmonary
angiogram (CTPA) could be requested for this patient, although
in some circumstances ventilation-perfusion single-photon
emission computed tomography (V/Q SPECT, p. 620) may be
a more suitable alternative. However, what if the scan cannot
be performed until the next day? Because pulmonary embolism
is potentially fatal and the risks of treatment in this case are
low, the patient should be started on treatment while awaiting
the scan.
Post-test probability
The patient’s scan result is subsequently reported as ‘no
pulmonary embolism’. Combined with the low pre-test probability,
this scan result reliably excludes pulmonary embolism.
| Cognitive biases
Imagine during this case that the patient had been handed
over to you as ‘nothing wrong - probably a pulled muscle’.
Cognitive biases (subconscious tendencies to respond in a
certain way) would come into play, such as the ‘framing effect’,
‘confirmation bias’ and ‘search satisficing’. The normal clinical
examination might confirm the diagnosis of musculoskeletal pain
in your mind, despite the examination being entirely consistent
with pulmonary embolism and despite the lack of history and
examination findings (e.g. chest wall tenderness) to support the
diagnosis of musculoskeletal chest pain.
Human factors
Imagine that, after you have seen the patient, a nurse
hands you some blood forms and asks you what tests you
would like to request on ‘this lady’. You request blood tests
including a D-dimer on the wrong patient. Luckily, this error is
intercepted.
Reducing cognitive error
The diagnosis of pulmonary embolism can be difficult. Clinical
prediction rules (e.g. modified Wells score), guidelines (e.g. from
the UK’s National Institute for Health and Care Excellence, or
NICE) and decision aids (e.g. simplified pulmonary embolism
severity index, or PESI) are frequently used in combination with
the doctor’s opinion, derived from information gathered in the
history and physical examination.
12 • CLINICAL DECISION-MAKING
I Person-centred EBM and information given
to patient
The patient is treated according to evidence-based guidelines
that apply to her particular situation. Tests alone do not make
a diagnosis and at the end of this process the patient is told
that the combination of history, examination and test results
mean she is extremely unlikely to have a pulmonary embolism.
Viral pleurisy is offered as an alternative diagnosis and she is
reassured that her symptoms are expected to settle over the
coming days with analgesia. She is advised to re-present to
hospital if her symptoms suddenly get worse.
Answers to problems
Harvard problem (p. 5)
Almost half of doctors surveyed said 95%, but they neglected to
take prevalence into account. If 1000 people are tested, there
will be 51 positive results: 50 false positives and 1 true positive.
The chance that a person found to have a positive result actually
has the disease is 1/51 or 2%.
Bat and ball problem (p. 6)
This puzzle is from the book, Thinking, Fast and Slow, by Nobel
laureate Daniel Kahneman (see ‘Further information’). He writes,
‘A number came to your mind. The number, of course, is lOp.
The distinctive mark of this easy puzzle is that it evokes an
answer that is intuitive, appealing - and wrong. Do the math,
and you will see.’ The correct answer is 5p.
Further information
Books and journal articles
Cooper N, Frain J (eds). ABC of clinical reasoning. Oxford:
Wiley-Blackwell; 2016.
Kahneman D. Thinking, fast and slow. Harmondsworth: Penguin;
2012.
McGee S. Evidence-based physical diagnosis, 3rd edn. Philadelphia:
Saunders; 2012.
Scott IA. Errors in clinical reasoning: causes and remedial strategies.
BMJ 2009; 338:b186.
Sox H, Higgins MC, Owens DK. Medical decision making, 2nd edn.
Chichester: Wiley-Blackwell; 2013.
Trowbridge RL, Rencic JJ, Durning SJ. Teaching clinical reasoning.
Philadelphia: American College of Physicians; 2015.
Vincent C. Patient safety. Edinburgh: Churchill Livingstone; 2006.
Websites
chfg.org UK Clinical Human Factors Group.
clinical-reasoning.org Clinical reasoning resources.
creme.org.uk UK Clinical Reasoning in Medical Education group.
improvediagnosis.org Society to Improve Diagnosis in Medicine.
vassarstats.net/index.html Suite of calculators for statistical
computation (Calculator 2 is a calculator for predictive values and
likelihood ratios).
Clinical therapeutics and
good prescribing
Principles of clinical pharmacology 14
Drug regulation and management 26
Pharmacodynamics 1 4
Drug development and marketing 26
Pharmacokinetics 1 7
Managing the use of medicines 27
Inter-individual variation in drug responses 19
Prescribing in practice 28
Adverse outcomes of drug therapy 21
Decision-making in prescribing 28
Adverse drug reactions 21
Prescribing in special circumstances 31
Drug interactions 23
Writing prescriptions 33
Medication errors 24
Monitoring drug therapy 34
14 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
Prescribing medicines is the major tool used by doctors to
restore or preserve the health of patients. Medicines contain
drugs (the specific chemical substances with pharmacological
effects), either alone or in combination with additional drugs, in
a formulation mixed with other ingredients. The beneficial effects
of medicines must be weighed against their cost and potential
adverse drug reactions and interactions. The latter two factors
are sometimes caused by injudicious prescribing decisions
and by prescribing errors. The modern prescriber must meet
the challenges posed by the increasing number of drugs and
formulations available and of indications for prescribing them,
and the greater complexity of treatment regimens followed by
individual patients (‘polypharmacy’, a particular challenge in the
ageing population). The purpose of this chapter is to elaborate
on the principles and practice that underpin good prescribing
(Box 2.1).
2.1 Steps in good prescribing
• Make a diagnosis
• Consider factors that might influence the patient’s response to
therapy (age, concomitant drug therapy, renal and liver function etc.)
• Establish the therapeutic goal*
• Choose the therapeutic approach*
• Choose the drug and its formulation (the ‘medicine’)
• Choose the dose, route and frequency
• Choose the duration of therapy
• Write an unambiguous prescription (or ‘medication order’)
• Inform the patient about the treatment and its likely effects
• Monitor treatment effects, both beneficial and harmful
• Review/alter the prescription
*These steps in particular take the patient’s views into consideration to establish
a therapeutic partnership (shared decision-making to achieve ‘concordance’).
Principles of clinical pharmacology
Prescribers need to understand what the drug does to the
body (pharmacodynamics) and what the body does to the drug
(pharmacokinetics) (Fig. 2.1). Although this chapter is focused on
the most common drugs, which are synthetic small molecules,
the same principles apply to the increasingly numerous ‘biological’
therapies (sometimes abbreviated to ‘biologies’) now in use,
which include peptides, proteins, enzymes and monoclonal
antibodies (see Box 4.2, p. 65).
Pharmacodynamics
|J)rug targets and mechanisms of action
Modern drugs are usually discovered by screening compounds
for activity either to stimulate or to block the function of a specific
molecular target, which is predicted to have a beneficial effect
in a particular disease (Box 2.2). Other drugs have useful but
less selective chemical properties, such as chelators (e.g. for
treatment of iron or copper overload), osmotic agents (used as
diuretics in cerebral oedema) or general anaesthetics (that alter
the biophysical properties of lipid membranes). The following
characteristics of the interaction of drugs with receptors illustrate
some of the important determinants of the effects of drugs:
• Affinity describes the propensity for a drug to bind to a
receptor and is related to the ‘molecular fit’ and the
Pharmacokinetics
Time
Dosage
regimen
‘what the body does
to a drug’
Monitoring
Measure plasma drug
concentration
Plasma
concentration
I
Concentration at
the site of action
Pharmacodynamics
Concentration
‘what a drug does
to the body’
Monitoring
Measure clinical
effects
Pharmacological
effects
Fig. 2.1 Pharmacokinetics and pharmacodynamics.
strength of the chemical bond. Some drug-receptor
interactions are irreversible, either because the affinity is so
strong or because the drug modifies the structure of its
molecular target.
• Selectivity describes the propensity for a drug to bind to
one target rather than another. Selectivity is a relative
term, not to be confused with absolute specificity. It is
common for drugs targeted at a particular subtype of
receptor to exhibit some effect at other subtypes. For
example, (3-adrenoceptors can be subtyped on the basis
of their responsiveness to the endogenous agonist
noradrenaline (norepinephrine): the concentration of
noradrenaline required to cause bronchodilatation (via
(32-adrenoceptors) is ten times higher than that required to
cause tachycardia (via -adrenoceptors). ‘Cardioselective’
(3-blockers have anti-anginal effects on the heart ((3^ but
may still cause bronchospasm in the lung ((32) and are
contraindicated for asthmatic patients.
• Agonists bind to a receptor to produce a conformational
change that is coupled to a biological response. As
agonist concentration increases, so does the proportion of
receptors occupied, and hence the biological effect. Partial
agonists activate the receptor but cannot produce a
maximal signalling effect equivalent to that of a full agonist,
even when all available receptors are occupied.
• Antagonists bind to a receptor but do not produce the
conformational change that initiates an intracellular signal.
A competitive antagonist competes with endogenous
ligands to occupy receptor-binding sites, with the resulting
antagonism depending on the relative affinities and
concentrations of drug and ligand. Non-competitive
antagonists inhibit the effect of an agonist by mechanisms
other than direct competition for receptor binding with the
agonist (e.g. by affecting post-receptor signalling).
Dose-response relationships
Plotting the logarithm of drug dose against drug response
typically produces a sigmoidal dose-response curve (Fig. 2.2).
Progressive increases in drug dose (which, for most drugs, is
proportional to the plasma drug concentration) produce increasing
Principles of clinical pharmacology • 15
2.2 Examples of target molecules for drugs
Drug target
Description
Examples
Receptors
Channel-linked receptors
Ligand binding controls a linked ion channel, known as ‘ligand-gated’
(in contrast to ‘voltage-gated’ channels that respond to changes in
membrane potential)
Nicotinic acetylcholine receptor
GABA receptor
Sulphonylurea receptor
G-protein-coupled receptors
(GPCRs)
Ligand binding affects one of a family of ‘G-proteins’ that mediate signal
transduction either by activating intracellular enzymes (such as adenylate
or guanylate cyclase, producing cyclic AMP or GMP, respectively) or by
controlling ion channels
Muscarinic acetylcholine receptor
p-adrenoceptors
Dopamine receptors
5 - Hy d roxytry ptam i n e (5-HT,
serotonin) receptors
Opioid receptors
Kinase-linked receptors
Ligand binding activates an intracellular protein kinase that triggers a
cascade of phosphorylation reactions
Insulin receptor
Cytokine receptors
Transcription factor receptors
Intracellular and also known as ‘nuclear receptors’; ligand binding
promotes or inhibits gene transcription and hence synthesis of new
proteins
Steroid receptors
Thyroid hormone receptors
Vitamin D receptors
Retinoid receptors
PPARy and a receptors
Other targets
Voltage-gated ion channels
Mediate electrical signalling in excitable tissues (muscle and nervous
system)
Na+ channels
Ca2+ channels
Enzymes
Catalyse biochemical reactions. Drugs interfere with binding of substrate
to the active site or of co-factors
Cyclo-oxygenase
ACE
Xanthine oxidase
Transporter proteins
Carry ions or molecules across cell membranes
5-HT re-uptake transporter
Na+/K+ ATPase
Cytokines and other
signalling molecules
Small proteins that are important in cell signalling (autocrine, paracrine
and endocrine), especially affecting the immune response
Tumour necrosis factors
Interleukins
Cell surface antigens
Block the recognition of cell surface molecules that modulate cellular
responses
Cluster of differentiation molecules
(e.g. CD20, CD80)
(ACE = angiotensin-converting enzyme; AMP = adenosine monophosphate; ATPase = adenosine triphosphatase; GABA = y-aminobutyric acid; GMP = guanosine
monophosphate; PPAR = peroxisome proliferator-activated receptor)
Drug dose (mg)
Fig. 2.2 Dose-response curve. The green curve represents the beneficial effect of the drug. The maximum response on the curve is the Emax and
the dose (or concentration) producing half this value (Emax/2) is the ED50 (or EC50). The red curve illustrates the dose-response relationship for the most
important adverse effect of this drug. This occurs at much higher doses; the ratio between the ED50 for the adverse effect and that for the beneficial effect
is the ‘therapeutic index’, which indicates how much margin there is for prescribers when choosing a dose that will provide beneficial effects without also
causing this adverse effect. Adverse effects that occur at doses above the therapeutic range are normally called ‘toxic effects’, while those occurring within
the therapeutic range are ‘side-effects’ and those below it are ‘hyper-susceptibility effects’.
16 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
response but only within a relatively narrow range of dose; further
increases in dose beyond this range produce little extra effect.
The following characteristics of the drug response are useful in
comparing different drugs:
• Efficacy describes the extent to which a drug can produce
a target-specific response when all available receptors or
binding sites are occupied (i.e. Emax on the dose-response
curve). A full agonist can produce the maximum response
of which the receptor is capable, while a partial agonist at
the same receptor will have lower efficacy. Therapeutic
efficacy describes the effect of the drug on a desired
biological endpoint and can be used to compare drugs
that act via different pharmacological mechanisms (e.g.
loop diuretics induce a greater diuresis than thiazide
diuretics and therefore have greater therapeutic efficacy).
• Potency describes the amount of drug required for a given
response. More potent drugs produce biological effects at
lower doses, so they have a lower ED50. A less potent
drug can still have an equivalent efficacy if it is given in
higher doses.
The dose-response relationship varies between patients
because of variations in the many determinants of pharmacokinetics
and pharmacodynamics. In clinical practice, the prescriber is
unable to construct a dose-response curve for each individual
patient. Therefore, most drugs are licensed for use within a
recommended range of doses that is expected to reach close to
the top of the dose-response curve for most patients. However,
it is sometimes possible to achieve the desired therapeutic
efficacy at doses towards the lower end of, or even below, the
recommended range.
Therapeutic index
The adverse effects of drugs are often dose-related in a similar
way to the beneficial effects, although the dose-response curve
for these adverse effects is normally shifted to the right (Fig. 2.2).
The ratio of the ED50 for therapeutic efficacy and for a major
adverse effect is known as the ‘therapeutic index’. In reality,
drugs have multiple potential adverse effects, but the concept of
therapeutic index is usually based on adverse effects that might
require dose reduction or discontinuation. For most drugs, the
therapeutic index is greater than 1 00 but there are some notable
exceptions with therapeutic indices of less than 10 (e.g. digoxin,
warfarin, insulin, phenytoin, opioids). The doses of such drugs
have to be titrated carefully for individual patients to maximise
benefits but avoid adverse effects.
Desensitisation and withdrawal effects
Desensitisation refers to the common situation in which the
biological response to a drug diminishes when it is given
continuously or repeatedly. It may be possible to restore the
response by increasing the dose of the drug but, in some cases,
the tissues may become completely refractory to its effect.
• Tachyphylaxis describes desensitisation that occurs very
rapidly, sometimes with the initial dose. This rapid loss of
response implies depletion of chemicals that may be
necessary for the pharmacological actions of the drug (e.g.
a stored neurotransmitter released from a nerve terminal)
or receptor phosphorylation.
• Tolerance describes a more gradual loss of response to a
drug that occurs over days or weeks. This slower change
implies changes in receptor numbers or the development
of counter- regulatory physiological changes that offset the
actions of the drug (e.g. accumulation of salt and water in
response to vasodilator therapy).
• Drug resistance is a term normally reserved for describing
the loss of effectiveness of an antimicrobial (p. 1 16) or
cancer chemotherapy drug.
• In addition to these pharmacodynamic causes of
desensitisation, reduced response may be the
consequence of lower plasma and tissue drug
concentrations as a result of altered pharmacokinetics
(see below).
When drugs induce chemical, hormonal and physiological
changes that offset their actions, discontinuation may allow
these changes to cause ‘rebound’ withdrawal effects (Box 2.3).
2.3 Examples of drugs associated with withdrawal effects
Drug
Symptoms
Signs
Treatment
Alcohol
Anxiety, panic, paranoid delusions,
visual and auditory hallucinations
Agitation, restlessness,
delirium, tremor, tachycardia,
ataxia, disorientation, seizures
Treat immediate withdrawal
syndrome with benzodiazepines
Barbiturates, benzodiazepines
Similar to alcohol
Similar to alcohol
Transfer to long-acting
benzodiazepine then gradually
reduce dosage
Glucocorticoids
Weakness, fatigue, decreased
appetite, weight loss, nausea,
vomiting, diarrhoea, abdominal pain
Hypotension, hypoglycaemia
Prolonged therapy suppresses the
hypothalamic-pituitary-adrenal axis
and causes adrenal insufficiency
requiring glucocorticoid replacement.
Withdrawal should be gradual after
prolonged therapy (p. 670)
Opioids
Rhinorrhoea, sneezing, yawning,
lacrimation, abdominal and leg
cramping, nausea, vomiting, diarrhoea
Dilated pupils
Transfer addicts to long-acting
agonist methadone
Selective serotonin re-uptake
inhibitors (SSRIs)
Dizziness, sweating, nausea, insomnia,
tremor, delirium, nightmares
Tremor
Reduce SSRIs slowly to avoid
withdrawal effects
Principles of clinical pharmacology • 17
Pharmacokinetics
Understanding ‘what the body does to the drug’ (Fig. 2.3) is
extremely important for prescribers because this forms the basis
on which the optimal route of administration and dose regimen
are chosen and explains the majority of inter-individual variation
in the response to drug therapy.
|_Drug absorption and routes of administration
Absorption is the process by which drug molecules gain access
to the blood stream. The rate and extent of drug absorption
depend on the route of administration (Fig. 2.3).
Enteral administration
These routes involve administration via the gastrointestinal
tract:
• Oral. This is the most common route of administration
because it is simple, convenient and readily used by
patients to self-administer their medicines. Absorption after
an oral dose is a complex process that depends on the
drug being swallowed, surviving exposure to gastric acid,
avoiding unacceptable food binding, being absorbed
across the small bowel mucosa into the portal venous
system, and surviving metabolism by gut wall or liver
enzymes (‘first-pass metabolism’). As a consequence,
absorption is frequently incomplete following oral
administration. The term ‘bioavailability’ describes the
proportion of the dose that reaches the systemic
circulation intact.
• Buccal, intranasal and sublingual (SL). These routes
have the advantage of enabling rapid absorption
into the systemic circulation without the uncertainties
associated with oral administration (e.g. organic nitrates
for angina pectoris, triptans for migraine, opioid
analgesics).
• Rectal (PR). The rectal mucosa is occasionally used
as a site of drug administration when the oral route is
compromised because of nausea and vomiting or
unconsciousness (e.g. diazepam in status epilepticus).
Parenteral administration
These routes avoid absorption via the gastrointestinal tract and
first-pass metabolism in the liver:
• Intravenous (IV). The IV route enables all of a dose to enter
the systemic circulation reliably, without any concerns
about absorption or first-pass metabolism (i.e. the dose is
100% bioavailable), and rapidly achieve a high plasma
concentration. It is ideal for very ill patients when a rapid,
certain effect is critical to outcome (e.g. benzathine
benzylpenicillin for meningococcal meningitis).
• Intramuscular (IM). IM administration is easier to achieve
than the IV route (e.g. adrenaline (epinephrine) for acute
anaphylaxis) but absorption is less predictable and
depends on muscle blood flow.
• Subcutaneous (SC). The SC route is ideal for drugs that
have to be administered parenteral ly because of low oral
bioavailability, are absorbed well from subcutaneous fat,
and might ideally be injected by patients themselves (e.g.
insulin, heparin).
• Transdermal. A transdermal patch can enable a drug to be
absorbed through the skin and into the circulation (e.g.
oestrogens, nicotine, nitrates).
Other routes of administration
• Topical application of a drug involves direct administration
to the site of action (e.g. skin, eye, ear). This has the
advantage of achieving sufficient concentration at this site
while minimising systemic exposure and the risk of
adverse effects elsewhere.
• Inhaled (INH) administration allows drugs to be delivered
directly to a target in the respiratory tree, usually the small
airways (e.g. salbutamol, beclometasone). However, a
significant proportion of the inhaled dose may be
absorbed from the lung or is swallowed and can reach the
systemic circulation. The most common mode of delivery
is the metered-dose inhaler but its success depends on
some degree of manual dexterity and timing (see Fig.
17.23, p. 571). Patients who find these difficult may use a
‘spacer’ device to improve drug delivery. A special mode
in faeces
Fig. 2.3 Pharmacokinetics summary. Most
drugs are taken orally, are absorbed from the
intestinal lumen and enter the portal venous
system to be conveyed to the liver, where they may
be subject to first-pass metabolism and/or
excretion in bile. Active drugs then enter the
systemic circulation, from which they may diffuse
(or sometimes be actively transported) in and out
of the interstitial and intracellular fluid
compartments. Drug that remains in circulating
plasma is subject to liver metabolism and renal
excretion. Drugs excreted in bile may be
reabsorbed, creating an enterohepatic circulation.
First-pass metabolism in the liver is avoided if
drugs are administered via the buccal or rectal
mucosa, or parenterally (e.g. by intravenous
injection).
18 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
of inhaled delivery is via a nebulised solution created by
using pressurised oxygen or air to break up solutions and
suspensions into small aerosol droplets that can be
directly inhaled from the mouthpiece of the device.
|Drug distribution
Distribution is the process by which drug molecules transfer into
and out of the blood stream. This is influenced by the drug’s
molecular size and lipid solubility, the extent to which it binds to
proteins in plasma, its susceptibility to drug transporters expressed
on cell surfaces, and its binding to its molecular target and to
other cellular proteins (which can be irreversible). Most drugs
diffuse passively across capillary walls down a concentration
gradient into the interstitial fluid until the concentration of free drug
molecules in the interstitial fluid is equal to that in the plasma.
As drug molecules in the blood are removed by metabolism or
excretion, the plasma concentration falls, drug molecules diffuse
back from the tissue compartment into the blood and eventually
all will be eliminated. Note that this reverse movement of drug
away from the tissues will be prevented if further drug doses
are administered and absorbed into the plasma.
Volume of distribution
The apparent volume of distribution (Vd) is the volume into which
a drug appears to have distributed following intravenous injection.
It is calculated from the equation
V6 = D/C0
where D is the amount of drug given and C0 is the initial plasma
concentration (Fig. 2.4A). Drugs that are highly bound to plasma
proteins may have a Vd below 10 L (e.g. warfarin, aspirin), while
those that diffuse into the interstitial fluid but do not enter cells
because they have low lipid solubility may have a Vd between 1 0
and 30 L (e.g. gentamicin, amoxicillin). It is an ‘apparent’ volume
because those drugs that are lipid-soluble and highly tissue-bound
may have a Vd of greater than 100 L (e.g. digoxin, amitriptyline).
Drugs with a larger Vd have longer half-lives (see below), take
longer to reach steady state on repeated administration and are
eliminated more slowly from the body following discontinuation.
|J)rug elimination
Drug metabolism
Metabolism is the process by which drugs are chemically altered
from a lipid-soluble form suitable for absorption and distribution
to a more water-soluble form that is necessary for excretion.
Some drugs, known as ‘prodrugs’, are inactive in the form in
which they are administered but are converted to an active
metabolite in vivo.
Phase I metabolism involves oxidation, reduction or hydrolysis
to make drug molecules suitable for phase II reactions or for
excretion. Oxidation is by far the most common form of phase
I reaction and chiefly involves members of the cytochrome
P450 family of membrane-bound enzymes in the endoplasmic
reticulum of hepatocytes.
Phase II metabolism involves combining phase I metabolites
with an endogenous substrate to form an inactive conjugate that
is much more water-soluble. Reactions include glucuronidation,
sulphation, acetylation, methylation and conjugation with
glutathione. This is necessary to enable renal excretion, because
lipid-soluble metabolites will simply diffuse back into the body
after glomerular filtration (p. 349).
E
Dose
Fig. 2.4 Drug concentrations in plasma following single and multiple
drug dosing. [A] In this example of first-order kinetics following a single
intravenous dose, the time period required for the plasma drug
concentration to halve (half-life, t1/2) remains constant throughout the
elimination process. [§] After multiple dosing, the plasma drug
concentration rises if each dose is administered before the previous dose
has been entirely cleared. In this example, the drug’s half-life is 30 hours,
so that with daily dosing the peak, average and trough concentrations
steadily increase as drug accumulates in the body (black line). Steady state
is reached after approximately 5 half-lives, when the rate of elimination
(the product of concentration and clearance) is equal to the rate of drug
absorption (the product of rate of administration and bioavailability). The
long half-life in this example means that it takes 6 days for steady state to
be achieved and, for most of the first 3 days of treatment, plasma drug
concentrations are below the therapeutic range. This problem can be
overcome if a larger loading dose (red line) is used to achieve steady-state
drug concentrations more rapidly.
Drug excretion
Excretion is the process by which drugs and their metabolites
are removed from the body.
Renal excretion is the usual route of elimination for drugs or
their metabolites that are of low molecular weight and sufficiently
water-soluble to avoid reabsorption from the renal tubule. Drugs
bound to plasma proteins are not filtered by the glomeruli. The
pH of the urine is more acidic than that of plasma, so that
some drugs (e.g. salicylates) become un-ionised and tend to
Principles of clinical pharmacology • 19
be reabsorbed. Alkalination of the urine can hasten excretion
(e.g. after a salicylate overdose; p. 138). For some drugs, active
secretion into the proximal tubule lumen, rather than glomerular
filtration, is the predominant mechanism of excretion (e.g.
methotrexate, penicillin).
Faecal excretion is the predominant route of elimination for
drugs with high molecular weight, including those that are excreted
in the bile after conjugation with glucuronide in the liver, and
any drugs that are not absorbed after enteral administration.
Molecules of drug or metabolite that are excreted in the bile
enter the small intestine, where they may, if they are sufficiently
lipid-soluble, be reabsorbed through the gut wall and return to
the liver via the portal vein (see Fig. 2.3). This recycling between
the liver, bile, gut and portal vein is known as ‘enterohepatic
circulation’ and can significantly prolong the residence of drugs
in the body.
Elimination kinetics
The net removal of drug from the circulation results from a
combination of drug metabolism and excretion, and is usually
described as ‘clearance’, i.e. the volume of plasma that is
completely cleared of drug per unit time.
For most drugs, elimination is a high-capacity process that does
not become saturated, even at high dosage. The rate of elimination
is therefore directly proportional to the drug concentration because
of the ‘law of mass action’, whereby higher drug concentrations
will drive faster metabolic reactions and support higher renal
filtration rates. This results in ‘first-order’ kinetics, when a constant
fraction of the drug remaining in the circulation is eliminated
in a given time and the decline in concentration over time is
exponential (Fig. 2.4A). This elimination can be described by
the drug’s half-life (t1/2), i.e. the time taken for the plasma drug
concentration to halve, which remains constant throughout the
period of drug elimination. The significance of this phenomenon
for prescribers is that the effect of increasing doses on plasma
concentration is predictable - a doubled dose leads to a doubled
concentration at all time points.
For a few drugs in common use (e.g. phenytoin, alcohol),
elimination capacity is exceeded (saturated) within the usual
dose range. This is called ‘zero-order’ kinetics. Its significance
for prescribers is that, if the rate of administration exceeds
the maximum rate of elimination, the drug will accumulate
progressively, leading to serious toxicity.
Repeated dose regimens
The goal of therapy is usually to maintain drug concentrations
within the therapeutic range (see Fig. 2.2) over several days (e.g.
antibiotics) or even for months or years (e.g. antihypertensives,
lipid-lowering drugs, thyroid hormone replacement therapy). This
goal is rarely achieved with single doses, so prescribers have
to plan a regimen of repeated doses. This involves choosing
the size of each individual dose and the frequency of dose
administration.
As illustrated in Figure 2.4B, the time taken to reach drug
concentrations within the therapeutic range depends on the
half-life of the drug. Typically, with doses administered regularly,
it takes approximately 5 half-lives to reach a ‘steady state’ in
which the rate of drug elimination is equal to the rate of drug
administration. This applies when starting new drugs and when
adjusting doses of current drugs. With appropriate dose selection,
steady-state drug concentrations will be maintained within the
therapeutic range. This is important for prescribers because it
means that the effects of a new prescription, or dose titration, for
a drug with a long half-life (e.g. digoxin - 36 hours) may not be
known for a few days. In contrast, drugs with a very short half-life
(e.g. dobutamine - 2 minutes) have to be given continuously by
infusion but reach a new steady state within minutes.
For drugs with a long half-life, if it is unacceptable to wait for
5 half-lives until concentrations within the therapeutic range are
achieved, then an initial ‘loading dose’ can be given that is much
larger than the maintenance dose and equivalent to the amount
of drug required in the body at steady state. This achieves a
peak plasma concentration close to the plateau concentration,
which can then be maintained by successive maintenance doses.
‘Steady state’ actually involves fluctuations in drug concentra¬
tions, with peaks just after administration followed by troughs
just prior to the next administration. The manufacturers of
medicines recommend dosing regimens that predict that, for
most patients, these oscillations result in troughs within the
therapeutic range and peaks that are not high enough to cause
adverse effects. The optimal dose interval is a compromise
between convenience for the patient and a constant level
of drug exposure. More frequent administration (e.g. 25 mg
4 times daily) achieves a smoother plasma concentration profile
than 100 mg once daily but is much more difficult for patients
to sustain. A solution to this need for compromise in dosing
frequency for drugs with half-lives of less than 24 hours is the
use of ‘modified-release’ formulations. These allow drugs to
be absorbed more slowly from the gastrointestinal tract and
reduce the oscillation in plasma drug concentration profile, which
is especially important for drugs with a low therapeutic index
(e.g. levodopa).
Inter-individual variation in drug responses
Prescribers have numerous sources of guidance about how to
use drugs appropriately (e.g. dose, route, frequency, duration)
for many conditions. However, this advice is based on average
dose-response data derived from observations in many individuals.
When applying this information to an individual patient, prescribers
must take account of inter-individual variability in response. Some
of this variability is predictable and good prescribers are able to
anticipate it and adjust their prescriptions accordingly to maximise
the chances of benefit and minimise harm. Inter-individual variation
in responses also mandates that effects of treatment should be
monitored (p. 34).
Some inter-individual variation in drug response is accounted
for by differences in pharmacodynamics. For example, the
beneficial natriuresis produced by the loop diuretic furosemide
is often significantly reduced at a given dose in patients with
renal impairment, while delirium caused by opioid analgesics
is more likely in the elderly. Differences in pharmacokinetics
more commonly account for different drug responses, however.
Examples of factors influencing the absorption, metabolism and
excretion of drugs are shown in Box 2.4.
It is hoped that a significant proportion of the inter-individual
variation in drug responses can be explained by studying genetic
differences in single genes (‘pharmacogenetics’; Box 2.5) or the
effects of multiple gene variants (‘pharmacogenomics’). The aim
is to identify those patients most likely to benefit from specific
treatments and those most susceptible to adverse effects. In
this way, it may be possible to select drugs and dose regimens
for individual patients to maximise the benefit-to-hazard ratio
(‘personalised medicine’).
20 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
2.4 Patient-specific factors that influence pharmacokinetics
Gastrointestinal function
• Drug metabolism is low in the fetus and newborn, may be enhanced
in young children, and becomes less effective with age
• Drug excretion falls with the age-related decline in renal function
Sex
• Women have a greater proportion of body fat than men, increasing the
volume of distribution and half-life of lipid-soluble drugs
Body weight
• Obesity increases volume of distribution and half-life of lipid-soluble
drugs
• Patients with higher lean body mass have larger body compartments
into which drugs are distributed and may require higher doses
Liver function
• Metabolism of most drugs depends on several cytochrome P450
enzymes that are impaired in patients with advanced liver disease
• Hypoalbuminaemia influences the distribution of drugs that are highly
protein-bound
Kidney function
• Renal disease and the decline in renal function with ageing may lead
to drug accumulation
• Small intestinal absorption of oral drugs may be delayed by reduced
gastric motility
• Absorptive capacity of the intestinal mucosa may be reduced in
disease (e.g. Crohn’s or coeliac disease) or after surgical resection
Food
• Food in the stomach delays gastric emptying and reduces the rate (but
not usually the extent) of drug absorption
• Some food constituents bind to certain drugs and prevent their
absorption
Smoking
• Tar in tobacco smoke stimulates the oxidation of certain drugs
Alcohol
• Regular alcohol consumption stimulates liver enzyme synthesis, while
binge drinking may temporarily inhibit drug metabolism
Drugs
• Drug-drug interactions cause marked variation in pharmacokinetics
(see Box 2.11)
I 2.5 Examples of pharmacogenetic variations that influence drug response
Genetic variant
Drug affected
Clinical outcome
Pharmacokinetic
Aldehyde dehydrogenase-2 deficiency
Ethanol
Elevated blood acetaldehyde causes facial flushing and
increased heart rate in -50% of Japanese, Chinese and other
Asian populations
Acetylation
Isoniazid, hydralazine, procainamide
Increased responses in slow acetylators, up to 50% of some
populations
Oxidation (CYP2D6)
Nortriptyline
Increased risk of toxicity in poor metabolisers
Codeine
Reduced responses with slower conversion of codeine to more
active morphine in poor metabolisers, 10% of European
populations
Increased risk of toxicity in ultra-fast metabolisers, 3% of
Europeans but 40% of North Africans
Oxidation (CYP2C18)
Proguanil
Reduced efficacy with slower conversion to active cycloguanil
in poor metabolisers
Oxidation (CYP2C9)
Warfarin
Polymorphisms known to influence dosages
Oxidation (CYP2C19)
Clopidogrel
Reduced enzymatic activation results in reduced antiplatelet
effect
Sulphoxidation
Penicillamine
Increased risk of toxicity in poor metabolisers
Pluman leucocyte antigen (HLA)-B*1 502
Carbamazepine
Increased risk of serious dermatological reactions (e.g.
Stevens-Johnson syndrome) for 1 in 2000 in Caucasian
populations (much higher in some Asian countries)
Pseudocholinesterase deficiency
Suxamethonium (succinylcholine)
Decreased drug inactivation leads to prolonged paralysis and
sometimes persistent apnoea requiring mechanical ventilation
until the drug can be eliminated by alternate pathways; occurs
in 1 in 1500 people
Pharmacodynamic
Glucose-6-phosphate dehydrogenase
Oxidant drugs, including antimalarials
Risk of haemolysis in G6PD deficiency
(G6PD) deficiency
(e.g. chloroquine, primaquine)
Acute intermittent porphyria
Enzyme-inducing drugs
Increased risk of an acute attack
SLC01B1 polymorphism
Statins
Increased risk of rhabdomyolysis
HLA-B*5701 polymorphism
Abacavir
Increased risk of skin hypersensitivity reactions
HLA-B*5801 polymorphism
Allopurinol
Increased risk of rashes in Flan Chinese
HLA-B*1 502 polymorphism
Carbamazepine
Increased risk of skin hypersensitivity reactions in Flan Chinese
Hepatic nuclear factor 1 alpha (HNF1A)
polymorphism
Sulphonylureas
Increased sensitivity to the blood glucose-lowering effects
Pluman epidermal growth factor receptor
Trastuzumab
Increased sensitivity to the inhibitory effects on growth and
2 (HER2)-positive breast cancer cells
division of the target cancer cells
Adverse outcomes of drug therapy • 21
Adverse outcomes of drug therapy
The decision to prescribe a drug always involves a judgement
of the balance between therapeutic benefits and risk of an
adverse outcome. Both prescribers and patients tend to be more
focused on the former but a truly informed decision requires
consideration of both.
Adverse drug reactions
Some important definitions for the adverse effects of drugs are:
• Adverse event. A harmful event that occurs while a patient
is taking a drug, irrespective of whether the drug is
suspected of being the cause.
• Adverse drug reaction (ADR). An unwanted or harmful
reaction that is experienced following the administration of
a drug or combination of drugs under normal conditions of
use and is suspected to be related to the drug. An ADR
will usually require the drug to be discontinued or the dose
reduced.
• Side-effect. Any effect caused by a drug other than the
intended therapeutic effect, whether beneficial, neutral
or harmful. The term ‘side-effect’ is often used
interchangeably with ‘ADR’, although the former usually
implies an ADR that occurs during exposure to normal
therapeutic drug concentrations (e.g. vasodilator-induced
ankle oedema).
• Hypersensitivity reaction. An ADR that occurs as a result
of an immunological reaction and often at exposure to
subtherapeutic drug concentrations. Some of these
reactions are immediate and result from the interaction of
drug antigens with immunoglobulin E (IgE) on mast cells
and basophils, which causes a release of vasoactive
biomolecules (e.g. penicillin-related anaphylaxis).
‘Anaphylactoid’ reactions present similarly but occur
through a direct non-immune-mediated release of the
same mediators or result from direct complement
activation (p. 75). Hypersensitivity reactions may occur via
other mechanisms such as antibody-dependent (IgM or
IgG), immune complex-mediated or cell-mediated
pathways.
• Drug toxicity. Adverse effects of a drug that occur
because the dose or plasma concentration has risen
above the therapeutic range, either unintentionally or
intentionally (drug overdose; see Fig. 2.2 and p. 137).
• Drug abuse. The misuse of recreational or therapeutic
drugs that may lead to addiction or dependence, serious
physiological injury (such as liver damage), psychological
harm (abnormal behaviour patterns, hallucinations,
memory loss) or death (p. 1184).
Prevalence of ADRs
ADRs are a common cause of illness, accounting in the UK
for approximately 3% of consultations in primary care and 7%
of emergency admissions to hospital, and affecting around
15% of hospital inpatients. Many ‘disease’ presentations are
eventually attributed to ADRs, emphasising the importance of
always taking a careful drug history (Box 2.6). Factors accounting
for the rising prevalence of ADRs are the increasing age of
patients, polypharmacy (higher risk of drug interactions), increasing
2.6 How to take a drug history
Information from the patient (or carer)
Use language that patients will understand (e.g. ‘medicines’ rather
than ‘drugs’, which may be mistaken for drugs of abuse) while
gathering the following information:
• Current prescribed drugs, including formulations (e.g. modified-
release tablets), doses, routes of administration, frequency and
timing, duration of treatment
• Other medications that are often forgotten (e.g. contraceptives,
over-the-counter drugs, herbal remedies, vitamins)
• Drugs that have been taken in the recent past and reasons for
stopping them
• Previous drug hypersensitivity reactions, their nature and time
course (e.g. rash, anaphylaxis)
• Previous ADRs, their nature and time course (e.g. ankle oedema
with amlodipine)
• Adherence to therapy (e.g. ‘Are you taking your medication
regularly?’)
Information from GP medical records and/or pharmacist
• Up-to-date list of medications
• Previous ADRs
• Last order dates for each medication
Inspection of medicines
• Drugs and their containers (e.g. blister packs, bottles, vials) should
be inspected for name, dosage, and the number of dosage forms
taken since dispensed
(ADR = adverse drug reaction)
i
Patient factors
• Elderly age (e.g. low physiological reserve)
• Gender (e.g. ACE inhibitor-induced cough in women)
• Polypharmacy (e.g. drug interactions)
• Genetic predisposition (see Box 2.5)
• Hypersensitivity/allergy (e.g. (3-lactam antibiotics)
• Diseases altering pharmacokinetics (e.g. hepatic or renal
impairment) or pharmacodynamic responses (e.g. bladder instability)
• Adherence problems (e.g. cognitive impairment)
Drug factors
• Steep dose-response curve (e.g. insulin)
• Low therapeutic index (e.g. digoxin, cytotoxic drugs)
Prescriber factors
• Inadequate understanding of principles of clinical pharmacology
• Inadequate knowledge of the patient
• Inadequate knowledge of the prescribed drug
• Inadequate instructions and warnings provided to patients
• Inadequate monitoring arrangements planned
(ACE = angiotensin-converting enzyme)
availability of over-the-counter medicines, increasing use of herbal
or traditional medicines, and the increase in medicines available
via the Internet that can be purchased without a prescription
from a health-care professional. Risk factors for ADRs are shown
in Box 2.7.
2.7 Risk factors for adverse drug reactions
22 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
ADRs are important because they reduce quality of life for
patients, reduce adherence to and therefore efficacy of beneficial
treatments, cause diagnostic confusion, undermine the confidence
of patients in their health-care professional(s) and consume
health-care resources.
Retrospective analysis of ADRs has shown that more than
half could have been avoided if the prescriber had taken more
care in anticipating the potential hazards of drug therapy.
For example, non-steroidal anti-inflammatory drug (NSAID)
use accounts for many thousands of emergency admissions,
gastrointestinal bleeding episodes and a significant number of
deaths. In many cases, the patients are at increased risk due
to their age, interacting drugs (e.g. aspirin, warfarin) or a past
history of peptic ulcer disease. Drugs that commonly cause
ADRs are listed in Box 2.8.
Prescribers and their patients ideally want to know the
frequency with which ADRs occur for a specific drug. Although
this may be well characterised for more common ADRs observed
in clinical trials, it is less clear for rarely reported ADRs when the
total numbers of reactions and patients exposed are not known.
The words used to describe frequency can be misinterpreted by
2.8 Drugs that are common causes of adverse
drug reactions
Drug or drug class
Common adverse drug reactions
ACE inhibitors
(e.g. lisinopril)
Renal impairment
Hyperkalaemia
Antibiotics
(e.g. amoxicillin)
Nausea
Diarrhoea
Anticoagulants
(e.g. warfarin, heparin)
Bleeding
Antipsychotics
(e.g. haloperidol)
Falls
Sedation
Delirium
Aspirin
Gastrotoxicity (dyspepsia,
gastrointestinal bleeding)
Benzodiazepines
(e.g. diazepam)
Drowsiness
Falls
(3-blockers
(e.g. atenolol)
Cold peripheries
Bradycardia
Calcium channel blockers
(e.g. amlodipine)
Ankle oedema
Digoxin
Nausea and anorexia
Bradycardia
Diuretics
(e.g. furosemide,
bendroflumethiazide)
Dehydration
Electrolyte disturbance
(hypokalaemia, hyponatraemia)
Hypotension
Renal impairment
Insulin
Hypoglycaemia
NSAIDs
(e.g. ibuprofen)
Gastrotoxicity (dyspepsia,
gastrointestinal bleeding)
Renal impairment
Opioid analgesics
(e.g. morphine)
Nausea and vomiting
Delirium
Constipation
(ACE = angiotensin-converting enzyme; NSAID = non-steroidal anti-inflammatory
drug)
patients but widely accepted meanings include: very common
(10% or more), common (1-10%), uncommon (0.1-1%), rare
(0.01-0.1%) and very rare (0.01% or less).
Classification of ADRs
ADRs have traditionally been classified into two major groups:
• Type A (‘augmented’) ADRs. These are predictable from
the known pharmacodynamic effects of the drug and are
dose-dependent, common (detected early in drug
development) and usually mild. Examples include
constipation caused by opioids, hypotension caused by
antihypertensives and dehydration caused by diuretics.
• Type B (‘bizarre’) ADRs. These are not predictable, are not
obviously dose-dependent in the therapeutic range, are
rare (remaining undiscovered until the drug is marketed)
and often severe. Patients who experience type B
reactions are generally ‘hyper-susceptible’ because of
unpredictable immunological or genetic factors (e.g.
anaphylaxis caused by penicillin, peripheral neuropathy
caused by isoniazid in poor acetylators).
This simple classification has shortcomings, and a more
detailed classification based on dose (see Fig. 2.2), timing and
susceptibility (DoTS) is now used by those analysing ADRs in
greater depth (Box 2.9). The AB classification can be extended
as a reminder of some other types of ADR:
• Type C (‘chronic/continuous’) ADRs. These occur only
after prolonged continuous exposure to a drug. Examples
include osteoporosis caused by glucocorticoids,
retinopathy caused by chloroquine, and tardive dyskinesia
caused by phenothiazines.
• Type D (‘delayed’) ADRs. These are delayed until long
after drug exposure, making diagnosis difficult. Examples
include malignancies that may emerge after
immunosuppressive treatment post -transplantation (e.g.
azathioprine, tacrolimus) and vaginal cancer occurring
many years after exposure to d iethy 1st i I boest rol .
• Type E (‘end-of -treatment’) ADRs. These occur after
abrupt drug withdrawal (see Box 2.3).
A teratogen is a drug with the potential to affect the development
of the fetus in the first 1 0 weeks of intrauterine life (e.g. phenytoin,
warfarin). The thalidomide disaster in the early 1960s highlighted
the risk of teratogenicity and led to mandatory testing of all new
drugs. Congenital defects in a live infant or aborted fetus should
2.9 DoTS classification of adverse drug reactions
Category
Example
Dose
Below therapeutic dose
In the therapeutic dose range
At high doses
Anaphylaxis with penicillin
Nausea with morphine
Hepatotoxicity with paracetamol
Timing
With the first dose
Early stages of treatment
On stopping treatment
Significantly delayed
Anaphylaxis with penicillin
Hyponatraemia with diuretics
Benzodiazepine withdrawal syndrome
Clear-cell cancer with
diethylstilboestrol
Susceptibility
See patient factors in Box 2.7
(INR = international normalised ratio)
Adverse outcomes of drug therapy • 23
provoke suspicion of an ADR and a careful exploration of drug
exposures (including self-medication and herbal remedies).
| Detecting ADRs - pharmacovigilance
Type A ADRs become apparent early in the development of a
new drug. By the time a new drug is licensed and launched
on to a possible worldwide market, however, a relatively small
number of patients (just several hundred) may have been exposed
to it, meaning that rarer but potentially serious type B ADRs
may remain undiscovered. Pharmacovigilance is the process of
detecting (‘signal generation’) and evaluating ADRs in order to
help prescribers and patients to be better informed about the
risks of drug therapy. Drug regulatory agencies may respond to
this information by placing restrictions on the licensed indications,
reducing the recommended dose range, adding special warnings
and precautions for prescribers in the product literature, writing
to all health-care professionals or withdrawing the product from
the market.
Voluntary reporting systems allow health-care professionals and
patients to report suspected ADRs to the regulatory authorities.
A good example is the ‘Yellow Card’ scheme that was set up
in the UK in response to the thalidomide tragedy. Reports are
analysed to assess the likelihood that they represent a true
ADR (Box 2.10). Although voluntary reporting is a continuously
operating and effective early-warning system for previously
unrecognised rare ADRs, its weaknesses include low reporting
rates (only 3% of all ADRs and 10% of serious ADRs are ever
reported), an inability to quantify risk (because the ratio of ADRs
to prescriptions is unknown), and the influence of prescriber
awareness on likelihood of reporting (reporting rates rise rapidly
following publicity about potential ADRs).
More systematic approaches to collecting information on
ADRs include ‘prescription event monitoring’, in which a sample
KM 2.10 TREND analysis of suspected adverse
drug reactions
Factor
Key question
Comment
Temporal
relationship
What is the time
interval between the
start of drug therapy
and the reaction?
Most ADRs occur soon after
starting treatment and
within hours in the case of
anaphylactic reactions
/?e-challenge
What happens when
the patient is
re-challenged with
the drug?
Re-challenge is rarely
possible because of the
need to avoid exposing
patients to unnecessary risk
Exclusion
Have concomitant
drugs and other
non-drug causes
been excluded?
ADR is a diagnosis of
exclusion following clinical
assessment and relevant
investigations for non-drug
causes
/Vovelty
Has the reaction
been reported
before?
The suspected ADR may
already be recognised and
mentioned in the SPC
approved by the regulatory
authorities
De-challenge
Does the reaction
improve when the
drug is withdrawn or
the dose is reduced?
Most, but not all, ADRs
improve on drug
withdrawal, although
recovery may be slow
(SPC = summary of product characteristics)
of prescribers of a particular drug are issued with questionnaires
concerning the clinical outcome for their patients, and the
collection of population statistics. Many health-care systems
routinely collect patient-identifiable data on prescriptions (a
surrogate marker of exposure to a drug), health-care events
(e.g. hospitalisation, operations, new clinical diagnoses) and
other clinical data (e.g. haematology, biochemistry). As these
records are linked, with appropriate safeguards for confidentiality
and data protection, they are providing a much more powerful
mechanism for assessing both the harms and benefits of drugs.
All prescribers will inevitably see patients experiencing ADRs
caused by prescriptions written by themselves or their colleagues.
It is important that these are recognised early. In addition to the
features in Box 2.10, features that should raise suspicion of an
ADR and the need to respond (by drug withdrawal, dosage
reduction or reporting to the regulatory authorities) include:
• concern expressed by a patient that a drug has
harmed them
• abnormal clinical measurements (e.g. blood pressure,
temperature, pulse, blood glucose and weight) or
laboratory results (e.g. abnormal liver or renal function, low
haemoglobin or white cell count) while on drug therapy
• new therapy started that could be in response to an ADR
(e.g. omeprazole, allopurinol, naloxone)
• the presence of risk factors for ADRs (see Box 2.7).
Drug interactions
A drug interaction has occurred when the administration of one
drug increases or decreases the beneficial or adverse responses
to another drug. Although the number of potential interacting drug
combinations is very large, only a small number are common in
clinical practice. Important drug interactions are most likely to
occur when the affected drug has a low therapeutic index, steep
dose-response curve, high first-pass or saturable metabolism,
or a single mechanism of elimination.
|j/lechanisms of drug interactions
Pharmacodynamic interactions occur when two drugs produce
additive, synergistic or antagonistic effects at the same drug
target (e.g. receptor, enzyme) or physiological system (e.g.
electrolyte excretion, heart rate). These are the most common
interactions in clinical practice and some important examples
are given in Box 2.1 1 .
Pharmacokinetic interactions occur when the administration
of a second drug alters the concentration of the first at its site
of action. There are numerous potential mechanisms:
• Absorption interactions. Drugs that either delay (e.g.
anticholinergic drugs) or enhance (e.g. prokinetic drugs)
gastric emptying influence the rate of rise in plasma
concentration of other drugs but not the total amount of
drug absorbed. Drugs that bind to form insoluble
complexes or chelates (e.g. aluminium-containing
antacids binding with ciprofloxacin) can reduce drug
absorption.
• Distribution interactions. Co-administration of drugs that
compete for protein binding in plasma (e.g. phenytoin and
diazepam) can increase the unbound drug concentration,
but the effect is usually short-lived due to increased
elimination and hence restoration of the pre-interaction
equilibrium.
24 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
2.11 Common drug interactions
Mechanism
Object drug
Precipitant drug
Result
Pharmaceutical
Chemical reaction
Sodium
bicarbonate
Calcium gluconate
Precipitation of insoluble calcium carbonate
Pharmacokinetic
Reduced absorption
Tetracyclines
Calcium, aluminium, and
magnesium salts
Reduced tetracycline absorption
Reduced protein binding
Phenytoin
Aspirin
Increased unbound and reduced total phenytoin
plasma concentration
Reduced metabolism:
CYP3A4
Amiodarone
Grapefruit juice
Cardiac arrhythmias because of prolonged QT
interval (p. 476)
Warfarin
Clarithromycin
Enhanced anticoagulation
CYP2C19
Phenytoin
Omeprazole
Phenytoin toxicity
CYP2D6
Clozapine
Paroxetine
Clozapine toxicity
Xanthine oxidase
Azathioprine
Allopurinol
Azathioprine toxicity
Monoamine oxidase
Catecholamines
Monoamine oxidase inhibitors
Hypertensive crisis due to monoamine toxicity
Increased metabolism (enzyme
induction)
Ciclosporin
St John’s wort
Loss of immunosuppression
Reduced renal elimination
Lithium
Diuretics
Lithium toxicity
Methotrexate
NSAIDs
Methotrexate toxicity
Pharmacodynamic
Direct antagonism at same receptor
Opioids
Naloxone
Reversal of opioid effects used therapeutically
Salbutamol
Atenolol
Inhibits bronchodilator effect
Direct potentiation in same organ
Benzodiazepines
Alcohol
Increased sedation
system
ACE inhibitors
NSAIDs
Increased risk of renal impairment
Indirect potentiation by actions in
Digoxin
Diuretics
Digoxin toxicity enhanced because of hypokalaemia
different organ systems
Warfarin
Aspirin, NSAIDs
Increased risk of bleeding because of gastrotoxicity
and antiplatelet effects
Diuretics
ACE inhibitors
Blood pressure reduction (may be therapeutically
advantageous) because of the increased activity of
the renin-angiotensin system in response to diuresis
Pharmaceutical interactions are related to the formulation of the drugs and occur before drug absorption.
(ACE = angiotensin-converting enzyme; NSAID
= non-steroidal anti-inflammatory drug)
• Metabolism interactions. Many drugs rely on metabolism
by different isoenzymes of cytochrome P450 (CYP) in the
liver. CYP enzyme inducers (e.g. phenytoin, rifampicin)
generally reduce plasma concentrations of other drugs,
although they may enhance activation of prodrugs. CYP
enzyme inhibitors (e.g. clarithromycin, cimetidine, grapefruit
juice) have the opposite effect. Enzyme induction effects
usually take a few days to manifest because of the need
to synthesise new CYP enzyme, in contrast to the rapid
effects of enzyme inhibition.
• Excretion interactions. These primarily affect renal
excretion. For example, drug-induced reduction in
glomerular filtration rate (e.g. diuretic-induced dehydration,
angiotensin-converting enzyme (ACE) inhibitors, NSAIDs)
can reduce the clearance and increase the plasma
concentration of many drugs, including some with a low
therapeutic index (e.g. digoxin, lithium, aminoglycoside
antibiotics). Less commonly, interactions may be due to
competition for a common tubular organic anion
transporter (e.g. methotrexate excretion may be inhibited
by competition with NSAIDs).
Avoiding drug interactions
Drug interactions are increasing as patients are prescribed more
medicines (polypharmacy). Prescribers can avoid the adverse
consequences of drug-drug interactions by taking a careful
drug history (see Box 2.6) before prescribing additional drugs,
only prescribing for clear indications, and taking special care
when prescribing drugs with a narrow therapeutic index (e.g.
warfarin). When prescribing an interacting drug is unavoidable,
good prescribers will seek further information and anticipate the
potential risk. This will allow them to provide special warnings for
the patient and arrange for monitoring, either of the clinical effects
(e.g. coagulation tests for warfarin) or of plasma concentration
(e.g. digoxin).
Medication errors
A medication error is any preventable event that may lead to
inappropriate medication use or patient harm while the medication
is in the control of the health-care professional or patient. Errors
may occur in prescribing, dispensing, preparing solutions,
administration or monitoring. Many ADRs are considered in
retrospect to have been ‘avoidable’ with more care or forethought;
in other words, an adverse event considered by one prescriber
to be an unfortunate ADR might be considered by another to
be a prescribing error.
Medication errors are very common. Several thousand
medication orders are dispensed and administered each day
in a medium-sized hospital. Recent UK studies suggest that
Adverse outcomes of drug therapy • 25
| 2.12 Hospital prescribing errors
Error type
Approximate
% of total
Omission on admission
30
Underdose
11
Overdose
8
Strength/dose missing
7
Omission on discharge
6
Administration times incorrect/missing
6
Duplication
6
Product or formulation not specified
4
Incorrect formulation
4
No maximum dose
4
Unintentional prescribing
3
No signature
2
Clinical contraindication
1
Incorrect route
1
No indication
1
Intravenous instructions incorrect/missing
1
Drug not prescribed but indicated
1
Drug continued for longer than needed
1
Route of administration missing
1
Start date incorrect/missing
1
Risk of drug interaction
<0.5
Controlled drug requirements incorrect/missing
<0.5
Daily dose divided incorrectly
<0.5
Significant allergy
<0.5
Drug continued in spite of adverse effects
<0.5
Premature discontinuation
<0.5
Failure to respond to out-of-range drug level
<0.5
7-9% of hospital prescriptions contain an error, and most are
written by junior doctors. Common prescribing errors in hospitals
include omission of medicines (especially failure to prescribe
regular medicines at the point of admission or discharge, i.e.
‘medicines reconciliation’), dosing errors, unintentional prescribing
and poor use of documentation (Box 2.12).
Most prescription errors result from a combination of failures
by the individual prescriber and the health-service systems in
which they work (Box 2.1 3). Health-care organisations increasingly
encourage reporting of errors within a ‘no-blame culture’ so
that they can be subject to ‘root cause analysis’ using human
error theory (Fig. 2.5). Prevention is targeted at the factors in
Box 2.13, and can be supported by prescribers communicating
and cross-checking with colleagues (e.g. when calculating doses
adjusted for body weight, or planning appropriate monitoring
after drug administration), and by health-care systems providing
clinical pharmacist support (e.g. for checking the patient’s previous
medications and current prescriptions) and electronic prescribing
(which avoids errors due to illegibility or serious dosing mistakes,
and may be combined with a clinical decision support system
to take account of patient characteristics and drug history,
and provide warnings of potential contraindications and drug
interactions).
2.13 Causes of prescribing errors
Systems factors
• Working hours of prescribers (and others)
• Patient throughput
• Professional support and supervision by colleagues
• Availability of information (medical records)
• Design of prescription forms
• Distractions
• Availability of decision support
• Checking routines (e.g. clinical pharmacy)
• Reporting and reviewing of incidents
Prescriber factors
Knowledge
• Clinical pharmacology principles
• Drugs in common use
• Therapeutic problems commonly encountered
• Knowledge of workplace systems
Skills
• Taking a good drug history
• Obtaining information to support prescribing
• Communicating with patients
• Numeracy and calculations
• Prescription writing
Attitudes
• Coping with risk and uncertainty
• Monitoring of prescribing
• Checking routines
Unintended
action
Slip
Prescription not
as intended
Prescriber unaware
Correct plan known
but not executed
(Causes include
workload, time
pressures, distractions)
Lapse
Prescription incomplete
or forgotten
Prescriber may remember
Planned
action
Prescribing
Correct
action
Intended
outcome
Intended
action
Mistake
Prescription as intended
but written based on
the wrong principles or
lack of knowledge
Prescriber unaware
Wrong plan selected
(Causes include
poor training and
lack of experience)
Violation
I
Deliberate deviations
from standard practice
Prescriber aware
Fig. 2.5 Human error theory. Unintended errors may occur because the
prescriber fails to complete the prescription correctly (a slip; e.g. writes
the dose in ‘mg’ not ‘micrograms’) or forgets part of the action that is
important for success (a lapse; e.g. forgets to co-prescribe folic acid with
methotrexate); prevention requires the system to provide appropriate
checking routines. Intended errors occur when the prescriber acts
incorrectly due to lack of knowledge (a mistake; e.g. prescribes atenolol for
a patient with known severe asthma because of ignorance about the
contraindication); prevention must focus on training the prescriber.
26 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
2.14 Clinical development of new drugs
Phase I
• Healthy volunteers (20-80)
• These involve initial single-dose, ‘first-into-man’ studies, followed by
repeated-dose studies. They aim to establish the basic
pharmacokinetic and pharmacodynamic properties, and short-term
safety
• Duration: 6-12 months
Phase II
• Patients (1 00-200)
• These investigate clinical effectiveness (‘proof of concept’), safety
and dose-response relationship, often with a surrogate clinical
endpoint, in the target patient group to determine the optimal
dosing regimen for larger confirmatory studies
• Duration: 1-2 years
Phase III
• Patients (1 00s— 1 000s)
• These are large, expensive clinical trials that confirm safety and
efficacy in the target patient population, using relevant clinical
endpoints. They may be placebo-controlled studies or comparisons
with other active compounds
• Duration: 1-2 years
Phase IV
• Patients (1 00s— 1 000s)
• These are undertaken after the medicine has been marketed for
its first indication to evaluate new indications, new doses or
formulations, long-term safety or cost-effectiveness
Responding when an error is discovered
All prescribers will make errors. When they do, their first duty
is to protect the patient’s safety. This will involve a clinical
review and the taking of any steps that will reduce harm (e.g.
remedial treatment, monitoring, recording the event in the notes,
informing colleagues). Patients should be informed if they have
been exposed to potential harm. For errors that do not reach
the patient, it is the prescriber’s duty to report them, so that
others can learn from the experience and take the opportunity to
reflect on how a similar incident might be avoided in the future.
Drug regulation and management
Given the powerful beneficial and potentially adverse effects
of drugs, the production and use of medicines are strictly
regulated (e.g. by the Food and Drug Administration in the USA,
Medicines and Healthcare Products Regulatory Agency in the
UK, and Central Drugs Standard Control Organisation in India).
Regulators are responsible for licensing medicines, monitoring
their safety (pharmacovigilance; p. 23), approving clinical trials,
and inspecting and maintaining standards of drug development
and manufacture.
In addition, because of the high costs of drugs and their
adverse effects, health-care services must prioritise their use in
light of the evidence of their benefit and harm, a process referred
to as ‘medicines management’.
Drug development and marketing
Naturally occurring products have been used to treat illnesses
for thousands of years and some remain in common use today.
Examples include morphine from the opium poppy (Papaver
somniferum), digitalis from the foxglove (Digitalis purpurea),
curare from the bark of a variety of species of South American
trees, and quinine from the bark of the Cinchona species.
Although plants and animals remain a source of discovery, the
majority of new drugs come from drug discovery programmes
that aim to identify small-molecule compounds with specific
interactions with a molecular target that will induce a predicted
biological effect.
The usual pathway for development of these small molecules
includes: identifying a plausible molecular target by investigating
pathways in disease; screening a large library of compounds for
those that interact with the molecular target in vitro; conducting
extensive medicinal chemistry to optimise the properties of lead
compounds; testing efficacy and toxicity of these compounds
in vitro and in animals; and undertaking a clinical development
programme (Box 2.14). This process typically takes longer than
10 years and may cost up to US$1 billion. Manufacturers have
a defined period of exclusive marketing of the drug while it
remains protected by an original patent, typically 10-15 years,
during which time they must recoup the costs of developing
the drug. Meanwhile, competitor companies will often produce
similar ‘me too’ drugs of the same class. Once the drug’s patent
has expired, ‘generic’ manufacturers may step in to produce
cheaper formulations of the drug. Paradoxically, if a generic drug
is produced by only one manufacturer, the price may actually
rise, sometimes substantially. Newer ‘biological’ products are
based on large molecules (e.g. human recombinant antibodies)
derived from complex manufacturing processes involving specific
cell lines, molecular cloning and purification processes. After the
patent for the originator product expires, other manufacturers
may develop similar products (‘biosimilars’) that share similar
pharmacological actions but are not completely identical.
‘Biosimilars’ are considered distinct from ‘generic’ medications, as
complex biological molecules are more susceptible to differences
in manufacturing processes than conventional small-molecule-type
pharmaceuticals.
The number of new drugs produced by the pharmaceutical
industry has declined in recent years. The traditional approach
of targeting membrane-bound receptors and enzymes with small
molecules (see Box 2.2) is now giving way to new targets, such
as complex second-messenger systems, cytokines, nucleic acids
and cellular networks. These require novel therapeutic agents,
which present new challenges for ‘translational medicine’, the
discipline of converting scientific discoveries into a useful medicine
with a well-defined benefit-risk profile (Box 2.15).
|J.icensing new medicines
New drugs are given a ‘market authorisation’, based on the
evidence of quality, safety and efficacy presented by the
manufacturer. The regulator not only will approve the drug
but also will take great care to ensure that the accompanying
information reflects the evidence that has been presented. The
summary of product characteristics (SPC), or ‘label’, provides
detailed information about indications, dosage, adverse effects,
warnings, monitoring and so on. If approved, drugs can be made
available with different levels of restriction:
• Controlled drug (CD). These drugs are subject to strict
legal controls on supply and possession, usually due to
their abuse potential (e.g. opioid analgesics).
Drug regulation and management • 27
j 2.15 Novel therapeutic alternatives to conventional small-molecule drugs
Approaches
Therapeutic indications
Challenges
Monoclonal antibodies
Targeting of receptors or other molecules
with relatively specific antibodies
Cancer
Chronic inflammatory diseases (e.g. rheumatoid
arthritis, inflammatory bowel disease)
Selectivity of action
Complex manufacturing process
Small interfering RNA (siRNA)
Inhibition of gene expression
Macular degeneration
Delivery to target
Gene therapy
Delivery of modified genes that supplement
or alter host DNA
Cystic fibrosis
Cancer
Cardiovascular disease
Delivery to target
Adverse effects of delivery vector (e.g. virus)
Stem cell therapy
Stem cells differentiate and replace damaged
host cells
Parkinson’s disease
Spinal cord injury
Ischaemic heart disease
Delivery to target
Immunological compatibility
Long-term effects unknown
• Prescription-only medicine (PoM). These are available only
from a pharmacist and can be supplied only if prescribed
by an appropriate practitioner.
• Pharmacy (P). These are available only from a pharmacist
but can be supplied without a prescription.
• General sales list (GSL). These medicines may be bought
‘over the counter’ (OTC) from any shop and without a
prescription.
Although the regulators take great care to agree the exact
indications for prescribing a medicine, based on the evidence
provided by the manufacturer, there are some circumstances in
which prescribers may direct its use outside the terms stated in
the SPC (‘off-label’ prescribing). Common situations where this
might occur include prescribing outside the approved age group
(e.g. prescribing for children) or using an alternative formulation
(e.g. administering a medicine provided in a solid form as an oral
solution). Other important examples might include prescribing
for an indication for which there are no approved medicines or
where all of the approved medicines have caused unacceptable
adverse effects. Occasionally, medicines may be prescribed
when there is no marketing authorisation in the country of use.
Examples include when a medicine licensed in another country
is imported for use for an individual patient (‘unlicensed import’)
or when a patient requires a specific preparation of a medicine
to be manufactured (‘unlicensed special’). When prescribing is
‘off-label’ or ‘unlicensed’, there is an increased requirement for
prescribers to be able to justify their actions and to inform and
agree the decision with the patient.
| Drug marketing
The marketing activities of the pharmaceutical industry are well
resourced and are important in the process of recouping the
massive costs of drug development. In some countries, such
as the USA, it is possible to promote a new drug by direct-to-
consumer advertising, although this is illegal in the countries of
the European Union. A major focus is on promotion to prescribers
via educational events, sponsorship of meetings, advertisements
in journals, involvement with opinion leaders, and direct contact
by company representatives. Such largesse has the potential to
cause significant conflicts of interest and might tempt prescribers
to favour one drug over another, even in the face of evidence
on effectiveness or cost-effectiveness.
Managing the use of medicines
Many medicines meet the three key regulatory requirements
of quality, safety and efficacy. Although prescribers are legally
entitled to prescribe any of them, it is desirable to limit the choice
so that treatments for specific diseases can be focused on
the most effective and cost-effective options, prescribers (and
patients) gain familiarity with a smaller number of medicines, and
pharmacies can concentrate stocks on them.
The process of ensuring optimal use of available medicines
is known as ‘medicines management’ or ‘quality use of
medicines’. It involves careful evaluation of the evidence of
benefit and harm from using the medicine, an assessment
of cost-effectiveness, and support for processes to implement
the resulting recommendations. These activities usually involve
both national (e.g. National Institute for Health and Care
Excellence (NICE) in the UK) and local organisations (e.g. drug
and therapeutics committees).
Evaluating evidence
The principles of evidence-based medicine are described on
page 10. Drugs are often evaluated in high-quality randomised
controlled trials, the results of which can be considered by
systematic review (Fig. 2.6). Ideally, data are available not only for
comparison with placebo but also for ‘head-to-head’ comparison
with alternative therapies. Trials are conducted in selected patient
populations, however, and are not representative of every clinical
scenario, so extrapolation to individual patients is not always
straightforward. Other subtle bias may be introduced because
of the sources of funding (e.g. pharmaceutical industry) and
the interests of the investigators in being involved in research
that has a ‘positive’ impact. These biases may be manifest in
the way the trials are conducted or in how they are interpreted
or reported. A common example of the latter is the difference
between relative and absolute risk of clinical events reported in
prevention trials. If a clinical event is encountered in the placebo
arm at a rate of 1 in 50 patients (2%) but only 1 in 1 00 patients
(1 %) in the active treatment arm, then the impact of treatment
can be described as either a 50% relative risk reduction or
1 % absolute risk reduction. Although the former sounds more
impressive, it is the latter that is of more importance to the
28 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
Odds ratio
Fig. 2.6 Systematic review of the evidence from randomised
controlled clinical trials. This forest plot shows the effect of warfarin
compared with placebo on the likelihood of stroke in patients with atrial
fibrillation in five randomised controlled trials that passed the quality
criteria required for inclusion in a meta-analysis. For each trial, the purple
box is proportionate to the number of participants. The tick marks show
the mean odds ratio and the black lines indicate its 95% confidence
intervals. Note that not all the trials showed statistically significant effects
(i.e. the confidence intervals cross 1.0). Flowever, the meta-analysis,
represented by the black diamond, confirms a highly significant statistical
benefit. The overall odds ratio is approximately 0.4, indicating a mean 60%
risk reduction with warfarin treatment in patients with the characteristics of
the participants in these trials.
individual patient. It means that the number of patients that needed
to be treated (NNT) for 1 to benefit (compared to placebo) was
100. This illustrates how large clinical trials of new medicines
can produce highly statistically significant and impressive relative
risk reductions and still predict a very modest clinical impact.
Evaluating cost-effectiveness
New drugs often represent an incremental improvement over
the current standard of care but are usually more expensive.
Health-care budgets are limited in every country and so it is
impossible to fund all new medicines. This means that very
difficult financial decisions have to be taken with due regard
to the principles of ethical justice. The main approach taken is
cost-effectiveness analysis (CEA), where a comparison is made
between the relative costs and outcomes of different courses of
action. CEA is usually expressed as a ratio where the denominator
is a gain in health and the numerator is the cost associated with
the health gain. A major challenge is to compare the value of
interventions for different clinical outcomes. One method is to
calculate the quality-adjusted life years (QALYs) gained if the
new drug is used rather than standard treatment. This analysis
involves estimating the ‘utility’ of various health states between
1 (perfect health) and 0 (dead). If the additional costs and any
savings are known, then it is possible to derive the incremental
cost-effectiveness ratio (ICER) in terms of cost/QALY. These
principles are exemplified in Box 2.16. There are, however,
inherent weaknesses in this kind of analysis: it usually depends
on modelling future outcomes well beyond the duration of the
clinical trial data that are available; it assumes that QALYs
gained at all ages are of equivalent value; and the appropriate
standard care against which the new drug should be compared
is often uncertain.
These pharmacoeconomic assessments are challenging and
resource-intensive, and are undertaken at national level in most
countries, e.g. in the UK by NICE.
i
A clinical trial lasting 2 years compares two interventions for the
treatment of colon cancer:
• Treatment A: standard treatment, cost £1 000/year, oral therapy
• Treatment B: new treatment, cost £6000/year, monthly intravenous
infusions, often followed by a week of nausea.
The new treatment (B) significantly increases the average time to
progression (18 months versus 12 months) and reduces overall
mortality (40% versus 60%). The health economist models the survival
curves from the trial in order to undertake a cost-utility analysis and
concludes that:
• Intervention A: allows an average patient to live for 2 extra years at
a utility 0.7= 1.4 QALYs (cost £2000)
• Intervention B: allows an average patient to live for 3 extra years at
a utility 0.6 = 1.8 QALYs (cost £18 000).
The health economists conclude that treatment B provides an extra
0.4 QALYs at an extra cost of £16 000, meaning that the ICER =
£40 000/QALY. They recommend that the new treatment should not
be funded on the basis that their threshold for cost acceptability is
£30 000/QALY.
(ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year)
| Implementing recommendations
Many recommendations about drug therapy are included in clinical
guidelines written by an expert group after systematic review of
the evidence. Guidelines provide recommendations rather than
obligations for prescribers and are helpful in promoting more
consistent and higher-quality prescribing. They are often written
without concern for cost-effectiveness, however, and may be
limited by the quality of available evidence. Guidelines cannot
anticipate the extent of the variation between individual patients
who may, for example, have unexpected contraindications to
recommended drugs or choose different priorities for treatment.
When deviating from respected national guidance, prescribers
should be able to justify their practice.
Additional recommendations for prescribing are often
implemented locally or imposed by bodies responsible for
paying for health care. Most health-care units have a drug and
therapeutics committee (or equivalent) comprised of senior
and junior medical staff, pharmacists and nurses, as well as
managers (because of the implications of the committee’s work
for governance and resources). This group typically develops
local prescribing policy and guidelines, maintains a local drug
formulary and evaluates requests to use new drugs. The local
formulary contains a more limited list than any national formulary
(e.g. British National Formulary) because the latter lists all licensed
medicines that can be prescribed legally, while the former contains
only those that the health-care organisation has approved for
local use. The local committee may also be involved, with local
specialists, in providing explicit protocols for management of
clinical scenarios.
Prescribing in practice
Decision-making in prescribing
Prescribing should be based on a rational approach to a series
of challenges (see Box 2.1).
2.16 Cost-effectiveness analysis
Prescribing in practice • 29
j Making a diagnosis
Ideally, prescribing should be based on a confirmed diagnosis
but, in reality, many prescriptions are based on the balance of
probability, taking into account the differential diagnosis (e.g.
proton pump inhibitors for post-prandial retrosternal discomfort).
Establishing the therapeutic goal
The goals of treatment are usually clear, particularly when relieving
symptoms (e.g. pain, nausea, constipation). Sometimes the goal
is less obvious to the patient, especially when aiming to prevent
future events (e.g. ACE inhibitors to prevent hospitalisation and
extend life in chronic heart failure). Prescribers should be clear
about the therapeutic goal against which they will judge success
or failure of treatment. It is also important to establish that the
value placed on this goal by the prescriber is shared by the
patient (concordance).
|j;hoosing the therapeutic approach
For many clinical problems, drug therapy is not absolutely
mandated. Having taken the potential benefits and harms into
account, prescribers must consider whether drug therapy is in
the patient’s interest and is preferred to no treatment or one
of a range of alternatives (e.g. physiotherapy, psychotherapy,
surgery). Assessing the balance of benefit and harm is often
complicated and depends on various features associated with
the patient, disease and drug (Box 2.17).
Ij^hoosing a drug
For most common clinical indications (e.g. type 2 diabetes,
depression), more than one drug is available, often from more
than one drug class. Although prescribers often have guidance
about which represents the rational choice for the average
patient, they still need to consider whether this is the optimal
choice for the individual patient. Certain factors may influence
the choice of drug:
Absorption
Patients may find some formulations easier to swallow than
others or may be vomiting and require a drug available for
parenteral administration.
Distribution
Distribution of a drug to a particular tissue sometimes dictates
choice (e.g. tetracyclines and rifampicin are concentrated in the
bile, and lincomycin and clindamycin in bones).
Metabolism
Drugs that are extensively metabolised should be avoided in
severe liver disease (e.g. opioid analgesics).
2.17 Factors to consider when balancing benefits
and harms of drug therapy
• Seriousness of the disease or symptom
• Efficacy of the drug
• Seriousness of potential adverse effects
• Likelihood of adverse effects
• Efficacy of alternative drugs or non-drug therapies
• Safety of alternative drugs or non-drug therapies
Excretion
Drugs that depend on renal excretion for elimination (e.g. digoxin,
aminoglycoside antibiotics) should be avoided in patients with
impaired renal function if suitable alternatives exist.
Efficacy
Prescribers normally choose drugs with the greatest efficacy in
achieving the goals of therapy (e.g. proton pump inhibitors rather
than H2-receptor antagonists). It may be appropriate, however,
to compromise on efficacy if other drugs are more convenient,
safer to use or less expensive.
Avoiding adverse effects
Prescribers should be wary of choosing drugs that are more
likely to cause adverse effects (e.g. cephalosporins rather than
alternatives for patients allergic to penicillin) or worsen coexisting
conditions (e.g. (3-blockers as treatment for angina in patients
with asthma).
Features of the disease
This is most obvious when choosing antibiotic therapy, which
should be based on the known or suspected sensitivity of the
infective organism (p. 116).
Severity of disease
The choice of drug should be appropriate to disease severity
(e.g. paracetamol for mild pain, morphine for severe pain).
Coexisting disease
This may be either an indication or a contraindication to therapy.
Hypertensive patients might be prescribed a (3-blocker if they
also have left ventricular impairment but not if they have asthma.
Avoiding adverse drug interactions
Prescribers should avoid giving combinations of drugs that might
interact, either directly or indirectly (see Box 2.1 1).
Patient adherence to therapy
Prescribers should choose drugs with a simple dosing schedule
or easier administration (e.g. the ACE inhibitor lisinopril once daily
rather than captopril 3 times daily for hypertension).
Cost
Prescribers should choose the cheaper drug (e.g. a generic
or biosimilar) if two drugs are of equal efficacy and safety.
Even if cost is not a concern for the individual patient, it is
important to remember that unnecessary expenditure will ultimately
limit choices for other prescribers and patients. Sometimes a
more costly drug may be appropriate (e.g. if it yields improved
adherence).
Genetic factors
There are already a small number of examples where genotype
influences the choice of drug therapy (see Box 2.5).
| Choosing a dosage regimen
Prescribers have to choose a dose, route and frequency of
administration (dosage regimen) to achieve a steady-state drug
concentration that provides sufficient exposure of the target
tissue without producing toxic effects. Manufacturers draw up
dosage recommendations based on average observations in
many patients but the optimal regimen that will maximise the
benefit to harm ratio for an individual patient is never certain.
30 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
Rational prescribing involves treating each prescription as an
experiment and gathering sufficient information to amend it if
necessary. There are some general principles that should be
followed, as described below.
Dose titration
Prescribers should generally start with a low dose and titrate
this slowly upwards as necessary. This cautious approach is
particularly important if the patient is likely to be more sensitive
to adverse pharmacodynamic effects (e.g. delirium or postural
hypotension in the elderly) or have altered pharmacokinetic
handling (e.g. renal or hepatic impairment), and when using
drugs with a low therapeutic index (e.g. benzodiazepines,
lithium, digoxin). There are some exceptions, however. Some
drugs must achieve therapeutic concentration quickly because
of the clinical circumstance (e.g. antibiotics, glucocorticoids,
carbimazole). When early effect is important but there may be a
delay in achieving steady state because of a drug’s long half-life
(e.g. digoxin, warfarin, amiodarone), an initial loading dose is
given prior to establishing the appropriate maintenance dose
(see Fig. 2.4).
If adverse effects occur, the dose should be reduced or an
alternative drug prescribed; in some cases, a lower dose may
suffice if it can be combined with another synergistic drug (e.g.
the immunosuppressant azathioprine reduces glucocorticoid
requirements in patients with inflammatory disease). It is
important to remember that the shape of the dose-response
curve (see Fig. 2.2) means that higher doses may produce
little added therapeutic effect and might increase the chances
of toxicity.
Route
There are many reasons for choosing a particular route of
administration (Box 2.18).
Frequency
Frequency of doses is usually dictated by a manufacturer’s
recommendation. Less frequent doses are more convenient
for patients but result in greater fluctuation between peaks and
troughs in drug concentration (see Fig. 2.4). This is relevant if the
peaks are associated with adverse effects (e.g. dizziness with
anti hypertensives) or the troughs are associated with troublesome
loss of effect (e.g. anti-Parkinsonian drugs). These problems
can be tackled either by splitting the dose or by employing a
modified-release formulation, if available.
Timing
For many drugs the time of administration is unimportant. There
are occasionally pharmacokinetic or therapeutic reasons, however,
for giving drugs at particular times (Box 2.19).
Formulation
For some drugs there is a choice of formulation, some for use by
different routes. Some are easier to ingest, particularly by children
(e.g. elixirs). The formulation is important when writing repeat
prescriptions for drugs with a low therapeutic index that come
in different formulations (e.g. lithium, phenytoin, theophylline).
Even if the prescribed dose remains constant, an alternative
formulation may differ in its absorption and bioavailability, and
hence plasma drug concentration. These are examples of the
small number of drugs that should be prescribed by specific
brand name rather than ‘generic’ international non-proprietary
name (INN).
^9 2.18 Factors influencing the route of
drug administration
Reason
Example
Only one route possible
Dobutamine (IV)
Gliclazide (oral)
Patient adherence
Phenothiazines and thioxanthenes
(2 weekly IM depot injections rather
than daily tablets, in schizophrenia)
Poor absorption
Furosemide (IV rather than oral, in
severe heart failure)
Rapid action
Haloperidol (IM rather than oral, in acute
behavioural disturbance)
Vomiting
Phenothiazines (PR or buccal rather
than oral, in nausea)
Avoidance of first-pass
metabolism
Glyceryl trinitrate (SL, in angina pectoris)
Certainty of effect
Amoxicillin (IV rather than oral, in acute
chest infection)
Direct access to the site
of action (avoiding
unnecessary systemic
exposure)
Bronchodilators (INH rather than oral, in
asthma)
Local application of drugs to skin, eyes
etc.
Ease of access
Diazepam (PR, if IV access is difficult in
status epilepticus)
Adrenaline (epinephrine) (IM, if IV
access is difficult in acute anaphylaxis)
Comfort
Morphine (SC rather than IV in terminal
care)
(IM = intramuscular; INH = by inhalation; IV = intravenous; PR = per rectum;
SC = subcutaneous; SL = sublingual)
Duration
Some drugs require a single dose (e.g. thrombolysis post
myocardial infarction), while for others the duration of the course
of treatment is certain at the outset (e.g. antibiotics). For most,
the duration will be largely at the prescriber’s discretion and will
depend on response and disease progression (e.g. analgesics,
antidepressants). For many, the treatment will be long-term (e.g.
insulin, antihypertensives, levothyroxine).
Involving the patient
Patients should, whenever possible, be engaged in making
choices about drug therapy. Their beliefs and expectations affect
the goals of therapy and help in judging the acceptable benefit/
harm balance when selecting treatments. Very often, patients
may wish to defer to the professional expertise of the prescriber.
Nevertheless, they play key roles in adherence to therapy and
in monitoring treatment, not least by providing early warning of
adverse events. It is important for them to be provided with the
necessary information to understand the choice that has been
made, what to expect from the treatment, and any measurements
that must be undertaken (Box 2.20).
A major drive to include patients has been the recognition that
up to half of the drug doses for chronic preventative therapy are
not taken. This is often termed ‘non-compliance’ but is more
appropriately called ‘non-adherence’, to reflect a less paternalistic
view of the doctor-patient relationship; it may or may not be
intentional. Non-adherence to the dose regimen reduces the
likelihood of benefits to the patient and can be costly in terms
Prescribing in practice • 31
2.19 Factors influencing the timing of drug therapy
Drug
Recommended timing
Reasons
Diuretics (e.g. furosemide)
Once in the morning
Night-time diuresis undesirable
Statins (e.g. simvastatin)
Once at night
HMG CoA reductase activity is greater at night
Antidepressants (e.g. amitriptyline)
Once at night
Allows adverse effects to occur during sleep
Salbutamol
Before exercise
Reduces symptoms in exercise-induced asthma
Glyceryl trinitrate
Paracetamol
When required
Relief of acute symptoms only
Regular nitrate therapy (e.g. isosorbide
mononitrate)
Eccentric dosing regimen (e.g. twice
daily at 8 a.m. and 2 p.m.)
Reduces development of nitrate tolerance by allowing
drug-free period each night
Aspirin
With food
Minimises gastrotoxic effects
Alendronate
Once in the morning before breakfast,
sitting upright
Minimises risk of oesophageal irritation
Tetracyclines
2 hours before or after food or
antacids
Divalent and trivalent cations chelate tetracyclines, preventing
absorption
Hypnotics (e.g. temazepam)
Once at night
Maximises therapeutic effect and minimises daytime sedation
Antihypertensive drugs (e.g. amlodipine)
Once in the morning
Blood pressure is higher during the daytime
(HMG CoA = 3-hydroxy-3-methylglutaryl-coenzyme A)
2.20 What patients need to know about their medicines
Knowledge
Comment
The reason for taking the medicine
How the medicine works
Reinforces the goals of therapy
How to take the medicine
May be important for the effectiveness (e.g. inhaled salbutamol in asthma) and safety (e.g. alendronate
for osteoporosis) of treatment
What benefits to expect
May help to support adherence or prompt review because of treatment failure
What adverse effects might occur
Discuss common and mild effects that may be transient and might not require discontinuation
Mention rare but serious effects that might influence the patient’s consent
Precautions that improve safety
Explain symptoms to report that might allow serious adverse effects to be averted, monitoring that will be
required and potentially important drug-drug interactions
When to return for review
This will be important to enable monitoring
*Many medicines are provided with patient information leaflets, which the patient should be encouraged to read.
of wasted medicines and unnecessary health-care episodes. An
important reason may be lack of concordance with the prescriber
about the goals of treatment. A more open and shared decision¬
making process might resolve any misunderstandings at the outset
and foster improved adherence, as well as improved satisfaction
with health-care services and confidence in prescribers. Fully
engaging patients in shared decision-making is sometimes
constrained by various factors, such as limited consultation
time and challenges in communicating complex numerical data.
Writing the prescription
The culmination of the planning described above is writing an
accurate and legible prescription so that the drug will be dispensed
and administered as planned (see ‘Writing prescriptions’ below).
| Monitoring treatment effects
Rational prescribing involves monitoring for the beneficial and
adverse effects of treatment so that the balance remains in favour
of a positive outcome (see ‘Monitoring drug therapy’ below).
Stopping drug therapy
It is also important to review long-term treatment at regular
intervals to assess whether continued treatment is required.
Elderly patients are keen to reduce their medication burden
and are often prepared to compromise on the original goals of
long-term preventative therapy to achieve this.
Prescribing in special circumstances
Prescribing for patients with renal disease
Patients with renal impairment are readily identified by having
a low estimated glomerular filtration rate (eGFR <60 mL/min)
based on their serum creatinine, age, sex and ethnic group
(p. 386). This group includes a large proportion of elderly patients.
If a drug (or its active metabolites) is eliminated predominantly by
the kidneys, it will tend to accumulate and so the maintenance
dose must be reduced. For some drugs, renal impairment makes
patients more sensitive to their adverse pharmacodynamic effects.
32 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
if
• Reduced drug elimination: partly due to impaired renal function.
• Increased sensitivity to drug effects: notably in the brain (leading
to sedation or delirium) and as a result of comorbidities.
• More drug interactions: largely as a result of polypharmacy.
• Lower starting doses and slower dose titration: often required,
with careful monitoring of drug effects.
• Drug adherence: may be poor because of cognitive impairment,
difficulty swallowing (dry mouth) and complex polypharmacy
regimens. Supplying medicines in pill organisers (e.g. dosette boxes
or calendar blister packs), providing automatic reminders, and
regularly reviewing and simplifying the drug regimen can help.
• Some drugs that require extra caution, and their mechanisms:
Digoxin: increased sensitivity of Na7K+ pump; hypokalaemia due
to diuretics; renal impairment favours accumulation -> increased
risk of toxicity.
Anti hypertensive drugs: reduced baroreceptor function ->
increased risk of postural hypotension.
Antidepressants, hypnotics, sedatives, tranquillisers: increased
sensitivity of the brain; reduced metabolism -> increased risk of
toxicity.
Warfarin: increased tendency to falls and injury and to bleeding
from intra- and extracranial sites; increased sensitivity to
inhibition of clotting factor synthesis increased risk of
bleeding.
Clomethiazole, lidocaine, nifedipine, phenobarbital, propranolol,
theophylline: metabolism reduced increased risk of toxicity.
Non-steroidal anti-inflammatory drugs: poor renal function ->
increased risk of renal impairment; susceptibility to gastrotoxicity
-> increased risk of upper gastrointestinal bleeding.
2.23 Prescribing in pregnancy
• Teratogenesis: a potential risk, especially when drugs are taken
between 2 and 8 weeks of gestation (4-1 0 weeks from last
menstrual period). Common teratogens include retinoids (e.g.
isotretinoin), cytotoxic drugs, angiotensin-converting enzyme
inhibitors, antiepileptics and warfarin. If there is inadvertent
exposure, then the timing of conception should be established,
counselling given and investigations undertaken for fetal
abnormalities.
• Adverse fetal effects in late gestation: e.g. tetracyclines may
stain growing teeth and bones; sulphonamides displace fetal
bilirubin from plasma proteins, potentially causing kernicterus;
opioids given during delivery may be associated with respiratory
depression in the neonate.
• Altered maternal pharmacokinetics: extracellular fluid volume
and Vd increase. Plasma albumin falls but other binding globulins
(e.g. for thyroid and steroid hormones) increase. Glomerular filtration
increases by approximately 70%, enhancing renal clearance.
Placental metabolism contributes to increased clearance, e.g. of
levothyroxine and glucocorticoids. The overall effect is a fall in
plasma levels of many drugs.
• In practice:
Avoid any drugs unless the risk:benefit analysis is in favour of
treating (usually the mother).
Use drugs for which there is some record of safety in humans.
Use the lowest dose for the shortest time possible.
Choose the least harmful drug if alternatives are available.
2.22 Prescribing in old age
2.21 Some drugs that require extra caution in
patients with renal or hepatic disease
Kidney disease
Liver disease
Pharmacodynamic effects enhanced
ACE inhibitors and ARBs (renal
Warfarin (increased
impairment, hyperkalaemia)
anticoagulation because of
Metformin (lactic acidosis)
reduced clotting factor synthesis)
Spironolactone (hyperkalaemia)
Metformin (lactic acidosis)
NSAIDs (impaired renal function)
Chloramphenicol (bone marrow
Sulphonylureas (hypoglycaemia)
suppression)
Insulin (hypoglycaemia)
NSAIDs (gastrointestinal
bleeding, fluid retention)
Sulphonylureas (hypoglycaemia)
Benzodiazepines (coma)
Pharmacokinetic handling altered (reduced clearance)
Aminoglycosides (e.g. gentamicin)
Phenytoin
Vancomycin
Rifampicin
Digoxin
Propranolol
Lithium
Warfarin
Other antibiotics (e.g.
Diazepam
ciprofloxacin)
Lidocaine
Atenolol
Allopurinol
Cephalosporins
Methotrexate
Opioids (e.g. morphine)
Opioids (e.g. morphine)
(ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker;
NSAID = non-steroidal anti-inflammatory drug)
Examples of drugs that require extra caution in patients with
renal disease are listed in Box 2.21 .
Prescribing for patients with hepatic disease
The liver has a large capacity for drug metabolism and hepatic
insufficiency has to be advanced before drug dosages need to
be modified. Patients who may have impaired metabolism include
those with jaundice, ascites, hypoalbuminaemia, malnutrition or
encephalopathy. Hepatic drug clearance may also be reduced
in acute hepatitis, in hepatic congestion due to cardiac failure,
and in the presence of intrahepatic arteriovenous shunting (e.g.
in hepatic cirrhosis). There are no good tests of hepatic drug-
metabolising capacity or of biliary excretion, so dosage should
be guided by the therapeutic response and careful monitoring
for adverse effects. The presence of liver disease also increases
the susceptibility to adverse pharmacological effects of drugs.
Some drugs that require extra caution in patients with hepatic
disease are listed in Box 2.21 .
Prescribing for elderly patients
The issues around prescribing in the elderly are discussed in
Box 2.22.
I Prescribing for women who are pregnant
or breastfeeding
Prescribing in pregnancy should be avoided if possible to minimise
the risk of adverse effects in the fetus. Drug therapy in pregnancy
may, however, be required either for a pre-existing problem (e.g.
epilepsy, asthma, hypothyroidism) or for problems that arise
during pregnancy (e.g. morning sickness, anaemia, prevention
of neural tube defects, gestational diabetes, hypertension).
About 35% of women take drug therapy at least once during
pregnancy and 6% take drug therapy during the first trimester
(excluding iron, folic acid and vitamins). The most commonly used
drugs are simple analgesics, antibacterial drugs and antacids.
Some considerations when prescribing in pregnancy are listed
in Box 2.23.
Prescribing in practice • 33
Drugs that are excreted in breast milk may cause adverse
effects in the baby. Prescribers should always consult the summary
of product characteristics for each drug or a reliable formulary
when treating a pregnant woman or breastfeeding mother.
Writing prescriptions
A prescription is a means by which a prescriber communicates
the intended plan of treatment to the pharmacist who dispenses
a medicine and to a nurse or patient who administers it. It should
be precise, accurate, clear and legible. The two main kinds of
prescription are those written, dispensed and administered in
hospital and those written in primary care (in the UK by a GP),
dispensed at a community pharmacy and self-administered by
the patient. The information supplied must include:
• the date
• the identification details of the patient
• the name of the drug
• the formulation
• the dose
• the frequency of administration
• the route and method of administration
• the amount to be supplied (primary care only)
• instructions for labelling (primary care only)
• the prescriber’s signature.
Prescribing in hospital
Although GP prescribing is increasingly electronic, most hospital
prescribing continues to be based around the prescription and
administration record (the ‘drug chart’) (Fig. 2.7). A variety of
charts are in use and prescribers must familiarise themselves
with the local version. Most contain the following sections:
• Basic patient information : will usually include name, age,
date of birth, hospital number and address. These details
are often ‘filled in’ using a sticky addressograph label but
this increases the risk of serious error.
• Previous adverse reactions/allergies: communicates
important patient safety information based on a careful
drug history and/or the medical record.
• Other medicines charts : notes any other hospital
prescription documents that contain current prescriptions
being received by the patient (e.g. anticoagulants, insulin,
oxygen, fluids).
• Once-only medications : for prescribing medicines to be
used infrequently, such as single-dose prophylactic
antibiotics and other pre-operative medications.
• Regular medications : for prescribing medicines to be taken
for a number of days or continuously, such as a course of
antibiotics, anti hypertensive drugs and so on.
• As required’ medications: for prescribing for symptomatic
relief, usually to be administered at the discretion of the
nursing staff (e.g. antiemetics, analgesics).
Prescribers should be aware of the risks of prescription error
(Box 2.24 and see Box 2.13), ensure they have considered the
rational basis for their prescribing decision described above, and
then follow the guidance illustrated in Figure 2.7 in order to write
the prescription. It is a basic principle that a prescription will be
followed by a judgement as to its success or failure and any
appropriate changes made (e.g. altered dosage, discontinuation
or substitution).
i
• Trying to amend an active prescription (e.g. altering the dose/
timing) - always avoid and start again
• Writing up drugs in the immediate presence of more than one
prescription chart or set of notes - avoid
• Allowing one’s attention to be diverted in the middle of completing a
prescription - avoid
• Prescribing ‘high-risk’ drugs (e.g. anticoagulants, opioids, insulin,
sedatives) - ask for help if necessary
• Prescribing parenteral drugs - take care
• Rushing prescribing (e.g. in the midst of a busy ward round)
- avoid
• Prescribing unfamiliar drugs - consult the formulary and ask for
help if necessary
• Transcribing multiple prescriptions from an expired chart to a new
one - take care to review the rationale for each medicine
• Writing prescriptions based on information from another source
such as a referral letter (the list may contain errors and some of the
medicines may be the cause of the patient’s illness) - review the
justification for each as if it is a new prescription
• Writing up ‘to take out’ drugs (because these will become the
patient’s regular medication for the immediate future) - take care
and seek advice if necessary
• Calculating drug doses - ask a colleague to perform an
independent calculation or use approved electronic dose
calculators
• Prescribing sound-alike or look-alike drugs (e.g. chlorphenamine
and chlorpromazine) - take care
Hospital discharge (‘to take out’) medicines
Most patients will be prescribed a short course of their medicines
at discharge. This prescription is particularly important because it
usually informs future therapy at the point of transfer of prescribing
responsibility to primary care. Great care is required to ensure
that this list is accurate. It is particularly important to ensure that
any hospital medicines that should be stopped are not included
and that those intended to be administered for a short duration
only are clearly identified. It is also important for any significant
ADRs experienced in hospital to be recorded and any specific
monitoring or review identified.
Prescribing in primary care
Most of the considerations above are equally applicable to
primary care (GP) prescriptions. In many health-care systems,
community prescribing is electronic, making issues of legibility
irrelevant and often providing basic decision support to limit
the range of doses that can be written and highlight potential
drug interactions. Important additional issues more relevant to
GP prescribing are:
• Formulation. The prescription needs to carry information
about the formulation for the dispensing pharmacist (e.g.
tablets or oral suspension).
• Amount to be supplied. In the hospital the pharmacist will
organise this. Elsewhere it must be specified either as the
precise number of tablets or as the duration of treatment.
Creams and ointments should be specified in grams and
lotions in mL.
• Controlled drugs. Prescriptions for ‘controlled’ drugs (e.g.
opioid analgesics, with potential for drug abuse) are
subject to additional legal requirements. In the UK, they
2.24 High-risk prescribing moments
34 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
[a] PRESCRIPTION AND ADMINISTRATION RECORD
Standard Chart
Hospital/Ward: \A/26 Consultant: MrA/XtirtUC
Weight: 78 Kj Height: 7 .84 WV
If rewritten, date: 14»2.18
DISCHARGE PRESCRIPTION
Date completed:- Completed by:-
Name of patient: J0fal Smith
Hospital number: WQH5522589
d.os, 16/10/64
(Attach printed label here)
OTHER MEDICINES CHARTS
PREVIOUS ADVERSE REACTIONS
(This must be completed before prescribing on this chart)
Date
Type of chart
Medicine
Description of reaction
Completed by
Date
14.2.18
Oxygen
Penicillin/
Serious resection/ (hospitalised) age/ 15
S. Jones
14.2.18
14.2.18
Warfarin
Cefalexin
Rash/ (discontinued) 2006
S. Jones
14.2.18
CODES FOR NON-ADMINISTRATION OF PRESCRIBED MEDICINE
If a dose is not administered as prescribed, intial and enter a code in the column with a circle drawn round the code according to the
reason as shown below. Inform the responsible doctor of the appropriate timescale.
1 . Patient refuses 6. Vomiting/nausea
2. Patient not present 7. Time varied on doctor’s instructions
3. Medicines not available - CHECK ORDERED 8. Once-only/as-required medicine given
4. Asleep/drowsy 9. Dose withheld on doctor’s instructions
5. Administration route not available - CHECK FOR ALTERNATIVE 1 0. Possible adverse reaction/side-effect
LBJ
ONCE-ONLY MEDICINES
Date
Time
Medicine (approved name)
Dose
Route
Prescriber - sign and print
Time
given
Given
by
14.2.18
16.00
MORPHINE SULFATE
5 mg
IV
S. JONES
16.20
ST
14.2.18
16.00
GLYCERYL TRINITRATE
2 mg
Buccal
S. JONES
16.10
VK
14.2.18
16.00
METOCLOFRAMIDE
10 mg
IV
S. JONES
16.20
ST
Fig. 2.7 Example of a hospital prescription and administration record (‘drug chart’). [A] Frontpage. The correct identification of the patient is
critical to reducing the risk of an administration error. This page also clearly identifies other prescriptions charts in use and previous adverse reactions to
drugs to minimise the risk of repeated exposure. Note also the codes employed by the nursing staff to indicate reasons why drugs may not have been
administered. The patient’s name and date of birth should be written on each page of the chart. The patient’s weight and height may be required to
calculate safe doses for many drugs with narrow therapeutic indices. \W\ ‘Once-only medicines’. This area is used for prescribing medicines that are
unlikely to be repeated on a regular basis. Note that the prescriber has written the names of all drugs legibly in block capitals. The generic international
non-proprietary name (INN) should be used in preference to the brand name (e.g. write ‘SIMVASTATIN’, not ‘ZOCOR’). The only exceptions are when
variation occurs in the properties of alternative branded formulations (e.g. modified-release preparations of drugs such as lithium, theophylline, phenytoin
and nifedipine) or when the drug is a combination product with no generic name (e.g. Kliovance). The only acceptable abbreviations for drug dose units
are ‘g’ and ‘mg’. ‘Units’ (e.g. of insulin or heparin) and ‘micrograms’ must always be written in full, never as ‘U’ or ‘jig’ (nor ‘meg’, nor ‘ug’). For liquid
preparations write the dose in mg; ‘mL’ can be written only for a combination product (e.g. Gaviscon liquid) or if the strength is not expressed in weight
(e.g. adrenaline (epinephrine) 1 in 1000). Use numbers/figures (e.g. 1 or ‘one’) to denote use of a sachet/enema but avoid prescribing numbers of tablets
without specifying their strength. Always include the dose of inhaled drugs in addition to stating numbers of ‘puffs’, as strengths can vary. Widely accepted
abbreviations for route of administration are: intravenous - ‘IV’; intramuscular - ‘IM’; subcutaneous - ‘SC’; sublingual - ‘SL’; per rectum - ‘PR’; per
vaginam - ‘PV’; nasogastric - ‘NG’; inhaled - ‘INH’; and topical - ‘TOP’. ‘ORAL’ is preferred to per oram - ‘PO’. Care should be taken in specifying
‘RIGHT’ or ‘LEFT’ for eye and ear drops. The prescriber should sign and print their name clearly so that they can be identified by colleagues. The
prescription should be dated and have an administration time. The nurse who administered the prescription has signed to confirm that the dose has been
administered.
must contain the address of the patient and prescriber
(not necessary on most hospital forms), the form and the
strength of the preparation, and the total quantity of the
preparation/number of dose units in both words and
figures.
• ‘Repeat prescriptions’. A large proportion of GP
prescribing involves ‘repeat prescriptions’ for chronic
medication. These are often generated automatically,
although the prescriber remains responsible for regular
review and for ensuring that the benefit-to-harm ratio
remains favourable.
Monitoring drug therapy
Prescribers should measure the effects of the drug, both beneficial
and harmful, to inform decisions about dose titration (up or down),
discontinuation or substitution of treatment. Monitoring can be
achieved subjectively by asking the patient about symptoms or,
more objectively, by measuring a clinical effect. Alternatively, if the
pharmacodynamic effects of the drug are difficult to assess, the
plasma drug concentration may be measured, on the basis that
it will be closely related to the effect of the drug (see Fig. 2.2).
Prescribing in practice • 35
0
REGULAR MEDICINES
Date - ►
Time 1
14
15
Fe
16
brtu
7s
ion
19
?
20
21
Drug (approved name)
AMOXICILLIN
6
(S)
X
t>K
RB
RB
VK
X
X
X
X
X
Dose
500 mg
Route
ORAL
12
Prescriber-sign and print
S. JONES
Start date
14. 02.18
@>
X
VK
2
RB
X
X
X
X
X
18
Notes
'Bov chest infection
Pharmacy
@
V
VK
RB
RB
X
X
X
X
X
Drug (approved name) /
AMLODIPINE
6
r-
(8)
X
viy
'RB
t
'fisco
ft tin
Med
dtu
*stO
Dose
SmS /
Roj/e
X ORAL
12
pw
sistt
wvta
utkl
2s
Prescriber-sign and lannt
Stones
Start date
14. 02.18
14
oeo
teuu
V
18
s.
Ma
sxun
illli
6.02
.18
Notes
*&f>v hypertension
Pharmacy
22-
_
Drug (approved name)
LISINOPRIL
6
CD
X
VK
RB
RB
VK
Dose
20 Mg
Route
ORAL
12
Prescriber-sign and print
S. JONES
Start date
14. 02.18
14
18
Notes Review- venal
Junction on 16. 2. 18
Pharmacy
22
0
AS-REQUIRED THERAPY
Drug (approved name)
PARACETAMOL
Date
16.2
Time
11.15
Dose and frequency
1g 4'brly
Route
ORAL
Dose
Initials
t>K
Prescriber-sign and print
^^S. JONES
Start date
16. 02.18
Date
Time
Indication/notes pain,
Maxinuun 4g/24 hr
Pharmacy
Dose
Initials
Drug (approved name)
GLYCERYL TRINITRATE
Date
Time
Dose and frequency
500 ndcrogvajMS
Route
Sublingual
Dose
Initials
Prescriber-sign and print
Start date
16. 02.18
Date
Time
Indication/notes EOV
car dine ischaemia,
Pharmacy
Dose
Initials
Fig. 2.7, cont’d [c] ‘Regular medicines’. This area is used for prescribing medicines that are going to be given regularly. In addition to the name, dose
and route, a frequency of administration is required for each medicine. Widely accepted Latin abbreviations for dose frequency are: once daily - ‘OD’;
twice daily - ‘BD’; 3 times daily - TDS’; 4 times daily - ‘QDS’; as required - ‘PRINT; in the morning - ‘OM’ (omni mane); at night - ‘ON’ (omni nocte);
and immediately - ‘stat’. The hospital chart usually requires specific times to be identified for regular medicines that coincide with nursing drug rounds and
these can be circled. If treatment is for a known time period, cross off subsequent days when the medicine is not required. The ‘notes’ box can be used
to communicate additional important information (e.g. whether a medicine should be taken with food, type of inhaler device used, and anything else that
the drug dispenser should know). State here the times for peak/trough plasma levels for drugs requiring therapeutic monitoring. Prescriptions should be
discontinued by drawing a vertical line at the point of discontinuation, horizontal lines through the remaining days on the chart, and diagonal lines through
the drug details and administration boxes. This action should be signed and dated and a supplementary note written to explain it (e.g. describing any
adverse effect). In this example, amlodipine has been discontinued because of ankle oedema. There is room for the ward pharmacist to sign to indicate
that the prescription has been reviewed and that a supply of the medicine is available. The administration boxes allow the nurse to sign to confirm that the
dose has been given. Note that these boxes also allow for recording of reasons for non-administration (in this example ‘2’ indicates that the patient was
not present on the ward at the time) and the prevention of future administration by placing an ‘X’ in the box. [D] ‘As-required medicines’. These
prescriptions leave the administration of the drug to the discretion of the nursing staff. The prescription must describe clearly the indication, frequency,
minimal time interval between doses, and maximum dose in any 24-hour period (in this case, the maximum daily dose of paracetamol is 4 g).
Clinical and surrogate endpoints
Ideally, clinical endpoints are measured directly and the drug
dosage titrated to achieve the therapeutic goal and avoid toxicity
(e.g. control of ventricular rate in a patient with atrial fibrillation).
Sometimes this is impractical because the clinical endpoint
is a future event (e.g. prevention of myocardial infarction by
statins or resolution of a chest infection with antibiotics); in
these circumstances, it may be possible to select a ‘surrogate’
endpoint that will predict success or failure. This may be an
intermediate step in the pathophysiological process (e.g. serum
cholesterol as a surrogate for risk of myocardial infarction) or a
36 • CLINICAL THERAPEUTICS AND GOOD PRESCRIBING
2.25 Drugs commonly monitored by plasma drug concentration
Drug
Half-life (hrs)
Comment
Digoxin
36
Steady state takes several days to achieve. Samples should be taken 6 hrs post dose. Measurement is
useful to confirm the clinical impression of toxicity or non-adherence but clinical effectiveness is better
assessed by ventricular heart rate. Risk of toxicity increases progressively at concentrations >1.5 pig/L,
and is likely at concentrations >3.0 pig/L (toxicity is more likely in the presence of hypokalaemia)
Gentamicin
2
Measure pre-dose trough concentration (should be <1 jig/mL) to ensure that accumulation (and the risk of
nephrotoxicity and ototoxicity) is avoided; see Fig. 6.18 (p. 122)
Levothyroxine
>120
Steady state may take up to 6 weeks to achieve (p. 640)
Lithium
24
Steady state takes several days to achieve. Samples should be taken 12 hrs post dose. Target range
0.4-1 mmol/L
Phenytoin
24
Measure pre-dose trough concentration (should be 10-20 mg/L) to ensure that accumulation is avoided.
Good correlation between concentration and toxicity. Concentration may be misleading in the presence of
hypoalbuminaemia
Theophylline (oral)
6
Steady state takes 2-3 days to achieve. Samples should be taken 6 hrs post dose. Target concentration is
1 0-20 mg/L but its relationship with bronchodilator effect and adverse effects is variable
Vancomycin
6
Measure pre-dose trough concentration (should be 10-15 mg/L) to ensure clinical efficacy and that
accumulation and the risk of nephrotoxicity are avoided (p. 123)
*Half-lives vary considerably with different formulations and between patients.
measurement that follows the pathophysiology, even if it is not a
key factor in its progression (e.g. serum C- reactive protein as a
surrogate for resolution of inflammation in chest infection). Such
surrogates are sometimes termed ‘biomarkers’.
Plasma drug concentration
The following criteria must be met to justify routine monitoring
by plasma drug concentration:
• Clinical endpoints and other pharmacodynamic (surrogate)
effects are difficult to monitor.
• The relationship between plasma concentration and clinical
effects is predictable.
• The therapeutic index is low. For drugs with a high
therapeutic index, any variability in plasma concentrations
is likely to be irrelevant clinically.
Some examples of drugs that fulfil these criteria are listed in
Box 2.25.
Measurement of plasma concentration may be useful
in planning adjustments of drug dose and frequency of
administration; to explain an inadequate therapeutic response
(by identifying subtherapeutic concentration or incomplete
adherence); to establish whether a suspected ADR is likely to
be caused by the drug; and to assess and avoid potential drug
interactions.
Timing of samples in relation to doses
The concentration of drug rises and falls during the dosage
interval (see Fig. 2.4B). Measurements made during the initial
absorption and distribution phases are unpredictable because
of the rapidly changing concentration, so samples are usually
taken at the end of the dosage interval (a ‘trough’ or ‘pre-dose’
concentration). This measurement is normally made in steady
state, which usually takes five half-lives to achieve after the
drug is introduced or the dose changed (unless a loading dose
has been given).
Interpreting the result
A target range is provided for many drugs, based on average
thresholds for therapeutic benefit and toxicity. Inter-individual
variability means that these can be used only as a guide. For
instance, in a patient who describes symptoms that could
be consistent with toxicity but has a drug concentration in
the top half of the target range, toxic effects should still be
suspected. Another important consideration is that some
drugs are heavily protein-bound (e.g. phenytoin) but only
the unbound drug is pharmacologically active. Patients with
hypoalbuminaemia may therefore have a therapeutic or even
toxic concentration of unbound drug, despite a low ‘total’
concentration.
Further information
Websites
bnf.org The British National Formulary (BNF) is a key reference
resource for UK NHS prescribes, with a list of licensed drugs,
chapters on prescribing in renal failure, liver disease, pregnancy and
during breastfeeding, and appendices on drug interactions.
cochrane.org The Cochrane Collaboration is a leading international
body that provides evidence-based reviews (around 7000 so far).
evidence.nhs.uk NHS Evidence provides a wide range of health
information relevant to delivering quality patient care.
icp.org. nz The Interactive Clinical Pharmacology site is designed to
increase understanding of principles in clinical pharmacology.
medicines.org.uk/emc/ The electronic Medicines Compendium (eMC)
contains up-to-date, easily accessible information about medicines
licensed by the UK Medicines and Healthcare Products Regulatory
Agency (MHRA) and the European Medicines Agency (EMA).
nice.org.uk The UK National Institute for Health and Care Excellence
makes recommendations to the UK NHS on new and existing
medicines, treatments and procedures.
who.int/medicines/en/ The World Health Organisation Essential
Medicines and Pharmaceutical Policies.
K Tatton-Brown
DR FitzPatrick
Clinical genetics
The fundamental principles of genomics 38
Interrogating the genome: the changing landscape of
The packaging of genes: DNA, chromatin and chromosomes 38
genomic technologies 51
From DNA to protein 38
Looking at chromosomes 51
Non-coding RNA 40
Looking at genes 52
Cell division, differentiation and migration 40
Genomics and clinical practice 56
Cell death, apoptosis and senescence 41
Genomics and health care 56
Genomics, health and disease 42
Treatment of genetic disease 58
Classes of genetic variant 42
Ethics in a genomic age 59
Consequences of genomic variation 44
Normal genomic variation 45
Constitutional genetic disease 46
Somatic genetic disease 50
38 • CLINICAL GENETICS
We have entered a genomic era. Powerful new technologies
are driving forward transformational change in health care.
Genetic sequencing has evolved from the targeted sequencing
of a single gene to the parallel sequencing of multiple genes. In
addition to improving the chances of identifying a genetic cause
of rare diseases, these technologies are increasingly directing
therapies and, in the future, are likely to be used in the diagnosis
and prevention of common diseases such as diabetes. In this
chapter we explore the fundamentals of genomics, the basic
principles underlying these new genomic technologies and how
the data generated can be applied safely for patient benefit. We
will review the use of genomic technology across a breadth of
medical specialties, including obstetrics, paediatrics, oncology
and infectious disease, and consider how health care is likely to
be transformed by technology over the coming decade. Finally,
we will consider the ethical impact that these technologies are
likely to have, both for the individual and for their wider family.
The fundamental principles
of genomics
The packaging of genes: DNA, chromatin
and chromosomes
Genes are functional units encoded in double-stranded
deoxyribonucleic acid (DNA), packaged as chromosomes
and located in the nucleus of the cell: a membrane-bound
compartment found in all cells except erythrocytes and platelets
(Fig. 3.1). DNA consists of a linear sequence of just four bases:
adenine (A,) cytosine (C), thymine (T) and guanine (G.) It forms
a ‘double helix’, a twisted ladder-like structure formed from
two complementary strands of DNA joined by hydrogen bonds
between bases on the opposite strand that can form only between
a C and a G base and an A and a T base. It is this feature of
DNA that enables faithful DNA replication and is the basis for
many of the technologies designed to interrogate the genome:
when the DNA double helix ‘unzips’, one strand can act as a
template for the creation of an identical strand.
A single copy of the human genome comprises approximately
3.1 billion base pairs of DNA, wound around proteins called
histones. The unit consisting of 1 47 base pairs wrapped around
four different histone proteins is called the nucleosome. Sequences
of nucleosomes (resembling a string of beads) are wound and
packaged to form chromatin: tightly wound, densely packed
chromatin is called heterochromatin and open, less tightly wound
chromatin is called euchromatin.
The chromatin is finally packaged into the chromosomes.
Humans are diploid organisms: the nucleus contains two copies
of the genome, visible microscopically as 23 chromosome
pairs (known as the karyotype). Chromosomes 1 through
to 22 are known as the autosomes and consist of identical
chromosomal pairs. The 23rd ‘pair’ of chromosomes are the
two sex chromosomes: females have two X chromosomes and
males an X and Y chromosome. A normal female karyotype is
therefore written as 46, XX and a normal male is 46, XY.
From DNA to protein
Genes are functional elements on the chromosome that are
capable of transmitting information from the DNA template
Fig. 3.1 The packaging of DNA, genes and chromosomes. From
bottom to top: the double helix and the complementary DNA bases;
chromatin; and a normal female chromosome pattern - the karyotype.
via the production of messenger ribonucleic acid (mRNA) to
the production of proteins. The human genome contains over
20000 genes, although many of these are inactive or silenced
in different cell types, reflecting the variable gene expression
responsible for cell-specific characteristics. The central dogma
is the pathway describing the basic steps of protein production:
transcription, splicing, translation and protein modification (Fig.
3.2). Although this is now recognised as an over-simplification
(contrary to this linear relationship, a single gene will often encode
many different proteins), it remains a useful starting point to
explore protein production.
Transcription: DNA to messenger RNA
Transcription describes the production of ribonucleic acid (RNA)
from the DNA template. For transcription to commence, an
enzyme called RNA polymerase binds to a segment of DNA at the
start of the gene: the promoter. Once bound, RNA polymerase
moves along one strand of DNA, producing an RNA molecule
complementary to the DNA template. In protein-coding genes
this is known as messenger RNA (mRNA). A DNA sequence
close to the end of the gene, called the polyadenylation
signal, acts as a signal for termination of the RNA transcript
(Fig. 3.3).
The fundamental principles of genomics • 39
Fig. 3.2 The central dogma of protein production. Double-stranded
DNA as a template for single-stranded RNA, which codes for the
production of a peptide chain of amino acids. Each of these chains has
an orientation. For DNA and RNA, this is 5' to 3'. For peptides, this is
N-terminus to C-terminus.
RNA differs from DNA in three main ways:
• RNA is single-stranded.
• The sugar residue within the nucleotide is ribose, rather
than deoxyribose.
• It contains uracil (U) in place of thymine (T).
The activity of RNA polymerase is regulated by transcription
factors. These proteins bind to specific DNA sequences at the
promoter or to enhancer elements that may be many thousands
of base pairs away from the promoter; a loop in the chromosomal
DNA brings the enhancer close to the promoter, enabling the
bound proteins to interact. The human genome encodes more
than 1200 different transcription factors. Mutations within
transcription factors, promoters and enhancers can cause disease.
For example, the blood disorder alpha-thalassaemia is usually
caused by gene deletions (see p. 954 and Box 3.4). Flowever,
it can also result from a mutation in an enhancer located more
than 1 00 000 base pairs (bp) from the a-globin gene promoter,
leading to greatly reduced transcription.
Gene activity, or expression, is influenced by a number of complex
interacting factors, including the accessibility of the gene promoter
to transcription factors. DNA can be modified by the addition of a
methyl group to cytosine molecules (methylation). If DNA methylation
occurs in promoter regions, transcription is silenced, as methyl
cytosines are usually not available for transcription factor binding.
A second mechanism determining promoter accessibility is the
structural configuration of chromatin. In open chromatin, called
euchromatin, gene promoters are accessible to RNA polymerase
and transcription factors; therefore it is transcriptionally active.
This contrasts with heterochromatin, which is densely packed and
transcriptionally silent. The chromatin configuration is determined
by modifications (such as methylation or acetylation) of specific
amino acid residues of histone protein tails.
Modifications of DNA and histones are termed epigenetic (‘epi-’
meaning ‘above’ the genome), as they do not alter the primary
sequence of the DNA code but have biological significance
in chromosomal function. Abnormal epigenetic changes are
increasingly recognised as important events in the progression
of cancer, allowing expression of normally silenced genes that
result in cancer cell de-differentiation and proliferation. They also
afford therapeutic targets. For instance, the histone deacetylase
inhibitor vorinostat has been successfully used to treat cutaneous
T-cell lymphoma, due to the re-expression of genes that had
Nucleus
Spliceosome
i
/
PolyA tail
Messenger RNA
(mRNA)
cap-
i
-AAAAA
Nuclear pore
inslat
i
Protein product
N-term ooooooooooooooooo C-term
Fig. 3.3 RNA synthesis and its translation into protein. Gene
transcription involves binding of RNA polymerase II to the promoter of genes
being transcribed with other proteins (transcription factors) that regulate the
transcription rate. The primary RNA transcript is a copy of the whole gene
and includes both introns and exons, but the introns are removed within
the nucleus by splicing and the exons are joined to form the messenger
RNA (mRNA). Prior to export from the nucleus, a methylated guanosine
nucleotide is added to the 5' end of the RNA (‘cap’) and a string of adenine
nucleotides is added to the 3' (‘polyA tail’). This protects the RNA from
degradation and facilitates transport into the cytoplasm. In the cytoplasm,
the mRNA binds to ribosomes and forms a template for protein production.
(tRNA = transfer RNA; UTR = untranslated region)
40 • CLINICAL GENETICS
previously been silenced in the tumour. These genes encode
transcription factors that promote T-cell differentiation as opposed
to proliferation, thereby causing tumour regression.
RNA splicing, editing and degradation
Transcription produces an RNA molecule that is a copy of the
whole gene, termed the primary or nascent transcript. This
nascent transcript then undergoes splicing, whereby regions
not required to make protein (the intronic regions) are removed
while those segments that are necessary for protein production
(the exonic regions) are retained and rejoined.
Splicing is a highly regulated process that is carried out by a
multimeric protein complex called the spliceosome. Following
splicing, the mRNA molecule is exported from the nucleus and
used as a template for protein synthesis. Many genes produce
more than one form of mRNA (and thus protein) by a process
termed alternative splicing, in which different combinations of
exons are joined together. Different proteins from the same
gene can have entirely distinct functions. For example, in
thyroid C cells the calcitonin gene produces mRNA encoding
the osteoclast inhibitor calcitonin (p. 634), but in neurons the
same gene produces an mRNA with a different complement of
exons via alternative splicing that encodes a neurotransmitter,
calcitonin-gene-related peptide (p. 772).
| Translation and protein production
Following splicing, the segment of mRNA containing the code
that directs synthesis of a protein product is called the open
reading frame (ORF). The inclusion of a particular amino acid in
the protein is specified by a codon composed of three contiguous
bases. There are 64 different codons with some redundancy in
the system: 61 codons encode one of the 20 amino acids, and
the remaining three codons - UAA, UAG and UGA (known as
stop codons) - cause termination of the growing polypeptide
chain. ORFs in humans most commonly start with the amino
acid methionine. All mRNA molecules have domains before and
after the ORF called the 5' untranslated region (UTR) and 3'UTR,
respectively. The start of the 5'UTR contains a cap structure that
protects mRNA from enzymatic degradation, and other elements
within the 5'UTR are required for efficient translation. The 3'UTR
also contains elements that regulate efficiency of translation and
mRNA stability, including a stretch of adenine bases known as
a polyA tail (see Fig. 3.3).
The mRNAs then leave the nucleus via nuclear pores and
associate with ribosomes, the sites of protein production (see
Fig. 3.3). Each ribosome consists of two subunits (40S and
60S), which comprise non-coding rRNA molecules (see Fig. 3.9,
p. 50) complexed with proteins. During translation, a different RNA
molecule known as transfer RNA (tRNA) binds to the ribosome.
The tRNAs deliver amino acids to the ribosome so that the newly
synthesised protein can be assembled in a stepwise fashion.
Individual tRNA molecules bind a specific amino acid and ‘read’
the mRNA ORF via an ‘anticodon’ of three nucleotides that is
complementary to the codon in mRNA (see Fig. 3.3). A proportion of
ribosomes is bound to the membrane of the endoplasmic reticulum
(ER), a complex tubular structure that surrounds the nucleus.
Proteins synthesised on these ribosomes are translocated
into the lumen of the ER, where they undergo folding and
processing. From here, the protein may be transferred to
the Golgi apparatus, where it undergoes post-translational
modifications, such as glycosylation (covalent attachment of
sugar moieties), to form the mature protein that can be exported
into the cytoplasm or packaged into vesicles for secretion.
The clinical importance of post-translational modification of
proteins is shown by the severe developmental, neurological,
haemostatic and soft tissue abnormalities that are associated
with the many different congenital disorders of glycosylation.
Post-translational modifications can also be disrupted by the
synthesis of proteins with abnormal amino acid sequences. For
example, the most common mutation in cystic fibrosis (AF508)
results in an abnormal protein that cannot be exported from the
ER and Golgi (see Box 3.4).
Non-coding RNA
Approximately 4500 genes in humans encode non-coding RNAs
(ncRNA) rather than proteins. There are various categories of
ncRNA, including transfer RNA (tRNA), ribosomal RNA (rRNA),
ribozymes and microRNA (miRNA). The miRNAs, which number
over 1000, have a role in post-translational gene expression:
they bind to mRNAs, typically in the 3'UTR, promoting target
mRNA degradation and gene silencing. Together, miRNAs affect
over half of all human genes and have important roles in normal
development, cancer and common degenerative disorders.
This is the subject of considerable research interest at present.
Cell division, differentiation and migration
In normal tissues, molecules such as hormones, growth factors
and cytokines provide the signal to activate the cell cycle: a
controlled programme of biochemical events that culminates in cell
division. In all cells of the body, except the gametes (the sperm
and egg cells, also known as the germ line), mitosis completes
cell division, resulting in two diploid daughter cells. In contrast,
the sperm and eggs cells complete cell division with meiosis,
resulting in four haploid daughter cells (Fig. 3.4).
The stages of cell division in the non-germ-line, somatic cells
are shown below:
• Cells not committed to mitosis are said to be in G0.
• Cells committed to mitosis must go through the
preparatory phase of interphase consisting of Gi,
S and G2:
• Gt (first gap): synthesis of the cellular components
necessary to complete cell division
• S (synthesis): DNA replication producing identical
copies of each chromosome called the sister
chromatids
• G2 (second gap): repair of any errors in the replicated
DNA before proceeding to mitosis.
• Mitosis (M) consists of four phases:
• Prophase: the chromosomes condense and become
visible, the centrioles move to opposite ends of the cell
and the nuclear membrane disappears.
• Metaphase: the centrioles complete their migration to
opposite ends of the cell and the chromosomes -
consisting of two identical sister chromatids - line up at
the equator of the cell.
• Anaphase: spindle fibres attach to the chromosome
and pull the sister chromatids apart.
• Telophase: the chromosomes decondense, the nuclear
membrane reforms and two daughter cells - each with
46 chromosomes - are formed.
The progression from one phase to the next is tightly controlled
by cell-cycle checkpoints. For example, the checkpoint between
The fundamental principles of genomics • 41
Father
Individual chromosome
pair (homologues)
DNA replication
Mother
l l
HH
Sister chromatids
Homologous pairing
I
Swapping of
genetic material
between homologues:
Recombination
Meiotic cell divisions
Non-disjunction of
chromosomes is a common
error in human meiosis,
resulting in trisomy of
individual chromosomes
or uniparental disomy
(both chromosomes from
Sperm
Fig. 3.4 Meiosis and gametogenesis: the main chromosomal stages
of meiosis in both males and females. A single homologous pair of
chromosomes is represented in different colours. The final step is the
production of haploid germ cells. Each round of meiosis in the male results
in four sperm cells; in the female, however, only one egg cell is produced,
as the other divisions are sequestered on the periphery of the mature egg
as peripheral polar bodies.
G2 and mitosis ensures that all damaged DNA is repaired prior
to segregation of the chromosomes. Failure of these control
processes is a crucial driver in the pathogenesis of cancer, as
discussed on page 1316.
• Meiosis is a special, gamete-specific, form of cell division
(Fig. 3.4). Like mitosis, meiosis consists of four phases
(prophase, metaphase, anaphase and telophase) but
differs from mitosis in the following ways:
• It consists of two separate cell divisions known as
meiosis I and meiosis II.
• It reduces the chromosome number from the
diploid to the haploid number via a tetraploid
stage, i.e. from 46 to 92 (Ml S) to 46 (Ml M) to
23 (Mil M) chromosomes, so that when a sperm
cell fertilises the egg, the resulting zygote will return
to a diploid, 46, chromosome complement. This
reduction to the haploid number occurs at the end
of meiosis II.
• The 92 chromosome stage consists of 23 homologous
pairs of sister chromatids, which then swap genetic
material, a process known as recombination. This
occurs at the end of Ml prophase and ensures that
the chromosome that a parent passes to his or her
offspring is a mix of the chromosomes that the
parent inherited from his or her own mother
and father.
The individual steps in meiotic cell division are similar in males
and females. However, the timing of the cell divisions is very
different. In females, meiosis begins in fetal life but does not
complete until after ovulation. A single meiotic cell division can
thus take more than 40 years to complete. As women become
older, the separation of chromosomes at meiosis II becomes
less efficient. That is why the risk of trisomies (p. 44) due to
non-disjunction grows greater with increasing maternal age.
In males, meiotic division does not begin until puberty and
continues throughout life. In the testes, both meiotic divisions
are completed in a matter of days.
Cell death, apoptosis and senescence
With the exception of stem cells, human cells have only a limited
capacity for cell division. The Hayflick limit is the number of
divisions a cell population can go through in culture before division
stops and enters a state known as senescence. This ‘biological
clock’ is of great interest in the study of the normal ageing
process. Rare human diseases associated with premature ageing,
called progeric syndromes, have been very helpful in identifying
the importance of DNA repair mechanisms in senescence
(p. 1034). For example, in Werner’s syndrome, a DNA helicase
(an enzyme that separates the two DNA strands) is mutated,
leading to failure of DNA repair and premature ageing. A distinct
mechanism of cell death is seen in apoptosis, or programmed
cell death.
Apoptosis is an active process that occurs in normal tissues
and plays an important role in development, tissue remodelling
and the immune response. The signal that triggers apoptosis is
specific to each tissue or cell type. This signal activates enzymes,
called caspases, which actively destroy cellular components,
including chromosomal DNA. This degradation results in cell
death, but the cellular corpse contains characteristic vesicles
called apoptotic bodies. The corpse is then recognised and
removed by phagocytic cells of the immune system, such
as macrophages, in a manner that does not provoke an
inflammatory response.
A third mechanism of cell death is necrosis. This is a pathological
process in which the cellular environment loses one or more of
the components necessary for cell viability. Hypoxia is probably
the most common cause of necrosis.
42 • CLINICAL GENETICS
Genomics, health and disease
Classes of genetic variant
There are many different classes of variation in the human
genome, categorised by the size of the DNA segment involved
and/or by the mechanism giving rise to the variation.
Nucleotide substitutions
The substitution of one nucleotide for another is the most common
type of genomic variation. Depending on their frequency and
functional consequences, these changes are known as point
mutations or single nucleotide polymorphisms (SNPs). They occur
by misincorporation of a nucleotide during DNA synthesis or by
chemical modification of the base. When these substitutions
occur within ORFs of a protein-coding gene, they are further
classified into:
• synonymous - resulting in a change in the codon without
altering the amino acid
• non-synonymous (also known as a missense mutation) -
resulting in a change in the codon and the encoded amino
acid
• stop gain (or nonsense mutation) - introducing a
premature stop codon and resulting in truncation of the
protein
• splicing - taking place at splice sites that most frequently
occur at the junction between an intron and an exon.
These different types of mutation are illustrated in Box 3.1
and examples are shown in Figures 3.5 and 3.6.
|jnsertions and deletions
One or more nucleotides may be inserted or lost in a DNA
sequence, resulting in an insertion/deletion (indel) polymorphism or
mutation (Box 3.1 and Fig. 3.5). If a multiple of three nucleotides
is involved, this is in-frame. If an indel change affects one or
two nucleotides within the ORF of a protein-coding gene, this
can have serious consequences because the triple nucleotide
sequence of the codons is disrupted, resulting in a frameshift
mutation. The effect on the gene is typically severe because the
amino acid sequence is totally disrupted.
3.1 Classes of genetics variant
The classes of genetic variant can be illustrated using the sentence
THE FAT FOX WAS ILL COS SHE ATE THE OLD CAT’
Synonymous
Silent polymorphism
with no amino acid
change
THE FAT FOX WAS ILL COS SHE ATE THE
OLD KAT
where the C is replaced with a K but the
meaning remains the same
Non-synonymous
Causing an amino acid
change
THE FAT BOX WAS ILL COS SHE ATE THE
OLD CAT
where the F of FOX is replaced by a B and
the original meaning of the sentence is lost
Stop gain (also called a nonsense mutation)
Causing the generation THE CAT
of a premature stop where the F of FAT is replaced by a C
codon generating a premature stop codon
Indel
Where bases are either
inserted or deleted;
disruption of the reading
frame is dependent on
the number of bases
inserted or deleted
THE FAT FOX WAS ILL ILL COS SHE ATE
THE OLD CAT
where the insertion of three bases results
in maintenance of the reading frame
THE FAT FOX WAW ASI LLC OSS HEA TET
HEO LDC AT
where the insertion of two bases results in
disruption of the reading frame
0
DNA
ATG
GCC
GGG
AAG
TGT
CGT
GGT
GTT
mRNA
AUG
GCC
GGG
AAG
UGU
CGU
GGU
GUU
Protein
Met
Ala
Gly
Lys
Cys
Arg
Gly
Val
DNA
ATG
GCC
GGG
AAA
TGT
CGT
GGT
GTT
mRNA
AUG
GCC
GGG
AAA
UGU
CGU
GGU
GUU
Protein
Met
Ala
Gly
Lys
Cys
Arg
Gly
Val
DNA
ATG
GCC
GGG
CAG
TGT
CGT
GGT
GTT
mRNA
AUG
GCC
GGG
CAG
UGU
CGU
GGU
GUU
Protein
Met
Ala
Gly
Gin
Cys
Arg
Gly
Val
DNA
ATG
GCC
GGG
0AA
GTG
TCG
TGG
TGT
mRNA
AUG
GCC
GGG
0AA
GUG
UCG
UGG
UGU
Protein
Met
Ala
Gly
Gin
Val
Ser
Trp
Cys
0
DNA
ATG
GCC
GGG
TAG
TGT
AGT
GGT
GTT
mRNA
Protein
AUG
Met
GCC
Ala
GGG
Gly
UAG
*
UGU
AGU
GGU
GUU
Normal
Silent polymorphism
(no amino acid change)
Missense mutation causing
Lys-GIn amino acid change
‘G’ insertion causing
frameshift mutation
Nonsense mutation causing
premature termination codon
Fig. 3.5 Different types of mutation affecting coding exons. [A] Normal sequence. [§] A synonymous nucleotide substitution changing the third base
of a codon; the resulting amino acid sequence is unchanged. [C] A missense mutation in which the nucleotide substitution results in a change in a single
amino acid from the normal sequence (AAG) encoding lysine to glutamine (CAG). [6] Insertion of a G residue (boxed) causes a frameshift mutation,
completely altering the amino acid sequence downstream. This usually results in a loss-of-function mutation. [I] A nonsense mutation resulting in a single
nucleotide change from a lysine codon (AAG) to a premature stop codon (TAG).
Genomics, health and disease • 43
[a] Normal
DNA
mRNA
Protein
Splice donor site
Splice acceptor site
Exon ■
Intron
Exon
ATG GCC GGG GTA GGG CGG TAG TTAG AAG TGT AGT GGT GTT
Intron removed by
splicing
AUG GCC GGG AAG TGU AGU GGU GUU
Met Ala Gly Lys Cys Ser Gly Val
|~b] Splice site mutation
Exon - - Intron Exon
ATG GCC GGG GGA GGG CGG TAG TTAG AAG TGT AGT GGT GTT
mRNA ‘reads through’ intron
\
AUG GCC GGG GGA GGG CGG TAG
Met Ala Gly Gly Gly Arg *
Abnormal protein with
premature stop codon
Fig. 3.6 Splice site mutations. ||@ The normal sequence is shown, illustrating two exons, and intervening intron (blue) with splice donor (AG) and splice
acceptor sites (GT) underlined. Normally, the intron is removed by splicing to give the mature messenger RNA that encodes the protein. 1M In a splice site
mutation the donor site is mutated. As a result, splicing no longer occurs, leading to read-through of the mRNA into the intron, which contains a premature
termination codon downstream of the mutation.
DNA
mRNA
Protein
3.2 Diseases associated with triplet and other repeat expansions
Repeat
No. of repeats
Normal Mutant
Gene
Gene location
Inheritance
Coding repeat expansion
Huntington’s disease
[CAG]
6-34
>35
Huntingtin
4p16
AD
Spinocerebellar ataxia (type 1)
[CAG]
6-39
>40
Ataxin
6p22— 23
AD
Spinocerebellar ataxia (types 2,
3, 6, 7)
[CAG]
Various
Various
Various
Various
AD
Dentatorubral-pallidoluysian
atrophy
[CAG]
7-25
>49
Atrophin
1 2p1 2—1 3
AD
Machado-Joseph disease
[CAG]
12-40
>67
MJD
14q32
AD
Spinobulbar muscular atrophy
[CAG]
11-34
>40
Androgen receptor
Xql 1—12
XL recessive
Non-coding repeat expansion
Myotonic dystrophy
[CTG]
5-37
>50
DMPK-3UTR
1 9q1 3
AD
Friedreich’s ataxia
[GAA]
7-22
>200
Frataxin -intronic
9q13
AR
Progressive myoclonic epilepsy
[CCCCGCCCCGCG]4-8
2-3
>25
Cy statin B-5'UTR
21 q
AR
Fragile X mental retardation
[CGG]
5-52
>200
FMRI-5'UTR
Xq27
XL dominant
Fragile site mental retardation 2
(FRAXE)
[GCC]
6-35
>200
FMR2
Xq28
XL, probably recessive
*The triplet repeat diseases fall into two major groups: those with disease stemming from expansion of [CAG]n repeats in coding DNA, resulting in multiple adjacent
glutamine residues (polyglutamine tracts), and those with non-coding repeats. The latter tend to be longer. Unaffected parents usually display ‘pre-mutation’ allele lengths
that are just above the normal range. (AD/AR = autosomal dominant/recessive; UTR = untranslated region; XL = X-linked)
Simple tandem repeat mutations
Variations in the length of simple tandem repeats of DNA are
thought to arise as the result of slippage of DNA during meiosis
and are termed microsatellite (small) or minisatellite (larger)
repeats. These repeats are unstable and can expand or contract
in different generations. This instability is proportional to the
size of the original repeat, in that longer repeats tend to be
more unstable. Many microsatellites and minisatellites occur in
introns or in chromosomal regions between genes and have
no obvious adverse effects. However, some genetic diseases
are caused by microsatellite repeats that result in duplication
of amino acids within the affected gene product or affect gene
expression (Box 3.2).
44 • CLINICAL GENETICS
|j2opy number variations
Variation in the number of copies of an individual segment of
the genome from the usual diploid (two copies) content can
be categorised by the size of the segment involved. Rarely,
individuals may gain (trisomy) or lose (monosomy) a whole
chromosome. Such numerical chromosome anomalies most
commonly occur by a process known as non-disjunction, where
pairs of homologous chromosomes do not separate at meiosis
II (p. 40). Common trisomies include Down’s syndrome (trisomy
21), Edward’s syndrome (trisomy 18) and Patau’s syndrome
(trisomy 13). Monosomy of the autosomes (present in all the
cells, as opposed to in a mosaic distribution) does not occur
but Turner’s syndrome, in which there is monosomy for the X
chromosome, affects approximately 1 in 2500 live births (Box 3.3).
Large insertions or deletions of chromosomal DNA also occur
and are usually associated with a learning disability and/or
congenital malformations. Such structural chromosomal anomalies
usually arise as the result of one of two different processes:
• non-homologous end-joining
• non-allelic homologous recombination.
Random double-stranded breaks in DNA are a necessary
process in meiotic recombination and also occur during mitosis
at a predictable rate. The rate of these breaks is dramatically
increased by exposure to ionising radiation. When such breaks
take place, they are usually repaired accurately by DNA repair
mechanisms within the cell. However, in a proportion of breaks,
segments of DNA that are not normally contiguous will be joined
(‘non-homologous end-joining’). If the joined fragments are from
different chromosomes, this results in a translocation. If they are
from the same chromosome, this will result in either inversion,
duplication or deletion of a chromosomal fragment (Fig. 3.7).
Large insertions and deletions may be cytogenetically visible
as chromosomal deletions or duplications. If the anomalies
are too small to be detected by microscopy, they are termed
microdeletions and microduplications. Many microdeletion
syndromes have been described and most result from non¬
allelic homologous recombination between repeats of highly
similar DNA sequences, which leads to recurrent chromosome
anomalies - and clinical syndromes - occurring in unrelated
individuals (Fig. 3.7 and Box 3.3).
Consequences of genomic variation
The consequence of an individual mutation depends on many
factors, including the mutation type, the nature of the gene product
and the position of the variant in the protein. Mutations can have
profound or subtle effects on gene and cell function. Variations
that have profound effects are responsible for ‘classical’ genetic
diseases, whereas those with subtle effects may contribute to
the pathogenesis of common disease where there is a genetic
component, such as diabetes.
• Neutral variants have no effect on quality or type of protein
produced.
• Loss-of-function mutations result in loss or reduction in the
normal protein function. Whole-gene deletions are the
archetypal loss-of-function variants but stop-gain or indel
mutations (early in the ORF), missense mutations affecting
a critical domain and splice-site mutations can also result
in loss of protein function.
3.3 Chromosome and contiguous gene disorders
Disease
Locus
Incidence
Clinical features
Numerical chromosomal abnormalities
Down’s syndrome (trisomy 21)
47,XY,+21 or 47,XX+21
1 in 800
Characteristic facies, IQ usually <50, congenital heart disease,
reduced life expectancy
Edwards’ syndrome (trisomy 1 8)
47,XY,+18 or 47, XX, +18
1 in 6000
Early lethality, characteristic skull and facies, frequent
malformations of heart, kidney and other organs
Patau’s syndrome (trisomy 13)
47,XY,+13 or 47, XX, +13
1 in
Early lethality, cleft lip and palate, polydactyly, small head,
15 000
frequent congenital heart disease
Klinefelter’s syndrome
47,XXY
1 in 1000
Phenotypic male, infertility, gynaecomastia, small testes
(p. 660)
XYY
47, XYY
1 in 1000
Usually asymptomatic, some impulse control problems
Triple X syndrome
47, XXX
1 in 1000
Usually asymptomatic, may have reduced IQ
Turner’s syndrome
45, X
1 in 5000
Phenotypic female, short stature, webbed neck, coarctation of
the aorta, primary amenorrhoea (p. 659)
Recurrent deletions, microdeletions and contiguous gene defects
Di George/velocardiofacial syndrome
22q11 .2
1 in 4000
Cardiac outflow tract defects, distinctive facial appearance,
thymic hypoplasia, cleft palate and hypocalcaemia. Major gene
seems to be TBX1 (cardiac defects and cleft palate)
Prader-Willi syndrome
1 5q1 1 — ql 3
1 in
Distinctive facial appearance, hyperphagia, small hands and
15 000
feet, distinct behavioural phenotype. Imprinted region, deletions
on paternal allele in 70% of cases
Angelman’s syndrome
1 5q1 1 — ql 3
1 in
Distinctive facial appearance, absent speech,
15 000
electroencephalogram (EEG) abnormality, characteristic gait.
Imprinted region, deletions on maternal allele encompassing
UBE3A
Williams’ syndrome
7q1 1 .23
1 in
Distinctive facial appearance, supravalvular aortic stenosis,
10 000
learning disability and infantile hypercalcaemia. Major gene for
supravalvular aortic stenosis is elastin
Smith-Magenis syndrome
1 7p1 1 .2
1 in
Distinctive facial appearance and behavioural phenotype,
25 000
self-injury and rapid eye movement (REM) sleep abnormalities.
Major gene seems to be RAI1
Genomics, health and disease • 45
[a~[ How structural chromosomal anomalies are described
Chromosome
9
Metacentric
Chromosome
14
(st)-!
-13 (sa) P
-Cen
—12
—21
—23
—24.2
—31
—32.2
Acrocentric
Reciprocal Robertsonian
translocation translocation
Inversions
N A
Deletions
Interstitial Terminal
N A N A
Duplications
Tandem Inverted
N A N A
i:=:
i
[b] Mechanism underlying recurrent deletions and duplication: non-allelic homologous recombination
Normal pairing
Abnormal pairing between DNA repeats
— DNA repeat
— Maternal chromosome
— Paternal chromosome
Fig. 3.7 Chromosomal analysis and structural chromosomal disorders. [A] Human chromosomes can be classed as metacentric if the centromere is
near the middle, or acrocentric if the centromere is at the end. The bands of each chromosome are given a number, starting at the centromere and
working out along the short (p) arm and long (q) arm. Translocations and inversions are balanced structural chromosome anomalies where no genetic
material is missing but it is in the wrong order. Translocations can be divided into reciprocal (direct swap of chromosomal material between non-
homologous chromosomes) and Robertsonian (fusion of acrocentric chromosomes). Deletions and duplications can also occur due to non-allelic
homologous recombination (illustrated in part B). Deletions are classified as interstitial if they lie within a chromosome, and terminal if the terminal region of
the chromosome is affected. Duplications can be either in tandem (where the duplicated fragment is inserted next to the region that is duplicated and
orientated in the correct direction) or inverted (where the duplicated fragment is in the wrong direction). (N = normal; A = abnormal) [§] A common error of
meiotic recombination, known as non-allelic homologous recombination, can occur (right panel), resulting in a deletion on one chromosome and a
duplication in the homologous chromosome. The error is induced by tandem repeats in the DNA sequences (green), which can misalign and bind to each
other, thereby ‘fooling’ the DNA into thinking the pairing prior to recombination is correct.
• Gain-of-function mutations result in a gain of protein
function. They are typically non-synonymous mutations
that alter the protein structure, leading to activation/
alteration of its normal function through causing either an
interaction with a novel substrate or a change in its normal
function.
• Dominant negative mutations are the result of non-
synonymous mutations or in-frame deletions/duplications
but may also, less frequently, be caused by triplet repeat
expansion mutations. Dominant negative mutations are
heterozygous changes that result in the production of an
abnormal protein that interferes with the normal functioning
of the wild-type protein.
Normal genomic variation
We each have 5-50 million variants in our genome, occurring
approximately every 300 bases. These variants are mostly
polymorphisms, arising in more than 1% of the population;
they have no or subtle effects on gene and cell function, and
are not associated with a high risk of disease. Polymorphisms
can occur within exons, introns or the intergenic regions that
comprise 98-99% of the human genome. Each of the classes of
genetic variant discussed on page 42 is present in the genome
as a common polymorphism. However, the most frequent is the
single nucleotide polymorphism, or SNP (pronounced ‘snip’),
describing the substitution of a single base.
Polymorphisms and common disease
The protective and detrimental polymorphisms associated
with common disease have been identified primarily through
genome-wide association studies (GWAS, p. 56) and are the
basis for many direct-to-consumer tests that purport to determine
individual risk profiles for common diseases or traits such as
cardiovascular disease, diabetes and even male-pattern baldness!
An example is the polymorphism in the gene SLC2A9 that not
only explains a significant proportion of the normal population
variation in serum urate concentration but also predisposes
‘high-risk’ allele carriers to the development of gout. However,
the current reality is that, until we have a more comprehensive
understanding of the full genomic landscape and knowledge of
the complete set of detrimental and protective polymorphisms,
we cannot accurately assess risk.
Evolutionary selection
Genetic variants play an important role in evolutionary selection,
with advantageous variants resulting in positive selection via
improved reproductive fitness, and variations that decrease
46 • CLINICAL GENETICS
reproductive fitness becoming excluded through evolution.
Given this simple paradigm, it would be tempting to assume that
common mutations are all advantageous and all rare mutations
are pathogenic. Unfortunately, it is often difficult to classify any
common mutation as either advantageous or deleterious - or,
indeed, neutral. Mutations that are advantageous in early life and
thus enhance reproductive fitness may be deleterious in later
life. There may be mutations that are advantageous for survival
in particular conditions (e.g. famine or pandemic) that may be
disadvantageous in more benign circumstances by causing a
predisposition to obesity or autoimmune disorders.
Constitutional genetic disease
Familial genetic disease is caused by constitutional mutations,
which are inherited through the germ line. However, different
mutations in the same gene can have different consequences,
depending on the genetic mechanism underlying that disease.
About 1 % of the human population carries constitutional mutations
that cause disease.
| Constructing a family tree
The family tree - or pedigree - is a fundamental tool of the
clinical geneticist, who will routinely take a three-generation family
history, on both sides of the family, enquiring about details of
all medical conditions in family members, consanguinity, dates
of birth and death, and any history of pregnancy loss or infant
death. The basic symbols and nomenclature used in drawing a
pedigree are shown in Figure 3.8.
| Patterns of disease inheritance
Autosomal dominant inheritance
Take some time to draw out the following pedigree:
Anne is referred to Clinical Genetics to discuss her personal
history of colon cancer (she was diagnosed at the age of 46 years)
and family history of colon/endometrial cancer: her mother was
diagnosed with endometrial cancer at the age of 60 years and
her cousin through her healthy maternal aunt was diagnosed
with colon cancer in her fifties. Both her maternal grandmother
and grandfather died of ‘old age’. There is no family history of
note on her father’s side of the family. He has one brother and
both his parents died of old age, in their eighties. Anne has two
healthy daughters, aged 1 2 and 1 4 years, and a healthy full sister.
This family history is typical of an autosomal dominant condition
(Fig. 3.8): in this case, a colon/endometrial cancer susceptibility
syndrome known as Lynch’s syndrome, associated with disruption
of one of the mismatch repair genes: MSH2, MSH6, MLH1 and
PMS2 (see p. 830 and Box 3.1 1 , p. 57).
0 Male
Female
Unknown sex
Deceased /x
individual /(y
(with age at death) ^ 50 y
Partners
Separated
Consanguinity
Monozygotic twins
Dizygotic twins
□ — O
7^
7\
(with gestation)
Miscarriage
(with gestation)
30Swk 39 wk
16 wk
Termination
Clinically affected ^ ^
Clinically affected, hi ^
several diagnoses HU
Carrier (#)
Positive pre- r~ r~i
symptomatic test LU
Dominant inheritance
2 3
HO*
3 —
fb • b
Transmission to 50% of offspring
independent of gender
X-linked recessive inheritance
Affected males related through
unaffected females
Recessive inheritance
I
IV
V
Consanguinity
Mitochondrial DNA disorder
Both sexes affected but only
inherited through female meiosis
Fig. 3.8 Drawing a pedigree and patterns of inheritance. [A] The main symbols used to represent pedigrees in diagrammatic form. [§] The main
modes of disease inheritance (see text for details).
Genomics, health and disease • 47
Features of an autosomal dominant pedigree include:
• There are affected individuals in each generation (unless
the mutation has arisen de novo, i.e. for the first time in an
affected individual). However, variable penetrance and
expressivity can influence the number of affected
individuals and the severity of disease in each generation.
Penetrance is defined as the proportion of individuals
bearing a mutated allele who develop the disease
phenotype. The mutation is said to be fully penetrant if all
individuals who inherit a mutation develop the disease.
Expressivity describes the level of severity of each aspect
of the disease phenotype.
• Males and females are usually affected in roughly equal
numbers (unless the clinical presentation of the condition
is gender-specific, such as an inherited susceptibility to
breast and/or ovarian cancer).
The offspring risk for an individual affected with an
autosomal dominant condition is 1 in 2 (or 50%). This offspring
risk is true for each pregnancy, since half the affected
individual gametes (sperm or egg cells) will contain the
affected chromosome/gene and half will contain the normal
chromosome/gene.
There is a long list of autosomal dominant conditions, some
of which are shown in Box 3.4.
3.4 Genetic conditions dealt with by clinicians in other specialties
Name of condition
Gene
Reference
Autosomal dominant conditions
Autosomal dominant polycystic kidney disease (ADPKD)
PKD1 (85%), PKD2 (1 5%)
p. 405
Box 15.28, p. 415
Tuberous sclerosis
TSC1
p. 1264
TSC2
p. 1264
Marfan’s syndrome
FBN1
p. 508
Long QT syndrome
KCNQ1
p. 476
Brugada’s syndrome
SCN5A
p. 477
Neurofibromatosis type 1
NF1
p. 1131
Box 25.77, p. 1132
Neurofibromatosis type 2
NF2
p. 1131
Box 25.77, p. 1132
Hereditary spherocytosis
ANK1
p. 947
Vascular Ehlers— Danlos syndrome (EDS type 4)
C0L3A1
p. 970
Hereditary haemorrhagic telangiectasia
ENG, ALK1, GDF2
p. 970
Osteogenesis imperfecta
C0L1A1, C0L1A2
p. 1055
Charcot— Marie— T ooth disease
PMP22, MPZ, GJB1
p. 1140
Hereditary neuropathy with liability to pressure palsies
PMP22
Autosomal recessive conditions
Familial Mediterranean fever
MEFV
p. 81
Mevalonic aciduria (mevalonate kinase deficiency)
MVK
p. 81
Autosomal recessive polycystic kidney disease (ARPKD)
PKHD1
Box 15.28, p. 415
Kartagener’s syndrome (primary ciliary dyskinesia)
DNAI1
Box 17.30, p. 578
Cystic fibrosis
CFTR1
p. 580
Box 17.30, p. 578
p. 842
Pendred’s syndrome
SLC26A4
p. 650
Congenital adrenal hyperplasia-21 hydroxylase deficiency
CYP21A
p. 676
Box 18.27, p. 658
Haemochromatosis
HFE
p. 895
Wilson’s disease
ATP7B
p. 896
Alph^ -antitrypsin deficiency
SERPINA1
p. 897
Gilbert’s syndrome
UGT1A1
p. 897
Benign recurrent intrahepatic cholestasis
ATP8B1
p. 902
Alpha-thalassaemia
HBA1 , HBA2
p. 951
p. 954
Beta-thalassaemia
HBB
p. 951
p. 953
Sickle cell disease
HBB
p. 951
Spinal muscular atrophy
SMN1
p. 1117
X-linked conditions
Alport’s syndrome
C0L4A5
Box 15.28, p. 415
p. 403
Primary agammaglobulinaemia
BTK
p. 78
Haemophilia A (factor VIII deficiency)
F8
p. 971
Haemophilia B (factor IX deficiency)
F9
p. 973
Duchenne muscular dystrophy
DMD
p. 1143 and
Box 25.91
48 • CLINICAL GENETICS
Autosomal recessive inheritance
As above, take some time to draw a pedigree representing
the following:
Mr and Mrs Kent, a non-consanguineous couple, are referred
because their son, Jamie, had severe neonatal liver disease.
Included among the many investigations that the paediatric
hepatologist undertook was testing for oq -antitrypsin deficiency
(Box 3.5). Jamie was shown to have the PiZZ phenotype. Testing
confirmed both parents as carriers with PiMZ phenotypes.
In the family, Jamie has an older sister who has no medical
problems. Mr Kent is one of four children with two brothers
and a sister and Mrs Kent has a younger brother. Both sets
of grandparents are alive and well. There is no family history of
a-i -antitrypsin deficiency.
This family history is characteristic of an autosomal recessive
disorder (Fig. 3.8), where both alleles of a gene must be mutated
before the disease is manifest in an individual; an affected
individual inherits one mutant allele from each of their parents,
who are therefore healthy carriers for the condition. An autosomal
recessive condition might be suspected in a family where:
• Males and females are affected in roughly equal
proportions.
• Parents are blood related; this is known as consanguinity.
Where there is consanguinity, the mutations are usually
homozygous, i.e. the same mutant allele is inherited from
both parents.
i
• Individuals within one sibship in one generation are
affected and so the condition can appear to have arisen
‘out of the blue’.
Approximately 1 in 4 children born to carriers of an autosomal
recessive condition will be affected. The offspring risk for carrier
parents is therefore 25% and the chances of an unaffected child,
with an affected sibling, being a carrier is 2/3.
Examples of some autosomal recessive conditions, discussed
elsewhere in this book, are shown in Box 3.4.
X-linked inheritance
The following is an exemplar of an X-linked recessive pedigree
(Fig. 3.8):
Edward has a diagnosis of Duchenne muscular dystrophy
(DMD, Box 3.6). His parents had suspected the diagnosis when
he was 3 years old because he was not yet walking and there
was a family history of DMD: Edward’s maternal uncle had been
affected and died at the age of 24 years. Edward’s mother has
no additional siblings. After Edward demonstrated a very high
creatinine kinase level, the paediatrician also requested genetic
testing, which identified a deletion of exons 2-8 of the dystrophin
gene. Edward has a younger, healthy sister and grandparents
on both sides of the family are well, although the maternal
grandmother has recently developed a cardiomyopathy. Edward’s
father has an older sister and an older brother who are both well.
Genetic diseases caused by mutations on the X chromosome
have specific characteristics:
• X-linked diseases are mostly recessive and restricted to
males who carry the mutant allele. This is because males
i
Inheritance pattern
• X-linked recessive
Genetic cause
• Mutations or deletions encompassing/within the DMD (dystrophin)
gene located at Xp21
Prevalence
• 1 in 3000-4000 live male births
Clinical presentation
• Delayed motor milestones
• Speech delay
• Grossly elevated creatine kinase (CK) levels (in the thousands)
• Ambulation is usually lost between the ages of 7 and 1 3 years
• Lifespan is reduced with a mean age of death, usually from
respiratory failure, in the mid-twenties
• Cardiomyopathy affects almost all boys with Duchenne muscular
dystrophy and some female carriers
Disease mechanism
• DMD encodes dystrophin, a major structural component of muscle
• Dystrophin links the internal cytoskeleton to the extracellular matrix
Disease variants
• Becker muscular dystrophy, although a separate disease, is also
caused by mutations in the dystrophin gene
• In Duchenne muscular dystrophy, there is no dystrophin protein,
whereas in Becker muscular dystrophy there is a reduction in the
amount or alteration in the size of the dystrophin protein
*See also page 1143.
Inheritance pattern
• Autosomal recessive
Genetic cause
• Two common mutations in the SERPINA1 gene: p.Glu342Lys and
p.Glu264Val
Prevalence
• 1 in 1500-3000 of European ancestry
Clinical presentation
• Variable presentation from neonatal period through to adulthood
• Neonatal period: prolonged jaundice with conjugated
hyperbilirubinaemia or (rarely) liver disease
• Adulthood: pulmonary emphysema and/or cirrhosis. Rarely, the skin
disease, panniculitis, develops
Disease mechanism
• SERPINA1 encodes -antitrypsin, which protects the body from the
effects of neutrophil elastase. The symptoms of a, -antitrypsin
deficiency result from the effects of this enzyme attacking normal
tissue
Disease variants
• M variant: if an individual has normal SERPINA1 genes and
produces normal levels of ocr -antitrypsin, they are said to have an
M variant
• S variant: p.Glu264Val mutation results in -antitrypsin levels
reduced to about 40% of normal
• Z variant: p.Glu342Lys mutation results in very little -antitrypsin
• PiZZ: individuals who are homozygous for the p.Glu342Lys mutation
are likely to have cx-i -antitrypsin deficiency and the associated
symptoms
• PiZS: individuals who are compound heterozygous for p.Glu342Lys
and p.Glu264Val are likely to be affected, especially if they smoke,
but usually to a milder degree
3.5 Alphai -antitrypsin deficiency
3.6 Duchenne muscular dystrophy
Genomics, health and disease • 49
have only one X chromosome, whereas females have
two (see Fig. 3.1). However, occasionally, female carriers
may exhibit signs of an X-linked disease due to a
phenomenon called skewed X-inactivation. All female
embryos, at about 1 00 cells in size, stably inactivate one
of their two X chromosomes in each cell. Where this
inactivation is random, approximately 50% of the cells will
express the genes from one X chromosome and 50% of
cells will express genes from the other. Where there is a
mutant gene, there is often skewing away from the
associated X chromosome, resulting in an unaffected
female carrier. However, if, by chance, there is a
disproportionate inactivation of the normal X chromosome
with skewing towards the mutant allele, then an affected
female carrier may be affected (albeit more mildly than
males).
• The gene can be transmitted from female carriers to their
sons: in families with an X-linked recessive condition, there
are often a number of affected males related through
unaffected females.
• Affected males cannot transmit the condition to their sons
(but all their daughters would be carriers).
The risk of a female carrier having an affected child is 25%
or half of her male offspring.
Mitochondrial inheritance
The mitochondrion is the main site of energy production
within the cell. Mitochondria arose during evolution via the
symbiotic association with an intracellular bacterium. They
have a distinctive structure with functionally distinct inner and
outer membranes. Mitochondria produce energy in the form
of adenosine triphosphate (ATP). ATP is mostly derived from
the metabolism of glucose and fat (Fig. 3.9). Glucose cannot
enter mitochondria directly but is first metabolised to pyruvate
via glycolysis. Pyruvate is then imported into the mitochondrion
and metabolised to acetyl -co-enzyme A (acetyl-CoA). Fatty acids
are transported into the mitochondria following conjugation
with carnitine and are sequentially catabolised by a process
called p-oxidation to produce acetyl-CoA. The acetyl-CoA
from both pyruvate and fatty acid oxidation is used in the
citric acid (Krebs) cycle - a series of enzymatic reactions that
produces C02, the reduced form of nicotinamide adenine
dinucleotide (NADH) and the reduced form of flavine adenine
dinucleotide (FADH2). Both NADH and FADH2 then donate
electrons to the respiratory chain. Here these elections are
transferred via a complex series of reactions, resulting in the
formation of a proton gradient across the inner mitochondrial
membrane. The gradient is used by an inner mitochondrial
membrane protein, ATP synthase, to produce ATP, which is
then transported to other parts of the cell. Dephosphorylation
of ATP is used to produce the energy required for many cellular
processes.
Each mitochondrion contains 2-10 copies of a 16-kilobase
(kB) double-stranded circular DNA molecule (mtRNA). This
mtDNA contains 13 protein-coding genes, all involved in the
respiratory chain, and the ncRNA genes required for protein
synthesis within the mitochondria (Fig. 3.9). The mutational
rate of mtDNA is relatively high due to the lack of protection by
chromatin. Several mtDNA diseases characterised by defects
in ATP production have been described. Mitochondria are most
numerous in cells with high metabolic demands, such as muscle,
retina and the basal ganglia, and these tissues tend to be the
ones most severely affected in mitochondrial diseases (Box 3.7).
There are many other mitochondrial diseases that are caused
by mutations in nuclear genes, which encode proteins that are
then imported into the mitochondrion and are critical for energy
production, e.g. most forms of Leigh’s syndrome (although
Leigh’s syndrome may also be caused by a mitochondrial
gene mutation).
The inheritance of mtDNA disorders is characterised by
transmission from females, but males and females generally
are equally affected (see Fig. 3.8). Unlike the other inheritance
patterns mentioned above, mitochondrial inheritance has nothing
to do with meiosis but reflects the fact that mitochondrial DNA
is transmitted by oocytes: sperm do not contribute mitochondria
to the zygote. Mitochondrial disorders tend to be variable in
penetrance and expressivity within families, and this is mostly
accounted for by the fact that only a proportion of multiple mtDNA
molecules within mitochondria contain the causal mutation (the
degree of mtDNA heteroplasmy).
Imprinting
Several chromosomal regions (loci) have been identified where
gene expression is inherited in a parent-of-origin-specific manner;
3.7 The structure of the respiratory chain complexes and the diseases associated with their dysfunction
Complex Enzyme
nDNA subunits
mtDNA subunits2 Diseases
1 NADH dehydrogenase
38
7
MELAS, MERRF bilateral striatal necrosis, LH0N, myopathy and
exercise intolerance, Parkinsonism, Leigh’s syndrome, exercise
myoglobinuria, leucodystrophy/myoclonic epilepsy
II Succinate dehydrogenase
4
0
Phaeochromocytoma, Leigh’s syndrome
III Cytochrome bCi complex
10
1
Parkinsonism/MELAS, cardiomyopathy, myopathy, exercise
myoglobinuria, Leigh’s syndrome
IV Cytochrome c oxidase
10
3
Sideroblastic anaemia, myoclonic ataxia, deafness, myopathy,
MELAS, MERRF mitochondrial encephalomyopathy, motor
neuron disease-like, exercise myoglobinuria, Leigh’s syndrome
V ATP synthase
14
2
Leigh’s syndrome, NARP, bilateral striatal necrosis
TDNA subunits. 2mtDNA subunits = number of different protein subunits in each complex that are encoded in the nDNA and mtDNA, respectively.
(ATP = adenosine triphosphate; LH0N = Leber hereditary optic neuropathy; MELAS = myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF =
myoclonic epilepsy and ragged red fibres; mtDNA = mitochondrial DNA; NADH = the reduced form of nicotinamide adenine dinucleotide; NARP = neuropathy, ataxia and
retinitis pigmentosa; nDNA = nuclear DNA)
50 • CLINICAL GENETICS
ffl
V\ strand
M 22 tRNAs
v stra/7<ySN
k □ NADH dehydrogenase 7
8k subunits
11 n Cytochrome B/C oxidase 4
■I subunits
mm □ 2 ribosomal RNA subunits
vj M2 ATP synthase subunits
M Intragenic DNA
Fig. 3.9 Mitochondria. [A] Mitochondrial structure. There is a smooth outer membrane surrounding a convoluted inner membrane, which has inward
projections called cristae. The membranes create two compartments: the inter-membrane compartment, which plays a crucial role in the electron
transport chain, and the inner compartment (or matrix), which contains mitochondrial DNA and the enzymes responsible for the citric acid (Krebs) cycle
and the fatty acid /3-oxidation cycle, jjff Mitochondrial DNA. The mitochondrion contains several copies of a circular double-stranded DNA molecule,
which has a non-coding region, and a coding region that encodes the genes responsible for energy production, mitochondrial transfer RNA (tRNA)
molecules and mitochondrial ribosomal RNA (rRNA) molecules. (ATP = adenosine triphosphate; NADH = the reduced form of nicotinamide adenine
dinucleotide) [C] Mitochondrial energy production. Fatty acids enter the mitochondrion conjugated to carnitine by carnitine-palmityl transferase type 1
(CPT I) and, once inside the matrix, are unconjugated by CPT II to release free fatty acids (FFA). These are broken down by the /3-oxidation cycle to
produce acetyl-co-enzyme A (acetyl-CoA). Pyruvate can enter the mitochondrion directly and is metabolised by pyruvate dehydrogenase (PDFI) to produce
acetyl-CoA. The acetyl-CoA enters the Krebs cycle, leading to the production of NADFI and flavine adenine dinucleotide (reduced form) (FADH2), which are
used by proteins in the electron transport chain to generate a hydrogen ion gradient across the inter-membrane compartment. Reduction of NADFI and
FADH2 by proteins I and II, respectively, releases electrons (e), and the energy released is used to pump protons into the inter-membrane compartment.
Coenzyme Q10/ubiquinone (Q) is an intensely hydrophobic electron carrier that is mobile within the inner membrane. As electrons are exchanged between
proteins in the chain, more protons are pumped across the membrane, until the electrons reach complex IV (cytochrome oxidase), which uses the energy
to reduce oxygen to water. The hydrogen ion gradient is used to produce ATP by the enzyme ATP synthase, which consists of a proton channel and
catalytic sites for the synthesis of ATP from ADP. When the channel opens, hydrogen ions enter the matrix down the concentration gradient, and energy is
released that is used to make ATP.
these are called imprinted loci. Within these loci the paternally
inherited gene may be active while the maternally inherited may
be silenced, or vice versa. Mutations within imprinted loci lead
to an unusual pattern of inheritance where the phenotype is
manifest only if inherited from the parent who contributes the
transcriptionally active allele. Examples of imprinting disorders
are given in Box 3.8.
Somatic genetic disease
Somatic mutations are not inherited but instead occur during
post-zygotic mitotic cell divisions at any point from embryonic
development to late adult life. An example of this phenomenon
is polyostotic fibrous dysplasia (McCune-Albright syndrome), in
Interrogating the genome: the changing landscape of genomic technologies • 51
3.8 Imprinting disorders
Disorder
Locus
Genes
Notes
Beckwith-Wiedemann
syndrome
11 pi 5
CDKN1C, IGF2,
H19
Increased growth, macroglossia, hemihypertrophy, abdominal wall defects, ear
lobe pits/creases and increased susceptibility to developing childhood tumours
Prader-Willi syndrome
1 5q1 1 — ql 3
SNRPN, Necdin
and others
Obesity, hypogonadism and learning disability. Lack of paternal contribution (due
to deletion of paternal 1 5q1 1— ql 3, or inheritance of both chromosome
1 5q1 1— ql 3 regions from the mother)
Angelman’s syndrome (AS)
1 5q1 1 — ql 3
UBE3A
Severe mental retardation, ataxia, epilepsy and inappropriate laughing bouts. Due
to loss-of-function mutations in the maternal UBE3A gene. The neurological
phenotype results because most tissues express both maternal and paternal
alleles of UBE3A, whereas the brain expresses predominantly the maternal allele
Pseudohypoparathyroidism
(p. 664)
20q13
GNAS1
Inheritance of the mutation from the mother results in hypocalcaemia,
hyperphosphataemia, raised parathyroid hormone (PTH) levels, ectopic
calcification, obesity, delayed puberty and shortened 4th and 5th metacarpals
(the syndrome known as Albright’s hereditary osteodystrophy, AHO). When the
mutation is inherited from the father, PTH, calcium and phosphate levels are
normal but the other features are present (pseudopseudohypoparathyroidism,
p. 664). These differences are due to the fact that, in the kidney (the main target
organ through which PTH regulates serum calcium and phosphate), the paternal
allele is silenced and the maternal allele is expressed, whereas both alleles are
expressed in other tissues.
which a somatic mutation in the Gs alpha gene causes constitutive
activation of downstream signalling, resulting in focal lesions in
the skeleton and endocrine dysfunction (p. 1055).
The most important example of human disease caused by
somatic mutations is cancer (see Ch. 33). Here, ‘driver’ mutations
occur within genes that are involved in regulating cell division or
apoptosis, resulting in abnormal cell growth and tumour formation.
The two general categories of cancer-causing mutation are
gain-of-function mutations in growth-promoting genes (oncogenes)
and loss-of-function mutations in growth-suppressing genes
(tumour suppressor genes). Whichever mechanism is acting,
most tumours require an initiating mutation in a single cell that
can then escape from normal growth controls. This cell replicates
more frequently or fails to undergo programmed death, resulting
in clonal expansion. As the size of the clone increases, one or
more cells may acquire additional mutations that confer a further
growth advantage, leading to proliferation of these subclones,
which may ultimately result in aggressive metastatic cancer.
The cell’s complex self-regulating machinery means that more
than one mutation is usually required to produce a malignant
tumour (see Fig. 33.3, p. 1318). For example, if a mutation
results in activation of a growth factor gene or receptor, then
that cell will replicate more frequently as a result of autocrine
stimulation. However, this mutant cell will still be subject to
normal cell-cycle checkpoints to promote DNA integrity in its
progeny. If additional mutations in the same cell result in defective
cell-cycle checkpoints, however, it will rapidly accumulate further
mutations, which may allow completely unregulated growth and/
or separation from its matrix and cellular attachments and/or
resistance to apoptosis. As cell growth becomes increasingly
dysregulated, cells de-differentiate, lose their response to normal
tissue environment and cease to ensure appropriate mitotic
chromosomal segregation. These processes combine to generate
the classical malignant characteristics of disorganised growth,
variable levels of differentiation, and numerical and structural
chromosome abnormalities. An increase in somatic mutation rate
can occur on exposure to external mutagens, such as ultraviolet
light or cigarette smoke, or if the cell has defects in DNA repair
systems. Cancer is thus a disease that affects the fundamental
processes of molecular and cell biology.
Interrogating the genome: the changing
landscape of genomic technologies
Looking at chromosomes
The analysis of metaphase chromosomes by light microscopy
was the mainstay of clinical cytogenetic analysis for decades,
the aim being to detect gain or loss of whole chromosomes
(aneuploidy) or large chromosomal segments (>4 million bp).
More recently, genome-wide microarrays (array comparative
genomic hybridisation or array CGH) have replaced chromosome
analysis, allowing rapid and precise detection of segmental
gain or loss of DNA throughout the genome (see Box 3.3).
Microarrays consist of grids of multiple wells containing short
DNA sequences (reference DNA) that are complementary to
known sequences in the genome. Patient and reference DNA are
each labelled with a coloured fluorescent dye (generally, patient
DNA is labelled with a green fluorescent dye and reference DNA
with a red fluorescent dye) and added to the microarray grid.
Where there is an equal quantity of patient and reference DNA
bound to the spot, this results in yellow fluorescence. Where
there is too much patient DNA (representing a duplication of a
chromosome region), the spot will be greener; it will be more red
(appears orange) where there is 2 : 1 ratio of the control: patient
DNA (representing heterozygous deletion of a chromosome
region; Fig. 3.10).
Array CGH and other array-based approaches can detect
small chromosomal deletions and duplications. They are also
generally more sensitive than conventional karyotyping at detecting
mosaicism (where there are two or more populations of cells,
derived from a single fertilised egg, with different genotypes).
52 • CLINICAL GENETICS
CGH
Patient
DNA
Normal control
DNA
Apply DNA mix to
glass slide with
high-density array
of different DNA -
probes with known
location in the
human genome
Patient/control
ratio = 0.5:1
-> deletion of
patient DNA
Patient/control
ratio = 1 .5:1
-» duplication
of patient DNA
Patient/control
ratio = 1 :1
-» normal
Fig. 3.10 Detection of chromosome abnormalities by comparative genomic hybridisation (CGH). Deletions and duplications are detected by looking
for deviation from the 1 : 1 ratio of patient and control DNA in a microarray. Ratios in excess of 1 indicate duplications, whereas ratios below 1 indicate
deletions.
However, array-based approaches will not detect balanced
chromosome rearrangements where there is no loss or gain
of genes/chromosome material, such as balanced reciprocal
translocations, or a global increase in copy number, such as
triploidy.
The widespread use of array-based approaches has brought
a number of challenges for clinical interpretation, including the
identification of copy number variants (CNVs) of uncertain clinical
significance, CNVs of variable penetrance and incidental findings.
A CNV of uncertain clinical significance describes a loss or gain
of chromosome material where there are insufficient data to
conclude whether or not it is associated with a learning disability
and/or medical problems. While this uncertainty can be difficult
to prepare families for and can be associated with considerable
anxiety, it is likely that there will be greater clarity in the future
as we generate larger CNV datasets.
A CNV of variable penetrance, also known as a
neurosusceptibility locus, describes a chromosome deletion or
duplication associated with a lower threshold for manifesting a
learning disability or autistic spectrum disorder. CNVs of variable
penetrance are therefore identified at greater frequencies among
individuals with a learning disability and/or autistic spectrum
disorder than in the general population. The current understanding
is that additional modifying factors (genetic, environmental or
stochastic) must influence the phenotypic expression of these
neurosusceptibility loci.
Finally, an incidental CNV finding describes a deletion or
duplication encompassing a gene or genes that are causative
of a phenotype or risk unrelated to the presenting complaint.
For instance, if, through the array CGH investigation for an
intellectual disability, a deletion encompassing the BRCA1 gene
were identified, this would be considered an incidental finding.
Looking at genes
BGene amplification: polymerase
chain reaction
The polymerase chain reaction (PCR) is a fundamental laboratory
technique that amplifies targeted sections of the human genome
for further analyses - most commonly, DNA sequencing. The
method utilises thermal cycling: repeated cycles of heating and
cooling allow the initial separation of double-stranded DNA into
two single strands (known as denaturation), each of which serves
as a template during the subsequent replication step, guided by
primers designed to anneal to a specific genomic region. This
cycle of heating/cooling and denatu ration/replication is repeated
many times, resulting in the exponential amplification of DNA
between primer sites (Fig. 3.11).
Gene sequencing
In the mid-1970s, a scientist called Fred Sanger pioneered a DNA
sequencing technique (‘Sanger sequencing’) that determined the
precise order and nucleotide type (thymine, cytosine, adenine
and guanine) in a molecule of DNA. Modern Sanger sequencing
uses fluorescently labelled, chain-terminating nucleotides that
are sequentially incorporated into the newly synthesised DNA,
generating multiple DNA chains of differing lengths. These DNA
chains are subject to capillary electrophoresis, which separates
them by size, allowing the fragments to be ‘read’ by a laser and
producing a sequence chromatogram that corresponds to the
target sequence (Fig. 3.12). Although transformative, Sanger
sequencing was difficult and costly to scale, as exemplified by
the Human Genome Project, which took 12 years to sequence
the entire human genome at a cost approaching 3 billion dollars.
Recently, DNA sequencing has been transformed again by a
group of technologies collectively known as ‘next-generation
sequencing’ (NGS; Fig. 3.13). This refers to a family of post-
Sanger sequencing technologies that utilise the same five basic
principles:
• Library preparation: DNA samples are fragmented (by
enzyme cleavage or ultrasound) and then modified with a
custom adapter sequence.
• Amplification : the library fragment is amplified to produce
DNA clusters, each originating from a single DNA
fragment. Each cluster will act as a single sequencing
reaction.
• Capture: if an entire genome is being sequenced, this step
will not be included. The capture step is required if
targeted resequencing is necessary, such as for a panel
gene test or an exome (Box 3.9).
• Sequencing: each DNA cluster is simultaneously
sequenced and the data from each captured; this is
known as a ‘read’ and is usually between 50 and
300 bases long sequenced (see Box 3.10 for a detailed
description of the three most commonly used sequencing
methods: synthesis, ligation and ion semiconductor
sequencing).
• Alignment and variant identification: specialised software
analyses read sequences and compares the data to a
reference template. This is known as ‘alignment’ or
‘mapping’ and, although there are 3 billion bases in the
Interrogating the genome: the changing landscape of genomic technologies • 53
Cycle
no. 1
Cycle
no. 2
DNA _ .
D . sample Po|y™r[?se
Primers . + dNTPs
\l/
1
Heat 95°C
DNA strands
separate
Primers bind
to DNA
DNA
replicated
t
Cool ~60°C
1'
Heat ~72°C
1
Heat 95°C
DNA strands
separate
Cool ~60°C
Primers
bind to
DNA
DNA
replicated
PCR cycles
Exponential amplification
of DNA between primer sites
Fig. 3.11 The polymerase chain reaction (PCR). PCR involves adding a
tiny amount of the patient’s DNA to a reaction containing primers (short
oligonucleotides 18-21 bp in length, which bind to the DNA flanking the
region of interest) and deoxynucleotide phosphates (dATP, dCTP, dGTP,
dTTP), which are used to synthesise new DNA and a heat-stable
polymerase. The reaction mix is first heated to 95°C, which causes the
double-stranded DNA molecules to separate. The reaction is then cooled to
50-60°C, which allows the primers to bind to the target DNA. The reaction
is then heated to 72°C, at which point the polymerase starts making new
DNA strands. These cycles are repeated 20-30 times, resulting in
exponential amplification of the DNA fragment between the primer sites.
The resulting PCR products can then be used for further analysis - most
commonly, DNA sequencing (see Fig. 3.12).
human genome, allows the remarkably accurate
determination of the genomic origin where a read consists
of 25 nucleotides or more. Variants are identified as
differences between the read and the reference genome.
For instance, if there is a different nucleotide in half the
reads at a given position compared to the reference
genome, this is likely to represent a heterozygous base
substitution. The number of reads that align at a given
point is called the ‘depth’ or ‘coverage’. The higher the
read depth, the more accurate the variant call. However,
in general, a depth of 30 or more reads is generally
accepted as producing diagnostic-grade results.
Rather than sequencing only one small section of DNA at a
time, NGS allows the analysis of many hundreds of thousands
of DNA strands in a single experiment and so is also commonly
referred to as multiple parallel sequencing technology. Today’s
NGS machines can sequence the entire human genome in a
single day at a cost approaching 1 000 US dollars.
NGS capture
Although we now have the capability to sequence the entire
genome in a single experiment, whole-genome sequencing
is not always the optimal use of NGS. NGS capture refers to
the ‘pull-down’ of a targeted region of the genome and may
constitute several to several hundred genes associated with a
given phenotype (a gene panel), the exons of all known coding
genes (an exome), or the exons of all coding genes known to
be associated with disease (a clinical exome). Each of these
targeted resequencing approaches is associated with a number
of advantages and disadvantages (see Box 3.9). In order for
NGS to be used for optimal patient benefit, it is essential for the
clinician to have a good understanding of which test is the best
one to request in any given clinical presentation.
Challenges of NGS technologies
Genomic technologies have the potential to transform the way
that we practise medicine, and ever faster and cheaper DNA
sequencing offers increasing opportunities to prevent, diagnose
and treat disease. However, genomic technologies are not without
their challenges: for instance, storing the enormous quantities
of data generated by NGS. While the A, C, T and G of our
genomic code could be stored on the memory of a smartphone,
huge computers, able to store several petabytes of data (where
1 petabyte is 1 million gigabytes of data), are required to store
the information needed to generate each individual’s genome.
Even if we can store and handle these huge datasets
successfully, we then need to be able to sift through the millions of
54 • CLINICAL GENETICS
New DNA molecules terminated by
incorporation of ddNTP
DNA _ .
p . sample Po&?,se
Primers . + ddNTPs
Key
O ddATP
OddGTP
OddCTP
OddTTP
\1/
PCR
ATATGCGCAG
IaaaaaaaaaaI
DNA sequence chromatogram
Qo — Qo o
. . .ATATGCGCAG . ATATGCGCAG. . .
Qo Qo Q
. . .ATATGCGCAG . ATATGCGCAG. . .
Largest fragments
migrate slowest
■ 1
Smallest fastest
(Capillary
electrophoresis
Fragments detected by laser fluorescence
Fig. 3.12 Sanger sequencing of DNA, which is very widely used in DNA diagnostics. This is performed using PCR-amplified fragments of DNA
corresponding to the gene of interest. The sequencing reaction is carried out with a combination dNTP and fluorescently labelled di-deoxy-dNTP (ddATP,
ddTTP, ddCTP and ddGTP), which become incorporated into the newly synthesised DNA, causing termination of the chain at that point. The reaction
products are then subject to capillary electrophoresis and the different-sized fragments are detected by a laser, producing a sequence chromatogram that
corresponds to the target DNA sequence.
3.9 The advantages and disadvantages of whole-genome sequencing, whole-exome sequencing and gene panels
Test
Advantages
Disadvantages
Whole-genome
sequencing (WGS)
The most comprehensive analysis of the genome available
More even coverage of genes, allowing better identification
of dosage abnormalities
Will potentially detect all gene mutations, including intronic
mutations
More expensive to generate and store
Will detect millions of variants in non-coding DNA, which can
be very difficult to interpret
Associated with a greater risk of identifying incidental findings
Shallow sequencing (few reads per gene) and so less sensitive
and less able to detect mosaicism
Whole-exome
sequencing (WES)
Cheaper than whole-genome sequencing
Analysis is not restricted to only those genes known to
cause a given condition
Fewer variants detected than in WGS and so easier
interpretation
Deeper sequencing than WGS increases sensitivity and
detection of mosaicism
Less even coverage of the genome and so dosage
abnormalities are more difficult to detect
Less comprehensive analysis (1-2% of the genome) than WGS
Increased risk of identifying incidental findings over targeted
gene sequencing
Gene panels
Cost-effective
Very deep sequencing, increasing the chances of mosaicism
being detected
Fewer variants detected and so data easier to interpret
As analysis is restricted to known genes, the likelihood of a
variant being pathogenic is greatly increased
Will only detect variation in genes known to cause a given
condition
Difficult to add new genes to the panel as they are discovered
normal variants to identity the single (or, rarely, several) pathogenic,
disease-causing mutation. While this can, to an extent, be
achieved through the application of complex algorithms, these take
time and considerable expertise to develop and are not infallible.
Furthermore, even after these data have been sifted by
bioinformaticians, it is highly likely that clinicians will be left with
some variants for which there are insufficient data to enable their
definitive categorisation as either pathogenic or non-pathogenic.
This may be because we simply do not know enough about
the gene, because the particular variant has not previously been
reported and/or it is identified in an unaffected parent. These
variants must be interpreted with caution and, more usually,
their interpretation will require input from a genetics expert in
the context of the clinical presentation, where an ‘innocent until
proven guilty’ approach is often adopted.
Finally, if we are to interrogate the entire genome or even the
exome, it is foreseeable that we will routinely identify ‘incidental’
or secondary findings - in other words, findings not related to
the initial diagnostic question. The UK has so far advocated a
conservative approach to incidental findings.
Uses of NGS
NGS is now frequently used, within diagnostic laboratories, to
identify base substitutions and indels (although the latter were
Interrogating the genome: the changing landscape of genomic technologies • 55
1 Library preparation
Genomic DNA
Fragmentation
Adapter ligation
2 Cluster amplification
Flow cell
4 Alignment and variant interpretation
Reference genome
Reads-
CCGATATCTAGCTTA
ATATCTAGC
CGATAGC
TATCTAGC
CCGATAGCTAGCTTA
Fig. 3.13 Sequencing by synthesis as used in the lllumina system.
(1) Library preparation: DNA is fragmented and specialist adapters are
ligated to the fragmented ends. (2) Cluster amplification: the library is
loaded to a flow cell and the adapters hybridise to the flow-cell surface.
Each bound fragment is hybridised. (3) Sequencing. (4) Alignment and
variant interpretation: reads are aligned to a reference sequence using
complex software and differences between reference and case genomes
are identified.
initially problematic). The current NGS challenge is to detect
large deletions or duplications spanning several hundreds or
thousands of bases and therefore exceeding any single read.
Increasingly, however, this dosage analysis is being achieved
using sophisticated computational methods, negating the
need for more traditional technologies such as array CGH.
Additional potential uses of NGS include detection of balanced
and unbalanced translocations and mosaicism: NGS has
proved remarkably sensitive at detecting the latter when there
is high read coverage for a given region. Of note, however,
3.10 Next-generation sequencing methods
Sequencing by synthesis (Fig. 3.13)
• The most frequently used NGS method
• Used in lllumina systems (commonly used in diagnostic laboratories)
• Uses fluorescently labelled, terminator nucleotides that are
sequentially incorporated into a growing DNA chain
• Library DNA samples (fragmented DNA flanked by DNA adapter
sequences) are anchored to a flow cell by hybridisation of the DNA
adapter sequence to probes on the flow-cell surface
• Amplification occurs by washing the flow cell in a mixture
containing all four fluorescently labelled terminator nucleotides: A,
C, T and G
• Once the nucleotide, complementary to the first base of the DNA
template, is incorporated, no further nucleotides can be added until
the mixture is washed away
• The nucleotide terminator is shed and the newly incorporated
nucleotide reverts to a regular, non-fluorescent nucleotide that can
be extended
• The process is then repeated with the incorporation of a second
base etc.
• Sequencing by synthesis is therefore space- and time-dependent: a
sensor will detect the order of fluorescent emissions for each spot
on the plate (representing the cluster) and determine the sequence
for that read
Sequencing by ligation
• Used in SOUD systems
• Uses DNA ligase rather than DNA polymerase (as is used in
sequencing by synthesis) and short oligonucleotides (as opposed to
single nucleotides)
• Library DNA samples are washed in a mixture containing
oligonucleotide probes representing 4-16 dinucleotide sequences.
Only one nucleotide in the probe is fluorescently labelled
• The complementary oligo probes will hybridise, using DNA ligase, to
the target sequence, initially at a primer annealed to the anchor site
and then progressively along the DNA strand
• After incorporation of each probe, fluorescence is measured and the
dye is cleaved off
• Eventually, a new strand is synthesised (composed of a series of
the oligo probes)
• A new strand is then synthesised but is offset by one nucleotide
• The process is repeated a number of times (5 rounds in the SOUD
system), providing overlapping templates that are analysed and a
composite of the target sequence determined
Ion semiconductor sequencing
• When a nucleotide is incorporated into a growing DNA strand, a
hydrogen ion is released that can be detected by an alteration in
the pH of the solution. This hydrogen ion release forms the basis of
ion semiconductor sequencing
• Each amplified DNA cluster is located above a semiconductor
transistor, capable of detecting differences in the pH of the solution
• The DNA cluster is washed in a mixture containing only one type of
nucleotide
• If the correct nucleotide, complementary to the next base on the
DNA template, is in the mixture and incorporated, a hydrogen ion is
released and detected
• If a homopolymer (sequence of two or more identical nucleotides) is
present, this will be detected as a decrease in pH proportionate to
the number of identical nucleotides in the sequence
NGS is still not able to interrogate the epigenome (and so will
not identify conditions caused by a disruption of imprinting,
such as Beckwith-Wiedemann, Silver-Russell, Angelman’s
and Prader-Willi syndromes) and will not detect triplet repeat
expansions such as those that cause Huntington’s disease,
56 • CLINICAL GENETICS
myotonic dystrophy and fragile X syndrome (see Boxes 3.8
and 3.2).
Third-generation sequencing
Increasingly, third-generation or single-molecule sequencing is
entering the diagnostic arena. As with next- or second-generation
sequencing, a number of different platforms are commercially
available. One of the most successful is SMRT technology
(single-molecule sequencing in real time), developed by Pacific
Biosciences. This system utilises a single-stranded DNA molecule
(as compared to the amplified clusters used in NGS), which acts
as a template for the sequential incorporation, using a polymerase,
of fluorescently labelled nucleotides. As each complementary
nucleotide is added, the fluorescence (and therefore the identity
of the nucleotide) is recorded before it is removed and another
nucleotide is added.
A key advantage of third-generation sequencing is the long
length of the read it generates: in the region of 1 0-1 5 kilobases.
It is also cheaper than NGS, as fewer reagents are required.
Given these inherent advantages, third-generation sequencing is
likely to supersede NGS in the near future. Given the confusion
surrounding the terminology of NGS and third-generation
sequencing, these technologies are increasingly referred to as
‘massively parallel sequencing’.
Genomics and clinical practice
Genomics and health care
I Genomics in rare
neurodevelopmental disorders
Although, by definition, the diagnosis of a rare disorder is made
infrequently, rare diseases, when considered together, affect
about 3 million people in the UK, the majority of whom are
children. NGS has transformed the ability to diagnose individuals
affected by a rare disease. Whereas previously, when we were
restricted to the sequential analysis of single genes, a clinician
would need to make a clinical diagnosis in order to target
testing, NGS allows the interrogation of multiple genes in a
single experiment. This might be done through a gene panel, a
clinical exome or an exome (see Box 3.9 and p. 53), and has
increased the diagnostic yield in neurodevelopmental disorders
to approximately 30%. Not only does the identification of the
genetic cause of a rare disorder potentially provide families with
answers, prognostic information and the opportunity to meet
and derive support from other affected families but also it can
provide valuable information for those couples planning further
children and wishing to consider prenatal testing in the future.
Genomics and common disease
Most common disorders are determined by interactions between
a number of genes and the environment. In this situation, the
genetic contribution to disease is termed polygenic. Until recently,
very little progress had been made in identifying the genetic
variants that predispose to common disorders, but this has been
changed by the advent of genome-wide association studies. A
GWAS typically involves genotyping many (> 500000) genetic
markers (SNPs) spread across the genome in a large group of
individuals with the disease and in controls. By comparing the
SNP genotypes in cases and controls, it is possible to identify
regions of the genome, and therefore genes, more strongly
associated with a given SNP profile and therefore more likely
to contribute to the disease under study.
Genomics and obstetrics
Prenatal genetic testing may be performed where a pregnancy
is considered at increased risk of being affected with a genetic
condition, either because of the ultrasound/biochemical screening
results or because of the family history. While invasive tests,
such as amniocentesis and chorionic villus sampling, have been
the mainstay of prenatal diagnosis for many years, they are
increasingly being superseded by non-invasive testing of cell-free
fetal DNA (cffDNA), originating from placental trophoblasts and
detectable in the maternal circulation from 4-5 weeks’ gestation;
it is present in sufficient quantities for testing by 9 weeks.
• Non-invasive prenatal testing (NIPT): the sequencing and
quantification, using NGS, of cffDNA chromosome-specific
DNA sequences to identify trisomy 13, 18 or 21 . The
accuracy of NIPT in detecting pregnancy-specific
aneuploidy approaches 98%. A false-negative result can
occur when there is too little cffDNA (possibly due to early
gestation or high maternal body mass index) or when
aneuploidy has arisen later in development and is confined
to the embryo and not represented in the placenta. False
positives can occur with confined placental mosaicism
(describing aneuploidy in the placenta, not the fetus) or
with an alternative cause of aneuploidy in the maternal
circulation, such a cell-free tumour DNA.
• Non-invasive prenatal diagnosis (NIPD): the identification of
a fetal single-gene defect that either has been paternally
inherited or has arisen de novo and so is not identifiable in
the maternal genome. Examples of conditions that are
currently amenable to NIPD include achondroplasia and the
craniosynostoses. Increasingly, however, NIPD is being
used for autosomal recessive conditions such as cystic
fibrosis, where parents are carriers for different mutations.
The free fetal DNA is tested to see whether the paternal
mutation is identified and, if absent, the fetus is not affected.
If the paternal mutation is identified, however, a definitive
invasive test is required to determine whether the maternal
mutation has also been inherited and the fetus is affected.
Where a genetic diagnosis is known in a family, a couple
may opt to undertake pre-implantation genetic diagnosis (PGD).
PGD is used as an adjunct to in vitro fertilisation and involves
the genetic testing of a single cell from a developing embryo,
prior to implantation.
^Genomics and oncology
Until recently, individuals were stratified to genetic testing if they
presented with a personal and/or family history suggestive of an
inherited cancer predisposition syndrome (Box 3.11). Relevant
clinical information included the age of cancer diagnosis and
number/type of tumours. For example, the diagnosis of bilateral
breast cancer in a woman in her thirties with a mother who had
ovarian cancer in her forties is suggestive of £F?G47/2-associated
familial breast/ovarian cancer. In many familial cancer syndromes,
somatic mutations act together with an inherited mutation to cause
specific cancers (p. 50). Familial cancer syndromes may be due
to germ-line loss-of-function mutations in tumour suppressor
genes encoding DNA repair enzymes or proto-oncogenes.
At the cellular level, loss of one copy of a tumour suppressor
Genomics and clinical practice • 57
i
3.11 Inherited cancer predisposition syndromes
Syndrome name
Gene
Associated cancers
Additional clinical features
Birt-Hogg-Dube syndrome
FLCN
Renal tumour (oncocytoma, chromophobe (and
mixed), renal cell carcinoma)
Fibrofolliculoma
Trichodiscoma
Pulmonary cysts
Breast/ovarian hereditary
BRCA1
Breast carcinoma
susceptibility
BRCA2
Ovarian carcinoma
Pancreatic carcinoma
Prostate carcinoma
Cowden’s syndrome
PTEN
Breast carcinoma
Thyroid carcinoma
Endometrial carcinoma
Macrocephaly
Intellectual disability/autistic spectrum disorder
Trichilemmoma
Acral keratosis
Papillomatous papule
Thyroid cyst
Lipoma
Haemangioma
intestinal hamartoma
Gorlin’s syndrome/basal
PTCH1
Basal cell carcinoma
Odontogenic keratocyst
cell naevus syndrome
Medulloblastoma
Palmar or plantar pits
Falx calcification
Rib abnormalities (e.g. bifid, fused or missing
ribs)
Macrocephaly
Cleft lip/palate
Li-Fraumeni syndrome
TP53
Sarcoma (e.g. osteosarcoma, chondrosarcoma,
rhabdomyosarcoma)
Breast carcinoma
Brain cancer (esp. glioblastoma)
Adrenocortical carcinoma
Brain
Lynch’s syndrome/
MLH1
Colorectal carcinoma (majority right-sided)
hereditary non-polyposis
MSH2
Endometrial carcinoma
colon cancer
MSH6
PMS2
Gastric carcinoma
Cholangiocarcinoma
Ovarian carcinoma (esp. mucinous)
Multiple endocrine
MEN1
Parathyroid tumour
Lipoma
neoplasia 1
Endocrine pancreatic tumour
Anterior pituitary tumour
Facial angiofibroma
Multiple endocrine
neoplasia 2 and 3 (also
known as 2a and 2b,
respectively)
RET
Medullary thyroid tumour
Phaeochromocytoma
Parathyroid tumour
Polyposis, familial
APC
Colorectal adenocarcinoma (FAP is characterised
Desmoid tumour
adenomatous (FAP)
by thousands of polyps from the second decade;
without colectomy, malignant transformation of
at least one of these polyps is inevitable)
Duodenal carcinoma
Hepatoblastoma
Congenital hypertrophy of the retinal pigment
epithelium (CHRPE)
Polyposis, MYH-associated
MYH(MUTYH)
Colorectal adenocarcinoma
Duodenal adenocarcinoma
Retinoblastoma, familial
RBI
Retinoblastoma
Osteosarcoma
gene does not have any functional consequences, as the cell
is protected by the remaining normal copy. However, a somatic
mutation affecting the normal allele is likely to occur in one cell
at some point during life, resulting in complete loss of tumour
suppressor activity and a tumour developing by clonal expansion
of that cell. This two-hit mechanism (one inherited, one somatic)
for cancer development is known as the Knudson hypothesis.
It explains why tumours may not develop for many years (or
ever) in some members of these cancer-prone families. In DNA
repair diseases, the inherited mutations increase the somatic
mutation rate. Autosomal dominant mutations in genes encoding
components of specific DNA repair systems are relatively common
causes of familial colon cancer and breast cancer (e.g. BRCA1).
Increasingly, genetics is moving into the mainstream, becoming
integrated into routine oncological care as new gene-specific
treatments are introduced. Testing for a genetic predisposition
58 • CLINICAL GENETICS
to cancer is therefore moving from the domain of clinical
genetics, where it has informed diagnosis, cascade treatment
and screening/prophylactic management, to oncology, where it
is informing the immediate management of the patient following
cancer diagnosis. This is exemplified by BRCA1 and BRCA2
(BRCA1 /2)-related breast cancer. Previously, women with a
mutation in either the BRCA1 or BRCA2 gene would have received
similar first-line chemotherapy to women with a sporadic breast
cancer without a known genetic association. More recently,
it has been shown that BRCA1/2 mutation-positive tumours
are sensitive to poly ADP ribose polymerase (PARP) inhibitors.
PARP inhibitors block the single-strand break-repair pathway.
In a BRCA1/2 mutation-positive tumour - with compromised
double-strand break repair - the additional loss of the single¬
strand break-repair pathway will drive the cell towards apoptosis.
Indeed, PARP inhibitors have been shown to be so effective
at destroying BRCA1/2 mutation-positive tumour cells, and
with such minimal side-effects, that BRCA1/2 gene testing is
increasingly determining patient management. It is likely, with a
growing understanding of the genomic architecture of tumours,
increasing accessibility of NGS and an expanding portfolio of
gene-directed therapies, that testing for many of the other
inherited cancer susceptibility genes will, in time, move into
the mainstream.
Genomics in infectious disease
NGS technologies are also transforming infectious disease. Given
that a microbial genome can be sequenced within a single day
at a current cost of less than 100 US dollars, microbiologists are
able to identify a causative microorganism and target effective
treatment rapidly and accurately. Moreover, microbial genome
sequencing enables the effective surveillance of infections to
reduce and prevent transmission. Finally, an understanding of
the microbial genome will drive the development of vaccines
and antibiotics, essential in an era characterised by increasing
microbial resistance to established antibiotic agents.
Treatment of genetic disease
Pharmacogenomics
Pharmacogenomics is the science of dissecting the genetic
determinants of drug kinetics and effects using information
from the human genome. For more than 50 years, it has been
appreciated that polymorphic mutations within genes can affect
individual responses to some drugs, such as loss-of-function
mutations in CYP2D6 that cause hypersensitivity to debrisoquine,
an adrenergic-blocking medication formerly used for the treatment
of hypertension, in 3% of the population. This gene is part of a
large family of highly polymorphic genes encoding cytochrome
P450 proteins, mostly expressed in the liver, which determine
the metabolism of a host of specific drugs. Polymorphisms in the
CYP2D6 gene also determine codeine activation, while those in
the CYP2C9 gene affect warfarin inactivation. Polymorphisms in
these and other drug metabolic genes determine the persistence
of drugs and, therefore, should provide information about dosages
and toxicity. With the increasing use of NGS, genetic testing for
assessment of drug response is seldom employed routinely,
but in the future it may be possible to predict the best specific
drugs and dosages for individual patients based on genetic
profiling: so-called ‘personalised medicine’. An example is the
enzyme thiopurine methyltransferase (TPMT), which catabolises
azathioprine, a drug that is used in the treatment of autoimmune
diseases and in cancer chemotherapy. Genetic screening for
polymorphic variants of TPMT can be useful in identifying patients
who have increased sensitivity to the effects of azathioprine and
who can be treated with lower doses than normal.
Gene therapy and genome editing
Replacing or repairing mutated genes (gene therapy) is
challenging in humans. Retroviral-mediated ex vivo replacement
of the defective gene in bone marrow cells for the treatment
of severe combined immune deficiency syndrome (p. 79) has
been successful. The major problems with clinical use of virally
delivered gene therapy have been oncogenic integration of the
exogenous DNA into the genome and severe immune response
to the virus.
Other therapies for genetic disease include PTC124, a
compound that can ‘force’ cells to read through a mutation
that results in a premature termination codon in an ORF with the
aim of producing a near-normal protein product. This therapeutic
approach could be applied to any genetic disease caused by
nonsense mutations.
The most exciting development in genetics for a generation has
been the discovery of accurate, efficient and specific techniques
to enable editing of the genome in cells and organisms. This
technology is known as CRISPR/Cas9 (clustered regularly
interspaced short palindromic repeats and CRISPR-associated)
genome editing. It is likely that ex vivo correction of genetic
disease will become commonplace over the next few years. In
vivo correction is not yet possible and will take much longer to
become part of clinical practice.
I Induced pluripotent stem cells and
regenerative medicine
Adult stem-cell therapy has been in wide use for decades in the
form of bone marrow transplantation. The identification of adult
stem cells for other tissues, coupled with the ability to purify
and maintain such cells in vitro, now offers exciting therapeutic
potential for other diseases. It was recently discovered that
many different adult cell types can be trans-differentiated to
form cells (induced pluripotent stem cells or iPS cells) with
almost all the characteristics of embryonal stem cells derived
from the early blastocyst. In mammalian model species, such
cells can be taken and used to regenerate differentiated tissue
cells, such as in heart and brain. They have great potential both
for the development of tissue models of human disease and for
regenerative medicine.
| Pathway medicine
The ability to manipulate pathways that have been altered
in genetic disease has tremendous therapeutic potential for
Mendelian disease, but a firm understanding of both disease
pathogenesis and drug action at a biochemical level is required.
An exciting example has been the discovery that the vascular
pathology associated with Marfan’s syndrome is due to the
defective fibrillin molecules causing up-regulation of transforming
growth factor (TGF)-(3 signalling in the vessel wall. Losartan is
an anti hypertensive drug that is marketed as an angiotensin II
receptor antagonist. However, it also acts as a partial antagonist
of TGF-p signalling and is effective in preventing aortic dilatation
in a mouse model of Marfan’s syndrome, showing promising
effects in early human clinical trials.
Further information • 59
Ethics in a genomic age
As genomic technology is increasingly moving into mainstream
clinical practice, it is essential for clinicians from all specialties
to appreciate the complexities of genetic testing and consider
whether genetic testing is the right thing to do in a given clinical
scenario. To exemplify the ethical considerations associated
with genetic testing, it may be helpful to think about them in
the context of a clinical scenario. As you read the scenario, try
to think what counselling/ethical issues might arise.
A 32-year-old woman is referred to discuss BRCA2 testing;
she is currently pregnant with her second child (she already
has a 2-year-old daughter) and has an identical twin sister. Her
mother, a healthy 65-year-old with Ashkenazi Jewish ancestry,
participated in direct-to-consumer testing (DCT) for ‘a bit of fun’
and a BRCA2 mutation - common in the Ashkenazi Jewish
population - was identified. There is no significant cancer family
history of note.
Consider the following issues:
• Pre-symptomatic/predictive testing : this describes testing
for a known familial gene mutation in an unaffected
individual (compared with diagnostic testing, where genetic
testing is undertaken in an affected individual). Although
this could be considered for the unaffected patient, in the
current scenario any testing would also have implications
for her identical twin sister. This needs to be fully explored
with the patient and her sister prior to testing. There is
also the potential issue of predictive testing in the patient’s
first child. A fundamental tenet in clinical genetics is that
predictive genetic testing should be avoided in childhood
for adult-onset conditions. This is because, if no benefit to
the patient is accrued through childhood testing, it is
better to retain the child’s right to decide for herself, when
she is old enough, whether she wishes to participate in
genetic testing or not.
• Prenatal testing : the principles behind predictive genetic
testing in childhood can be extended to prenatal testing,
i.e. if a pregnancy is being continued, a baby should not
be tested for an adult-onset condition that cannot be
prevented or treated in childhood. However, prenatal
testing itself is hugely controversial and there is much
debate as to how severe a condition should be to justify
prenatal diagnosis, which would determine ongoing
pregnancy decisions.
• DCT. while DCT can be interesting and empowering for
individuals wishing to find out more about their genetic
backgrounds, it also has several drawbacks. Perhaps the
main one is that, unlike face-to-face genetic counselling
(which usually precedes any genetic testing, certainly
where there are serious health implications for the
individual and their family, such as is associated with
BRCA1/2 mutations), DCT is undertaken in isolation with
no direct access to professional support. Furthermore, in
addition to some (common) single-gene mutations, such
as the founder BRCA1/2 mutations frequently identified in
the Ashkenazi Jewish population and discussed in this
example, current DCT packages utilise a series of SNPs to
determine an overall risk profile; they evaluate the number
of detrimental and protective SNPs for a given disease.
However, given that only a minority of the risk SNPs have
so far been characterised, this is often inaccurate.
Individuals may be falsely reassured that they are not at
increased risk of a genetic condition despite a family
history suggesting otherwise, resulting in inadequate
surveillance and/or management.
The ethical considerations listed in this clinical scenario give just
a flavour of some of the issues frequently encountered in clinical
genetics. They are not meant to be an exhaustive summary and
whole textbooks and meetings are devoted to the discussion of
hugely complex ethical issues in genetics. However, a guiding
principle is that, although each counselling situation will be
unique with specific communication and ethical challenges, a
genetic result is permanent and has implications for the whole
family, not just the individual. Where possible, therefore, an
informed decision regarding genetic testing should be taken by
a competent adult following counselling by an experienced and
appropriately trained clinician.
Further information
Books and journal articles
Alberts B, Bray D, Hopkin K et al. Essential cell biology, 4th edn.
New York: Garland Science; 201 3.
Firth H, Hurst JA. Oxford desk reference: clinical genetics. Oxford:
Oxford University Press; 2005.
Read A, Donnai D. New clinical genetics, 2nd edn. Banbury: Scion;
2010.
Strachan T, Read A. Human molecular genetics, 4th edn. New York:
Garland Science; 2010.
Websites
bsgm.org.uk British Society for Genetic Medicine; has a report on
genetic testing of children.
decipher.sanger.ac.uk Excellent, comprehensive genomic database.
ensembl.org Annotated genome databases from multiple organisms.
futurelearn.com/courses/the-genomics-era Has a Massive Open Online
Course on genomics, for which one of the authors of the current
chapter is the lead educator.
genome.ucsc.edu Excellent source of genomic information.
ncbi.nlm.nih.gov Online Mendelian Inheritance in Man (OMIM).
ncbi.nlm.nih.gov/books/NBK1 116/ Gene Reviews: excellent US-based
source of information about many rare genetic diseases.
orpha.net/consor/cgi-bin/index.php Orphanet: European-based
database on rare disease.
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SE Marshall
SL Johnston
Clinical immunology
Functional anatomy and physiology 62
Periodic fever syndromes 81
The innate immune system 62
Amyloidosis 81
The adaptive immune system 67
Autoimmune disease 81
The inflammatory response 70
Allprnw QA
Acute inflammation 70
Hiiuryy
Chronic inflammation 71
Angioedema 87
Laboratory features of inflammation 71
Transplantation and graft rejection 88
Presenting problems in immune disorders 73
Transplant rejection 88
Recurrent infections 73
Complications of transplant immunosuppression 89
Intermittent fever 74
Organ donation 90
Anaphylaxis 75
Tumour immunology 90
Immune deficiency 77
Primary phagocyte deficiencies 77
Complement pathway deficiencies 78
Primary antibody deficiencies 78
Primary T-lymphocyte deficiencies 79
Secondary immune deficiencies 80
62 • CLINICAL IMMUNOLOGY
The immune system has evolved to identify and destroy pathogens
while minimising damage to host tissue. Despite the ancient
observation that recovery from an infectious disease frequently
results in protection against that condition, the existence of the
immune system as a functional entity was not recognised until the
end of the 1 9th century. More recently, it has become clear that
the immune system not only protects against infection but also
regulates tissue repair following injury, and when dysregulated,
governs the responses that can lead to autoimmune and
auto-inflammatory diseases. Dysfunction or deficiency of the
immune response can lead to a wide variety of diseases that
may potentially involve every organ system in the body.
The aim of this chapter is to provide a general understanding
of the immune system, how it contributes to human disease and
how manipulation of the immune system can be put to therapeutic
use. A review of the key components of the immune response
is followed by sections that illustrate the clinical presentation
of the most common forms of immune dysfunction: immune
deficiency, inflammation, autoimmunity and allergy. More detailed
discussion of individual conditions can be found in the relevant
organ-specific chapters of this book.
Functional anatomy and physiology
The immune system consists of an intricately linked network of
lymphoid organs, cells and proteins that are strategically placed
to protect against infection (Fig. 4.1). Immune defences are
normally categorised into the innate immune response, which
provides immediate protection against an invading pathogen, and
the adaptive or acquired immune response, which takes more
time to develop but confers exquisite specificity and long-lasting
protection.
The innate immune system
Innate defences against infection include anatomical barriers,
phagocytic cells, soluble molecules such as complement and
acute phase proteins, and natural killer cells. The innate immune
system recognises generic microbial structures present on
non-mammalian tissue and can be mobilised within minutes.
A specific stimulus will elicit essentially identical responses in
different individuals, in contrast with adaptive antibody and T-cell
responses, which vary greatly between individuals.
| Physical barriers
The tightly packed keratinised cells of the skin physically limit
colonisation by microorganisms. The hydrophobic oils that
are secreted by sebaceous glands further repel water and
microorganisms, and microbial growth is inhibited by the skin’s
low pH and low oxygen tension. Sweat also contains lysozyme,
an enzyme that destroys the structural integrity of bacterial cell
walls; ammonia, which has antibacterial properties; and several
Adenoids
Lymph nodes
Tonsils
Thoracic
duct
Liver
Spleen
Lymph node section
Appendix
Bone
marrow
Lymphatics
Cortex
B cells in primary
lymphoid follicles
Paracortex
T cells
Dendritic cells
Germinal centre
Proliferating B cells after
antigen exposure
Afferent lymph
Capsule
Medulla
Plasma cells
Sinuses with
macrophages
— Blood vessels
-Efferent lymph
B lymphocyte T lymphocyte
Antigen-presenting cell
Cells of the adaptive immune
system
Thymus
Peyer’s patches in small
intestine
system
Fig. 4.1 Anatomy of the immune system.
Functional anatomy and physiology • 63
antimicrobial peptides such as defensins. Similarly, the mucous
membranes of the respiratory, gastrointestinal and genitourinary
tracts provide a physical barrier to infection. Secreted mucus
traps invading pathogens, and immunoglobulin A (IgA), generated
by the adaptive immune system, prevents bacteria and viruses
attaching to and penetrating epithelial cells. As in the skin,
lysozyme and antimicrobial peptides within mucosal membranes
directly kill invading pathogens, and lactoferrin acts to starve
invading bacteria of iron. Within the respiratory tract, cilia directly
trap pathogens and contribute to removal of mucus, assisted
by physical manoeuvres such as sneezing and coughing. In the
gastrointestinal tract, hydrochloric acid and salivary amylase
chemically destroy bacteria, while normal peristalsis and induced
vomiting or diarrhoea assist clearance of invading organisms.
The microbiome, which is made up of endogenous commensal
bacteria, provides an additional constitutive defence against
infection. Approximately 1014 bacteria normally reside at epithelial
surfaces in symbiosis with the human host (p. 1 02). They compete
with pathogenic microorganisms for scarce resources, including
space and nutrients, and produce fatty acids and bactericidins
that inhibit the growth of many pathogens. In addition, recent
research has demonstrated that commensal bacteria help to
shape the immune response by inducing specific regulatory T
cells within the intestine. Eradication of the normal flora with
broad-spectrum antibiotics commonly results in opportunistic
infection by organisms such as Clostridium difficile, which rapidly
colonise an undefended ecological niche.
These constitutive barriers are highly effective, but if external
defences are breached by a wound or pathogenic organism,
the specific soluble proteins and cells of the innate immune
system are activated.
Phagocytes
Phagocytes (‘eating cells’) are specialised cells that ingest and
kill microorganisms, scavenge cellular and infectious debris, and
produce inflammatory molecules that regulate other components
of the immune system. They include neutrophils, monocytes
and macrophages, and are particularly important for defence
against bacterial and fungal infections. Phagocytes express a
wide range of surface receptors, including pattern recognition
receptors (PRRs), which recognise pathogen-associated molecular
patterns (PAMPs) on invading microorganisms, allowing their
identification. The PRRs include Toll-like receptors, nucleotide
oligomerisation domain (NOD) protein-like receptors and mannose
receptors, whereas the PAMPs they recognise are molecular
motifs not present on mammalian cells, including bacterial cell
wall components, bacterial DNA and viral double-stranded RNA.
While phagocytes can recognise microorganisms through PRRs
alone, engulfment of microorganisms is greatly enhanced by
opsonisation. Opsonins include acute phase proteins produced by
the liver, such as C-reactive protein and complement. Antibodies
generated by the adaptive immune system also act as opsonins.
They bind both to the pathogen and to phagocyte receptors,
acting as a bridge between the two to facilitate phagocytosis (Fig.
4.2). This is followed by intracellular pathogen destruction and
downstream activation of pro-inflammatory genes, resulting in the
generation of pro-inflammatory cytokines as discussed below.
Microbes
gene expression
Fig. 4.2 Phagocytosis and opsonisation. Phagocytosis of microbes can be augmented by several opsonins, such as C-reactive protein, antibodies and
complement fragments like C3b, which enhance the ability of phagocytic cells to engulf microorganisms and destroy them. Phagocytes also recognise
components of microbes, such as lipopolysaccharide, peptidoglycans, DNA and RNA, collectively as pathogen-associated molecular patterns (PAMPs).
These activate pattern recognition receptors (PRRs), such as Toll-like receptors and nucleotide oligomerisation domain (NOD)-like receptors, which promote
inflammatory gene expression through the nuclear factor kappa beta (NFkB) pathway. Uric acid and other crystals can also promote inflammation through
the NOD pathway.
64 • CLINICAL IMMUNOLOGY
Neutrophils
Neutrophils, also known as polymorphonuclear leucocytes,
are derived from the bone marrow and circulate freely in the
blood. They are short-lived cells with a half-life of 6 hours, and
are produced at the rate of 1011 cells daily. Their functions are
to kill microorganisms, to facilitate rapid transit of cells through
tissues, and to amplify the immune response non-specifically.
These functions are mediated by enzymes contained in granules,
which also provide an intracellular milieu for the killing and
degradation of microorganisms.
Two main types of granule are recognised: primary or azurophil
granules, and the more numerous secondary or specific granules.
Primary granules contain myeloperoxidase and other enzymes
important for intracellular killing and digestion of ingested
microbes. Secondary granules are smaller and contain lysozyme,
collagenase and lactoferrin, which can be released into the
extracellular space. Enzyme production is increased in response
to infection, which is reflected by more intense granule staining
on microscopy, known as ‘toxic granulation’.
Changes in damaged or infected cells trigger local production
of inflammatory molecules and cytokines. These cytokines
stimulate the production and maturation of neutrophils in the
bone marrow, and their release into the circulation. Neutrophils
are recruited to specific sites of infection by chemotactic agents,
such as interleukin 8 (IL-8), and by activation of local endothelium.
Up-regulation of cellular adhesion molecules on neutrophils and
the endothelium also facilitates neutrophil migration. The transit
of neutrophils through the blood stream is responsible for the rise
in neutrophil count that occurs in early infection. Once present
within infected tissue, activated neutrophils seek out and engulf
invading microorganisms. These are initially enclosed within
membrane-bound vesicles, which fuse with cytoplasmic granules
to form the phagolysosome. Within this protected compartment,
killing of the organism occurs through a combination of oxidative
and non-oxidative killing. Oxidative killing, also known as the
respiratory burst, is mediated by the nicotinamide adenine
dinucleotide phosphate (NADPH)-oxidase enzyme complex, which
converts oxygen into reactive oxygen species such as hydrogen
peroxide and superoxide that are lethal to microorganisms.
The myeloperoxidase enzyme within neutrophils produces
hypochlorous acid, which is a powerful oxidant and antimicrobial
agent. Non-oxidative (oxygen-independent) killing occurs through
the release of bactericidal enzymes into the phagolysosome.
Each enzyme has a distinct antimicrobial spectrum, providing
broad coverage against bacteria and fungi.
An additional, recently identified form of neutrophil-mediated
killing is neutrophil extracellular trap (NET) formation. Activated
neutrophils can release chromatin with granule proteins such as
elastase to form an extracellular matrix that binds to microbial
proteins. This can immobilise or kill microorganisms without
requiring phagocytosis. The process of phagocytosis and NET
formation (NETosis) depletes neutrophil glycogen reserves and
is followed by neutrophil death. As the cells die, their contents
are released and lysosomal enzymes degrade collagen and
other components of the interstitium, causing liquefaction of
closely adjacent tissue. The accumulation of dead and dying
neutrophils results in the formation of pus, which, if extensive,
may lead to abscess formation.
Monocytes and macrophages
Monocytes are the precursors of tissue macrophages. They are
produced in the bone marrow and enter the circulation, where they
i
Amplification of the inflammatory response
• Stimulate the acute phase response (through production of IL-1
and IL-6)
• Activate vascular endothelium (IL-1 , TNF-a)
• Stimulate neutrophil maturation and chemotaxis (IL-1, IL-8)
• Stimulate monocyte chemotaxis
Killing of microorganisms
• Phagocytosis
• Microbial killing through oxidative and non-oxidative mechanisms
Clearance, resolution and repair
• Scavenging of necrotic and apoptotic cells
• Clearance of toxins and other inorganic debris
• Tissue remodelling (elastase, collagenase, matrix proteins)
• Down-regulation of inflammatory cytokines
• Wound healing and scar formation (IL-1, platelet-derived growth
factor, fibroblast growth factor)
Link between innate and adaptive immune systems
• Activate T cells by presenting antigen in a recognisable form
• T cell-derived cytokines increase phagocytosis and microbicidal
activity of macrophages in a positive feedback loop
(IL = interleukin; TNF = tumour necrosis factor)
constitute about 5% of leucocytes. From the blood stream they
migrate to peripheral tissues, where they differentiate into tissue
macrophages and reside for long periods. Specialised populations
of tissue macrophages include Kupffer cells in the liver, alveolar
macrophages in the lung, mesangial cells in the kidney, and
microglial cells in the brain. Macrophages, like neutrophils, are
capable of phagocytosis and killing of microorganisms but also
play an important role in the amplification and regulation of the
inflammatory response (Box 4.1). They are particularly important
in tissue surveillance and constantly survey their immediate
surroundings for signs of tissue damage or invading organisms.
Dendritic cells
Dendritic cells are specialised antigen-presenting cells that are
present in tissues in contact with the external environment, such
as the skin and mucosal membranes. They can also be found
in an immature state in the blood. They sample the environment
for foreign particles and, once activated, carry microbial antigens
to regional lymph nodes, where they interact with T cells and
B cells to initiate and shape the adaptive immune response.
Cytokines
Cytokines are signalling proteins produced by cells of the immune
system and a variety of other cell types. More than 1 00 have
been identified. Cytokines have complex and overlapping roles in
cellular communication and regulation of the immune response.
Subtle differences in cytokine production, particularly at the
initiation of an immune response, can have a major impact on
outcome. Cytokines bind to specific receptors on target cells and
activate downstream intracellular signalling pathways, ultimately
leading to changes in gene transcription and cellular function.
Two important signalling pathways are illustrated in Figure 4.3.
The nuclear factor kappa B (NFkB) pathway is activated by
tumour necrosis factor (TNF), by other members of the TNF
superfamily such as receptor activator of nuclear kappa B ligand
4.1 Functions of macrophages
Functional anatomy and physiology • 65
IL-6
Fig. 4.3 Cytokines signalling pathways and
the immune response. Cytokines regulate the
immune response through binding to specific
receptors that activate a variety of intracellular
signalling pathways, two of which are shown.
Members of the tumour necrosis factor (TNF)
superfamily and the Toll-like receptors and
NOD-like receptors (Fig. 4.2) signal through the
nuclear factor kappa B (NFkB) pathway. Several
other cytokines, including interleukin-2 (IL-2),
IL-6 and interferons, employ the Janus kinase/
signal transducer and activator of transcription
(JAK-STAT) pathway to regulate cellular
function (see text for more details). (IkB =
inhibitor of kappa B; IKK = I kappa B kinase;
P = phosphorylation of the signalling protein;
TRAF = tumour necrosis factor receptor-
associated factor)
4.2 Important cytokines in the regulation of the immune response
Cytokine
Source
Actions
Biologic therapies
Interferon-alpha
(IFN-cx)
T cells and
macrophages
Antiviral activity
Activates NK cells, CD8+ T cells and macrophages
Recombinant IFN-a used in hepatitis
C and some malignancies
Interferon-gamma
(IFN-y)
T cells and NK cells
Increases antimicrobial activity of macrophages
Regulates cytokine production by T cells and macrophages
Used in chronic granulomatous
disease
Tumour necrosis
factor alpha
(TNF-a)
Macrophages, NK
cells and others,
including T cells
Pro-inflammatory
Increases expression of other cytokines and adhesion
molecules
Causes apoptosis of some target cells
Directly cytotoxic
TNF-a inhibitors used in rheumatoid
arthritis, inflammatory bowel disease,
psoriasis and many other
inflammatory conditions
lnterleukin-1
(IL-1)
Macrophages and
neutrophils
Stimulates neutrophil recruitment, fever, and T-cell and
macrophage activation as part of the inflammatory response
IL-1 inhibitors used in systemic
juvenile rheumatoid arthritis, periodic
fever syndromes and acute gout
lnterleukin-2
(IL-2)
CD4+ T cells
Stimulates proliferation and differentiation of antigen-
specific T lymphocytes
lnterleukin-4
(IL-4)
CD4+ T cells
Stimulates maturation of B and T cells, and production of
IgE antibody
Antibodies to IL-4 receptor used in
severe atopic dermatitis
lnterleukin-6
(IL-6)
Monocytes and
macrophages
Stimulates neutrophil recruitment, fever, and T-cell and
macrophage activation as part of the inflammatory
response, stimulates maturation of B cells into plasma cells
Antibodies to IL-6 receptor used in
rheumatoid arthritis
lnterleukin-12
(IL-12)
Monocytes and
macrophages
Stimulates IFN-y and TNF-a release by T cells
Activates NK cells
Antibody to p40 subunit of IL-12 used
in psoriasis and psoriatic arthritis
lnterleukin-17
(IL-17)
Th17 cells (T helper),
NK cells, NK-T cells
Pro-inflammatory cytokine
Involved in mucosal immunity and control of extracellular
pathogens, synergy with IL-1 and TNF
Antibody to IL-17 used in psoriasis,
psoriatic arthritis and ankylosing
spondylitis
lnterleukin-22
(IL-22)
Th17 cells
Induction of epithelial cell proliferation and antimicrobial
proteins in keratinocytes
(IgE = immunoglobulin E; NK = natural killer)
(RANKL; p. 985), and by the Toll-like receptors and NOD-like
receptors (see Fig. 4.2). In the case of TNF superfamily members,
receptor binding causes the inhibitor of kappa B kinase (IKK)
complex of three proteins to be recruited to the receptor by
binding TNF receptor-associated proteins (TRAF). This activates
IKK, which in turn leads to phosphorylation of the inhibitor of
nuclear factor kappa B protein (IkB), causing it to be degraded,
and allowing NFkB to translocate to the nucleus and activate
gene transcription. The Janus kinase/signal transducers and
activators of transcription (JAK-STAT) pathway is involved in
66 • CLINICAL IMMUNOLOGY
transducing signals downstream of many cytokine receptors,
including those for IL-2, IL-6 and interferon-gamma (IFN-y). On
receptor binding, JAK proteins are recruited to the intracellular
portion of the receptor and are phosphorylated. These in turn
phosphorylate STAT proteins, which translocate to the nucleus
and activate gene transcription, altering cellular function. The
function and disease associations of several important cytokines
are shown in Box 4.2. Cytokine inhibitors are now routinely used
in the treatment of autoimmune diseases, most of which are
monoclonal antibodies to cytokines or their receptors. In addition,
small-molecule inhibitors have been developed that inhibit the
intracellular signalling pathways used by cytokines. These include
the Janus kinase inhibitors tofacitinib and baracitinib, which are
used in rheumatoid arthritis (p. 1026), and the tyrosine kinase
inhibitor imatinib, which is used in chronic myeloid leukaemia
(p. 959).
| Integrins
Integrins are transmembrane proteins that play important roles
in cell-cell and cell-matrix interactions. They mediate attachment
of the cell to the extracellular matrix, signal transduction and cell
migration. Their role in autoimmune disease has been extensively
studied. Targeted therapy with a recombinant humanised anti-a4
integrin antibody, natalizumab, is an effective treatment for
multiple sclerosis, which works by preventing immune cells from
traversing the vascular endothelium and entering the central
nervous system (p. 1109).
Ijtomplement
The complement system comprises a group of more than 20
tightly regulated, functionally linked proteins that act to promote
inflammation and eliminate invading pathogens. Complement
proteins are produced in the liver and are present in inactive form
in the circulation. When the complement system is activated, it
sets in motion a rapidly amplified biological cascade analogous
to the coagulation cascade (p. 918).
There are three mechanisms by which the complement cascade
can be activated (Fig. 4.4):
• The alternate pathway is triggered directly by binding of
C3 to bacterial cell-wall components, such as
lipopolysaccharide of Gram-negative bacteria and teichoic
acid of Gram-positive bacteria.
• The classical pathway is initiated when two or more IgM or
IgG antibody molecules bind to antigen. The associated
conformational change exposes binding sites on the
antibodies for the first protein in the classical pathway, Cl ,
which is a multiheaded molecule that can bind up to six
antibody molecules. Once two or more ‘heads’ of a Cl
molecule are bound to antibody, the classical cascade is
triggered. An important inhibitor of the classical pathway is
Cl inhibitor (Clinh), as illustrated in Figure 4.4.
• The lectin pathway is activated by the direct binding
of mannose-binding lectin to microbial cell surface
carbohydrates. This mimics the binding of Cl to immune
complexes and directly stimulates the classical pathway,
bypassing the need for immune complex formation.
Activation of complement by any of these pathways results in
activation of C3. This in turn activates the final common pathway,
in which the complement proteins C5-C9 assemble to form the
membrane attack complex (MAC). This can puncture the cell wall,
leading to osmotic lysis of target cells. This step is particularly
Classical Lectin Alternate
pathway pathway pathway
Antibody-antigen Mannose-
complexes binding lectin
Fig. 4.4 The complement pathway. The classical pathway is activated
by binding of antigen-antibody complexes to Cl but is blocked by Cl
inhibitor (Clinh), whereas mannose-binding lectins, which are
macromolecules that bind to various microorganisms, activate the pathway
by binding C4. Bacteria can directly activate the pathway through C3,
which plays a pivotal role in complement activation through all three
pathways.
important in the defence against encapsulated bacteria such as
Neisseria spp. and Haemophilus influenzae.
Complement fragments generated by activation of the cascade
can also act as opsonins, rendering microorganisms more
susceptible to phagocytosis by macrophages and neutrophils
(see Fig. 4.2). In addition, they are chemotactic agents, promoting
leucocyte trafficking to sites of inflammation. Some fragments act
as anaphylotoxins, binding to complement receptors on mast
cells and triggering release of histamine, which increases vascular
permeability. The products of complement activation also help to
target immune complexes to antigen-presenting cells, providing
a link between the innate and the acquired immune systems.
Finally, activated complement products dissolve the immune
complexes that triggered the cascade, minimising bystander
damage to surrounding tissues.
A monoclonal antibody directed against the central complement
molecule C5, eculizumab, has been developed for therapeutic use
in paroxysmal nocturnal haemoglobinuria and atypical haemolytic
uraemic syndromes (p. 408). Invasive infection, including
meningococcal sepsis, has been reported with eculizumab
therapy, highlighting the importance of the complement system
in preventing such infections.
Mast cells and basophils
Mast cells and basophils are bone marrow-derived cells that play
a central role in allergic disorders. Mast cells reside predominantly
in tissues exposed to the external environment, such as the
skin and gut, while basophils circulate in peripheral blood and
are recruited into tissues in response to inflammation. Both
contain large cytoplasmic granules that enclose vasoactive
substances such as histamine (see Fig. 4.14). Mast cells and
Functional anatomy and physiology • 67
basophils express IgE receptors on their cell surface, which I
bind IgE antibody. On encounter with specific antigen, the cell is
triggered to release histamine and other mediators present within
the granules and to synthesise additional mediators, including
leukotrienes, prostaglandins and cytokines. An inflammatory
cascade is initiated that increases local blood flow and vascular
permeability, stimulates smooth muscle contraction, and increases
secretion at mucosal surfaces.
Natural killer cells
Natural killer (NK) cells are large granular lymphocytes that play a
major role in defence against tumours and viruses. They exhibit
features of both the adaptive and the innate immune systems
in that they are morphologically similar to lymphocytes and
recognise similar ligands, but they are not antigen-specific and
cannot generate immunological memory. NK cells express a
variety of cell surface receptors, some of which are stimulatory
and others inhibitory. The effects of inhibitory receptors normally
predominate. These recognise human leucocyte antigen (HLA)
molecules that are expressed on normal nucleated cells,
preventing NK cell-mediated attack, whereas the stimulatory
receptors recognise molecules that are expressed primarily
when cells are damaged. This allows NK cells to remain tolerant
to healthy cells but not to damaged ones. When cells become
infected by viruses or undergo malignant change, expression of
HLA class I molecules on the cell surface can be down -regulated.
This is an important mechanism by which these cells then evade
adaptive T-lymphocyte responses. In this circumstance, however,
NK cell defences becomes important, as down -regulation of HLA
class I abrogates the inhibitory signals that normally prevent NK
activation. The net result is NK attack on the abnormal target cell.
NK cells can also be activated by binding of antigen-antibody
complexes to surface receptors. This physically links the NK
cell to its target in a manner analogous to opsonisation and
is known as antibody-dependent cellular cytotoxicity (ADCC).
Activated NK cells can kill their targets in various ways. They
secrete pore-forming proteins such as perforin into the membrane
of the target cell, and proteolytic enzymes called granzymes
into the target cell, which cause apoptosis. In addition, NK cells
produce a variety of cytokines such as TNF-a and IFN-y, which
have direct antiviral and anti-tumour effects.
The adaptive immune system
If the innate immune system fails to provide effective protection
against an invading pathogen, the adaptive immune system
is mobilised (see Fig. 4.1). This has three key characteristics:
• It has exquisite specificity and can discriminate between
very small differences in molecular structure.
• It is highly adaptive and can respond to an almost
unlimited number of molecules.
• It possesses immunological memory, and changes
consequent to initial activation by an antigen allow a more
effective immune response on subsequent encounters.
There are two major arms of the adaptive immune response.
Humoral immunity involves the production of antibodies by B
lymphocytes, and cellular immunity involves the activation of
T lymphocytes, which synthesise and release cytokines that
affect other cells, as well as directly killing target cells. These
interact closely with each other and with the components of
the innate immune system to maximise effectiveness of the
immune response.
|Lymphoid organs
The primary lymphoid organs are involved in lymphocyte
development. They include the bone marrow, where T and B
lymphocytes differentiate from haematopoietic stem cells (p. 914)
and where B lymphocytes also mature, and the thymus, the site
of T-cell maturation (see Fig. 4.1). After maturation, lymphocytes
migrate to the secondary lymphoid organs. These include the
spleen, lymph nodes and mucosa-associated lymphoid tissue.
These trap and concentrate foreign substances and are the major
sites of interaction between naive lymphocytes and microorganisms.
The thymus
The thymus is a bi-lobed structure in the anterior mediastinum,
and is organised into cortical and medullary areas. The cortex
is densely populated with immature T cells, which migrate to
the medulla to undergo selection and maturation. The thymus
is most active in the fetal and neonatal period, and involutes
after puberty. Failure of thymic development is associated with
profound T-cell immune deficiency (p. 79) but surgical removal
of the thymus in childhood (usually during major cardiac surgery)
is not associated with significant immune dysfunction.
The spleen
The spleen is the largest of the secondary lymphoid organs.
It is highly effective at filtering blood and is an important site
of phagocytosis of senescent erythrocytes, bacteria, immune
complexes and other debris, and of antibody synthesis. It is
important for defence against encapsulated bacteria, and asplenic
individuals are at risk of overwhelming Streptococcus pneumoniae
and H. influenzae infection (see Box 4.5).
Lymph nodes
These are positioned to maximise exposure to lymph draining
from sites of external contact, and are highly organised (Fig. 4.1)
• The cortex contains primary lymphoid follicles, which are
the site of B-lymphocyte interactions. When B cells
encounter antigen, they undergo intense proliferation,
forming germinal centres.
• The paracortex is rich in T lymphocytes and dendritic cells.
• The medulla is the major site of antibody-secreting plasma
cells.
• Within the medulla there are many sinuses, which contain
large numbers of macrophages.
Mucosa-associated lymphoid tissue
Mucosa-associated lymphoid tissue (MALT) consists of diffusely
distributed lymphoid cells and follicles present along mucosal
surfaces. It has a similar function to the more organised, encapsulated
lymph nodes. They include the tonsils, adenoids and Peyer’s patches
in the small intestine.
Lymphatics
Lymphoid tissue is connected by a network of lymphatics, with
three major functions: it provides access to lymph nodes, returns
interstitial fluid to the venous system, and transports fat from
the small intestine to the blood stream (see Fig. 14.13, p. 372).
The lymphatics begin as blind-ending capillaries, which come
together to form lymphatic ducts, entering and leaving regional
lymph nodes as afferent and efferent ducts, respectively. They
eventually coalesce and drain into the thoracic duct and left
subclavian vein. Lymphatics may be either deep or superficial,
and follow the distribution of major blood vessels.
68 • CLINICAL IMMUNOLOGY
Humoral immunity
Humoral immunity is mediated by B lymphocytes, which
differentiate from haematopoietic stem cells in the bone marrow.
Their major functions are to produce antibody and interact with
T cells, but they are also involved in antigen presentation. Mature
B lymphocytes can be found in the bone marrow, lymphoid
tissue, spleen and, to a lesser extent, the blood stream. They
Fig. 4.5 B-cell activation. Activation of B cells is initiated through
binding of an antigen with the immunoglobulin receptor on the cell surface.
For activation to proceed, an interaction with T-helper cells is also
required, providing additional signals through binding of CD40 ligand
(CD40L) to CD40; an interaction between the T-cell receptor (TCR) and
processed antigenic peptides presented by human leucocyte antigen (HLA)
molecules on the B-cell surface; and cytokines released by the T-helper
cells. Fully activated B cells undergo clonal expansion with differentiation
towards plasma cells that produce antibody. Following activation, memory
cells are generated that allow rapid antibody responses when the same
antigen is encountered on a second occasion. (CD = cluster of
differentiation; IL = interleukin)
express a unique immunoglobulin receptor on their cell surface,
the B-cell receptor, which binds to soluble antigen targets
(Fig. 4.5). Encounters with antigen usually occur within lymph
nodes. If provided with appropriate cytokines and other signals
from nearby T lymphocytes, antigen-specific B cells respond
by rapidly proliferating in a process known as clonal expansion
(Fig. 4.5). This is accompanied by a highly complex series of
genetic rearrangements known as somatic hypermutation, which
generates B-cell populations that express receptors with greater
affinity for antigen than the original. These cells differentiate into
either long-lived memory cells, which reside in the lymph nodes,
or plasma cells, which produce antibody. Memory cells allow
production of a more rapid and more effective response on
subsequent exposure to that pathogen.
| Immunoglobulins
Immunoglobulins (Ig) play a central role in humoral immunity.
They are soluble proteins produced by plasma cells and are
made up of two heavy and two light chains (Fig. 4.6). The
heavy chain determines the antibody class or isotype, such
as IgG, IgA, IgM, IgE or IgD. Subclasses of IgG and IgA also
occur. The antigen is recognised by the antigen-binding regions
(Fab) of both heavy and light chains, while the consequences of
antibody binding are determined by the constant region of the
heavy chain (Fc) (Box 4.3). Antibodies have several functions.
Fig. 4.6 The structure of an immunoglobulin (antibody) molecule.
The variable region is responsible for antigen binding, whereas the
constant region can interact with immunoglobulin receptors expressed on
immune cells.
4.3 Classes and properties of antibody
Antibody
Concentration
in adult serum
Complement
activation*
Opsonisation
Presence in external
secretions
Other properties
IgG
6.0-16.0 g/L
IgGI +++
lgG2 +
Ig G3 +- 1— i-
IgGI ++
lgG3 ++
++
Four subclasses: IgGI, lgG2, lgG3, lgG4
Distributed equally between blood and extracellular fluid,
and transported across placenta
lgG2 is particularly important in defence against
polysaccharides antigens
IgA
1. 5-4.0 g/L
++++
Two subclasses: IgAI , lgA2
Highly effective at neutralising toxins
Particularly important at mucosal surfaces
IgM
0. 5-2.0 g/L
++++
-
+
Highly effective at agglutinating pathogens
igE
0.003-0.04 g/L
Majority of IgE is bound to mast cells, basophils and
eosinophils
Important in allergic disease and defence against
parasite infection
IgD
Not detected
-
-
-
Function in B-cell development
*Activation of the classical pathway, also called 'complement fixation’.
Functional anatomy and physiology • 69
They facilitate phagocytosis by acting as opsonins (see Fig.
4.2) and facilitate cell killing by cytotoxic cells, particularly NK
cells by antibody-dependent cellular cytotoxicity. Binding of
antibodies to antigen can trigger activation of the classical
complement pathway (see Fig. 4.4). In addition, antibodies can
directly neutralise the biological activity of their antigen target.
This is a particularly important feature of IgA antibodies, which
act predominantly at mucosal surfaces.
The humoral immune response is characterised by
immunological memory, in which the antibody response to
successive exposures to an antigen is qualitatively and
quantitatively improved from the first exposure. When a previously
unstimulated or ‘naive’ B lymphocyte is activated by antigen,
the first antibody to be produced is IgM, which appears in the
serum after 5-1 0 days. Depending on additional stimuli provided
by T lymphocytes, other antibody classes (IgG, IgA and IgE) are
produced 1-2 weeks later. If the memory B cell is subsequently
re-exposed to the same antigen, the lag time between exposure
and production of antibody is decreased to 2-3 days, the amount
of antibody produced is increased, and the response is dominated
by IgG antibodies of high affinity. Furthermore, in contrast to
the initial antibody response, secondary antibody responses do
not require additional input from T lymphocytes. This allows the
rapid generation of highly specific responses on re-exposure to
a pathogen and is an important mechanism in vaccine efficacy.
Cellular immunity
Cellular immunity is mediated by T lymphocytes, which play
important roles in defence against viruses, fungi and intracellular
bacteria. They also play an important immunoregulatory role, by
orchestrating and regulating the responses of other components
of the immune system. T-lymphocyte precursors differentiate
from haematopoietic stem cells in the bone marrow and are
exported to the thymus when they are still immature (see Fig.
4.1). Individual T cells express a unique receptor that is highly
Fig. 4.7 T-cell activation. Activation of T cells is initiated when an antigenic peptide bound to a human leucocyte antigen (HLA) molecule on antigen-
presenting cells interacts with the T-cell receptor expressed by T lymphocytes. Additional signals are required for T-cell activation, however. These include
binding of the co-stimulatory molecules CD80 and CD86 with CD28 on the T cell, and interleukin 2 (IL-2), which is produced in an autocrine manner by T
cells that are undergoing activation. Other molecules are present that can inhibit T-cell activation, however, including cytotoxic T-lymphocyte-associated
protein 4 (CTLA4), which competes with CD28 for binding to CD80 and CD86; and PD1, which, by binding PDL1, is also inhibitory. Following activation, T
cells proliferate and, depending on their subtype, have various functions with distinct patterns of cytokine production, as indicated. Memory cells are also
generated that can mount a rapid immune response on encountering the same antigen. (CD = cluster of differentiation; CD40L = CD40 ligand; IFN-y =
interferon-gamma; IL = interleukin; PD1 = programmed cell death 1; PDL1 = programmed death ligand 1; TGF-p = transforming growth factor beta;
TNF-a = tumour necrosis factor alpha)
70 • CLINICAL IMMUNOLOGY
specific for a single antigen. Within the thymus T cells undergo
a process of stringent selection to ensure that autoreactive
cells are destroyed. Mature T lymphocytes leave the thymus
and expand to populate other organs of the immune system. It
has been estimated that an individual possesses 1 07— 1 09 T-cell
clones, each with a unique T-cell receptor, ensuring at least
partial coverage for any antigen encountered.
Unlike B cells, T cells cannot recognise intact protein antigens
in their native form. Instead, the protein must be broken down into
component peptides by antigen-presenting cells for presentation
to T lymphocytes in association with HLA molecules on the
antigen-presenting cell surface. This process is known as
antigen processing and presentation, and it is the complex of
peptide and HLA together that is recognised by individual T
cells (Fig. 4.7). The structure of HLA molecules varies widely
between individuals. Since each HLA molecule has the capacity
to present a subtly different peptide repertoire to T lymphocytes,
this ensures enormous diversity in recognition of antigens by
the T-cell population. All nucleated cells have the capacity to
process and present antigens, but cells with specialised antigen-
presenting functions include dendritic cells, macrophages and B
lymphocytes. These carry additional co-stimulatory molecules,
such as CD80 and CD86, providing the necessary ‘second
signal’ for full T-cell activation.
T lymphocytes can be divided into two subgroups on the
basis of function and recognition of HLA molecules. These are
designated CD4+ and CD8+ T cells, according to the ‘cluster of
differentiation’ (CD) antigen number of key proteins expressed
on their cell surface.
CDF T lymphocytes
These cells recognise antigenic peptides in association with HLA\
class I molecules (HLA-A, HLA-B, HLA-C). They kill infected
cells directly through the production of pore-forming molecules
such as perforin and release of digesting enzymes triggering
apoptosis of the target cell, and are particularly important in
defence against viral infection.
CD4+ T lymphocytes
These cells recognise peptides presented on HLA class II
molecules (HLA-DR, HLA-DP and HLA-DQ) and have mainly
immunoregulatory functions. They produce cytokines and provide
co-stimulatory signals that support the activation of CD8+ T
lymphocytes and assist the production of mature antibody by
B cells. In addition, their close interaction with phagocytes
determines cytokine production by both cell types. CD4+
lymphocytes can be further subdivided into subsets on the
basis of the cytokines they produce:
• Thl (T helper) cells typically produce IL-2, IFN-y and
TNF-a, and support the development of delayed-type
hypersensitivity responses (p. 83).
• Th2 cells typically produce IL-4, IL-5, IL-10 and IL-13, and
promote allergic responses (p. 84).
• T-regulatory cells (T regs) are a further subset of
specialised CD4+ lymphocytes that are important in
actively suppressing activation of other cells and
preventing autoimmune disease.
• Thl 7 cells are pro-inflammatory cells defined by their
production of IL-17. They are related to regulatory T cells,
and play a role in immune defence at mucosal surfaces
T-cell activation is regulated by a balance between co-stimulatory
molecules, the second signal required for activation, and inhibitory
molecules that down-regulate T-cell activity. One such inhibitory
molecule, CTLA4, has been harnessed therapeutically in the
form of abatacept, which is a fusion protein comprised of the
Fc fragment of immunoglobulin linked to CTLA4. This is used
to inhibit T-cell activation in rheumatoid arthritis and solid organ
transplantation.
The inflammatory response
Inflammation is the response of tissues to injury or infection, and
is necessary for normal repair and healing. This section focuses
on the general principles of the inflammatory response and its
multisystem manifestations. The role of inflammation in specific
diseases is discussed in many other chapters of this book.
Acute inflammation
Acute inflammation is the result of rapid and complex interplay
between the cells and soluble molecules of the innate immune
system. The classical external signs include heat, redness, pain
and swelling (Fig. 4.8). The inflammatory process is initiated by
local tissue injury or infection. Damaged epithelial cells produce
cytokines and antimicrobial peptides, causing early infiltration
of phagocytic cells. Production of leukotrienes, prostaglandins,
histamine, kinins, anaphylotoxins and inducible nitric oxide
synthase also occurs within inflamed tissue. These mediators
cause vasodilatation and increased vascular permeability,
causing trafficking of fluid and cells into the affected tissue. In
addition, pro- inflammatory cytokines, such as IL-1 , TNF-a and
IL-6 produced at the site of injury, are released systemically
and act on the hypothalamus to cause fever, and on the liver
to stimulate production of acute phase proteins.
The acute phase response
The acute phase response refers to the production of a
variety of proteins by the liver in response to inflammatory
stimuli. These proteins have a wide range of activities.
Circulating levels of C-reactive protein (CRP) and serum amyloid
A may be increased 1000-fold, contributing to host defence and
stimulating repair and regeneration. Fibrinogen plays an essential
role in wound healing, and a-, -antitrypsin and a^antichymotrypsin
control the pro-inflammatory cascade by neutralising the enzymes
produced by activated neutrophils, preventing widespread tissue
destruction. In addition, antioxidants such as haptoglobin and
manganese superoxide dismutase scavenge for oxygen free
radicals, while increased levels of iron-binding proteins such as
ferritin and lactoferrin decrease the iron available for uptake by
bacteria (p. 941). Immunoglobulins are not acute phase proteins
but are often increased in chronic inflammation.
Septic shock
Septic shock is the clinical manifestation of overwhelming
inflammation (p. 196). It is characterised by excessive production
of pro-inflammatory cytokines by macrophages, causing
hypotension, hypovolaemia and tissue oedema. In addition,
uncontrolled neutrophil activation causes release of proteases and
oxygen free radicals within blood vessels, damaging the vascular
endothelium and further increasing capillary permeability. Direct
activation of the coagulation pathway combines with endothelial
cell disruption to form clots within the damaged vessels. The
The inflammatory response • 71
Headache
Delirium
Anorexia
Low blood pressure
Liver:
TSynthesis of acute
phase proteins
Enlarged draining
lymph nodes
Ascending
lymphangitis
Local cellulitis
Pain
Redness
Swelling
2 x
jkJ
r
1
0 j
L
- Hypothalamus:
Change in temperature set point
Fever
Sweating
Neuro-endocrine and autonomic stress responses
Flushing
t Respiratory rate
THeart rate, flow murmur
Adrenal release of glucocorticoids
and catecholamines
Release of insulin
from pancreas
Bone marrow:
TProduction and mobilisation
of neutrophils
Local infection
Bacteria
Tissue damage
Inflammatory mediators
rand cytokines
Phagocytosis
rQ) Cytokine production
//as., * ... Vasodilatation
Vasodilatation ^ Neutrophils f Local vascular
tLocal vascular + permeability
permeability
Macrophages tLeucocyte influx
Fig. 4.8 Clinical features of acute inflammation. In this example, the response is to a penetrating injury and infection of the foot.
clinical consequences include cardiovascular collapse, acute
respiratory distress syndrome, disseminated intravascular
coagulation, multi-organ failure and often death. Septic shock
most frequently results from infection with Gram-negative bacteria,
because lipopolysaccharide produced by these organisms is
particularly effective at activating the inflammatory cascade.
Early recognition and appropriate early intervention can improve
patient outcome (p. 196).
Resolution of inflammation
Resolution of an inflammatory response is crucial for normal
healing. This involves active down-modulation of inflammatory
stimuli and repair of bystander damage to local tissues.
Extravasated neutrophils undergo apoptosis and are phagocytosed
by macrophages, along with the remains of microorganisms.
Macrophages also synthesise collagenase and elastase, which
break down local connective tissue and aid in the removal
of debris. Normal tissue homeostasis is also associated with
reversion of parenchymal cells to a non-inflammatory phenotype.
Macrophage-derived cytokines, including transforming growth
factor-beta (TGF-p) and platelet-derived growth factor, stimulate
fibroblasts and promote the synthesis of new collagen, while
angiogenic factors stimulate new vessel formation.
Chronic inflammation
In most instances, the development of an active immune response
results in clearance and control of the inflammatory stimulus and
resolution of tissue damage. Failure of this process may result
in chronic inflammation, with significant associated bystander
damage, known as hypersensitivity responses. Persistence
of microorganisms can result in ongoing accumulation of
neutrophils, macrophages and activated T lymphocytes within
the lesion. If this is associated with local deposition of fibrous
tissue, a granuloma may form. Granulomas are characteristic
of tuberculosis and leprosy (Hansen’s disease), in which the
microorganism is protected by a robust cell wall that shields it
from killing, despite phagocytosis.
Laboratory features of inflammation
Inflammation is associated with changes in many laboratory
investigations. Leucocytosis is common, and reflects the transit
of activated neutrophils and monocytes to the site of infection.
The platelet count may also be increased. The most widely used
laboratory measure of acute inflammation is CRP. Circulating
72 • CLINICAL IMMUNOLOGY
levels of many other acute phase reactants, including fibrinogen,
ferritin and complement components, are also increased in
response to acute inflammation, while albumin levels are reduced.
Chronic inflammation is frequently associated with a normocytic
normochromic anaemia (p. 943).
C-reactive protein
C-reactive protein (CRP) is an acute phase reactant synthesised
by the liver, which opsonises invading pathogens. Circulating
concentrations of CRP increase within 6 hours of the start of an
inflammatory stimulus. Serum concentrations of CRP provide
a direct biomarker of acute inflammation and, because the
serum half-life of CRP is 18 hours, levels fall promptly once the
inflammatory stimulus is removed. Sequential measurements
are useful in monitoring disease activity (Box 4.4). For reasons
that remain unclear, some diseases are associated with only
minor elevations of CRP despite unequivocal evidence of active
inflammation. These include systemic lupus erythematosus
(SLE), systemic sclerosis, ulcerative colitis and leukaemia. An
important practical point is that if the CRP is raised in these
conditions, it suggests intercurrent infection rather than disease
activity. Since the CRP is a more sensitive early indicator of
the acute phase response, it is generally used in preference
to the erythrocyte sedimentation rate (ESR). If both ESR
and CRP are used, any discrepancy should be resolved by
assessing the individual determinants of the ESR, which are
discussed below.
Erythrocyte sedimentation rate
The ESR is an indirect measure of inflammation. It measures
how fast erythrocytes fall through plasma, which is determined
by the composition of plasma proteins and the morphology of
circulating erythrocytes. These factors govern the propensity
of red cells to aggregate, the major determinant of the ESR.
Erythrocytes are inherently negatively charged, which prevents
them from clumping together in the blood stream. Since plasma
proteins are positively charged, an increase in plasma protein
concentrations neutralises the negative charge of erythrocytes,
overcoming their inherent repulsive forces and causing them
aggregate, resulting in rouleaux formation. Rouleaux have a
higher mass-to-surface area ratio than single red cells, and
therefore sediment faster. The most common reason for an
increased ESR is an acute phase response, which causes an
increase in the concentration of acute phase proteins, including
CRP. However, other conditions that do not affect acute phase
proteins may alter the composition and concentration of other
plasma protein (Box 4.4). For example, immunoglobulins comprise
a significant proportion of plasma proteins but do not participate
in the acute phase response. Thus any condition that causes an
increase in serum immunoglobulins will increase the ESR without
a corresponding increase in CRP. In addition, abnormal red cell
morphology can make rouleaux formation impossible. For these
reasons, an inappropriately low ESR occurs in spherocytosis
and sickle-cell anaemia.
| Plasma viscosity
Plasma viscosity is another surrogate measure of plasma protein
concentration. Like the ESR, it is affected by the concentration of
large plasma proteins, including fibrinogen and immunoglobulins.
It is not affected by properties of erythrocytes and is generally
considered to be more reliable than the ESR as a marker of
inflammation.
4.4 Conditions commonly associated with abnormal C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR)
Condition
Consequence
Effect on CRP1
Effect on ESR2
Acute bacterial, fungal or viral
infection
Stimulates acute phase response
Increased (range 50-150 mg/L;
in severe infections may be
>300 mg/L)
Increased
Necrotising bacterial infection
Stimulates profound acute
inflammatory response
Greatly increased (may be
>300 mg/L)
Increased
Chronic bacterial or fungal infection
Localised abscess, bacterial
endocarditis or tuberculosis
Stimulates acute and chronic
inflammatory response with polyclonal
increase in immunoglobulins,
as well as increased acute phase
proteins
Increased (range 50-1 50 mg/L)
Increased
disproportionately
to CRP
Acute inflammatory diseases
Crohn’s disease, polymyalgia
rheumatica, inflammatory arthritis
Stimulates acute phase response
Increased (range 50-1 50 mg/L)
Increased
Systemic lupus erythematosus,
Sjogren’s syndrome, ulcerative
colitis
Chronic inflammatory response
Normal
Increased
Multiple myeloma
Monoclonal increase in serum
immunoglobulin without acute
inflammation
Normal
Increased
Pregnancy, old age, end-stage renal
disease
Increased fibrinogen
Normal
Moderately increased
Reference range <10 mg/L. Reference range: adult males <10 mm/hr, adult females <20 mm/hr.
Presenting problems in immune disorders • 73
Presenting problems in
immune disorders
Recurrent infections
Infections can occur in otherwise healthy individuals but recurrent
infection raises suspicion of an immune deficiency. Depending
on the component of the immune system affected, the infections
may involve bacteria, viruses, fungi or protozoa, as summarised in
Box 4.5. T-cell deficiencies can involve pathogens from all groups.
Aetiology
Infections secondary to immune deficiency occur because of
defects in the number or function of phagocytes, B cells, T cells
or complement, as described later in this chapter.
Clinical assessment
Clinical features that may indicate immune deficiency are listed in
Box 4.6. Frequent or severe infections, or ones caused by unusual
organisms or at unusual sites are typical of immune deficiency.
Investigations
Initial investigations should include full blood count and white
cell differential, CRP, renal and liver function tests, urine dipstick,
serum immunoglobulins with protein electrophoresis, and HIV
testing. Additional microbiological tests, virology and imaging are
required to identify the causal organism and localise the site of
infection, as outlined in Box 4.7. If primary immune deficiency is
suspected on the basis of initial investigations, more specialised
tests should be considered, as summarised in Box 4.8.
Management
If an immune deficiency is suspected but has not yet been formally
characterised, patients should not receive live vaccines because
of the risk of vaccine-induced disease. Further management
depends on the underlying cause and details are provided later.
4.6 Warning signs of primary immune deficiency
In children
In adults
>4 new ear infections within
1 year
>2 new ear infections within
1 year
>2 serious sinus infections
within 1 year
>2 new sinus infections
within 1 year, in the absence
of allergy
>2 months on antibiotics with
little effect
Recurrent viral infections
>2 pneumonias within 1 year
>1 pneumonia per year for more
than 1 year
Failure of an infant to
gain weight or grow
normally
Chronic diarrhoea with weight loss
Recurrent deep skin or organ
abscesses
Recurrent deep skin or organ
abscesses
Persistent thrush in mouth
or elsewhere on skin after
infancy
Persistent thrush or fungal
infection on skin or elsewhere
Need for intravenous antibiotics
to clear infections
Recurrent need for
intravenous antibiotics to
clear infections
>2 deep-seated infections
such as sepsis, meningitis or
cellulitis
Infection with atypical
mycobacteria
A family history of
primary immune
deficiency
A family history of primary immune
deficiency
*The presence of two or more of the above features may indicate the
presence of an underlying primary immunodeficiency.
© Jeffrey Model 1 Foundation.
4.5 Immune deficiencies and common patterns of infection
Phagocyte deficiency
Complement deficiency
Antibody deficiency
T-lymphocyte deficiency
Bacteria
Staphylococcus aureus
Pseudomonas aeruginosa
Serratia marcescens
Burkholderia cenocepacia
Nocardia
Mycobacterium tuberculosis
Atypical mycobacteria
Neisseria meningitidis
Neisseria gonorrhoeae
Haemophilus influenzae
Streptococcus pneumoniae
Haemophilus influenzae
Streptococcus pneumoniae
Staphylococcus aureus
Mycobacterium tuberculosis
Atypical mycobacteria
Fungi
Candida spp.
Aspergillus spp.
-
-
Candida spp.
Aspergillus spp.
Pneumocystis jirovecii
Viruses
Cytomegalovirus (CMV)
Enteroviruses
Epstein— Barr virus (EBV)
Herpes zoster virus
Fluman papillomavirus
Fluman herpesvirus 8
Protozoa
-
Giardia lamblia
Toxoplasma gondii
Cryptosporidia
74 • CLINICAL IMMUNOLOGY
4.7 Initial investigations in suspected immune deficiency
Test
Value
Comment
Full blood count
Full white cell differential
May define pathway for further investigation
Acute phase reactants
Help determine presence of active infection
Serum immunoglobulins
Detection of antibody deficiency
Serum protein electrophoresis
Detection of paraprotein
May be the cause of immune paresis; paraprotein
should be excluded prior to diagnosis of primary
antibody deficiency
Serum free light chains/Bence Jones proteins
Detection of paraprotein
Human immunodeficiency virus (HIV) test
To exclude HIV as cause of secondary
immune deficiency
Imaging according to history and examination
findings
Detection of active infection/end-organ
damage
May support treatment decisions, e.g. if there is
evidence of bronchiectasis
4.8 Specialist investigations in suspected immune deficiency
Test
Value
Comment
Complement
(C3/C4/CH50/AP50)
Investigation of recurrent pyogenic bacterial infection
Inherited complement deficiency likely to give low/
absent results on functional assays
Test vaccination
Determination of functional humoral immune response
Helpful in patients with borderline low or normal
immunoglobulins but confirmed recurrent infection
Neutrophil function
Investigation of recurrent invasive bacterial and fungal
infection, especially with catalase-positive organisms
Investigation of leucocyte adhesion deficiency
Respiratory burst low/absent in chronic
granulomatous disease
Leucocytosis with absent CD1 1 a, b, c expression
Lymphocyte immunophenotyping
(by flow cytometry)
Determination of specific lymphocyte subsets, T cell,
B cell, NK cell
May define specific primary immune deficiency,
e.g. absent B cells in X-linked agammaglobulinaemia
Lymphocyte proliferation
Determination of lymphocyte proliferation in response
to mitogenic stimulation
Poor responses seen in certain T-cell immune
deficiencies
Cytokine production
To determine T-cell immune function in response to
antigen stimulation; limited availability, not routine
Can be helpful, for example, in investigation of
atypical mycobacterial infection
Genetic testing
Under specialist supervision when specific primary
immune deficiency suspected
May confirm genetic cause, with implications for
family members and future antenatal testing
(NK = natural killer)
Intermittent fever
Intermittent fever has a wide differential diagnosis, including
recurrent infection, malignancy and certain rheumatic disorders,
such as Still’s disease, vasculitis and SLE (pp. 1040 and 1034),
but a familial fever syndrome is a potential cause.
Aetiology
Familial fever syndromes are genetic disorders caused by
mutations in genes responsible for regulating the inflammatory
response. The symptoms are caused by activation of intracellular
signalling pathways involved in the regulation of inflammation,
with over-production of pro-inflammatory cytokines such as IL-1 .
Clinical assessment
A full clinical history and physical examination should be
performed, paying attention to the patient’s ethnic background
and any family history of a similar disorder. If this assessment
shows no evidence of underlying infection, malignancy or a
rheumatic disorder and there is a positive family history and early
age at onset, then the likelihood of a familial fever syndrome
is increased.
Investigations
Blood should be taken for a full blood count, measurement
of ESR and CRP, and assessment of renal and liver function.
Serum ferritin should be checked, as very high levels support the
diagnosis of Still’s disease. Blood and urine cultures should also
be performed, along with an autoimmune screen that includes
measurement of antinuclear antibodies and consideration of
antineutrophil cytoplasmic antibodies to check for evidence
of SLE or vasculitis, respectively. Imaging may be required
to exclude occult infection. If these investigations provide no
evidence of infection or another cause, then genetic analysis
should be considered to confirm the diagnosis of a familial fever
syndrome (p. 81). Negative genetic testing does not, however,
entirely exclude a periodic fever syndrome.
Management
Symptomatic management with non-steroidal anti-inflammatory drugs
(NSAIDs) should be initiated, pending the results of investigations.
If the response to NSAIDs is inadequate, glucocorticoids can be
tried, provided that infection has been excluded. If a familial fever
syndrome is confirmed, then definitive therapy should be initiated,
depending on the underlying diagnosis (p. 81).
Presenting problems in immune disorders • 75
Anaphylaxis
Anaphylaxis is a potentially life-threatening, systemic allergic
reaction characterised by circulatory collapse, bronchospasm,
laryngeal stridor, often associated with angioedema, and urticaria.
The risk of death is increased in patients with pre-existing asthma,
particularly if this is poorly controlled, and in situations where
treatment with adrenaline (epinephrine) is delayed.
Aetiology
Anaphylaxis occurs when an allergen binds to and cross-links
membrane-bound IgE on mast cells in a susceptible individual,
causing release of histamine, tryptase and other vasoactive
mediators from mast cells. These mediators have a variety of
effects, including vasodilatation, increased capillary permeability
i
4.9 Clinical features of mast cell degranulation
Mediator
Biological effects
Pre-formed and stored within granules
Histamine
Vasodilatation, chemotaxis,
bronchoconstriction, increased
capillary permeability and
increased mucus secretion
Tryptase
Bronchoconstriction, activates
complement C3
Eosinophil chemotactic factor
Eosinophil chemotaxis
Neutrophil chemotactic factor
Neutrophil chemotaxis
Synthesised on activation of mast cells
Leukotrienes
Increase vascular permeability,
chemotaxis, mucus secretion and
smooth muscle contraction
Prostaglandins
Bronchoconstriction, platelet
aggregation and vasodilatation
Thromboxanes
Bronchoconstriction
Platelet-activating factor
Bronchoconstriction, chemotaxis of
eosinophils and neutrophils
leading to hypotension, and bronchoconstriction, as summarised
in Box 4.9. It can be difficult to distinguish IgE-mediated
anaphylaxis clinically from non-specific degranulation of mast
cells on exposure to drugs, chemicals or other triggers where
IgE is not involved, previously known as anaphylactoid reactions.
Common triggers are shown in Box 4.10.
Clinical assessment
The clinical features of anaphylaxis and ‘anaphylactoid’ reactions
are indistinguishable and are summarised in Figure 4.9. Several
other conditions can mimic anaphylaxis and these are listed
in Box 4.1 1 .
It is important to assess the severity of the reaction, and the
time between allergen exposure and onset of symptoms provides
4.10 Common causes of systemic allergic reactions
Anaphylaxis: IgE-mediated mast cell degranulation
Foods
• Peanuts
• Milk
• Tree nuts
• Eggs
• Fish and shellfish
• Soy products
Insect stings
• Bee venom
• Wasp venom
Chemicals, drugs and other foreign proteins
• Intravenous anaesthetic agents
• Penicillin and other antibiotics
(suxamethonium)
• Latex
Anaphylactoid: non-lgE-mediated mast cell degranulation
Drugs
• Aspirin and non-steroidal
• Opiates
anti-inflammatory drugs
• Radiocontrast media
(NSAIDs)
Physical
• Exercise
• Cold
Idiopathic
• No cause is identified in 20% of patients with anaphylaxis
Feeling of impending doom,
loss of consciousness
Conjunctival injection -
Flushing -
Sweating
Wheeze, -
bronchoconstriction
Angioedema
of lips and mucous
membrane
Laryngeal obstruction
Stridor
Hypotension
Urticaria
Itching of
palms, soles of feet
and genitalia
Abdominal
pain
Diarrhoea
Wasp sting
Cardiac
arrhythmias
Fig. 4.9 Clinical manifestations of anaphylaxis. In this
example, the response is to an insect sting containing
venom to which the patient is allergic. This causes release
of histamine and other vasoactive mediators, which cause
the characteristic features of anaphylaxis that are
illustrated.
76 • CLINICAL IMMUNOLOGY
4.1 1 Differential diagnosis of anaphylaxis
Causes of hypotension
• Vasovagal syncope
• Cardiac arrhythmia
• Cardiogenic shock
Causes of respiratory distress
• Status asthmaticus
• Pulmonary embolus
Causes of laryngeal obstruction
• Cl inhibitor deficiency
• Idiopathic angioedema
Causes of generalised flushing
• Systemic mastocytosis
• Carcinoid syndrome
• Phaeochromocytoma
4.12 Emergency management of anaphylaxis
Treatment
Comment
Prevent further contact with allergen
Prevents ongoing mast cell
activation
Ensure airway patency
Prevents hypoxia
Administer adrenaline (epinephrine)
promptly:
0.3-1 .0 mL 1:1000 solution IM
in adults
Repeat at 5-1 0-min intervals if
initial response is inadequate
Intramuscular route important
because of peripheral
vasoconstriction
Acts within minutes
Increases blood pressure
Reverses bronchospasm
Administer antihistamines:
Chlorphenamine 10 mg IM or
slow IV injection
Blocks effect of histamine on
target cells
Administer glucocorticoids:
Hydrocortisone 200 mg IV
Reduces cytokine release
Prevents rebound symptoms in
severe cases
Provide supportive treatment:
Nebulised (32-agonists
IV fluids
Oxygen
Reverses bronchospasm
Restores plasma volume
Reverses hypoxia
(IM = intramuscular; IV = intravenous)
a guide. Enquiry should be made about potential triggers. If none
is immediately obvious, a detailed history of the previous 24 hours
may be helpful. The most common triggers of anaphylaxis are
foods, latex, insect venom and drugs (see Box 4.10). A history
of previous local allergic responses to the offending agent is
common. The route of allergen exposure may influence the
principal clinical features of a reaction; for example, if an allergen
is inhaled, the major symptom is frequently wheezing. Features
of anaphylaxis may overlap with the direct toxic effects of drugs
and venoms (Chs 7 and 8). Potentiating factors, such as exercise
or alcohol, can lower the threshold for an anaphylactic event. It
is important to identify precipitating factors so that appropriate
avoidance measures may be taken in the longer term.
Investigations
Measurement of serum mast cell tryptase concentrations is
useful to confirm the diagnosis but cannot distinguish between
anaphylaxis and non-lgE-mediated anaphylactoid reactions.
Specific IgE tests may be useful in confirming hypersensitivity
and may be preferable to skin-prick tests when investigating
patients with a history of anaphylaxis.
4.13 How to prescribe self-injectable
adrenaline (epinephrine)
Prescription (normally initiated by an immunologist or allergist)
• Specify the brand of autoinjector, as they have different triggering
mechanisms
• Prescribe two devices
Indications
• Anaphylaxis to allergens that are difficult to avoid:
Insect venom
Foods
• Idiopathic anaphylactic reactions
• History of severe localised reactions with high risk of future
anaphylaxis:
Reaction to trace allergen
Likely repeated exposure to allergen
• History of severe localised reactions with high risk of adverse outcome:
Poorly controlled asthma
Lack of access to emergency care
Patient and family education
• Know when and how to use the device
• Carry the device at all times
• Seek medical assistance immediately after use
• Wear an alert bracelet or necklace
• Include the school in education for young patients (see ‘Further
information’)
Other considerations
• Caution with (3-blockers in anaphylactic patients as they may
increase the severity of an anaphylactic reaction and reduce the
response to adrenaline (epinephrine)
S
* Resolution of childhood allergy: most children affected by allergy
to milk, egg, soybean or wheat will grow out of their food allergies
by adolescence but allergies to peanuts, tree nuts, fish and shellfish
are frequently life-long.
• Risk-taking behaviour and fatal anaphylaxis: serious allergy is
increasingly common in adolescents and this is the highest risk
group for fatal, food-induced anaphylaxis. This is associated with
increased risk-taking behaviour, and food-allergic teenagers are
more likely than adults to eat unsafe foods, deny reaction symptoms
and delay emergency treatment.
R Emotional impact of food allergies: some adolescents may neglect
to carry a prescribed adrenalin autoinjector because of the associated
nuisance and/or stigma. Surveys of food-allergic teens reveal that
many take risks because they feel socially isolated by their allergy.
4.14 Allergy in adolescence
Management
The principles of management of the acute event are summarised
in Box 4.12. Individuals who have recovered from an anaphylactic
event should be referred for specialist assessment. The aim is
to identify the trigger factor, to educate the patient regarding
avoidance and management of subsequent episodes, and to
establish whether specific treatment, such as immunotherapy,
is indicated. If the trigger factor cannot be identified or avoided,
recurrence is common. Patients who have previously experienced
an anaphylactic event should be prescribed self-injectable
adrenaline (epinephrine) and they and their families or carers
should be instructed in its use (Box 4.13). The use of a MedicAlert
(or similar) bracelet will increase the likelihood of the injector being
administered in an emergency. Allergy in adolescence requires
additional consideration and management, as set out in Box 4.14.
Immune deficiency • 77
Immune deficiency
The consequences of immune deficiency include recurrent infection,
autoimmunity as a result of immune dysregulation, and increased
susceptibility to malignancy, especially malignancy driven by viral
infections such as Epstein-Barr virus. Immune deficiency may arise
through intrinsic defects in immune function but is much more
commonly due to secondary causes, including infection, drug
therapy, malignancy and ageing. This section gives an overview of
primary immune deficiencies. More than a hundred such deficiencies
have been described, most of which are genetically determined
and present in childhood or adolescence. The presentation of
immune deficiency depends on the component of the immune
system that is defective (see Box 4.5). There is considerable
overlap and redundancy in the immune network, however, and
some diseases do not fall easily into this classification.
Primary phagocyte deficiencies
Primary phagocyte deficiencies typically present with recurrent
bacterial and fungal infections, which may involve unusual sites.
Affected patients require aggressive management of infections,
including intravenous antibiotics and surgical drainage of
abscesses, and long-term prophylaxis with antibacterial and
antifungal agents. The most important examples are illustrated
in Figure 4.10 and discussed below.
Chronic granulomatous disease
This is caused by mutations in genes that encode NADPH
oxidase enzymes, which results in failure of oxidative killing.
The defect leads to susceptibility to catalase-positive organisms
such as Staphylococcus aureus, Burkholderia cenocepacia and
Aspergillus. Intracellular killing of mycobacteria in macrophages
is also impaired. Infections most commonly involve the lungs,
lymph nodes, soft tissues, bone, skin and urinary tract, and are
characterised histologically by granuloma formation. Most cases
are X-linked (p. 48).
Leucocyte adhesion deficiencies
These very rare disorders of phagocyte migration occur because
of failure to express adhesion molecules on the surface of
leucocytes, resulting in their inability to exit the blood stream.
The most common cause is loss-of-function mutations affecting the
ITGB2 gene, which encodes the integrin p-2 chain, a component of
the adhesion molecule LFA1 . They are characterised by recurrent
bacterial infections but sites of infection lack evidence of neutrophil
infiltration, such as pus formation. Peripheral blood neutrophil counts
may be very high during acute infection because of the failure of
mobilised neutrophils to exit blood vessels. Specialised tests show
reduced or absent expression of adhesion molecules on neutrophils.
Normal
through binding of LFA1 to ICAM1
Cytokines activate
macrophages
IL-12
IFN-y
Destruction of microorganisms through
NADPH oxidase-mediated killing
Primary phagocyte deficiency
Leucocyte adhesion deficiency
Neutrophils cannot traverse
endothelium due to defects in
ITGB2, a component of LFA1
Cytokine defects
IFN-y
x
Phagocytes cannot be
activated due to defects in
cytokines or their receptors
Chronic granulomatous
disease
Microorganisms cannot be
destroyed in lysosomes due
to NADPH oxidase deficiency
Fig. 4.10 Normal phagocyte function and mechanisms of primary phagocyte deficiency. Under normal circumstances, neutrophils traverse the
endothelium to enter tissues by the cell surface molecule lymphocyte function-associated antigen 1 (LFA1), which binds to intercellular adhesion molecule
1 (ICAM1) on endothelium. In order for macrophages to engulf and kill microorganisms, they need to be activated by cytokines and also require
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate free radicals. Primary phagocyte deficiencies can occur as the result of
leucocytes being unable to traverse endothelium due to defects in LFA1, because of mutations in cytokines or their receptors, or because of defects in
NADPH oxidase. (IFN-y = interferon-gamma; IL = interleukin)
78 • CLINICAL IMMUNOLOGY
Defects in cytokines and cytokine receptors
Mutations of the genes encoding cytokines such as IFN-y,
IL-12, IL-23 or their receptors result in failure of intracellular
killing by macrophages, and affected individuals are particularly
susceptible to mycobacterial infections.
Complement pathway deficiencies
Loss-of-function mutations have been identified in almost all
the complement pathway proteins (see Fig. 4.4). While most
complement deficiencies are rare, mannose-binding lectin deficiency
is common and affects about 5% of the northern European
population, many of whom are asymptomatic (see below).
Clinical features
Patients with deficiency in complement proteins can present in
different ways. In some cases, the presenting feature is recurrent
infection with encapsulated bacteria, particularly Neisseria spp.,
reflecting the importance of the membrane attack complex in
defence against these organisms. However, genetic deficiencies of
the classical complement pathway (Cl , C2 and C4) also present
with an increased risk of autoimmune disease, particularly SLE
(p. 1 034). Individuals with mannose-binding lectin deficiency have
an increased incidence of bacterial infections if subjected to an
additional cause of immune compromise, such as premature
birth or chemotherapy. The significance of this condition has
been debated, however, since population studies have shown
no overall increase in infectious disease or mortality in patients
with this disorder. Deficiency of the regulatory protein Cl inhibitor
is not associated with recurrent infection but causes recurrent
angioedema (p. 87).
Investigations
Screening for complement deficiencies usually involves specialised
functional tests of complement-mediated haemolysis. These
are known as the CH50 (classical haemolytic pathway 50) and
AP50 (alternative pathway 50) tests. If abnormal, haemolytic
tests are followed by measurement of individual complement
components.
Management
Patients with complement deficiencies should be vaccinated with
meningococcal, pneumococcal and H. influenzae B vaccines to
boost their adaptive immune responses. Lifelong prophylactic
penicillin to prevent meningococcal infection is recommended,
as is early access to acute medical assessment in the event of
infection. Patients should also carry a MedicAlert or similar. At-risk
family members should be screened for complement deficiencies
with functional complement assays. The management of Cl
esterase deficiency is discussed elsewhere.
Primary antibody deficiencies
Primary antibody deficiencies occur as the result of abnormalities
in B-cell function, as summarised in Figure 4.11. They are
characterised by recurrent bacterial infections, particularly of the
respiratory and gastrointestinal tract. The most common causative
organisms are encapsulated bacteria such as Streptococcus
pneumoniae and H. influenzae. These disorders usually present
in infancy, when the protective benefit of placental transfer of
maternal immunoglobulin has waned. The most important causes
are discussed in more detail below.
X-linked agammaglobulinaemia
This rare X-linked disorder (p. 48) is caused by mutations in the
BTK gene, which encodes Bruton tyrosine kinase, a signalling
protein that is required for B-cell development. Affected males
present with severe bacterial infections during infancy. There is
a marked reduction in B-cell numbers and immunoglobulin levels
are low or undetectable. Management is with immunoglobulin
replacement therapy and antibiotics to treat infections.
Selective IgA deficiency
This is the most common primary antibody deficiency, affecting
1 : 600 northern Europeans. Although IgA deficiency is usually
asymptomatic with no clinical sequelae, about 30% of individuals
experience recurrent mild respiratory and gastrointestinal
infections. The diagnosis can be confirmed by measurement of
IgA levels, which are low or undetectable (<0.05 g/L). In some
Failure of production of IgG antibodies:^
Common variable immune deficiency
Specific antibody deficiency _ J
Immature
B cells
IgM-producing ^
B cells
/Failure of B-cell maturation:
-jX-linked agammaglobulinaemia
Lymphoid
progenitors
^Failure of lymphocyte precursors:
^Severe combined immune deficiency
Stem cells
Bone marrow
Fig. 4.11 B lymphocytes and primary antibody deficiencies (green boxes). (Ig = immunoglobulin)
Failure of IgA production: j
Selective IgA deficiency J
Immune deficiency • 79
4.15 Investigation of primary antibody deficiencies
Circulating lymphocyte
Serum immunoglobulin (Ig) concentrations numbers
IgM
IgG
IgA
igE
B cells
T cells
Test immunisation
Selective IgA
deficiency
Normal
Often elevated
Absent
Normal
Normal
Normal
Not applicable*
Common variable
immune deficiency
Normal or low
Low
Low or absent
Low or absent
Variable
Variable
No antibody response
Specific antibody
Normal
Normal
Normal
Normal
Normal
Normal
No antibody response to
deficiency polysaccharide antigens
*Test immunisation is not usually performed in IgA deficiency but some patients may have impaired responses.
patients, there is a compensatory increase in serum IgG levels.
Specific treatment is generally not required.
Common variable immune deficiency
Common variable immune deficiency (CVID) is characterised by
low serum IgG levels and failure to make antibody responses
to exogenous pathogens. It is a heterogeneous adult-onset
primary immune deficiency of unknown cause. The presentation
is with recurrent infections, and bronchiectasis is a recognised
complication. Paradoxically, antibody-mediated autoimmune
diseases, such as idiopathic thrombocytopenic purpura and
autoimmune haemolytic anaemia, are common in CVID. It is
also associated with an increased risk of malignancy, particularly
lymphoproliferative disease.
Functional IgG antibody deficiency
This is a poorly characterised condition resulting in defective
antibody responses to polysaccharide antigens. Some patients
are also deficient in the antibody subclasses lgG2 and lgG4, and
this condition was previously called IgG subclass deficiency. There
is overlap between specific antibody deficiency, IgA deficiency
and CVID, and some patients may progress to a more global
antibody deficiency over time.
Investigations
Serum immunoglobulins (Box 4.1 5) should be measured in conjunction
with protein and urine electrophoresis to exclude secondary causes of
hypogammaglobulinaemia, and B- and T-lymphocyte subsets should
be measured. Specific antibody responses to known pathogens
should be assessed by measuring IgG antibodies against tetanus,
H. influenzae and S. pneumoniae (most patients will have been
exposed to these antigens through infection or immunisation). If
specific antibody levels are low, immunisation with the appropriate
killed vaccine should be followed by repeat antibody measurement
6-8 weeks later; failure to mount a response indicates a significant
defect in antibody production. These functional tests have generally
superseded IgG subclass quantitation.
Management
Patients with antibody deficiencies generally require aggressive
treatment of infections and prophylactic antibiotics may be
indicated. An exception is deficiency of IgA, which usually does not
require treatment. The mainstay of treatment in most patients with
antibody deficiency is immunoglobulin replacement therapy. This
is derived from plasma from hundreds of donors and contains IgG
antibodies to a wide variety of common organisms. Replacement
immunoglobulin may be administered either intravenously or
subcutaneously, with the aim of maintaining trough IgG levels (the
IgG level just prior to an infusion) within the normal range. This
has been shown to minimise progression of end-organ damage
and improve clinical outcome. Treatment may be self-administered
and is life-long. Benefits of immunisation are limited because of
the defect in IgG antibody production, and as with all primary
immune deficiencies, live vaccines should be avoided.
Primary T-lymphocyte deficiencies
These are a group of diseases characterised by recurrent viral,
protozoal and fungal infections (see Box 4.5). Many T-cell
deficiencies are also associated with defective antibody production
because of the importance of T cells in providing help for B cells.
These disorders generally present in childhood. Several causes
of T-cell deficiency are recognised. These are summarised in
Figure 4.12 and discussed in more detail below.
DiGeorge syndrome
This results from failure of development of the third and fourth
pharyngeal pouches, and is usually caused by a deletion of
chromosome 22q1 1 . The immune deficiency is accounted for by
failure of thymic development; however, the immune deficiency
can be very heterogeneous. Affected patients tend to have very
low numbers of circulating T cells despite normal development
in the bone marrow. It is associated with multiple developmental
anomalies, including congenital heart disease, hypoparathyroidism,
tracheo-oesophageal fistulae, cleft lip and palate.
Bare lymphocyte syndromes
These rare disorders are caused by mutations in a variety of
genes that regulate expression of HLA molecules or their transport
to the cell surface. If HLA class I molecules are affected, CD8+
lymphocytes fail to develop normally, while absent expression
of HLA class II molecules affects CD4+ lymphocyte maturation.
In addition to recurrent infections, failure to express HLA class I
is associated with systemic vasculitis caused by uncontrolled
activation of NK cells.
Severe combined immune deficiency
Severe combined immune deficiency (SCID) results from mutations
in a number of genes that regulate lymphocyte development,
with failure of T-cell maturation, with or without accompanying
B- and NK-cell maturation. The most common cause is X-linked
SCID, resulting from loss-of-f unction mutations in the interleukin-2
receptor gamma (IL2RG) gene. The gene product is a component
of several interleukin receptors, including those for IL-2, IL-7
and IL-15, which are absolutely required for T-cell and NK
development. This results in T-cell-negative, NK-cell-negative,
80 • CLINICAL IMMUNOLOGY
Failure of thymic
development:
DiGeorge syndrome^
Failure of expression
of HLA molecules:
Bare lymphocyte
Lymphoid progenitors
Failure of lymphocyte
precursors:
Severe combined
immune deficiency
Thymus
Export of mature
T lymphocytes
to periphery
Proliferation and
maturation of thymocytes
Stem
cells
Failure of apoptosis:
Autoimmune lymphoproliferative
syndromes
Failure of cytokine production:
Cytokine deficiencies
Apoptotic cell death
T-lymphocyte activation
and effector function
Fig. 4.12 T-lymphocyte function and dysfunction (green boxes). (HLA = human leucocyte antigen)
B-cell-positive SCID. Another cause is deficiency of the enzyme
adenosine deaminase (ADA), which causes lymphocyte death due
to accumulation of toxic purine metabolites intracellularly, resulting
in T-cell-negative, B-cell-negative and NK-cell-negative SCID.
The absence of an effective adaptive immune response causes
recurrent bacterial, fungal and viral infections soon after birth. Bone
marrow transplantation (BMT; p. 936) is the treatment option of
first choice. Gene therapy has been approved for treatment of
ADA deficiency when there is no suitable donor for BMT and is
under investigation for a number of other causes of SCID.
Investigations
The principal tests for T-lymphocyte deficiencies are a total
lymphocyte count and quantitation of individual lymphocyte
subpopulations. Serum immunoglobulins should also be measured.
Second-line, functional tests of T-cell activation and proliferation
may be indicated. Patients in whom T-lymphocyte deficiencies
are suspected should be tested for HIV infection (p. 310).
Management
Patients with T-cell deficiencies should be considered for anti-
Pneumocystis and antifungal prophylaxis, and require aggressive
management of infections when they occur. Immunoglobulin
replacement is indicated for associated defective antibody
production. Stem cell transplantation (p. 936) or gene therapy
may be appropriate in some disorders. Where a family history is
known and antenatal testing confirms a specific defect, stem cell
therapy prior to recurrent invasive infection can improve outcome.
| Autoimmune lymphoproliferative syndrome
This rare disorder is caused by failure of normal lymphocyte
apoptosis, most commonly due to mutations in the FAS gene,
which encodes Fas, a signalling protein that regulates programmed
cell death in lymphocytes. This results in massive accumulation
of autoreactive T cells, which cause autoimmune-mediated
anaemia, thrombocytopenia and neutropenia. Other features
include lymphadenopathy, splenomegaly and a variety of other
autoimmune diseases. Susceptibility to infection is increased
because of the neutropenia.
Secondary immune deficiencies
Secondary immune deficiencies are much more common than
primary immune deficiencies and occur when the immune system
is compromised by external factors (Box 4.16). Common causes
include infections, such as HIV and measles, and cytotoxic
4.16 Causes of secondary immune deficiency
Physiological
• Ageing
• Pregnancy
• Prematurity
Infection
• HIV infection
• Mycobacterial infection
• Measles
Iatrogenic
• Immunosuppressive therapy
• Stem cell transplantation
• Anti neoplastic agents
• Radiation injury
• Glucocorticoids
• Antiepileptic agents
Malignancy
• B-cell malignancies including
• Solid tumours
leukaemia, lymphoma and
• Thymoma
myeloma
Biochemical and nutritional disorders
• Malnutrition
• Specific mineral deficiencies
• Renal insufficiency/dialysis
(iron, zinc)
• Diabetes mellitus
Other conditions
• Burns
• Asplenia/hyposplenism
Autoimmune disease • 81
£
and immunosuppressive drugs, particularly those used in the
management of transplantation, autoimmunity and cancer.
Physiological immune deficiency occurs at the extremes of life; the
decline of the immune response in the elderly is known as immune
senescence (Box 4.17). Management of secondary immune
deficiency is described in the relevant chapters on infectious
diseases (Ch. 11), HIV (Ch. 12), haematological disorders
(Ch. 23) and oncology (Ch. 33).
Periodic fever syndromes
These rare disorders are characterised by recurrent episodes
of fever and organ inflammation, associated with an elevated
acute phase response (p. 74).
^Familial Mediterranean fever
Familial Mediterranean fever (FMF) is the most common of the
familial periodic fevers, predominantly affecting Mediterranean
people, including Arabs, Turks, Sephardic Jews and Armenians. It
results from mutations of the MEFV gene, which encodes a protein
called pyrin that regulates neutrophil-mediated inflammation by
indirectly suppressing the production of IL-1 . FMF is characterised
by recurrent painful attacks of fever associated with peritonitis,
pleuritis and arthritis, which last for a few hours to 4 days and
are associated with markedly increased CRP levels. Symptoms
resolve completely between episodes. Most individuals have
their first attack before the age of 20. The major complication
of FMF is AA amyloidosis (see below). Colchicine significantly
reduces the number of febrile episodes in 90% of patients but
is ineffective during acute attacks.
I Mevalonic aciduria (mevalonate
kinase deficiency)
Mevalonate kinase deficiency, previously known as hyper-lgD
syndrome, is an autosomal recessive disorder that causes recurrent
attacks of fever, abdominal pain, diarrhoea, lymphadenopathy,
arthralgia, skin lesions and aphthous ulceration. Most patients
are from Western Europe, particularly the Netherlands and
northern France. It is caused by loss-of-function mutations in
the gene encoding mevalonate kinase, which is involved in the
metabolism of cholesterol. It remains unclear why this causes an
inflammatory periodic fever. Serum IgD and IgA levels may be
persistently elevated, and CRP levels are increased during acute
attacks. Standard anti-inflammatory drugs, including colchicine
and glucocorticoids, are ineffective in suppressing the attacks
but IL-1 inhibitors, such as anakinra, and TNF inhibitors, such as
etanercept, may improve symptoms and can induce complete
remission in some patients.
| TNF receptor-associated periodic syndrome
TNF receptor-associated periodic syndrome (TRAPS) also known
as Hibernian fever, is an autosomal dominant syndrome caused
by mutations in the TNFRSF1A gene. The presentation is with
recurrent attacks of fever, arthralgia, myalgia, serositis and
rashes. Attacks may be prolonged for 1 week or more. During a
typical attack, laboratory findings include neutrophilia, increased
CRP and elevated IgA levels. The diagnosis can be confirmed
by low serum levels of the soluble type 1 TNF receptor and by
mutation screening of the TNFRSF1A gene. As in FMF, the major
complication is amyloidosis, and regular screening for proteinuria
is advised. Acute episodes respond to systemic glucocorticoids.
Therapy with IL-1 inhibitors, such as anakinra, can be effective
in preventing attacks.
Amyloidosis
Amyloidosis is the name given to a group of acquired and
hereditary disorders characterised by the extracellular deposition
of insoluble proteins.
Pathophysiology
Amyloidosis is caused by deposits consisting of fibrils of
the specific protein involved, linked to glycosaminoglycans,
proteoglycans and serum amyloid P. Protein accumulation may
be localised or systemic, and the clinical manifestations depend
on the organ(s) affected. Amyloid diseases are classified by the
aetiology and type of protein deposited (Box 4.18).
Clinical features
The clinical presentation may be with nephrotic syndrome
(p. 395), cardiomyopathy (p. 538) or peripheral neuropathy
(p. 1138). Amyloidosis should always be considered as a potential
diagnosis in patients with these disorders when the cause is
unclear.
Investigations
The diagnosis is established by biopsy, which may be of an
affected organ, rectum or subcutaneous fat. The pathognomonic
histological feature is apple-green birefringence of amyloid
deposits when stained with Congo red dye and viewed under
polarised light. Immunohistochemical staining can identify the
type of amyloid fibril present. Quantitative scintigraphy with
radiolabelled serum amyloid P is a valuable tool in determining
the overall load and distribution of amyloid deposits.
Management
The aims of treatment are to support the function of affected
organs and, in acquired amyloidosis, to prevent further amyloid
deposition through treatment of the primary cause. When the latter
is possible, regression of existing amyloid deposits may occur.
Autoimmune disease
Autoimmunity can be defined as the presence of immune responses
against self-tissue. This may be a harmless phenomenon, identified
4.17 Immune senescence
• T-cell responses: decline, with reduced delayed-type
hypersensitivity responses.
• Antibody production: decreased for many exogenous antigens.
Although autoantibodies are frequently detected, autoimmune
disease is less common.
• Response to vaccination: reduced; 30% of healthy older people
may not develop protective immunity after influenza vaccination.
• Allergic disorders and transplant rejection: less common.
• Susceptibility to infection: increased; community-acquired
pneumonia by threefold and urinary tract infection by 20-fold.
Latent infections, including tuberculosis and herpes zoster, may be
reactivated.
• Manifestations of inflammation: may be absent, with lack of
pyrexia or leucocytosis.
• Secondary immune deficiency: common.
82 • CLINICAL IMMUNOLOGY
4.18 Causes of amyloidosis
Disorder
Pathological basis
Predisposing conditions
Other features
Acquired systemic amyloidosis
Reactive (AA) amyloidosis
Increased production of serum amyloid
Chronic infection (tuberculosis,
90% of patients present with
(P- 81)
A as part of prolonged or recurrent
bronchiectasis, chronic abscess,
non-selective proteinuria or nephrotic
acute inflammatory response
osteomyelitis)
Chronic inflammatory diseases
(untreated rheumatoid arthritis,
familial Mediterranean fever)
syndrome
Light chain amyloidosis (AL)
Increased production of monoclonal
Monoclonal gammopathies,
Restrictive cardiomyopathy, peripheral
light chain
including myeloma, benign
and autonomic neuropathy, carpal
gammopathies and plasmacytoma
tunnel syndrome, proteinuria,
spontaneous purpura, amyloid
nodules and plaques
Macroglossia occurs rarely but is
pathognomonic
Prognosis is poor
Dialysis-associated (A(32M)
Accumulation of circulating
Renal dialysis
Carpal tunnel syndrome, chronic
amyloidosis
p2-microglobulin due to failure of renal
arthropathy and pathological fractures
catabolism in kidney failure
secondary to amyloid bone cyst
formation
Manifestations occur 5-1 0 years
after the start of dialysis
Senile systemic amyloidosis
Normal transthyretin protein deposited
Age >70 years
Feature of normal ageing (affects
in tissues
>90% of 90-year-olds)
Usually asymptomatic
Hereditary systemic amyloidosis
>20 forms of hereditary Production of protein with an abnormal Autosomal dominant inheritance Peripheral and autonomic neuropathy,
systemic amyloidosis structure that predisposes to amyloid cardiomyopathy
fibril formation. Most commonly due to Renal involvement unusual
mutations in transthyretin gene 1 0% of gene carriers are
asymptomatic throughout life
only by the presence of low-titre autoantibodies or autoreactive
T cells. However, if these responses cause significant organ
damage, autoimmune diseases occur. These are a major cause
of chronic morbidity and disability, affecting up to 1 in 30 adults
at some point during life.
Pathophysiology
Autoimmune diseases result from the failure of immune tolerance,
the process by which the immune system recognises and
accepts self-tissue. Central immune tolerance occurs during
lymphocyte development, when T and B lymphocytes that
recognise self-antigens are eliminated before they develop into
fully immunocompetent cells. This process is most active in fetal
life but continues throughout life as immature lymphocytes are
generated. Some autoreactive cells inevitably evade deletion and
escape into the circulation, however, and are controlled through
peripheral tolerance mechanisms. Peripheral immune tolerance
mechanisms include the suppression of autoreactive cells by
regulatory T cells; the generation of functional hyporesponsiveness
(anergy) in lymphocytes that encounter antigen in the absence of
the co-stimulatory signals that accompany inflammation; and cell
death by apoptosis. Autoimmune diseases develop when self¬
reactive lymphocytes escape from these tolerance mechanisms.
Multiple genetic and environmental factors contribute to the
development of autoimmune disease. Autoimmune diseases are
much more common in women than in men, for reasons that
remain unclear. Many are associated with genetic variations in
the HLA loci, reflecting the importance of HLA genes in shaping
lymphocyte responses. Other important susceptibility genes include
4.19 Association of specific gene polymorphisms
with autoimmune diseases
Gene
Function
Diseases
HLA
complex
Key determinants of
antigen presentation to
T cells
Most autoimmune
diseases
PTPN22
Regulation of T- and
B-cell receptor signalling
Rheumatoid arthritis, type
1 diabetes, systemic
lupus erythematosus
CTLA4
Important co-stimulatory
molecule that transmits
inhibitory signals to T
cells
Rheumatoid arthritis, type
1 diabetes
IL23R
Cytokine-mediated
control of T cells
Inflammatory bowel
disease, psoriasis,
ankylosing spondylitis
TNFRSF1A
Control of tumour
necrosis factor network
Multiple sclerosis
ATG5
Autophagy
Systemic lupus
erythematosus
those determining cytokine activity, co-stimulation (the expression
of second signals required for full T-cell activation; see Fig. 4.7)
and cell death. Many of the same gene variants underlie multiple
autoimmune disorders, reflecting their common pathogenesis
(Box 4.19). Even though some of these associations are the
strongest that have been identified in complex genetic diseases,
Autoimmune disease • 83
they have very limited predictive value and are generally not
useful in determining management of individual patients. Several
environmental factors may be associated with autoimmunity in
genetically predisposed individuals, including infection, cigarette
smoking and hormone levels. The most widely studied of these is
infection, as occurs in acute rheumatic fever following streptococcal
infection or reactive arthritis following bacterial infection. Several
mechanisms have been invoked to explain the autoimmunity
that occurs after an infectious trigger. These include cross¬
reactivity between proteins expressed by the pathogen and the
host (molecular mimicry), such as Guillain-Barre syndrome and
Campylobacter infection (p. 1140); release of sequestered antigens
from tissues that are damaged during infections that are not usually
visible to the immune system; and production of inflammatory
cytokines that overwhelm the normal control mechanisms that
prevent bystander damage. Occasionally, autoimmune disease may
be an adverse effect of drug treatment. For example, metabolic
products of the anaesthetic agent halothane can bind to liver
enzymes, resulting in a structurally novel protein that is recognised
as a foreign antigen by the immune system. This can provoke
the development of autoantibodies and activated T cells, which
can cause hepatic necrosis.
Clinical features
The clinical presentation of autoimmune disease is highly variable.
Autoimmune diseases can be classified by organ involvement or
by the predominant mechanism responsible for tissue damage.
The Gell and Coombs classification of hypersensitivity is the most
widely used, and distinguishes four types of immune response
that result in tissue damage (Box 4.20).
• Type I hypersensitivity is relevant in allergy but is not
associated with autoimmune disease.
• Type II hypersensitivity causes injury to a single tissue or
organ and is mediated by specific autoantibodies.
• Type III hypersensitivity results from deposition of immune
complexes, which initiates activation of the classical
complement cascade, as well as recruitment and
activation of phagocytes and CD4+ lymphocytes. The site
of immune complex deposition is determined by the
relative amount of antibody, size of the immune
complexes, nature of the antigen and local
haemodynamics. Generalised deposition of immune
complexes gives rise to systemic diseases such as SLE.
• Type IV hypersensitivity is mediated by activated T cells
and macrophages, which together cause tissue damage.
Investigations
Autoantibodies
Many autoantibodies have been identified and are used in the
diagnosis and monitoring of autoimmune diseases, as discussed
elsewhere in this book. Antibodies can be quantified either by
titre (the maximum dilution of the serum at which the antibody
can be detected) or by concentration in standardised units using
an enzyme-linked immunosorbent assay (ELISA) in which the
antigen is used to coat microtitre plates to which the patient’s
serum is added (Fig. 4.13A). Qualitative tests are also employed
for antinuclear antibodies in which the pattern of nuclear staining
is recorded (Fig. 4.1 3B).
Quantitate on
plate reader
/QQQ\
/ooo\
/C3C3C5\
Nucleolar Homogenous Speckled
Fig. 4.13 Autoantibody testing. [A] Measurement of antibody levels by
enzyme-linked immunosorbent assay (ELISA). The antigen of interest is
used to coat microtitre plates to which patient serum is added. If
autoantibodies are present, these bind to the target antigen on the
microtitre plate. The amount of bound antibody is quantitated by adding a
secondary antibody linked to an enzyme that converts a colourless
substrate to a coloured one, which can be detected by a plate reader.
Hfl Qualitative analysis of autoantibodies by patterns of nuclear staining.
In this assay, patient serum is added to cultured cells and a secondary
antibody is added with a fluorescent label to detect any bound antibody.
If antinuclear antibodies are present, they are detected as bright green
staining. Different antinuclear antibody patterns may be seen in different
types of connective tissue disease (Ch. 24). B (Nucleolar and
Homogenous), Courtesy of Juliet Dunphy, Biomedical Scientist, Royal
United Hospital Bath, previously of Bath Institute of Rheumatic Diseases,
UK; (Speckled), Courtesy of Mr Richard Brown, Clinical Scientist in
Immunology, Southwest Pathology Services, UK.
[a] Antibodies Detection of
bind to target bound antibody
Target antigen Target antigen
4.20 Gell and Coombs classification of hypersensitivity diseases
Type
Mechanism
Example of disease in
response to exogenous agent
Example of autoimmune disease
Type 1
Immediate hypersensitivity
IgE-mediated mast cell degranulation
Allergic disease
None described
Type II
Antibody-mediated
Binding of cytotoxic IgG or IgM antibodies
to antigens on cell surface causes cell
killing
ABO blood transfusion reaction
Hyperacute transplant rejection
Autoimmune haemolytic anaemia
Idiopathic thrombocytopenic purpura
Goodpasture’s disease
Type III
Immune complex-mediated
IgG or IgM antibodies bind soluble antigen
to form immune complexes that trigger
classical complement pathway activation
Serum sickness
Farmer’s lung
Systemic lupus erythematosus
Cryoglobulinaemia
Type IV
Delayed type
Activated T cells, and phagocytes
Acute cellular transplant rejection
Nickel hypersensitivity
Type 1 diabetes
Hashimoto’s thyroiditis
84 • CLINICAL IMMUNOLOGY
4.21 Classification of cryoglobulins
Type 1
Type II
Type III
Immunoglobulin (Ig)
isotype and specificity
Isolated monoclonal IgM
paraprotein with no particular
specificity
Immune complexes formed by monoclonal
IgM paraprotein directed towards constant
region of IgG
Immune complexes formed by
polyclonal IgM or IgG directed towards
constant region of IgG
Prevalence
25%
25%
50%
Disease association
Lymphoproliferative disease,
especially Waldenstrom
macroglobulinaemia (p. 966)
Infection, particularly hepatitis C;
lymphoproliferative disease
Infection, particularly hepatitis C;
autoimmune disease, including
rheumatoid arthritis and systemic lupus
erythematosus
Symptoms
Hyperviscosity:
Raynaud’s phenomenon
Acrocyanosis
Retinal vessel occlusion
Arterial and venous thrombosis
Small -vessel vasculitis:
Purpuric rash
Arthralgia
Neuropathy
Cutaneous ulceration, hepatosplenomegaly,
glomerulonephritis, Raynaud’s phenomenon
Small -vessel vasculitis:
Purpuric rash, arthralgia
Cutaneous ulceration
Hepatosplenomegaly,
glomerulonephritis
Raynaud’s phenomenon
Protein electrophoresis
Monoclonal IgM paraprotein
Monoclonal IgM paraprotein
No monoclonal paraprotein
Rheumatoid factor
Negative
Strongly positive
Strongly positive
Complement
Usually normal
Decreased C4
Decreased C4
Serum viscosity
Raised
Normal
Normal
Complement
Measurement of complement components can be useful in the
evaluation of immune complex- mediated diseases. Classical
complement pathway activation leads to a decrease in circulating
C4 levels and is often also associated with decreased C3 levels.
Serial measurement of C3 and C4 is a useful surrogate measure
of disease activity in conditions such as SLE.
Cryoglobulins
Cryoglobulins are antibodies directed against other
immunoglobulins, forming immune complexes that precipitate
in the cold. They can lead to type III hypersensitivity reactions,
with typical clinical manifestations including purpuric rash, often
of the lower extremities, arthralgia and peripheral neuropathy.
Cryoglobulins are classified into three types, depending on the
properties of the immunoglobulin involved (Box 4.21). Testing
for cryoglobulins requires the transport of a serum specimen to
the laboratory at 37°C. Cryoglobulins should not be confused
with cold agglutinins; the latter are autoantibodies specifically
directed against the l/i antigen on the surface of red cells, which
can cause intravascular haemolysis in the cold (p. 950).
Management
The management of autoimmune disease depends on the organ
system involved and further details are provided elsewhere
in this book. In general, treatment of autoimmune diseases
involves the use of glucocorticoids and immunosuppressive
agents, which are increasingly used in combination with biologic
agents targeting disease-specific cytokines and their receptors.
Not all conditions require immune suppression, however. For
example, the management of coeliac disease involves dietary
gluten withdrawal, while autoimmune hypothyroidism requires
appropriate thyroxine supplementation.
Allergy
Allergic diseases are a common and increasing cause of illness,
affecting between 1 5% and 20% of the population at some time.
They comprise a range of disorders from mild to life-threatening
and affect many organs. Atopy is the tendency to produce
an exaggerated IgE immune response to otherwise harmless
environmental substances, while an allergic disease can be
defined as the clinical manifestation of this inappropriate IgE
immune response.
Pathophysiology
The immune system does not normally respond to the many
environmental substances to which it is exposed on a daily basis.
In allergic individuals, however, an initial exposure to a normally
harmless exogenous substance (known as an allergen) triggers
the production of specific IgE antibodies by activated B cells.
These bind to high-affinity IgE receptors on the surface of mast
cells, a step that is not itself associated with clinical sequelae.
However, re-exposure to the allergen binds to and cross-links
membrane-bound IgE, which activates the mast cells, releasing
a variety of vasoactive mediators (the early phase response;
Fig. 4.14 and see Box 4.9). This type I hypersensitivity reaction
forms the basis of an allergic reaction, which can range from
sneezing and rhinorrhoea to anaphylaxis (Box 4.22). In some
individuals, the early phase response is followed by persistent
activation of mast cells, manifest by ongoing swelling and local
inflammation. This is known as the late phase reaction and is
mediated by mast cell metabolites, basophils, eosinophils and
macrophages. Long-standing or recurrent allergic inflammation
may give rise to a chronic inflammatory response characterised
by a complex infiltrate of macrophages, eosinophils and T
lymphocytes, in addition to mast cells and basophils. Once
this has been established, inhibition of mast cell mediators
with antihistamines is clinically ineffective in isolation. Mast cell
activation may also be non-specifically triggered through other
signals, such as neuropeptides, anaphylotoxins and bacterial
peptides.
The increasing incidence of allergic diseases is largely
unexplained but one widely held theory is the ‘hygiene hypothesis’.
This proposes that infections in early life are critically important
in maturation of the immune response and bias the immune
system against the development of allergies; the high prevalence
Allergy • 85
Fig. 4.14 Type I (immediate) hypersensitivity response. [A] After an encounter with allergen, B cells produce immunoglobulin E (IgE) antibody
against the allergen. H Specific IgE antibodies bind to circulating mast cells via high-affinity IgE cell surface receptors. [C] On re-encounter with allergen,
the allergen binds to the IgE antibody-coated mast cells. This cross-linking of the IgE triggers mast cell activation with release of vasoactive mediators
(see Box 4.9).
4.22 Clinical manifestations of allergy
Dermatological
• Urticaria
• Atopic eczema if chronic
Respiratory
• Allergic contact eczema
• Angioedema
• Asthma
• Atopic rhinitis
Ophthalmological
• Allergic conjunctivitis
Gastrointestinal
• Food allergy
Other
• Anaphylaxis
• Drug allergy
• Allergy to insect venom
of allergic disease is the penalty for the decreased exposure
to infection that has resulted from improvements in sanitation
and health care. Genetic factors also contribute strongly to the
development of allergic diseases. A positive family history is
common in patients with allergy, and genetic association studies
have identified a wide variety of predisposing variants in genes
controlling innate immune responses, cytokine production, IgE
levels and the ability of the epithelial barrier to protect against
environmental agents. The expression of a genetic predisposition
is complex; it is governed by environmental factors, such as
pollutants and cigarette smoke, and the incidence of bacterial
and viral infection.
Clinical features
Common presentations of allergic disease are shown in Box
4.22. Those that affect the respiratory system and skin are
discussed in more detail in Chapters 17 and 29, respectively.
Here we focus on general principles of the approach to the
allergic patient, some specific allergies and anaphylaxis.
Insect venom allergy
Local non-lgE-mediated reactions to insect stings are common
and may cause extensive swelling around the site lasting up to
7 days. These usually do not require specific treatment. Toxic
reactions to venom after multiple (50-100) simultaneous stings
may mimic anaphylaxis. In addition, exposure to large amounts
of insect venom frequently stimulates the production of IgE
antibodies, and thus may be followed by allergic reactions to
single stings. Allergic IgE-mediated reactions vary from mild to
life-threatening. Antigen-specific immunotherapy (desensitisation;
see below) with bee or wasp venom can reduce the incidence
of recurrent anaphylaxis from 50-60% to approximately 1 0%
but requires up to 5 years of treatment.
Peanut allergy
Peanut allergy is the most common food-related allergy. More
than 50% of patients present before the age of 3 years and
some individuals react to their first known exposure to peanuts,
thought to result from sensitisation to arachis oil in topical creams.
Peanuts are ubiquitous in the Western diet, and every year up
to 25% of peanut-allergic individuals experience a reaction as
a result of inadvertent exposure.
Birch oral allergy syndrome
This syndrome is characterised by the combination of birch pollen
hay fever and local oral symptoms, including itch and angioedema,
after contact with certain raw fruits, raw vegetables and nuts.
Cooked fruits and vegetables are tolerated without difficulty. It
is due to shared or cross- reactive allergens that are destroyed
by cooking or digestion, and can be confirmed by skin prick
testing using fresh fruit. Severe allergic reactions are unusual.
Diagnosis
When assessing a patient with a complaint of allergy, it is important
to identify what the patient means by the term, as up to 20%
of the UK population describe themselves as having a food
allergy; in fact, less than 1 % have true allergy, as defined by an
IgE-mediated hypersensitivity reaction confirmed on double-blind
challenge. The nature of the symptoms should be established
and specific triggers identified, along with the predictability of a
reaction, and the time lag between exposure to a potential allergen
and onset of symptoms. An allergic reaction usually occurs within
minutes of exposure and provokes predictable, reproducible
symptoms such as angioedema, urticaria and wheezing. Specific
enquiry should be made about other allergic symptoms, past and
present, and about a family history of allergic disease. Potential
allergens in the home and workplace should be identified. A
detailed drug history should always be taken, including details
of adherence to medication, possible adverse effects and the
use of over-the-counter or complementary therapies.
86 • CLINICAL IMMUNOLOGY
Investigations
Skin-prick tests
Skin-prick testing is a key investigation in the assessment
of patients suspected of having allergy. A droplet of diluted
standardised allergen is placed on the forearm and the skin is
superficially punctured through the droplet with a sterile lancet.
Positive and negative control material must be included in the
assessment. After 1 5 minutes, a positive response is indicated
by a local weal and flare response 2 mm or more larger than
the negative control. A major advantage of skin-prick testing is
that patient can clearly see the results, which may be useful in
gaining adherence to avoidance measures. Disadvantages include
the remote risk of a severe allergic reaction, so resuscitation
facilities should be available. Results are unreliable in patients
with extensive skin disease. Antihistamines inhibit the magnitude
of the response and should be discontinued for at least 3 days
before testing; low-dose glucocorticoids do not influence
test results. A number of other prescribed medicines can
also lead to false-negative results, including amitriptyline and
risperidone.
Specific IgE tests
An alternative to skin-prick testing is the quantitation of IgE directed
against the suspected allergen. The sensitivity and specificity of
specific IgE tests (previously known as radioallergosorbent tests,
RAST) are lower than those of skin-prick tests. However, IgE
tests may be very useful if skin testing is inappropriate, such
as in patients taking antihistamines or those with severe skin
disease or dermatographism. They can also be used to test for
cross-reactivity - for example, with multiple insect venoms, where
component-resolved diagnostics, using recombinant allergens,
is increasingly used rather than crude allergen extract. Specific
IgE tests can also be used post-mortem to identify allergens
responsible for lethal anaphylaxis.
Supervised exposure to allergen
Tests involving supervised exposure to an allergen (allergen
challenge) are usually performed in specialist centres on carefully
selected patients, and include bronchial provocation testing,
nasal challenge, and food or drug challenge. These may be
particularly useful in the investigation of occupational asthma or
food allergy. Patients can be considered for challenge testing
when skin tests and/or IgE tests are negative, as they can be
helpful in ruling out allergic disease.
Mast cell tryptase
Measurement of serum mast cell tryptase is extremely useful in
investigating a possible anaphylactic event. Ideally, measurements
should be made at the time of the reaction following appropriate
resuscitation, and 3 hours and 24 hours later. The basis of the
test is the fact that circulating levels of mast cell degranulation
products rise dramatically to peak 1-2 hours after a systemic
allergic reaction. Tryptase is the most stable of these and is
easily measured in serum.
Serum total IgE
Serum total IgE measurements are not routinely indicated in
the investigation of allergic disease, other than to aid in the
interpretation of specific IgE results, as false-positive specific
IgEs are common in patients with atopy, who often have a high
total IgE level. Although atopy is the most common cause of an
elevated total IgE in developed countries, there are many other
causes, including parasitic and helminth infections (pp. 299 and
288), lymphoma (p. 961), drug reactions and eosinophilic granu¬
lomatosis with polyangiitis (previously known as Churg-Strauss
vasculitis; p. 1 043). Normal total IgE levels do not exclude allergic
disease.
Eosinophilia
Peripheral blood eosinophilia is common in atopic individuals but
lacks specificity. Eosinophilia of more than 20% or an absolute
eosinophil count over 1.5x109/L should initiate a search for a
non-atopic cause, such as eosinophilic granulomatosis with
polyangiitis or parasitic infection (p. 928).
Management
Several approaches can be deployed in the management of
allergic individuals, as discussed below.
Avoidance of the allergen
This is indicated in all cases and should be rigorously attempted,
with the advice of specialist dietitians and occupational physicians
if necessary.
Antihistamines
Antihistamines are useful in the management of allergy as they
inhibit the effects of histamine on tissue H1 receptors. Long-acting,
non-sedating preparations are particularly useful for prophylaxis.
Glucocorticoids
These are highly effective in allergic disease, and if used topically,
adverse effects can be minimised.
Sodium cromoglicate
Sodium cromoglicate stabilises the mast cell membrane, inhibiting
release of vasoactive mediators. It is effective as a prophylactic
agent in asthma and allergic rhinitis but has no role in management
of acute attacks. It is poorly absorbed and therefore ineffective
in the management of food allergies.
Antigen-specific immunotherapy
This involves the sequential administration of increasing doses of
allergen extract over a prolonged period of time. The mechanism
of action is not fully understood but it is highly effective in the
prevention of insect venom anaphylaxis and of allergic rhinitis
secondary to grass pollen. The traditional route of administration
is by subcutaneous injection, which carries a risk of anaphylaxis
and should be performed only in specialised centres. Sublingual
immunotherapy is also increasingly used. Clinical studies to date
do not support the use of allergen immunotherapy for food
hypersensitivity, although this is an area of active investigation.
Omalizumab
Omalizumab is a monoclonal antibody directed against IgE;
it inhibits the binding of IgE to mast cells and basophils. It is
licensed for treatment of refractory chronic spontaneous urticaria
and also for severe persistent allergic asthma that has failed to
respond to standard therapy (p. 572). The dose and frequency
are determined by baseline IgE (measured before the start of
treatment) and body weight. It is under investigation for allergic
rhinitis but not yet approved for this indication.
Adrenaline (epinephrine)
Adrenaline given by injection in the form of a pre-loaded self-
injectable device can be life-saving in the acute management
of anaphylaxis (see Box 4.12).
Angioedema • 87
Angioedema
Angioedema is an episodic, localised, non-pitting swelling of
submucous or subcutaneous tissues.
Pathophysiology
The causes of angioedema are summarised in Box 4.23. It may
be a manifestation of allergy or non-allergic degranulation of mast
cells in response to drugs and toxins. In these conditions the
main cause is mast cell degranulation with release of histamine
and other vasoactive mediators. In hereditary angioedema,
the cause is Cl inhibitor deficiency, which causes increased
local release of bradykinin. Angiotensin-converting enzyme
(ACE) inhibitor-induced angioedema also occurs as the result
of increased bradykinin levels due to inhibition of its breakdown.
Clinical features
Angioedema is characterised by soft-tissue swelling that most
frequently affects the face (Fig. 4.15) but can also affect the
extremities and genitalia. Involvement of the larynx or tongue
may cause life-threatening respiratory tract obstruction, and
oedema of the intestinal mucosa may cause abdominal pain
and distension.
Investigations
Differentiating the mechanism of angioedema is important in
determining the most appropriate treatment. A clinical history
of allergy or drug exposure can give clues to the underlying
diagnosis. If no obvious trigger can be identified, measurement
of complement C4 is useful in differentiating hereditary and
acquired angioedema from other causes. If C4 levels are low,
further investigations should be initiated to look for evidence of
Cl inhibitor deficiency.
Management
Management depends on the underlying cause. Angioedema
associated with allergen exposure generally responds to
antihistamines and glucocorticoids. Following acute management
of angioedema secondary to drug therapy, drug withdrawal
Fig. 4.15 Angioedema. This young man has hereditary angioedema.
[A] Normal appearance. [§] During an acute attack. From Helbert M.
Flesh and bones of immunology. Edinburgh: Churchill Livingstone, Elsevier
Ltd; 2006.
4.23 Types of angioedema
Allergic reaction to
specific trigger
Idiopathic angioedema
Hereditary angioedema
ACE-inhibitor associated
angioedema
Pathogenesis
IgE-mediated degradation
of mast cells
Non-lgE-mediated degranulation
of mast cells
Cl inhibitor deficiency, with
resulting increased local
bradykinin concentration
Inhibition of breakdown of
bradykinin
Key mediator
Histamine
Histamine
Bradykinin
Bradykinin
Prevalence
Common
Common
Rare autosomal dominant
disorder
0.1 -0.2% of patients treated
with ACE inhibitors
Clinical
features
Usually associated with
urticaria
History of other allergies
common
Follows exposure to specific
allergen, in food, animal
dander or insect venom
Usually associated with urticaria
May be triggered by physical
stimuli such as heat, pressure
or exercise
Dermatographism common
Occasionally associated with
underlying infection or thyroid
disease
Not associated with urticaria
or other features of allergy
Does not cause anaphylaxis
May cause life-threatening
respiratory tract obstruction
Can cause severe
abdominal pain
Not associated with urticaria
Does not cause anaphylaxis
Usually affects the head and
neck, and may cause
life-threatening respiratory
tract obstruction
Can occur years after the
start of treatment
Investigations
Specific IgE tests or
skin-prick tests
Specific IgE tests and skin-prick
tests often negative
Hypothyroidism should be
excluded
Complement C4 (invariably
low in acute attacks)
Cl inhibitor levels
No specific investigations
Treatment
Allergen avoidance
Antihistamines
Antihistamines are mainstay of
treatment and prophylaxis
Unresponsive to
antihistamines
Anabolic steroids
Cl inhibitor concentrate or
icatibant for acute attacks
ACE inhibitor should be
discontinued
ARBs should be avoided if
possible unless there is a
strong indication
Associated
drug reactions
Specific drug allergies
NSAIDs
Opioids, radiocontrast media
ACE inhibitors, ARBs
(ACE = angiotensin-converting enzyme; ARBs = angiotensin II receptor blockers; NSAIDs = non-steroidal anti-inflammatory drugs)
88 • CLINICAL IMMUNOLOGY
should prevent further attacks, although ACE inhibitor-induced
angioedema can continue for a limited period post drug
withdrawal. Management of angioedema associated with Cl
inhibitor deficiency is discussed below.
Hereditary angioedema
Hereditary angioedema (HAE), also known as inherited Cl
inhibitor deficiency, is an autosomal dominant disorder caused
by decreased production or activity of Cl inhibitor protein. This
complement regulatory protein inhibits spontaneous activation of
the classical complement pathway (see Fig. 4.4). It also acts as
an inhibitor of the kinin cascade, activation of which increases
local bradykinin levels, giving rise to local pain and swelling.
Clinical features
The angioedema in HAE may be spontaneous or triggered by
local trauma or infection. Multiple parts of the body may be
involved, especially the face, extremities, upper airway and
gastrointestinal tract. Oedema of the intestinal wall causes
severe abdominal pain and many patients with undiagnosed HAE
undergo exploratory laparotomy. The most important complication
is laryngeal obstruction, often associated with minor dental
procedures, which can be fatal. Episodes of angioedema are
self-limiting and usually resolve within 48 hours. Patients with HAE
generally present in adolescence but may go undiagnosed for
many years. A family history can be identified in 80% of cases.
HAE is not associated with allergic diseases and is specifically
not associated with urticaria.
Investigations
Acute episodes are accompanied by low C4 levels; a low C4
during an episode of angioedema should therefore trigger further
investigation. The diagnosis can be confirmed by measurement
of Cl inhibitor levels and function.
Management
Severe acute attacks should be treated with purified Cl inhibitor
concentrate or the bradykinin receptor antagonist icatibant.
Anabolic steroids, such as danazol, can be used to prevent attacks
and act by increasing endogenous production of complement
proteins. Tranexamic acid can be helpful as prophylaxis in some
patients. Patients can be taught to self-administer therapy and
should be advised to carry a MedicAlert or similar.
Acquired Cl inhibitor deficiency
This rare disorder is clinically indistinguishable from HAE but
presents in late adulthood. It is associated with autoimmune
and lymphoproliferative diseases. Most cases are due to the
4.24 Immunological diseases in pregnancy
Allergic disease
• Maternal dietary restrictions during pregnancy or lactation:
current evidence does not support these for prevention of allergic
disease.
• Breastfeeding for at least 4 months: prevents or delays the
occurrence of atopic dermatitis, cow’s milk allergy and wheezing in
early childhood, as compared with feeding formula milk containing
intact cow’s milk protein.
Autoimmune disease
• Suppressed T-cell-mediated immune responses in pregnancy:
may suddenly reactivate post-partum. Some autoimmune diseases
may improve during pregnancy but flare immediately after delivery.
Systemic lupus erythematosus (SLE) is an exception, however, as it
is prone to exacerbation in pregnancy or the puerperium.
• Passive transfer of maternal antibodies: can mediate
autoimmune disease in the fetus and newborn, including SLE,
Graves’ disease and myasthenia gravis.
• Antiphospholipid syndrome (p. 977): an important cause of fetal
loss, intrauterine growth restriction and pre-eclampsia.
• HIV in pregnancy: see p. 326.
development of autoantibodies to Cl inhibitor, but the condition
can also be caused by autoantibodies that activate Cl . Treatment
of the underlying disorder may induce remission of angioedema.
As with HAE, a low C4 is seen during acute episodes.
Transplantation and graft rejection
Transplantation provides the opportunity for definitive treatment
of end-stage organ disease. The major complications are
graft rejection, drug toxicity and infection consequent to
immunosuppression. Transplant survival continues to improve,
as a result of the introduction of less toxic immunosuppressive
agents and increased understanding of the processes of transplant
rejection. Stem cell transplantation and its complications are
discussed on page 936.
Transplant rejection
Solid organ transplantation inevitably stimulates an aggressive
immune response by the recipient, unless the transplant is between
monozygotic twins. The type and severity of the rejection response
is determined by the genetic disparity between the donor and
recipient, the immune status of the host and the nature of the tissue
transplanted (Box 4.25). The most important genetic determinant
4.25 Classification of transplant rejection
Type
Time
Pathological findings
Mechanism
Treatment
Hyperacute rejection
Minutes to hours
Thrombosis, necrosis
Pre-formed antibody to donor
antigens results in complement
activation (type II hypersensitivity)
None - irreversible graft loss
Acute cellular rejection
5-30 days
Cellular infiltration
CD4+ and CD8+ T cells (type IV
hypersensitivity)
Increase immunosuppression
Acute vascular rejection
5-30 days
Vasculitis
Antibody and complement activation
Increase immunosuppression
Chronic allograft failure
>30 days
Fibrosis, scarring
Immune and non-immune
mechanisms
Minimise drug toxicity, control
hypertension and hyperlipidaemia
Transplantation and graft rejection • 89
is the difference between donor and recipient HLA proteins
(p. 67). The extensive polymorphism of these proteins means that
donor HLA antigens are almost invariably recognised as foreign
by the recipient immune system, unless an active attempt has
been made to minimise incompatibility.
• Hyperacute rejection results in rapid and irreversible
destruction of the graft (Box 4.25). It is mediated by
pre-existing recipient antibodies against donor HLA
antigens, which arise as a result of previous exposure
through transplantation, blood transfusion or pregnancy.
It is very rarely seen in clinical practice, as the use of
screening for anti-HLA antibodies and pre-transplant
cross-matching ensures the prior identification of
recipient-donor incompatibility.
• Acute cellular rejection is the most common form of graft
rejection. It is mediated by activated T lymphocytes and
results in deterioration in graft function. If allowed to
progress, it may cause fever, pain and tenderness over
the graft. It is usually amenable to increased
immunosuppressive therapy.
• Acute vascular rejection is mediated by antibody formed
de novo after transplantation. It is more curtailed than the
hyperacute response because of the use of intercurrent
immunosuppression but it is also associated with reduced
graft survival. Aggressive immunosuppressive therapy is
indicated and physical removal of antibody through
plasmapheresis may be indicated in severe causes. Not all
post-transplant anti-donor antibodies cause graft damage;
their consequences are determined by specificity and
ability to trigger other immune components, such as the
complement cascade.
• Chronic allograft failure, also known as chronic rejection,
is a major cause of graft loss. It is associated with
proliferation of transplant vascular smooth muscle,
interstitial fibrosis and scarring. The pathogenesis is poorly
understood but contributing factors include immunological
damage caused by subacute rejection, hypertension,
hyperlipidaemia and chronic drug toxicity.
Investigations
Pre-transplantation testing
HLA typing determines an individual’s HLA polymorphisms and
facilitates donor-recipient matching. Potential transplant recipients
are also screened for the presence of anti-HLA antibodies. The
recipient is excluded from receiving a transplant that carries
these alleles.
Donor-recipient cross-matching is a functional assay that
directly tests whether serum from a recipient (which potentially
contains anti-donor antibodies) is able to bind and/or kill donor
lymphocytes. It is specific to a prospective donor-recipient pair
and is done immediately prior to transplantation. A positive
cross-match is a contraindication to transplantation because of
the risk of hyperacute rejection.
Post-transplant biopsy: C4d staining
C4d is a fragment of the complement protein C4 (see Fig. 4.4).
Deposition of C4d in graft capillaries indicates local activation
of the classical complement pathway and provides evidence of
anti body- mediated damage. This is useful in the early diagnosis
of vascular rejection.
Complications of transplant
immunosuppression
Transplant recipients require indefinite treatment with immuno¬
suppressive agents. In general, two or more immunosuppressive
drugs are used in synergistic combination in order to minimise
adverse effects (Box 4.26). The major complications of long-term
immunosuppression are infection and malignancy. The risk of
some opportunistic infections may be minimised through the use
of prophylactic medication, such as ganciclovir for cytomegalovirus
prophylaxis and trimethoprim-sulfamethoxazole for Pneumocystis
prophylaxis. Immunisation with killed vaccines is appropriate,
although the immune response may be curtailed. Live vaccines
should not be given.
4.26 Immunosuppressive drugs used in transplantation
Drug
Mechanism of action
Major adverse effects
Anti-proliferative agents
Azathioprine, mycophenolate
mofetil
Inhibit lymphocyte proliferation by blocking DNA synthesis
May be directly cytotoxic at high doses
Increased susceptibility to infection
Leucopenia
Hepatotoxicity
Calcineurin inhibitors
Ciclosporin, tacrolimus
Inhibit T-cell signalling; prevent lymphocyte activation;
block cytokine transcription
Increased susceptibility to infection
Hypertension
Nephrotoxicity
Diabetogenic (especially tacrolimus)
Gingival hypertrophy, hirsutism (ciclosporin)
Glucocorticoids
Decrease phagocytosis and release of proteolytic enzymes;
decrease lymphocyte activation and proliferation; decrease
cytokine production; decrease antibody production
Increased susceptibility to infection
Multiple other complications (p. 670)
Anti-thymocyte globulin (ATG)
Antibodies to cell surface proteins deplete or block
T cells
Profound non-specific immunosuppression
Increased susceptibility to infection
Basiliximab
Monoclonal antibody directed against CD25 (IL-2Ra
chain), expressed on activated T cells
Increased susceptibility to infection
Gastrointestinal side-effects
Belatacept
Selectively inhibits T-cell activation through blockade of
CTLA4
Increased susceptibility to infection and malignancy
Gastrointestinal side-effects
Hypertension
Anaemia/leucopenia
90 • CLINICAL IMMUNOLOGY
The increased risk of malignancy arises because T-cell
suppression results in failure to control viral infections associated
with malignant transformation. Virus-associated tumours include
lymphoma (associated with Epstein-Barr virus), Kaposi’s sarcoma
(associated with human herpesvirus 8) and skin tumours
(associated with human papillomavirus). Immunosuppression
is also linked with a small increase in the incidence of common
cancers not associated with viral infection (such as lung, breast
and colon cancer), reflecting the importance of T cells in anti¬
cancer surveillance.
Organ donation
The major problem in transplantation is the shortage of organ
donors. Cadaveric organ donors are usually previously healthy
individuals who experience brainstem death (p. 211), frequently
as a result of road traffic accidents or cerebrovascular events.
Even if organs were obtained from all potential cadaveric donors,
though, their numbers would be insufficient to meet current needs.
An alternative is the use of living donors. Altruistic living donation,
usually from close relatives, is widely used in renal transplantation.
Living organ donation is inevitably associated with some risk
to the donor and it is highly regulated to ensure appropriate
appreciation of the risks involved. Because of concerns about
coercion and exploitation, non-altruistic organ donation (the sale
of organs) is illegal in most countries.
Tumour immunology
Surveillance by the immune system is critically important in
monitoring and removing damaged and mutated cells as they
arise. The ability of the immune system to kill cancer cells
effectively is influenced by tumour immunogenicity and specificity.
Many cancer antigens are poorly expressed and specific antigens
can mutate, either spontaneously or in response to treatment,
which can result in evasion of immune responses. In addition,
the inhibitory pathways that are used to maintain self-tolerance
and limit collateral tissue damage during antimicrobial immune
responses can be co-opted by cancerous cells to evade immune
destruction. Recognition and understanding of these immune
checkpoint pathways has led to the development of a number
of new treatments for cancers that are otherwise refractory to
treatment. For example, antibodies to CTLA4, a co-stimulatory
molecule normally involved in down-regulation of immune
responses, have been licensed for refractory melanoma, and
antibodies to PD1 (programmed cell death protein 1) are used in
melanoma, non-small-cell lung cancer and renal cell carcinoma.
Potential risks include the development of autoimmunity,
reflecting the importance of these pathways in the control of
self-tolerance.
Further information
allergy.org.au An Australasian site providing information on allergy,
asthma and immune diseases.
allergyuk.org UK site for patients and health-care professionals.
anaphylaxis.org.uk Provides information and support for patients with
severe allergies.
info4pi.org A US site managed by the non-profit Jeffrey Model!
Foundation, which provides extensive information about primary
immune deficiencies.
niaid.nih.gov National Institute of Allergy and Infectious Diseases:
provides useful information on a variety of allergic diseases, immune
deficiency syndromes and autoimmune diseases.
Population health
and epidemiology
92 • POPULATION HEALTH AND EPIDEMIOLOGY
The UK Faculty of Public Health defines public health as ‘the
science and art of promoting and protecting health and well-being,
preventing ill-health and prolonging life through the organised
efforts of society’. This definition recognises that there is a
collective responsibility for the health of the population that
requires partnerships between government, health services
and others to promote and protect health and prevent disease.
Population health has been defined as ‘the health outcomes
of a group of individuals, including the distribution of such
outcomes within the group’. Medical doctors can play a role
in all these efforts to improve health both through their clinical
work and through their support of broader actions to improve
public health.
Global burden of disease and
underlying risk factors
The Global Burden of Disease (GBD) exercise was initiated by
the World Bank in 1992, with first estimates appearing in 1993.
Regular updated figures have been published since, together with
projections of future disease burden. The aim was to produce
reliable and internally consistent estimates of disease burden
for all diseases and injuries, and to assess their physiological,
behavioural and social risk factors, so that this information
could be made available to health workers, researchers and
policy-makers.
The GBD exercise adopted the metric ‘disability adjusted
life year’ (DALY) to describe population health. This combines
information about premature mortality in a population (measured
as Years of Life Lost from an ‘expected’ life expectancy) and years
of life lived with disability (Years of Life lived with Disability, which
is weighted by a severity factor). The International Classification
of Disease (ICD) rules, which assign one cause to each death,
are followed. All estimates are presented by age and sex groups
and by regions of the world. Many countries now also report
their own national burden of disease data.
Life expectancy
Global life expectancy at birth increased from 61 .7 years in 1 980
to 71.8 years in 2015, an increase of 0.29 years per calendar
year. This change is due to a substantial fall in child mortality
(mainly caused by common infections), partly offset by rises in
mortality from adult conditions such as diabetes and chronic
kidney disease. Some areas have not shown these increases
in life expectancy in men, often due to war and interpersonal
violence.
Global causes of death and disability
Box 5.1 shows a ranked list of the major causes of global
premature deaths in 2015. Communicable, maternal, neonatal
and nutritional causes accounted for about one-quarter of deaths
worldwide, down from about one-third in 1990. In contrast, deaths
from non-communicable diseases are increasing in importance
and now account for about two-thirds of all deaths globally,
including about 13 million from ischaemic heart disease and
stroke, and about 8 million from cancer. The age-standardised
death rates for most diseases globally are falling. However, despite
this, the numbers of deaths from many diseases are rising due
to global population growth and the change in age structure of
5.1 Global premature mortality: top 15 ranked
causes, 2015
1 . Ischaemic heart disease (4)
2. Cerebrovascular disease (5)
3. Lower respiratory infections (1)
4. Neonatal preterm birth complications (2)
5. Diarrhoeal diseases (3)
6. Neonatal encephalopathy (6)
7. HIV/AIDS (29)
8. Road injuries (10)
9. Malaria (7)
10. Chronic obstructive pulmonary disease (12)
1 1 . Congenital anomalies (9)
12. Tuberculosis (11)
13. Lung cancer3 (20)
14. Self-harm (16)
15. Diabetes (>30)
Ty Years of Life Lost (YLL). 2Rank in 1990 is shown in brackets. 3'AII cancers
combined’ would rank in the top three causes.
i
1 . Lower back and neck pain (1)
2. Sense organ diseases (3)
3. Depressive disorders (4)
4. Iron deficiency anaemia (2)
5. Skin diseases (5)
6. Diabetes (9)
7. Migraine (6)
8. Other musculoskeletal conditions3 (7)
9. Anxiety disorders (8)
10. Oral disorders (11)
11. Asthma (10)
12. Schizophrenia (13)
13. Osteoarthritis (19)
14. Chronic obstructive pulmonary disease (14)
15. Falls (12)
^y Years of Life lived with Disability (YLD). 2Rank in 1990 is shown in brackets.
3Not otherwise classified as specific conditions such as osteoarthritis.
the population to older ages, and this is placing an increasing
burden on health systems. For a few conditions (e.g. HIV/AIDS,
diabetes mellitus and chronic kidney disease), age-standardised
death rates continue to rise. Within this overall pattern, significant
regional variations exist: for example, communicable, maternal,
neonatal and nutritional causes still account for about two-thirds
of premature mortality in sub-Saharan Africa.
GBD also provides estimates of disability from disease (Box
5.2). This has raised awareness of the importance of conditions
like depression, low back and neck pain, and asthma, which
account for a relatively large disease burden but relatively few
deaths. This, in turn, has resulted in greater health policy priority
being given to these conditions. Since the policy focus in national
health systems is increasingly on keeping people healthy rather
than only on reducing premature deaths, it is important to have
measures of these health outcomes.
It is also essential to recognise that, although these estimates
represent the best overall picture of burden of disease, they
are based on imperfect data. Nevertheless, the quality of data
underlying the estimates and the modelling processes are
5.2 Global disability: top 15 ranked causes, 2015
Social determinants of health • 93
5.3 Global risk factors: top 15 ranked causes, 2015
1 . High blood pressure (3)
2. Smoking/second-hand smoke exposure (5)
3. High fasting blood glucose (10)
4. High body mass index (13)
5. Childhood underweight (1)
6. Ambient particulate matter pollution (6)
7. High total cholesterol (12)
8. Household air pollution (4)
9. Alcohol use (11)
10. High sodium intake (14)
11. Low wholegrain intake (15)
12. Unsafe sex (20)
13. Low fruit intake (16)
14. Unsafe water (2)
15. Low glomerular filtration rate (21)
% percentage of burden of disease they cause. 2Rank in 1990 is shown in
brackets. 3AII dietary risk factors and physical inactivity combined accounted for
10% of global burden of disease. Low physical activity was ranked 21, iron
deficiency 16 and suboptimal breastfeeding 22 in 2015.
improving over time and provide an increasingly robust basis for
evidence-based health planning and priority setting.
Risk factors underlying disease
Box 5.3 shows a ranked list of the main risk factors that underlay
GBD in 2015 and how this ranking has changed in recent years.
Social determinants of health
Health emerges from a highly complex interaction between a
person’s genetic background and environmental factors (aspects
of the physical, biological (microbes), built and social environments,
and also distant influences such as the global ecosystem; Fig. 5.1).
The hierarchy of systems - from molecules
to ecologies
Influences on health exist at many levels and extend beyond
the individual to include the family, community, population and
ecology. Box 5.4 shows an example of this for determinants
of coronary heart disease and demonstrates the importance of
considering not only the disease process in a patient but also its
context. Health care is not the only determinant - and is usually
not the major determinant - of health status in the population.
The concept of ‘global health’ recognises the global dimension
of health problems, whether these be emerging or pandemic
infections or global economic influences on health.
The life course
The determinants of health operate over the whole lifespan. Values
and behaviours acquired during childhood and adolescence have
a profound influence on educational outcomes, job prospects and
risk of disease. These can have a strong influence, for example,
on whether a young person takes up damaging behaviour like
smoking, risky sexual activity and drug misuse. Influences on
health can operate even before birth. Low birth weight can lead
Fig. 5.1 Hierarchy of systems that influence population health.
Adapted from an original model by Whitehead M, Dahlgren G. What can be
done about inequalities in health? Lancet 1991; 338:1059-1063.
^9 5.4 ‘Hierarchy of systems’ applied to
ischaemic heart disease
Level in the
hierarchy
Example of effect
Molecular
ApoB mutation causing hypercholesterolaemia
Cellular
Macrophage foam cells accumulate in vessel wall
Tissue
Atheroma and thrombosis of coronary artery
Organ
Ischaemia and infarction of myocardium
System
Cardiac failure
Person
Limited exercise capacity, impact on employment
Family
Passive smoking, diet
Community
Shops and leisure opportunities
Population
Prevalence of obesity
Society
Policies on smoking, screening for risk factors
Ecology
Agriculture influencing fat content in diet
to higher risk of hypertension and type 2 diabetes in young
adults, and of cardiovascular disease in middle age. It has been
suggested that under-nutrition during middle to late gestation
permanently ‘programs’ cardiovascular and metabolic responses.
This ‘life course’ perspective highlights the cumulative effect on
health of exposures to illness, adverse environmental conditions
and behaviours that damage health.
Preventive medicine
The complexity of interactions between physical, social and
economic determinants of health means successful prevention
is often difficult. Moreover, the life-course perspective illustrates
that it may be necessary to intervene early in life or even before
birth, to prevent important disease later. Successful prevention
is likely to require many interventions across the life course
and at several levels in the hierarchy of systems. The examples
below illustrate this.
94 • POPULATION HEALTH AND EPIDEMIOLOGY
| Alcohol
Alcohol use is an increasingly important risk factor underlying GBD
(see Box 5.3). Reasons for increasing rates of alcohol-related
harm vary by place and time but include the falling price of
alcohol (in real terms), increased availability and cultural change
fostering higher levels of consumption. Public, professional and
governmental concern has now led to a minimum price being
charged for a unit of alcohol, tightening of licensing regulations
and curtailment of some promotional activity in many countries.
However, even more aggressive public health measures will
be needed to reverse the levels of harm in the population. The
approach for individual patients suffering adverse effects of alcohol
is described elsewhere (e.g. pp. 1184 and 880).
^Smoking
Smoking is one of the top three risk factors underlying GBD (see
Box 5.3). It is responsible for a substantial majority of cases of
chronic obstructive pulmonary disease (COPD) and lung cancer
(pp. 573 and 598), and most smokers die either from these or
from ischaemic heart disease. Smoking also causes cancers
of the upper respiratory and gastrointestinal tracts, pancreas,
bladder and kidney, and increases risks of peripheral vascular
disease, stroke and peptic ulceration. Maternal smoking is an
important cause of fetal growth retardation. Moreover, there is
evidence that passive (‘second-hand’) smoking has adverse
effects on cardiovascular and respiratory health.
The decline in smoking in many high-income countries has
been achieved not only by warning people of the health risks
but also by increasing taxation of tobacco, banning advertising,
legislating against smoking in public places and giving support for
smoking cessation to maintain this decline. However, smoking
rates remain high in many poorer areas and are increasing
among young women. In many developing countries, tobacco
companies have found new markets and rates are rising.
A complex hierarchy of systems interacts to cause smokers
to initiate and maintain their habit. At the molecular and cellular
levels, nicotine acts on the nervous system to create dependence
and maintain the smoking habit. There are also strong influences
at the personal and social level, such as young female smokers
being motivated to ‘stay thin’ or ‘look cool’ and peer pressure.
Other important influences include cigarette advertising, with the
advertising budget of the tobacco industry being much greater
than that of health services. Strategies to help individuals stop
smoking (such as nicotine replacement therapy, anti-smoking
advice and behavioural support) are cost-effective and form an
important part of the overall strategy.
Obesity
Obesity is an increasingly important risk factor underlying GBD (see
Box 5.3). The weight distribution of almost the whole population
is shifting upwards: the slim are becoming less slim while the fat
are getting fatter (p. 698). In the UK, this translates into a 1 kg
increase in weight per adult per year (on average over the adult
population). The current obesity epidemic cannot be explained
simply by individual behaviour and poor choice but also requires
an understanding of the obesogenic environment that encourages
people to eat more and exercise less. This includes the availability
of cheap and heavily marketed energy-rich foods, the increase
in labour-saving devices (e.g. lifts and remote controls) and the
rise in passive transport (cars as opposed to walking, cycling, or
walking to public transport hubs). To combat the health impact
of obesity, therefore, we not only need to help those who are
already obese but also develop strategies that impact on the
whole population and reverse the obesogenic environment.
|Poverty and affluence
The adverse health and social consequences of poverty are well
documented: high birth rates, high death rates and short life
expectancy. Typically, with industrialisation, the pattern changes:
low birth rates, low death rates and longer life expectancy.
Instead of infections, chronic conditions such as heart disease
dominate in an older population. Adverse health consequences
of excessive affluence are also becoming apparent. Despite
experiencing sustained economic growth for the last 50 years,
people in many industrialised countries are not growing any
happier and the litany of socioeconomic problems - crime,
congestion, inequality - persists.
Many countries are now experiencing a ‘double burden’. They
have large populations still living in poverty who are suffering from
problems such as diarrhoea and malnutrition, alongside affluent
populations (often in cities) who suffer from chronic illness such
as diabetes and heart disease.
Atmospheric pollution
Emissions from industry, power plants and motor vehicles of
sulphur oxides, nitrogen oxides, respirable particles and metals are
severely polluting cities and towns in Asia, Africa, Latin America
and Eastern Europe. Burning of fossil and biomass fuels, with
production of short-lived carbon pollutants (SLCPs - methane,
ozone, black carbon and hydrofluorocarbons), contributes
to increased death rates from respiratory and cardiovascular
disease in vulnerable adults, such as those with established
respiratory disease and the elderly, while children experience
an increase in bronchitic symptoms. Developing countries also
suffer high rates of respiratory disease as a result of indoor
pollution caused mainly by heating and cooking using solid
biomass fuels.
Climate change and global warming
Climate change is arguably the world’s most important
environmental health issue. A combination of habitat destruction
and increased production of carbon dioxide and SLCPs, caused
primarily by human activity, seems to be the main cause.
The temperature of the globe is rising, and if current trends
continue, warming by 4°C is predicted by 2050. The climate
is being affected, putting millions of people at risk of rising sea
levels, flooding, droughts and failed crops These have already
claimed millions of lives during the past 20 years and have
adversely affected the lives of many more. The economic costs
of property damage and the impact on agriculture, food supplies
and prosperity have also been substantial. Global warming
will also include changes in the geographical range of some
vector-borne infectious diseases. Currently, politicians cannot
agree an effective framework of actions to tackle the problem,
but reducing emissions of C02 and SLCPs is essential.
Principles of screening
Screening is the application of a test to a large number of
asymptomatic people with the aim of reducing morbidity or
mortality from a disease. The World Health Organisation (WHO)
Epidemiology • 95
has identified a set of (‘Wilson and Jungner’) criteria to guide
health systems in deciding when it is appropriate to implement
screening programmes. The essential criteria are:
• Is the disease an important public health problem?
• Is there a suitable screening test available?
• Is there a recognisable latent or early stage?
• Is there effective treatment for the disease at this stage
that improves prognosis?
A suitable screening test is one that is cheap, acceptable,
easy to perform and safe, and gives a valid result in terms of
sensitivity and specificity (p. 4). Screening programmes should
always be evaluated in trials so that robust evidence is provided
in favour of their adoption. These evaluations are prone to
several biases - self-selection bias, lead-time bias and length
bias - and these need to be accounted for in the analysis.
Examples of large-scale programmes in the UK include breast,
colorectal and cervical cancer national screening programmes
and a number of screening tests carried out in pregnancy and
in the newborn, such as the:
• diabetic eye screening programme
• fetal anomaly screening programme
• infectious diseases in pregnancy screening programme
• newborn and infant physical examination screening
programme
• newborn blood spot screening programme
• newborn hearing screening programme
• sickle-cell and thalassaemia screening programme.
These are illustrated in Figure 5.2.
Problems with screening include:
• over-diagnosis (of a disease that would not have come to
attention on its own or would not have led to death)
• false reassurance
• diversion of resources from investments that could control
the disease more cost-effectively.
An example of these problems is the use of prostate-specific
antigen (PSA) testing as a screening test for the diagnosis of
prostate cancer (p. 438).
Epidemiology
Epidemiologists study disease in free-living humans, seeking
to describe patterns of health and disease and to understand
how different exposures cause or prevent disease (Box 5.5).
Chronic diseases and risk factors (e.g. smoking, obesity etc.)
are often described in terms of their prevalence. A prevalence is
simply a proportion: e.g. the prevalence of diabetes in people
aged 80 and older in developed countries is around 10%.
Events such as deaths, hospitalisations and first occurrences
of a disease are described using incidence rates: e.g. if there
are 1 00 new cases of a disease in a single year in a population
of 1 000, the incidence rate is 1 05 per 1 000 person-years, not
100, because of the effect of ‘person-time’. Person-time is the
sum of the total ‘exposed’ time for the population and in this
example is 950 person-years. The reason person-time is less
than 1 000 is that 1 00 people experienced the event. These 1 00
people are assumed to have had an event, on average, halfway
through the time period, removing 100x0.5 person-years from
the exposure time (as it is not possible to have a first occurrence
of a disease twice). Hence, the incidence per 1 000 person-years
is 105, not 100.
i
Prevalence
• The ratio of the number of people with a longer-term disease or
condition, at a specified time, to the number of people in the
population
Incidence
• The number of events (new cases or episodes) occurring in the
population at risk during a defined period of time
Attributable risk
• The difference between the risk (or incidence) of disease in exposed
and non-exposed populations
Attributable fraction
• The ratio of the attributable risk to the incidence
Relative risk
• The ratio of the risk (or incidence) in the exposed population to the
risk (or incidence) in the non-exposed population
A similar measure is the cumulative incidence or risk, which
is the number of new cases as a proportion of the total people
at risk at the beginning of the exposure time. If, in the example
above, the same 1000 people were observed for a year (i.e.
with no one joining or leaving the group), then the 1 -year risk is
10% (100/1000). The time period should always be specified.
These rates and proportions are used to describe how diseases
(and risk factors) vary according to time, person and place.
Temporal variation may occur seasonally (e.g. malaria occurs
in the wet season but not the dry) or as longer-term ‘secular’
trends (e.g. malaria may re-emerge due to drug resistance).
Person comparisons include age, sex, socioeconomic status,
employment, and lifestyle characteristics. Place comparisons
include the local environment (e.g. urban versus rural) and
international comparisons.
Understanding causes and effect
Epidemiological research complements that based on animal, cell
and tissue models, the findings of which do not always translate
to humans. For example, only a minority of drug discoveries
from laboratory research are effective when tested in people.
However, differentiating causes from mere non-causal
associations is a considerable challenge for epidemiology.
This is because while laboratory researchers can directly
manipulate conditions to isolate and understand causes,
such approaches are impossible in free-living populations.
Epidemiologists have developed a different approach, based
around a number of study designs (Box 5.6). Of these, the
clinical trial is closest to the laboratory experiment. An early
example of a clinical trial is shown in Figure 5.3, along with ‘effect
measures’, which are used to quantify the difference in rates
and risks.
In clinical trials, patients are usually allocated randomly to
treatments so that, on average, groups are similar, apart from
the intervention of interest. Nevertheless, for any particular
trial, especially a small trial, the laws of probability mean that
differences can and do occur by chance. Poorly designed or
executed trials can also limit comparability between groups.
Allocation may not be truly random (e.g. because of inadequate
concealment of the randomisation sequence), and there may
5.5 Calculation of risk using descriptive epidemiology
96 • POPULATION HEALTH AND EPIDEMIOLOGY
Key
Newborn hearing
Infectious diseases
in pregnancy
m
T21 , T18, T13 and fetal
■
Newborn and infant
■
anomaly ultrasound
physical examination
u
Sickle cell and
thalassaemia
Newborn blood spot
■
Diabetic eye
Fig. 5.2 UK NHS Pregnancy and Newborn Screening Programmes: optimum times for testing. (GA1 = glutaric aciduria type 1 ; HCU =
homocystinuria; IVA = isovaleric acidaemia; MCADD = medium-chain acyl-CoA dehydrogenase deficiency; MSUD = maple syrup urine disease;
PKU = phenylketonuria; T1 3, 1 8, 21 = trisomy 1 3, 1 8 and 21) Based on Version 8. 1, March 2016, Gateway ref: 2014696, Public Health England.
Health data/informatics • 97
5.6 Epidemiological study designs
Design
Description
Example
Clinical trial
Enrols a sample from a population and compares outcomes
after randomly allocating patients to an intervention
Medical Research Council (MRC) Streptomycin Trial -
demonstrated effectiveness of streptomycin in tuberculosis
Cohort
Enrols a sample from a population and compares outcomes
according to exposures
Framingham Study - identified risk factors for cardiovascular
disease
Case-control
Enrols cases with an outcome of interest and controls
without that outcome and compares exposures between
the groups
Doll R, Hill AB. Smoking and carcinoma of the lung. British Medical
Journal 1950 - demonstrated that smoking caused lung cancer
Cross-sectional
Enrols a cross-section (sample) of people from the
population of interest; obtains data on exposures and
outcomes
World Health Organisation Demographic and Health Survey -
captures risk factor data in a uniform way across many countries
Enrolled 107 patients
with tuberculosis
r
Random allocation
Streptomycin
55 patients
Bed rest
52 patients
Follow-up and count deaths
Events
Risk
Odds
4
7.3%
0.068
Events 1 5
Risk 28.8%
Odds 0.224
Effect measures
Risk ratio (relative risk, RR)
0.25
Odds ratio (OR)
0.30
Absolute risk reduction (ARR)
21.6%
Relative risk reduction (RRR)
74.8%
Number needed to treat to prevent
one death (NNT= 1/ARR)
4.6
Fig. 5.3 An example of a clinical trial: streptomycin versus bed rest
in tuberculosis. Both prevalences and risks are, in fact, proportions, and
are therefore frequently expressed as odds. The reasons for doing so are
beyond the scope of this text.
be systematic differences (biases) in the way people allocated
to different groups are treated or studied.
Such biases also occur in observational epidemiological study
designs, such as cohort, case-control and cross-sectional studies
(Box 5.6). These designs are also much more subject to the
problem of confounding than are randomised trials.
Confounding is where the relationship between an exposure
and outcome of interest is confused by the presence of some
other causal factor. For example, coffee consumption may be
associated with lung cancer because smoking is more common
among coffee-drinkers. Here, smoking is said to confound the
association between coffee and lung cancer.
Despite these limitations, for most causes of diseases,
randomised controlled trials are not feasible because of ethical,
or more often practical, considerations. Epidemiologists therefore
seek to minimise bias and confounding by good study analysis
and design. They subsequently make causal inferences by
balancing the probability that an observed association has been
caused by chance, bias and/or confounding against the alternative
probability that the relationship is causal. This weighing-up
requires an understanding of the frequency and importance of
different sources of bias and confounding, as well as the scientific
rationale of the putative causal relationship. It was this approach,
collectively and over a number of years, that settled the fact that
smoking causes lung cancer and, subsequently, heart disease.
Health data/informatics
As patients pass through health and social care systems,
data are recorded concerning their family background, lifestyle
and disease states, which is of potential interest to health¬
care organisations seeking to deliver services, policy-makers
concerned with improving health, scientific researchers trying to
understand health, and also pharmaceutical and other commercial
organisations aiming to identify markets.
There is a long tradition of maintaining health information
systems. In most countries, registration of births and deaths is
required by law, and in the majority, the cause of death is also
recorded (Fig. 5.4). There are many challenges in ensuring such
data are useful, especially for comparisons across time and place:
• A system of standard terminologies is needed, such as the
WHO International Classification of Diseases (ICD-10),
which provides a list of diagnostic codes attempting to
cover every diagnostic entity.
• These terms must be understood to refer to the same, or
at least similar, diseases in different places.
• Access to diagnostic skill and facilities is required.
• Standard protocols for assigning clinical diagnoses to
ICD-10 codes are needed
• Robust quality control processes are needed to maintain
some level of data completeness and accuracy.
Many countries employ similar systems for hospitalisations, to
allow recovery of health-care utilisation costs or to manage and
plan services. Similar data are rarely collected for community-
based health care, nor are detailed data on health-care processes
generally included in national data systems. Consequently, there
has been considerable interest in using data from information
technology systems used to deliver care, such as electronic
98 • POPULATION HEALTH AND EPIDEMIOLOGY
INTERNATIONAL FORM OF MEDICAL CERTIFICATE OF CAUSE OF DEATH
Cause of death
1 Acute, myocardial
Disease or condition directly (a) urf^ctlokt 121.9
Approximate
interval between
onset and death
2 days
leading to death*
due to (or as a consequence of)
Familial
mm » , ,.x ItyperdvoLesteroUiemlto F78 0
Antecedent causes (b) ./f. . .
SO years
Morbid conditions, if any,
..... due to (or as a consequence of)
giving rise to the above cause, v M '
stating the underlying
condition last (c) .
due to (or as a consequence of)
(d) .
10 years
11 Brochiectosls J47
Other significant conditions .
contributing to the death, but
not related to the disease or
condition causing it .
*This does not mean the mode of dying, e.g. heart failure, respiratory failure.
It means the disease, injury, or complication that caused death.
Fig. 5.4 Completed death certificate. International Classification of Diseases 10 (ICD-10) codes are appended in red. WHO ICD-10, vol. 2; 1990.
A vailable at https ://commons. m. wiki media. org/wiki/File:lnternational_form_of_medical_certificate_oLcause_of_death.png.
patient records, drug-dispensing databases, radiological software
and clinical laboratory information systems.
Data from such systems are, of course, much less structured
than those obtained from vital registrations. Moreover, the
completeness of such data depends greatly on local patterns
of health-care utilisation, as well as how clinicians and others
use information technology systems within different settings. As
such, deriving useful, unbiased information from such data is a
considerable challenge.
Much of the discipline of health informatics is concerned
with addressing this challenge. One approach has been to
develop comprehensive standard classification systems such as
SNOMED-CT, ‘a standardised, multilingual vocabulary of terms
relating to the care of the individual’, which has been designed
for electronic health-care records.
An alternative has been to use statistical methods such as
natural language processing to derive information automatically
from free text (such as culling diagnoses from radiological reports),
or to employ ‘machine learning’, in which software algorithms
are applied to data in order to derive useful insights. Such
approaches are suited to large, messy data where the costs
of systematisation would be prohibitive. It is likely that such
innovations will, over the coming years, provide useful information
to complement that obtained from more traditional health
information systems.
Further information
Books and journal articles
GBD 2015 Disease and Injury Incidence and Prevalence Collaborators.
Global, regional, and national incidence, prevalence, and years lived
with disability for 31 0 diseases and injuries, 1 990-201 5: a
systematic analysis for the Global Burden of Disease Study 201 5.
Lancet 2016; 388:1545-1602.
GBD 2015 Mortality and Causes of Death Collaborators. Global,
regional, and national life expectancy, and cause-specific mortality
for 249 causes of death, 1 980-201 5: a systematic analysis for
the Global Burden of Disease Study 201 5. Lancet 201 6;
388:1459-1544.
GBD 2015 Risk Factors Collaborators. Global, regional, and national
comparative risk assessment of 79 behavioural, environmental and
occupational, and metabolic risks or clusters of risks, 1990-2015: a
systematic analysis for the Global Burden of Disease Study 201 5.
Lancet 2016; 388:1659-1724.
Kindig D, Stoddart G. What is population health? Am J Public Health
2003; 93:380-383.
Websites
fph.org.uk UK Faculty of Public Flealth: What is public
health?
gov.uk UK Government: population screening
programmes.
Principles of infectious disease
Infectious agents 1 00
Antimicrobial stewardship 115
Normal microbial flora 102
Treatment of infectious diseases 116
Host-pathogen interactions 104
Investigation of infection 1 05
Direct detection of pathogens 1 05
Culture 106
Indirect detection of pathogens 1 06
Antimicrobial susceptibility testing 1 09
Principles of antimicrobial therapy 116
Antibacterial agents 1 20
Antimycobacterial agents 1 25
Antifungal agents 1 25
Antiviral agents 1 26
Antiparasitic agents 1 28
Epidemiology of infection 110
Infection prevention and control 1 1 1
Health care-associated infection 1 1 1
Outbreaks of infection 1 1 4
Immunisation 114
100 • PRINCIPLES OF INFECTIOUS DISEASE
‘Infection’ in its strict sense describes the situation where
microorganisms or other infectious agents become established
in the host organism’s cells or tissues, replicate, cause harm and
induce a host response. If a microorganism survives and replicates
on a mucosal surface without causing harm or illness, the host
is said to be ‘colonised’ by that organism. If a microorganism
survives and lies dormant after invading host cells or tissues,
infection is said to be ‘latent’. When the infectious agent, or the
host response to it, is sufficient to cause illness or harm, then
the process is termed an ‘infectious disease’. Most pathogens
(infectious agents that can cause disease) are microorganisms but
some are multicellular organisms. The manifestations of disease
may aid pathogen dissemination (e.g. diarrhoea).
The term ‘infection’ is often used interchangeably with ‘infectious
disease’ but not all infections are ‘infectious’, i.e. transmissible
from person to person. Infectious diseases transmitted between
hosts are called communicable diseases, whereas those caused
by organisms that are already colonising the host are described
as endogenous. The distinction is blurred in some situations,
including health care-associated infections such as meticillin-
resistant Staphylococcus aureus (MRSA) or Clostridium difficile
infection (CDI), in which colonisation precedes infection but the
colonising bacteria may have been recently transmitted between
patients. The chain of infection (Fig. 6.1) describes six essential
elements for communicable disease transmission.
Despite dramatic advances in hygiene, immunisation and
antimicrobial therapy, infectious agents still cause a massive
burden of disease worldwide. Key challenges remain in
Fig. 6.1 Chain of infection. The infectious agent is the organism that
causes the disease. The reservoir is the place where the population of an
infectious agent is maintained. The portal of exit is the point from which
the infectious agent leaves the reservoir. Transmission is the process by
which the infectious agent is transferred from the reservoir to the human
host, either directly or via a vector or fomite. The portal of entry is the body
site that is first accessed by the infectious agent. Finally, in order for
disease to ensue, the person to whom the infectious agent is transmitted
must be a susceptible host.
tackling infection in resource-poor countries. Microorganisms
are continually mutating and evolving; the emergence of new
infectious agents and antimicrobial-resistant microorganisms is
therefore inevitable. This chapter describes the biological and
epidemiological principles of infectious diseases and the general
approach to their prevention, diagnosis and treatment. Specific
infectious diseases are described in Chapters 11-13 and many
of the organ-based chapters.
Infectious agents
The concept of an infectious agent was established by Robert
Koch in the 19th century (Box 6.1). Although fulfilment of
‘Koch’s postulates’ became the standard for the definition of
an infectious agent, they do not apply to uncultivable organisms
(e.g. Mycobacterium leprae, Tropheryma whipplei) or members
of the normal human flora (e.g. Escherichia coli, Candida spp.).
The following groups of infectious agents are now recognised.
] Viruses
Viruses are incapable of independent replication. Instead, they
subvert host cellular processes to ensure synthesis of their nucleic
acids and proteins. Viruses’ genetic material (the genome) consists
of single- or double-stranded DNA or RNA. Retroviruses transcribe
their RNA into DNA in the host cell by reverse transcription. An
antigenically unique protein coat (capsid) encloses the genome,
and together these form the nucleocapsid. In many viruses, the
nucleocapsid is packaged within a lipid envelope. Enveloped
viruses are less able to survive in the environment and are
spread by respiratory, sexual or blood-borne routes, including
arthropod-based transmission. Non-enveloped viruses survive
better in the environment and are predominantly transmitted by
faecal-oral or, less often, respiratory routes. A generic virus life
cycle is shown in Figure 6.2. A virus that infects a bacterium is
a bacteriophage (phage).
I Prokaryotes: bacteria (including mycobacteria
and actinomycetes)
Prokaryotic cells are capable of synthesising their own proteins
and nucleic acids, and are able to reproduce autonomously,
although they lack a nucleus. The bacterial cell membrane is
bounded by a peptidoglycan cell wall, which is thick (20-80 nm)
in Gram-positive organisms and thin (5-1 0 nm) in Gram-negative
ones. The Gram-negative cell wall is surrounded by an outer
membrane containing lipopolysaccharide. Genetic information is
contained within a chromosome but bacteria may also contain
rings of extra-chromosomal DNA, known as plasmids, which
can be transferred between organisms, without cells having to
divide. Bacteria may be embedded in a polysaccharide capsule,
6.1 Definition of an infectious agent -
Koch’s postulates
1 . The same organism must be present in every case of the disease
2. The organism must be isolated from the diseased host and grown
in pure culture
3. The isolate must cause the disease, when inoculated into a healthy,
susceptible animal
4. The organism must be re-isolated from the inoculated, diseased
animal
Infectious agents • 101
Interaction between host receptor
molecule and virus ligand
(determines host-specificity of the virus)
Adsorption
Lipid envelope—
Capsid
Nucleic acid
Release 6
Complete virus particles are
released by budding of host cell
membrane (shown here) or
disintegration of host cell
Assembly 5
Assembly of virus components
is mediated by host and/or
viral enzymes
*4
Synthesis
Nucleic acid and protein synthesis is mediated by
host and/or viral enzymes. This takes place in nucleus
or cytoplasm, depending on the specific virus
2 Penetration
Receptor-mediated endocytosis
or, in some enveloped viruses,
membrane fusion (shown here)
Uncoating
Nucleic acid is liberated from the
phagosome (if endocytosed)
and/or capsid by complex
enzymatic and/or receptor-mediated
processes
Fig. 6.2 A generic virus life cycle. Life cycle components common to most viruses are host cell attachment and penetration, virus uncoating, nucleic
acid and protein synthesis, virus assembly and release. Virus release is achieved either by budding, as illustrated, or by lysis of the cell membrane. Life
cycles vary between viruses.
■■
6.2 How bacteria are identified
Gram stain reaction (see Fig. 6.3)
Motility
• Gram-positive (thick peptidoglycan layer), Gram-negative (thin
peptidoglycan) or unstainable
Microscopic morphology
• Cocci (round cells) or bacilli (elongated cells)
• Motile or non-motile
Antibiotic susceptibility
• Identifies organisms with invariable susceptibility (e.g. to optochin in
Streptococcus pneumoniae or metronidazole in obligate anaerobes)
• Presence or absence of capsule
Matrix-assisted laser desorption/ionisation time-of-flight mass
Cell association
spectrometry (MALDI-TOF-MS)
• Association in clusters, chains or pairs
• A rapid technique that identifies bacteria and some fungi from their
Colonial characteristics
specific molecular composition
Sequencing bacterial 16s ribosomal RNA gene
• Colony size, shape or colour
• Effect on culture media (e.g. (3-haemolysis of blood agar in
haemolytic streptococci; see Fig. 6.4)
• A highly specific test for identification of organisms in pure culture
and in samples from normally sterile sites
Atmospheric requirements
• Strictly aerobic (requires 02), strictly anaerobic (requires absence of
02), facultatively aerobic (grows with or without 02) or micro-
aerophilic (requires reduced 02)
Whole-genome sequencing
• Although not yet in routine use, whole-genome sequencing (WGS)
offers the potential to provide rapid and simultaneous identification,
sensitivity testing and typing of organisms from pure culture and/or
Biochemical reactions
• Expression of enzymes (oxidase, catalase, coagulase)
• Ability to ferment or hydrolyse various biochemical substrates
directly from clinical samples. As such, WGS is likely to replace many
of the technologies described above over the next few years (p. 58)
and motile bacteria are equipped with flagella. Although many
prokaryotes are capable of independent existence, some (e.g.
Chlamydia trachomatis, Coxiella burnetii) are obligate intracellular
organisms. Bacteria that can grow in artificial culture media are
classified and identified using a range of characteristics (Box
6.2); examples are shown in Figures 6.3 and 6.4.
Eukaryotes: fungi, protozoa and helminths
Eukaryotic cells contain membrane-bound organelles, including
nuclei, mitochondria and Golgi apparatus. Pathogenic eukaryotes
are unicellular (e.g. fungi, protozoa) or complex multicellular
organisms (e.g. nematodes, trematodes and cestodes, p. 288).
102 • PRINCIPLES OF INFECTIOUS DISEASE
Gram stain
Gram-positive
cocci
Gram-positive v > v
bacilli i1
Gram-negative
cocci
Gram-negative
bacilli
Colony morphology (e.g.
haemolysis), Gram stain
appearance, agglutination
reactions, coagulase test,
catalase
Colony morphology, growth
characteristics (e.g. growth
in anaerobic atmosphere),
Gram stain appearance,
MALDI-TOF-MS identification
Colony morphology, growth
characteristics, oxidase
reaction, sugar
fermentation/MALDI-TOF-MS
identification
Colony morphology, growth
characteristics, lactose
fermentation, oxidase
reaction, MALDI-TOF-MS
identification
Gram-positive cocci-clusters
Examples
Staphylococcus
aureus
Coagulase-negative
staphylococci
V-
or
Gram-positive cocci-chains
Examples
Oral streptococci
Streptococcus
< K
pneumoniae (often
, J
pairs)
i
Beta-haemolytic strepto-
COCCI
Enterococci (short chains)
Examples
Actinomycetes
Arcanobacterium haemo-
lyticum
Bacillus spp.
Corynebacterium diphtheriae
Lactobacillus spp.
Listeria monocytogenes
Nocard ia spp.
Clostridium spp.
Examples
Neisseria meningitidis
Neisseria gonorrhoeae
Moraxella catarrhalis
Examples
Escherichia coli
Klebsiella pneumoniae
Proteus spp.
Enterobacter spp.
Serratia spp.
Salmonella spp.
Shigella spp.
Yersinia spp.
Vibrio spp.
Pseudomonas aeruginosa
Fig. 6.3 Flow chart for bacterial identification, including Gram film appearances on light microscopy (xlOO). (MALDI-TOF-MS = matrix-assisted
laser desorption/ionisation time-of-flight mass spectroscopy)
Fig. 6.4 Beta-haemolytic streptococci (A) and alpha-haemolytic
streptococci (B) spread on each half of a blood agar plate (backlit).
This image is half life size. x0.5. Beta-haemolysis renders the agar
transparent around the colonies (A) and alpha-haemolysis imparts a green
tinge to the agar (B).
Fungi exist as either moulds (filamentous fungi) or yeasts.
Dimorphic fungi exist in either form, depending on environmental
conditions (see Fig. 1 1 .59, p. 300). The fungal plasma membrane
differs from the human cell membrane in that it contains the sterol,
ergosterol. Fungi have a cell wall made up of polysaccharides,
chitin and mannoproteins. In most fungi, the main structural
component of the cell wall is (3-1 ,3-D-glucan, a glucose polymer.
These differences from mammalian cells are important because
they offer useful therapeutic targets.
Protozoa and helminths are often referred to as parasites.
Many parasites have complex multi-stage life cycles, which
involve animal and/or plant hosts in addition to humans.
Prions
Although prions are transmissible and have some of the
characteristics of infectious agents, they are not microorganisms
and are not diagnosed in microbiology laboratories. Prions are
covered on page 250.
Normal microbial flora
The human body is colonised by large numbers of microorganisms
(collectively termed the human microbiota). These colonising
Normal microbial flora • 103
Scalp -
As for skin
Oral cavity
Oral streptococci (a-haemolytic)
Anaerobic Gram-positive bacilli
(including Actinomyces spp.)
Anaerobic Gram-negative bacilli
Prevotella spp.
Fusobacterium spp.
Candida spp.
Skin
Coagulase-negative staphylococci
Staph . aureus
Corynebacterium spp.
Propionibacterium spp.
Malassezia spp.
Hands -
Resident: as for skin
Transient: skin flora (including
meticillin-resistant and other
Staph, aureus), bowel flora
(including Clostridium difficile,
Candida spp. and Enterobacteriaceae)
Vagina
Lactobacillus spp.
Staph, aureus
Candida spp.
Enterobacteriaceae
Strep, agalactiae (group B)
Perineum
As for skin
As for large bowel
Nares
Staph, aureus
Coagulase-negative staphylococci
Pharynx
Haemophilus spp.
Moraxella catarrhalis
Neisseria spp. (including N. meningitidis)
Staph, aureus
Strep, pneumoniae
Strep, pyogenes (group A)
Oral streptococci (a-haemolytic)
Small bowel
Distally, progressively increasing
numbers of large bowel bacteria
Candida spp.
Large bowel
Enterobacteriaceae
Escherichia coli
Klebsiella spp.
Enterobacter spp.
Proteus spp.
Enterococci
E. faecalis
E. faecium
Streptococcus anginosus group
Strep, anginosus
Strep, intermedius
Strep, constellatus
Anaerobic Gram-positive bacilli
Clostridium spp.
Anaerobic Gram-negative bacilli
Bacteroides spp.
Prevotella spp.
Candida spp.
Fig. 6.5 Human non-sterile sites and normal flora in health.
bacteria, also referred to as the ‘normal flora’, are able to survive
and replicate on skin and mucosal surfaces. The gastrointestinal
tract and the mouth are the two most heavily colonised sites in
the body and their microbiota are distinct, in both composition
and function. Knowledge of non-sterile body sites and their normal
flora is required to inform microbiological sampling strategies
and interpret culture results (Fig. 6.5).
The microbiome is the total burden of microorganisms, their
genes and their environmental interactions, and is now recognised
to have a profound influence over human health and disease.
Maintenance of the normal flora is beneficial to health. For
example, lower gastrointestinal tract bacteria synthesise and
excrete vitamins (e.g. vitamins K and B12); colonisation with
normal flora confers ‘colonisation resistance’ to infection with
pathogenic organisms by altering the local environment (e.g.
lowering pH), producing antibacterial agents (e.g. bacteriocins
(small antimicrobial peptides/proteins), fatty acids and metabolic
waste products), and inducing host antibodies that cross-react
with pathogenic organisms.
Conversely, normally sterile body sites must be kept sterile. The
mucociliary escalator transports environmental material deposited
in the respiratory tract to the nasopharynx. The urethral sphincter
prevents flow from the non-sterile urethra to the sterile bladder.
Physical barriers, including the skin, lining of the gastrointestinal
tract and other mucous membranes, maintain sterility of the
submucosal tissues, blood stream and peritoneal and pleural
cavities, for example.
The normal flora contribute to endogenous disease mainly
by translocation to a sterile site but excessive growth at the
‘normal’ site (overgrowth) can also cause disease. Overgrowth
is exemplified by dental caries, vaginal thrush and ‘blind loop’
syndrome (p. 808). Translocation results from spread along a
surface or penetration though a colonised surface, e.g. urinary
tract infection caused by perineal/enteric flora, and surgical site
infections, particularly of prosthetic materials, caused by skin flora
such as staphylococci. Normal flora also contribute to disease
by cross-infection, in which organisms that are colonising one
individual cause disease when transferred to another, more
susceptible, individual.
The importance of limiting perturbations of the microbiota by
antimicrobial therapy is increasingly recognised. Probiotics are
microbes or mixtures of microbes that are given to a patient to
prevent or treat infection and are intended to restore a beneficial
profile of microbiota. Although probiotics have been used in a
number of settings, whether they have demonstrable clinical
benefits remains a subject of debate.
104 • PRINCIPLES OF INFECTIOUS DISEASE
Host-pathogen interactions
‘Pathogenicity’ is the capability of an organism to cause disease
and ‘virulence’ is the extent to which a pathogen is able to cause
disease. Pathogens produce proteins and other factors, termed
virulence factors, which contribute to disease.
• Primary pathogens cause disease in a proportion of
individuals to whom they are exposed, regardless of the
host’s immunological status.
• Opportunistic pathogens cause disease only in individuals
whose host defences are compromised, e.g. by an
intravascular catheter, or when the immune system is
compromised, by genetic susceptibility or
immunosuppressive therapy.
Characteristics of successful pathogens
Successful pathogens have a number of attributes. They compete
with host cells and colonising flora by various methods, including
sequestration of nutrients and production of bacteriocins. Motility
enables pathogens to reach their site of infection, often sterile
sites that colonising bacteria do not reach, such as the distal
airway. Many microorganisms, including viruses, use ‘adhesins’ to
attach to host cells initially. Some pathogens can invade through
tissues. Many bacterial and fungal infections form ‘biofilms’. After
initial adhesion to a host surface, bacteria multiply in biofilms
to form complex three-dimensional structures surrounded by a
matrix of host and bacterial products that afford protection to
the colony and limit the effectiveness of antimicrobials. Biofilms
forming on man-made medical devices such as vascular catheters
or grafts can be particularly difficult to treat.
Pathogens may produce toxins, microbial molecules that cause
adverse effects on host cells, either at the site of infection, or
remotely following carriage through the blood stream. Endotoxin is
the lipid component of Gram-negative bacterial outer membrane
lipopolysaccharide. It is released when bacterial cells are damaged
and has generalised inflammatory effects. Exotoxins are proteins
released by living bacteria, which often have specific effects on
target organs (Box 6.3).
Intracellular pathogens, including viruses, bacteria (e.g.
Salmonella spp., Listeria monocytogenes and Mycobacterium
tuberculosis), parasites (e.g. Leishmania spp.) and fungi (e.g.
6.3 Exotoxin-mediated bacterial diseases
Disease
Organism
Antibiotic-associated diarrhoea/
pseudomembranous colitis
Clostridium difficile (p. 230)
Botulism
Clostridium botulinum (p. 1 1 26)
Cholera
Vibrio cholerae (p. 264)
Diphtheria
Corynebacterium diphtheriae
(p. 265)
Haemolytic uraemic syndrome
Enterohaemorrhagic Escherichia
coli ( E . coli 01 57 and other
strains) (p. 263)
Necrotising pneumonia
Staphylococcus aureus (p. 250)
Tetanus
Clostridium tetani (p. 1 1 25)
Toxic shock syndrome
Staphylococcus aureus (p. 252)
Streptococcus pyogenes (p. 253)
Histoplasma capsulatum), are able to survive in intracellular
environments, including after phagocytosis by macrophages.
Pathogenic bacteria express different genes, depending on
environmental stress (pH, iron starvation, 02 starvation etc.)
and anatomical location.
Genetic diversity enhances the pathogenic capacity of bacteria.
Some virulence factor genes are found on plasmids or in phages
and are exchanged between different strains or species. The
ability to acquire genes from the gene pool of all strains of
the species (the ‘bacterial supragenome’) increases diversity
and the potential for pathogenicity. Viruses exploit their rapid
reproduction and potential to exchange nucleic acid with host
cells to enhance diversity. Once a strain acquires a particularly
effective combination of virulence genes, it may become an
epidemic strain, accounting for a large subset of infections in
a particular region. This phenomenon accounts for influenza
pandemics (see Box 6.10).
The host response
Innate and adaptive immune and inflammatory responses, which
humans use to control the normal flora and respond to pathogens,
are reviewed in Chapter 4.
| Pathogenesis of infectious disease
The harmful manifestations of infection are determined by a
combination of the virulence of the organism and the host
response to infection. Despite the obvious benefits of an intact
host response, an excessive response is undesirable. Cytokines
and antimicrobial factors contribute to tissue injury at the site of
infection, and an excessive inflammatory response may lead to
hypotension and organ dysfunction (p. 196). The contribution of
the immune response to disease manifestations is exemplified by
the immune reconstitution inflammatory syndrome (IRIS). This is
seen, for example, in human immunodeficiency virus (HIV) infection,
post-transplantation neutropenia or tuberculosis (which causes
suppression of T-cell function): there is a paradoxical worsening
of the clinical condition as the immune dysfunction is corrected,
caused by an exuberant but dysregulated inflammatory response.
The febrile response
Thermoregulation is altered in infectious disease, which may cause
both hyperthermia (fever) and hypothermia. Fever is mediated
mainly by ‘pyrogenic cytokines’ (e.g. interleukins IL-1 and IL-6,
and tumour necrosis factor alpha (TNF-a)), which are released
in response to various immunological stimuli including activation
of pattern recognition receptors (PRRs) by microbial pyrogens
(e.g. lipopolysaccharide) and factors released by injured cells.
Their ultimate effect is to induce the synthesis of prostaglandin
E2, which binds to specific receptors in the preoptic nucleus of
the hypothalamus (thermoregulatory centre), causing the core
temperature to rise.
Rigors are a clinical symptom (or sign if they are witnessed)
characterised by feeling very cold (‘chills’) and uncontrollable
shivering, usually followed by fever and sweating. Rigors occur
when the thermoregulatory centre attempts to correct a core
temperature to a higher level by stimulating skeletal muscle
activity and shaking.
There are data to support the hypothesis that raised body
temperature interferes with the replication and/or virulence of
pathogens. The mechanisms and possible protective role of
infection-driven hypothermia, however, are poorly understood,
and require further study.
Investigation of infection • 105
Investigation of infection
The aims of investigating a patient with suspected infection
are to confirm the presence of infection, identify the specific
pathogen(s) and identify its susceptibility to specific antimicrobial
agents in order to optimise therapy. The presence of infection
may be suggested by identifying proteins that are produced
in response to pathogens as part of the innate immune and
acute phase responses (p. 70). Pathogens may be detected
directly (e.g. by culturing a normally sterile body site) or their
presence may be inferred by identifying the host response to
the organism, (‘indirect detection’, Box 6.4). Careful sampling
increases the likelihood of diagnosis (Box 6.5). Culture results
must be interpreted in the context of the normal flora at the
sampled site (see Fig. 6.5). The extent to which a microbiological
test result supports or excludes a particular diagnosis depends
on its statistical performance (e.g. sensitivity, specificity, positive
and negative predictive value, p. 4). Sensitivity and specificity
vary according to the time between infection and testing, and
positive and negative predictive values depend on the prevalence
of the condition in the test population. The complexity of test
interpretation is illustrated in Figure 6.8 below, which shows the
‘windows of opportunity’ afforded by various testing methods.
Given this complexity, effective communication between the
clinician and the microbiologist is vital to ensure accurate test
interpretation.
Direct detection of pathogens
Some direct detection methods provide rapid results and enable
detection of organisms that cannot be grown easily on artificial
culture media, such as Chlamydia spp.; they can also provide
information on antimicrobial sensitivity, e.g. Mycobacterium
tuberculosis.
|J)etection of whole organisms
Whole organisms are detected by examination of biological fluids
or tissue using a microscope.
• Bright field microscopy (in which the test sample is
interposed between the light source and the objective
lens) uses stains to enhance visual contrast between the
6.4 Tests used to diagnose infection
Non-specific markers of inflammation/infection
• e.g. White cell count in blood sample (WCC), plasma C-reactive
protein (CRP), procalcitonin, serum lactate, cell counts in urine or
cerebrospinal fluid (CSF), CSF protein and glucose
Direct detection of organisms or organism components
• Microscopy
• Detection of organism components (e.g. antigen, toxin)
• Nucleic acid amplification (e.g. polymerase chain reaction)
Culture of organisms
• ± Antimicrobial susceptibility testing
Tests of the host’s specific immune response
• Antibody detection
• Interferon-gamma release assays (IGRA)
organism and its background. Examples include Gram
staining of bacteria and Ziehl-Neelsen or auramine staining
of acid- and alcohol-fast bacilli (AAFB) in tuberculosis
(the latter requires an ultraviolet light source). In
histopathological examination of tissue samples, multiple
stains are used to demonstrate not only the presence of
microorganisms but also features of disease pathology.
• Dark field microscopy (in which light is scattered to make
organisms appear bright on a dark background) is used,
for example, to examine genital chancre fluid in suspected
syphilis.
• Electron microscopy may be used to examine stool and
vesicle fluid to detect enteric and herpesviruses,
respectively, but its use has largely been supplanted by
nucleic acid detection (see below).
• Flow cytometry can be used to analyse liquid samples
(e.g. urine) for the presence of particles based on
properties such as size, impedance and light scatter. This
technique can detect bacteria but may misidentify other
particles as bacteria too.
6.5 How to provide samples for
microbiological sampling
Communicate with the laboratory
• Discuss samples that require processing urgently or that may
contain hazardous or unusual pathogens with laboratory staff before
collection
• Communication is key to optimising microbiological diagnosis. If
there is doubt about any aspect of sampling, it is far better to
discuss it with laboratory staff beforehand than to risk diagnostic
delay by inappropriate sampling or sample handling
Take samples based on a clinical diagnosis
• Sampling in the absence of clinical evidence of infection is rarely
appropriate (e.g. collecting urine, or sputum for culture)
Use the correct container
• Certain tests (e.g. nucleic acid and antigen detection tests) require
proprietary sample collection equipment
Follow sample collection procedures
• Failure to follow sample collection instructions precisely can result
in false-positive (e.g. contamination of blood culture samples) or
false- negative (e.g. collection of insufficient blood for culture) results
Label sample and request form correctly
• Label sample containers and request forms according to local
policies, with demographic identifiers, specimen type and time/date
collected
• Include clinical details on request forms
• Identify samples carrying a high risk of infection (e.g. blood liable to
contain a blood-borne virus) with a hazard label
Use appropriate packaging
• Close sample containers tightly and package securely (usually in
sealed plastic bags)
• Attach request forms to samples but not in the same compartment
(to avoid contamination, should leakage occur)
Manage storage and transport
• Transport samples to the microbiology laboratory quickly
• If pre-transport storage is required, conditions (e.g. refrigeration,
incubation, storage at room temperature) vary with sample type
• Notify the receiving laboratory prior to arrival of unusual or urgent
samples, to ensure timely processing
106 • PRINCIPLES OF INFECTIOUS DISEASE
Detection of components of organisms
Components of microorganisms detected for diagnostic
purposes include nucleic acids, cell wall molecules, toxins and
other antigens. Commonly used examples include Legionella
pneumophila serogroup 1 antigen in urine and cryptococcal
polysaccharide antigen in cerebrospinal fluid (CSF). Most antigen
detection methods are based on in vitro binding of specific
antigen/antibody and are described below. Other methods may
be used, such as tissue culture cytotoxicity assay for C. difficile
toxin. In toxin -mediated disease, detection of toxin may be of
greater relevance than identification of the organism itself (e.g.
stool C. difficile toxin).
Nucleic acid amplification tests
In a nucleic acid amplification test (NAAT), specific sequences
of microbial DNA and RNA are identified using a nucleic acid
primer that is amplified exponentially by enzymes to generate
multiple copies of a target nucleotide sequence. The most
commonly used amplification method is the polymerase chain
reaction (PCR; see Fig. 3.11, p. 53). Reverse transcription (RT)
PCR is used to detect RNA from RNA viruses (e.g. hepatitis C
virus and HIV-1). The use of fluorescent labels in the reaction
enables ‘real-time’ detection of amplified DNA; quantification is
based on the principle that the time taken to reach the detection
threshold is proportional to the initial number of copies of the
target nucleic acid sequence. In multiplex PCR, multiple primer
pairs are used to enable detection of several different organisms
at once.
Determination of nucleotide sequences in a target gene(s) can
be used to assign microorganisms to specific strains, which may
be relevant to treatment and/or prognosis (e.g. in hepatitis C
infection, p. 877). Genes that are relevant to pathogenicity (such
as toxin genes) or antimicrobial resistance can also be detected;
for example, the mecA gene is used to screen for MRSA.
NAATs are the most sensitive direct detection methods
and are also relatively rapid. They are used widely in virology,
where the possibility of false-positive results from colonising or
contaminating organisms is remote, and are applied to blood,
respiratory samples, stool and urine. In bacteriology, PCR is used
to examine CSF, blood, tissue and genital samples, and multiplex
PCR is being developed for use in faeces. PCR is particularly
helpful for microorganisms that cannot be readily cultured, e.g.
Tropheryma whipplei, and is being used increasingly in mycology
and parasitology.
Culture
Microorganisms may be both detected and further characterised
by culture from clinical samples (e.g. tissue, swabs and body
fluids).
• Ex vivo culture (tissue or cell culture) was widely used in
the isolation of viruses but has been largely supplanted
by NAAT.
• In vitro culture (in artificial culture media) of bacteria and
fungi is used to confirm the presence of pathogens, allow
identification, test antimicrobial susceptibility and subtype
the organism for epidemiological purposes.
Culture has its limitations: results are not immediate, even
for organisms that are easy to grow, and negative cultures
rarely exclude infection. Organisms such as Mycobacterium
tuberculosis are slow-growing, typically taking at least 2 weeks,
even in rapid-culture systems. Certain organisms, such as
Mycobacterium leprae and Tropheryma whipplei, cannot be
cultivated on artificial media, and others (e.g. Chlamydia spp.
and viruses) grow only in culture systems, which are slow and
labour-intensive.
Blood culture
The terms ‘bacteraemia’ and ‘fungaemia’ describe the presence
of bacteria and fungi in the blood. ‘Blood-stream infection’
(p. 225) is the association of bacteraemia/fungaemia with clinical
evidence of infection. The presence of bacteraemia/fungaemia
can be determined by inoculating a liquid culture medium with
freshly drawn blood, which is then incubated in a system that
monitors it constantly for growth of microorganisms (e.g. by
detecting products of microbial respiration using fluorescence;
Fig. 6.6). If growth is detected, organisms are identified and
sensitivity testing is performed. Traditionally, identification has
been achieved by Gram stain appearance and biochemical
reactions. However, matrix-assisted laser desorption/ionisation
time-of-flight mass spectroscopy (MALDI-TOF-MS; see Box 6.2)
is being used increasingly to identify organisms. MALDI-TOF-MS
produces a profile of proteins of different sizes from the target
microorganism and uses databases of such profiles to identify
the organism (Fig. 6.7). It is rapid and accurate. Taking multiple
blood samples for culture at different times allows differentiation
of transient (one or two positive samples) and persistent (majority
are positive) bacteraemia. This can be clinically important in the
identification of the source of infection (p. 530).
Indirect detection of pathogens
Tests may be used to detect the host’s immune (antibody)
response to a specific microorganism, and can enable the
diagnosis of infection with organisms that are difficult to detect
by other methods or are no longer present in the host. The term
‘serology’ describes tests carried out on serum and includes
both antigen (direct) and antibody (indirect) detection.
Antibody detection
Organism-specific antibody detection is applied mainly to blood
(Fig. 6.8). Results are typically expressed as titres: that is, the
reciprocal of the highest dilution of the serum at which antibody
is detectable (for example, detection at serum dilution of 1 : 64
gives a titre of 64). ‘Seroconversion’ is defined as either a
change from negative to positive detection or a fourfold rise in
titre between acute and convalescent serum samples. An acute
sample is usually taken during the first week of disease and the
convalescent sample 2-4 weeks later. Earlier diagnosis can be
achieved by detection of immunoglobulin M (IgM) antibodies,
which are produced early in infection (p. 68). A limitation of
these tests is that antibody production requires a fully functional
host immune system, so there may be false-negative results
in immunocompromised patients. Also, other than in chronic
infections and with IgM detection, antibody tests usually provide
a retrospective diagnosis.
Antibody detection methods are described below (antigen
detection methods are also described here as they share similar
methodology).
Enzyme-linked immunosorbent assay
The principles of the enzyme-linked immunosorbent assay (ELISA,
EIA) are illustrated in Figure 6.9. These assays rely on linking
Investigation of infection • 107
1 Patient sampling
Contamination minimised by
aseptic technique. Maximise
sensitivity by sampling correct
volume
V J
2 Sample handling
Follow local instructions for safety,
labelling, and numbers of samples and
bottles required
s .
3 Specimen transport
Transport samples to laboratory as quickly
as possible. Follow manufacturer’s
instructions for the blood culture system
used if temporary storage is required
v _ _ _ _ _ y
4 Incubation
Incubate at 35-37°C for 5-7 days.
Microbial growth is usually detected
by constant automatic monitoring of
C02. If no growth, specimen is
negative and discarded
5 Growth detection
Time to positivity (TTP) is usually
12-24 hrs in significant bacteraemia,
but may be shorter in overwhelming
sepsis or longer with fastidious
organisms (e.g. Brucella spp.)
6 Preliminary results
A Gram film of the blood culture medium is examined and
results are communicated immediately to the clinician
to guide antibiotic therapy
7 Incubation
&
A small amount of the medium
is incubated on a range of
culture media. Preliminary
susceptibility testing may be
carried out
8 Culture results*
Preliminary
susceptibility results
are communicated to
the clinician
Further overnight incubation
is often required for definitive
identification of organisms (by
biochemical testing) and additional
susceptibility testing; identification
by MALDI-TOF MS (Fig. 6.7) is
more rapid
10 Reporting
A final summary is released when all testing is complete. For
clinical care, communication of interim results (Gram film,
preliminary identification and susceptibility) is usually more
important than the final report. Effective clinical-laboratory
communication is vital
Overnight incubation required
Urgent communication required
Fig. 6.6 An overview of the processing of blood cultures. In laboratories equipped with MALDI-TOF-MS (p. 106), rapid definitive organism
identification may be achieved at stage 6 and/or stage 8.
an antibody with an enzyme that generates a colour change on
exposure to a chromogenic substrate. Various configurations allow
detection of antigens or specific subclasses of immunoglobulin
(e.g. IgG, IgM, IgA). ELISA may also be adapted to detect PCR
products, using immobilised oligonucleotide hybridisation probes
and various detection systems.
Immunoblot (Western blot)
Microbial proteins are separated according to molecular weight
by polyacrylamide gel electrophoresis (PAGE) and transferred
(blotted) on to a nitrocellulose membrane, which is incubated
with patient serum. Binding of specific antibody is detected
with an enzyme-anti-immunoglobulin conjugate similar to that
used in ELISA, and specificity is confirmed by its location on
the membrane. Immunoblotting is a highly specific test, which
may be used to confirm the results of less specific tests such
as ELISA (e.g. in Lyme disease, p. 255).
Immunofluorescence assays
Indirect immunofluorescence assays (IFAs) detect antibodies
by incubating a serum sample with immobilised antigen (e.g.
cells known to be infected with virus on a glass slide); any
virus-specific antibody present in the serum binds to antigen
and is then detected using a fluorescent-labelled anti-human
immunoglobulin (‘secondary’ antibody). Fluorescence is visualised
using a microscope. This method can also detect organisms in
clinical samples (usually tissue or centrifuged cells) using a specific
antibody in place of immobilised antigen to achieve capture.
Complement fixation test
In a complement fixation test (CFT), patient serum is heat-treated
to inactivate complement and mixed with the test antigen. Any
specific antibody in the serum will complex with the antigen.
Complement is then added to the reaction. If antigen-antibody
108 • PRINCIPLES OF INFECTIOUS DISEASE
complexes are present, the complement will be ‘fixed’ (consumed).
Sheep erythrocytes, coated with an anti -erythrocyte antibody,
are added. The degree of erythrocyte lysis reflects the remaining
complement and is inversely proportional to the quantity of the
specific antigen-antibody complex present.
Agglutination tests
When antigens are present on the surface of particles (e.g.
cells, latex particles or microorganisms) and cross-linked with
antibodies, visible clumping (or ‘agglutination’) occurs.
• In direct agglutination, patient serum is added to a
suspension of organisms that express the test antigen.
Fig. 6.7 The workings of matrix-assisted laser desorption/ionisation
time-of-flight mass spectrometry (MALDI-TOF MS). Adapted from
Sobin K, Hameer D, Ruparel T. Digital genotyping using molecular affinity
and mass spectrometry. Nature Rev Genet 2003; 4:1001-1008.
For example, in the Weil-Felix test, if a patient’s serum
contains antibodies to rickettsial species they cause
agglutination when Proteus spp. surface (O) antigens are
added because the antibodies cross-react with the
Proteus antigens. The test lacks sensitivity and specificity
but is still used to diagnose rickettsial infection in
resource-limited settings. The Widal test reaction uses a
suspension of Salmonella typhi and S. paratyphi ‘A’ and
‘B’, treated to retain only ‘O’ and ‘H’ antigens. These
antigens are kept to detect corresponding antibodies in
serum from a patient suspected of having typhoid fever.
The test is not specific but is still used in some parts of
the world.
• In indirect (passive) agglutination, specific antigen is
attached to the surface of carrier particles, which
agglutinate when incubated with patient samples that
contain specific antibodies.
• In reverse passive agglutination (an antigen detection test),
the carrier particle is coated with antibody rather than
antigen.
Other tests
Immunodiffusion involves antibodies and antigen migrating through
gels, with or without the assistance of electrophoresis, and
forming insoluble complexes where they meet. The complexes
are seen on staining as ‘precipitin bands’. Immunodiffusion is
used in the diagnosis of dimorphic fungi (p. 300) and some
forms of aspergillosis (p. 596).
Immunochromatography is used to detect antigen. The system
consists of a porous test strip (e.g. a nitrocellulose membrane), at
one end of which there is target-specific antibody, complexed with
coloured microparticles. Further specific antibody is immobilised
in a transverse narrow line some distance along the strip. Test
material (e.g. blood or urine) is added to the antibody-particle
complexes, which then migrate along the strip by capillary action.
If these are complexed with antigen, they will be immobilised by
the specific antibody and visualised as a transverse line across
the strip. If the test is negative, the antibody-particle complexes
will bind to a line of immobilised anti-immunoglobulin antibody
placed further along the strip, which acts as a negative control.
Immunochromatographic tests are rapid and relatively cheap to
perform, and are appropriate for point-of-care testing, e.g. in
FHIV 1 and malaria (p. 276).
Fig. 6.8 Detection of antigen, nucleic acid and
antibody in infectious disease. The acute sample is
usually taken during the first week of illness, and the
convalescent sample 2-4 weeks later. Detection limits
and duration of detectability vary between tests and
diseases, although in most diseases immunoglobulin
M (IgM) is detectable within the first 1-2 weeks.
Investigation of infection • 109
jp ® [§ @
Antibody detection Antibody capture Competitive antibody Double antibody sandwich
ELISA
ELISA
• o
detection ELISA
ELISA (for antigen detection)
• o
V
• o
V
A
_ A _
T
aYu
A
•
IMI
YYYY
MM
YYYY
Patient Ab
>-C
Antibody-enzyme
conjugate
Ig subclass-specific Ab
Specific Ag
O Chromogenic substrate
Ab specific to Ag from
the disease-causing
organism
Fig. 6.9 Antibody (Ab) and antigen (Ag) detection by enzyme-linked immunosorbent assay (ELISA). This can be configured in various ways.
A] Patient Ab binds to immobilised specific Ag and is detected by addition of anti-immunoglobulin-enzyme conjugate and chromogenic substrate.
¥] Patient Ab binds to immobilised Ig subclass-specific Ab and is detected by addition of specific Ag, followed by antibody-enzyme conjugate and
chromogenic substrate. [C] Patient Ab and antibody-enzyme conjugate bind to immobilised specific Ag. Magnitude of colour change reaction is inversely
proportional to concentration of patient Ab. [D] Patient Ag binds to immobilised Ab and is detected by addition of antibody-enzyme conjugate and
chromogenic substrate. In A, the conjugate Ab is specific for human immunoglobulin. In B-D, it is specific for Ag from the disease-causing organism.
I Antibody-independent specific
immunological tests
The interferon-gamma release assay (IGRA) is being used
increasingly to diagnose latent tuberculosis infection (LTBI). The
principle behind IGRA is discussed on page 594. IGRA cannot
distinguish between latent and active tuberculosis infection
and is therefore appropriate for use only in countries where the
background incidence of tuberculosis is low.
Antimicrobial susceptibility testing
If growth of microorganisms in culture is inhibited by the addition
of an antimicrobial agent, the organism is considered to be
susceptible to that antimicrobial. Bacteriostatic agents cause
reversible inhibition of growth and bactericidal agents cause
cell death; the terms fungistatic/fungicidal are equivalent for
antifungal agents, and virustatic/virucidal for antiviral agents.
The lowest concentration of antimicrobial agent at which growth
is inhibited is the minimum inhibitory concentration (MIC), and
the lowest concentration that causes cell death is the minimum
bactericidal concentration (MBC). If the MIC is less than or
equal to a predetermined breakpoint threshold, the organism
is considered susceptible, and if the MIC is greater than the
breakpoint, it is resistant.
Breakpoints are determined for each antimicrobial agent from
a combination of pharmacokinetic (p. 17) and clinical data. The
relationship between in vitro antimicrobial susceptibility and clinical
response is complex, as response also depends on immune
status, pharmacokinetic variability (p. 17), comorbidities that may
influence pharmacokinetics or pharmacodynamics, and antibiotic
dosing, as well as MIC/MBC. Thus, although treating a patient
according to the results of susceptibility testing increases the
likelihood of recovery, it does not guarantee therapeutic success.
Susceptibility testing is often carried out by disc diffusion
(Fig. 6.10). Antibiotic-impregnated filter paper discs are placed
on agar plates containing bacteria; antibiotic diffuses into the
agar, resulting in a concentration gradient centred on the disc.
Bacteria are unable to grow where the antibiotic concentration
exceeds the MIC, which may therefore be inferred from the
size of the zone of inhibition. The MIC is commonly measured
in diagnostic laboratories using ‘diffusion strips’.
Fig. 6.10 Antimicrobial susceptibility testing by disc diffusion
(panels 1-4) and minimum inhibitory concentration (MIC, panel 5).
1 . The test organism is spread over the surface of an agar plate.
2. Antimicrobial-impregnated discs (A-F) are placed on the surface and
the plate is incubated (e.g. overnight). 3-4. After incubation, zones of
growth inhibition may be seen. The organism is considered susceptible if
the diameter of the zone of inhibition exceeds a pre-determined threshold.
5. In a ‘diffusion strip’ test, the strip is impregnated with antimicrobial
at a concentration gradient that decreases steadily from top to bottom.
The system is designed so that the MIC value is the point at which
the ellipse cuts a scale on the strip (arrow). 4, Kindly supplied by
Charlotte Symes.
110 • PRINCIPLES OF INFECTIOUS DISEASE
Epidemiology of infection
The communicability of infectious disease means that, once
a clinician has diagnosed an infectious disease, potential
exposure of other patients must also be considered. The
patient may require separation from other patients (‘isolation’),
or an outbreak of disease may need to be investigated in
the community (Ch. 5). The approach will be specific to the
microorganism involved (Chs 11-13) but the principles are
outlined below.
I Geographical and temporal patterns
of infection
Endemic disease
Endemic disease has a constant presence within a given
geographical area or population. The infectious agent may have
a reservoir, vector or intermediate host that is geographically
restricted, or may itself have restrictive environmental requirements
(e.g. temperature range, humidity). The population affected
may be geographically isolated or the disease may be limited
to unvaccinated populations. Factors that alter geographical
restriction include:
• expansion of an animal reservoir (e.g. Lyme disease from
reforestation)
• vector escape (e.g. airport malaria)
• extension of host range (e.g. schistosomiasis from dam
construction)
• human migration (e.g. carbapenemase-producing
Klebsiella pneumoniae)
• public health service breakdown (e.g. diphtheria in
unvaccinated areas)
• climate change (e.g. dengue virus and Rift Valley fever).
Emerging and re-emerging disease
An emerging infectious disease is one that has newly appeared in
a population, or has been known for some time but is increasing
in incidence or geographical range. If the disease was previously
known and thought to have been controlled or eradicated, it is
considered to be re-emerging. Many emerging diseases are
caused by organisms that infect animals and have undergone
adaptations that enable them to infect humans. This is exemplified
by HIV-1 , which is believed to have originated in higher primates
in Africa. The geographical pattern of some recent emerging and
re-emerging infections is shown in Figure 6.11.
| Reservoirs of infection
The US Centers for Disease Control (CDC) define a reservoir
of infection as any person, other living organism, environment
or combination of these in which the infectious agent lives and
replicates and on which the infectious agent is dependent for its
survival. The infectious agent is transmitted from this reservoir
to a susceptible host.
Human reservoirs
Both colonised individuals and those with infection can act as
reservoirs, e.g. with Staph, aureus (including MRSA), Strep,
pyogenes and C. difficile. For infected humans to act as
reservoirs, the infections caused must be long-lasting in at least
a proportion of those affected, to enable onward transmission
(e.g. tuberculosis, sexually transmitted infections). Humans are
the only reservoir for some infections (e.g. measles).
Animal reservoirs
The World Health Organization (WHO) defines a zoonosis as ‘a
disease or infection that is naturally transmissible from vertebrate
animals to humans’. Infected animals may be asymptomatic.
Zoonotic agents may be transmitted via any of the routes
described below. Primary infection with zoonoses may be
transmitted onward between humans, causing secondary disease
(e.g. Q fever, brucellosis, Ebola).
Environmental reservoirs
Many infective pathogens are acquired from an environmental
source. However, some of these are maintained in human or
animal reservoirs, with the environment acting only as a conduit
for infection.
Fig. 6.11 Geographical locations of some infectious disease outbreaks, with examples of emerging and re-emerging diseases. (CPE =
carbapenemase-producing Enterobacteriaceae; MDR-TB = multidrug-resistant tuberculosis; MERS-Co-V = Middle East respiratory syndrome coronavirus;
XDR-TB = extensively drug-resistant tuberculosis)
Infection prevention and control • 111
6.6 Incubation periods of important infections
Infection
Incubation period
Short incubation periods
Anthrax, cutaneous3
9 hrs to 2 weeks
Anthrax, inhalational3
2 days2
Bacillary dysentery5
1-6 days
Cholera3
2 hrs to 5 days
Dengue haemorrhagic fever6
3-1 4 days
Diphtheria6
1-10 days
Gonorrhoea4
2-1 0 days
Influenza5
1-3 days
Meningococcaemia3
2-1 0 days
Norovirus1
1-3 days
SARS coronavirus3
2-7 days2
Scarlet fever5
2-4 days
Intermediate incubation periods
Amoebiasis6
1-4 weeks
Brucellosis4
5-30 days
Chickenpox5
11-20 days
Lassa fever3
3-21 days
Malaria3
1 0-1 5 days
Measles5
6-1 9 days
Mumps5
1 5-24 days
Poliomyelitis6
3-35 days
Psittacosis4
1-4 weeks
Rubella5
1 5-20 days
Typhoid5
5-31 days
Whooping cough5
5-21 days
Long incubation periods
Hepatitis A5
3-7 weeks
Hepatitis B4
6 weeks to 6 months
Leishmaniasis, cutaneous6
Weeks to months
Leishmaniasis, visceral6
Months to years
Leprosy (Hansen’s disease)3
5-20 years
Rabies4
2-8 weeks2
Trypanosoma brucei gambiense infection6
Months to years
Tuberculosis5
1-12 months
incubation periods are approximate and may differ from local or national
guidance. 2Longer incubation periods have been reported. 3WH0. 4Health
Protection Agency (now Health Protection England). 5Richardson M, Elliman D,
Maguire H, et al. Pediatr Infect Dis J 2001 ; 20:380-388. Centers for Disease
Control, USA.
(SARS = severe acute respiratory syndrome)
| Transmission of infection
Communicable diseases may be transmitted by one or more
of the following routes:
• Respiratory route: inhalation.
• Faecal-oral route: ingestion of material originating from
faeces.
• Sexually transmitted infections: direct contact between
mucous membranes.
• Blood -borne infections: direct inoculation of blood or body
fluids.
• Direct contact: very few organisms are capable of causing
infection by direct contact with intact skin. Most infection
by this route requires contact with damaged skin (e.g.
surgical wound).
• Via a vector or fomite: the vector/fomite bridges the gap
between the infected host or reservoir and the uninfected
host. Vectors are animate, and include mosquitoes in
malaria, dengue and Zika virus infection, fleas in plague
6.7 Periods of infectivity in common childhood
infectious diseases
Disease
Infectious period
Chickenpox
From 4 days before until 5 days after
appearance of the rash (transmission before
48 hrs prior to the onset of rash is rare)4
Measles2
From 4 days before onset to 4 days after
onset of the rash
Mumps3
From 2-3 days before to 5 days after
disease onset5
Rubella3
From 10 days before until 15 days after the
onset of the rash, but most infectious during
prodromal illness4
Scarlet fever1
Unknown6
Whooping cough1
Unknown6'7
Tram Richardson M, Elliman D, Maguire H, et al. Pediatr Infect Dis J 2001 ;
20:380-388. Tenters for Disease Control, USA; cdc.gov/measles/hcp/. 3Bennett
JE, Dolin R, Blaser MJ. Mandell, Douglas and Bennett’s Principles and practice
of infectious diseases, 8th edn. Philadelphia: Elsevier; 2015. 4_6Exclude from
contact with non-immune and immunocompromised people for 5 days from
4onset of rash, 5onset of parotitis, or 6start of antibiotic treatment. 7Exclude for
3 weeks if untreated.
Durations are approximate and vary between information sources, and these
recommendations may differ from local or national guidance.
and humans in MRSA. Fomites are inanimate objects such
as door handles, water taps and ultrasound probes, which
are particularly associated with health care-associated
infection (HCAI).
The likelihood of infection following transmission of a pathogen
depends on organism factors (virulence, p. 104) and host
susceptibility. The incubation period is the time between exposure
and development of symptoms, and the period of infectivity is
the period after exposure during which the patient is infectious
to others. Knowledge of incubation periods and of periods
of infectivity is important in controlling the spread of disease,
although for many diseases these estimates are imprecise
(Boxes 6.6 and 6.7).
Deliberate release
Deliberate release of pathogens with the intention of causing
disease is known as biological warfare or bioterrorism, depending
on the scale and context. Deliberate release incidents have
included a 750-person outbreak of Salmonella typhimurium
caused by contamination of salads in 1984 (Oregon, USA) and
22 cases of anthrax (five fatal) from the mailing of finely powdered
(weaponised) anthrax spores in 2001 (New Jersey, USA). Diseases
with high potential for deliberate release include anthrax, plague,
tularaemia, smallpox and botulism (through toxin release).
Infection prevention and control
Infection prevention and control (IPC) describes the measures
applied to populations with the aim of breaking the chain of
infection (see Fig. 6.1, p. 100).
Health care-associated infection
The risk of developing infection following admission to a
health-care facility (health care-associated infection, HCAI) in
112 • PRINCIPLES OF INFECTIOUS DISEASE
External ventricular drain and
ventriculoperitoneal shunt infection
Coagulase-negative staphylococci
Staphylococcus aureus
Diphtheroids
Pseudomonas aeruginosa
Cuffed/tunnelled central venous
catheter infection
Coagulase-negative staphylococci
Staphylococcus aureus (incl. MRSA)
Conforms
Candida
Pseudomonas spp.
Enterococcus spp.
Surgical site infection
Staphylococcus aureus
Beta-haemolytic streptococci
Coliforms
Anaerobes
Prosthetic joint infection
Coagulase-negative staphylococci
Staphylococcus aureus
Streptococci
Conforms
Propionibacterium acnes
Temporary central venous
catheter infection
Staphylococcus aureus (incl. MRSA)
Coagulase-negative staphylococci
Conforms
Candida
Breast implant infection
Staphylococcus aureus
Coagulase-negative staphylococci
Peritoneal dialysis-related peritonitis
Staphylococcus aureus
Coagulase-negative staphylococci
Conforms
Pseudomonas spp.
Fig. 6.12 Commonly encountered health care-associated infections (HCAIs) and the factors that predispose to them.
6.8 Measures used in infection prevention and control (IPC)
Institutions
Clinical practice
• Handling, storage and disposal of clinical waste
• Containment and safe removal of spilled blood and body fluids
• Cleanliness of environment and medical equipment
• Specialised ventilation (e.g. laminar flow, air filtration, controlled
pressure gradients)
• Sterilisation and disinfection of instruments and equipment
• Food hygiene
• Laundry management
• Antibiotic stewardship (p. 115)
• Aseptic technique
• Perioperative antimicrobial prophylaxis
• Screening patients for colonisation or infection (e.g. MRSA, GRE, CPE)
Response to infections
• Surveillance to detect alert organism (see text) outbreaks and
antimicrobial resistance
• Antibiotic chemoprophylaxis in infectious disease contacts, if indicated
(see Box 6.18)
Health-care staff
• Education
• Hand hygiene, including hand-washing (see Fig. 6.13)
• Sharps management and disposal
• Use of personal protective equipment (masks, sterile and non-sterile
gloves, gowns and aprons)
• Screening health workers for disease (e.g. tuberculosis, hepatitis B
virus, MRSA)
• Immunisation and post-exposure prophylaxis
• Isolation (see Box 6.9)
• Reservoir control
• Vector control
(CPE = carbapenemase-producing Enterobacteriaceae; GRE = glycopeptide-resistant enterococci; MRSA = meticillin-resistant Staphylococcus aureus)
the developed world is about 10%. Many nosocomial bacterial
infections are caused by organisms that are resistant to numerous
antibiotics (multi-resistant bacteria), including MRSA, extended-
spectrum (3-lactamases (ESBLs) and carbapenemase-producing
Enterobacteriaceae (CPE), and glycopeptide- resistant enterococci
(GRE). Other infections of particular concern in hospitals include
C. difficile (p. 264) and norovirus (p. 249). Some examples are
shown in Figure 6.12.
IPC measures are described in Box 6.8. The most important
is maintenance of good hand hygiene (Fig. 6.13). Hand
Infection prevention and control • 113
Wash hands only when visibly soiled! Otherwise use handrub!
) Duration of the entire procedure: 40-60 sec.
Wet hands with water using Apply enough soap to cover Rub hands palm to palm Right palm over left dorsum Palm to palm with fingers
elbow-operated or non¬
touch taps (if available)
all hand surfaces
with interlaced fingers
and vice versa
interlaced
(11
\
f
L
m \
V
\ J
Rotational rubbing of left
thumb clasped in right
palm and vice versa
Rotational rubbing,
backwards and forwards
with clasped fingers of
right hand in left palm
and vice versa
Rinse hands with water
Dry thoroughly with a
single-use towel
Backs of fingers to
opposing palms with
fingers interlaced
If hand-operated taps have
been used, use towel to
turn off tap
..and your hands are clean
Fig. 6.13 Hand-washing. Good hand hygiene, whether with soap/water or alcohol handrub, includes areas that are often missed, such as fingertips, web
spaces, palmar creases and the backs of hands. Adapted from the 'How to Handwash’ URL: who.int/gpsc/5may/How_To_Handwash_Poster.pdf© World
Health Organization 2009. All rights reserved.
i
6.9 Types of isolation precaution
Airborne transmission Contact transmission
Droplet transmission
Precautions
Negative pressure room with air
exhausted externally or filtered
N95 masks or personal respiratiors for
staff; avoid using non-immune staff
Infections managed with these precautions
Private room preferred (otherwise, inter-patient
spacing > 1 m)
Gloves and gown for staff in contact with patient or
contaminated areas
Measles
Tuberculosis, pulmonary or laryngeal,
confirmed or suspected
Enteroviral infections in young children (diapered or
incontinent)
Norovirus2
C. difficile infection
Multidrug-resistant organisms (e.g. MRSA, ESBL,
GRE, VRSA, penicillin-resistant Strep, pneumoniae f
Parainfluenza in infants and young children
Rotavirus
RSV in infants, children and immunocompromised
Viral conjunctivitis, acute
Private room preferred (otherwise, inter-patient
spacing > 1 m)
Surgical masks for staff in close contact with patient
Diphtheria, pharyngeal
Haemophilus influenzae type B infection
Herpes simplex virus, disseminated or severe
Influenza
Meningococcal infection
Mumps
Mycoplasma pneumoniae
Parvovirus (erythrovirus) B19 (erythema infectiosum,
fifth disease)
Pertussis
Plague, pneumonic/bubonic
Rubella
Strep, pyogenes (group A), pharyngeal
Infections managed with multiple precautions
< - Smallpox, monkeypox, VZV (chickenpox or disseminated disease)4
< - Adenovirus pneumonia -
< - SARS, viral haemorrhagic fever2 -
Recommendations based on 2007 CDC guideline for isolation precautions. May differ from local or national recommendations. 2Not a CDC recommendation. 3Subject to
local risk assessment. 40r in any immunocompromised patient until possibility of disseminated infection excluded. (ESBL = extended-spectrum p-lactamase; GRE =
glycopeptide-resistant enterococci; MRSA = meticillin-resistant Staph, aureus ; RSV = respiratory syncytial virus; SARS = severe acute respiratory syndrome; VRSA =
vancomycin-resistant Staph, aureus; VZV = varicella zoster virus)
decontamination (e.g. using alcohol gel or washing) is mandatory
before and after every patient contact. Decontamination with
alcohol gel is usually adequate but hand-washing (with hot
water, liquid soap and complete drying) is required after any
procedure that involves more than casual physical contact, or
if hands are visibly soiled. In situations where the prevalence of
C. difficile is high (e.g. a local outbreak), alcohol gel decontamination
between patient contacts is inadequate as it does not kill
C. difficile spores, and hands must be washed.
Some infections necessitate additional measures to prevent
cross-infection (Box 6.9). To minimise risk of infection, invasive
procedures must be performed using strict aseptic technique.
114 • PRINCIPLES OF INFECTIOUS DISEASE
Outbreaks of infection
Descriptive terms are defined in Box 6.10. Confirmation of an
infectious disease outbreak usually requires evidence from ‘typing’
that the causal organisms have identical phenotypic and/or
genotypic characteristics. If this is found not to be the case, the
term pseudo-outbreak is used. When an outbreak of infection
is suspected, a case definition is agreed. The number of cases
that meet the case definition is then assessed by case-finding,
using methods ranging from administration of questionnaires
to national reporting systems. Case-finding usually includes
microbiological testing, at least in the early stages of an outbreak.
Temporal changes in cases are noted in order to plot an outbreak
curve, and demographic details are collected to identify possible
sources of infection. A case-control study, in which recent
activities (potential exposures) of affected ‘cases’ are compared
to those of unaffected ‘controls’, may be undertaken to establish
the outbreak source, and measures are taken to manage the
outbreak and control its spread. Good communication between
relevant personnel during and after the outbreak is important to
inform practice in future outbreaks.
Surveillance ensures that disease outbreaks are either
prevented or identified early. In hospitals, staff are made aware
of the isolation of alert organisms, which have the propensity
to cause outbreaks, and alert conditions, which are likely to
be caused by such organisms. Analogous systems are used
nationally; many countries publish lists of organisms and diseases,
which, if detected (or suspected), must be reported to public
health authorities (reportable or notifiable diseases). Reasons for
a disease to be classified as reportable are shown in Box 6.1 1 .
Term
6.10 Terminology in outbreaks of infection
Definition
Classification of related cases of infectious disease
Cluster An aggregation of cases of a disease that are
closely grouped in time and place, and may or
may not exceed the expected number
Epidemic The occurrence of more cases of disease than
expected in a given area or among a specific
group of people over a particular period of time
Outbreak Synonymous with epidemic. Alternatively, a
localised, as opposed to generalised, epidemic
Pandemic An epidemic occurring over a very wide area
(several countries or continents) and usually
affecting a large proportion of the population
Classification of affected patients (cases)
Index case The first case identified in an outbreak
Primary cases Cases acquired from a specific source of infection
Secondary cases Cases acquired from primary cases
Types of outbreak
Common source
outbreak
Point source
outbreak
Person-to-
person spread
Exposure to a common source of infection (e.g.
water-cooling tower, medical staff member
shedding MRSA). New primary cases will arise
until the source is no longer present
Exposure to a single source of infection at a
specific point in time (e.g. contaminated food at a
party). Primary cases will develop disease
synchronously
Outbreak with both primary and secondary cases.
May complicate point source or common source
outbreak
*Adapted from cdc.gov. (MRSA = meticillin-resistant Staphylococcus aureus)
^9 6.1 1 Reasons for including an infectious disease on
a regional/national list of reportable diseases
Reason for inclusion
Examples
Endemic/local disease with the
potential to spread and/or cause
outbreaks
Influenza, Salmonella ,
tuberculosis
Imported disease with the
propensity to spread and/or cause
outbreaks
Typhoid, cholera (depending
on local epidemiology)
Evidence of a possible breakdown
in health protection/public health
functions
Legionella , Cryptosporidium
Evidence of a possible breakdown
in food safety practices
Botulism, verotoxigenic E. coli
Evidence of a possible failure of a
vaccination programme
Measles, poliomyelitis,
pertussis
Disease with the potential to be a
novel or increasing threat to
human health
SARS, MERS-CoV,
multi-resistant bacteria
Evidence of expansion of the
range of a reservoir/vector
Lyme disease, rabies, West
Nile encephalitis
Evidence of possible deliberate
release
Anthrax, tularaemia, plague,
smallpox, botulism
*Given the different geographical ranges of individual diseases and wide national
variations in public health services, vaccination programmes and availability of
resources, reporting regulations vary between regions, states and countries. Many
diseases are reportable for more than one reason. (MERS-CoV = Middle East
respiratory syndrome coronavirus; SARS = severe acute respiratory syndrome)
Immunisation
Immunisation may be passive or active. Passive immunisation
is achieved by administering antibodies targeting a specific
pathogen. Antibodies are obtained from blood, so confer some of
the risks associated with blood products (p. 933). The protection
afforded by passive immunisation is immediate but of short
duration (a few weeks or months); it is used to prevent or
attenuate infection before or after exposure (Box 6.12).
Vaccination
Active immunisation is achieved by vaccination with whole
organisms or organism components (Box 6.13).
Types of vaccine
Whole-cell vaccines consist of live or inactivated (killed)
microorganisms. Component vaccines contain only extracted or
synthesised components of microorganisms (e.g. polysaccharides
or proteins). Live vaccines contain organisms with attenuated
(reduced) virulence, which cause only mild symptoms but induce
T-lymphocyte and humoral responses (p. 68) and are therefore
more immunogenic than inactivated whole-cell vaccines. The
use of live vaccines in immunocompromised individuals is not
generally recommended, but they may be used by specialists
following a risk/benefit assessment.
Component vaccines consisting only of polysaccharides,
such as the pneumococcal polysaccharide vaccine (PPV), are
poor activators of T lymphocytes and produce a short-lived
antibody response without long-lasting memory. Conjugation of
polysaccharide to a protein, as in the Haemophilus influenzae
type B (Hib) vaccine and the protein conjugate pneumococcal
Antimicrobial stewardship • 115
6.12 Indications for post-exposure prophylaxis
with immunoglobulins
Human normal immunoglobulin (pooled immunoglobulin)
• Hepatitis A (unvaccinated contacts*)
• Measles (exposed child with heart or lung disease)
Human specific immunoglobulin
• Hepatitis B (sexual partners, inoculation injuries, infants born to
infected mothers)
• Tetanus (high-risk wounds or incomplete or unknown immunisation
status)
• Rabies
• Chickenpox (immunosuppressed children and adults, pregnant
women)
*Active immunisation is preferred if contact is with a patient who is within 1 week
of onset of jaundice.
6.14 Guidelines for vaccination against
infectious disease
• The principal contraindication to inactivated vaccines is an
anaphylactic reaction to a previous dose or a vaccine component
• Live vaccines should not be given during an acute infection, to
pregnant women or to the immunosuppressed, unless the
immunosuppression is mild and the benefits outweigh the risks
• If two live vaccines are required, they should be given either
simultaneously in opposite arms or 4 weeks apart
• Live vaccines should not be given for 3 months after an injection of
human normal immunoglobulin (HNI)
• HNI should not be given for 2 weeks after a live vaccine
• Hay fever, asthma, eczema, sickle-cell disease, topical
glucocorticoid therapy, antibiotic therapy, prematurity and chronic
heart and lung diseases, including tuberculosis, are not
contraindications to vaccination
6.13 Vaccines in current clinical use
Live attenuated vaccines
• Measles, mumps, rubella (MMR)
• Oral poliomyelitis (OPV, not used in UK)
• Rotavirus
• Tuberculosis (bacille Calmette— Guerin, BCG)
• Typhoid (oral typhoid vaccine)
• Varicella zoster virus
Inactivated (killed) whole-cell vaccines
• Cholera
• Hepatitis A
• Influenza
• Poliomyelitis (inactivated polio virus, IP V)
• Rabies
Component vaccines
• Anthrax (adsorbed extracted antigens)
• Diphtheria (adsorbed toxoid)
• Hepatitis B (adsorbed recombinant hepatitis B surface antigen,
HBsAg)
• Haemophilus influenzae type B (conjugated capsular polysaccharide)
• Human papillomavirus (recombinant capsid proteins)
• Meningococcal, quadrivalent A, C, Y, W135 (conjugated capsular
polysaccharide)
• Meningococcal, serogroup C (conjugated capsular polysaccharide)
• Pertussis (adsorbed extracted antigens)
• Pneumococcal conjugate (PCV; conjugated capsular polysaccharide,
1 3 serotypes)
• Pneumococcal polysaccharide (PPV; purified capsular
polysaccharide, 23 serotypes)
• Tetanus (adsorbed toxoid)
• Typhoid (purified Vi capsular polysaccharide)
vaccinated to curtail further spread. Vaccination is aimed mainly
at preventing infectious disease. However, vaccination against
human papillomavirus (HPV) was introduced to prevent cervical
and other cancers that complicate HPV infection. Vaccination
guidelines for individuals are shown in Box 6.14.
Vaccination becomes successful once the number of
susceptible hosts in a population falls below the level required
to sustain continued transmission of the target organism (herd
immunity). Naturally acquired smallpox was declared to have been
eradicated worldwide in 1980 through mass vaccination. In 1988,
the WHO resolved to eradicate poliomyelitis by vaccination; the
number of cases worldwide has since fallen from approximately
350000 per annum to 74 in 2015. Recommended vaccination
schedules vary between countries. In addition to standard
vaccination schedules, catch-up schedules are specified for
individuals who join vaccination programmes later than the
recommended age.
Antimicrobial stewardship
Antimicrobial stewardship (AMS) refers to the systems and
processes applied to a population to optimise the use of
antimicrobial agents. The populations referred to here may
be a nation, region, hospital, or a unit within a health-care
organisation (e.g. ward or clinic). AMS aims to improve patient
outcomes and reduce antimicrobial resistance (AMR). IPC and
AMS complement each other (Fig. 6.14). Elements of AMS
include treatment guidelines, antimicrobial formularies and ward
rounds by infection specialists.
vaccine (PCV), activates T lymphocytes, which results in a
sustained response and immunological memory. Toxoids are
bacterial toxins that have been modified to reduce toxicity but
maintain antigenicity. Vaccine response can be improved by
co-administration with mildly pro-inflammatory adjuvants, such
as aluminium hydroxide.
Use of vaccines
Vaccination may be applied to entire populations or to
subpopulations at specific risk through travel, occupation or
other activities. In ring vaccination, the population immediately
surrounding a case or outbreak of infectious disease is
Fig. 6.14 The relationship between infection prevention and control
(IPC) and antimicrobial stewardship (AMS).
116 • PRINCIPLES OF INFECTIOUS DISEASE
6.15 Target and mechanism of action of common
antibacterial agents
Aminoglycosides, chloramphenicol, macrolides,
lincosamides, oxazolidinones
• Inhibition of bacterial protein synthesis by binding to subunits of
bacterial ribosomes
Tetracyclines
• Inhibition of protein synthesis by preventing transfer RNA binding to
ribosomes
Beta-lactams
• Inhibition of cell wall peptidoglycan synthesis by competitive
inhibition of transpeptidases (‘penicillin-binding proteins’)
Cyclic lipopeptide (daptomycin)
• Insertion of lipophilic tail into plasma membrane causing
depolarisation and cell death
Glycopeptides
• Inhibition of cell wall peptidoglycan synthesis by forming complexes
with D-alanine residues on peptidoglycan precursors
Nitroimidazoles
• The reduced form of the drug causes strand breaks in DNA
Quinolones
• Inhibition of DNA replication by binding to DNA topoisomerases
(DNA gyrase and topoisomerase IV), preventing supercoiling and
uncoiling of DNA
Rifamycins
• Inhibition of DNA synthesis by inhibiting DNA-dependent RNA
polymerase
Sulphonamides and trimethoprim
• Inhibition of folate synthesis by dihydropteroate synthase
(sulphonamides) and dihydrofolate reductase (trimethoprim) inhibition
Treatment of infectious diseases
Key components of treating infection are:
• optimising antimicrobial therapy while minimising selection
for antimicrobial resistance and the impact on commensal
flora
• addressing predisposing factors, e.g. glycaemic control in
diabetes mellitus; viral load control in H I V-1 -associated
opportunistic infection
• considering adjuvant therapy, e.g. removal of an infected
medical device or necrotic tissue
• managing complications, e.g. severe sepsis (systemic
inflammatory response syndrome, or SIRS, p. 196) and
acute kidney injury (p. 411).
For communicable disease, treatment must also take into
account contacts of the infected patient, and may include
IPC interventions such as isolation, antimicrobial prophylaxis,
vaccination and contact tracing.
Principles of antimicrobial therapy
In some situations (e.g. pneumonia) it is important to start
appropriate antimicrobial therapy promptly, whereas in others
prior confirmation of the diagnosis and pathogen is preferred.
The principles underlying the choice of antimicrobial agent(s)
are discussed below. The WHO ‘World Antibiotic Awareness
Week’ campaign is a yearly event aimed at highlighting the
importance of prudent antimicrobial prescribing (see ‘Further
information’).
| Antimicrobial action and spectrum
Antimicrobial agents may kill or inhibit microorganisms by
targeting essential and non-essential cellular processes,
respectively. The range, or spectrum, of microorganisms that
is killed or inhibited by a particular antimicrobial agent needs
consideration when selecting therapy. Mechanisms of action
of the major classes of antibacterial agent are listed in Box
6.15 and appropriate agents for some common infecting
organisms are shown in Box 6.16. In severe infections and/
or immunocompromised patients, it is customary to use
bactericidal agents in preference to bacteriostatic agents.
Empiric versus targeted therapy
Empiric antimicrobial therapy is selected to treat a suspected
infection (e.g. meningitis) before the microbiological cause is
known. Targeted or ‘directed’ therapy can be prescribed when
the pathogen(s) is known. Empirical antimicrobial regimens need
to have activity against the range of pathogens that could be
causing the infection in question; because broad-spectrum
agents affect many more bacteria than needed, they select for
antimicrobial resistance. ‘Start Smart - Then Focus’ (Fig. 6.15)
describes the principle of converting from empiric therapy to
narrow-spectrum targeted therapy. Optimum empiric therapy
depends on the site of infection, patient characteristics and local
antimicrobial resistance patterns. National or local guidelines
are often used to inform antimicrobial prescribing decisions.
Combination therapy
It is sometimes appropriate to combine antimicrobial agents:
• when there is a need to increase clinical effectiveness (e.g.
biofilm infections)
• when no single agent’s spectrum covers all potential
pathogens (e.g. polymicrobial infection)
• when there is a need to reduce development of
antimicrobial resistance in the target pathogen, as the
organism would need to develop resistance to multiple
agents simultaneously (e.g. antituberculous chemotherapy,
p. 592; antiretroviral therapy (ART), p. 324).
Antimicrobial resistance
Microorganisms have evolved in the presence of naturally occurring
antibiotics and have therefore developed resistance mechanisms
(categorised in Fig. 6.16) to all classes of antimicrobial agent
(antibiotics and their derivatives). Intrinsic resistance is an innate
property of a microorganism, whereas acquired resistance arises
by spontaneous mutation or horizontal transfer of genetic material
from another organism (e.g. via a plasmid, p. 100). Plasmids
often encode resistance to multiple antibiotics.
The mecA gene encodes a penicillin-binding protein, which
has a low affinity for penicillins and therefore confers resistance
to p-lactam antibiotics in staphylococci. Extended-spectrum
p-lactamases (ESBLs) are frequently encoded on plasmids,
which are transferred relatively easily between bacteria, including
Enterobacteriaceae. Plasmid-encoded carbapenemases have
been detected in strains of Klebsiella pneumoniae (e.g. New Delhi
metallo-p-lactamase 1, NDM-1). Strains of MRSA have been
described that also have reduced susceptibility to glycopeptides
through the development of a relatively impermeable cell wall.
Treatment of infectious diseases • 117
i
6.16 Antimicrobial options for common infecting bacteria
Organism
Antimicrobial options
Gram-positive organisms
Enterococcus faecalis
Ampicillin, vancomycin/teicoplanin
Enterococcus faecium
Vancomycin/teicoplanin, linezolid
Glycopeptide- resistant enterococci
Linezolid, tigecycline, daptomycin
MRSA
Clindamycin, vancomycin, rifampicin (never used as monotherapy), linezolid, daptomycin,
tetracyclines, tigecycline, co-trimoxazole
Staphylococcus aureus
Flucloxacillin, clindamycin
Streptococcus pyogenes
Penicillin, clindamycin, vancomycin
Streptococcus pneumoniae
Penicillin, cephalosporins, levofloxacin, vancomycin
Gram-negative organisms
Escherichia coli, ‘conforms’ (enteric Gram-negative bacilli)
Amoxicillin, trimethoprim, cefuroxime, ciprofloxacin, co-amoxiclav
Enterobacter spp . , Citrobacter spp .
Ciprofloxacin, meropenem, ertapenem, aminoglycosides
ESBL-producing Enterobacteriaceae
Ciprofloxacin, meropenem, ertapenem (if sensitive), temocillin, aminoglycosides
Carbapenemase-producing Enterobacteriaceae
Ciprofloxacin, aminoglycosides, tigecycline, colistin
Haemophilus influenzae
Amoxicillin, co-amoxiclav, macrolides, cefuroxime, cefotaxime, ciprofloxacin
Legionella pneumophila
Azithromycin, levofloxacin, doxycycline
Neisseria gonorrhoeae
Ceftriaxone/cefixime, spectinomycin
Neisseria meningitidis
Penicillin, cefotaxime/ceftriaxone, chloramphenicol
Pseudomonas aeruginosa
Ciprofloxacin, piperacillin— tazobactam, aztreonam, meropenem, aminoglycosides,
ceftazi d i m e/cef ep i m e
Salmonella typhi
Ceftriaxone, azithromycin (uncomplicated typhoid), chloramphenicol (resistance common)
Strict anaerobes
Bacteroides spp.
Metronidazole, clindamycin, co-amoxiclav, piperacillin— tazobactam, meropenem
Clostridium difficile
Metronidazole, vancomycin (oral), fidaxomicin
Clostridium spp.
Penicillin, metronidazole, clindamycin
Fusobacterium spp.
Penicillin, metronidazole, clindamycin
Other organisms
Chlamydia trachomatis
Azithromycin, doxycycline
Treponema pallidum
Penicillin, doxycycline
*Antibiotic selection depends on multiple factors, including local susceptibility patterns, which vary enormously between geographical areas. There are many appropriate
alternatives to those listed. (ESBL = extended-spectrum p-lactamase; MRSA = meticillin-resistant Staphylococcus aureus )
Clinical diagnosis
Laboratory investigations:
microbiological diagnosis
Antimicrobial
susceptibility results
Information available:
• Organ system involved
• Endogenous or
exogenous infection
• Likely pathogens
Antimicrobial
spectrum of
agent(s)
used
• Infecting organism(s)
• Likely antimicrobial
susceptibility
• Antimicrobial
susceptibility
of infecting
organism(s)
Level of
knowledge
of infecting
organism(s)
1 Empiric therapy
Based on:
• Predicted susceptibility
of likely pathogens
• Local antimicrobial
policies
2 Targeted therapy
Based on:
• Predicted susceptibility
of infecting organism(s)
• Local antimicrobial policies
3 Susceptibility-guided therapy
Based on:
• Susceptibility testing results
Fig. 6.15 Stages in the selection and refinement of antimicrobial therapy: ‘Start Smart - Then Focus’.
118 • PRINCIPLES OF INFECTIOUS DISEASE
Active efflux of antimicrobial agent
Tetracycline resistance in Gram-positive
and Gram-negative bacteria
Fluconazole resistance in Candida spp.
Target modification
(3-lactam resistance in MRSA - altered
penicillin-binding protein
Glycopeptide resistance in enterococci - altered
peptidoglycan amino acid sequence
Rifampicin resistance in M. tuberculosis - RNA
polymerase mutation
Ciprofloxacin resistance in Enterobacteriaceae -
gyrase mutation
Linezolid resistance in staphylococci and
enterococci - 23S rRNA methylation
DNA
Impermeability/reduced permeability
Carbapenem resistance in Pseudomonas spp.
Aminoglycoside resistance in anaerobes
(uptake requires 02-dependent transport
mechanism)
Enzymatic degradation of agent
(3-lactam resistance in many organisms
(penicillinase in Staph, aureus ; ESBLs, ampC and
NDM-1 in Enterobacteriaceae)
Chloramphenicol resistance in staphylococci (CAT)
Antimicrobial target
% Antimicrobial agent
Fig. 6.16 Examples of mechanisms of antimicrobial resistance. (CAT = chloramphenicol acetyltransferase; ESBLs = extended -spectrum
(3-lactamases; MRSA = meticillin-resistant Staph. aureus\ NDM-1 = New Delhi metallo-(3-lactamase 1).
Factors promoting antimicrobial resistance include the
inappropriate use of antibiotics (e.g. to treat viral infections),
inadequate dosage or unnecessarily prolonged treatment, and
use of antimicrobials as growth promoters in agriculture. However,
any antimicrobial use exerts a selection pressure that favours the
development of resistance. Combination antimicrobial therapy
may reduce the emergence of resistance in the target pathogen
but not in the normal flora that it also affects. Despite use of
combination therapy for M. tuberculosis, multidrug-resistant
tuberculosis (MDR-TB, resistant to isoniazid and rifampicin)
and extremely drug-resistant tuberculosis (XDR-TB, resistant
to isoniazid and rifampicin, any fluoroquinolone and at least
one injectable antimicrobial antituberculous agent) have been
reported worldwide and are increasing in incidence.
The term ‘post-antibiotic era’ has been coined to describe a
future in which the acquisition of resistance by bacteria will have
been so extensive that antibiotic therapy is rendered useless. A
more realistic scenario, which is currently being experienced, is
a gradual but inexorable progression of resistance, necessitating
the use of ever more toxic and expensive antimicrobials.
| Duration of therapy
Treatment duration reflects the severity of infection and
accessibility of the infected site to antimicrobial agents. For
most infections, there is limited evidence available to support
a specific duration of treatment (Box 6.17). Depending on the
indication, initial intravenous therapy can often be switched to
oral as soon as the patient is apyrexial and improving. In the
absence of specific guidance, antimicrobial therapy should
be stopped when there is no longer any clinical evidence
of infection.
| Pharmacokinetics and pharmacodynamics
Pharmacokinetics of antimicrobial agents determine whether
adequate concentrations are obtained at the sites of infection.
Septic patients often have poor gastrointestinal absorption, so
the preferred initial route of therapy is intravenous. Knowledge of
anticipated antimicrobial drug concentrations at sites of infection
is critical. For example, achieving a ‘therapeutic’ blood level
of gentamicin is of little practical use in treating meningitis, as
CSF penetration of the drug is poor. Knowledge of routes of
antimicrobial elimination is also critical; for instance, urinary
tract infection is ideally treated with a drug that is excreted
unchanged in the urine.
Pharmacodynamics describes the relationship between
antimicrobial concentration and microbial killing. For many
agents, antimicrobial effect can be categorised as ‘concentration-
dependent’ or ‘time-dependent’. The concentration of antimicrobial
achieved after a single dose is illustrated in Figure 6.17. The
maximum concentration achieved is Cmax and the measure of
overall exposure is the area under the curve (AUC). The efficacy
of antimicrobial agents whose killing is concentration-dependent
(e.g. aminoglycosides) increases with the amount by which
Cmax exceeds the minimum inhibitory concentration (Cmax : MIC
ratio). For this reason, it has become customary to administer
aminoglycosides (e.g. gentamicin) infrequently at high doses
(e.g. 7 mg/kg) rather than frequently at low doses. This has the
added advantage of minimising toxicity by reducing the likelihood
Treatment of infectious diseases • 119
i
6.17 Duration of antimicrobial therapy for some
common infections
Infection
Duration of therapy
Viral infections
Herpes simplex encephalitis
2-3 weeks
Bacterial infections
Gonorrhoea
Single dose
Infective endocarditis (streptococcal,
4 weeks ± gentamicin for first
native valve)
2 weeks
Infective endocarditis (prosthetic
valve)
6 weeks
Osteomyelitis
6 weeks
Pneumonia (community-acquired,
7-10 days (no organism
severe)
identified), 14-21 days [Staph,
aureus or Legionella spp.)
Septic arthritis
2-4 weeks
Urinary tract infection (male)
2 weeks
Urinary tract infection, upper tract,
7 days
uncomplicated (female)
Urinary tract infection, lower (female)
3 days
Mycobacterial infections
Tuberculosis (meningeal)
1 2 months
Tuberculosis (pulmonary)
6 months
Fungal infections
Invasive pulmonary aspergillosis
Until clinical/radiological
resolution and reversal of
predisposition
Candidaemia (acute disseminated)
2 weeks after last positive
blood culture and resolution of
signs and symptoms
*AII recommendations are indicative. Actual duration takes into account
predisposing factors, specific organisms and antimicrobial susceptibility, adjuvant
therapies, current guidelines and clinical response.
Fig. 6.17 Antimicrobial pharmacodynamics. The curve represents drug
concentrations after a single dose of an antimicrobial agent. Factors that
determine microbial killing are Cmax : MIC ratio (concentration-dependent
killing), time above MIC (time-dependent killing) and AUC:MIC ratio.
of drug accumulation. Conversely, the (3-lactam antibiotics and
vancomycin exhibit time-dependent killing, and their efficacy
depends on Cmax exceeding the MIC for a certain time (which is
different for each class of agent). This is reflected in the dosing
interval of benzylpenicillin, which is usually given every 4 hours
in severe infection (e.g. meningococcal meningitis), and may
be administered by continuous infusion. For other antimicrobial
agents, the pharmacodynamic relationships are more complex
and often less well understood. With some agents, bacterial
inhibition persists after antimicrobial exposure (post-antibiotic
and post-antibiotic sub-MIC effects).
Therapeutic drug monitoring
Therapeutic drug monitoring is used to confirm that levels
of antimicrobial agents with a low therapeutic index (e.g.
aminoglycosides) are not excessive, and that levels of agents
with marked pharmacokinetic variability (e.g. vancomycin) are
adequate. Specific recommendations for monitoring depend on
individual clinical circumstances; for instance, different pre- and
post-dose levels of gentamicin are recommended, depending
on whether it is being used in traditional divided doses, once
daily or for synergy in endocarditis (p. 530).
| Antimicrobial prophylaxis
Antimicrobial prophylaxis is the use of antimicrobial agents to
prevent infection. Primary prophylaxis is used to reduce the risk
of infection following certain medical procedures (e.g. colonic
resection or prosthetic hip insertion), following exposure to
a specific pathogen (e.g. Bordetella pertussis) or in specific
situations such as post-splenectomy (Box 6.18). It should be
6.18 Recommendations for antimicrobial prophylaxis
in adults
Infection risk Recommended antimicrobial
Bacterial
Diphtheria (prevention of secondary
cases)
Gas gangrene (after high
amputation or major trauma)
Lower gastrointestinal tract surgery
Meningococcal disease (prevention
of secondary cases)
Rheumatic fever (prevention of
recurrence)
Tuberculosis (prevention of
secondary cases)
Whooping cough (prevention of
secondary cases)
Viral
HIV, occupational exposure (sharps
injury)
Influenza A (prevention of secondary
cases in adults with chronic
respiratory, cardiovascular or renal
disease, immunosuppression or
diabetes mellitus)
Fungal
Aspergillosis (in high-risk
haematology patients)
Pneumocystis pneumonia
(prevention in HIV and other
immunosuppressed states)
Protozoal
Malaria (prevention of travel- Specific antimalarials depend
associated disease) on travel itinerary (p. 278)
*These are based on current UK practice. Recommendations may vary locally or
nationally. Antimicrobial prophylaxis for infective endocarditis during dental
procedures is not currently recommended in the UK.
Posaconazole (voriconazole or
itraconazole alternatives if
intolerant)
Co-trimoxazole, pentamidine or
dapsone
Combination tenofovir/
emtricitabine and raltegravir.
Modified if index case’s virus
known to be resistant
Oseltamivir
Erythromycin
Penicillin or metronidazole
Cefuroxime + metronidazole,
gentamicin + metronidazole, or
co-amoxiclav (single dose only)
Rifampicin or ciprofloxacin
Phenoxymethylpenicillin or
sulfadiazine
Isoniazid ± rifampicin
Erythromycin
120 • PRINCIPLES OF INFECTIOUS DISEASE
associated with minimal adverse effects. In the case of exposure,
it may be combined with passive immunisation (see Box 6.12).
Secondary prophylaxis is used in patients who have been treated
successfully for an infection but remain predisposed to it. It is
used in haemato-oncology patients in the context of fungal
infection and in HIV-positive individuals with an opportunistic
infection until a defined level of immune reconstitution is achieved.
Antibacterial agents
For details of antibacterial usage in pregnancy and old age, see
Boxes 6.19 and 6.20.
6.19 Antimicrobial agents in pregnancy
Contraindicated
• Chloramphenicol: neonatal ‘grey baby’ syndrome - collapse,
hypotension and cyanosis
• Fluconazole: teratogenic in high doses
• Quinolones: arthropathy in animal studies
• Sulphonamides: neonatal haemolysis and methaemoglobinaemia
• Tetracyclines, glycylcyclines: skeletal abnormalities in animals in
first trimester; fetal dental discoloration and maternal hepatotoxicity
with large parenteral doses in second or third trimesters
• Trimethoprim: teratogenic in first trimester
Relatively contraindicated
• Aminoglycosides: potential damage to fetal auditory and vestibular
nerves in second and third trimesters
• Metronidazole: avoidance of high dosages is recommended2
Not known to be harmful; use only when necessary
• Aciclovir
• Cephalosporins
• Clarithromycin
• Clindamycin
• Erythromycin
• Glycopeptides
• Linezolid
• Meropenem
• Penicillins
Tata extracted from Joint Formulary Committee. British National Formulary
(online). London: BMJ Group and Pharmaceutical Press; (medicinescomplete.
com) [accessed on 16 March 2013]. theoretical risk of teratogenicity, not
supported by available clinical evidence.
(C
• Clostridium difficile infection: all antibiotics predispose to some
extent, but second- and third-generation cephalosporins,
co-amoxiclav and fluoroquinolones (e.g. ciprofloxacin) especially so.
• Hypersensitivity reactions: rise in incidence due to increased
previous exposure.
• Renal impairment: may be significant in old age, despite ‘normal’
creatinine levels (p. 386).
• Nephrotoxicity: more likely, e.g. first-generation cephalosporins,
aminoglycosides.
• Accumulation of (3-lactam antibiotics: may result in myoclonus,
seizures or coma.
• Reduced gastric acid production: gastric pH is higher, which
causes increased penicillin absorption.
• Reduced hepatic metabolism: results in a higher risk of
isoniazid- related hepatotoxicity.
• Quinolones: associated with delirium and may increase the risk of
seizures.
6.20 Problems with antimicrobial therapy in old age
Beta-lactam antibiotics
These antibiotics have a (3-lactam ring structure and exert a
bactericidal action by inhibiting enzymes involved in cell wall
synthesis (penicillin-binding proteins, PBPs). They are classified
in Box 6.21 .
Pharmacokinetics
• Good drug levels are achieved in lung, kidney, bone,
muscle and liver, and in pleural, synovial, pericardial and
peritoneal fluids.
• CSF levels are low, except when meninges are inflamed.
• Activity is not inhibited in abscess (e.g. by low pH and
P02, high protein or neutrophils).
• Beta-lactams are subject to an ‘inoculum effect’ - activity
is reduced in the presence of a high organism burden
(PBP expression is down-regulated by high organism
density).
• Generally safe in pregnancy (except imipenem/cilastatin).
Adverse effects
Immediate (IgE-mediated) allergic reactions are rare but life-
threatening. Approximately 90% of patients who report a penicillin
allergy do not have a true IgE-mediated allergy. Other reactions,
such as rashes, fever and haematological effects (e.g. low
white cell count), usually follow more prolonged therapy (more
than 2 weeks). A large proportion of patients with infectious
mononucleosis develop a rash if given aminopenicillins; this
does not imply lasting allergy. The relationship between allergy to
penicillin and allergy to cephalosporins depends on the specific
cephalosporin used; there is significant cross-reactivity with
first-generation cephalosporins but cross- reactivity to second-/
third-generation cephalosporins is less common. Avoidance of
cephalosporins, however, is recommended in patients who have
IgE-mediated penicillin allergy (p. 84). Cross- reactivity between
penicillin and carbapenems is rare (approximately 1 % by skin
testing) and carbapenems may be administered if there are no
suitable alternatives and appropriate resuscitation facilities are
available. The monobactam aztreonam (p. 121) is the (3-lactam
least likely to cross-react in patients with penicillin allergy.
Gastrointestinal upset and diarrhoea are common, and a mild
reversible hepatitis is recognised with many (3-lactams. More
severe forms of hepatitis can be observed with flucloxacillin
and co-amoxiclav. Leucopenia, thrombocytopenia, coagulation
6.21 Beta-lactam antibiotics
Penicillins
• Natural penicillins: benzylpenicillin, phenoxymethylpenicillin
• Penicillinase-resistant penicillins: meticillin, flucloxacillin, nafcillin,
oxacillin
• Aminopenicillins: ampicillin, amoxicillin
• Carboxy- and ureido-penicillins: ticarcillin, piperacillin, temocillin
Cephalosporins
• See Box 6.22
Monobactams
• Aztreonam
Carbapenems
• Imipenem, meropenem, ertapenem, doripenem
Treatment of infectious diseases • 121
deficiencies, interstitial nephritis and potentiation of aminoglycoside-
mediated kidney damage are also recognised (p. 1 22). Seizures
and encephalopathy have been reported, particularly with high
doses in the presence of renal insufficiency. Thrombophlebitis
occurs in up to 5% of patients receiving parenteral (3-lactams.
Drug interactions
Synergism occurs in combination with aminoglycosides in vitro.
Ampicillin decreases the biological effect of oral contraceptives
and the whole class is significantly affected by concurrent
administration of probenecid, producing a 2-4-fold increase in
the peak serum concentration.
Penicillins
Natural penicillins are primarily effective against Gram-positive
organisms (except staphylococci, most of which produce a
penicillinase) and anaerobic organisms. Strep, pyogenes has
remained sensitive to natural penicillins worldwide. According
to the European Antimicrobial Resistance Surveillance Network
(EARS-Net), the prevalence of non-susceptibility to penicillin in
Strep, pneumoniae in Europe in 2014 varied widely from 0%
(Cyprus) to 46.7% (Romania).
Penicillinase-resistant penicillins are the mainstay of treatment
for infections with Staph, aureus, other than MRSA. However,
EARS-Net data from 2014 indicate that MRSA rates in Europe
vary widely from 0.9% (Netherlands) to 56% (Romania).
Aminopenicillins have the same spectrum of activity as the
natural penicillins, with additional Gram-negative cover against
Enterobacteriaceae. Amoxicillin has better oral absorption than
ampicillin. Unfortunately, resistance to these agents is widespread
(57.1% of E. coli Europe-wide in 2014, range 34.7-73%), so
they are no longer appropriate for empirical use in Gram-negative
infections. In many organisms, resistance is due to |3-lactamase
production, which can be overcome by the addition of (3-lactamase
inhibitors (clavulanic acid or sulbactam).
Carboxypenicillins (e.g. ticarcillin) and ureidopenicillins (e.g.
piperacillin) are particularly active against Gram-negative
organisms, especially Pseudomonas spp., which are resistant
to the aminopenicillins. Beta-lactamase inhibitors may be added
to extend their spectrum of activity (e.g. piperacillin-tazobactam).
Temocillin is derived from ticarcillin; it has good activity against
Enterobacteriaceae, including those that produce ESBL enzymes,
but poor activity against Pseudomonas aeruginosa and Gram¬
positive bacteria.
Cephalosporins and cephamycins
Cephalosporins are broad-spectrum agents. Unfortunately,
their use is associated with CDI (p. 264). With the exception of
ceftobiprole, the group has no activity against enterococci. Only
the cephamycins have anti-anaerobic activity. All cephalosporins
are inactivated by ESBL. Cephalosporins are arranged in
‘generations’ (Box 6.22).
• First-generation compounds have excellent activity against
Gram-positive organisms and some activity against
Gram -negatives.
• Second-generation drugs retain Gram-positive activity but
have extended Gram-negative activity. Cephamycins (e.g.
cefoxitin), included in this group, are active against
anaerobic Gram-negative bacilli.
• Third-generation agents further improve anti-Gram-
negative cover. For some (e.g. ceftazidime), this is
extended to include Pseudomonas spp. Cefotaxime
and ceftriaxone have excellent Gram-negative activity and
6.22 Cephalosporins
First generation
• Cefalexin, cefradine (oral) • Cefazolin (IV)
Second generation
• Cefuroxime (oral/IV)
• Cefoxitin (IV)
• Cefaclor (oral)
Third generation
• Cefixime (oral)
• Ceftriaxone (IV)
• Cefotaxime (IV)
• Ceftazidime (IV)
Fourth generation
• Cefepime (IV)
Fifth generation (also referred to as ‘next generation’)
• Ceftobiprole (IV) • Ceftaroline (IV)
retain good activity against Strep, pneumoniae and
(3-haemolytic streptococci. Ceftriaxone is administered
once daily and is therefore a suitable agent for outpatient
intravenous (parenteral) antimicrobial therapy (OPAT).
• Fourth-generation agents, e.g. cefipime, have a broad
spectrum of activity, including streptococci and some
Gram-negatives, including P. aeruginosa.
• Fifth -generation agents, such as ceftobiprole and
ceftaroline, have an enhanced spectrum of Gram-positive
activity that includes MRSA, and also have activity against
Gram-negative bacteria; some, such as ceftobiprole, are
active against P. aeruginosa.
The spectrum of cephalosporins has also been enhanced by
adding (3-lactamase inhibitors.
Monobactams
Aztreonam is the only available monobactam. It is active against
Gram-negative bacteria, except ESBL-producing organisms,
but inactive against Gram-positive organisms or anaerobes.
It is a parenteral-only agent and may be used safely in most
penicillin-allergic patients other than those with an allergy to
ceftazidime, which shares a common side chain with aztreonam.
Carbapenems
These intravenous agents have the broadest antibiotic activity
of the (3-lactam antibiotics, covering most clinically significant
bacteria, including anaerobes (e.g. imipenem, meropenem,
ertapenem).
Macrolide and lincosamide antibiotics
Macrolides (e.g. erythromycin, clarithromycin and azithromycin)
and lincosamides (e.g. clindamycin) are bacteriostatic agents.
Both classes bind to the same component of the ribosome,
so they are not administered together. Macrolides are used for
Legionella, Mycoplasma, Chlamydia and Bordetella infections.
Azithromycin is employed for single-dose/short-course therapy for
genitourinary Chlamydia/Mycoplasma spp. infections. Clindamycin
is used primarily for skin, soft tissue, bone and joint infections.
Pharmacokinetics
Macrolides
• Variable bioavailability (intravenous and oral preparations
available).
122 • PRINCIPLES OF INFECTIOUS DISEASE
• Frequency of administration: erythromycin is administered
4 times daily, clarithromycin twice daily, azithromycin
once daily.
• High protein binding.
• Excellent intracellular accumulation.
Lincosamides (e.g. clindamycin)
• Good oral bioavailability.
• Food has no effect on absorption.
• Good bone/joint penetration; limited CSF penetration.
Adverse effects
• Gastrointestinal upset, especially in young adults
(erythromycin 30%).
• Cholestatic jaundice with erythromycin estolate.
• Prolongation of QT interval can cause torsades de pointes
(p. 476).
• Clindamycin predisposes to CDI.
Aminoglycosides and spectinomycin
Aminoglycosides are effective mainly in Gram-negative
infections and are therefore commonly used in regimens
for intra-abdominal infection. Some aminoglycosides, e.g.
amikacin, are important components of therapy for MDR-TB.
Because they act synergistically with (3-lactam antibiotics they
are used in combinations to treat biofilm infections, including
infective endocarditis and orthopaedic implant infections. They
cause very little local irritation at injection sites and negligible
allergic responses. Oto- and nephrotoxicity must be avoided
by monitoring of renal function and drug levels and by use of
short treatment regimens. Aminoglycosides are not subject to
an inoculum effect (p. 120) and they all exhibit a post-antibiotic
effect (p. 119).
Pharmacokinetics
• Negligible oral absorption.
• Hydrophilic, so excellent penetration to extracellular fluid in
body cavities and serosal fluids.
• Very poor intracellular penetration (except hair cells in
cochlea and renal cortical cells).
• Negligible CSF and corneal penetration and may require
intrathecal administration during neurosurgical infections.
• Peak plasma levels 30 minutes after infusion.
• Monitoring of therapeutic levels required.
Gentamicin dosing
• Except in certain forms of endocarditis, pregnancy, severe
burns, end-stage renal disease and paediatric patients,
gentamicin is administered at 7 mg/kg body weight. The
appropriate dose interval depends on drug clearance and
is determined by reference to the Hartford nomogram
(Fig. 6.18).
• In streptococcal and enterococcal endocarditis, gentamicin
is used with a cell wall active agent (usually a (3-lactam), to
provide synergy. Commonly used doses are 1 mg/kg 2-3
times daily for enterococcal endocarditis and 3 mg/kg
once daily for most strains of oral streptococci. Target
pre- and post-dose levels are < 1 mg/L and 3-5 mg/L,
respectively, when gentamicin is dosed 3 times daily.
• When not used according to the Hartford regimen or for
endocarditis, gentamicin is administered twice or 3 times
daily at 3-5 mg/kg/day. Target pre- and post-dose levels
Fig. 6.18 Dosing of aminoglycosides using the Hartford nomogram.
The nomogram is used to determine the dose interval for 7 mg doses of
gentamicin or tobramycin, using measurements of drug levels in plasma
6-14 hours after a single dose.
are < 1 mg/L and 5-1 0 mg/L (7-1 0 mg/L with less
sensitive organisms, e.g. P. aeruginosa), respectively.
• For other aminoglycosides, consult local guidance.
Adverse effects
• Renal toxicity (usually reversible) accentuated by other
nephrotoxic agents.
• Cochlear toxicity (permanent) more likely in older people
and those with a predisposing mitochondrial gene
mutation.
• Neuromuscular blockade after rapid intravenous infusion
(potentiated by calcium channel blockers, myasthenia
gravis and hypomagnesaemia).
Spectinomycin
Chemically similar to the aminoglycosides and given
intramuscularly, spectinomycin was developed to treat strains
of Neisseria gonorrhoeae resistant to (3-lactam antibiotics.
Unfortunately, resistance to spectinomycin is very common.
Its only indication is the treatment of gonococcal urethritis in
pregnancy or in patients allergic to (3-lactam antibiotics.
Quinolones and fluoroquinolones
These are effective and generally well-tolerated bactericidal
agents. The quinolones have purely anti-Gram-negative activity,
whereas the fluoroquinolones are broad-spectrum agents (Box
6.23). Ciprofloxacin has anti-pseudomonal activity but resistance
emerges rapidly. In 2014, European surveillance showed that
resistance to fluoroquinolones in E. coli ranged between 7.8%
(Iceland) and 46.4% (Cyprus). Quinolones and fluoroquinolones
are used for a variety of common infections, including urinary
tract infection and pneumonia, and less common problems
like MDR-TB.
Pharmacokinetics
• Well absorbed after oral administration but delayed by
food, antacids, ferrous sulphate and multivitamins.
• Wide volume of distribution; tissue concentrations twice
those in serum.
• Good intracellular penetration, concentrating in
phagocytes.
Treatment of infectious diseases • 123
i
6.23 Quinolones and fluoroquinolones
Agent
Route of
administration
Typical antimicrobial spectrum
Quinolones
Nalidixic acid
Oral
Enteric Gram-negative bacilli (not
Pseudomonas aeruginosa)
Fluoroquinolones
Ciprofloxacin
IV/oral
Enteric Gram-negative bacilli,
Norfloxacin
Oral
P. aeruginosa, Haemophilus spp.
Ofloxacin
IV/oral/topical
‘atypical’ respiratory pathogens*
Levofloxacin
(L- isomer of
ofloxacin)
IV/oral
Haemophilus spp., Strep,
pneumoniae, ‘atypical’ respiratory
pathogens*
Moxifloxacin
Oral
Strep, pneumoniae, Staph, aureus,
‘atypical’ respiratory pathogens*,
Mycobacteria and anaerobes
‘‘Atypical’ pathogens include Mycoplasma pneumoniae and Legionella spp.
Fluoroquinolones have variable activity against M. tuberculosis and other
mycobacteria.
Adverse effects
• Gastrointestinal side-effects in 1-5%.
• Rare skin reactions (phototoxicity).
• Tendinitis and Achilles tendon rupture, especially in older
people.
• Central nervous system effects (delirium, tremor, dizziness
and occasional seizures in 5-12%), especially in older
people.
• Reduces clearance of xanthines and theophyllines,
potentially inducing insomnia and increased seizure
potential.
• Prolongation of QT interval on ECG, cardiac arrhythmias.
• Ciprofloxacin use is associated with the acquisition of
MRSA and emergence of C. difficile ribotype 027 (p. 264).
Glycopeptides
Glycopeptides (vancomycin and teicoplanin) are effective against
Gram-positive organisms only, and are used against MRSA
and ampicillin-resistant enterococci. Some staphylococci and
enterococci demonstrate intermediate sensitivity or resistance.
Vancomycin use should be restricted to limit emergence of
resistant strains. Teicoplanin is not available in all countries.
Neither drug is absorbed after oral administration but vancomycin
is used orally to treat CDI.
Pharmacokinetics
Vancomycin
• Administered by slow intravenous infusion, good tissue
distribution and short half-life.
• Enters the CSF only in the presence of inflammation and
may require intrathecal administration during neurosurgical
infections.
• Therapeutic monitoring of intravenous vancomycin is
recommended, to maintain pre-dose levels of >10 mg/L
(15-20 mg/L in serious staphylococcal infections).
Teicoplanin
• Long half-life allows once-daily dosing.
Adverse effects
• Histamine release due to rapid vancomycin infusion
produces a ‘red man’ reaction (rare with modern
preparations).
• Nephrotoxicity is rare but may occur with concomitant
aminoglycoside use, as may ototoxicity.
• Teicoplanin can cause rash, bronchospasm, eosinophilia
and anaphylaxis.
Lipopeptides
Daptomycin is a cyclic lipopeptide with bactericidal activity
against Gram-positive organisms (including MRSA and GRE)
but not Gram -negatives. It is not absorbed orally, and is used
intravenously to treat Gram-positive infections, such as soft tissue
infections and Staph, aureus infective endocarditis. Daptomycin
is not effective for community-acquired pneumonia. Treatment
can be associated with increased levels of creatine kinase and
eosinophilic pneumonitis.
Polymyxins
Colistin is a polymyxin antibiotic that binds and disrupts the outer
cell membrane of Gram-negative bacteria, including P. aeruginosa
and Acinetobacter baumannii. Its use has increased with the
emergence and spread of multi-resistant Gram-negative bacteria,
including CPEs. It can be administered by oral, intravenous and
nebulised routes. Significant adverse effects include neurotoxicity,
including encephalopathy, and nephrotoxicity.
| Folate antagonists
These are bacteriostatic antibacterials (p. 109). A combination
of a sulphonamide and either trimethoprim or pyrimethamine is
most commonly used, which interferes with two consecutive
steps in the metabolic pathway. Available combinations include
trimethoprim/sulfamethoxazole (co-trimoxazole) and pyrimethamine
with either sulfadoxine (used to treat malaria) or sulfadiazine
(used in toxoplasmosis). Co-trimoxazole is the first-line drug for
Pneumocystis jirovecii infection, the second-line drug for treatment
and prevention of B. pertussis (whooping cough) infection, and
is also used for a variety of other infections, including Staph,
aureus. Dapsone is used to treat leprosy (Hansen’s disease) and
to prevent toxoplasmosis and pneumocystis when patients are
intolerant of other medications. Folinic acid should be given to
prevent myelosuppression if these drugs are used long-term or
unavoidably in early pregnancy.
Pharmacokinetics
• Well absorbed orally.
• Sulphonamides are hydrophilic, distributing well to the
extracellular fluid.
• Trimethoprim is lipophilic with high tissue concentrations.
Adverse effects
• Trimethoprim is generally well tolerated, with few adverse
effects.
• Sulphonamides and dapsone may cause haemolysis in
glucose-6-phosphate dehydrogenase deficiency (p. 948).
• Sulphonamides and dapsone cause skin and
mucocutaneous reactions, including Stevens-Johnson
syndrome and ‘dapsone syndrome’ (rash, fever and
lymphadenopathy).
• Dapsone causes methaemoglobinaemia (p. 135) and
peripheral neuropathy.
124 • PRINCIPLES OF INFECTIOUS DISEASE
Ijetracyclines and glycylcyclines
Tetracyclines
Of this mainly bacteriostatic class, the newer drugs doxycycline
and minocycline show better absorption and distribution than
older ones. Many streptococci and Gram-negative bacteria
are now resistant, in part due to their use in animals (which is
banned in Europe). Tetracyclines are indicated for Mycoplasma
spp., Chlamydia spp., Rickettsia spp., Coxiella spp., Bartonella
spp., Borrelia spp., Helicobacter pylori, Treponema pallidum
and atypical mycobacterial infections. Tetracyclines can also
be used for malaria prevention.
Pharmacokinetics
• Best oral absorption is in the fasting state (doxycycline is
1 00% absorbed unless gastric pH rises) and absorption is
inhibited by cations, e.g. calcium or iron, which should not
be administered at the same time.
Adverse effects
• All tetracyclines except doxycycline are contraindicated in
renal failure.
• Dizziness with minocycline.
• Binding to metallic ions in bones and teeth causes
discoloration (avoid in children and pregnancy) and enamel
hypoplasia.
• Oesophagitis/oesophageal ulcers with doxycycline.
• Phototoxic skin reactions.
Glycylcyclines (tigecycline)
Chemical modification of tetracycline has produced tigecycline,
a broad-spectrum, parenteral-only antibiotic with activity against
resistant Gram-positive and Gram-negative pathogens, such as
MRSA and ESBL (but excluding Pseudomonas spp.). Re-analysis
of trial data has shown that there was excess mortality following
tigecycline treatment as opposed to comparator antibiotics, so
tigecycline should be used only when there has been adequate
assessment of risk versus benefit.
Nitroimidazoles
Nitroimidazoles are highly active against strictly anaerobic bacteria,
especially Bacteroides fragilis, C. difficile and other Clostridium
spp. They also have significant antiprotozoal activity against
amoebae and Giardia lamblia.
Pharmacokinetics
• Almost completely absorbed after oral administration (60%
after rectal administration).
• Well distributed, especially to brain and CSF.
• Safe in pregnancy.
Adverse effects
• Metallic taste (dose-dependent).
• Severe vomiting if taken with alcohol - ‘Antabuse effect’.
• Peripheral neuropathy with prolonged use.
Phenicols
Chloramphenicol is the only example in clinical use. In developed
countries its use tends to be reserved for severe and life-
threatening infections when other antibiotics are either unavailable
or impractical, largely because of concerns about toxicity. It is
bacteriostatic to most organisms but apparently bactericidal to
H. influenzae, Strep, pneumoniae and N. meningitidis. It has a
very broad spectrum of activity against aerobic and anaerobic
organisms, spirochaetes, Rickettsia, Chlamydia and Mycoplasma
spp. It competes with macrolides and lincosamides for ribosomal
binding sites, so should not be used in combination with these
agents. Significant adverse effects are ‘grey baby’ syndrome
in infants (cyanosis and circulatory collapse due to inability to
conjugate drug and excrete the active form in urine); reversible
dose-dependent bone marrow depression in adults receiving
high cumulative doses; and severe aplastic anaemia in 1 in
25000-40000 exposures (unrelated to dose, duration of therapy
or route of administration).
Oxazolidinones
Linezolid and tedizolid are examples and their good activity
against Gram-positive organisms means they are often used to
treat skin and soft tissue infections. They may also be used in
infection caused by resistant Gram-positive bacteria, including
MRSA and GRE. Administration can be intravenous or oral.
Common linezolid adverse effects include mild gastrointestinal
upset and tongue discoloration. Myelodysplasia and peripheral
and optic neuropathy can occur with prolonged use. Linezolid has
monoamine oxidase inhibitor (MAOI) activity, and co-administration
with other MAOIs or serotonin re-uptake inhibitors should
be avoided, as this may precipitate a ‘serotonin syndrome’
(p. 1199).
Other antibacterial agents
Fusidic acid
This antibiotic, active against Gram-positive bacteria, is available
in intravenous, oral or topical formulations. It is lipid-soluble and
distributes well to tissues. Its antibacterial activity is, however,
unpredictable. Fusidic acid is used in combination, typically with
antistaphylococcal penicillins, or for MRSA with clindamycin
or rifampicin. It interacts with coumarin derivatives and oral
contraceptives.
Nitrofurantoin
This drug has very rapid renal elimination and is active against
aerobic Gram-negative and Gram-positive bacteria, including
enterococci. It is used only for treatment of urinary tract infection,
being generally safe in pregnancy and childhood. With prolonged
treatment, however, it can cause eosinophilic lung infiltrates,
fever, pulmonary fibrosis, peripheral neuropathy, hepatitis and
haemolytic anaemia so its use must be carefully balanced
against risks.
Fidaxomicin
Fidaxomicin is an inhibitor of RNA synthesis, and was introduced
for the treatment of CDI in 2012. In non-severe CDI it is non¬
inferior to oral vancomycin and is associated with a lower
recurrence rate. Its effectiveness has not been assessed in
severe CDI.
Fosfomycin
Fosfomycin acts by inhibiting cell wall synthesis. It has activity
against Gram-negative but also Gram-positive bacteria and can
demonstrate in vitro synergy against MRSA when combined
with other antimicrobials. It is used for treatment of urinary
tract infections but can be employed in other situations against
multi-resistant bacteria.
Treatment of infectious diseases • 125
Antimycobacterial agents
Isoniazid
Isoniazid is bactericidal for replicating bacteria and bacteriostatic
for non-replicating bacteria. It is activated by mycobacterial
catalase-peroxidase (KatG) and inhibits the InhA gene product, a
reductase involved in mycolic acid synthesis. Mutations in KatG
or InhA result in isoniazid resistance, which was reported in 15%
of cases of M. tuberculosis infection globally in 201 3. Isoniazid is
well absorbed orally and metabolised by acetylation in the liver.
The major side-effects are hepatitis, neuropathy (ameliorated by
co-administration of pyridoxine) and hypersensitivity reactions.
Rifampicin
Rifampicin inhibits DNA-dependent RNA polymerase and is
bactericidal against replicating bacteria. It is also active in necrotic
foci, where mycobacteria have low levels of replication, and
is therefore important in sterilisation and sputum conversion.
Resistance most often involves the (3-subunit of RNA polymerase
and most often occurs with isoniazid-resistant MDR-TB. Rifampicin
is well absorbed orally. It is metabolised by the liver via the
microsomal cytochrome P450 system and is one the most
potent inducers of multiple P450 isoenzymes, so is subject to
extensive drug-drug interactions. Common side-effects include
hepatitis, influenza-like symptoms and hypersensitivity reactions.
Orange discoloration of urine and body secretions is expected.
Pyrazinamide
The mechanism of action of pyrazinamide is incompletely defined
but includes inhibition of fatty acid synthase and ribosomal
trans-translation. Pyrazinamide is often bacteriostatic but can
be bactericidal and is active against semidormant bacteria in a
low-pH environment. Primary resistance is rare but MDR-TB strains
are frequently pyrazinamide-resistant and intrinsic resistance is
a feature of Mycobacterium bovis strains. Pyrazinamide is well
absorbed orally and metabolised by the liver. Side-effects include
nausea, hepatitis, asymptomatic elevation of uric acid and myalgia.
Ethambutol
Ethambutol is a bacteriostatic agent. It inhibits arabinosyl
transferase, which is involved in the synthesis of arabinogalactan,
a component of the mycobacterial cell wall. Resistance is usually
seen when resistance to other antimycobacterial agents is also
present, e.g. in MDR-TB strains. It is orally absorbed but, in
contrast to the first- line agents described above, it achieves poor
CSF penetration and is renal ly excreted. The major side-effect
is optic neuritis with loss of red-green colour discrimination and
impaired visual acuity. It can also cause hepatitis.
Streptomycin
Streptomycin is an aminoglycoside whose mechanism of action
and side-effects are similar to those of other aminoglycosides.
It is administered intramuscularly.
Other antituberculous agents
Second-line agents used in MDR or XDR strains (p. 1 1 6) include
aminoglycosides (amikacin, capreomycin or kanamycin) and
fluoroquinolones (moxifloxacin or levofloxacin), discussed above.
Other established second-line agents administered orally are
cycloserine (which causes neurological side-effects); ethionamide
or prothionamide (which are not active with //iM-gene-mediated
resistance but have reasonable CSF penetration; their side-effect
profile includes gastrointestinal disturbance, hepatotoxicity and
neurotoxicity); and paraminosalicylic acid (which causes rashes
and gastrointestinal upset). Linezolid may also be used and has
good CSF penetration, while meropenem with co-amoxiclav is
occasionally chosen. New drugs developed forXDR-TB include
delamanid and bedaquiline; their adverse effects include OT
prolongation and cardiac arrhythmias. Their co-administration with
other agents with a similar side-effect profile (e.g. fluoroquinolones)
therefore requires careful risk assessment.
Clofazimine
Clofazimine is used against M. leprae and resistant strains of M.
tuberculosis. Its mode of action may involve induction of oxidative
stress and it is weakly bactericidal. Oral absorption is variable
and it is excreted in the bile. Side-effects include gastrointestinal
upset, dry eyes and skin, and skin pigmentation, especially in
those with pigmented skin.
Antifungal agents
See Box 6.24.
6.24 Antifungal agents
Agent
Usual route(s) of
administration
Clinically relevant
antifungal spectrum
Imidazoles
Miconazole
Econazole
Clotrimazole
■ Topical
Candida spp.,
dermatophytes
Ketoconazole
Topical, oral
Malassezia spp.,
dermatophytes, agents of
eu mycetoma
Triazoles
Fluconazole
Oral, IV
Yeasts ( Candida and
Cryptococcus spp.)
Itraconazole
Oral, IV
Yeasts, dermatophytes,
dimorphic fungi (p. 300),
Aspergillus spp.
Voriconazole
Oral, IV
Yeasts and most
filamentous fungi (excluding
mucoraceous moulds)
Posaconazole
Oral, IV
Yeasts and many
filamentous fungi (including
most mucoraceous moulds)
Isavuconazole
Oral, IV
Yeasts and many filamentous
fungi (variable activity against
mucoraceous moulds)
Echinocandins
Anidulafungin
Caspofungin
Micafungin
| IV only
Candida spp., Aspergillus
spp. (no activity against
Cryptococcus spp. or
mucoraceous moulds)
Polyenes
Amphotericin B
Nystatin
IV
Topical
Yeasts and most dimorphic
and filamentous fungi
(including mucoraceous
moulds)
Others
5-fluorocytosine
Oral, IV
Yeasts
Griseofulvin
Oral
Dermatophytes
Terbinafine
Topical, oral
Dermatophytes
126 • PRINCIPLES OF INFECTIOUS DISEASE
Azole antifungals
The azoles (imidazoles and triazoles) inhibit synthesis of ergosterol,
a constituent of the fungal cell membrane. Side-effects vary but
include gastrointestinal upset, hepatitis and rash. Azoles are
inhibitors of cytochrome P450 enzymes, so tend to increase
exposure to cytochrome P450-metabolised drugs (p. 24).
Imidazoles
Miconazole, econazole, clotrimazole and ketoconazole are
relatively toxic and therefore administered topically. Clotrimazole
is used extensively to treat superficial fungal infections. Triazoles
are used for systemic treatment because they are less toxic.
Triazoles
Fluconazole is effective against yeasts (Candida and Cryptococcus
spp.) and has a long half-life (approximately 30 hours) and an
excellent safety profile. The drug is highly water-soluble and
distributes widely to all body sites and tissues, including CSF.
Itraconazole is lipophilic and distributes extensively, including to
toenails and fingernails. CSF penetration is poor. Because oral
absorption is erratic, therapeutic drug monitoring is required.
Voriconazole is well absorbed orally but variability in levels requires
therapeutic drug monitoring. It is used mainly in aspergillosis
(p. 596). Side-effects include photosensitivity, hepatitis and
transient retinal toxicity. Posaconazole and isavuconazole are
broad-spectrum azoles, with activity against Candida spp.,
Aspergillus spp. and some mucoraceous moulds. Isavuconazole
is non-inferior to voriconazole in the management of invasive
aspergillosis and may be considered as an alternative when
voriconazole is not tolerated.
Echinocandins
The echinocandins inhibit p-1 ,3-glucan synthesis in the fungal
cell wall. They have few significant adverse effects. Caspofungin,
anidulafungin and micafungin are used to treat systemic
candidosis, and caspofungin is also used in aspergillosis.
Polyenes
Amphotericin B (AmB) deoxycholate causes cell death by binding
to ergosterol and damaging the fungal cytoplasmic membrane. Its
use in resource-rich countries has been largely supplanted by less
toxic agents. Its long half-life enables once-daily administration.
CSF penetration is poor.
Adverse effects include immediate anaphylaxis, other infusion-
related reactions and nephrotoxicity. Nephrotoxicity may be
sufficient to require dialysis and occurs in most patients who
are adequately dosed. It may be ameliorated by concomitant
infusion of normal saline. Irreversible nephrotoxicity occurs with
large cumulative doses of AmB.
Nystatin has a similar spectrum of antifungal activity to
AmB. Its toxicity limits it to topical use, e.g. in oral and vaginal
candidiasis.
Lipid formulations of amphotericin B
Lipid formulations of AmB have been developed to reduce AmB
toxicity and have replaced AmB deoxycholate in many regions.
They consist of AmB encapsulated in liposomes (liposomal AmB,
L-AmB) or complexed with phospholipids (AmB lipid complex,
ABLC). The drug becomes active on dissociating from its lipid
component. Adverse effects are similar to, but considerably
less frequent than, those with AmB deoxycholate, and efficacy
is similar. Lipid formulations of AmB are used in invasive fungal
disease, as empirical therapy in patients with neutropenic fever
(p. 1327), and also in visceral leishmaniasis (p. 282).
Other antifungal agents
Flucytosine
Flucytosine (5-fluorocytosine) has particular activity against
yeasts. When it is used as monotherapy, acquired resistance
develops rapidly, so it should be given in combination with another
antifungal agent. Adverse effects include myelosuppression,
gastrointestinal upset and hepatitis.
Griseofulvin
Griseofulvin has been largely superseded by terbinafine and
itraconazole for treatment of dermatophyte infections, except
in children, for whom these agents remain largely unlicensed. It
is deposited in keratin precursor cells, which become resistant
to fungal invasion.
Terbinafine
Terbinafine distributes with high concentration to sebum and
skin, with a half-life of more than 1 week. It is used topically for
dermatophyte skin infections and orally for onychomycosis. The
major adverse reaction is hepatic toxicity (approximately 1 : 50 000
cases). Terbinafine is not recommended for breastfeeding mothers.
Antiviral agents
Most viral infections in immunocompetent individuals resolve
without intervention. Antiviral therapy is available for a limited
number of infections only (Box 6.25).
Antiretroviral agents
These agents, used predominantly against HIV, are discussed
on page 324.
Anti-herpesvirus agents
Aciclovir, valaciclovir, penciclovir and famciclovir
These antivirals are acyclic analogues of guanosine, which inhibit
viral DNA polymerase after being phosphorylated by virus-derived
thymidine kinase (TK). Aciclovir is poorly absorbed after oral
dosing; better levels are achieved intravenously or by use of the
prodrug valaciclovir. Famciclovir is the prodrug of penciclovir.
Resistance is mediated by viral TK or polymerase mutations.
Ganciclovir
Chemical modification of the aciclovir molecule allows preferential
phosphorylation by protein kinases of cytomegalovirus (CMV)
and other p-herpesviruses (e.g. human herpesvirus (HHV) 6/7)
and hence greater inhibition of the DNA polymerase, but at
the expense of increased toxicity. Ganciclovir is administered
intravenously or as a prodrug (valganciclovir) orally.
Cidofovir
Cidofovir inhibits viral DNA polymerases with potent activity
against CMV, including most ganciclovir-resistant CMV. It also has
activity against aciclovir- resistant herpes simplex virus (HSV) and
varicella zoster virus (VZV), HHV6 and occasionally adenovirus,
poxvirus, papillomavirus or polyoma virus, and may be used to
treat these infections in immunocompromised hosts.
Treatment of infectious diseases • 127
6.25 Antiviral agents
Drug
Route(s) of
administration
Indications
Significant side-effects
Antiretroviral therapy
(ART, p. 324)
Oral
HIV infection (including AIDS)
CNS symptoms, anaemia, lipodystrophy
Anti-herpesvirus agents
Aciclovir
Topical/oral/IV
Herpes zoster
Chickenpox (esp. in immunosuppressed)
Herpes simplex infections: encephalitis
(IV only), genital tract, oral, ophthalmic
Significant side-effects rare
Hepatitis, renal impairment and neurotoxicity reported
rarely
Valaciclovir
Oral
Herpes zoster, herpes simplex
As for aciclovir
Famciclovir
Oral
Herpes zoster, herpes simplex (genital)
As for aciclovir
Penciclovir
Topical
Labial herpes simplex
Local irritation
Ganciclovir
IV
Treatment and prevention of CMV
infection in immunosuppressed
Gastrointestinal symptoms, liver dysfunction,
neurotoxicity, myelosuppression, renal impairment,
fever, rash, phlebitis at infusion sites
Potential teratogenicity
Valganciclovir
Oral
Treatment and prevention of CMV
infection in immunosuppressed
As for ganciclovir but neutropenia is predominant
Cidofovir
IV/topical
HIV-associated CMV infections and
occasionally other viruses (see text)
Renal impairment, neutropenia
Foscarnet
IV
CMV and aciclovir-resistant HSV and
VZV infections in immunosuppressed
Gastrointestinal symptoms, renal impairment, electrolyte
disturbances, genital ulceration, neurotoxicity
Anti-influenza agents
Zanamivir
Inhalation
Influenza A and B
Allergic reactions (very rare)
Oseltamivir
Oral
Influenza A and B
Gastrointestinal side-effects, rash, hepatitis (very rare)
Peramivir
IV, IM
Amantadine, rimantadine
Oral
Influenza A (but see text)
CNS symptoms, nausea
Agents used in other virus infections*
Ribavirin Oral/IV/inhalation
Lassa fever (IV)
RSV infection in infants (inhalation)
Haemolytic anaemia, cough, dyspnoea, bronchospasm
and ocular irritation (when given by inhalation)
*Antiviral agents used in viral hepatitis are discussed on pages 875 and 878. (AIDS = acquired immunodeficiency syndrome; CMV = cytomegalovirus; CNS = central nervous
system; HIV = human immunodeficiency virus; HSV = herpes simplex virus; IM = intramuscular; IV = intravenous; RSV = respiratory syncytial virus; VZV = varicella zoster
virus)
Foscarnet
This analogue of inorganic pyrophosphate acts as a non-competitive
inhibitor of HSV, VZV, HHV6/7 or CMV DNA polymerase. It does
not require significant intracellular phosphorylation and so may
be effective when HSV or CMV resistance is due to altered drug
phosphorylation. It has variable CSF penetration.
Anti-influenza agents
Zanamivir and oseltamivir
These agents inhibit influenza A and B neuraminidase, which
is required for release of virus from infected cells (see Fig. 6.2,
p. 1 01 ). They are used in the treatment and prophylaxis of influenza.
Administration within 48 hours of disease onset reduces the
duration of symptoms by approximately 1-1% days. In the UK,
their use is limited mainly to adults with chronic respiratory or renal
disease, significant cardiovascular disease, immunosuppression
or diabetes mellitus, during known outbreaks. Peramivir has been
developed as a distinct chemical structure, which means that it
retains activity against some oseltamivir- and zanamivir-resistant
strains. It has poor oral bioavailability and has been developed as
an intravenous or intramuscular formulation for treatment of severe
cases of influenza, e.g. in intensive care units. It is now approved for
use in adults in a number of countries. An intravenous formulation of
zanamivir is also in development for critically ill patients. Laninamivir
is approved as an intranasal formulation in Japan.
Amantadine and rimantadine
These drugs reduce replication of influenza A by inhibition of viral
M2 protein ion channel function, which is required for uncoating
(see Fig. 6.2). Resistance develops rapidly and is widespread,
and amantadine and rimantadine should be used only if the
prevalence of resistance locally is known to be low. They are
no longer recommended for treatment or prophylaxis in the UK
or USA, having been superseded by zanamivir and oseltamivir.
However, they may still be indicated to treat oseltamivir- resistant
influenza A in patients unable to take zanamivir (e.g. ventilated
patients).
Other agents used to treat viruses
Antiviral agents used to treat hepatitis B and C virus are discussed
on pages 875 and 878, and those used against HIV-1 are
described on page 324.
128 • PRINCIPLES OF INFECTIOUS DISEASE
Ribavirin
Ribavirin is a guanosine analogue that inhibits nucleic acid
synthesis in a variety of viruses. It is used in particular in the
treatment of hepatitis C virus but also against certain viral
haemorrhagic fevers, e.g. Lassa fever, although it has not been
useful against Ebola virus.
Antiparasitic agents
| Antimalarial agents
Artemisinin (qinghaosu) derivatives
Artemisinin originates from a herb (sweet wormwood, Artemisia
annua), which was used in Chinese medicine to treat fever.
Its derivatives, artemether and artesunate, were developed
for use in malaria in the 1970s. Their mechanism of action is
unknown. They are used in the treatment, but not prophylaxis,
of malaria, usually in combination with other antimalarials, and
are effective against strains of Plasmodium spp. that are resistant
to other antimalarials. Artemether is lipid-soluble and may be
administered via the intramuscular and oral routes. Artesunate is
water-soluble and is administered intravenously or orally. Serious
adverse effects are uncommon. Current advice for malaria in
pregnancy is that the artemisinin derivatives should be used to
treat uncomplicated falciparum malaria in the second and third
trimesters, but should not be prescribed in the first trimester
until more information becomes available.
Atovaquone
Atovaquone inhibits mitochondrial function. It is an oral agent,
used for treatment and prophylaxis of malaria, in combination
with proguanil (see below), without which it is ineffective. It is
also employed in the treatment of mild cases of Pneumocystis
jirovecii pneumonia, where there is intolerance to co-trimoxazole.
Significant adverse effects are uncommon.
Folate synthesis inhibitors (proguanil,
pyrimethamine-sulfadoxine)
Proguanil inhibits dihydrofolate reductase and is used for malaria
prophylaxis. Pyrimethamine-sulfadoxine may be used in the
treatment of malaria.
Quinoline-containing compounds
Chloroquine and quinine are believed to act by intraparasitic
inhibition of haem polymerisation, resulting in toxic build-up of
intracellular haem. The mechanisms of action of other agents in
this group (quinidine, amodiaquine, mefloquine, primaquine, etc.)
may differ. They are employed in the treatment and prophylaxis
of malaria. Primaquine is used for radical cure of malaria due to
Plasmodium vivax and P. ovale (destruction of liver hypnozoites).
Chloroquine may also be given for extra- intestinal amoebiasis.
Chloroquine can cause a pruritus sufficient to compromise
adherence to therapy. If used in long-term, high-dose regimens,
it causes an irreversible retinopathy. Overdosage leads to life-
threatening cardiotoxicity. The side-effect profile of mefloquine
includes neuropsychiatric effects ranging from mood change,
nightmares and agitation to hallucinations and psychosis. Quinine
may cause hypoglycaemia and cardiotoxicity, especially when
administered parenterally. Primaquine causes haemolysis in
people with glucose-6-phosphate dehydrogenase deficiency
(p. 948), which should be excluded before therapy. Chloroquine is
considered safe in pregnancy but mefloquine should be avoided
in the first trimester.
Lumefantrine
Lumefantrine is used in combination with artemether to treat
uncomplicated falciparum malaria, including chloroquine-resistant
strains. Its mechanism of action is unknown. Significant adverse
effects are uncommon.
Drugs used in trypanosomiasis
Benznidazole
Benznidazole is an oral agent used to treat South American
trypanosomiasis (Chagas’ disease, p. 279). Significant and
common adverse effects include dose-related peripheral
neuropathy, purpuric rash and granulocytopenia.
Eflornithine
Eflornithine inhibits biosynthesis of polyamines by ornithine
decarboxylase inhibition, and is used in West African
trypanosomiasis (T. brucei gambiense infection) of the central
nervous system. It is administered as an intravenous infusion 4
times daily, which may be logistically difficult in the geographical
areas affected by this disease. Significant adverse effects are
common and include convulsions, gastrointestinal upset and
bone marrow depression.
Melarsoprol
This is an arsenical agent, used to treat central nervous system
infections in East and West African trypanosomiasis (T. brucei
rhodesiense and gambiense). It is administered intravenously.
Melarsoprol treatment is associated with peripheral neuropathy
and reactive arsenical encephalopathy (RAE), which carries a
significant mortality.
Nifurtimox
Nifurtimox is administered orally to treat South American
trypanosomiasis (Chagas’ disease). Gastrointestinal and
neurological adverse effects are common.
Pentamidine isetionate
Pentamidine is an inhibitor of DNA replication used in West African
trypanosomiasis (T. brucei gambiense) and, to a lesser extent,
in visceral and cutaneous leishmaniasis. It is also prescribed
in Pneumocystis jirovecii pneumonia. It is administered via
intravenous or intramuscular routes. It is a relatively toxic drug,
commonly causing rash, renal impairment, profound hypotension
(especially on rapid infusion), electrolyte disturbances, blood
dyscrasias and hypoglycaemia.
Suramin
Suramin is a naphthaline dye derivative, used to treat East
African trypanosomiasis (T. brucei rhodesiense). It is administered
intravenously. Adverse effects are common and include rash,
gastrointestinal disturbance, blood dyscrasias, peripheral
neuropathies and renal impairment.
Other antiprotozoal agents
Pentavalent antimonials
Sodium stibogluconate and meglumine antimoniate inhibit
protozoal glycolysis by phosphofructokinase inhibition. They
are used parenterally (intravenous or intramuscular) to treat
leishmaniasis. Adverse effects include arthralgia, myalgias, raised
hepatic transaminases, pancreatitis and electrocardiogram
changes. Severe cardiotoxicity leading to death is not uncommon.
Further information • 129
Diloxanide furoate
This oral agent is used to eliminate luminal cysts following
treatment of intestinal amoebiasis, or in asymptomatic cyst
excreters. The drug is absorbed slowly (enabling luminal
persistence) and has no effect in hepatic amoebiasis. It is a
relatively non-toxic drug, the most significant adverse effect
being flatulence.
lodoquinol (di-iodohydroxyquinoline)
lodoquinol is a quinoline derivative (p. 128) with activity against
Entamoeba histolytica cysts and trophozoites. It is used orally to
treat asymptomatic cyst excreters or, in association with another
amoebicide (e.g. metronidazole), to treat extra-intestinal amoebiasis.
Long-term use of this drug is not recommended, as neurological
adverse effects include optic neuritis and peripheral neuropathy.
Nitazoxanide
Nitazoxanide is an inhibitor of pyruvate-ferredoxin oxidoreductase-
dependent anaerobic energy metabolism in protozoa. It is a
broad-spectrum agent, active against various nematodes,
tapeworms, flukes and intestinal protozoa. Nitazoxanide also
has activity against some anaerobic bacteria and viruses. It is
administered orally in giardiasis and cryptosporidiosis. Adverse
effects are usually mild and involve the gastrointestinal tract (e.g.
nausea, diarrhoea and abdominal pain).
Paromomycin
Paromomycin is an aminoglycoside (p. 122) that is used to
treat visceral leishmaniasis and intestinal amoebiasis. It is not
significantly absorbed when administered orally, and is therefore
given orally for intestinal amoebiasis and by intramuscular injection
for leishmaniasis. It showed early promise in the treatment of
HIV-associated cryptosporidiosis but subsequent trials have
demonstrated that this effect is marginal at best.
|j)rugs used against helminths
Benzimidazoles (albendazole, mebendazole)
These agents act by inhibiting both helminth glucose uptake,
causing depletion of glycogen stores, and fumarate reductase.
Albendazole is used for hookworm, ascariasis, threadworm,
Strongyloides infection, trichinellosis, Taenia solium (cysticercosis)
and hydatid disease. Mebendazole is used for hookworm,
ascariasis, threadworm and whipworm. The drugs are administered
orally. Absorption is relatively poor but is increased by a fatty
meal. Significant adverse effects are uncommon.
Bithionol
Bithionol is used to treat fluke infections with Fasciola
hepatica. It is well absorbed orally. Adverse effects are mild
(e.g. nausea, vomiting, diarrhoea, rashes) but relatively common
(approximately 30%).
Diethylcarbamazine
Diethylcarbamazine (DEC) is an oral agent used to treat filariasis
and loiasis. Treatment of filariasis is often followed by fever,
headache, nausea, vomiting, arthralgia and prostration. This is
caused by the host response to dying microfilariae, rather than the
drug, and may be reduced by pre-treatment with glucocorticoids.
Ivermectin
Ivermectin binds to helminth nerve and muscle cell ion channels,
causing increased membrane permeability. It is an oral agent,
used in Strongyloides infection, filariasis and onchocerciasis.
Significant side-effects are uncommon.
Niclosamide
Niclosamide inhibits oxidative phosphorylation, causing paralysis
of helminths. It is an oral agent, used in Taenia saginata and
intestinal T. solium infection. Systemic absorption is minimal and
it has few significant side-effects.
Piperazine
Piperazine inhibits neurotransmitter function, causing helminth
muscle paralysis. It is an oral agent, used in ascariasis and
threadworm (Enterobius vermicularis) infection. Significant adverse
effects are uncommon but include neuropsychological reactions
such as vertigo, delirium and convulsions.
Praziquantel
Praziquantel increases membrane permeability to Ca2+, causing
violent contraction of worm muscle. It is the drug of choice
for schistosomiasis and is also used in T. saginata, T. solium
(cysticercosis) and fluke infections (Clonorchis, Paragonimus)
and in echinococcosis. It is administered orally and is well
absorbed. Adverse effects are usually mild and transient, and
include nausea and abdominal pain.
Pyrantel pamoate
This agent causes spastic paralysis of helminth muscle through
a suxamethonium-like action. It is used orally in ascariasis and
threadworm infection. Systemic absorption is poor and adverse
effects are uncommon.
Thiabendazole
Thiabendazole inhibits fumarate reductase, which is required for
energy production in helminths. It is used orally in Strongyloides
infection and topically to treat cutaneous larva migrans. Significant
adverse effects are uncommon.
Further information
Websites
cdc.gov Centers for Disease Control and Prevention, Atlanta, USA.
Provides information on all aspects of communicable disease,
including prophylaxis against malaria.
dh.gov.uk UK Department of Health. The publications section provides
current UK recommendations for immunisation.
ecdc.europa.eu European Centre for Disease Prevention and
Control. Includes data on prevalence of antibiotic resistance in
Europe.
gov.uk/government/organisations/public-health-england Public Health
England. Provides information on infectious diseases relating mainly
to England, including community infection control.
idsociety.org Infectious Diseases Society of America. Publishes
up-to-date, evidence-based guidelines.
who.int World Health Organization. Provides up-to-date information on
global aspects of infectious disease, including outbreak updates.
Also has information on the ‘World Antibiotic Awareness Week’
campaign.
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Poisoning
SHL Thomas
Comprehensive evaluation of the poisoned patient 132
General approach to the poisoned patient ] 34
Triage and resuscitation 134
Clinical assessment and investigations 1 34
Psychiatric assessment 1 35
General management 1 35
Poisoning by specific pharmaceutical agents 137
Analgesics 1 37
Antidepressants 1 38
Cardiovascular medications 1 40
Iron 1 40
Antipsychotic drugs 1 41
Antidiabetic agents 1 41
Pharmaceutical agents less commonly taken in poisoning 141
Drugs of misuse 141
Depressants 1 41
Stimulants and entactogens 1 43
Hallucinogens 143
Dissociative drugs 1 44
Volatile substances 144
Body packers and body stutters 1 44
Chemicals and pesticides 144
Carbon monoxide 1 44
Organophosphorus insecticides and nerve agents 1 45
Carbamate insecticides 1 46
Paraquat 1 47
Methanol and ethylene glycol 1 47
Corrosive substances 1 47
Aluminium and zinc phosphide 148
Copper sulphate 1 48
Chemicals less commonly taken in poisoning 148
Chemical warfare agents 149
Environmental poisoning 149
Food-related poisoning 149
Plant poisoning 150
132 • POISONING
Comprehensive evaluation of the poisoned patient
1 Airway, breathing, circulation
Respiration rate,
oxygen saturation,
pulse, BP,
dysrhythmias
2 Level of consciousness
Presence of seizures,
delirium, agitation
or psychosis
3 Chest
Evidence of aspiration,
bronchoconstriction
4 Movement and muscles
Tone, fasciculations,
myoclonus, tremor,
paralysis, ataxia
5 Reflexes
Tendon reflexes, plantar
responses, inducible clonus
6 Eyes
Miosis or mydriasis,
diplopia or strabismus,
lacrimation
A Pinpoint pupil
A Injected conjunctiva
7 Abdomen
Hepatic or epigastric
tenderness, ileus,
palpable bladder
10 Psychiatric evaluation
Features of psychiatric illness,
mental capacity
9 Mouth
Dry mouth, excessive salivation
8 Skin
Temperature, cyanosis,
flushing, sweating,
blisters, pressure areas,
piloerection,
evidence of self-harm
A Self-cutting
A Chemical burn
A Needle tracks
Insets (Self-cutting) From Douglas G, Nicol F, Robertson C (eds). Macleod’s Clinical examination, 1 1th edn. Churchill Livingstone, Elsevier Ltd; 2005.
(Chemical burn) www.firewiki.net. (Needle tracks) www.deep6inc.com. (Pinpoint pupil) http://drugrecognition.com/images. (Injected conjunctiva) http://
knol.google.com.
Taking a history in poisoning
• What toxin(s) have been taken and how much?
• What time were they taken and by what route?
• Has alcohol or any other substance (or substances, including drugs
of misuse) been taken as well?
• Obtain details from witnesses (e.g. family, friends, ambulance
personnel) of the circumstances of the overdose
• Assess immediate suicide risk in those with apparent self-harm (full
psychiatric evaluation when patient has recovered physically)
• Assess capacity to make decisions about accepting or refusing
treatment
• Establish past medical history, drug history and allergies, social and
family history
• Record all information carefully
Comprehensive evaluation of the poisoned patient • 133
Pupil size
Small: opioids, clonidine,
organophosphorus compounds
Large: tricyclic antidepressants,
amphetamines, cocaine
Respiratory rate
Reduced: opioids, benzodiazepines
Increased: salicylates
Blood pressure
Hypotension: tricyclic
antidepressants, haloperidol
Hypertension: cocaine,
a-adrenoceptor agonists
Right upper quadrant /renal angle
tenderness
Paracetamol hepatotoxicity,
renal toxicity
Epigastric tenderness
NSAIDs, salicylates
Rhabdomyolysis
Amphetamines, caffeine
Cerebellar signs
Some anticonvulsants, alcohol
Extrapyramidal signs
Phenothiazines, haloperidol,
metoclopramide
Cyanosis
Any CNS depressant drug or agent
(N.B. consider methaemoglobinaemia
caused by dapsone, amyl nitrite etc.)
Heart rate
Tachycardia or tachyarrhythmias:
tricyclic antidepressants, theophylline,
digoxin, antihistamines
Bradycardia or bradyarrhythmias:
digoxin, (3-blockers, calcium channel
blockers, opioids, organophosphates
Needle tracks
Drugs of misuse: opioids etc.
Body temperature
Hyperthermia and sweating:
ecstasy, serotonin re- uptake inhibitors,
salicylates
Hypothermia: any CNS depressant
drug, opioids, chlorpromazine
Clinical signs of poisoning by pharmaceutical agents and drugs of misuse.
External decontamination
Direct eye contact -
Eye irrigation - remove contact lenses
Wash eyes thoroughly for at least 15
mins with normal saline or water
Remove particles from palpebral
fissures
If pain persists, insert fluorescein
drops and perform slit-lamp
examination for corneal damage
Skin contact (hazardous chemicals/
pesticides) -
Remove clothing
Wash with copious amounts of soap
and water
Gastrointestinal decontamination
Gastrointestinal tract -
Single-dose oral activated charcoal
Gastric lavage
Enhancing elimination
Blood
Haemodialysis
Haemoperfusion
-Kidneys
Urinary alkalinisation
-Gastrointestinal tract
Multiple-dose activated charcoal
Decontamination and enhanced elimination. One of the key aspects in the evaluation of a poisoned patient is deciding if decontamination and/or
enhanced elimination is required.
134 • POISONING
Acute poisoning is common, accounting for about 1 % of hospital
admissions in the UK. Common or otherwise important substances
involved are shown in Box 7.1. In developed countries, the
most frequent cause is intentional drug overdose in the context
of self-harm, often involving prescribed or ‘over-the-counter’
medicines. Accidental poisoning is also common, especially
in children and the elderly (Box 7.2). Toxicity also results from
alcohol or recreational substance use, or following occupational
or environmental exposure. Poisoning is a major cause of death
in young adults, but most deaths occur before patients reach
medical attention, and mortality is low (<1%) in those admitted
to hospital.
In developing countries, the frequency of self-harm is more
difficult to estimate. Because of their widespread availability and
use, household and agricultural products, such as pesticides
and herbicides, are common sources of poisoning and have
a much higher case fatality. In China and South-east Asia,
pesticides account for about 300000 suicides each year. Snake
bite and other forms of envenomation are also important causes
of morbidity and mortality internationally and are discussed in
Chapter 8.
i
In the UK
• Analgesics: paracetamol and non-steroidal anti-inflammatory drugs
(NSAIDs)
• Antidepressants: tricyclic antidepressants (TCAs), selective serotonin
re-uptake inhibitors (SSRIs) and lithium
• Cardiovascular agents: (3-blockers, calcium channel blockers and
cardiac glycosides
• Drugs of misuse: depressants (e.g. opiates, benzodiazepines),
stimulants and entactogens (e.g. amphetamines, MDMA,
mephedrone, cocaine), hallucinogens (e.g. cannabis, synthetic
cannabinoid receptor agonists, LSD)
• Carbon monoxide
• Alcohol
In South and South-east Asia
• Organophosphorus and carbamate insecticides
• Aluminium and zinc phosphide
• Oleander
• Corrosives
• Snake venoms (Ch. 8)
General approach to the
poisoned patient
A general approach is shown on pages 132-133. In many
countries, poisons centres are available to provide advice on
management of suspected poisoning with specific substances.
Information is also available online (p. 150).
Triage and resuscitation
Patients who are seriously poisoned must be identified early so
that appropriate management is not delayed. Triage involves:
• immediately assessing vital signs
• identifying the poison(s) involved and obtaining adequate
information about them
• identifying patients at risk of further attempts at self-harm
and removing any remaining hazards.
Those with possible external contamination with chemical or
environmental toxins should undergo appropriate decontamination
(p. 133). Critically ill patients must be resuscitated (p. 174).
The Glasgow Coma Scale (GCS) is commonly employed to
assess conscious level, although not specifically validated in
poisoning. The AVPU (alert/verbal/painful/unresponsive) scale
is also a rapid and simple method. An electrocardiogram (ECG)
should be performed and cardiac monitoring instituted in all
patients with cardiovascular features or where exposure to
potentially cardiotoxic substances is suspected. Patients who
may need antidotes should be weighed if possible, so that
appropriate weight-related doses can be prescribed.
Substances unlikely to be toxic in humans should be identified
so that inappropriate admission and intervention are avoided
(Box 7.3).
Clinical assessment and investigations
History and examination are described on page 132. Occasionally,
patients may be unaware of or confused about what they have
taken, or may exaggerate (or, less commonly, underestimate) the
size of the overdose, but rarely mislead medical staff deliberately.
In regions of the world where self-poisoning is illegal, patients
may be reticent about giving a history.
Toxic causes of abnormal physical signs are shown on
page 133. The patient may have a cluster of clinical features
(‘toxidrome’) suggestive of poisoning with a particular drug type,
e.g. anticholinergic, serotoninergic (see Box 7.10), stimulant,
sedative, opioid (see Box 7.12) or cholinergic (see Box 7.14)
feature clusters. Poisoning is a common cause of coma, especially
i
• Writing/educational materials, e.g. pencil lead, crayons, chalk
• Decorating products, e.g. emulsion paint, wallpaper paste
• Cleaning/bathroom products (except dishwasher tablets and liquid
laundry detergent capsules, which can be corrosive)
• Pharmaceuticals: oral contraceptives, most antibiotics (but not
tetracyclines or antituberculous drugs), vitamins B, C and E,
prednisolone, emollients and other skin creams, baby lotion
• Miscellaneous: plasticine, silica gel, most household plants, plant
food, pet food, soil
(LSD = lysergic acid diethylamide; MDMA = 3,4-methylene¬
dioxymethamphetamine, ecstasy)
• Aetiology: may result from accidental poisoning (e.g. due to
delirium or dementia) or drug toxicity as a consequence of impaired
renal or hepatic function or drug interaction. Toxic prescription
medicines are more likely to be available.
• Psychiatric illness: self-harm is less common than in younger
adults but more frequently associated with depression and other
psychiatric illness, as well as chronic illness and pain. There is a
higher risk of subsequent suicide.
• Severity of poisoning: increased morbidity and mortality result
from reduced renal and hepatic function, lower functional reserve,
increased sensitivity to sedative agents and frequent comorbidity.
7.2 Poisoning in old age
7.1 Important substances involved in poisoning
7.3 Substances of very low toxicity
General approach to the poisoned patient • 135
Causes
Non-toxic
• Congenital methaemoglobinaemias
Toxic (Oxidising agents)
• Organic nitrites
• Nitrates
• Benzocaine
• Dapsone
• Chloroquine
• Aniline dyes
• Chlorobenzene
• Naphthalene
• Copper sulphate
Consequences
• Haemoglobin-oxygen
dissociation curve is shifted
to the left (see Fig. 23.5)
• Oxygen delivery to tissues
is reduced
• There is apparent ‘cyanosis’
• Breathlessness, fatigue,
headache and chest pain
occur
• Delirium, impaired
consciousness and seizures
may occur in severe cases
Treatment
• Methylthioninium chloride
(‘methylene blue’) 1-2 mg/kg
(intravenous) is given
• Reduces methaemoglobin
(see below)
• Used for symptomatic
patients with severe
methaemoglobinaemia
(e.g. >30%)
• Patients with anaemia or
other comorbidities may
need treatment at lower
concentrations
NADP*
NADPH
Fig. 7.1 Methaemoglobinaemia.
i
7.4 Causes of acidosis in the poisoned patient
Cause Normal lactate*
High lactate
Toxic
Salicylates
Metformin
Methanol
Iron
Ethylene glycol
Cyanide
Paraldehyde
Sodium valproate
Carbon monoxide
Other
Renal failure
Ketoacidosis
Severe diarrhoea
Shock
*Unless circulatory shock is present, when it will be high in any case.
in younger people, but it is important to exclude other potential
causes (p. 194).
Urea, electrolytes and creatinine should be measured in
all patients with suspected systemic poisoning. Arterial blood
gases should be checked in those with significant respiratory or
circulatory compromise, or after poisoning with substances likely to
affect acid-base status (Box 7.4). Calculation of anion and osmolar
gaps may help to inform diagnosis and management (Box 7.5).
Potent oxidising agents may cause methaemoglobinaemia, with
consequent blue discoloration of skin and blood, and reduced
oxygen delivery to the tissues (Fig. 7.1).
For some substances, management may be facilitated by
7.5 Anion and osmolar gaps in poisoning
Anion gap
Osmolar gap
Calculation
[Na+ + K+] -
[CC + HC031
[Measured osmolality] -
[(2 x Na) + Urea +
Glucose]1
Reference
range
12-16 mmol/L
<10
Common toxic
causes of
elevation2
Ethanol
Ethylene glycol
Methanol
Salicylates
Iron
Cyanide
Ethanol
Ethylene glycol
Methanol
^11 units should be in mmol/L, except osmolality, which should be in mOsmol/kg.
For non-SI units, the corresponding formula is [Measured osmolality (mOsmol/kg)]
- [(2 x Na (mEq/L)) + Urea/2.8 (mg/dL) + Glucose/18 (mg/dL)]. 2Box 14.19
(p. 365) gives non-toxic causes.
health professional with appropriate training (p. 1 1 87). This should
occur after they have recovered from poisoning, unless there
is an urgent issue, such as uncertainty about their capacity to
decline medical treatment.
General management
measurement of the amount of toxin in the blood. Qualitative
urine screens for potential toxins, including near-patient testing
kits, have a limited clinical role.
Patients presenting with eye/skin contamination should undergo
local decontamination measures. These are described on
page 133.
Psychiatric assessment
Patients presenting with drug overdose in the context of self-harm
should undergo psychiatric evaluation prior to discharge by a
Gastrointestinal decontamination
Patients who have ingested potentially life-threatening quantities
of toxins may be considered for gastrointestinal decontamination
if poisoning has been recent (p. 133).
136 • POISONING
Activated charcoal
Given orally as a slurry, activated charcoal absorbs toxins in
the bowel as a result of its large surface area. It can prevent
absorption of an important proportion of the ingested dose of
toxin, but efficacy decreases with time and current guidelines
do not encourage use more than 1 hour after overdose, unless
a sustained-release preparation has been taken or when gastric
emptying may be delayed. Use is ineffective for some toxins
that do not bind to activated charcoal (Box 7.6). In patients
with impaired swallowing or a reduced level of consciousness,
activated charcoal, even via a nasogastric tube, carries a risk of
aspiration pneumonitis, which can be reduced (but not eliminated)
by protecting the airway with a cuffed endotracheal tube.
Multiple doses of oral activated charcoal (50 g 6 times daily
in an adult) may enhance the elimination of some substances at
any time after poisoning (Box 7.7). This interrupts enterohepatic
circulation or reduces the concentration of free drug in the gut
lumen, to the extent that drug diffuses from the blood back into
the bowel to be absorbed on to the charcoal (‘gastrointestinal
dialysis’). A laxative is generally given with the charcoal to reduce
the risk of constipation or intestinal obstruction by charcoal
‘briquette’ formation in the gut lumen.
Evidence suggests that single or multiple doses of activated
charcoal do not improve clinical outcomes after poisoning with
pesticides or oleander.
Gastric aspiration and lavage
Gastric aspiration and/or lavage is very infrequently indicated in
acute poisoning, as it is no more effective than activated charcoal
7.6 Substances poorly adsorbed by
activated charcoal
Medicines
• Iron • Lithium
Chemicals
• Acids* • Mercury
• Alkalis* • Methanol
• Ethanol • Petroleum distillates*
• Ethylene glycol
for most substances and complications are common, especially
pulmonary aspiration. It is contraindicated if strong acids, alkalis
or petroleum distillates have been ingested. Use may be justified
for life-threatening overdoses of those substances that are not
absorbed by activated charcoal (see Box 7.6).
Whole bowel irrigation
This involves the administration of large quantities of osmotically
balanced polyethylene glycol and electrolyte solution (1-2 U
hr for an adult), usually by a nasogastric tube, until the rectal
effluent is clear. It is occasionally indicated to enhance the
elimination of ingested packets of illicit drugs or slow-release
tablets such as iron and lithium that are not absorbed by
activated charcoal. Contraindications include inadequate
airway protection, haemodynamic instability, gastrointestinal
haemorrhage, obstruction or ileus. Whole bowel irrigation may
precipitate nausea and vomiting, abdominal pain and electrolyte
disturbances.
j Urinary alkalinisation
Urinary excretion of weak acids and bases is affected by urinary
pH, which changes the extent to which they are ionised. Highly
ionised molecules pass poorly through lipid membranes and
therefore little tubular reabsorption occurs and urinary excretion is
increased. If the urine is alkalinised (pH >7.5) by the administration
of sodium bicarbonate (e.g. 1.5 L of 1 .26% sodium bicarbonate
over 2 hrs), weak acids (e.g. salicylates, methotrexate) are highly
ionised, resulting in enhanced urinary excretion.
Urinary alkalinisation is currently recommended for patients
with clinically significant salicylate poisoning when the criteria
for haemodialysis are not met (see below). It is also sometimes
used for poisoning with methotrexate. Complications include
alkalaemia, hypokalaemia and occasionally alkalotic tetany
(p. 367). Hypocalcaemia may occur but is rare.
Haemodialysis and haemoperfusion
These techniques can enhance the elimination of poisons that
have a small volume of distribution and a long half-life after
overdose; use is appropriate when poisoning is sufficiently
severe. The toxin must be small enough to cross the dialysis
membrane (haemodialysis) or must bind to activated charcoal
(haemoperfusion) (see Box 7.7). Haemodialysis can also correct
acid-base and metabolic disturbances associated with poisoning
(p. 135).
|J.ipid emulsion therapy
Lipid emulsion therapy is increasingly used for poisoning
with lipid-soluble agents, such as local anaesthetics, tricyclic
antidepressants, calcium channel blockers and lipid-soluble
(3-adrenoceptor antagonists (p-blockers) such as propranolol. It
involves intravenous infusion of 20% lipid emulsion (e.g. Intralipid,
suggested initial dose 1 .5 mL7kg, followed by a continued infusion
of 0.25 mL7kg/min until there is clinical improvement). It is thought
that lipid-soluble toxins partition into the intravenous lipid, reducing
target tissue concentrations. The elevated myocardial free fatty
acid concentrations may also have beneficial effects on myocardial
metabolism and performance by counteracting the inhibition of
myocardial fatty acid oxidation produced by some cardiotoxins,
enabling increased adenosine triphosphate (ATP) synthesis and
energy production. Some animal studies have suggested efficacy
and case reports of use in human poisoning have also been
*Gastric lavage contraindicated.
7.7 Poisons effectively eliminated by multiple
doses of activated charcoal, haemodialysis
or haemoperfusion
Multiple doses of activated charcoal
• Carbamazepine • Quinine
• Dapsone • Theophylline
• Phenobarbital
Haemodialysis
• Ethylene glycol
• Salicylates
• Isopropanol
• Sodium valproate
• Methanol
• Lithium
Haemoperfusion
• Theophylline
• Phenobarbital
• Phenytoin
• Amobarbital
• Carbamazepine
Poisoning by specific pharmaceutical agents • 137
1 7.8 Complications of poisoning and their management
Complication
Examples of causative agents
Management
Coma
Sedative agents
Appropriate airway protection and ventilatory support
Oxygen saturation and blood gas monitoring
Pressure area and bladder care
Identification and treatment of aspiration pneumonia
Seizures
NSAIDs
Anticonvulsants
TCAs
Theophylline
Appropriate airway and ventilatory support
IV benzodiazepine (e.g. diazepam 10-20 mg, lorazepam 2-4 mg)
Correction of hypoxia, acid-base and metabolic abnormalities
Acute dystonias
Typical antipsychotics
Metoclopramide
Procyclidine, benzatropine or diazepam
Hypotension
Due to vasodilatation
Vasodilator antihypertensives
Anticholinergic agents
TCAs
IV fluids
Vasopressors (rarely indicated; p. 206)
Due to myocardial suppression
(3-blockers
Calcium channel blockers
TCAs
Optimisation of volume status
Inotropic agents (p. 206)
Ventricular tachycardia
Monomorphic, associated with QRS
prolongation
Sodium channel blockers
Correction of electrolyte and acid-base abnormalities and hypoxia
Sodium bicarbonate (e.g. 50 mL 8.4% solution, repeated if necessary)
Torsades de pointes, associated with
QTC prolongation
Anti-arrhythmic drugs (quinidine,
amiodarone, sotalol)
Antimalarials
Organophosphate insecticides
Antipsychotic agents
Antidepressants
Antibiotics (erythromycin)
Correction of electrolyte and acid-base abnormalities and hypoxia
Magnesium sulphate, 2 g IV over 1-2 mins, repeated if necessary
(NSAID = non-steroidal anti-inflammatory drug; TCA = tricyclic antidepressant)
encouraging, with recovery of circulatory collapse reported in
cases where other treatment modalities have been unsuccessful.
No controlled trials of this technique have been performed,
however, and efficacy remains uncertain.
| Supportive care
For most poisons, antidotes and methods to accelerate elimination
are inappropriate, unavailable or incompletely effective. Outcome
is dependent on appropriate nursing and supportive care, and
treatment of complications (Box 7.8).
Antidotes
Antidotes are available for some poisons and work by a variety
of mechanisms (Box 7.9). The use of some of these in the
management of specific poisons is described below.
Poisoning by specific
pharmaceutical agents
Analgesics
Paracetamol
Paracetamol (acetaminophen) is the drug most commonly used
in overdose in the UK. Toxicity is caused by an intermediate
reactive metabolite that binds covalently to cellular proteins,
1 7.9 Specific antidotes used to treat poisoning
Mechanism of action
Examples of
antidote
Poisoning
treated
Glutathione repleters
Acetylcysteine
Methionine
Paracetamol
Receptor antagonists
Naloxone
Opioids
Flumazenil
Benzodiazepines
Atropine
Organophosphorus
compounds
Carbamates
Alcohol dehydrogenase
inhibitors
Fomepizole
Ethanol
Ethylene glycol
Methanol
Chelating agents
Desferrioxamine
Iron
Hydroxocobalamin
Dicobalt edetate
Cyanide
DMSA
Sodium calcium
edetate
Lead
Reducing agents
Methylthioninium
chloride
Organic nitrites
Cholinesterase
reactivators
Pralidoxime
Organophosphorus
compounds
Antibody fragments
Digoxin Fab
fragments
Digoxin
(DMSA = dimercaptosuccinic acid)
138 • POISONING
causing cell death. This results in hepatic and occasionally renal
failure. In therapeutic doses, the toxic metabolite is detoxified
in reactions requiring glutathione, but in overdose, glutathione
reserves become exhausted.
Management
Activated charcoal may be used in patients presenting within
1 hour. Antidotes for paracetamol act by replenishing hepatic
glutathione and should be administered to all patients with acute
poisoning and paracetamol concentrations above a ‘treatment line’
provided on paracetamol poisoning nomograms (Fig. 7.2). The
threshold used for these nomograms varies between countries,
however, and local guidance should be followed. Acetylcysteine
given intravenously (or orally in some countries) is highly efficacious
if administered within 8 hours of the overdose. However, efficacy
declines thereafter, so administration should not be delayed
in patients presenting after 8 hours to await a paracetamol
blood concentration result. The antidote can be stopped if the
paracetamol concentration is shown to be below the nomogram
treatment line. Liver and renal function, International Normalised
Ratio (INR) and a venous bicarbonate should also be measured.
Arterial blood gases and lactate should be assessed in patients
with reduced bicarbonate or severe liver function abnormalities;
metabolic acidosis indicates severe poisoning.
Anaphylactoid reactions are the most important adverse
effects of acetylcysteine and are related to dose-related histamine
release. Common features are itching and urticaria, and in severe
cases, bronchospasm and hypotension. Most cases can be
managed by temporary discontinuation of acetylcysteine and
administration of an antihistamine.
An alternative antidote is methionine 2.5 g orally (adult
dose) every 4 hours to a total of four doses, but this may
be less effective, especially after delayed presentation. Liver
transplantation should be considered for paracetamol poisoning
with life-threatening liver failure (p. 856).
If multiple ingestions of paracetamol have taken place over
several hours (‘staggered overdose’) or days (e.g. chronic
therapeutic excess), acetylcysteine may be indicated; specific
treatment recommendations vary between countries.
Fig. 7.2 Paracetamol treatment nomogram (UK). Above the treatment
line, benefits of treatment outweigh risk. Below it, risks of treatment
outweigh benefits.
Salicylates (aspirin)
Clinical features
Salicylate overdose commonly causes nausea, vomiting, sweating,
tinnitus and deafness. Direct stimulation of the respiratory centre
produces hyperventilation and respiratory alkalosis. Peripheral
vasodilatation with bounding pulses and profuse sweating occurs
in moderately severe cases. Serious poisoning is associated with
metabolic acidosis, hypoprothrombinaemia, hyperglycaemia,
hyperpyrexia, renal failure, pulmonary oedema, shock and cerebral
oedema. Agitation, delirium, coma and fits may occur, especially
in children. Toxicity is enhanced by acidosis, which increases
salicylate transfer across the blood-brain barrier.
Management
Activated charcoal should be administered if the patient presents
within 1 hour. Multiple doses may enhance salicylate elimination
but are not routinely recommended.
The plasma salicylate concentration should be measured
at least 2 (symptomatic patients) or 4 hours (asymptomatic
patients) after overdose and repeated in suspected serious
poisoning, as concentrations may continue to rise for several
hours. Clinical status, however, is more important than the
salicylate concentration when assessing severity.
Dehydration should be corrected carefully because of the risk
of pulmonary oedema. Metabolic acidosis should be treated with
intravenous sodium bicarbonate (8.4%), after plasma potassium
has been corrected. Urinary alkalinisation is indicated for adults
with salicylate concentrations above 500 mg/L.
Haemodialysis is very effective for removing salicylate and
correcting associated acid-base and fluid balance abnormalities.
It should be considered when serum concentrations are above
700 mg/L in adults with severe toxic features, or in renal failure,
pulmonary oedema, coma, convulsions or refractory acidosis.
|Non-steroidal anti-inflammatory drugs
Clinical features
Overdose of most non-steroidal anti-inflammatory drugs (NSAIDs)
usually causes only minor abdominal discomfort, vomiting and/
or diarrhoea, but convulsions can occur occasionally, especially
with mefenamic acid. Coma, prolonged seizures, apnoea, liver
dysfunction and renal failure may follow substantial overdose but
are rare. Features of toxicity are unlikely to develop in patients
who are asymptomatic more than 6 hours after overdose.
Management
Electrolytes, liver function tests and a full blood count should
be checked in all but the most trivial cases. Activated charcoal
may be given if the patient presents within 1 hour. Symptomatic
treatment for nausea and gastrointestinal irritation may be needed.
Antidepressants
|jricyclic antidepressants
Overdose with tricyclic antidepressants (TCAs) carries a high
morbidity and mortality because of their sodium channel-blocking,
anticholinergic and a-adrenoceptor-blocking effects.
Clinical features
Anticholinergic effects are common (Box 7.10). Severe complica¬
tions include convulsions, coma and arrhythmias (ventricular
Poisoning by specific pharmaceutical agents • 139
j 7.1 0 Anticholinergic and serotonergic feature clusters
Anticholinergic
Serotonin syndrome
Common causes
Benzodiazepines
Antipsychotics
TCAs
Antihistamines
Scopolamine
Benzatropine
Belladonna
Some plants and
mushrooms (see
Box 7.18)
SSRIs
MAOIs
TCAs
Amphetamines
Tryptamines
Buspirone
Bupropion (especially
in combination)
Clinical features
Cardiovascular
Tachycardia,
hypertension
Tachycardia, hyper- or
hypotension
Central nervous
system
Delirium,
hallucinations,
sedation
Delirium,
hallucinations,
sedation, coma
Muscle
Myoclonus
Shivering, tremor,
myoclonus, raised
creatine kinase
Temperature
Fever
Fever
Eyes
Diplopia, mydriasis
Normal pupil size
Abdomen
Ileus, palpable bladder
Diarrhoea, vomiting
Mouth
Dry
Skin
Flushing, hot, dry
Flushing, sweating
Complications
Seizures
Seizures
Rhabdomyolysis
Renal failure
Metabolic acidosis
Coagulopathies
(MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin re-uptake
inhibitor; TCA = tricyclic antidepressant)
Fig. 7.3 ECG in severe tricyclic antidepressant poisoning. This rhythm
strip shows a broad QRS complex due to impaired conduction.
tachycardia, ventricular fibrillation and, less commonly, heart
block). Hypotension results from inappropriate vasodilatation or
impaired myocardial contractility. Serious complications appear
more common with dosulepin and amitriptyline.
Management
Activated charcoal should be administered if the patient presents
within 1 hour. A 12-lead ECG should be taken and continuous
cardiac monitoring maintained for at least 6 hours. Prolongation
of the QRS interval (especially if >0.16 secs) indicates severe
sodium channel blockade and a high risk of arrhythmia (Fig. 7.3).
QT interval prolongation may also occur. Arterial blood gases
should be measured in suspected severe poisoning.
In patients with arrhythmias, significant QRS or QT prolongation
or acidosis, intravenous sodium bicarbonate (50 ml_ of 8.4%
solution) should be administered and repeated to correct pH.
The correction of the acidosis and the sodium loading that
results may bring about rapid improvement in ECG features and
arrhythmias. Hypoxia and electrolyte abnormalities should also
be corrected. Anti-arrhythmic drugs should only be given on
specialist advice. Prolonged seizures should be treated initially
with intravenous benzodiazepines (see Box 7.8).
I Selective serotonin and noradrenaline
re-uptake inhibitors
Selective serotonin re-uptake inhibitor (SSRI) antidepressants
(e.g. fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram,
escitalopram) are increasingly used to treat depression and
are less toxic in overdose than TCAs. The related serotonin-
noradrenaline re-uptake inhibitors (SNRIs), such as venlafaxine
and duloxetine, are also commonly used but are more toxic
than SSRIs in overdose.
Clinical features and management
Overdose of SSRIs may produce nausea and vomiting, tremor,
insomnia and sinus tachycardia. Agitation, drowsiness and
convulsions occur infrequently and may be delayed for several
hours. Serotonin syndrome may occur (see Box 7.10), especially
if SSRIs are taken in combination or with other serotonergic
agents. Cardiac arrhythmias occur infrequently and most patients
require supportive care only. The toxic effects of SNRIs are
similar but tachycardia, hypertension or hypotension and ECG
changes (QRS and QT prolongation) may be more prominent
and hypoglycaemia can also arise.
| Lithium
Severe lithium toxicity is uncommon after intentional acute
overdose but is more often encountered in patients taking
therapeutic doses, frequently as a result of interactions with drugs
such as diuretics or NSAIDs. Severe toxicity is more common
after acute overdose in patients already taking chronic therapy
(‘acute on chronic’ poisoning).
Clinical features
Nausea, diarrhoea, polyuria, dizziness and tremor may progress
to muscular weakness, drowsiness, delirium, myoclonus,
fasciculations, choreoathetosis and renal failure. Coma, seizures,
ataxia, cardiac dysrhythmias such as heart block, blood pressure
disturbances and renal failure may occur in severe poisoning.
Management
Activated charcoal is ineffective. Early gastric lavage is of
theoretical benefit, but lithium tablets are likely to remain intact
in the stomach and may be too large for aspiration via a lavage
tube. Whole bowel irrigation is often used after substantial
overdose but efficacy is unproven.
Lithium concentrations should be measured immediately
(symptomatic patients) or after at least 6 hours (asymptomatic
patients) following acute overdose. The usual therapeutic range
is 0.4-1 .0 mmol/L. Adequate hydration should be maintained
with intravenous fluids. Seizures should be treated as in Box 7.8.
Haemodialysis should be considered for severe toxicity
associated with high lithium concentrations (e.g. >4.0 mmol/L
after chronic or ‘acute on chronic’ poisoning, or >7.5 mmol/L
after acute poisoning). Lithium concentrations are reduced
substantially during dialysis, but rebound increases occur after
discontinuation and multiple sessions are usually required.
140 • POISONING
Cardiovascular medications
Although not common, cardiovascular drug overdose is important
because features of toxicity are often severe.
Beta-blockers
Major features of toxicity are bradycardia and hypotension; heart
block, pulmonary oedema and cardiogenic shock occur in severe
poisoning. Those with additional sodium channel-blocking effects
(e.g. propranolol, acebutolol, carvedilol) may cause seizures,
delirium and coma, while sotalol, which also blocks potassium
channels, may cause QTC prolongation and torsades de pointes
(Box 7.8 and p. 476).
Management
Intravenous fluids may reverse hypotension but care is required
to avoid pulmonary oedema. Bradycardia and hypotension
may respond to high doses of atropine (up to 3 mg in an
adult) or an infusion of isoproterenol. Glucagon (5-10 mg over
10 mins, then 1-5 mg/hr by infusion) counteracts |3-blockade by
stimulating intracellular cyclic adenosine monophosphate (cAMP)
production and is now more commonly used. In severe cases,
‘hyperinsulinaemia euglycaemic therapy’ has been used, as
described under calcium channel blockers below. The efficacy
of lipid emulsion therapy in severe poisoning with lipid-soluble
(3-blockers, such as propranolol, carvedilol and oxprenolol, is
uncertain.
Calcium channel blockers
L-type calcium channel blockers are highly toxic in overdose.
Dihydropyridines (e.g. nifedipine, amlodipine) cause vasodilatation,
whereas diltiazem and verapamil have predominantly cardiac
effects, including bradycardia and reduced myocardial contractility.
Clinical features
Hypotension due to vasodilatation or myocardial depression
is common and bradycardias and heart block may also
occur, especially with verapamil and diltiazem. Gastrointestinal
disturbances, delirium, metabolic acidosis, hyperglycaemia and
hyperkalaemia may also be present.
Management
Hypotension should be corrected with intravenous fluids, taking
care to avoid pulmonary oedema. Persistent hypotension may
respond to intravenous calcium gluconate (10 mg IV over
5 mins, repeated as required). Isoproterenol and glucagon
may also be useful. Successful use of intravenous insulin with
glucose (10-20% dextrose with insulin initially at 0. 5-2.0 U/kg/
hr, increasing to 5-10 U/kg/hr according to clinical response),
so-called ‘hyperinsulinaemia euglycaemic therapy’, has been
reported in patients unresponsive to other strategies. The
mechanism of action remains to be fully elucidated, but in
states of shock myocardial metabolism switches from use of
free fatty acids to glucose. Calcium channel blocker poisoning
is also associated with hypoinsulinaemia and insulin resistance,
impeding glucose uptake by myocytes. High doses of insulin
inhibit lipolysis and increase glucose uptake and the efficiency
of glucose utilisation. Cardiac pacing may be needed for severe
unresponsive bradycardias or heart block. Lipid emulsion therapy
has also been used in severe poisoning with apparent benefit,
although evidence is largely anecdotal.
Digoxin and oleander
Poisoning with digoxin is usually accidental, arising from
prescription of an excessive dose, impairment of renal function
or drug interactions. In South Asia, deliberate self-poisoning
with yellow oleander ( Thevetia peruviana), containing cardiac
glycosides, is common.
Clinical features
Cardiac effects include tachyarrhythmias (either atrial or ventricular)
and bradycardias, with or without atrioventricular block. Ventricular
bigeminy is common and atrial tachycardia with evidence of
atrioventricular block is highly suggestive of the diagnosis. Severe
poisoning is often associated with hyperkalaemia. Non-cardiac
features include delirium, headache, nausea, vomiting, diarrhoea
and (rarely) altered colour vision. Digoxin poisoning can be
confirmed by elevated plasma concentration (usual therapeutic
range 1 .3-2.5 mmol/L). After chronic exposure, concentrations
>5 mmol/L suggest serious poisoning.
Management
Activated charcoal is commonly administered to patients
presenting soon after acute ingestion, although evidence of benefit
is lacking. Urea, electrolytes and creatinine should be measured,
a 12-lead ECG performed and cardiac monitoring instituted.
Hypoxia, hypokalaemia (sometimes caused by concurrent
diuretic use), hypomagnesaemia and acidosis increase the risk
of arrhythmias and should be corrected. Significant bradycardias
may respond to atropine, although temporary pacing is sometimes
needed. Ventricular arrhythmias may respond to intravenous
magnesium (see Box 7.8). If available, digoxin-specific antibody
fragments should be administered when there are severe refractory
ventricular arrhythmias or bradycardias. These are effective for
both digoxin and yellow oleander poisoning.
Iron
Overdose with iron can cause severe and sometimes fatal
poisoning, with toxicity of individual iron preparations related to
their elemental iron content.
Clinical features
Early features include gastrointestinal disturbance with the
passage of grey or black stools, progressing to hyperglycaemia,
leucocytosis, haematemesis, rectal bleeding, drowsiness,
convulsions, coma, metabolic acidosis and cardiovascular collapse
in severe cases. Early symptoms may improve or resolve within
6-1 2 hours, but hepatocellular necrosis can develop 1 2-24 hours
after overdose and occasionally progresses to hepatic failure.
Gastrointestinal strictures are late complications.
Management
Activated charcoal is ineffective but gastric lavage may be
considered in patients presenting soon after substantial overdose,
although efficacy is unknown. Serum iron concentration should
be measured at least 4 hours after overdose or earlier if there are
features of toxicity. Desferrioxamine chelates iron and should be
administered immediately in patients with severe features, without
waiting for serum iron concentrations, as well as symptomatic
patients with high serum iron concentrations (e.g. >5 mg/L).
Desferrioxamine may cause hypotension, allergic reactions
and occasionally pulmonary oedema. Otherwise, treatment is
supportive and directed at complications.
Drugs of misuse • 141
Antipsychotic drugs
Antipsychotic drugs (p. 1 1 98) are often prescribed for patients at
high risk of self-harm or suicide and are often taken in overdose.
Clinical features
Anticholinergic features (see Box 7.10) including drowsiness,
tachycardia and hypotension, are common and convulsions may
occur. Acute dystonias, including oculogyric crisis, torticollis and
trismus, may occur after overdose with typical antipsychotics
like haloperidol or chlorpromazine. QT interval prolongation and
torsades de pointes can occur with some typical (e.g. haloperidol)
and atypical (e.g. quetiapine, amisulpride, ziprasidone) agents.
Management
Activated charcoal may be of benefit if given early. Cardiac
monitoring should be undertaken for at least 6 hours. Management
is largely supportive, with treatment directed at complications
(see Box 7.8).
Antidiabetic agents
Overdose is uncommon but toxic effects can be severe.
Clinical features
Sulphonylureas, meglitinides (e.g. nateglinide, repaglinide) and
parenteral insulin cause hypoglycaemia when taken in overdose,
although insulin is non-toxic if ingested by mouth. The duration of
hypoglycaemia depends on the half-life or release characteristics
of the preparation and may be prolonged over several days with
long-acting agents such as glibenclamide, insulin zinc suspension
or insulin glargine.
Features of hypoglycaemia include nausea, agitation, sweating,
aggression, delirium, tachycardia, hypothermia, drowsiness,
convulsions and coma (p. 738). Permanent neurological damage
can occur if hypoglycaemia is prolonged. Hypoglycaemia can
be diagnosed using bedside glucose strips but venous blood
should also be sent for laboratory confirmation.
Metformin is uncommonly associated with hypoglycaemia.
Its major toxic effect is lactic acidosis, which can have a high
mortality, and is particularly common in older patients and
those with renal or hepatic impairment, or when ethanol has
been co-ingested. Other features of metformin overdose are
nausea, vomiting, diarrhoea, abdominal pain, drowsiness, coma,
hypotension and cardiovascular collapse.
There is limited experience of overdose involving
thiazolidinediones (e.g. pioglitazone) and dipeptidyl peptidase
4 (DPP-4) inhibitors (e.g. sitagliptin) but significant hypoglycaemia
is unlikely.
Management
Activated charcoal should be considered for recent substantial
overdose. Venous blood glucose and urea and electrolytes
should be measured and measurement repeated regularly.
Hypoglycaemia should be corrected using oral or intravenous
glucose (50 ml_ of 50% dextrose); an infusion of 1 0-20% dextrose
may be required to prevent recurrence. Intramuscular glucagon
can be used as an alternative, especially if intravenous access is
unavailable. Failure to regain consciousness within a few minutes
of normalisation of the blood glucose can indicate that a central
nervous system (CNS) depressant has also been ingested, the
hypoglycaemia has been prolonged, or there is another cause
of coma (e.g. cerebral haemorrhage or oedema).
7.1 1 Clinical features and specific management of
drugs less commonly involved in poisoning
Substance
Clinical features
Management
Anticonvulsants
Carbamazepine,
phenytoin
Cerebellar signs
Convulsions
Cardiac arrhythmias
Coma
Multiple-dose activated
charcoal (carbamazepine)
Sodium
valproate
Coma
Metabolic acidosis
Haemodialysis for severe
poisoning
Isoniazid
Peripheral
neuropathy
Convulsions
Activated charcoal
IV pyridoxine
Theophylline
Cardiac arrhythmias
Convulsions
Coma
Multiple-dose activated
charcoal
Antimalarial drugs
Chloroquine
Acidosis and
hypokalaemia
Visual loss
Convulsions, coma
ECG changes and
arrhythmias
Correction of pH (but not
potassium)
Monitoring and treatment
of cardiac rhythm
High-dose diazepam with
mechanical ventilation
Quinine
Tremor, tinnitus,
deafness, ataxia,
convulsions, coma
Haemolysis
ECG changes and
arrhythmias
Retinal toxicity
Correction of pH (but not
potassium)
Monitoring and treatment
of cardiac rhythm
Multiple-dose activated
charcoal
No effective treatment
for visual loss
Arterial blood gases and plasma lactate should be taken
after metformin overdose; acidosis should be corrected with
intravenous sodium bicarbonate (250 ml_ 1 .26% solution or
50 ml_ 8.4% solution, repeated as necessary). In severe cases,
haemodialysis or haemodiafiltration is used.
Pharmaceutical agents less commonly
taken in poisoning
An overview of the clinical features and management for drugs
less commonly involved in poisoning is provided in Box 7.11.
Drugs of misuse
Drugs of misuse are common causes of toxicity requiring hospital
admission. Management has recently become more complex
because of the emergence of ‘novel psychoactive substances’
(NPS). These are often chemically related to traditional drugs
of misuse, but with structural modifications made to evade
legal control. The constituents of branded NPS products are
often unknown and knowledge about the clinical features and
management of NPS toxicity is limited.
Depressants
These produce CNS depression, including drowsiness, ataxia,
delirium and coma, sometimes with respiratory depression,
airway compromise, aspiration pneumonia and respiratory arrest
142 • POISONING
1 7.12 Stimulant, sedative and opioid feature clusters
Stimulant
Sedative hypnotic
Opioid
Common
causes
Amphetamines
MDMA (‘ecstasy’)
Ephedrine
Pseudoephedrine
Cocaine
Cannabis
Phencyclidine
Cathinones (e.g. mephedrone)
Benzylpiperazine
Benzodiazepines
Barbiturates
Ethanol
GHB
Heroin
Morphine
Methadone
Fentanyl and derivatives
Oxycodone
Dihydrocodeine
Codeine
Pethidine
Buprenorphine
Dextropropoxyphene
Tramadol
Clinical features
Respiratory
Tachypnoea
Reduced respiratory rate and ventilation1
Reduced respiratory rate and ventilation
Cardiovascular
Tachycardia, hypertension
Hypotension
Hypotension, relative bradycardia
Central nervous
system
Restlessness, anxiety, anorexia, insomnia
Hallucinations
Delirium, hallucinations, slurred speech
Sedation, coma1
Delirium, hallucinations, slurred speech
Sedation, coma2
Muscle
Tremor
Ataxia, reduced muscle tone
Ataxia, reduced muscle tone
Temperature
Fever
Hypothermia
Hypothermia
Eyes
Mydriasis
Diplopia, strabismus, nystagmus
Normal pupil size
Miosis
Abdomen
Abdominal pain, diarrhoea
-
Ileus
Mouth
Dry
-
-
Skin
Piloerection
Blisters, pressure sores
Needle tracks2
Complications
Seizures
Myocardial infarction
Dysrhythmias
Rhabdomyolysis
Renal failure
Intracerebral haemorrhage or infarction
Respiratory failure1
Aspiration
Respiratory failure2
Non-cardiogenic pulmonary oedema
Aspiration
1 Especially barbiturates. 2IV use.
(GHB = gamma hydroxybutyrate; MDMA = 3,4-methylene-dioxymethamphetamine)
(Box 7.12). Other complications of coma include pressure blisters
or sores and rhabdomyolysis. Effects are potentiated by other
CNS depressants, including alcohol.
Essential supportive care is detailed in Box 7.8. Antidotes are
available for some depressants.
Benzodiazepines
Benzodiazepines (e.g. diazepam) and related substances (e.g.
zopiclone) are of low toxicity when taken alone in overdose but
can enhance CNS and respiratory depression when taken with
other sedative agents, including alcohol. They are more hazardous
in the elderly and those with chronic lung or neuromuscular
disease (see Box 7.12).
The specific benzodiazepine antagonist flumazenil (0.5 mg IV,
repeated if needed) increases conscious level in patients with
benzodiazepine overdose, but carries a risk of seizures and is
contraindicated in patients co-ingesting pro-convulsants (e.g.
TCAs) and those with a history of epilepsy.
Opioids
Toxicity may result from misuse of illicit drugs such as heroin
or from intentional or accidental overdose of medicinal opiates.
Intravenous or smoked heroin gives a rapid, intensely pleasurable
experience, often accompanied by heightened sexual arousal.
Physical dependence occurs within a few weeks of regular
high-dose use. Withdrawal can start within 12 hours, causing
intense craving, rhinorrhoea, lacrimation, yawning, perspiration,
shivering, piloerection, vomiting, diarrhoea and abdominal cramps.
Examination reveals tachycardia, hypertension, mydriasis and
facial flushing.
Commonly encountered opioids and clinical features of
poisoning are shown in Box 7.12. Needle tracks may be visible
in intravenous users and there may be drug-related paraphernalia.
Methadone may also cause QTC prolongation and torsades de
pointes. Features of opioid poisoning can be prolonged for up
to 48 hours after use of long-acting agents such as methadone
or oxycodone.
Use of the specific opioid antagonist naloxone (0.4-2 mg IV
in an adult, repeated if necessary) may obviate the need for
intubation, although excessive doses may precipitate acute
withdrawal in chronic opiate users and breakthrough pain in those
receiving opioids for pain management. Repeated doses or an
infusion are often required because the half-life of the antidote
is short compared to that of most opiates, especially those
with prolonged elimination. Patients should be monitored for at
least 6 hours after the last naloxone dose. Rare complications
of naloxone therapy include fits, ventricular arrhythmias and
pulmonary oedema.
Drugs of misuse • 143
Gamma hydroxybutyrate
Gamma hydroxybutyrate (GHB), and the related compounds
gamma butyrolactone (GBL) and 1 ,4 butanediol are sedative
liquids with psychedelic and body-building effects.
As well as sedative hypnotic features (see Box 7.12), toxicity
may cause nausea, diarrhoea, vertigo, tremor, myoclonus,
extrapyramidal signs, euphoria, bradycardia, convulsions,
metabolic acidosis, hypokalaemia and hyperglycaemia. Coma
usually resolves abruptly within a few hours but occasionally
persists for several days. Dependence may develop in regular
users, who experience severe, prolonged withdrawal effects if
use is discontinued suddenly.
Management is largely supportive. All patients should be
observed for a minimum of 2 hours and until symptoms resolve,
with monitoring of blood pressure, heart rate, respiratory rate
and oxygenation. Withdrawal symptoms may require treatment
with very high doses of benzodiazepine.
Stimulants and entactogens
These are sympathomimetic and serotonergic amines that have
overlapping clinical features, depending on the balance of their
stimulant (see Box 7.12) and serotonergic (see Box 7.10) effects.
As well as traditional drugs such as cocaine, amphetamines
and ecstasy, the group includes many more recently emerging
novel psychoactive substances, including cathinones (e.g.
mephedrone), piperazines (e.g. benzylpiperazine), piperadines
(e.g. ethylphenidate), benzofurans (e.g. 5-aminopropylbenzofuran)
and NBOMe compounds (e.g. 251-NBOMe).
Cocaine
Cocaine is available as a water-soluble hydrochloride salt powder
suitable for nasal inhalation (‘snorting’), or as insoluble free-base
(‘crack’ cocaine) ‘rocks’ that, unlike the hydrochloride salt,
vaporise at high temperature and can be smoked, giving a more
rapid and intense effect.
Effects appear rapidly after inhalation and especially after
smoking. Sympathomimetic stimulant effects predominate (see
Box 7.12). Serious complications usually occur within 3 hours
of use and include coronary artery spasm, leading to myocardial
ischaemia or infarction, hypotension and ventricular arrhythmias.
Cocaine toxicity should be considered in younger adults presenting
with ischaemic chest pain. Hyperpyrexia, rhabdomyolysis, acute
renal failure and disseminated intravascular coagulation may occur.
A 12-lead ECG and ECG monitoring should be undertaken.
ST segment elevation may occur in the absence of myocardial
infarction and troponin T estimations are the most sensitive and
specific markers of myocardial damage. Benzodiazepines and
intravenous nitrates are useful for managing patients with chest
pain or hypertension. Acidosis should be corrected and physical
cooling measures used for hyperthermia. Beta-blockers may be
contraindicated because of the risk of unopposed a-adrenoceptor
stimulation, but this is debated. Coronary angiography should
be considered in patients with myocardial infarction or acute
coronary syndromes.
Amphetamines and cathinones
Amphetamine-related compounds include amphetamine sulphate
(‘speed’), methylamphetamine (‘crystal meth’) and 3,4-methylene¬
dioxymethamphetamine (MDMA, ‘ecstasy’). Synthetic cathinones
include mephedrone and methylenedioxypyrovalerone. Tolerance
is common, leading regular users to seek ever higher doses.
Toxic features usually appear within a few minutes of use and
last 4-6 hours, or substantially longer after a large overdose.
Sympathomimetic stimulant and serotonergic effects are common
(see Boxes 7.10 and 7.12). Some users develop hyponatraemia as
a result of excessive water-drinking or inappropriate vasopressin
(antidiuretic hormone, ADH) secretion. Muscle rigidity, pain and
bruxism (clenching of the jaw), hyperpyrexia, rhabdomyolysis,
metabolic acidosis, acute renal failure, disseminated intravascular
coagulation, hepatocellular necrosis, acute respiratory distress
syndrome (ARDS) and cardiovascular collapse have all been
described following MDMA use. Cerebral infarction and
haemorrhage have been reported, especially after intravenous
amphetamine use.
Management is supportive and directed at complications
(see Box 7.8).
Hallucinogens
I Cannabis
Derived from the dried leaves and flowers of Cannabis sativa,
cannabis produces euphoria, perceptual alterations and
conjunctival injection, followed by enhanced appetite, relaxation
and occasionally hypertension, tachycardia, slurred speech and
ataxia. Effects occur 10-30 minutes after smoking or 1-3 hours
after ingestion, and last 4-8 hours. High doses may produce
anxiety, delirium, hallucinations and psychosis. Psychological
dependence is common, but tolerance and withdrawal symptoms
are unusual. Long-term use is thought to increase the lifetime risk
of psychosis. Serious acute toxicity is uncommon and supportive
treatment is all that is required.
Synthetic cannabinoid receptor agonists
Large numbers of synthetic cannabinoid receptor agonists
(SCRAs), synthetic compounds sometimes referred to collectively
as ‘spice’, are now used as legal alternatives to cannabis; examples
include PB-22, 5F-PB-22, 5F-AKB-48, STS-135, SF-ADB and
MDMB-CHMICA. They are usually sprayed on to a herbal smoking
mix and packaged as smoking products with appealing brand
names. These may contain more than one SCRA and content
may change with time.
The toxic effects of SCRAs differ from those of cannabis,
being generally more marked and including agitation, panic,
delirium, hallucinations, tachycardia, ECG changes, hypertonia,
dyspnoea and vomiting. Coma, respiratory acidosis, seizures,
hypokalaemia and renal dysfunction are also reported. Treatment
of intoxication is supportive.
|jYyptamines
These are predominantly 5-hydroxytryptamine (5-HT, serotonin;
especially 5-HT2a) agonists with associated stimulant effects.
Typical clinical features include hallucinations, agitation, delirium,
hypertension, tachycardia, sweating, anxiety and headache.
Serotonin syndrome may occur (see Box 7.10), especially if
tryptamines are used in combination with other serotonergic
agents. Naturally occurring examples are psilocin and psilocybin,
found in ‘magic mushrooms’, and dimethyltryptamine (DMT)
in traditional ayahuasca brews. Synthetic tryptamines, such
as alpha-methyltryptamine (AMT), have been encountered
recently.
144 • POISONING
tf-Lysergic acid diethylamide
d- Lysergic acid diethylamide (LSD) is a synthetic ergoline usually
ingested as small squares of impregnated absorbent paper
(often printed with a distinctive design) or as ‘microdots’. The
drug causes perceptual effects, such as heightened visual
awareness of colours or distortion of images. Hallucinations may
be pleasurable or terrifying (‘bad trip’). Other features are delirium,
agitation, aggression, dilated pupils, hypertension, pyrexia and
metabolic acidosis. Psychosis may sometimes last several days.
Patients with psychotic reactions or CNS depression should
be observed in hospital, preferably in a quiet, dimly lit room to
minimise external stimulation. A benzodiazepine that can be
used for sedation is required, avoiding antipsychotics if possible,
as they may precipitate cardiovascular collapse or convulsions.
Dissociative drugs
Ketamine, its A/-ethyl derivative methoxetamine and phencyclidine
(now rarely encountered) produce a sense of dissociation from
reality, often associated with visual and auditory distortions.
Memory loss, impaired consciousness, agitation, hallucinations,
tremors and numbness may also occur. Long-term ketamine (and
probably methoxetamine) use can cause severe chronic cystitis
with dysuria, frequency, urgency, haematuria and incontinence.
Treatment of intoxication is supportive.
Volatile substances
Inhalation of volatile nitrites (e.g. amyl nitrite, isobutyl nitrite), often
sold in bottles or vials as ‘poppers’, is reported to produce a
feeling of pleasure and warmth, relax the anal sphincter and
prolong orgasm. These potent vasodilators commonly provoke
headache, dizziness, hypotension and tachycardia. They also
oxidise haemoglobin to produce methaemoglobinaemia, with
resulting breathlessness and delirium. Severe cases are treated
with methylthioninium chloride (‘methylene blue’, see Fig 7.1).
Several volatile solvents found in household products, such
as propane, butane, toluene and trichloroethylene, have a mild
euphoriant effect if inhaled. Serious toxic effects can occur,
including reduced level of consciousness, seizures and cardiac
arrhythmias; there is also a risk of asphyxia from some methods
of inhalation.
Nitrous oxide is an anaesthetic gas, but small canisters of it
are sold for the domestic production of whipped cream and the
contents of these can be transferred to balloons for inhalation.
The gas has euphoriant effects (‘laughing gas’), but hazards
include asphyxia from inhalation without oxygen, or vitamin B12
inactivation from chronic use leading to megaloblastic anaemia,
psychosis and other neurological sequelae.
Body packers and body stuffers
Body packers (‘mules’) attempt to smuggle illicit drugs (usually
cocaine, heroin or amphetamines) by ingesting multiple small
packages wrapped in several layers of clingfilm or in condoms.
Body stuffers are those who have ingested unpackaged or poorly
wrapped substances, often to avoid arrest. Both groups are at
risk of severe toxicity if the packages rupture. This is more likely
for body stuffers, who may develop symptoms of poisoning
within 8 hours of ingestion. The risk of poisoning depends on
the quality of the wrapping, and the amount and type of drug
Fig. 7.4 Abdominal X-ray of a body packer showing multiple
drug-filled condoms.
ingested. Cocaine, for example, presents a much higher risk than
heroin because of its high toxicity and lack of a specific antidote.
Patients suspected of body packing or stuffing should be
admitted for observation. A careful history taken in private is
important, but for obvious reasons patients may withhold details
of the drugs involved. The mouth, rectum and vagina should
be examined as possible sites for concealed drugs. A urine
toxicology screen performed at intervals may provide evidence
of leakage, although positive results may reflect earlier drug
use. Packages may be visible on plain abdominal films (Fig.
7.4) but ultrasound and computed tomography (CT) are more
sensitive. One of these (preferably CT) should be performed in
all suspected body packers.
Antimotility agents are often used by body packers to prevent
premature passage of packages; it can take several days for
packages to pass spontaneously, during which the carrier is at
risk from package rupture. Whole bowel irrigation is commonly
used to accelerate passage and is continued until all packages
have passed. Surgery may be required when there is mechanical
bowel obstruction or when evolving clinical features suggest
package rupture, especially with cocaine.
Chemicals and pesticides
Carbon monoxide
Carbon monoxide (CO) is a colourless, odourless gas produced
by faulty appliances burning organic fuels. It is also present in
vehicle exhaust fumes and sometimes in smoke from house fires.
It binds with haemoglobin and cytochrome oxidase, reducing
tissue oxygen delivery and inhibiting cellular respiration. CO is
a common cause of death by poisoning and most patients die
before reaching hospital.
Clinical features
Early features include headache, nausea, irritability, weakness
and tachypnoea. The cause of these non-specific features
may not be obvious if the exposure is occult, such as from a
Chemicals and pesticides • 145
faulty domestic appliance. Subsequently, ataxia, nystagmus,
drowsiness and hyper-reflexia may develop, progressing
to coma, convulsions, hypotension, respiratory depression,
cardiovascular collapse and death. Myocardial ischaemia may
result in arrhythmias or myocardial infarction. Cerebral oedema
is common and rhabdomyolysis may cause myoglobinuria and
renal failure. In those who recover from acute toxicity, longer-term
neuropsychiatric effects are common, such as personality change,
memory loss and concentration impairment. Extrapyramidal
effects, urinary or faecal incontinence, and gait disturbance may
also occur. Poisoning during pregnancy may cause fetal hypoxia
and intrauterine death.
Management
Patients should be removed from exposure as soon as possible
and resuscitated as necessary. A high concentration of oxygen
should be administered via a tightly fitting facemask; this reduces
the half-life of carboxyhaemoglobin from 4-6 hours to about
40 minutes. Measurement of carboxyhaemoglobin is useful for
confirming exposure; levels >20% suggest significant exposure
but do not correlate well with the severity of poisoning, partly
because concentrations fall rapidly after removal of the patient
from exposure, especially if supplemental oxygen has been given.
An ECG should be performed in all patients with acute CO
poisoning, especially those with pre-existing heart disease.
Arterial blood gas analysis should be checked in those with
serious poisoning. Pulse oximetry may provide misleading oxygen
saturations because carboxyhaemoglobin and oxyhaemoglobin
are both measured. Excessive intravenous fluid administration
should be avoided, particularly in the elderly, because of the
risk of pulmonary and cerebral oedema. Convulsions should
be controlled with diazepam.
Hyperbaric oxygen therapy is controversial. At 2.5 atmospheres,
this reduces the half-life of carboxyhaemoglobin to about
20 minutes and increases the amount of oxygen dissolved in
plasma 10-fold, but systematic reviews have not consistently
shown improved clinical outcomes. The logistical difficulties of
transporting sick patients to hyperbaric chambers and managing
them therein are substantial.
Organophosphorus insecticides and
nerve agents
Organophosphorus (OP) compounds (Box 7.13) are widely used
as pesticides, especially in developing countries. Case fatality
following deliberate ingestion is high (5-20%).
Nerve agents, developed for chemical warfare, are derived
from OP insecticides and are much more toxic. They are
commonly classified as G (originally synthesised in Germany)
or V (‘venomous’) agents. The ‘G’ agents, such as tabun, sarin
and soman, are volatile, absorbed by inhalation or via the skin,
and dissipate rapidly after use. ‘V’ agents, such as VX, are
contact poisons unless aerosolised, and contaminate ground
for weeks or months.
The toxicology and management of nerve agent and pesticide
poisoning are similar.
|jVlechanism of toxicity
OP compounds inactivate acetylcholinesterase (AChE), resulting
in the accumulation of acetylcholine (ACh) in cholinergic synapses
(Fig. 7.5). Initially, spontaneous hydrolysis of the OP-enzyme
1 7.13 Organophosphorus compounds
Nerve agents
• G agents: sarin, tabun, soman
• V agents: VX,VE
Insecticides
Dimethyl compounds
Diethyl compounds
• Dichlorvos
• Chlorpyrifos
• Fenthion
• Diazinon
• Malathion
• Parathion-ethyl
• Methamidophos
• Quinalphos
AChE-OH + X-P-OR
Acetylcholinesterase
enzyme
QP Organophosphate
AChE-O-X-P-OR, En^,bf aK
ORo
O
II
AChE-0-P-0R1 +:XH-
y K's,
Am
Elimination of
‘leaving group’
O
AChE-OH + HO-P-OR
I
Spontaneous OR2
reactivation
AChE-O-P-OR
I
O*
‘Ageing’: reactivation
not possible
OXIME = N-OH
Reactivation with oxime
O
AChE-OH + OXIME = N-P-OR
I
ORo
Fig. 7.5 Mechanism of toxicity of organophosphorus compounds and
treatment with oxime.
complex allows reactivation of the enzyme but, subsequently,
loss of a chemical group from the OP-enzyme complex prevents
further enzyme reactivation. After this process (termed ‘ageing’)
has taken place, new enzyme needs to be synthesised before
function can be restored. The rate of ‘ageing’ is an important
determinant of toxicity and is more rapid with dimethyl (3.7 hrs)
than diethyl (31 hrs) compounds (Box 7.13) and especially rapid
after exposure to nerve agents (soman in particular), which cause
‘ageing’ within minutes.
Clinical features and management
OP poisoning causes an acute cholinergic phase, which may
occasionally be followed by the intermediate syndrome or
organophosphate-induced delayed polyneuropathy (OPIDN).
The onset, severity and duration of poisoning depend on the
route of exposure and agent involved.
146 • POISONING
1 7.14 Cholinergic features in poisoning
Muscarinic
Nicotinic
Respiratory
Bronchorrhoea,
bronchoconstriction
Reduced ventilation
Circulation
Bradycardia, hypotension
Tachycardia,
hypertension
Higher mental
function
Anxiety, delirium, psychosis
Muscle
-
Fasciculation,
paralysis
Temperature
Fever
-
Eyes
Diplopia, miosis, lacrimation
Mydriasis
Abdomen
Vomiting, profuse diarrhoea
-
Mouth
Salivation
-
Skin
Sweating
-
Complications
Coma, seizures, respiratory depression
*Both muscarinic and nicotinic features occur in OP poisoning. Nicotinic features
occur in nicotine poisoning and black widow spider bites. Cholinergic features
are sometimes seen with some mushrooms.
Acute cholinergic syndrome
This usually starts within a few minutes of exposure and
nicotinic or muscarinic features may be present (Box 7.14).
Vomiting and profuse diarrhoea are typical following ingestion.
Bronchoconstriction, bronchorrhoea and salivation may cause
severe respiratory compromise. Excess sweating and miosis are
characteristic and the presence of muscular fasciculations strongly
suggests the diagnosis, although this feature is often absent,
even in serious poisoning. Subsequently, generalised flaccid
paralysis may develop and affect respiratory and ocular muscles,
resulting in respiratory failure. Ataxia, coma, convulsions, cardiac
repolarisation abnormalities and torsades de pointes may occur.
Management
The airway should be cleared of excessive secretions, breathing
and circulation assessed, high-flow oxygen administered and
intravenous access obtained. Appropriate external decontamination
is needed (p. 133). Gastric lavage or activated charcoal may be
considered if the patient presents sufficiently early. Seizures
should be treated as described in Box 7.8. The ECG, oxygen
saturation, blood gases, temperature, urea and electrolytes,
amylase and glucose should be monitored closely.
Early use of sufficient doses of atropine is potentially life-saving
in patients with severe toxicity. Atropine reverses ACh-induced
bronchospasm, bronchorrhoea, bradycardia and hypotension.
When the diagnosis is uncertain, a marked increase in heart
rate associated with skin flushing after a 1 mg intravenous dose
makes OP poisoning unlikely. In OP poisoning, atropine (2 mg IV)
should be administered and this dose should be doubled every
5-10 minutes until clinical improvement occurs. Further bolus
doses should be given until secretions are controlled, the skin
is dry, blood pressure is adequate and heart rate is >80 bpm.
Large doses may be needed, but excessive doses may cause
anticholinergic effects (see Box 7.10).
In severe poisoning requiring atropine, an oxime such as
pralidoxime chloride or obidoxime is generally recommended,
if available, although efficacy is debated. This may reverse or
prevent muscle weakness, convulsions or coma, especially if
given rapidly after exposure. Oximes reactivate AChE that has not
undergone ‘ageing’ and are therefore less effective with dimethyl
compounds and nerve agents, especially soman. Oximes may
provoke hypotension, especially if administered rapidly.
Intravenous magnesium sulphate has been reported to increase
survival in animals and in small human studies of OP poisoning;
however, further clinical trial evidence is needed before this can
be recommended routinely.
Ventilatory support should be instituted before the patient
develops respiratory failure. Benzodiazepines may be used
to treat agitation, fasciculations and seizures and for sedation
during mechanical ventilation.
Exposure is confirmed by measurement of plasma or red
blood cell cholinesterase activity but antidote use should not
be delayed pending results. Plasma cholinesterase is reduced
more rapidly but is less specific than red cell cholinesterase.
Values correlate poorly with the severity of clinical features but
are usually <10% in severe poisoning, 20-50% in moderate
poisoning and >50% in subclinical poisoning.
The acute cholinergic phase usually lasts 48-72 hours, with
most patients requiring intensive cardiorespiratory support and
monitoring. Cholinergic features may be prolonged over several
weeks with some lipid-soluble agents.
Intermediate syndrome
About 20% of patients with OP poisoning develop weakness that
spreads rapidly from the ocular muscles to those of the head and
neck, proximal limbs and the muscles of respiration, resulting
in ventilatory failure. This ‘intermediate syndrome’ generally
develops 1-4 days after exposure, often after resolution of the
acute cholinergic syndrome, and may last 2-3 weeks. There is
no specific treatment and supportive care is needed, including
maintenance of airway and ventilation.
Organophosphate-induced delayed polyneuropathy
Organophosphate-induced delayed polyneuropathy (OPIDN) is
a rare complication that usually occurs 2-3 weeks after acute
exposure. It is a mixed sensory/motor polyneuropathy, affecting
long myelinated neurons especially, and appears to result from
inhibition of enzymes other than AChE. It is a feature of poisoning
with some OPs such as triorthocresyl phosphate but is less
common with nerve agents. Early clinical features are muscle
cramps followed by numbness and paraesthesiae, proceeding to
flaccid paralysis of the lower and subsequently the upper limbs,
with foot and wrist drop and a high-stepping gait, progressing
to paraplegia. Sensory loss may also be present but is variable.
Initially, tendon reflexes are reduced or lost but mild spasticity
may develop later.
There is no specific therapy for OPIDN. Regular physiotherapy
may limit deformity caused by muscle-wasting. Recovery is
often incomplete and may be limited to the hands and feet,
although substantial functional recovery after 1-2 years may
occur, especially in younger patients.
Carbamate insecticides
Carbamate insecticides such as bendiocarb, carbofuran, carbaryl
and methomyl inhibit a number of tissue esterases, including
AChE. The mechanism, clinical features and management
of toxicity are similar to those of OP compounds. However,
clinical features are usually less severe and of shorter duration,
because the carbamate-AChE complex dissociates quickly, with
a half-life of 30-40 minutes, and does not undergo ageing. Also,
carbamates penetrate the CNS poorly. Intermediate syndrome
Chemicals and pesticides • 147
and OPIDN are not common features of carbamate poisoning.
In spite of this, case fatality can be high for some carbamates,
depending on their formulation.
Atropine may be given intravenously as for OP poisoning
(p. 146). Diazepam may be used to relieve anxiety. The use of
oximes is unnecessary.
Paraquat
Paraquat is a herbicide that is widely used across the world,
although it has been banned in the European Union and some
other countries for several years. It is highly toxic if ingested,
with clinical features including oral burns, vomiting and diarrhoea,
progressing to pneumonitis, pulmonary fibrosis and multi-organ
failure.
Exposure can be confirmed by a urinary dithionite test, while
the plasma paraquat concentration indicates prognosis. There
is no specific antidote but activated charcoal is commonly
administered. Immunosuppression with glucocorticoids and
cyclophosphamide is sometimes used but evidence for benefit is
weak. Irrespective of treatment, death is common and may occur
within 24 hours with substantial poisoning or after 1-2 weeks with
lower doses.
Methanol and ethylene glycol
Ethylene glycol (1 ,2-ethanediol) is found in antifreeze, brake fluids
and, in lower concentrations, windscreen washes. Methanol is
present in some antifreeze products and commercially available
industrial solvents, and in low concentrations in some screen
washes and methylated spirits. It may also be an adulterant of
illicitly produced alcohol. Both are rapidly absorbed after ingestion.
Methanol and ethylene glycol are not of high intrinsic toxicity but
are converted via alcohol dehydrogenase to toxic metabolites
that are largely responsible for their clinical effects (Fig. 7.6).
Clinical features
Early features of poisoning with either methanol or ethylene glycol
include vomiting, ataxia, drowsiness, dysarthria and nystagmus.
As toxic metabolites are formed, metabolic acidosis, tachypnoea,
coma and seizures may develop.
Toxic effects of ethylene glycol include ophthalmoplegia,
cranial nerve palsies, hyporeflexia and myoclonus. Renal pain
and acute tubular necrosis occur because of renal calcium
oxalate precipitation. Hypocalcaemia, hypomagnesaemia and
hyperkalaemia are common.
Methanol poisoning causes headache, delirium and vertigo.
Visual impairment and photophobia develop, associated with optic
disc and retinal oedema and impaired pupil reflexes. Blindness
may be permanent, although some recovery may occur over
several months. Pancreatitis and abnormal liver function have
also been reported.
Management
Urea and electrolytes, chloride, bicarbonate, glucose, calcium,
magnesium, albumin, plasma osmolarity and arterial blood gases
should be measured in all patients with suspected methanol or
ethylene glycol toxicity. The osmolar and anion gaps should be
calculated (see Box 7.5). Initially, poisoning is associated with an
increased osmolar gap, but as toxic metabolites are produced,
an increased anion gap develops, associated with metabolic
acidosis. The diagnosis can be confirmed by measurement of
ethylene glycol or methanol concentrations but assays are not
widely available.
An antidote, ideally fomepizole but otherwise ethanol, should be
administered to all patients with suspected significant exposure
while awaiting the results of laboratory investigations. These
block alcohol dehydrogenase and delay the formation of toxic
metabolites until the parent drug is eliminated in the urine or by
dialysis. The antidote should be continued until ethylene glycol
or methanol concentrations are undetectable. Metabolic acidosis
should be corrected with sodium bicarbonate (e.g. 250 mL of
1 .26% solution, repeated as necessary). Convulsions should be
treated with an intravenous benzodiazepine. In ethylene glycol
poisoning, hypocalcaemia should be corrected only if there are
severe ECG features or if seizures occur, as this may increase
calcium oxalate crystal formation. In methanol poisoning, folinic
acid should be administered to enhance the metabolism of the
toxic metabolite, formic acid.
Haemodialysis or haemodiafiltration should be used in severe
poisoning, especially if renal failure is present or there is visual
loss in the context of methanol poisoning. It should be continued
until acute toxic features are no longer present and ethylene
glycol/methanol concentrations are undetectable.
Corrosive substances
Ethylene
glycol
Ethanol or
fomepizole
I'
Methanol
Inhibits
Alcohol
dehydrogenase
Glycoaldehyde
r
Glycolic acid
Glyoxylic acid
Oxalic acid
Formaldehyde
Formic acid
TOXIC METABOLITES
Fig. 7.6 Metabolism of methanol and ethylene glycol.
Products containing strong acids (e.g. hydrochloric or sulphuric
acid) or alkalis (e.g. sodium hydroxide, calcium carbonate)
may be ingested, accidentally or intentionally, causing
gastrointestinal pain, ulceration and necrosis, with risk of
perforation.
External decontamination (p. 133), if needed, should be
performed after initial resuscitation. Gastric lavage should not be
attempted and neutralising chemicals should not be administered
after large ingestions because of the risk of tissue damage
from heat release. Cardiorespiratory monitoring is necessary
and full blood count, renal function, coagulation and acid-base
status should be assessed. An erect chest X-ray should be
performed if perforation is suspected and may show features
of mediastinitis or gas under the diaphragm. Strong analgesics
should be administered for pain.
Severe abdominal or chest pain, abdominal distension, shock
or acidosis may indicate perforation and should prompt an
urgent CT scan of chest and abdomen and surgical review.
In the absence of perforation, drooling, dysphagia, stridor or
oropharyngeal burns suggest possible severe oesophageal
148 • POISONING
damage and early endoscopy by an experienced operator should
be considered. Delayed endoscopy (e.g. after several days) may
carry a higher risk of perforation.
Aluminium and zinc phosphide
These rodenticides and fumigants are a common means of
self-poisoning in northern India. The mortality rate for aluminium
phosphide ingestion has been estimated at 60%; zinc phosphide
ingestion appears less toxic, at about 2%. When ingested,
both compounds react with gastric acid to form phosphine, a
potent pulmonary and gastrointestinal toxicant. Clinical features
include severe gastrointestinal disturbances, chest tightness,
cough and breathlessness progressing to ARDS and respiratory
failure, tremor, paraesthesiae, convulsions, coma, tachycardia,
metabolic acidosis, electrolyte disturbances, hypoglycaemia,
myocarditis, liver and renal failure, and leucopenia. Ingestion of
a few tablets can be fatal.
Treatment is supportive and directed at correcting electrolyte
abnormalities and treating complications; there is no specific
antidote. Early gastric lavage is sometimes used, often with
vegetable oil to reduce the release of toxic phosphine, but the
benefit is uncertain.
Copper sulphate
This is used as a fungicide. If it is ingested, clinical features of
toxicity include nausea, vomiting, abdominal pain, diarrhoea,
discoloured (blue/green) secretions, corrosive effects on the
gastrointestinal tract, renal or liver failure, methaemoglobinaemia,
haemolysis, rhabdomyolysis, convulsions and coma. Treatment
is as for other corrosive substances (see above) and should
address complications, including use of methylthioninium chloride
for methaemoglobinaemia (see Fig. 7.1). Chelation therapy is
unlikely to be beneficial after acute exposure.
Chemicals less commonly taken
in poisoning
An overview of the clinical features and management for chemicals
less commonly involved in poisoning is provided in Box 7.15.
7.15 Clinical features and specific management of chemicals less commonly involved in poisoning
Substance
Clinical features
Management
Lead
e.g. Chronic occupational
exposure, leaded paint, water
contaminated by lead pipes,
use of kohl cosmetics
Abdominal pain
Microcytic anaemia with basophilic stippling
Headache and encephalopathy
Motor neuropathy
Nephrotoxicity
Hypertension
Hypocalcaemia
Prevention of further exposure
Measurement of blood lead concentration, full blood count
and blood film, urea and electrolytes, liver function tests
and calcium
Abdominal X-ray in children to detect pica
Bone X-ray for ‘lead lines’
Chelation therapy with DMSA or sodium calcium edetate
Petroleum distillates
e.g. White spirit, kerosene
Vomiting
Aspiration pneumonitis
Gastric lavage contraindicated
Activated charcoal ineffective
Oxygen and nebulised bronchodilators
Chest X-ray to assess pulmonary effects
Organochlorines
e.g. DDT, lindane, dieldrin,
endosulfan
Nausea, vomiting
Agitation
Fasciculation
Paraesthesiae (face, extremities)
Convulsions
Coma
Respiratory depression
Cardiac arrhythmias
Hyperthermia
Rhabdomyolysis
Pulmonary oedema
Disseminated intravascular coagulation
Activated charcoal (with nasogastric aspiration for liquid
preparations) within 1 hr of ingestion
Cardiac monitoring
Pyrethroid insecticides
e.g. Cypermethrin, permethrin,
imiprothrin
Skin contact: dermatitis, skin paraesthesiae
Eye contact: lacrimation, photophobia and oedema
of the eyelids
Inhalation: dyspnoea, nausea, headaches
Ingestion: epigastric pain, nausea, vomiting,
headache, coma, convulsions, pulmonary oedema
Symptomatic and supportive care
Washing contaminated skin makes irritation worse
Anticoagulant rodenticides
e.g. Brodifacoum, bromadialone
and warfarin
Abnormal bleeding (prolonged)
Monitor INR/prothrombin time
Vitamin ^ by slow IV injection if there is coagulopathy
Fresh frozen plasma or specific clotting factors for bleeding
(DMSA = dimercaptosuccinic acid)
Food-related poisoning • 149
1 7.16 Chemical warfare agents
Examples
Clinical effects
Antidotes
Nerve agents
Tabun
Sarin
Soman
VX
See page 145 and
Box 7.13
Atropine
Oximes
(p. 145)
Blistering agents
Nitrogen/sulphur
Mustard
Lewisite
Eyes: watering,
blepharospasm, corneal
ulceration
Skin: erythema, blistering
Respiratory: cough,
hoarseness, dyspnoea,
pneumonitis
None
Choking agents
Chlorine
Phosgene
Eyes: watering,
blepharospasm, corneal
ulceration
Respiratory: cough,
hoarseness, dyspnoea,
pneumonitis
None
Blood agents
Cyanide
Cardiovascular: dizziness,
shock
Respiratory: dyspnoea,
cyanosis
CNS: anxiety, headache,
delirium, convulsions,
coma, fixed dilated pupils
Other: vomiting, lactic
acidosis
Dicobalt edetate
Hydroxocobalamin
*Appropriate resuscitation, decontamination and supportive care are essential
after exposure to all chemical warfare agents. Use appropriate personal
protective equipment.
Chemical warfare agents
Some toxins have been developed for use as chemical warfare
agents. These are summarised in Box 7.16.
Environmental poisoning
Arsenism
Chronic arsenic exposure from drinking water has been reported
in many countries, especially India, Bangladesh, Nepal, Thailand,
Taiwan, China, Mexico and South America, where a large
proportion of the drinking water (ground water) has a high
arsenic content, placing large populations at risk. The World
Health Organisation (WHO) guideline value for arsenic content
in tube well water is 1 0 jig/L.
Health effects associated with chronic exposure to arsenic in
drinking water are shown in Box 7.17. In exposed individuals,
high concentrations of arsenic are present in bone, hair and
nails. Specific treatments are of no benefit in chronic arsenic
toxicity and recovery from the peripheral neuropathy may never
be complete, so the emphasis should be on prevention.
Fluorosis
Fluoride poisoning can result from exposure to excessive
quantities of fluoride (> 1 0 ppm) in drinking water, industrial
i
Gastrointestinal tract
• Anorexia, vomiting, weight loss, diarrhoea, increased salivation,
metallic taste
Neurological
• Peripheral neuropathy (sensory and motor) with muscle wasting and
fasciculation, ataxia
Skin
• Hyperpigmentation, palmar and plantar keratosis, alopecia, multiple
epitheliomas, Mee’s lines (transverse white lines on fingernails)
Eyes
• Conjunctivitis, corneal necrosis and ulceration
Bone marrow
• Aplastic anaemia
Other
• Low-grade fever, vasospasm and gangrene, jaundice,
hepatomegaly, splenomegaly
Increased risk of malignancy
• Lung, liver, bladder, kidney, larynx and lymphoid system
exposure to fluoride dust or consumption of brick teas. Clinical
features include yellow staining and pitting of permanent teeth,
osteosclerosis, soft tissue calcification, deformities (e.g. kyphosis)
and joint ankylosis. Changes in the bones of the thoracic cage
may lead to rigidity that causes dyspnoea on exertion. Very high
doses of fluoride may cause abdominal pain, nausea, vomiting,
seizures and muscle spasm. In calcium-deficient children,
the toxic effects of fluoride manifest even at marginally high
exposures to fluoride.
In endemic areas, such as Jordan, Turkey, Chile, India,
Bangladesh, China and Tibet, fluorosis is a major public health
problem, especially in communities engaged in physically
strenuous agricultural or industrial activities. Dental fluorosis is
endemic in East Africa and some West African countries.
Food-related poisoning
Paralytic shellfish poisoning
Paralytic shellfish poisoning is caused by consumption of bivalve
molluscs (e.g. mussels, clams, oysters, cockles and scallops)
contaminated with saxitoxins, which are concentrated in the
shellfish as a result of constant filtration of toxic algae during algal
blooms (e.g. ‘red tide’). Symptoms develop within 10-120 minutes
of eating the contaminated shellfish and include gastrointestinal
disturbances, paraesthesia around the mouth or in the extremities,
ataxia, mental state changes and dysphagia. In severe cases,
paralysis and respiratory failure can develop. There is no specific
antidote and treatment is supportive. Most cases resolve over
a few days.
| Ciguatera poisoning
Ciguatera toxin and related toxins are produced by dinoflagellate
plankton that adhere to algae and seaweed. These accumulate
in the tropical herbivorous fish that feed on these and in their
larger predators (e.g. snapper, barracuda), especially in the
7.17 Clinical features of chronic arsenic poisoning
150 • POISONING
1 7.18 Some poisonous plants and fungi, with their clinical effects
Species (common name)
Toxins
Important features of toxicity
Plants
Abrus precatorius (jequirity bean)
Abrin
Gastrointestinal effects, drowsiness, delirium, convulsions, multi-organ
Ricinus communis (castor oil plant)
Ricin
failure
Aconitum napellus (aconite, wolf’s bane,
Aconite
Gastrointestinal effects, paraesthesiae, convulsions, ventricular
monkshood)
Aconitum ferox (Indian aconite, bikh)
tachycardia
Atropa belladonna (deadly nightshade)
Atropine, scopolamine,
Anticholinergic toxidrome (see Box 7.10)
Datura stramonium (Jimson weed, thorn apple)
Brugmansia spp. (angel’s trumpet)
hyocyamine
Colchicum autumnale (autumn crocus)
Colchicine
Gastrointestinal effects, hypotension, cardiogenic shock
Conium macu latum (hemlock)
Toxic nicotinic alkaloids
Hypersalivation, gastrointestinal effects, followed by muscular paralysis
Digitalis purpurea (foxglove)
Nerium oleander (pink oleander)
Thevetia peruviana (yellow oleander)
Cardiac glycosides
Cardiac glycoside toxicity (p. 140)
Laburnum anagyroides (laburnum)
Cytosine
Gastrointestinal effects; convulsions in severe cases
Taxus baccata (yew)
Taxane alkaloids
Hypotension, bradycardia, respiratory depression, convulsions, coma,
arrhythmias
Fungi
Amanita phalloides
(death cap mushroom)
Amatoxins
Gastrointestinal effects, progressing to liver failure
Cortinarius spp.
Orellanine
Gastrointestinal effects, fever, progressing to renal failure
Psilocybe semilanceata
(‘magic mushrooms’)
Psilocybin, psilocin
Hallucinations
Pacific and Caribbean. Human exposure occurs through eating
contaminated fish, even if well cooked. Nausea, vomiting,
diarrhoea and abdominal pain develop within a few hours,
followed by paraesthesia, ataxia, blurred vision, ataxia and
tremor. Convulsions and coma can occur, although death is
uncommon. Fatigue and peripheral neuropathy can be long-term
effects. There is no specific treatment. In the South Pacific and
Caribbean, there are approximately 50000 cases per year, with
a case fatality of 0.1 %.
Scombrotoxic fish poisoning
Under poor storage conditions, histidine in scombroid fish
(e.g. tuna, mackerel, bonito, skipjack and the canned dark
meat of sardines) may be converted by bacteria to histamine
and other chemicals. Within minutes of consumption, flushing,
burning, sweating, urticaria, pruritus, headache, colic, nausea
and vomiting, diarrhoea, bronchospasm and hypotension may
occur. Management is with nebulised salbutamol, intravenous
antihistamines and, occasionally, intravenous fluid replacement.
Plant poisoning
A substantial number of plants and fungi are potentially toxic
if consumed, with patterns of poisoning depending on their
geographical distribution. Some toxic examples and the clinical
features of toxicity are shown in Box 7.18.
Further information
Books and journal articles
Bateman DN, Jefferson R, Thomas SHL, et al. (eds). Oxford
desk reference: toxicology. Oxford: Oxford University Press;
2014.
Benson BE, Hoppu K, Troutman WG, et al. Position paper update:
gastric lavage for gastrointestinal decontamination. Clin Toxicol
2013; 51:140-146.
Chyka PA, Seger D, Krenzelok EP, et al. Position paper: single-dose
activated charcoal. Clin Toxicol 2005; 43:61-87.
Thompson JP, Watson ID, Thanacoody HK, et al. Guidelines for
laboratory analyses for poisoned patients in the United Kingdom.
Ann Clin Biochem 2014; 51:312-325.
Websites
curriculum.toxicology.wikispaces.net/ Free access to educational
material related to poisoning.
toxbase.org Toxbase, the clinical toxicology database of the UK
National Poisons Information Service. Free for UK health
professionals but registration is required. Access for overseas
users by special arrangement. Low-cost smartphone app
available.
toxnet.nlm.nih.gov US National Library of Medicine’s Toxnet: a
hazardous substances databank, including Toxline for references to
literature on drugs and other chemicals.
who.int/gho/phe/chemical_safety/poisons_centres/en/ World directory
of poisons centres held by the WHO, including interactive map and
contact details.
J White
Envenomation
Comprehensive evaluation of the envenomed patient 152
Envenomation by specific animals 160
Geographical distribution of venomous snakes 153
Venomous snakes 1 60
Bedside tests in the envenomed patient 153
Scorpions 1 61
Spiders 1 61
Overview of envenomation 154
Paralysis ticks 1 61
Venom 1 54
Venomous insects 1 61
Venomous animals 1 54
Marine venomous and poisonous animals 162
Clinical effects 155
General approach to the envenomed patient 156
First aid 1 56
Assessment and management in hospital 1 58
Treatment 159
Follow-up 160
152 • ENVENOMATION
Comprehensive evaluation of the envenomed patient
1 Airway, breathing, circulation
Blood pressure
Pulse
Respiration rate
Oxygen saturation
Dysrhythmias
2 Level of consciousness
Confusion
Agitation
Seizures
3 Mouth, gums
Evidence of bleeding
Increased salivation
Drooling
4 Cranial nerves
Drooling
Dysarthria
Dysphagia
Upper airway compromise
^Bilateral mild ptosis
A Ptosis and lateral
ophthalmoplegia
AFixed dilated pupils
5 Chest
Pulmonary oedema
Diminished respiration
0
12 Eyes
Miosis or mydriasis
Increased lacrimation
Corneal injury (venom spit injury)
AChemosis - can indicate
capillary leak syndrome
11 Skin
In addition to (6):
Piloerection
Erythema
Blistering
Infection
A Local increased sweating
10 Abdomen
Intra-abdominal, retroperitoneal
or renal pathology
9 Lymph nodes
Tender or enlarged nodes
draining bite/sting area
8 Muscles
Weakness
Tenderness
Pain
7 Reflexes
Decreased or absent reflexes
6 Bite/sting site
Pain
Swelling
Bruising
Discoloration
Necrosis
ALocal bleeding, blistering
■ fifet
*’ *1*
" Mm
ALocal bleeding
Copyright © Julian White.
Bedside tests in the envenomed patient • 153
Indian krait
Bungarus caeruleus
European adder
Vipera aspis
Russell’s viper
Daboia russelii
Green pit viper
Trimeresurus gramineus
Geographical distribution of venomous snakes
South American
rattlesnake
Crotalus durissus
Black-necked
spitting cobra
Naja nigricollis
Common Indian cobra
Naja naja
Monacled cobra
Naja kaouthia
The geographical location of a snakebite determines the likely animal(s) involved and the nature and risks of the envenomation. Copyright ©
Julian White.
Bedside tests in the envenomed patient
Examination of urine. Haematuria may indicate
a coagulopathy. Dark urine is suggestive of
myoglobinuria, which is a sign of extensive
rhabdomyolysis. Copyright © Julian White.
(CD
1 Obtain a clean glass container
(test tube or bottle) that is
either new, or has only been
washed with water (not
detergent/soap)
2 Place 2-3 mL venous blood
in the glass container
3 Allow to stand undisturbed
for 20 mins
4 Gently invert/tip the glass
container checking for
presence of a blood clot
4a Clot present = negative test
(no coagulopathy present)
4b Clot absent = positive test
(coagulopathy present)
Twenty-minute whole-blood clotting test (20WBCT). The presence of coagulopathy is a
key indicator of major envenoming for some species. While full laboratory coagulation studies
may be the ideal, the 20WBCT has emerged as a simple standardised bedside test of
coagulopathy, applicable even in areas with limited health facilities. Copyright © Julian White.
154 • ENVENOMATION
Overview of envenomation
Envenomation occurs when a venomous animal injects sufficient
venom by a bite or a sting into a prey item or perceived predator
to cause deleterious local and/or systemic effects. This is defined
as a venom-induced disease (VI D). Venomous animals generally
use their venom to acquire and, in some cases, pre-digest prey,
with defensive use a secondary function for many species.
Accidental encounters between venomous animals and humans
are frequent, particularly in the rural tropics, where millions of
cases of venomous bites and stings occur annually. Globally,
an increasing number of exotic venomous animals are kept
privately, so cases of envenoming may present to hospitals
where doctors have insufficient knowledge to manage potentially
complex presentations. Doctors everywhere should thus be
aware of the basic principles of management of envenomation
and how to seek expert support. It is important for doctors to
know what types of venomous animal are likely to occur in their
geographical area (hospital hinterland; p. 153) and the types of
envenoming they may cause.
Venom
Venom is a complex mixture of diverse components (notably
toxins), often with several separate toxins that can cause
adverse effects in humans, and each is potentially capable of
multiple effects (Box 8.1). Venom is produced at considerable
metabolic cost, so is used sparingly; thus only some bites/
stings by venomous animals result in significant envenoming,
the remainder being ‘dry bites’. The concept of dry bites is
important in understanding approaches to first aid and medical
management.
Venomous animals
There are many animal groups that contain venomous species
(Box 8.2). The epidemiological estimates reflect the importance of
snakes and scorpions as causes of severe or lethal envenomation,
but also the fragmentary nature of the data. For snakes, recent
studies have proposed widely varying estimates of epidemiological
impact, but even the higher estimates may be too low. A recent
8.2 Venomous animals and human envenoming
Phyla
Principal
venomous
animal groups
Estimated
number of
human
cases/year
Estimated
number of
human
deaths/year
Chordata
Snakes
>2.5 million
>100 000
Spiny fish
? >100 000
Close to zero
Stingrays
? >100 000
? <10
Arthropoda
Scorpions
>1 million
? <5000
Spiders
? >100 000
? <100
Paralysis ticks
? >1000
? <10
Insects
? >1 million
? >1000*
Mollusca
Cone snails
? <1000
? <10
Blue-ringed
? <100
? <10
octopus
Coelenterata
Jellyfish
? >1 million
? <10
*Social insect stings cause death by anaphylaxis rather than primary venom
toxicity, except for massive multiple sting attacks.
Copyright © Julian White.
i
8.1 Key venom effects
Venom component Clinical effects
Type of venomous animal
Neurotoxin
Paralytic Flaccid paralysis Some snakes
Paralysis ticks
Cone snails
Blue-ringed octopus
Excitatory Neuroexcitation: autonomic storm, cardiotoxicity, Some scorpions, spiders, jellyfish (irukandji)
pulmonary oedema
Myotoxins
Systemic or local myolysis
Some snakes
Cardiotoxins
Direct or indirect cardiotoxicity; cardiac collapse, shock
Some snakes, scorpions, spiders and jellyfish (box
jellyfish)
Haemostasis system
toxins
Variation from rapid coagulopathy and bleeding to
thrombosis, deep venous thrombosis and pulmonary
emboli
Many snakes and a few scorpions ( Hemiscorpius )
Brazilian caterpillars [Lonomia)
Haemorrhagic toxins
Local vessel damage, fluid extravasation, blistering,
ecchymosis, shock
Mainly some snakes
Nephrotoxins
Renal damage
Some snakes, massed bee and wasp stings
Necrotoxins
Local tissue injury/necrosis, shock
Some snakes, a few scorpions ( Hemiscorpius ), spiders
(recluse spiders), jellyfish and stingrays
Allergic toxins
Induction of acute allergic response (direct and
indirect)
Almost all venoms but particularly those of social insects
(i.e. bees, wasps, ants)
*AII venom components have lethal potential.
Copyright © Julian White.
Overview of envenomation • 155
comprehensive study in India indicated there are at least 45000
snakebite- related deaths in that country annually, far above both
government figures and previous estimates. In many areas of
the poor rural tropics, health resources are limited and few
envenoming cases are either seen or recorded within the official
hospital system, compared to the actual community burden of
disease. While fatal cases may gain most attention, long-term
disability from envenomation affects significantly more people
and has a major social and economic cost.
Stings by social insects such as bees and wasps may also
cause lethal anaphylaxis. Other venomous animals may commonly
envenom humans but cause mostly non-lethal effects. A few
animals only rarely envenom humans but have a high potential
for severe or lethal envenoming. These include box jellyfish,
cone snails, blue-ringed octopus, paralysis ticks and Australian
funnel web spiders. Within any given group, particularly snakes,
there may be a wide range of clinical presentations. Some are
described here but for a more detailed discussion of the types
of venomous animal, their venoms and their effects on humans,
see toxinology.com.
Clinical effects
With the exception of dry bites, where no significant toxin effects
occur, venomous bites/stings can result in three broad classes
of effect.
Local effects
These vary from trivial to severe (Box 8.3). There may be minimal
or no local effects with some snakebites (not even pain), yet lethal
systemic envenoming may still be present. For other species,
8.3 Local and systemic effects of envenomation
Local effects
• Pain
•
Blistering
• Sweating
•
Necrosis
• Erythema
•
Swelling
• Major direct tissue trauma
•
Bleeding and bruising
(e.g. stingray injuries)
Non-specific systemic effects
• Headache
•
Pulmonary oedema
• Nausea
•
Dizziness
• Vomiting and diarrhoea
•
Collapse
• Abdominal pain
•
Convulsions
• Tachycardia or bradycardia
•
Shock
• Hypertension or
•
Cardiac arrest
hypotension
Specific systemic effects
• Neurotoxic flaccid paralysis (descending or ascending)
• Excitatory neurotoxicity (catecholamine storm-like and similar)
• Rhabdomyolysis (systemic or local)
• Coagulopathy (procoagulant/fibrinolytic or anticoagulant or
thrombotic or antiplatelet)
• Cardiotoxicity (decreased/abnormal cardiac function or arrhythmia or
arrest)
• Acute kidney injury (polyuria or oliguria or anuria or isolated elevated
creatinine/urea)
Copyright © Julian White.
local effects predominate over systemic, and for some, such
as certain snakes, both are important (p. 152). Some species
commonly cause local necrosis, notably some snakes, brown
recluse spiders, an Iranian scorpion [I Hemiscorpius lepturus)
and some stingrays.
General systemic effects
By definition, these are non-specific (Box 8.3). Shock is an
important complication of major local envenoming by some
snake species and, if inadequately treated, can prove lethal,
especially in children.
Specific systemic effects
These are important in both diagnosis and treatment.
• Neurotoxic flaccid paralysis can develop very rapidly,
progressing from mild weakness to full respiratory paralysis
in less than 30 minutes (blue-ringed octopus bite, cone
snail sting), or may develop far more slowly, over hours
(some snakes) to days (paralysis tick). For neurotoxic
snakes, the cranial nerves are usually involved first, with
ptosis a common initial sign, often progressing to partial
and later complete ophthalmoplegia, fixed dilated pupils,
drooling and loss of upper airway protection (p. 152).
From this, paralysis may extend to the limbs, with
weakness and loss of deep tendon reflexes, the neck
(‘broken neck’ sign), then finally respiratory paralysis
affecting the diaphragm.
• Excitatory neurotoxins cause an ‘autonomic storm’, often
with profuse sweating (p. 152), variable cardiac effects and
cardiac failure, sometimes with pulmonary oedema
(notably, Australian funnel web spider bite, some
scorpions such as Indian red scorpion). This type of
envenomation can be rapidly fatal (many scorpions, funnel
web spiders), or may cause distressing symptoms but
constitute a lesser risk of death (widow spiders, banana
spiders).
• Myotoxicity can be localised in the bitten limb, or
systemic, affecting mostly skeletal muscles. It can
initially be silent, then present with generalised muscle
pain, tenderness, myoglobinuria (p. 153) and huge rises
in serum creatine kinase (CK). Secondary renal failure
can precipitate potentially lethal hyperkalaemic
cardiotoxicity.
• Cardiotoxicity is often secondary but symptoms and signs
are non-specific in most cases. For some scorpions,
envenomation can cause direct cardiac effects, including
decreased cardiac output, arrhythmias and pulmonary
oedema.
• Haemostasis system toxins cause a variety of effects,
depending on the type of toxin (Fig. 8.1). Coagulopathy
may present as bruising and bleeding from the bite site
(p. 152), gums and intravenous sites. Surgical interventions
are high-risk in such cases. Other venoms cause
thrombosis, usually presenting as deep venous thrombosis
(DVT), pulmonary embolus or stroke (particularly
Caribbean/Martinique vipers).
• Haemorrhagic toxins cause vascular damage, especially in
the bitten limb, with extravasation of fluid and sometimes
hypotensive shock; this is a problem associated with some
snakebites. The role of these toxins in causing late-
developing capillary leak syndrome (p. 152), again
156 • ENVENOMATION
“Clotting
factor pathways
Factor II
Factor lla
Fibrinogen
Fibrin
{T) Haemorrhagic metalloproteinases and disintegrins
Damage blood vessel wall, cause leakage of blood,
degrade platelet plug response
<2 Procoagulants
Activate specific coagulation factors to activate clotting
cascade and promote formation of fibrin clots. Can also
activate fibrinolytic system, resulting in defibrination and
reduced ability to form protective clots
<§) Direct fibrinolytics
Split fibrinogen, often abnormally, resulting in poor clot
formation and a bleeding tendency
<?) Other haemostasis system toxins
Target various parts of haemostasis, either as activators
(e.g. plasminogen activators), or as inhibitors of coagulation
(e.g. serpin inactivators, platelet aggregation inhibitors)
Fig. 8.1 Sites of action of venoms on the haemostasis system. Copyright © Julian White.
associated with some snakebites (notably Russell’s viper),
is uncertain.
• Renal damage in envenoming is mostly secondary,
although some species, such as Russell’s vipers, can
cause primary renal damage. The presentation is similar in
both cases, with changes in urine output (polyuria, oliguria
or anuria) or rises in creatinine and urea. In cases with
intravascular haemolysis, secondary renal damage is likely.
The clinical effects of specific animals in different regions
of the world are shown in Boxes 8. 4-8. 6.
General approach to
the envenomed patient
First aid
First aid can be crucial in determining the outcome for envenomed
patients, yet throughout much of the world inappropriate and
dangerous first aid is often administered.
8.4 Selected important venomous animals in Asia
Scientific name
Common name
Clinical effects
Antivenom/antidote/treatment
Indian subcontinent
Bungarus spp. (E)
Kraits
Flaccid paralysis2,3, myolysis4, hyponatraemia5
Indian PV or specific
Naja spp. (E)
Cobras
Flaccid paralysis3, local necrosis/blistering, shock
Indian PV or specific
Ophiophagus hannah (E)
King cobra
Flaccid paralysis3, local necrosis, shock
Indian PV or specific
Echis spp. (Vv)
Saw-scaled vipers
Procoagulant coagulopathy, local necrosis/blistering,
renal failure
Indian PV or specific
Daboia russelii (Vv)
Russell’s viper
Procoagulant coagulopathy, local necrosis/blistering,
myolysis, renal failure, shock, flaccid paralysis2
Indian PV or specific
Hypnale spp. (Vc)
Hump-nosed vipers
Procoagulant coagulopathy, shock, renal failure
Try Indian PV
Trimeresurus 6 spp. (Vc)
Green pit vipers
Procoagulant coagulopathy, local necrosis, shock
Indian PV or specific
Hottentotta spp. (Sc)
Indian scorpions
Neuroexcitation, cardiotoxicity
Indian specific AV
Prazosin
East Asia
Bungarus spp. (E)
Kraits
Flaccid paralysis2,3
Specific AV from country
Naja spp. (E)
Cobras (some spitters)
Flaccid paralysis3, local necrosis/blistering, shock
Specific AV from country
Ophiophagus hannah (E)
King cobra
Flaccid paralysis3, local necrosis, shock
King cobra AV
Calloselasma rhodostoma (Vc)
Malayan pit viper
Procoagulant coagulopathy, local necrosis/blistering,
renal failure, shock
Specific AV from country
Daboia siamensis (Vv)
Russell’s viper
Procoagulant coagulopathy, local necrosis/blistering,
renal failure, shock
Specific AV from country
Gloydius spp. (Vc)
Mamushis, pit vipers
Procoagulant coagulopathy, local necrosis/blistering,
shock, renal failure, flaccid paralysis2
Specific AV from country
Trimeresurus 6 spp. (Vc)
Green pit vipers, habus
Procoagulant coagulopathy, local necrosis/blistering,
shock
Specific AV from country
Tamily names: C = ‘Colubridae’ (mostly ‘non-venomous’; family subject to major taxonomic revisions); E = Elapidae (all venomous); Sc
= Scorpionoidea; Vc = Viperidae
Crotalinae (New World and Asian vipers); Vv = Viperidae viperinae (Old World vipers). 2Pre-synaptic. 3Post-synaptic. 40nly reported so far for B. candidus, B. niger and
B. caeruleus. 50nly reported so far for B. multicinctus and B. candidus.
6Genus is subject to major taxonomic change (split into at least eight genera).
(AV = antivenom; PV = polyvalent)
More information is available from WHO-SEARO Guidelines for the management of snake-bites and from toxinology.com.
Copyright © Julian White.
General approach to the envenomed patient • 157
8.5 Selected important venomous animals in the Americas and Australia
Scientific name
Common name
Clinical effects
Antivenom/antidote/treatment
North America
Crotalus spp. (Vc)
Rattlesnakes
Procoagulant coagulopathy, local necrosis/
blistering (flaccid paralysis2 rare), shock
CroFab A V or Bioclon Antivipmyn A V
Sistrurus spp. (Vc)
Massasaugas
Procoagulant coagulopathy, local necrosis/
blistering, shock
CroFab A V or Bioclon Antivipmyn A V
Agkistrodon spp. (Vc)
Copperheads and moccasins
Procoagulant coagulopathy, local necrosis/
blistering, shock
CroFab AV or Bioclon Antivipmyn A V
Micrurus spp. (E)
Coral snakes
Flaccid paralysis3
Bioclon Coralmyn AV
Latrodectus mactans
Widow spider
Neuroexcitation
MSD Widow spider AV
Centruroides
sculpturatus
Arizona bark scorpion
Neuroexcitation
Bioclon Anascorp AV
Central and South America
Crotalus spp. (Vc)
Rattlesnakes
Flaccid paralysis2, myolysis, procoagulant
coagulopathy, shock, renal failure
Specific AV from country
Bothrops spp. (Vc)
Lancehead vipers
Procoagulant coagulopathy, local necrosis/
blistering, shock, renal failure
Specific AV from country
Bothriechis spp. (Vc)
Eyelash pit vipers
Shock, pain and swelling
Specific AV from country
Lachesis spp. (Vc)
Bushmasters
Procoagulant coagulopathy, shock, renal
failure, local necrosis/blistering
Specific AV from country
Micrurus spp. (E)
Coral snakes
Flaccid paralysis2,3, myolysis, renal failure
Specific AV from country
Tityus serrulatus
Brazilian scorpion
Neuroexcitation, shock
Institute Butantan scorpion AV
Loxosceles spp.
Recluse spiders
Local necrosis
Institute Butantan spider AV
Phoneutria nigriventer
Banana spider
Neuroexcitation, shock
Institute Butantan spider AV
Potamotrygon,
Freshwater stingrays
Necrosis of bite area, shock, severe pain
No available AV; good wound care
Dasyatis spp.
and oedema
Australia
Pseudonaja spp. (E)
Brown snakes
Procoagulant coagulopathy, renal failure,
flaccid paralysis2 (rare)
CSL brown snake AV or PVAV
Notech is spp. (E)
Tiger snakes
Procoagulant coagulopathy, myolysis, flaccid
paralysis2,3, renal failure
CSL tiger snake AV or PVAV
Oxyuranus spp. (E)
Taipans
Procoagulant coagulopathy, flaccid
paralysis2,3, myolysis, renal failure
CSL taipan or PVAV
Acanthophis spp. (E)
Death adders
Flaccid paralysis3
CSL death adder or PVAV
Pseudechis spp.
Black and mulga snakes
Anticoagulant coagulopathy, myolysis, renal
failure
CSL black snake AV or PVAV
Enhydrina schistosa
Sea snakes (all species globally)
Flaccid paralysis and/or myolysis
CSL sea snake AV
At rax, Hadronyche spp.
Funnel web spiders
Neuroexcitation, shock
CSL funnel web spider AV
Latrodectus hasseltii
Red back spider
Neuroexcitation, pain and sweating
CSL red back spider AV
Chironex flecked
Box jellyfish
Neuroexcitation, cardiotoxicity, local necrosis
CSL box jellyfish AV
Synanceia spp.
Stonefish
Severe local pain
CSL stonefish AV
Tor family name, see Box 8.4. 2Pre-synaptic. 3Post-synaptic.
(PVAV = polyvalent antivenom)
Copyright © Julian White.
A significant proportion of venom is transported from the bite/
sting site via the lymphatic system, particularly for venoms with
larger molecular weight toxins, such as many snake venoms. It
is recommended that for most forms of envenoming, the patient
should be kept still, the bitten limb immobilised with a splint
and vital systems supported, where required. A patent upper
airway should be specifically ensured and respiratory support
provided, if required. For some animals, notably snakes in certain
regions, the use of a local pressure pad bandage over the bite
site (Myanmar) or a pressure immobilisation bandage (Australia,
New Guinea) is recommended.
Ineffective or dangerous first aid, such as suction devices,
‘cut and suck’, local chemicals, snake stones (stones of some
sort placed over the snakebite) and tourniquets, should not be
used. Tourniquets, in particular, have the potential to cause
catastrophic distal limb injuries in snakebite when applied too
narrowly or too tightly, or left on too long.
transporting patients
Where possible, transport should be brought to the patient. It
is also vital to obtain medical assessment and intervention at
the earliest opportunity, however, so any delay in transporting
the patient to a medical facility should be avoided. Severely
envenomed patients may develop life-threatening problems,
such as shock or respiratory failure, during transport, so ideally
the transport method used should allow for management of
these problems en route.
In resource-poor environments, simple solutions for
rapid transport have been successfully employed, such as
motorbikes or similar with the patient supported between the
driver in front and another person behind the patient. However,
this method cannot cope with a patient developing airway
compromise or respiratory failure, such as from developing
neurotoxicity.
158 • ENVENOMATION
i
8.6 Selected important venomous animals in Africa and Europe
Scientific name Common name Clinical effects
Antivenom/antidote/treatment
Africa
Naja spp. (E) Cobras
Non-spitters
Spitters
Dendroaspis spp. (E)
Mambas
Hemachatus
Rinkhals
haemachatus (E)
Athens spp. (Vv)
Bush vipers
Bids spp. (Vv)
Puff adders etc.
Causus spp. (Vv)
Night adders
Echis spp. (Vv)
Carpet vipers
Cerastes spp. (Vv)
Horned desert vipers
Dispholidus typus (C)
Boomslang
Androctonus spp.
North African
scorpions
Lelurus
Yellow scorpion
quinquestriatus
Flaccid paralysis3 ± local necrosis/blistering
Local necrosis/blistering (flaccid paralysis3
uncommon)
Mamba neurotoxic flaccid paralysis and muscle
fasciculation, shock, necrosis (uncommon)
Flaccid paralysis3, local necrosis, shock
Procoagulant coagulopathy, shock, pain and
swelling
Procoagulant coagulopathy, shock, cardiotoxicity,
local necrosis/blistering
Pain and swelling
Procoagulant coagulopathy, shock, renal failure,
local necrosis/blistering
Procoagulant coagulopathy, local necrosis, shock
Procoagulant coagulopathy, shock
Neuroexcitation
Neuroexcitation, shock
South African P V or Sanofi Pasteur FavAfrica A V
South African P V or Sanofi Pasteur FavAfrica A V
South African P V or Sanofi Pasteur FavAfrica A V
South African PV
No available A V (can try South African A V)
South African PV or Sanofi Pasteur FavAfrica AV
No available AV
Specific anti-EcA/s AV for species/geographical
region or Sanofi Pasteur FavAfrica AV
Specific or polyspecific AV covering Cerastes
from country of origin
Boomslang AV
Specific scorpion AV (Algeria, Tunisia, Sanofi
Pasteur Scorpifav)
Specific scorpion AV (Algeria, Tunisia, Sanofi
Pasteur Scorpifav)
Europe
Vipera spp. (Vv) Vipers and adders Shock, local necrosis/blistering, procoagulant ViperaTab AV or Zagreb AV or SanofiPasteur
coagulopathy (flaccid paralysis2 rare) Viperfav AV
Tor family name, see Box 8.4. 2Pre-synaptic. 3Post-synaptic.
More information is available from WHO Guidelines for the prevention and clinical management of snakebite in Africa and from toxinology.com.
Copyright © Julian White.
Assessment and management in hospital
On arrival at a health station or hospital, there are two immediate
priorities:
• identifying and treating any life-threatening problems (e.g.
circulatory shock, respiratory failure; see Ch. 16)
• determining whether envenoming is present and if that
requires urgent treatment.
I Assessment and management of
life-threatening problems
Patients who are seriously envenomed must be identified early
so that appropriate management is not delayed. Critically ill
patients must be resuscitated (p. 202) and this takes precedence
over administration of any antivenom. Clinicians should look
for signs of:
• shock/hypotension
• airway and/or respiratory compromise (likely to be
secondary to flaccid paralysis)
• major bleeding, including internal bleeding (especially
intracranial)
• impending limb compromise from inappropriate first aid
(e.g. a tourniquet) - though beware sudden envenoming
on removal of a tourniquet.
In a patient with severe neurotoxic flaccid paralysis, who is
still able to maintain sufficient respiratory function for survival,
clinical assessment may suggest irretrievable brain injury (fixed
dilated pupils, absent reflexes, no withdrawal response to painful
stimuli, no movement of limbs, fixed forward gaze with gross
ptosis; p. 152) when, in fact, the patient is conscious.
Assessment for evidence of envenoming
As in other areas of medicine, comprehensive assessment of
a patient bitten/stung by a venomous animal requires a good
history, a careful targeted examination and, where appropriate,
‘laboratory’ testing (though the latter may just consist of simple
bedside tests performed by the doctor; p. 153). Animals that
are unlikely to cause serious envenomation in humans should
be identified so that inappropriate admission and intervention are
avoided. Occasionally, patients may be unaware they have been
bitten/stung and thus provide a misleading history. In regions of
the world where keeping or handling venomous animals is illegal,
patients may be reticent in giving a truthful history. Multiple bites
or stings are more likely to cause major envenoming.
The following key questions should be asked:
• When was the patient exposed to the venomous
bite/sting?
• Was the organism causing it seen and what did it look like
(size, colour)?
• What were the circumstances (on land, in water etc.)?
• Was there more than one bite/sting?
• What first aid was used, when and for how long?
• What symptoms has the patient had (local and systemic)?
• Are there symptoms suggesting systemic envenoming
(paralysis, rhabdomyolysis, coagulopathy etc.)?
General approach to the envenomed patient • 159
• Is there any significant past medical history and
medication use?
• Is there a past exposure to antivenom/venom and
allergies?
If patients state that they have been bitten by a particular
species, ensure this information is accurate. Private keepers of
venomous animals may not have accurate knowledge of what they
are keeping, and misidentification of a snake, scorpion or spider
can have dire consequences if the wrong antivenom is used.
An outline of some principal findings on examination of the
envenomed patient is shown on page 152. The patient may
have a cluster of clinical features suggestive of a particular type
of envenoming (see Box 8.1).
Even with dangerously venomous animals, some bites/stings
will be dry bites and will not require antivenom. The time to
onset of first symptoms and signs of envenomation is variable,
depending on both animal and patient factors. It may range
from a matter of minutes post- bite/sting to 24 hours later in
some cases. Therefore, the initial assessment, if normal, must
be repeated multiple times during the first 24 hours. Some types
of envenomation will not cause symptoms or signs at all, or they
may appear very late, long after the optimum time for treatment
has passed. Evidence of envenomation may become apparent
only through laboratory testing.
Laboratory investigations
Specific tests for venom are currently commercially available
only for Australian snakebites but are likely to be developed
for snakebites in other regions. They are not available for other
types of envenomation, where venom concentrations are low.
For snakebite, a screen for envenoming includes full blood count,
coagulation screen, urea and electrolytes, creatinine, CK and
electrocardiogram (ECG). Lung function tests, peripheral oximetry
or arterial blood gases may be indicated in cases with potential
or established respiratory failure. In areas without access to
routine laboratory tests, the 20-minute whole-blood clotting test
(20WBCT) is useful (p. 153).
Treatment
Once a diagnosis of likely envenoming has been made, the next
and urgent decision is whether to give antivenom. Antivenom
may not be the only crucial treatment, however. For a snakebite
by a potentially lethal species such as Russell’s viper, the patient
might have local effects with oedema, blistering, necrosis, and
resultant fluid shifts causing shock, and at the same time have
systemic effects such as intractable vomiting, coagulopathy,
paralysis and secondary renal failure. Specific treatment with
antivenom will be required to reverse the coagulopathy and may
prevent worsening of the paralysis and reduce the vomiting,
but will not greatly affect the local tissue damage or the renal
failure or shock. The latter will require intravenous fluid therapy,
possibly respiratory support, renal dialysis and local wound care,
perhaps including antibiotics.
Each venomous animal will cause a particular pattern of
envenomation, requiring a tailored response. Listing all of these is
beyond the scope of this chapter (see ‘Further information’ below).
Antivenom
Antivenom, sometimes inappropriately labelled as ‘anti¬
snake venom’ (ASV), is the most important tool in treating
8.7 Indications for antivenom
General indications
• Shock/cardiac collapse
• Respiratory compromise
• Rapidly increasing swelling of
the bitten limb
Specific indications
• Developing paralytic features
(ptosis etc.)
• Developing rhabdomyolysis
• Developing coagulopathy
• Active bleeding
• Intractable non-specific
symptoms, including recurrent
vomiting
• Developing renal failure
• Developing neuroexcitatory
envenoming
Copyright © Julian White.
envenoming. It is made by hyperimmunising an animal, usually
horses, to produce antibodies against venom. Once refined,
these bind to venom toxins and render them inactive or allow
their rapid clearance. Antivenom is available only for certain
venomous animals and cannot reverse all types of envenoming.
With a few exceptions, it should be given intravenously, with
adrenaline (epinephrine) ready in case of anaphylaxis. It should
be used only when clearly indicated, and indications will vary
between venomous animals (Box 8.7). It is critical that the correct
antivenom is used at the appropriate dose. Doses vary widely
between antivenoms. In some situations (such as the Indian
subcontinent), pre-treatment with subcutaneous adrenaline may
reduce the chance of anaphylaxis to antivenom.
Antivenom can sometimes reverse post-synaptic neurotoxic
paralysis (a-bungarotoxin-like neurotoxins) but will not usually
reverse established pre-synaptic paralysis ((3-bungarotoxin-like
neurotoxins), so should be given before major paralysis has
occurred (Fig. 8.2). Coagulopathy is best reversed by antivenom,
but even after all venom is neutralised, there may be a delay of
hours before normal coagulation is restored. More antivenom
should not be given because coagulopathy has failed to normalise
fully in the first 1-3 hours (except in very particular circumstances).
Thrombocytopenia may persist for days, despite antivenom. The
role of antivenom in reversing established rhabdomyolysis and
renal failure is uncertain. Antivenom may help limit local tissue
effects or injury in the bitten limb but this is quite variable and
time-dependent. Neuroexcitatory envenoming can respond
very well to antivenom (Australian funnel web spider bites and
Mexican, South American and Indian scorpion stings) but there
is controversy about the effectiveness of antivenom for some
species (some North African and Middle Eastern scorpions).
The role of antivenom in limiting local venom effects, including
necrosis, is also controversial; it is most likely to be effective
when given early.
All patients receiving antivenom are at risk of both early and
late adverse reactions, including anaphylaxis (early; not always
related to immunoglobulin E (IgE)) and serum sickness (late).
Non-antivenom treatments
Anticholinesterases are used as an adjunctive treatment for
post-synaptic paralysis.
Prazosin (an a-adrenoceptor antagonist) is used in the
management of hypertension or pulmonary oedema in scorpion
sting cardiotoxicity, particularly for Indian red scorpion stings,
though antivenom is now the preferred treatment.
160 • ENVENOMATION
neurotoxins membrane potential change
Fig. 8.2 Principal snake venom neurotoxins acting at the
neuromuscular junction (NMJ). The pre-synaptic neurotoxins
(p-bungarotoxin-like) bind to the cell membrane of the terminal axon (1),
form a synaptosome (2) and enter the cell, where they disrupt acetylcholine
(ACh) production (3) and damage intracellular structures, including ion
channels (4). On initial entry, they cause release of excess ACh, followed
by cessation of all ACh release, causing irreversible paralysis until the
cell is repaired (days to weeks later). The post-synaptic neurotoxins
(oc-bungarotoxin-like) bind adjacent to the ACh receptor on the external
surface of the muscle end plate and block ACh binding (5), thereby
ceasing neurotransmission. Because this action is external to the cell and
does not cause cell damage, it is potentially a reversible paralysis.
Copyright © Julian White.
Antibiotics are not routinely required for most bites/stings,
though a few animals, such as some South American pit vipers
and stingrays, regularly cause significant wound infection or
abscess. Tetanus is a risk in some types of bite or sting, such
as snakebite, but intramuscular toxoid should not be given until
any coagulopathy is reversed.
Mechanical ventilation (p. 202) is vital for established
respiratory paralysis that will not reverse with antivenom and may
be required for prolonged periods (up to several months in
some cases).
Fasciotomy as a treatment for potential compartment syndrome
or severe limb swelling is an overused and often disastrous
surgical intervention in snakebite and is associated with poor
functional outcomes. It should be reserved as a treatment of last
resort and be used only in cases where compartment syndrome
is confirmed by intracompartment pressure measurement and
after first trying limb elevation and antivenom, and ensuring that
any coagulopathy has resolved.
Follow-up
Cases with significant envenomation and those receiving
antivenom should be followed up to ensure any complications
have resolved and to identify any delayed envenoming.
Envenomation by specific animals
Venomous snakes
Venomous snakes represent the single most important cause
of envenomation globally, affecting millions of humans annually
and resulting in large numbers of deaths and patients left with
long-term disability. Of the 3000-plus snake species, more
than 1000 either are venomous or produce oral toxins. The
most important venomous snake families are the Viperidae
(vipers; includes typical vipers (subfamily Viperinae) and pit-
vipers, with heat-sensing pit organs (subfamily Crotalinae))
and the Elapidae (cobras, kraits, mambas, coral snakes, sea
snakes, Australian snakes). However, there are also dangerous
species among the Atractaspididae (side-fanged burrowing
vipers of Africa and the Middle East) and the non-front-
fanged colubrids (NFFC snakes; several families, including the
‘back-fanged’ boomslang and vine snakes of Africa and the
keel backs of Asia).
A selection of important species is included in Boxes 8. 4-8.6.
Clinical features and management
As with other forms of envenoming, the management of snakebite
follows the standard assessment guidelines described previously
(p. 152). The nature of the risks posed will depend on the specific
snake fauna in a given region (p. 1 53). For example, in the Indian
subcontinent, the major snakebite risks are claimed to come
from the ‘big four’: cobras, kraits, Russell’s viper and saw-scaled
vipers. This list is misleading, though, as it omits other important
snakes, including the hump-nosed vipers, king cobra and green
pit vipers, all of which can cause severe or lethal envenoming
and may not be covered by current Indian antivenoms. Even
for those snakes recognised as causing envenoming, there
may be major geographical variation in venom and features
of envenoming. For Russell’s viper (Daboia spp.), Sri Lankan
specimens can cause rhabdomyolysis and flaccid paralysis, in
addition to classic severe coagulopathy, haemorrhage, local bite
site injury and acute kidney injury (AKI). Indian populations of
the same snake are not associated with either rhabdomyolysis
or paralysis, but in parts of Southern India may cause anterior
pituitary haemorrhage and/or capillary leak syndrome (hypotensive
shock plus vascular leakage resulting in pulmonary oedema).
Capillary leak syndrome is also encountered with populations
of Burmese Russell’s viper (Myanmar), where AKI is especially
common and severe.
Antivenom raised against venom from one population of
these snakes is often poorly effective against bites from snakes
from other regions. Similarly, each of the several species of
saw-scaled vipers (Echis spp.) spread from West Africa across
the Middle East to the Indian subcontinent, including Sri
Lanka, has specific venoms that may not be neutralised by
antivenoms raised against other species in the genus; Indian
antivenoms are ineffective against African species. It follows that,
in managing snakebite envenomation, it is critically important
to choose the appropriate antivenom and to understand that
Envenomation by specific animals • 161
this may not include every antivenom claiming to cover a I
given species.
It is unwise to assume that everything is known about
envenoming by snakes because new clinical information and
syndromes are emerging as more detailed studies are carried
out. For instance, krait bites (Bungarus spp.), long associated
with ‘painless’ bites, later development of devastating flaccid
paralysis and a high mortality rate, are now known to have some
venom diversity. At least some species can cause rhabdomyolysis
and/or severe hyponatraemia, and while bites may be painless,
systemic envenomation can cause severe abdominal pain in at
least some patients. Among cobra bites, the previous division into
‘non-spitting’, neurotoxic species and ‘spitting’, less neurotoxic
species that cause local necrosis is less clear. Non-spitters are
now known to spit in parts of their range (e.g. Naja kaouthia
in West Bengal) and may cause local necrosis in addition to
paralysis. Previously clear diagnostic indicators for envenomation
by particular types of snakes, such as Russell’s vipers and
saw-scaled vipers causing coagulopathy, have also become less
sure, as it is now known that other snakes, such as hump-nosed
vipers (Hypnale spp.) and green pit vipers (Trimeresurus spp.),
found in similar regions, can also cause marked coagulopathy
and yet are often not covered by available antivenoms. The
ability to cause life-threatening coagulopathy, associated with
snakes previously considered harmless, such as the keelbacks
in Asia (Rhabdophis spp.), can further complicate the diagnostic
and management process, as antivenom against these snakes
is currently available only in Japan.
Scorpions
Scorpions are second only to snakes in their venomous impact on
humankind. Most medically important scorpions are in the family
Buthidae and have complex neuroexcitatory venoms with highly
specific ion-channel toxins. Classically, stings by these scorpions
(some key genera listed in Boxes 8. 4-8. 6) cause moderate to
severe local pain and rapid-onset systemic envenoming with
development of a catecholamine storm-like syndrome as the
toxins target the nervous system. There may be tachycardia or
bradycardia, hyper- or hypotension, profuse sweating, salivation,
cardiac dysfunction and pulmonary oedema. Cardiac collapse
can occur, especially in children. Other clinical features may
vary, depending on the scorpion species.
The Iranian scorpion, Hemiscorpius lepturus (principally south¬
west Iran), causes a quite different presentation, with an initial
minor sting, followed by progressive development of bite site
or limb necrosis and a potentially lethal systemic envenoming,
characterised by intravascular haemolysis, disseminated
intravascular coagulation (DIC), secondary renal failure and shock.
Clinical features and management
The approach to management varies with species and region.
In Latin America, specific antivenoms are routinely used and
associated with improved outcomes and dramatic falls in mortality
rate. In India, the past reliance on prazosin has been replaced
with use of specific antivenom, again with improved outcomes.
In contrast, in parts of North Africa, past reliance on antivenom
has been replaced with use of cardiac support and arguably
poorer outcomes.
In Iran, H. lepturus stings are treated with antivenom, though
as presentation is often delayed because the sting initially appears
to be minor, the role of late antivenom is unclear.
Spiders
There are vast numbers and great species diversity of spiders, with
two broad taxonomic groupings: the more ‘primitive’ Mygalomorphs
(several medically important species, especially Australian funnel
web spiders (/■ \trax , Hadronyche and lllawarra)) and the far more
diverse Araneomorphs (main clinically important species in the
genera Latrodectus (widow spiders), Loxosceles (brown recluse
spiders) and Phoneutria (banana or wandering spiders)).
Clinical features and management
While spiders and spider bites are common, only those genera
noted above commonly cause medically significant effects. In
most cases this is a neuroexcitatory envenoming, sometimes
similar to severe scorpion envenoming (notable from Australian
funnel web spiders), but the recluse spiders cause an often
painless bite that develops into local skin necrosis and sometimes
a systemic illness similar to that caused by the Iranian scorpion,
H. lepturus, and with similar lethal potential.
For most of these spiders, antivenom remains the key treatment
and is life-saving in some cases. Recent studies suggesting
that anti -Latrodectus antivenom is ineffective have not been
confirmed by independent studies and are in contrast to decades
of positive clinical experience.
Paralysis ticks
Most ticks are vectors for disease but a few species in Australia,
North America and parts of Africa can cause flaccid paralysis.
Toxins in the saliva act as potent pre-synaptic neurotoxins that
can cause gradual-onset ascending flaccid paralysis.
There are no antivenoms for tick paralysis. Treatment is based
on removal of all ticks and supportive care, including intubation/
ventilation where required. The paralysis usually resolves by
about 48 hours following removal of all ticks.
Venomous insects
A number of insects are venomous but very few cause significant
envenoming in humans.
Venomous lepidopterans
The Lonomia caterpillars of South America, especially Brazil,
have numerous protective venomous spines that, on contact
with the skin, can discharge a potent procoagulant venom that
can cause a progressive and sometimes fatal consumptive
coagulopathy, with terminal haemorrhagic and/or organ failure
events. Treatment includes use of a Brazilian specific antivenom
and supportive care.
Venomous hymenopterans
Many bees, wasps, hornets and some ants have modified
ovipositors in the abdomen that act as stings, attached to
venom glands. The quantity of venom injected in a single sting
is insufficient to cause significant envenomation, but as many
of these venoms are potently allergenic, it can cause severe
and sometimes fatal anaphylaxis in sensitised persons (p. 75).
Massed stings by hundreds of these insects in a swarm, however,
can cause life-threatening systemic envenoming, often with
intravascular haemolysis, DIC, shock and multi-organ failure.
‘Africanised’ bees are a particular risk for such attacks in South
162 • ENVENOMATION
America and now in parts of North America. The giant wasps
and hornets of Asia can similarly cause systemic envenoming
with multiple attacks. Invasive ants, such as Solenopsis spp.,
are colonising new regions and can cause both allergic reactions
and unpleasant local reactions.
Marine venomous and poisonous animals
The marine environment is dominated by animal life, and many
species utilise toxins, either self-produced or taken up from the
environment, to arm themselves for either defence or predation.
Many of these animals can cause adverse effects in humans,
either as a direct venom effect on bites/stings (venomous spiny
fish, sea snakes, stingrays, jellyfish, sea urchins, some starfish,
cone snails, selected octopuses etc.), or through poisoning if
eaten (fugu, ciguatera, scombroid, several types of shellfish
poisoning; p. 149).
For venomous marine animals, there is antivenom available only
for sea snakes, which can cause rhabdomyolysis and/paralytic
neurotoxicity; box jellyfish, which can cause very rapid cardiac
collapse; and stonefish, which cause intense sting-site pain.
In general, marine venoms respond to heat; thus a hot water
immersion or shower (about 45°C) is effective at reducing local
pain, particularly for jellyfish, stinging fish and stingray stings. For
stingray stings, the venom may cause local tissue damage both
through sting trauma and a venom effect; wounds penetrating the
abdomen or chest are potentially lethal and wounds should be
adequately explored, cleaned and allowed to heal by secondary
intention. For bites by the blue-ringed octopus and stings by
cone snails, rapid-acting venom can cause early cardiovascular
collapse and flaccid paralysis. Supportive care is crucial in
ensuring survival from these potentially lethal and seemingly
trivial local wounds. Sea urchin and venomous starfish wounds
can result in multiple penetrating spines, which cause pain and
act as a nidus for secondary infection, but surgical removal of
spines can be difficult and unrewarding.
Further information
Books and journal articles
Meier J, White J. Handbook of clinical toxicology of animal venoms
and poisons. Boca Raton: CRC Press; 1995.
World Health Organisation, Regional Office for Africa. Guidelines for the
prevention and clinical management of snakebite in Africa; 201 0
(afro.who.int).
World Health Organisation, Regional Office for South-East Asia.
Guidelines for the management of snake-bites; 201 0 (searo
.who.int).
Websites
toxinology.com Clinical toxinology guide from the University
of Adelaide.
M Byers
Environmental medicine
Radiation exposure 164
Extremes of temperature 65
High altitude 168
Under water 169
Humanitarian crisis 171
164 • ENVIRONMENTAL MEDICINE
Environmental medicine deals with the interactions between
the environment and human health. While previously concerned
mainly with controlling infectious diseases, the focus at present
is predominantly on the multiple physical, chemical, biological
and social factors that pose risks to human health. As the
environment continually alters, whether through population
growth, economic development or climate change, it plays an
important role in disease causation - one that may increase
over time. This chapter deals principally with acute effects of
environmental hazards on individuals and should be read in
conjunction with the chapters on Poisoning (Ch. 7) and Acute
Medicine and Critical Illness (Ch. 10). Chapter 5 deals with more
general effects of environmental factors on population health.
Radiation exposure
Radiation includes ionising (Fig. 9.1) and non-ionising radiations
(ultraviolet (UV), visible light, laser, infrared and microwave).
While global industrialisation and the generation of fluorocarbons
have raised concerns about loss of the ozone layer, leading to
an increased exposure to UV rays, and disasters such as the
Chernobyl and Fukushima nuclear power station explosions
have demonstrated the harm of ionising radiation, it is important
to remember that it can be harnessed for medical benefit.
Ionising radiation is used in X-rays, computed tomography (CT),
radionuclide scans and radiotherapy, and non-ionising UV for
therapy in skin diseases and laser therapy for diabetic retinopathy.
| Types of ionising radiation
These include charged subatomic alpha and beta particles,
uncharged neutrons or high-energy electromagnetic radiations
such as X-rays and gamma rays. When they interact with
atoms, energy is released and the resulting ionisation can lead
to molecular damage. The clinical effects of different forms of
radiation depend on their range in air and tissue penetration
(Fig. 9.1).
Dosage and exposure
The dose of radiation is based on the energy absorbed by a
unit mass of tissue and is measured in grays (Gy), with 1 Gy
representing 1 J/kg. To take account of different types of radiation
and variations in the sensitivity of various tissues, weighting
factors are used to produce a unit of effective dose, measured
in sieverts (Sv). This value reflects the absorbed dose weighted
for the damaging effects of a particular form of radiation and is
most valuable in evaluating the long-term effects of exposure.
‘Background radiation’ refers to our exposure to naturally
occurring radioactivity (e.g. radon gas and cosmic radiation). This
produces an average annual individual dose of approximately
2.6 mSv per year, although this figure varies according to local
geology.
Effects of radiation exposure
Effects on the individual are classified as either deterministic
or stochastic.
Deterministic effects
Deterministic (threshold) effects occur with increasing severity as
the dose of radiation rises above a threshold level. Tissues with
actively dividing cells, such as bone marrow and gastrointestinal
mucosa, are particularly sensitive to ionising radiation. Lymphocyte
depletion is the most sensitive marker of bone marrow injury, and
after exposure to a fatal dose, marrow aplasia is a common cause
of death. However, gastrointestinal mucosal toxicity may cause
earlier death due to profound diarrhoea, vomiting, dehydration
and sepsis. The gonads are highly radiosensitive and radiation
may result in temporary or permanent sterility. Eye exposure can
lead to cataracts and the skin is susceptible to radiation burns.
Irradiation of the lung may induce acute inflammatory reactions or
pulmonary fibrosis, and irradiation of the central nervous system
may cause permanent neurological deficit. Bone necrosis and
lymphatic fibrosis are characteristic following regional irradiation,
particularly for breast cancer. The thyroid gland is not inherently
sensitive but its ability to concentrate iodine makes it susceptible
to damage after exposure to relatively low doses of radioactive
iodine isotopes, such as those released from Chernobyl.
Stochastic effects
Stochastic (chance) effects occur with increasing probability as
the dose of radiation increases. Carcinogenesis represents a
stochastic effect. With acute exposures, leukaemias may arise
after an interval of around 2-5 years and solid tumours after an
Protection
Fig. 9.1 Properties of different ionising radiations.
Extremes of temperature • 165
interval of about 10-20 years. Thereafter the incidence rises with
time. An individual’s risk of developing cancer depends on the
dose received, the time to accumulate the total dose and the
interval following exposure.
| Management of radiation exposure
Exposed people should be removed from ongoing exposure
(‘get inside, stay inside’), and should take off affected clothing
and shower to stop further contamination. If contamination
of food and water supplies may have occurred, only bottled
water and food in sealed containers should be consumed. The
principal problems after large-dose exposures are maintenance
of adequate hydration, control of sepsis and management of
marrow aplasia. Associated injuries such as thermal burns need
specialist management within 48 hours of active resuscitation.
Internal exposure to radioisotopes should be treated with chelating
agents (such as Prussian blue used to chelate 137caesium after
ingestion). White-cell colony stimulation and haematopoietic stem
cell transplantation may need to be considered for marrow aplasia.
Extremes of temperature
| Thermoregulation
Body heat is generated by basal metabolic activity and muscle
movement, and lost by conduction (which is more effective
in water than in air), convection, evaporation and radiation
(most important at lower temperatures when other mechanisms
conserve heat) (Box 9.1). Body temperature is controlled in the
hypothalamus, which is directly sensitive to changes in core
temperature and indirectly responds to temperature-sensitive
neurons in the skin. The normal ‘set-point’ of core temperature is
tightly regulated within the range 37±0.5°C, which is necessary
to preserve the normal function of many enzymes and other
metabolic processes. The temperature set-point is increased
in response to infection (p. 218).
In a cold environment, protective mechanisms include
cutaneous vasoconstriction and shivering; however, any muscle
activity that involves movement may promote heat loss by
increasing convective loss from the skin, and respiratory heat
loss by stimulating ventilation. In a hot environment, sweating
is the main mechanism for increasing heat loss. This usually
occurs when the ambient temperature rises above 32.5°C or
during exercise.
Hypothermia
Hypothermia exists when the body’s normal thermal regulatory
mechanisms are unable to maintain heat in a cold environment
and core temperature falls below 35°C (Fig. 9.2). Moderate
hypothermia occurs below 32°C and severe hypothermia
below 28°C. Other systems define hypothermia on the basis
of symptoms rather than absolute temperature.
While infants are susceptible to hypothermia because of
their poor thermoregulation and high body surface area to
weight ratio, it is the elderly who are at highest risk (Box 9.2).
Hypothyroidism is often a contributory factor in old age, while
Definitions
Clinical features
-
Heat
stroke
Hot and not sweating
Multiple organ failure, confusion,
aggression, shock
Heat
Hot and sweating
Headache, weakness, fatigue,
exhaustion
irritability, tachycardia, dehydration
Tachycardia, vasoconstriction
Cold and shivering
‘Mumble, stumble, tumble’
Mild Lethargy
hypothermia Dehydration
Tachypnoea
9.1 Thermoregulation: responses to hot and cold
environments
Mechanism
Hot
environment
Cold environment
Heat
production
Basal
metabolic
rate
— >
si in hypothermia
Muscle
activity
i by lethargy
T by shivering
si in severe
hypothermia
Heat loss
Conduction*
T by
vasodilatation
si by vasoconstriction
TT in water < 31 °C
Convection*
T by
vasodilatation
si by lethargy
si by vasoconstriction
T by wind and
movement
Evaporation*
TT by
sweating
si by high
humidity
T by hyperventilation
Radiation
T by
vasodilatation
si by vasoconstriction
(but is the major heat
loss in dry cold)
*These losses are dependent on the relative ambient and skin temperatures.
<32
Violent shivering
Slurred speech
Slow, laboured movements
Moderate Ataxia, mild confusion
hypothermia Pale with blue lips
<28
23
20
Severe
hypothermia
Cold and not shivering
Cold, pale skin
Depressed consciousness
Muscle stiffness
Bradycardia and hypotension
Coma
Dilated, unreactive pupils
Cardiac standstill
Fig. 9.2 Clinical features of abnormal core temperature. The
hypothalamus normally maintains core temperature at 37°C, but this
set-point is altered in, for example, fever (pyrexia, p. 218), and may be lost
in hypothalamic disease (p. 679). In these circumstances, the clinical
picture at a given core temperature may be different.
166 • ENVIRONMENTAL MEDICINE
Fig. 9.3 Electrocardiogram showing J waves (arrows) in a
hypothermic patient.
alcohol and other drugs (e.g. phenothiazines) commonly impede
the thermoregulatory response in younger people. More rarely,
hypothermia is secondary to hypothyroidism, glucocorticoid
insufficiency, stroke, hepatic failure or hypoglycaemia.
Hypothermia also occurs in healthy individuals whose
thermoregulatory mechanisms are intact but insufficient to
cope with the intensity of the thermal stress. Typical examples
include immersion in cold water, when core temperature may fall
rapidly (acute hypothermia), exposure to extreme climates such
as during hill walking (subacute hypothermia), and slow-onset
hypothermia, as develops in an immobilised older individual
(subchronic hypothermia). This classification is important, as it
determines the method of rewarming.
Clinical features
Diagnosis is dependent on recognition of the environmental
circumstances and measurement of core (rectal) body temperature.
Clinical features depend on the degree of hypothermia (Fig. 9.2).
In a cold patient, it is very difficult to diagnose death reliably
by clinical means. It has been suggested that, in extreme
environmental conditions, irreversible hypothermia is probably
present if there is asystole (no carotid pulse for 1 min), the
chest and abdomen are rigid, the core temperature is <13°C
and serum potassium is >12 mmol/L. However, in general,
resuscitative measures should continue until the core temperature
is normal and only then should a diagnosis of brain death be
considered (p. 211).
Investigations
Blood gases, a full blood count, electrolytes, chest X-ray
and electrocardiogram (ECG) are all essential investigations.
Haemoconcentration and metabolic acidosis are common,
and the ECG may show characteristic J waves, which occur
at the junction of the QRS complex and the ST segment (Fig.
9.3). Cardiac arrhythmias, including ventricular fibrillation, may
occur. Although the arterial oxygen tension may be normal when
measured at room temperature, the arterial P02 in the blood falls
by 7% for each 1 °C fall in core temperature. Serum aspartate
aminotransferase and creatine kinase may be elevated secondary
to muscle damage and the serum amylase is often high due
to subclinical pancreatitis. If the cause of hypothermia is not
obvious, additional investigations for thyroid and pituitary-adrenal
dysfunction (p. 633), hypoglycaemia (p. 725) and the possibility
of drug intoxication (p. 134) should be performed.
Management
Following resuscitation, the objectives of management are
to rewarm the patient in a controlled manner while treating
associated hypoxia (by oxygenation and ventilation if necessary),
fluid and electrolyte disturbance, and cardiovascular abnormalities,
particularly arrhythmias. Careful handling is essential to avoid
precipitating the latter. The method of rewarming is dependent not
on the absolute core temperature, but on haemodynamic stability
and the presence or absence of an effective cardiac output.
Mild hypothermia
Outdoors, continued heat loss is prevented by sheltering the
patient from the cold, replacing wet clothing, covering the head
and insulating him or her from the ground. Once in hospital,
even in the presence of profound hypothermia, if there is an
effective cardiac output then forced-air rewarming, heat packs
placed in axillae and groins and around the abdomen, inhaled
warmed air and correction of fluid and electrolyte disturbances
are usually sufficient. Rewarming rates of 1-2°C per hour are
effective in leading to a gradual and safe return to physiological
normality. Underlying conditions should be treated promptly
(e.g. hypothyroidism with triiodothyronine 10 jig IV 3 times
daily; p. 640).
Severe hypothermia
In the case of severe hypothermia (<28°C), patients with
cardiopulmonary arrest (non-perfusing rhythm), or those with
cardiac instability (systolic blood pressure <90 mmHg or
ventricular arrhythmias), the aim is to restore perfusion, and
rapid rewarming at a rate of >2°C per hour is required. This
is best achieved by cardiopulmonary bypass or extracorporeal
membrane oxygenation (ECMO). If these are unavailable, then
veno-veno haemofiltration, and pleural, peritoneal, thoracic or
bladder lavage with warmed fluids are alternatives. Direct heat
sources, such as hot water or heat pads, should be used with
caution, as these can provoke cardiac arrhythmias or cause
burns. Monitoring of cardiac rhythm and arterial blood gases,
including H+ (pH), is essential. Significant acidosis may require
correction (p. 364).
Cold injury
Freezing cold injury (frostbite)
This represents the direct freezing of body tissues and usually
affects the extremities: in particular, the fingers, toes, ears and
face. Risk factors include smoking, peripheral vascular disease,
dehydration and alcohol consumption. The tissues may become
anaesthetised before freezing and, as a result, the injury often
goes unrecognised at first. Frostbitten tissue is initially pale and
doughy to the touch and insensitive to pain (Fig. 9.4). Once
frozen, the tissue is hard.
Rewarming should not occur until it can be achieved rapidly
in a water bath. Give oxygen and aspirin 300 mg as soon as
possible. Frostbitten extremities should be rewarmed in warm
water at 37-39°C, with antiseptic added. Adequate analgesia
is necessary, as rewarming is very painful. Vasodilators such as
9.2 Thermoregulation in old age
• Age-associated changes: impairments in vasomotor function,
skeletal muscle response and sweating mean that older people
react more slowly to changes in temperature.
• Increased comorbidity: thermoregulatory problems are more likely
in the presence of pathology such as atherosclerosis and
hypothyroidism, and medication such as sedatives and hypnotics.
• Hypothermia: this may arise as a primary event, but more
commonly complicates other acute illness, e.g. pneumonia, stroke
or fracture.
• Ambient temperature: financial pressures and older equipment
may result in inadequate heating during cold weather.
Extremes of temperature • 167
Fig. 9.4 Frostbite in a female Everest sherpa.
pentoxifylline (a phosphodiesterase inhibitor) have been shown
to improve tissue survival. Once it has thawed, the injured part
must not be re-exposed to the cold, and should be dressed and
rested. While wound debridement may be necessary, amputations
should be delayed for 60-90 days, as good recovery may occur
over an extended period. As yet, the role of hyperbaric oxygen
in the treatment of frostbite requires further research.
Non-freezing cold injury (trench or immersion foot)
This results from prolonged exposure to cold, damp conditions.
The limb (usually the foot) appears cold, ischaemic and numb,
but there is no freezing of the tissue. On rewarming, the limb
appears mottled and thereafter becomes hyperaemic, swollen
and painful. Recovery may take many months, during which
period there may be chronic pain and sensitivity to cold. The
pathology remains uncertain but probably involves endothelial
injury. Gradual rewarming is associated with less pain than
rapid rewarming. The pain and associated paraesthesia are
difficult to control with conventional analgesia and may require
amitriptyline (50 mg nocte), best instituted early. The patient is
at risk of further damage on subsequent exposure to the cold.
Chilblains
Chilblains are tender, red or purplish skin lesions that occur in
the cold and wet. They are often seen in horse riders, cyclists
and swimmers, and are more common in women than men.
They are short-lived and, although painful, not usually serious.
Heat-related illness
When generation of heat exceeds the body’s capacity for heat
loss, core temperature rises. Non-exertional heat illness (NEHI)
occurs with a high environmental temperature in those with
attenuated thermoregulatory control mechanisms: the elderly,
the young, those with comorbidity or those taking drugs that
affect thermoregulation (particularly phenothiazines, diuretics and
alcohol). Exertional heat illness (EHI), on the other hand, typically
develops in athletes when heat production exceeds the body’s
ability to dissipate it.
Acclimatisation mechanisms to environmental heat include
stimulation of the sweat mechanism with increased sweat volume,
reduced sweat sodium content and secondary hyperaldosteronism
to maintain body sodium balance. The risk of heat-related illness
falls as acclimatisation occurs. Heat illness can be prevented to a
9.3 Differential diagnosis in patients with elevated
core body temperature
• Heat illness (heat exhaustion, heat stroke)
• Sepsis, including meningitis
• Malaria
• Drug overdose
• Serotonin syndrome (pp. 139 and 1199)
• Malignant hyperpyrexia
• Thyroid storm (p. 639)
large extent by adequate replacement of salt and water, although
excessive water intake alone should be avoided because of the
risk of dilutional hyponatraemia (p. 357).
A spectrum of illnesses occurs in the heat (see Fig. 9.2). The
cause is usually obvious but the differential diagnosis should be
considered (Box 9.3).
Heat cramps
These painful muscle contractions occur following vigorous
exercise and profuse sweating in hot weather. There is no
elevation of core temperature. The mechanism is considered
to be extracellular sodium depletion as a result of persistent
sweating, exacerbated by replacement of water but not salt.
Symptoms usually respond rapidly to rehydration with oral
rehydration salts or intravenous saline.
Heat syncope
This is similar to a vasovagal faint (p. 181) and is related to
peripheral vasodilatation in hot weather.
Heat exhaustion
Heat exhaustion occurs with prolonged exertion in hot and
humid weather, profuse sweating and inadequate salt and water
replacement. There is an elevation in core (rectal) temperature
to between 37°C and 40°C, leading to the clinical features
shown in Figure 9.2. Blood analyses may show evidence of
dehydration with mild elevation of the blood urea, sodium and
haematocrit. Treatment involves removal of the patient from
the heat, and active evaporative cooling using tepid sprays and
fanning (‘strip-spray-fan’). Fluid losses are replaced with either
oral rehydration mixtures or intravenous isotonic saline. Up to
5 L positive fluid balance may be required in the first 24 hours.
Untreated, heat exhaustion may progress to heat stroke.
Heat stroke
Heat stroke occurs when the core body temperature rises
above 40°C and is a life-threatening condition. The symptoms
of heat exhaustion progress to include headache, nausea and
vomiting. Neurological manifestations include a coarse muscle
tremor and confusion, aggression or loss of consciousness. The
patient’s skin feels very hot, and sweating is often absent due to
failure of thermoregulatory mechanisms. Complications include
hypovolaemic shock, lactic acidosis, disseminated intravascular
coagulation, rhabdomyolysis, hepatic and renal failure, and
pulmonary and cerebral oedema.
Duration of hyperthermia is key to the outcome and immediate
cooling should begin at the scene, before transfer to hospital.
The aim should be to reduce core temperature by >0.2°C per
minute to approximately 39°C, while avoiding overshooting and
hypothermia. The patient should be resuscitated with evaporative or
convective cooling. Fluid resuscitation with crystalloid intravenous
fluids should be instituted but solutions containing potassium
168 • ENVIRONMENTAL MEDICINE
should be avoided. Intravenous dextrose may be necessary,
as hypoglycaemia can occur. Appropriate monitoring of fluid
balance, including central venous pressure, is important, as over-
aggressive fluid replacement may precipitate pulmonary oedema
or further metabolic disturbance. Investigations for complications
include routine haematology and biochemistry, coagulation
screen, hepatic transaminases (aspartate aminotransferase and
alanine aminotransferase), creatine kinase and chest X-ray. Once
emergency treatment is established, heat stroke patients are
best managed in intensive care.
Heat stroke is an emergency with a significant mortality.
However, where temperatures can be reduced to <40°C within
30 minutes of collapse, death rates can approach zero. Patients
who have had core temperatures of >40°C should be monitored
carefully for later onset of rhabdomyolysis, renal damage and
other complications before discharge from hospital. Clear advice
to avoid heat and heavy exercise during recovery is important.
High altitude
The physiological effects of high altitude are significant. On
Everest, the barometric pressure of the atmosphere falls from
sea level by approximately 50% at base camp (5400 m) and
approximately 70% at the summit (8848 m). The proportions of
oxygen, nitrogen and carbon dioxide in air do not change with
the fall in pressure but their partial pressure falls in proportion
to barometric pressure (Fig. 9.5). Oxygen tension within the
pulmonary alveoli is further reduced at altitude because the
partial pressure of water vapour is related to body temperature
and not barometric pressure, and so is proportionately greater
at altitude, accounting for only 6% of barometric pressure at
sea level but 19% at 8848 m.
Physiological effects of high altitude
Reduction in oxygen tension results in a fall in arterial oxygen satu¬
ration (Fig. 9.5). This varies widely between individuals, depending
Highest
Pressurised permanent Summit
aircraft cabin habitation of Everest
(< 2400 m) (< 5200 m) (8848 m)
Fig. 9.5 Change in inspired oxygen tension and blood oxygen
saturation at altitude. The blue curve shows changes in oxygen
availability at altitude and the red curve shows the typical resultant
changes in arterial oxygen saturation in a healthy person. Oxygen
saturation varies between individuals according to the shape of the
oxygen-haemoglobin dissociation curve and the ventilatory response to
hypoxaemia. (To convert kPa to mmHg, multiply by 7.5.)
on the shape of the sigmoid oxygen-haemoglobin dissociation
curve (see Fig. 23.5, p. 917) and the ventilatory response.
Acclimatisation to hypoxaemia at high altitude involves a shift
in this dissociation curve (dependent on 2,3-diphosphoglycerate
(2,3-DPG)), erythropoiesis, haemoconcentration, and hyperventila¬
tion resulting from hypoxic drive, which is then sustained despite
hypocapnia by restoration of cerebrospinal fluid pH to normal in
prolonged hypoxia. This process takes several days, so travellers
need to plan accordingly.
| Illnesses at high altitude
Ascent to altitudes up to 2500 m or travel in a pressurised
aircraft cabin is harmless to healthy people. Above 2500 m
high-altitude illnesses may occur in previously healthy people,
and above 3500 m these become common. Sudden ascent to
altitudes above 6000 m, as experienced by aviators, balloonists
and astronauts, may result in decompression illness with the
same clinical features as seen in divers (see below), or even
loss of consciousness. However, most altitude illness occurs
in travellers and mountaineers.
Acute mountain sickness
Acute mountain sickness (AMS) is a syndrome comprised
principally of headache, together with fatigue, anorexia, nausea
and vomiting, difficulty sleeping or dizziness. Ataxia and peripheral
oedema may be present. The aetiology of AMS is not fully
understood but it is thought that hypoxaemia increases cerebral
blood flow and hence intracranial pressure. Symptoms occur
within 6-1 2 hours of an ascent and vary in severity from trivial to
completely incapacitating. The incidence in travellers to 3000 m
may be 40-50%, depending on the rate of ascent.
Treatment of mild cases consists of rest and simple analgesia;
symptoms usually resolve after 1-3 days at a stable altitude,
but may recur with further ascent. Occasionally, there is
progression to cerebral oedema. Persistent symptoms indicate
the need to descend but may respond to acetazolamide, a
carbonic anhydrase inhibitor that induces a metabolic acidosis
and stimulates ventilation; acetazolamide may also be used as
prophylaxis if a rapid ascent is planned.
High-altitude cerebral oedema
The cardinal symptoms of high-altitude cerebral oedema
(HACE) are ataxia and altered consciousness. HACE is rare,
life-threatening and usually preceded by AMS. In addition to
features of AMS, the patient suffers confusion, disorientation,
visual disturbance, lethargy and ultimately loss of consciousness.
Papilloedema and retinal haemorrhages are common and focal
neurological signs may be found.
Treatment is directed at improving oxygenation. Descent is
essential and dexamethasone (8 mg immediately and 4 mg 4
times daily) should be given. If descent is impossible, oxygen
therapy in a portable pressurised bag may be helpful.
High-altitude pulmonary oedema
High-altitude pulmonary oedema (HAPE) is a life-threatening
condition that usually occurs in the first 4 days after ascent
above 2500 m. Unlike HACE, HAPE may occur de novo without
the preceding signs of AMS. Presentation is with symptoms
of dry cough, exertional dyspnoea and extreme fatigue. Later,
the cough becomes wet and sputum may be blood-stained.
Tachycardia and tachypnoea occur at rest and crepitations
may often be heard in both lung fields. There may be profound
hypoxaemia, pulmonary hypertension and radiological evidence
Under water • 169
of diffuse alveolar oedema. It is not known whether the alveolar
oedema is a result of mechanical stress on the pulmonary
capillaries associated with the high pulmonary arterial pressure,
or an effect of hypoxia on capillary permeability. Reduced arterial
oxygen saturation is not diagnostic but is a marker for disease
progression.
Treatment is directed at reversal of hypoxia with immediate
descent and oxygen administration. Nifedipine (20 mg 4 times
daily) should be given to reduce pulmonary arterial pressure,
and oxygen therapy in a portable pressurised bag should be
used if descent is delayed.
Chronic mountain sickness (Monge’s disease)
This occurs on prolonged exposure to altitude and has been
reported in residents of Colorado, South America and Tibet.
Patients present with headache, poor concentration and other
signs of polycythaemia. The haemoglobin concentration is high
(>200 g/L) and the haematocrit raised (>65%). Affected individuals
are cyanosed and often have finger clubbing.
High-altitude retinal haemorrhage
This occurs in over 30% of trekkers at 5000 m. The haemorrhages
are usually asymptomatic and resolve spontaneously. Visual
defects can occur with haemorrhage involving the macula but
there is no specific treatment.
Venous thrombosis
This has been reported at altitudes of >6000 m. Risk factors
include dehydration, inactivity and the cold. The use of the oral
contraceptive pill at high altitude should be considered carefully,
as this is an additional risk factor.
Refractory cough
A cough at high altitude is common and usually benign. It may be
due to breathing dry, cold air and to increased mouth breathing,
with consequent dry oral mucosa. This may be indistinguishable
from the early signs of HAPE.
Air travel
Commercial aircraft usually cruise at 10000-12000 m, with the
cabin pressurised to an equivalent of around 2400 m. At this
altitude, the partial pressure of oxygen is 16 kPa (120 mmHg),
leading to a Pa02 in healthy people of 7.0-8.5 kPa (53-64 mmHg).
Oxygen saturation is also reduced but to a lesser degree (see
Fig. 9.5). Although well tolerated by healthy people, this degree
of hypoxia may be dangerous in patients with respiratory disease.
Advice for patients with respiratory disease
The British Thoracic Society has published guidance on the
management of patients with respiratory disease who want to
fly. Specialist pre-flight assessment is advised for all patients
who have hypoxaemia (oxygen saturation <95%) at sea level,
and includes spirometry and a hypoxic challenge test with 15%
oxygen (performed in hospital). Air travel may have to be avoided
or undertaken only with inspired oxygen therapy during the flight.
Asthmatic patients should be advised to carry their inhalers in
their hand baggage. Following pneumothorax, flying should
be avoided while air remains in the pleural cavity, but can be
considered after proven resolution or definitive (surgical) treatment.
Advice for other patients
Other circumstances in which patients are more susceptible to
hypoxia require individual assessment. These include cardiac
arrhythmia, sickle-cell disease and ischaemic heart disease. Most
airlines decline to carry pregnant women after the 36th week
of gestation. In complicated pregnancies it may be advisable
to avoid air travel at an earlier stage. Patients who have had
recent abdominal surgery, including laparoscopy, should avoid
flying until all intraperitoneal gas is reabsorbed. Divers should
not fly for 24 hours after a dive requiring decompression stops.
Ear and sinus pain due to changes in gas volume are common
but usually mild, although patients with chronic sinusitis and
otitis media may need specialist assessment. A healthy mobile
tympanic membrane visualised during a Valsalva manoeuvre
usually suggests a patent Eustachian tube.
On long-haul flights, patients with diabetes mellitus may need
to adjust their insulin or oral hypoglycaemic dosing according to
the timing of in-flight and subsequent meals (p. 750). Advice is
available from Diabetes UK and other websites. Patients should
be able to provide documentary evidence of the need to carry
needles and insulin.
Deep venous thrombosis
Air travellers have an increased risk of venous thrombosis
(p. 975), due to a combination of factors, including loss of venous
emptying because of prolonged immobilisation (lack of muscular
activity) and reduced barometric pressure on the tissues, together
with haemoconcentration as a result of oedema and perhaps a
degree of hypoxia-induced diuresis.
Venous thrombosis can probably be prevented by avoiding
dehydration and excess alcohol, and by exercising muscles during
the flight. Without a clear cost-benefit analysis, prophylaxis with
aspirin or heparin cannot be recommended routinely, but may
be considered in high-risk cases.
Under water
^Drowning and near-drowning
Drowning is defined as death due to asphyxiation following
immersion in a fluid, while near-drowning is defined as survival
for longer than 24 hours after suffocation by immersion. Drowning
remains a common cause of accidental death throughout the
world and is particularly common in young children (Box 9.4). In
about 1 0% of cases, no water enters the lungs and death follows
intense laryngospasm (‘dry’ drowning). Prolonged immersion in
cold water, with or without water inhalation, results in a rapid fall
in core body temperature and hypothermia (p. 165).
Following inhalation of water, there is a rapid onset of ventilation-
perfusion imbalance with hypoxaemia, and the development
170 • ENVIRONMENTAL MEDICINE
of diffuse pulmonary oedema. Fresh water is hypotonic and,
although rapidly absorbed across alveolar membranes, impairs
surfactant function, which leads to alveolar collapse and right-
to-left shunting of unoxygenated blood. Absorption of large
amounts of hypotonic fluid can result in haemolysis. Salt water
is hypertonic and inhalation provokes alveolar oedema, but the
overall clinical effect is similar to that of freshwater drowning.
Clinical features
Those rescued alive (near-drowning) are often unconscious and
not breathing. Hypoxaemia and metabolic acidosis are inevitable
features. Acute lung injury usually resolves rapidly over 48-
72 hours, unless infection occurs (Fig. 9.6). Complications include
dehydration, hypotension, haemoptysis, rhabdomyolysis, renal
failure and cardiac arrhythmias. A small number of patients, mainly
the more severely ill, progress to develop the acute respiratory
distress syndrome (ARDS; p. 198).
Survival is possible after immersion for up to 30 minutes
in very cold water, as the rapid development of hypothermia
after immersion may be protective, particularly in children.
Long-term outcome depends on the severity of the cerebral
hypoxic injury and is predicted by the duration of immersion,
delay in resuscitation, intensity of acidosis and the presence of
cardiac arrest.
Management
Initial management requires cardiopulmonary resuscitation with
administration of oxygen and maintenance of the circulation
(p. 456). It is important to clear the airway of foreign bodies
and protect the cervical spine. Continuous positive airways
pressure (CPAP; p. 202) should be considered for spontaneously
breathing patients with oxygen saturations of <94%. Observation
is required for a minimum of 24 hours. Prophylactic antibiotics are
only required if exposure was to obviously contaminated water.
Fig. 9.6 Near-drowning. Chest X-ray of a 39-year-old farmer, 2 weeks
after immersion in a polluted freshwater ditch for 5 min before rescue.
Airspace consolidation and cavities in the left lower lobe reflect secondary
staphylococcal pneumonia and abscess formation.
Diving-related illness
The underwater environment is extremely hostile. Other than
drowning, most diving illness is related to changes in barometric
pressure and its effect on gas behaviour.
Ambient pressure under water increases by 101 kPa
(1 atmosphere, 1 ata) for every 1 0 metres of seawater (msw)
or 33 eet of seawater (fsw) depth. As divers descend, the partial
pressures of the gases they are breathing increase (Box 9.5),
and the blood and tissue concentrations of dissolved gases rise
accordingly. Nitrogen is a weak anaesthetic agent, and if the
inspiratory pressure of nitrogen is allowed to increase above
320 kPa (3.2 ata; i.e. a depth of approximately 30 msw), it
produces ‘narcosis’, resulting in impairment of cognitive function
and manual dexterity, not unlike alcohol intoxication. For this
reason, compressed air can be used only for shallow diving.
Oxygen is also toxic at inspired pressures above approximately
40 kPa (0.4 ata; inducing apprehension, muscle twitching,
euphoria, sweating, tinnitus, nausea and vertigo), so 100%
oxygen cannot be used as an alternative. For dives deeper than
approximately 30 msw, mixtures of oxygen with nitrogen and/
or helium are used.
While drowning remains the most common diving-related
cause of death, another important group of disorders usually
present once the diver returns to the surface: decompression
illness (DCI) and barotrauma.
Clinical features
Decompression illness
This includes decompression sickness (DCS) and arterial gas
embolism (AGE). While the vast majority of symptoms of DCI
present within 6 hours of a dive, they can also be provoked by
flying (further decompression), and thus patients may present to
medical services at sites far removed from the dive.
Exposure of individuals to increased partial pressures of
nitrogen results in additional nitrogen being dissolved in body
tissues; the amount dissolved depends on the depth/pressure
and on the duration of the dive. On ascent, the tissues become
supersaturated with nitrogen, and this places the diver at risk
of producing a critical quantity of gas (bubbles) in tissues if the
ascent is too fast. The gas so formed may cause symptoms
locally, peripherally due to bubbles passing through the pulmonary
vascular bed (Box 9.6) or by embolisation elsewhere. Arterial
embolisation may occur if the gas load in the venous system
exceeds the lungs’ abilities to excrete nitrogen, or when bubbles
pass through a patent foramen ovale (present asymptomatically
il
9.5 Physics of breathing compressed air while diving
in sea water
Depth
Lung
volume
Barometric
pressure
Pi02
P/l\l2
Surface
100%
101 kPa
(1 ata)
21 kPa
(0.21 ata)
79 kPa
(0.78 ata)
10m
50%
202 kPa
(2 ata)
42 kPa
(0.42 ata)
159 kPa
(1.58 ata)
20 m
33%
303 kPa
(3 ata)
63 kPa
(0.63 ata)
239 kPa
(2.34 ata)
30 m
25%
404 kPa
(4 ata)
84 kPa
(0.84 ata)
31 9 kPa
(3.12 ata)
Humanitarian crisis • 171
9.6 Assessment of a patient with
decompression illness
Evolution
• Progressive
• Static
• Relapsing
• Spontaneously improving
Manifestations
• Pain: often large joints, e.g. shoulder (‘the bends’)
• Neurological: any deficit is possible
• Audiovestibular: vertigo, tinnitus, nystagmus; may mimic inner ear
barotrauma
• Pulmonary: chest pain, cough, haemoptysis, dyspnoea; may be due
to arterial gas embolism (AGE)
• Cutaneous: itching, erythematous rash
• Lymphatic: tender lymph nodes, oedema
• Constitutional: headache, fatigue, general malaise
Dive profile
• Depth
• Type of gas used
• Duration of dive
Information required by diving specialists to decide appropriate treatment. See
contact details on page 172.
in 25-30% of adults; p. 531). Although DCS and AGE can be
indistinguishable, their early treatment is the same.
Barotrauma
During the ascent phase of a dive, the gas in the diver’s lungs
expands due to the decreasing pressure. The diver must
therefore ascend slowly and breathe regularly; if ascent is
rapid or the diver holds his/her breath, the expanding gas may
cause lung rupture (pulmonary barotrauma). This can result in
pneumomediastinum, pneumothorax or AGE as a result of gas
passing directly into the pulmonary venous system. Other air-filled
body cavities may be subject to barotrauma, including the ear and
sinuses.
Management
The patient is nursed horizontally and airway, breathing and
circulation are assessed. Treatment includes the following:
• High-flow oxygen is given by a tight-fitting mask using a
rebreathing bag. This assists in the washout of excess
inert gas (nitrogen) and may reduce the extent of local
tissue hypoxia resulting from focal embolic injury.
• Fluid replacement (oral or intravenous) corrects the
intravascular fluid loss from endothelial bubble injury and
dehydration associated with immersion. Maintenance of
an adequate peripheral circulation is important for the
excretion of excess dissolved gas.
• Recompression is the definitive therapy. Transfer to a
recompression facility may be by surface or air, provided
that the altitude remains low (<300 m) and the patient
continues to breathe 100% oxygen. Recompression
reduces the volume of gas within tissues (Boyle’s law),
forces nitrogen back into solution and is followed by
slow decompression, allowing the nitrogen load to be
excreted.
The majority of patients make a complete recovery with
treatment, although a small but significant proportion are left
with neurological disability.
Humanitarian crisis
Humanitarian crises are common. If the medical profession is
to help, it must understand that the emergency treatment of a
few sick and injured people is not always the priority and that
there is a set of basic needs that must be addressed in order
to do the most for the most.
A humanitarian crisis can take many forms: an environmental
disaster, mass emigration due to drought, conflict or famine, a
disease outbreak or any number of natural or man-made events.
When this event overwhelms the resources of the affected
country’s government, then the international community will
often step in to help. Although a full examination of the subject is
beyond the scope of this book, there are a few basic principles
for managing a humanitarian crisis.
The response is broken down into four phases:
1 . recognition (first week)
2. emergency response (first month)
3. consolidation phase (to crisis resolution or crisis
containment)
4. handover and withdrawal.
Recognition
Recognition of a disaster may be obvious in a sudden event
such as an earthquake or a tidal wave, but less obvious in a
disease outbreak or when it stems from internal conflict. The
recognition phase is for the host nation rather than the international
community, and requests for support will come from the affected
country’s government.
Emergency response
During the emergency phase, responders (whether international,
governmental or the charity sector) will undertake an initial
assessment of need, set objectives, mobilise resources, coordinate
with other agencies and deploy to the crisis in order to deliver
an initial response.
| Consolidation phase
The consolidation phase involves matching resources to need,
dealing with the crisis, building resilience, supporting infrastructure
(human and physical) and instituting systems to manage the
ongoing health needs of the population.
Handover and withdrawal
Once the crisis is under control and the country is able to manage
within resources, a phased withdrawal can occur.
Health-care priorities
When the normal infrastructure of a country or area fails, then
populations are at risk, whether they shelter in place or flee,
leading to mass migration. For health-care teams, rather than
logisticians, rescue teams or security forces, there are well-
defined priorities, which must be in place (Box 9.7). This must
all occur during the emergency phase and is followed by the
172 • ENVIRONMENTAL MEDICINE
i
1 . Assessment of population need
2. Safe water and sanitation
3. Food and nutrition
4. Shelter and warmth
5. Emergency health care
6. Immunisation of risk groups
7. Control of communicable diseases
8. Ongoing health surveillance and reporting
9. Training and deployment of indigenous health-care
workers
10. Handover of responsibility to local authorities
implementation of a public health surveillance and reporting
system and the mobilisation of local human resources, and their
training and deployment during the consolidation phase in order
to prepare for handover to the local competent authority and
withdrawal.
Further information
Websites
altitude.org A website written by doctors with expertise and experience
of expedition and altitude medicine and critical care.
diversalertnetwork.org Advice on the clinical management of diving
illness and emergency assistance services.
emergency.cdc.gov/radiation/ The Centers for Disease Control and
Prevention provides information and links on all forms of radiation
for patients and professionals.
msf.org Information and advice about all aspects of responding to
humanitarian crises around the world.
Telephone numbers
Two organisations can offer national and international advice on
diving emergencies and recompression facilities:
• Within the UK, the National Diving Accident Helpline on
+44 (0)7831 151523 (24 hours).
• Outside the UK, contact the Divers Alert Network
International Emergency Hotline +1 -91 9-684-91 1 1 .
9.7 Priorities in a humanitarian crisis
VR Tallentire
MJ MacMahon
Acute medicine and
critical illness
Clinical examination in critical care 174
Monitoring 175
Acute medicine 176
The decision to admit to hospital 176
Ambulatory care 1 76
Presenting problems in acute medicine 176
Chest pain 176
Acute breathlessness 179
Syncope/presyncope 1 81
Delirium 183
Headache 1 85
Unilateral leg swelling 1 86
Identification and assessment of deterioration 188
Early warning scores and the role of the medical emergency team 1 88
Immediate assessment of the deteriorating patient 1 88
Selecting the appropriate location for ongoing management 1 89
Common presentations of deterioration 190
Tachypnoea 1 90
Hypoxaemia 190
Tachycardia 191
Hypotension 1 93
Hypertension 193
Decreased conscious level 1 94
Decreased urine outpul/deteriorating renal function 1 95
Disorders causing critical illness 196
Sepsis and the systemic inflammatory response 196
Acute respiratory distress syndrome 1 98
Acute circulatory failure (cardiogenic shock) 1 99
Post cardiac arrest 200
Other causes of multi-organ failure 201
Critical care medicine 201
Decisions around intensive care admission 201
Stabilisation and institution of organ support 202
Respiratory support 202
Cardiovascular support 204
Renal support 208
Neurological support 208
Daily clinical management in intensive care 208
Clinical review 208
Sedation and analgesia 209
Delirium in intensive care 209
Weaning from respiratory support 209
Extubation 210
Tracheostomy 210
Nutrition 21 0
Other essential components of intensive care 21 0
Complications and outcomes of critical illness 211
Adverse neurological outcomes 21 1
Other long-term problems 21 2
The older patient 21 2
Withdrawal of active treatment and death in intensive care 213
Discharge from intensive care 21 3
Critical care scoring systems 213
174 • ACUTE MEDICINE AND CRITICAL ILLNESS
Clinical examination in critical care
A Airway
Is the airway patent?
Is the end-tidal CO2 trace
normal?
Are there any signs of airway
obstruction?
I Infection
What is the temperature?
Review recent infective
markers and trend
What antibiotics are being
given and what is the
duration of treatment?
H Haematology
What are the haemoglobin/
platelet levels?
Are there any signs of
bleeding?
G Glucose
What is the glucose level?
Is insulin being administered?
/J /
/
\
F Fluids, electrolytes and
renal system
What is the fluid balance?
Urine volume and colour?
Is there any oedema?
Review the renal biochemistry
and electrolyte levels
E Enteral/exposure
Feeding regime
Stool frequency
Abdominal tenderness/bowel
sounds present?
B Breathing
Is the physiology normal
(Sp02, respiratory rate, tidal
volume)?
What is the level of support?
Are there any abnormal signs
on chest examination?
Review the ventilator settings,
arterial blood gases and
recent chest X-ray
C Circulation
Is the physiology normal
(heart rate, blood pressure,
peripheral temperature,
lactate, urine output)?
How much support is required
(inotrope, vasopressor)?
D Disability
Level of responsiveness
Delirium screen
Pupillary responses
Doses of sedative drugs
'?
Monitoring • 175
Monitoring
Electrocardiography
Heart rate, rhythm and QRS morphology
Arterial line trace
Size of the area under the curve is proportional to stroke
volume
Narrow peaks suggest low stroke volume as shown here
Oxygen saturation
Saturation of haemoglobin measured by plethysmography
(Sp02). Gives an indication of adequacy of oxygenation,
and the quality of tissue perfusion can also be inferred -
a flat trace suggests poor peripheral perfusion
Central venous pressure trace
A non-specific guide to volume status and right ventricular
function. Increased values in fluid overload and right
ventricular failure
kPa mmHg
= Capnography
Numerical value of end-tidal C02 (ETCO2) is less than
arterial PC02 (PaCC>2) by a variable amount. Shape of
trace can signify airway displacement/obstruction,
bronchospasm or a low cardiac output (as shown below)
Steep ‘upstroke’ Shallow ‘upstroke’
-40 in early expiration in early expiration
Decreasing cardiac output
Decreasing size of
ETCO2 waveform
Time (secs)
Normal
Bronchospasm
Partial obstruction/displacement
of airway device
No ventilation
(from any cause)
Bedside physiological data commonly monitored in an intensive care unit setting.
Plethysmography (Sp02)
Basic principles
• Uses the different red and infrared
absorption profiles of oxyhaemoglobin
and deoxyhaemoglobin to estimate
arterial oxyhaemoglobin saturation
(Sa02)
• Only pulsatile absorption is
measured
• A poor trace correlates with poor
perfusion
Sources of error
• Carboxyhaemoglobin - absorption profile
is the same as oxyhaemoglobin: falsely
elevated Sp02
• Methaemoglobinaemia - Sp02 will tend
towards 85%
• Ambient light/poor application of probe/
severe tricuspid regurgitation (pulsatile
venous flow): falsely depressed Sp02
• Reduced accuracy below 80% saturation
• Hyperbilirubinaemia does not affect Sp02
176 • ACUTE MEDICINE AND CRITICAL ILLNESS
Hospital medicine is becoming ever more specialised and people
are living longer while accruing increasing numbers of chronic
disease diagnoses. Rather than diminishing the role of the
generalist, these factors paradoxically create a need for experts
in the undifferentiated presentation. In the UK such physicians
are known as ‘general physicians’, while in the US they are
referred to as ‘hospitalists’.
Acute illness can present in a large variety of ways, depending
on the nature of the illness, the underlying health of the individual,
and their cultural and religious background. The skills of prompt
diagnosis formation and provision of appropriate treatment rely on
the integration of information from all the available sources, along
with careful consideration of underlying chronic health problems.
Patients who deteriorate while in hospital make up a small
but important cohort. If they are well managed, in-hospital
cardiac arrest rates will be low. This can be achieved through
the combined effects of prompt resuscitation and appropriate
end-of-life decision-making. Early recognition of deterioration by
ward teams and initial management by health-care professionals
operating within a functioning rapid response system are the
central tenets of any system designed to improve the outcomes
of deteriorating ward patients.
Intensive care medicine has developed into a prominent
specialty, central to the safe functioning of a modern acute
hospital. Scientific endeavour has resulted in a much better
understanding of the molecular pathophysiology of processes
such as sepsis and acute respiratory distress syndrome, which
account for much premature death worldwide.
Acute medicine
Acute medicine is the part of general medicine that is concerned
with the immediate and early management of medical patients
who require urgent care. As a specialty, it is closely aligned
with emergency medicine and intensive care medicine, but is
firmly rooted within general medicine. Acute physicians manage
the adult medical take and lead the development of acute care
pathways that aim to reduce variability, improve care and cut
down hospital admissions.
The decision to admit to hospital
Every patient presenting to hospital should be assessed by a
clinician who is able to determine whether or not admission
is required. The requirement for admission is determined by
many factors, including the severity of illness, the patient’s
physiological reserve, the need for urgent investigations, the nature
of proposed treatments and the patient’s social circumstances.
In many cases, it is clear early in the assessment process that a
patient requires admission. In such cases, a move into a medical
receiving unit - often termed a medical admissions unit (MAU) or
acute medical unit (AMU) - should be facilitated as soon as the
initial assessment has been completed and urgent investigations
and/or treatments have been instigated. In hospitals where
such units do not exist, patients will need to be moved to a
downstream ward once treatment has been commenced and
they have been deemed sufficiently stable. Following the initial
assessment, it may be possible to discharge stable patients
home with a plan for early follow-up (such as a rapid-access
specialist clinic appointment).
Ambulatory care
In some hospitals, it is increasingly possible for patient care to
be coordinated in an ambulatory setting, negating the need for
a patient to remain in hospital overnight. In the context of acute
medicine, ambulatory care can be employed for conditions that
are perceived by either the patient or the referring practitioner as
requiring prompt clinical assessment by a competent decision¬
maker with access to appropriate diagnostic resources. The
patient may return on several occasions for investigation,
observation, consultation or treatment. Some presentations,
such as a unilateral swollen leg (p. 186), lend themselves to
this type of management (Box 10.1). If indicated, a Doppler
ultrasound can be arranged, and patients with confirmed deep
vein thromboses can be anticoagulated on an outpatient basis.
Successful ambulatory care requires careful patient selection;
while many patients may cherish the opportunity to sleep at
home, others may find frequent trips to hospital or clinic too
difficult due to frailty, poor mobility or transport difficulties.
Presenting problems in acute medicine
Chest pain
Chest pain is a common symptom in patients presenting to
hospital. The differential diagnosis is wide (Box 10.2), and a
10.1 Groups of patients who are potentially suitable for ambulatory care
Group
Example(s)
Quality and safety issues
Diagnostic exclusion group
Chest pain - possible myocardial infarction;
breathlessness - possible pulmonary embolism
Even when a specific condition has been excluded, there is still
a need to explain the patient’s symptoms through the diagnostic
process
Low-risk stratification group
Non-variceal upper gastrointestinal bleed with
low Blatchford score (p. 780); community-
acquired pneumonia with low CURB-65 score
(p. 583)
Appropriate treatment plans should be in place
Specific procedure group
Replacement of percutaneous endoscopic
gastrostomy (PEG) tube; drainage of pleural
effusion/ascites
The key to implementation is how ambulatory care for this group
of patients can be delivered when they present out of hours
Outpatient group with
supporting infrastructure
Deep vein thrombosis (DVT); cellulitis
These are distinct from the conditions listed above because the
infrastructure required to manage them is quite different
Presenting problems in acute medicine • 177
f 10.2 Differential diagnosis of chest pain
Central
Cardiac
• Myocardial ischaemia (angina)
• Pericarditis
• Myocardial infarction
• Mitral valve prolapse
• Myocarditis
syndrome
Aortic
• Aortic dissection
• Aortic aneurysm
Oesophageal
• Oesophagitis
• Oesophageal perforation
• Oesophageal spasm
(Boerhaave’s syndrome)
• Mallory— Weiss syndrome
Pulmonary embolus
Mediastinal
• Malignancy
Anxiety/emotion1
Peripheral
Lungs/pleura
• Pulmonary infarct
• Malignancy
• Pneumonia
• Tuberculosis
• Pneumothorax
• Connective tissue disorders
Musculoskeletal2
• Osteoarthritis
• Intercostal muscle injury
• Rib fracture/injury
• Epidemic myalgia (Bornholm
• Acute vertebral fracture
disease)
• Costochondritis (Tietze’s
syndrome)
Neurological
• Prolapsed intervertebral disc
• Thoracic outlet syndrome
• Herpes zoster
^ay also cause peripheral chest pain.
2Can sometimes cause central chest pain.
detailed history and thorough clinical examination are paramount
to ensure that the subsequent investigative pathway is appropriate.
Presentation
Chest ‘pain’ is clearly a subjective phenomenon and may be
described by patients in a variety of different ways. Whether
the patient describes ‘pain’, ‘discomfort’ or ‘pressure’ in the
chest, there are some key features that must be elicited from
the history.
Site and radiation
Pain secondary to myocardial ischaemia is typically located in the
centre of the chest. It may radiate to the neck, jaw, and upper
or even lower arms. Occasionally, it may be experienced only
at the sites of radiation or in the back. The pain of myocarditis
or pericarditis is characteristically felt retrosternal ly, to the left of
the sternum, or in the left or right shoulder. The severe pain of
aortic dissection is typically central with radiation through to the
back. Central chest pain may also occur with tumours affecting
the mediastinum, oesophageal disease (p. 791) or disease of the
thoracic aorta (p. 505). Pain situated over the left anterior chest
and radiating laterally is unlikely to be due to cardiac ischaemia
and may have many causes, including pleural or lung disorders,
musculoskeletal problems or anxiety. Rarely, sharp, left-sided
chest pain that is suggestive of a musculoskeletal problem may
be a feature of mitral valve prolapse (p. 520).
Characteristics
Pleurisy, a sharp or ‘catching’ chest pain aggravated by deep
breathing or coughing, is indicative of respiratory pathology,
particularly pulmonary infection or infarction. However, the pain
associated with myocarditis or pericarditis is often also described
as ‘sharp’ and may ‘catch’ during inspiration, coughing or lying
flat. It typically varies in intensity with movement and the phase
of respiration. A malignant tumour invading the chest wall or
ribs can cause gnawing, continuous local pain. The pain of
myocardial ischaemia is typically dull, constricting, choking or
‘heavy’, and is usually described as squeezing, crushing, burning
or aching. Patients often emphasise that it is a discomfort rather
than a pain. Angina occurs during (not after) exertion and is
promptly relieved (in less than 5 minutes) by rest. It may also be
precipitated or exacerbated by emotion but tends to occur more
readily during exertion, after a large meal or in a cold wind. In
crescendo or unstable angina, similar pain may be precipitated
by minimal exertion or at rest. The increase in venous return or
preload induced by lying down may also be sufficient to provoke
pain in vulnerable patients (decubitus angina). Patients with
reversible airways obstruction, such as asthma, may also describe
exertional chest tightness that is relieved by rest. This may be
difficult to distinguish from myocardial ischaemia. Bronchospasm
may be associated with wheeze, atopy and cough (p. 556).
Musculoskeletal chest pain is variable in site and intensity but
does not usually fall into any of the patterns described above.
The pain may vary with posture or movement of the upper body,
or be associated with a specific movement (bending, stretching,
turning). Many minor soft tissue injuries are related to everyday
activities, such as driving, manual work and sport.
Onset
The pain associated with myocardial infarction (Ml) typically takes
several minutes or even longer to develop to its maximal intensity;
similarly, angina builds up gradually in proportion to the intensity
of exertion. Pain that occurs after, rather than during, exertion
is usually musculoskeletal or psychological in origin. The pain
of aortic dissection (severe and ‘tearing’), massive pulmonary
embolism (PE) or pneumothorax is usually very sudden in onset.
Other causes of chest pain tend to develop more gradually, over
hours or even days.
Associated features
The pain of Ml, massive PE or aortic dissection is often
accompanied by autonomic disturbance, including sweating,
nausea and vomiting. Some patients describe a feeling of
impending death, referred to as ‘angor animi’. Breathlessness,
due to pulmonary congestion arising from transient ischaemic
left ventricular dysfunction, is often a prominent feature of
myocardial ischemia. Breathlessness may also accompany any
of the respiratory causes of chest pain and can be associated
with cough, wheeze or other respiratory symptoms. Patients
with myocarditis or pericarditis may describe a prodromal viral
illness. Gastrointestinal disorders, such as gastro-oesophageal
reflux or peptic ulceration, may present with chest pain that is
hard to distinguish from myocardial ischaemia; it may even be
precipitated by exercise and be relieved by nitrates. However, it
is usually possible to elicit a history relating chest pain to supine
posture or eating, drinking or oesophageal reflux. The pain of
gastro-oesophageal reflux often radiates to the interscapular region
and dysphagia may be present. Severe chest pain arising after
retching or vomiting, or following oesophageal instrumentation,
should raise the possibility of oesophageal perforation.
178 • ACUTE MEDICINE AND CRITICAL ILLNESS
Location
I 1
Radiation
I 1 -
Character
I I -
Precipitation
l l -
Relieving factors
Associated
features
Fig. 10.1 Identifying ischaemic cardiac pain: the ‘balance’ of evidence.
>►
>►
>►
>►
>►
>►
Peripheral, localised
Other or no radiation
Sharp, stabbing, catching
Spontaneous, not related to exertion,
provoked by posture, respiration or palpation
Not relieved by rest
Slow or no response to nitrates
Respiratory, gastrointestinal,
locomotor or psychological
Breathlessness
/■
V
Central, diffuse
r
Jaw/neck/shoulder/arm
>
V
(occasionally back)
Tight, squeezing, choking
\
\ _
J
s
Precipitated by exertion
■>
V _
and/or emotion
s
Rest
\ _
Quick response to nitrates
_ J
M
M
M
M
M
EZ
Anxiety-induced chest pain may be associated with
breathlessness (without hypoxaemia), throat tightness, perioral
tingling and other evidence of emotional distress. It is important
to remember, however, that chest pain itself can be an extremely
frightening experience, and so psychological and organic features
often coexist. Anxiety may amplify the effects of organic disease
and a confusing clinical picture may result.
A detailed and clear history is key to narrowing the differential
diagnosis of chest pain. Figure 10.1 shows how certain features
of the history, particularly when combined, can tip the balance
of evidence towards or away from ischaemic cardiac chest pain.
Clinical assessment
Cardiorespiratory examination may detect clinical signs that help
guide ongoing investigation. Patients with a history compatible with
myocardial ischaemia should have a 12-lead electrocardiogram
(ECG) performed while clinical examination proceeds. Ongoing
chest pain with clinical features of shock or pulmonary oedema,
or ECG evidence of ventricular arrhythmia or complete heart
block should prompt urgent cardiology review and referral to a
higher level of care.
Chest pain that is accompanied by clinical evidence of
increased intracardiac pressure (especially a raised jugular venous
pressure) increases the likelihood of myocardial ischaemia or
massive PE. The legs should be examined for clinical evidence
of deep vein thrombosis.
A large pneumothorax should be evident on clinical examination,
with absent breath sounds and a hyper-resonant percussion
note on the affected side. Other unilateral chest signs, such
as bronchial breathing or crackles, are most likely to indicate a
respiratory tract infection, and a chest X-ray should be expedited.
Pericarditis may be accompanied by a pericardial friction
rub. In aortic dissection, syncope or neurological deficit may
occur. Examination may reveal asymmetrical pulses, features of
undiagnosed Marfan’s syndrome (p. 508) or a new early diastolic
murmur representing aortic regurgitation.
Any disease process involving the pleura may restrict rib
movement and a pleural rub may be audible on the affected
side. Local tenderness of the chest wall is likely to indicate
musculoskeletal pain but can also be found in pulmonary
infarction.
Subdiaphragmatic inflammatory pathology, such as a liver
abscess, cholecystitis or ascending cholangitis, can mimic
pneumonia by causing fever, pleuritic chest pain and a small
sympathetic pleural effusion, usually on the right. Likewise,
acute pancreatitis can present with thoracic symptoms, and an
amylase or lipase level should be requested where appropriate.
It is imperative that the abdomen is examined routinely in all
patients presenting with pleuritic chest pain.
Initial investigations
Chest X-ray, ECG and biomarkers (e.g. troponin, D-dimer) play a
pivotal role in the evaluation of chest pain. However, indiscriminate
ordering of such investigations may result in diagnostic confusion
and over-investigation. The choice of investigation(s) is intimately
linked to the history and examination findings. A chest X-ray
and 12-lead ECG should be performed in the vast majority of
patients presenting to hospital with chest pain. Pregnancy is not
a contraindication to chest X-ray, but particular consideration
should be given to whether the additional diagnostic information
justifies breast irradiation.
The chest X-ray may confirm the suspected diagnosis,
particularly in the case of pneumonia. Small pneumothoraces
are easily missed, as are rib fractures or small metastatic deposits,
and all should be considered individually during chest X-ray review.
A widened mediastinum suggests acute aortic dissection but a
normal chest X-ray does not exclude the diagnosis. Provided it
has been more than 1 hour since the onset of pain, chest X-ray
in oesophageal rupture may reveal subcutaneous emphysema,
pneumomediastinum or a pleural effusion.
Patients with a history compatible with myocardial ischaemia
require an urgent 12-lead ECG. Acute chest pain with ECG
changes indicating a ST segment elevation myocardial infarction
(STEMI) suggests that the patient is likely to benefit from immediate
reperfusion therapy. Specific information relating to cocaine or
amphetamine use should be sought, particularly in younger
Presenting problems in acute medicine • 179
10.3 Causes of elevated serum troponin other than
acute coronary syndrome
Cardiorespiratory causes
• Pulmonary embolism
• Acute pulmonary oedema
• Tachyarrhythmias
• Myocarditis/myopericarditis
Non-cardiorespiratory causes
• Prolonged hypotension
• Severe sepsis
• Severe burns
Aortic dissection
Cardiac trauma
Cardiac surgery/ablation
Stroke
Subarachnoid haemorrhage
End-stage renal failure
patients. In the context of a compatible history, an ECG showing
ischaemic changes that do not meet STEMI criteria should prompt
regular repeat ECGs and treatment for non-ST segment elevation
myocardial infarction (NSTEMI)/unstable angina. Measurement
of serum troponin concentration on admission is often helpful in
cases where there is diagnostic doubt, but a negative result should
always prompt a repeat sample 6-12 hours after maximal pain.
Acute coronary syndrome may be diagnosed with confidence in
patients with a convincing history of ischaemic pain (Fig. 10.1)
and either ECG evidence of ischaemia or an elevated serum
troponin. If an elevated serum troponin is found in a patient
who has an atypical history or is at low risk of ischaemic heart
disease, then alternative causes of raised troponin should be
considered (Box 10.3). Further management of acute coronary
syndromes is discussed on page 498.
In the absence of convincing ECG evidence of myocardial
ischaemia, other life-threatening causes of chest pain, such as
aortic dissection, massive PE and oesophageal rupture, should
be considered. Suspicion of aortic dissection (background of
hypertension, trauma, pregnancy or previous aortic surgery)
should prompt urgent thoracic computed tomography (CT) or
transoesophageal echocardiography. An ECG in the context of
massive PE most commonly reveals only a sinus tachycardia,
but may show new right axis deviation, right bundle branch block
or a dominant R wave in The classical finding of SiQ3T3 (a
deep S wave in lead I, with a Q wave and T wave inversion in
lead III) is rare. If massive PE is suspected and the patient is
haemodynamically unstable, a transthoracic echocardiogram,
to seek evidence of right heart strain and exclude alternative
diagnoses such as tamponade, is extremely useful.
If the patient is deemed to be at low risk of PE, a D-dimer test
can be informative, as a negative result effectively excludes the
diagnosis. The D-dimer test should be performed only if there
is clinical suspicion of PE, as false-positive results can lead to
unnecessary investigations. If the D-dimer is positive, there is
high clinical suspicion, or there is other convincing evidence of
PE (such as features of right heart strain on the ECG), prompt
imaging should be arranged (p. 619 and Fig. 17.67).
Acute breathlessness
In acute breathlessness, the history, along with a rapid but
careful examination, will usually suggest a diagnosis that can
be confirmed by routine investigations including chest X-ray,
12-lead ECG and arterial blood gas (ABG) sampling.
Presentation
A key feature of the history is the speed of onset of breathlessness.
Acute severe breathlessness (over minutes or hours) has a distinct
Fig. 10.2 Inhaled foreign body. [A] Chest X-ray showing a tooth lodged
in a main bronchus. [§] Bronchoscopic appearance of inhaled foreign body
(tooth) with a covering mucous film.
differential diagnosis list to chronic exertional breathlessness. The
presence of associated cardiovascular (chest pain, palpitations,
sweating and nausea) or respiratory symptoms (cough, wheeze,
haemoptysis, stridor) can narrow the differential diagnosis yet
further. A previous history of left ventricular dysfunction, asthma or
exacerbations of chronic obstructive pulmonary disease (COPD)
is important. In the severely ill patient, it may be necessary to
obtain the history from accompanying witnesses. In children,
the possibility of inhalation of a foreign body (Fig. 10.2) or acute
epiglottitis should always be considered. There is often more
than one underlying diagnosis; a thorough assessment should
continue, even after a possible diagnosis has been reached,
particularly if the severity of symptoms does not seem to be
adequately explained. The causes of acute severe breathlessness
are covered here; chronic exertional dyspnoea is discussed
further on page 557.
Clinical assessment
Airway obstruction, anaphylaxis and tension pneumothorax
require immediate identification and treatment. If any of these
is suspected, treatment should not be delayed while additional
investigations are performed, and anaesthetic support is likely
to be required. In the absence of an immediately life-threatening
cause, the following should be assessed and documented:
• level of consciousness
• degree of central cyanosis
• work of breathing (rate, depth, pattern, use of accessory
muscles)
• adequacy of oxygenation (Sp02)
180 • ACUTE MEDICINE AND CRITICAL ILLNESS
• ability to speak (in single words or sentences)
• cardiovascular status (heart rate and rhythm, blood
pressure (BP) and peripheral perfusion).
Pulmonary oedema is suggested by a raised jugular venous
pressure and bi-basal crackles or diffuse wheeze, while asthma
or COPD is characterised by wheeze and prolonged expiration.
A hyper-resonant hemithorax with absent breath sounds raises
the possibility of pneumothorax, while severe breathlessness
with normal breath sounds may indicate PE. Leg swelling may
suggest cardiac failure or, if asymmetrical, venous thrombosis.
The presence of wheeze is not always indicative of
bronchospasm. In acute left heart failure, an increase in the
left ventricular diastolic pressure causes the pressure in the left
atrium, pulmonary veins and pulmonary capillaries to rise. When
the hydrostatic pressure of the pulmonary capillaries exceeds the
oncotic pressure of plasma (about 25-30 mmHg), fluid moves
from the capillaries into the interstitium. This stimulates respiration
through a series of autonomic reflexes, producing rapid, shallow
respiration, and congestion of the bronchial mucosa may cause
wheeze (sometimes known as cardiac asthma). Sitting upright or
standing may provide some relief by helping to reduce congestion
at the apices of the lungs. The patient may be unable to speak
and is typically distressed, agitated, sweaty and pale. Respiration
is rapid, with recruitment of accessory muscles, coughing and
wheezing. Sputum may be profuse, frothy and blood-streaked
or pink. Extensive crepitations and rhonchi are usually audible
in the chest and there may also be signs of right heart failure.
Any arrhythmia may cause breathlessness, but usually does
so only if the heart is structurally abnormal, such as with the
onset of atrial fibrillation in a patient with mitral stenosis. In such
cases, the classic mid-diastolic rumbling murmur with pre-systolic
accentuation may be heard. Patients sometimes describe chest
tightness as ‘breathlessness’. However, myocardial ischaemia
may also induce true breathlessness by provoking transient left
ventricular dysfunction. When breathlessness is the dominant
or sole feature of myocardial ischaemia, it is known as ‘angina
equivalent’. A history of chest tightness or close correlation with
exercise should be sought.
Initial investigations
As shown in Box 10.4, amalgamation of a clear history and
thorough clinical examination with chest X-ray, ECG and ABG
findings will usually indicate the primary cause of breathlessness.
If bronchospasm is suspected, measurement of peak expiratory
flow will assist in the assessment of severity and should be
performed whenever possible. An ABG will often provide additional
information to Sp02 measurement alone, particularly if there is
clinical evidence (drowsiness, delirium, asterixis) or a strong
likelihood of hypercapnia. An acute rise in PaC02 will increase
the HC03“ by only a small amount, resulting in inadequate
buffering and acidaemia. Renal compensation and a large rise in
HC03“ will take at least 1 2 hours. In acute type II respiratory failure
(p. 565), the rate of rise of PaC02 is a better indicator of severity
than the absolute value.
An ABG is essential in the context of smoke inhalation
to measure carboxyhaemoglobin level, and is central to the
identification of metabolic acidosis or the diagnosis of psychogenic
hyperventilation (Box 10.4). If ‘angina equivalent’ is suspected,
10.4 Clinical features in acute breathlessness
Condition
History
Signs
Chest X-ray
ABG
ECG
Pulmonary
oedema
Chest pain, palpitations,
orthopnoea, cardiac
history*
Central cyanosis, TJVP,
sweating, cool extremities,
basal crackles*
Cardiomegaly,
oedema/pleural
effusions*
iPa02
iPaC02
Sinus tachycardia,
ischaemia*,
arrhythmia
Massive
pulmonary
embolus
Risk factors, chest pain,
pleurisy, syncope*,
dizziness*
Central cyanosis, TJVP*,
absence of signs in the
lung*, shock (tachycardia,
hypotension)
Often normal
Prominent hilar
vessels, oligaemic
lung fields*
iPa02
iPaC02
Sinus tachycardia,
RBBB, pattern
tr (v,-v4)
Acute severe
asthma
History of asthma,
asthma medications,
wheeze*
Tachycardia, pulsus
paradoxus, cyanosis (late),
— >JVP*, ipeak flow,
wheeze*
Hyperinflation only
(unless complicated
by pneumothorax)*
iPa02
iPaC02 (T PaC02 in
extremis)
Sinus tachycardia
(bradycardia in
extremis)
Acute
exacerbation
of COPD
Previous episodes*,
smoker. If in type II
respiratory failure, may
be drowsy
Cyanosis, hyperinflation*,
signs of C02 retention
(flapping tremor, bounding
pulses)*
Hyperinflation*,
bullae, complicating
pneumothorax
or \L\LPaO2
TPaC02 in type II failure
± Th+, THCXV in
chronic type II failure
Normal, or signs of
right ventricular
strain
Pneumonia
Prodromal illness*,
fever*, rigors*, pleurisy*
Fever, delirium, pleural
rub*, consolidation*,
cyanosis (if severe)
Pneumonic
consolidation*
iPa02
iPaC02 (T in extremis)
Tachycardia
Metabolic
acidosis
Evidence of diabetes
mellitus or renal disease,
aspirin or ethylene glycol
overdose
Fetor (ketones),
hyperventilation without
heart or lung signs*,
dehydration*, air hunger
Normal
Pa02 normal
UPaC02, TH+
IHCO3-
Psychogenic
Previous episodes, digital
or perioral dysaesthesia
No cyanosis, no heart or
lung signs, carpopedal
Normal
Pa02 normal*
UPaC02, lH+*
spasm
"Valuable discriminatory feature.
(ABG = arterial blood gas; COPD = chronic obstructive pulmonary disease; JVP = jugular venous pressure; RBBB = right bundle branch block)
Presenting problems in acute medicine • 181
objective evidence of myocardial ischaemia from stress testing
may help to establish the diagnosis.
Syncope/presyncope
The term ‘syncope’ refers to sudden loss of consciousness
due to reduced cerebral perfusion. ‘Presyncope’ refers to
lightheadedness, in which the individual thinks he or she may
‘black out’. Dizziness and presyncope are particularly common
in old age (Box 10.5). Symptoms are disabling, undermine
confidence and independence, and can affect a person’s ability
to work or to drive.
There are three principal mechanisms that underlie recurrent
presyncope or syncope:
• cardiac syncope due to mechanical cardiac dysfunction or
arrhythmia
• neurocardiogenic syncope (also known as vasovagal or
reflex syncope), in which an abnormal autonomic reflex
causes bradycardia and/or hypotension
• postural hypotension, in which physiological peripheral
vasoconstriction on standing is impaired, leading to
hypotension.
There are, however, other causes of loss of consciousness,
and differentiating syncope from seizure is a particular challenge.
Psychogenic blackouts (also known as non-epileptic seizures or
pseudoseizures) also need to be considered in the differential
diagnosis.
J
• Prevalence: common, affecting up to 30% of people aged
>65 years.
• Symptoms: most frequently described as a combination of
unsteadiness and lightheadedness.
• Most common causes: postural hypotension and cardiovascular
disease. Many patients have more than one underlying cause.
• Arrhythmia: can present with lightheadedness either at rest or on
activity.
• Anxiety: frequently associated with dizziness but rarely the only
cause.
• Falls: multidisciplinary workup is required if dizziness is associated
with falls.
Presentation
The history from the patient and a witness is the key to establishing
a diagnosis. The terms used for describing the symptoms
associated with syncope vary so much among patients that
they should not be taken for granted. Some patients use the
term ‘blackout’ to describe a purely visual symptom, rather
than loss of consciousness. Some may understand ‘dizziness’
to mean an abnormal perception of movement (vertigo), some
will consider this a feeling of faintness, and others will regard
it as unsteadiness. The clinician thus needs to elucidate the
exact nature of the symptoms that the patient experiences. The
potential differential diagnoses of syncope and presyncope, on
the basis of the symptoms described, is shown in Figure 10.3.
The history should always be supplemented by a direct eye¬
witness account if available. Careful history with corroboration
will usually establish whether there has been full consciousness,
altered consciousness, vertigo, transient amnesia or something
else. Attention should be paid to potential triggers (e.g. medication,
micturition, exertion, prolonged standing), the patient’s appearance
(e.g. colour, seizure activity), the duration of the episode, and
the speed of recovery (Box 10.6). Cardiac syncope is usually
sudden but can be associated with premonitory lightheadedness,
palpitation or chest discomfort. The blackout is usually brief and
recovery rapid. Exercise-induced syncope can be the presenting
feature of a number of serious pathologies (such as hypertrophic
obstructive cardiomyopathy or exercise-induced arrhythmia) and
always requires further investigation. Neurocardiogenic syncope
will often be associated with a situational trigger (such as pain
or emotion), and the patient may experience flushing, nausea,
malaise and clamminess for several minutes afterwards. Recovery
is usually quick and without subsequent delirium, provided the
patient has assumed a supine position. There is often some brief
stiffening and limb-twitching, which requires differentiation from
seizure-like movements. It is rare for syncope to cause injury or to
cause amnesia after regaining awareness. Patients with seizures
do not exhibit pallor, may have abnormal movements, usually
take more than 5 minutes to recover and are often confused.
Aspects of the history that can help to differentiate seizure from
syncope are shown in Box 10.7.
A diagnosis of psychogenic blackout (also known as non¬
epileptic seizure, pseudoseizure or psychogenic seizure) may be
suggested by specific emotional triggers, dramatic movements
10.5 Dizziness in old age
10.6 Typical features of cardiac syncope, neurocardiogenic syncope and seizures
Cardiac syncope
Neurocardiogenic syncope
Seizures
Premonitory symptoms
Often none
Lightheadedness
Palpitation
Chest pain
Breathlessness
Nausea
Lightheadedness
Sweating
Delirium
Hyperexcitability
Olfactory hallucinations
‘Aura’
Unconscious period
Extreme ‘death-like’ pallor
Pallor
Prolonged (>1 min)
unconsciousness
Motor seizure activity*
Tongue-biting
Urinary incontinence
Recovery
Rapid (<1 min)
Flushing
Slow
Nausea
Lightheadedness
Prolonged delirium (>5 mins)
Headache
Focal neurological signs
*N.B. Cardiac syncope can also cause convulsions by inducing cerebral anoxia.
182 • ACUTE MEDICINE AND CRITICAL ILLNESS
Funny turn
or blackout
Loss of
balance?
-►
Ataxia
Weakness
Loss of joint position sense
Gait dyspraxia
• Joint disease
• Visual disturbance
• Fear of falling (Chs 24 and 25)
Sensation of
movement?
(vertigo)
Central vestibular dysfunction
• ‘Physiological’ (visual-
vestibular mismatch)
• Demyelination
• Migraine
• Posterior fossa mass lesion
• Vertebro-basilar ischaemia
• Other (e.g. disorders of
cranio-vertebral junction)
Labyrinthine dysfunction
• Infection
• ‘Vestibular neuronitis’
• Benign positional vertigo
• Meniere’s disease
• Ischaemia/infarction
• Trauma
• Perilymph fistula
• Other (e.g. drugs, otosclerosis)
• Anxiety*
• Hyperventilation
• Post-concussive syndrome
• Panic attack
• Non-epileptic attack
Loss of
consciousness
# (‘blackout’)
s*
• Hypoglycaemia (Ch. 20)
Presyncope
(reduced cerebral
perfusion)
Impaired cerebral perfusion
Cardiac disease
• Arrhythmia
• Left ventricular dysfunction
• Aortic stenosis
• Hypertrophic obstructive
cardiomyopathy
Other causes
• Vasovagal syncope
• Postural hypotension
• Micturition syncope
• Cough syncope
• Carotid sinus sensitivity
Syncope
(loss of cerebral
perfusion)
* Anxiety is the most
common cause of
dizziness in those
under 65 years
Other
description
• Epileptic seizure
Fig. 10.3 The differential diagnosis of syncope and presyncope.
[W
10.7 How to differentiate seizures from syncope
Seizure
Syncope
Aura (e.g. olfactory)
+
-
Cyanosis
+
-
Lateral tongue-biting
+
-/+
Post-ictal delirium
+
-
Post-ictal amnesia
+
-
Post-ictal headache
+
-
Rapid recovery
-
+
or vocalisation, or by very prolonged duration (hours). A history
of rotational vertigo is suggestive of a labyrinthine or vestibular
disorder (p. 1086). Postural hypotension is normally obvious from
the history, with presyncope or, less commonly, syncope occurring
within a few seconds of standing. The history should include
enquiry about predisposing medications (diuretics, vasodilators,
antidepressants) and conditions (such as diabetes mellitus and
Parkinson’s disease).
Clinical assessment
Examination of the patient may be entirely normal, but may
reveal clinical signs that favour one form of syncope. The
systolic murmurs of aortic stenosis or hypertrophic obstructive
Presenting problems in acute medicine • 183
cardiomyopathy are important findings, particularly if paired with
a history of lightheadedness or syncope on exertion. BP taken
when supine and then after 1 and 3 minutes of standing may,
when combined with symptoms, provide robust evidence of
symptomatic postural hypotension.
Clinical suspicion of hypersensitive carotid sinus syndrome
(sensitivity of carotid baroreceptors to external pressure such
as a tight collar) should prompt monitoring of the ECG and BP
during carotid sinus pressure, provided there is no carotid bruit
or history of cerebrovascular disease. A positive cardio-inhibitory
response is defined as a sinus pause of 3 seconds or more; a
positive vasodepressor response is defined as a fall in systolic
BP of more than 50 mmHg. Carotid sinus pressure will produce
positive findings in about 10% of elderly individuals, but fewer
than 25% of these experience spontaneous syncope. Symptoms
should not, therefore, be attributed to hypersensitive carotid sinus
syndrome unless they are reproduced by carotid sinus pressure.
Initial investigations
A 12-lead ECG is essential in all patients presenting with
syncope or presyncope. Lightheadedness may occur with many
arrhythmias, but blackouts (Stokes-Adams attacks, p. 477) are
usually due to profound bradycardia or malignant ventricular
tachyarrhythmias. The ECG may show evidence of conducting
system disease (e.g. sinus bradycardia, atrioventricular block,
bundle branch block), which would predispose a patient to
bradycardia, but the key to establishing a diagnosis is to obtain
an ECG recording while symptoms are present. Since minor
rhythm disturbances are common, especially in the elderly,
symptoms must occur at the same time as a recorded arrhythmia
before a diagnosis can be made. Ambulatory ECG recordings
are helpful only if symptoms occur several times per week.
Patient-activated ECG recorders are useful for examining the
rhythm in patients with recurrent dizziness but are not helpful
in assessing sudden blackouts. When these investigations fail
to establish a cause in patients with presyncope or syncope, an
implantable ECG recorder can be sited subcutaneously over the
upper left chest. This device continuously records the cardiac
rhythm and will activate automatically if extreme bradycardia or
tachycardia occurs. The ECG memory can also be tagged by
the patient, using a hand-held activator as a form of ‘symptom
diary’. Stored ECGs can be accessed by the implanting centre,
using a telemetry device in a clinic, or using a home monitoring
system via an online link.
Head-up tilt-table testing is a provocation test used to establish
the diagnosis of vasovagal syncope. It involves positioning the
patient supine on a padded table that is then tilted to an angle of
60-70° for up to 45 minutes, while the ECG and BP responses
are monitored. A positive test is characterised by bradycardia
(cardio-inhibitory response) and/or hypotension (vasodepressor
response), associated with typical symptoms.
Delirium
Delirium is a syndrome of transient, reversible cognitive dysfunction
that is more common in old age. It is associated with high rates
of mortality, complications and institutionalisation, and with
longer lengths of stay. The recognised risk factors for delirium
are shown in Box 10.8.
Presentation
Delirium manifests as a disturbance of arousal with global
impairment of mental function, causing drowsiness with
10.8 Risk factors for delirium
Predisposing factors
• Old age
•
Sensory impairment
• Dementia
•
Polypharmacy
• Frailty
•
Renal impairment
Precipitating factors
• Intercurrent illness
•
Dehydration
• Surgery
•
Pain
• Change of environment
•
Constipation
or ward
•
Urinary catheterisation
• Sensory deprivation
•
Acute urinary retention
(e.g. darkness) or overload
•
Hypoxia
(e.g. noise)
•
Fever
• Medications (e.g. opioids,
•
Alcohol withdrawal
psychotropics)
10.9 How to make a diagnosis of delirium: the 4AT
1. Alertness
This includes patients who may be markedly drowsy (e.g. difficult to
rouse and/or obviously sleepy during assessment) or agitated/
hyperactive. Observe the patient. If asleep, attempt to wake with
speech or gentle touch on shoulder. Ask the patient to state their
name and address to assist rating:
• Normal (fully alert, but not agitated, throughout assessment) 0
• Mild sleepiness for <10 secs after waking, then normal 0
• Clearly abnormal 4
2. AMT4
Age, date of birth, place (name of the hospital or building), current
year:
• No mistakes 0
• 1 mistake 1
• >2 mistakes/untestable 2
3. Attention
Say to the patient: ‘Please tell me the months of the year in backwards
order, starting at December.’ To assist initial understanding, one
prompt of ‘What is the month before December?’ is permitted:
• Achieves >7 months correctly 0
• Starts but scores <7 months/refuses to start 1
• Untestable (cannot start because unwell, drowsy, inattentive) 2
4. Acute change or fluctuating course
Evidence of significant change or fluctuation in: alertness, cognition,
other mental function (e.g. paranoia, hallucinations) arising over the
last 2 weeks and still evident in last 24 hrs:
• No 0
• Yes 4
Total 4AT score (maximum possible score 12)
>4: possible delirium ± cognitive impairment
1-3: possible cognitive impairment
0: delirium or severe cognitive impairment unlikely (but delirium still
possible if information in 4 incomplete)
(AMT4 = Abbreviated Mental Test 4)
disorientation, perceptual errors and muddled thinking. The
three broad subtypes of delirium - hypoactive, hyperactive
and mixed - can be differentiated on the basis of psychomotor
changes. Patients with hyperactive delirium are often agitated
and restless, whereas hypoactive delirium can present as lethargy
and sedation, and is frequently misdiagnosed as depression or
dementia. Fluctuation is typical and delirium is often worse at
184 • ACUTE MEDICINE AND CRITICAL ILLNESS
night, when delirious patients can present significant management
difficulties. Emotional disturbance (anxiety, irritability or depression)
is common. History-taking from a delirious patient is frequently
impossible, and every effort should be made to obtain a
collateral history from a close friend or relative. As delirium is
particularly common in patients with dementia, the collateral
history should ask specifically about onset and course of delirium,
along with any functional consequences in comparison to the
patient’s norm.
Clinical assessment
In order to manage delirium effectively, the first step is to make
a diagnosis. Tools such as the 4AT (Box 10.9) or the Confusion
Assessment Method (CAM) can be used to detect delirium
and differentiate it from dementia; such screening tools should
be applied to all older patients admitted to hospital. Once a
diagnosis of delirium has been established, attempts should
be made to identify all of the reversible precipitating factors.
Symptoms suggestive of a physical illness, such as an infection
or stroke, should be elicited. An accurate drug and alcohol history
is required, especially to ascertain whether any drugs have
been recently stopped or started (see Fig. 10.4 for commonly
implicated drugs). Although not always possible in its entirety,
a full physical examination of all delirious patients should be
attempted, noting in particular:
• pyrexia and any signs of infection in the chest, skin,
abdomen or urine (on dipstick testing)
• oxygen saturation and signs of C02 retention
• signs of alcohol withdrawal or psychoactive drug use,
such as tremor or sweating
• any focal neurological signs.
Certain psychiatric conditions, such as depressive pseudo¬
dementia and dissociative disorder, can easily be mistaken for
delirium. Mental state examination is necessary to seek evidence of
associated mood disorder, hallucinations, delusions or behavioural
abnormalities. Examination should also include cognitive testing
with a tool such as the Mini-Mental State Examination (MMSE)
or the Montreal Cognitive Assessment (MoCA) (p. 1181).
Investigations and management
Common causes of delirium, along with appropriate investigative
pathways, are shown in Figure 10.4. Alongside investigation
and treatment of underlying causes, delirium and disorientation
should be minimised by a well-lit and quiet environment, with
hearing aids and glasses readily available. Good nursing is
needed to preserve orientation, prevent pressure sores and falls,
and maintain hydration, nutrition and continence. Sedatives may
worsen delirium and should be used as a last resort. Resolution of
delirium, particularly in the elderly, may be slow and incomplete.
Many patients fail to recover to their pre-morbid level of cognition.
Pneumonia
r A
UTI
m I
Skin: cellulitis, abscess
Gram-negative sepsis
Acute renal impairment
Hyponatraemia/hypernatraemia
Hypercalcaemia
Hypoglycaemia
Hepatic encephalopathy
Thiamin deficiency
Hypothyroidism*
B12 deficiency*
Any drug but particularly
• Anticholinergics
• Digoxin
• Opiates
• Psychotropics
• High-dose glucocorticoids
Withdrawal of alcohol, opiate, SSRI
or benzodiazepine
Acute stroke
Subdural haematoma
Encephalitis or meningitis
Seizure (post-ictal) _
Space-occupying lesion, e.g. tumour
o
Pulmonary embolism
Pneumonia
Pulmonary oedema
COPD exacerbation
Acute Ml
Infection
Metabolic
disturbance
Toxic insult
Acute
neurological
conditions
Pain, hypoxia
Full blood count, CRP
Chest X-ray
Urinalysis and culture
Others as appropriate: sputum,
blood cultures, wound swabs
Urea and electrolytes
Plasma calcium
Capillary blood and plasma glucose
Liver function tests
Thyroid function tests
B12 and folate
Digoxin level if prescribed
CT brain: only when intracranial
lesion is suspected (focal neurological
signs, recent fall or head injury) or no
other physical cause of delirium is
identified
Lumbar puncture: only if meningitis or
encephalitis is suspected
Pulse oximetry (arterial blood gases
if low)
Chest X-ray
ECG
Fig. 10.4 Common causes and investigation of delirium. All investigations are performed routinely, except those in italics. *Tend to present over
weeks to months rather than hours to days. The chest X-ray shows right mid- and lower zone consolidation. The CT scan shows a subdural haematoma.
(COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; Ml = myocardial infarction; SSRI = selective serotonin re-uptake inhibitor; UTI =
urinary tract infection)
Presenting problems in acute medicine • 185
Headache
Headache is common and causes considerable worry amongst
both patients and clinicians, but rarely represents sinister disease.
The causes may be divided into primary or secondary, with primary
headache syndromes being vastly more common (Box 10.10).
Presentation
The primary purpose of the history and clinical examination in
patients presenting with headache is to identify the small minority
of patients with serious underlying pathology. Key features of the
history include the temporal evolution of a headache; a headache
that reached maximal intensity immediately or within 5 minutes
of onset requires rapid assessment for possible subarachnoid
haemorrhage. Other ‘red flag’ symptoms are shown in Box 10.1 1 .
It is important to establish whether the headache comes and
goes, with periods of no headache in between (usually migraine),
or whether it is present all or almost all of the time. Associated
features, such as preceding visual symptoms, nausea/vomiting or
10.10 Primary and secondary headache syndromes
Primary headache syndromes
• Migraine (with or without aura)
• Tension-type headache
• Trigeminal autonomic cephalalgia (including cluster headache)
• Primary stabbing/coughing/exertional/sex-related headache
• Thunderclap headache
• New daily persistent headache syndrome
Secondary causes of headache
• Medication overuse headache (chronic daily headache)
• Intracranial bleeding (subdural haematoma, subarachnoid or
intracerebral haemorrhage)
• Raised intracranial pressure (brain tumour, idiopathic intracranial
hypertension)
• Infection (meningitis, encephalitis, brain abscess)
• Inflammatory disease (temporal arteritis, other vasculitis, arthritis)
• Referred pain from other structures (orbit, temporomandibular
joint, neck)
10.11 ‘Red flag’ symptoms in headache
Symptom Possible explanation
Sudden onset (maximal immediately or
within 5 mins)
Subarachnoid haemorrhage
Cerebral venous sinus
thrombosis
Pituitary apoplexy
Meningitis
Focal neurological symptoms (other
than for typically migrainous)
Intracranial mass lesion:
Vascular
Neoplastic
Infection
Constitutional symptoms:
Weight loss
General malaise
Pyrexia
Meningism
Rash
Meningitis
Encephalitis
Neoplasm (lymphoma or
metastases)
Inflammation (vasculitis)
Raised intracranial pressure (worse on
waking/lying down, associated vomiting)
Intracranial mass lesion
New onset aged >60 years
Temporal arteritis
photophobia/phonophobia, may support a diagnosis of migraine
but others, such as progressive focal symptoms or constitutional
upset like weight loss, may suggest a more sinister cause. The
headache of cerebral venous thrombosis may be ‘throbbing’ or
‘band-like’ and associated with nausea, vomiting or hemiparesis.
Raised intracranial pressure (ICP) headache tends to be worse
in the morning and when lying flat or coughing, and associated
with nausea and/or vomiting.
A description of neck stiffness along with headache and
photophobia should raise the suspicion of meningitis (Box 10.12),
although this may present in atypical ways in immunosuppressed,
alcoholic or pregnant patients. The behaviour of the patient
during headache is often instructive; migraine patients typically
retire to bed to sleep in a dark room, whereas cluster headache
often induces agitated and restless behaviour. The pain of a
subarachnoid haemorrhage frequently causes significant distress.
Headache duration is also important to elicit; headaches that
have been present for months or years are almost never sinister,
whereas new-onset headache, especially in the elderly, is more
of a concern. In a patient over 60 years with head pain localised
to one or both temples, scalp tenderness or jaw claudication,
temporal arteritis (p. 1042) should be considered.
Clinical assessment
An assessment of conscious level (using the Glasgow Coma
Scale (GCS); Fig. 10.5) should be performed early and constantly
reassessed. A decreased conscious level suggests raised ICP
and urgent CT scanning (with airway protection if necessary) is
indicated. A full neurological examination may provide clues as to
the pathology involved; for example, brainstem signs in the context
of acute-onset occipital headache may indicate vertebrobasilar
dissection. Neurological signs may, however, be ‘falsely localising’,
as in large subarachnoid haemorrhage or bacterial meningitis.
Care should be taken to examine for other evidence of meningitis
such as a rash (not always petechial), fever or signs of shock.
Unilateral headache with agitation, ipsilateral lacrimation, facial
sweating and conjunctival injection is typical of cluster headache.
Conjunctival injection may also be seen in acute glaucoma,
accompanied by peri- or retro-orbital pain, clouding of the cornea,
decreased visual acuity and, often, systemic upset. Temporal
headaches in patients over 60 should prompt examination for
enlarged or tender temporal arteries and palpation of temporal
pulses (often absent in temporal arteritis). Visual acuity should be
assessed promptly, as visual loss is an important complication
of temporal arteritis.
Initial investigations
If there is any alteration of conscious level, focal neurological signs,
new-onset seizures or a history of head injury, then CT scanning
of the head is indicated. The urgency of scanning will depend
on the clinical picture and trajectory but in many circumstances
10.12 Identification of bacterial meningitis
In patients presenting with headache, identification of those with
bacterial meningitis is a top priority to facilitate rapid antibiotic
treatment. In almost all cases there will be one of the following
features:
• meningism (neck stiffness, photophobia, positive Kernig’s sign)
• fever >38°C
• signs of shock (tachycardia, hypotension, elevated serum lactate)
• rash (not always petechial)
186 • ACUTE MEDICINE AND CRITICAL ILLNESS
Fig. 10.5 Assessment of the Glasgow Coma Scale (GCS) score in an
obtunded patient. Avoid using a sternal rub, as it causes bruising.
will be immediately required. Intracranial haemorrhage or a
space-occupying lesion with mass effect should prompt urgent
neurosurgical referral. If bacterial meningitis is suspected (Box
10.12), cerebrospinal fluid (CSF) analysis is required to make a
definite diagnosis. Antibiotics should not be delayed for lumbar
puncture (LP), which needs to be preceded by CT scanning only if
raised ICP is suspected. In cases of thunderclap headache (peak
intensity within 5 minutes and lasting over an hour), a normal CT
scan should be followed by an LP performed more than 12 hours
after headache onset, to look for evidence of xanthochromia. It is
increasingly accepted, however, that a negative CT scan within 6
hours of headache onset has such a high degree of sensitivity for
excluding subarachnoid haemorrhage that an LP is not necessary.
In such circumstances, a CT angiogram should be considered
to exclude other pathology, such as arterial dissection. Many
headaches require prompt involvement of specialists. Features of
acute glaucoma, for example, require immediate ophthalmological
review for measurement of intraocular pressures. Suspected
temporal arteritis with an erythrocyte sedimentation rate (ESR) of
>50 mm/hr should prompt immediate glucocorticoid therapy and
rheumatological referral (see p. 1042 for management). Features
of raised ICP in the absence of a mass lesion on neuroimaging
may indicate idiopathic intracranial hypertension; CSF opening
pressure is likely to be informative.
Unilateral leg swelling
Most leg swelling is caused by oedema, the accumulation of
fluid within the interstitial space. There are three explanatory
mechanisms for development of oedema that are described
in Box 10.13. Unilateral swelling usually indicates a localised
pathology in either the venous or the lymphatic system, while
bilateral oedema often represents generalised fluid overload
combined with the effects of gravity. However, all causes of
unilateral leg swelling may present bilaterally, and generalised
fluid overload may present with asymmetrical (and therefore
apparently unilateral) oedema. Fluid overload may be the result of
cardiac failure, pulmonary hypertension (even in the absence of
right ventricular failure), renal failure, hypoalbuminaemia or drugs
(calcium channel blockers, glucocorticoids, mineralocorticoids,
non-steroidal anti-inflammatory drugs (NSAIDs) and others);
see Box 16.14 (p. 463) for other causes. The remainder of this
section focuses on the causes of ‘unilateral’ oedema.
Presentation
Any patient who presents with unilateral leg swelling should
be assessed with the possibility of deep vein thrombosis (DVT)
in mind. The pain and swelling of a DVT is often fairly gradual
in onset, over hours or even days. Sudden-onset pain in the
posterior aspect of the leg is more consistent with gastrocnemius
muscle tear (which may be traumatic or spontaneous) or a
ruptured Baker’s cyst. Leg swelling and pain associated with
paraesthesia or paresis, or in the context of lower limb injury
or reduced conscious level, should always prompt concern
regarding the possibility of compartment syndrome (Box 10.14).
Clinical assessment
Lower limb DVT characteristically starts in the distal veins,
causing an increase in temperature of the limb and dilatation
of the superficial veins. Often, however, symptoms and signs
are minimal.
i
There are three explanatory mechanisms for the development of
oedema that may occur in isolation or combination:
• increased hydrostatic pressure in the venous system due to
increased intravascular volume or venous obstruction
• decreased oncotic pressure secondary to a decrease in the plasma
proteins that retain fluid within the circulation
• obstruction to lymphatic drainage (‘lymphoedema’)
10.13 Mechanisms of oedema
Presenting problems in acute medicine • 187
10.14 Identification of compartment syndrome
• Compartment syndrome classically occurs following extrinsic
compression of a limb due to trauma or reduced conscious level
(especially when caused by drugs or alcohol)
• It usually presents with a tense, firm and exquisitely painful limb
• The pain is characteristically exacerbated by passive muscle
stretching or squeezing the compartment
• Altered sensation may be evident distally
• Absent peripheral pulses are a late sign and their presence does
not exclude the diagnosis
• Clinical suspicion of compartment syndrome should prompt
measurement of creatine kinase and urgent surgical review
Cellulitis is usually characterised by erythema and skin warmth
localised to a well-demarcated area of the leg and may be
associated with an obvious source of entry of infection (e.g. leg
ulcer or insect bite). The patient may be febrile and systemically
unwell. Superficial thrombophlebitis is more localised; erythema
and tenderness occur along the course of a firm, palpable vein.
Examination of any patient presenting with leg swelling should
include assessment for malignancy (evidence of weight loss, a
palpable mass or lymphadenopathy). Malignancy is a risk factor
for DVT, but pelvic or lower abdominal masses can also produce
leg swelling by compressing the pelvic veins or lymphatics.
Early lymphoedema is indistinguishable from other causes of
oedema. More chronic lymphoedema is firm and non-pitting,
often with thickening of the overlying skin, which may develop
a ‘cobblestone’ appearance.
Chronic venous insufficiency is a cause of long-standing
oedema that, particularly when combined with another cause
of leg swelling, may acutely worsen. Characteristic skin changes
(haemosiderin deposition, hair loss, varicose eczema, ulceration)
and prominent varicosities are common, and sometimes cause
diagnostic confusion with cellulitis. See Box 10.14 for the
examination findings associated with compartment syndrome.
Initial investigations
Clinical criteria can be used to rank patients according to their
likelihood of DVT, by using scoring systems such as the Wells
score (Box 10.15). Figure 10.6 gives an algorithm for investigation
of suspected DVT based on initial Wells score. In patients with
a low (‘unlikely’) pre-test probability of DVT, D-dimer levels can
be measured; if these are normal, further investigation for DVT is
unnecessary. In those with a moderate or high (‘likely’) probability
of DVT or with elevated D-dimer levels, objective diagnosis of
DVT should be obtained using appropriate imaging, usually a
Doppler ultrasound scan. The investigative pathway for DVT,
therefore, differs according to the pre-test probability (p. 11) of
DVT. For low-probability DVT, the negative predictive value of
the D-dimer test (the most important parameter in this context)
is over 99%; if the test is negative, the clinician can discharge
the patient with confidence. In patients with a high probability
of DVT, the negative predictive value of a D-dimer test falls to
somewhere in the region of 97-98%. While this may initially
appear to be a high figure, to discharge 2 or 3 patients in every
100 incorrectly would generally be considered an unacceptable
error rate. Hence, with the exception of pregnancy (Box 10.16),
a combination of clinical probability and blood test results should
be used in the diagnosis of venous thromboembolism.
If cellulitis is suspected, serum inflammatory markers, skin
swabs and blood cultures should be sent, ideally before antibiotics
-ve
+ve
Fig. 10.6 Investigation of suspected deep vein thrombosis. Pre-test
probability is calculated in Box 10.15. See also page 11.
Treat
▼
Exclude
-ve
Repeat compression
ultrasound in 7 days
Probability low,
or moderate
with -ve D-dimer
Probability high,
or moderate
with +ve D-dimer
k
i
4i
10.15 Predicting the pre-test probability of deep vein
thrombosis (DVT) using the Wells score
Clinical characteristic
Score
Previous documented DVT
1
Active cancer (patient receiving treatment for cancer
within previous 6 months or currently receiving
palliative treatment)
1
Paralysis, paresis or recent plaster immobilisation of
lower extremities
1
Recently bedridden for >3 days, or major surgery
within previous 4 weeks
1
Localised tenderness along distribution of deep venous
system
1
Entire leg swollen
1
Calf swelling at least 3 cm larger than that on
asymptomatic side (measured 1 0 cm below tibial
tuberosity)
1
Pitting oedema confined to symptomatic leg
1
Collateral superficial veins (non-varicose)
1
Alternative diagnosis at least as likely as DVT
-2
Clinical probability
Total score
DVT low probability
<1
DVT moderate probability
1-2
DVT high probability
>2
*A dichotomised revised Wells score, which classifies patients as ‘unlikely’ or
‘likely’, may also be used.
From Wells PS. Evaluation of D-dimer in the diagnosis of suspected deep-vein
thrombosis. N Engl J Med 2003; 349:1227; copyright © 2003 Massachusetts
Medical Society.
are given. Ruptured Baker’s cyst and calf muscle tear can both
be readily diagnosed on ultrasound. If pelvic or lower abdominal
malignancy is suspected, a prostate-specific antigen (PSA)
level should be measured in males and appropriate imaging
with ultrasound (transabdominal or transvaginal) or CT should
be undertaken.
188 • ACUTE MEDICINE AND CRITICAL ILLNESS
10.16 Swollen legs in pregnancy
Benign swollen legs: common in pregnancy; this is usually
benign.
DVT: pregnancy is a significant risk factor, however.
D-dimer: should not be measured in pregnancy; it has not been
validated in this group.
Imaging: should be arranged on the basis of clinical suspicion
alone, and the threshold for undertaking a definite diagnostic test
should be low.
Identification and assessment
of deterioration
Early warning scores and the role of the
medical emergency team
There are many systems that have been developed with the aim
of rapidly identifying and managing physiological deterioration.
These are referred to as ‘rapid response systems’. One popular
example of a rapid response system is a medical emergency
team (MET). A MET system operates on the basis that when a
patient meets certain physiological criteria, the team is alerted.
The team is expected to make a rapid assessment and institute
immediate management. This may include escalation to critical
care or, following liaison with the parent clinical team, ongoing
ward -based care.
The trigger for a ‘MET’ call may be a single parameter - such
as a low BP or tachycardia - or may consist of a composite
early warning score. Early warning score systems function by the
observer allocating a value between 0 and 3 for abnormalities in
respiratory rate, Sp02, temperature, BP, heart rate, neurological
response and urine output (Fig. 10.7). The values are summed
and the composite score gives an indication of the severity
of physiological derangement. Early warning systems can be
automated into an electronic format that calculates the score and
even alerts the responsible clinician(s) by email or text message.
There are advantages and disadvantages to having a separate
MET system, compared with allowing the responsible clinical
team to manage deterioration, and to having a composite score
or a single parameter detection system. These are outlined in
Box 10.17.
Immediate assessment of the
deteriorating patient
An approach to assessment of the deteriorating patient can be
summarised by the mnemonic ‘C-A-B-C-D-E’.
| C - Control of obvious problem
For example, if the patient has ventricular tachycardia on the
monitor or significant blood loss is apparent, immediate action
is required.
A and B - Airway and breathing
If the patient is talking in full sentences, then the airway is clear
and breathing is adequate. A rapid history should be obtained
while the initial assessment is undertaken. Breathing should
be assessed with a focused respiratory examination. Oxygen
saturations and ABGs should be checked early (p. 190).
0
NEWS Key
®0HI|3|
Date:
Time:
Respiratory
Rate
>25
21-24
12-20
9-11
<8
Sp02
Medical signature
required to use scale
for patients with
Chronic Hypoxia
Hypoxia Default
>88 >91
94-95
86-87 92-93
<85 <91
Sign
Unrecordable
Inspired 02
% or litres
son°
QQ°
Temperature
oo
07°
O /
op.o
oo
NEWS
SCORE
uses
Systolic BP
If manual BP
mark as
M
oqn
oon
c.£\j
o-i n
c. 1 u
°nn
^-UU
i no
1 UU
i ftn
1 ou
1 70
1 l U
i on
1 ou
i ro
1 ou
140
1 *+u
1 ^0
1 ou
1 °0
1 cXj
110
1 1 u
1 OO
1 uu
00
JU
on
ou
70
l u
fiO
OU
go
OU
Unrecordable
Heart Rate
^ i a.n
> 1 *+U
1 ^0
1 OU
1 °0
110
1 1 u
1 00
1 uu
00
uu
on
ou
70
/ u
RO
ou
RO
ou
40
H-U
00
ou
Regular Y/N
Conscious
Level
Alert
V/P/U
New confusion
Fig. 10.7 Identifying and responding to physiological deterioration.
[A] An example of an early warning score chart. (NEWS = National Early
Warning Score; V/P/U = Verbal/Pain/Unresponsive)
Identification and assessment of deterioration • 189
^Regardless of NEWS always escalate if concerned about a patient’s condition
NEWS Score Frequency of Observations
^Total 0*
Total 1-4* *
Total 5-6*
or
3 in one
parameter
Minimum 12 hourly/4 hourly
in admission areas
Minimum 4 hourly
| Consider Structured Response Tool;
Consider Fluid Balance Chart
Increase frequency to a
minimum of 1 hourly
Start Structured Response Tool
Start Fluid Balance Chart
Continuous monitoring
of vital signs
Start Structured Response Tool
Start Fluid Balance Chart
► Inform registered nurse
► Registered nurse assessment using ABCDE
► Review frequency of observations
► Inform Nurse in Charge
► If ongoing concern, escalate to Medical Team
• Registered nurse assessment
• Inform Nurse in Charge
• Escalate to Medical Team as per local escalation
• Urgent medical assessment
• Management plan to be discussed with Senior Trainee or above
• Consider level of monitoring required in relation to clinical care
• Registered nurse to assess immediately
• Inform Nurse in Charge
• Request immediate assessment by Senior Trainee or above
• Case to be discussed with supervising Consultant
• If appropriate contact Critical Care for review
Fig. 10.7, cont’d 83 Responses to physiological deterioration. A and B, From Royal College of Physicians. National Early Warning Score (NEWS):
standardising the assessment of acute-illness severity in the NHS. Report of a working party. London: RCP, 2012.
1 10.17 Advantages and disadvantages of different rapid response systems
System
Advantages
Disadvantages
Single parameter trigger
High sensitivity. Probably picks up subclinical
deterioration and allows optimisation
Low specificity. Much time will be spent with patients who are
not deteriorating
Composite early warning
scoring system,
e.g. NEWS or MEWS score
Combines good sensitivity with improved
specificity
May miss single parameter deterioration that is still significant,
e.g. a drop of 2 GCS points may not trigger an alert
MET system
Brings expertise in deteriorating patients
immediately to the bedside
Expensive to have well-trained individuals who are free from
other clinical duties. May deskill the ward-based teams in acute
care. May not have expertise in highly specific areas of medicine
Clinical team review
Patient is seen by clinicians familiar with the
patient and condition
Clinical team may be busy with other urgent duties. There may
not be expertise in acute care within the ward-based team
(GCS = Glasgow Coma Scale; MET =
= Medical Emergency Team; MEWS = Modified Early Warning Score; NEWS = National Early Warning Score)
C - Circulation
i
E - Exposure and evidence
A focused cardiovascular examination should include heart rate
and rhythm, jugular venous pressure, evidence of bleeding,
signs of shock and abnormal heart sounds. The carotid pulse
should be palpated in the collapsed or unconscious patient, but
peripheral pulses also should be checked in conscious patients.
The radial, brachial, foot and femoral pulses may disappear as
shock progresses, and this indicates the severity of circulatory
compromise.
| D - Disability
Conscious level should be assessed using the GCS (see Fig. 10.5
and Box 1 0.24, pp. 1 86 and 1 94). A brief neurological examination
looking for focal signs should be performed. Capillary blood
glucose should always be measured to exclude hypoglycaemia
or severe hyperglycaemia.
‘Exposure’ indicates the need for targeted clinical examination
of the remaining body systems, particularly the abdomen and
lower limbs. ‘Evidence’ may be gathered via a collateral history
from other health-care professionals or family members, recent
investigations, prescriptions or monitoring charts.
Selecting the appropriate location for
ongoing management
Any patient who will gain benefit from a critical care area should be
admitted. Such patients generally fall into two groups: those with
organ dysfunction severe enough to require organ support and
those in whom the disease process is clearly setting them on a
downward trajectory and in whom early, aggressive management
may alter the outcome. Whether an individual patient should be
190 • ACUTE MEDICINE AND CRITICAL ILLNESS
i
10.18 Levels of care and the corresponding admission criteria for intensive care unit (ICU) and high-dependency unit (HDU)
Level of care Criteria
Appropriate location
3
Patients requiring/likely to require endotracheal intubation and invasive mechanical ventilatory support
Patients requiring support of two or more organ systems (e.g. inotropes and haemofiltration)
Patients with chronic impairment of one or more organ systems (e.g. C0PD or severe ischaemic heart
disease) who require support for acute reversible failure of another organ
ICU
2
Patients requiring detailed observation or monitoring that cannot be provided at ward level:
Direct arterial BP monitoring
CVP monitoring
Fluid balance
Neurological observations, regular GCS recording
Patients requiring support for a single failing organ system, excluding invasive ventilatory support (IPPV):
Non-invasive respiratory support (p. 202)
Moderate inotropic or vasopressor support
Renal replacement therapy in an otherwise stable patient
Step-down from intensive care requiring additional monitoring or single organ support
HDU
1
Patients in whom frequent but intermittent observations and medical review are sufficient
General ward setting
(BP = blood pressure; C0PD = chronic obstructive pulmonary disease; CVP = central venous pressure; GCS = Glasgow Coma Scale; IPPV =
ventilation)
intermittent positive pressure
admitted to the intensive care or high-dependency unit (ICU/
HDU) will depend on local arrangements. A useful tool to assist
with the decision regarding location is the ‘level of care’ required
(Box 10.18). Many intensive care units are a mix of level 2 and
level 3 beds, which streamlines the admission process.
Common presentations of deterioration
As patients become critically unwell, they usually manifest
physiological derangement. The principle underpinning critical
care is the simultaneous assessment of illness severity and
the stabilisation of life-threatening physiological abnormalities.
The goal is to prevent deterioration and effect improvements,
as the diagnosis is established and treatment of the underlying
disease process is initiated.
It can be useful to consider the physiological changes as a
starting point to help delineate urgent investigations and supportive
treatment, which should proceed alongside the search for a
definitive diagnosis.
Tachypnoea
Pathophysiology
A raised respiratory rate (tachypnoea) is the earliest and most
sensitive sign of clinical deterioration. Tachypnoea may be primary
(i.e. a problem within the respiratory system) or secondary to
pathology elsewhere in the body. Cardiopulmonary causes
of tachypnoea have been covered on page 179. Secondary
tachypnoea is usually due to a metabolic acidosis, most commonly
observed in the context of sepsis, haemorrhage, ketoacidosis
or visceral ischaemia. More detailed information on metabolic
acidosis can be found on page 364.
Assessment and management
A simple assessment of a patient’s clinical status and basic
physiology will usually indicate whether urgent intervention is
required. In the examination, attention should be paid to the
adequacy of chest expansion, air entry and the presence of
added sounds such as wheeze.
Analysis of an arterial blood sample is especially helpful
in narrowing the differential diagnosis and confirming clinical
suspicion of severity. The ‘base excess’ provides rapid
quantification of the component of disease that is metabolic
in origin. A base excess lower than -2 mEq/L (or, put another
way, a ‘base deficit’ of more than 2 mEq/L) is likely to represent
a metabolic acidosis. A simple rule of thumb is that a lactate of
more than 4 mmol/L or a base deficit of more than 10 mEq/L
should cause concern and trigger escalation to a higher level of
care. In addition to clinical examination, chest radiography and
bedside ultrasound can help to distinguish the cause of poor
air entry; consolidation and effusion can be readily identified
and a significant pneumothorax can be excluded (as shown
in Fig. 10.8).
Hypoxaemia
Pathophysiology
Low arterial partial pressure of oxygen (Pa02) is termed
hypoxaemia. It is a common presenting feature of deterioration.
Hypoxia is defined as an inadequate amount of oxygen in tissues
(or the inability of cells to use the available oxygen for cellular
respiration). Hypoxia may be due to hypoxaemia, or may be
secondary to impaired cardiac output, the presence of inadequate
or dysfunctional haemoglobin, or intracellular dysfunction (such
as in cyanide poisoning, where oxygen utilisation at the cellular
level is impaired).
Over 97% of oxygen carried in the blood is bound to
haemoglobin. The haemoglobin-oxygen dissociation curve
delineates the relationship between the percentage saturation
of haemoglobin with oxygen (S02) and the partial pressure
(P02) of oxygen in the blood. A shift in the curve will influence
the uptake and release of oxygen by the haemoglobin
molecule. As capillary PC02 rises, the curve moves to the
right, increasing the offloading of oxygen in the tissues (the
Bohr effect). This increases capillary P02 and hence cellular
oxygen supply. Shifts of the oxyhaemoglobin dissociation curve
can have significant implications in certain disease processes
(Fig. 10.9).
Common presentations of deterioration • 191
Normal
(no pneumothorax)
Abnormal
(pneumothorax cannot
be excluded)
Normal Abnormal
(no pneumothorax) (pneumothorax cannot
be excluded)
Fig. 10.8 Using ultrasound to rule out an anterior pneumothorax. [A] Probe position and orientation. \W\ and [C] Two-dimensional (2D) ultrasound
images. [D] and[E] M-mode ultrasound images. Key: (1) Intercostal muscle. (2) Rib. (3) Normal bright pleural line -‘shimmering appearance’ of sliding
pleura. (4) Lung. (5) Absent ‘shimmering’ in pneumothorax and lung not visible. (6) Normal - ‘sea shore’ sign excludes pneumothorax at that location.
The ‘sea shore’ is represented by the bright granular line with lung (sea) deeper to the bright line. (7) Absent granular pleural line and a repeating linear
pattern or ‘barcode’ sign suggest the presence of pneumothorax.
kPa 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
mmHg 0 25 50 75 100
P02 (kPa or mmHg)
Fig. 10.9 The haemoglobin-oxygen dissociation curve and the effect
of C02 on oxygen saturations. In pulmonary embolism, compensatory
hyperventilation often occurs. PaC02 decreases, shifting the
oxyhaemoglobin saturation curve to the left (green line). Therefore, despite
a low Pa02 (8 kPa/60 mmHg), the saturation reading is 93%.
Due to the shape of the curve, a small drop in arterial P02
(Pa02) below 8 kPa (60 mmHg) will cause a marked fall in Sa02.
Relative hypoxaemia refers to the comparison between the
observed Pa02 and that which might be expected for a given
fraction of inspired oxygen (P/02). With the patient breathing
air, Pa02 of 12-14 kPa (90-105 mmHg) would be expected;
with the patient breathing 100% oxygen, a Pa02 of >60 kPa
(450 mmHg) would be normal.
Assessment and management
Oxygen therapy should be titrated to avoid hyperoxia (too high a
Pa02; Box 1 0.1 9). Hyperoxia is theoretically harmful via a number
of mechanisms. This has a clinically significant effect in patients
10.19 Prescribing oxygen in critical illness
Oxygen should be prescribed to achieve a target saturation of
94-98% for most critically unwell patients.
88-92% is a more appropriate target range for those at risk of
hypercapnic respiratory failure.
with acute stroke, those with Ml and those who chronically retain
C02. Adverse effects of hyperoxia include:
• free radical-induced tissue damage
• less efficient buffering of carbon dioxide by
oxyhaemoglobin (compared to deoxyhaemoglobin)
• less efficient ventilation-perfusion matching in lung units
(due to loss of hypoxic vasoconstriction of under-ventilated
lung units)
• decreased hypoxic respiratory drive in individuals with
chronic hypercapnia.
When attempting to determine the cause of hypoxaemia,
it is useful to consider whether the primary physiological
mechanism is a type of shunt, or one of the many causes
of ventilation-perfusion mismatch, such as alveolar or central
hypoventilation (Fig. 10.10). A classification of common causes
of hypoxaemia in hospitalised patients is shown in Box 10.20.
In reality, the observed physiological abnormality may represent
a combination of inter-related processes, such as severe
pulmonary oedema leading to exhaustion, which in turn causes
hypoventilation.
Evaluation of risk factors, history and examination will help to
differentiate the likely aetiology and guide specific management.
Further management of respiratory failure is discussed on page 202.
Tachycardia
Pathophysiology
A heart rate of >110 beats/min in an adult should always be
considered abnormal and not attributed to anxiety until other
causes have been excluded. Intrinsic cardiac causes (atrial
fibrillation (AF), atrial flutter, supraventricular tachycardia and
192 • ACUTE MEDICINE AND CRITICAL ILLNESS
0
Terminal bronchus
m
Alveolus filled with blood/secretions
or collapsed. Blood will pass this
alveolus without becoming oxygenated
a
Interstitium thickened by fluid,
inflammatory exudate or cells
Fig. 10.10 Theoretical mechanisms of hypoxaemia. [A] Normal physiology. [§] Shunt caused by alveolar filling, e.g. in pneumonia or alveolar
haemorrhage. The mixture of oxygenated and deoxygenated blood causes arterial desaturation. [C] Shunt caused by interstitial pathology, e.g. pulmonary
oedema or fibrosis. Interstitial thickening causes inadequate transfer of oxygen from the alveolus to the blood, Jeading to shunting and arterial desaturation.
Because minute volume is usually maintained, this causes type I respiratory failure. [D] Ventilation-perfusion (V/Q) mismatch caused by alveolar
hypoventilation, e.g. in chronic obstructive pulmonary disease (COPD)/asthma. Alveoli are under-ventilated relative to perfusion. Alveolar P02 falls and PC 02
rises, causing type II respiratory failure. [E] V/Q mismatch caused by central hypoventilation, e.g. in neuromuscular disease or narcotic use. The alveoli are
relatively over-perfused, causing type II respiratory failure. [F] V/Q mismatch caused by a perfusion defect, e.g. a small pulmonary embolism. Pulmonary
blood flow is diverted to other alveoli, causing them to be relatively over-perfused and thus reducing alveolar P02. Minute volume is increased, so PC 02 is
not elevated.
10.20 Common causes of hypoxaemia in
hospitalised patients
Hypoxaemia due to shunt
• Lung collapse
• Consolidation/alveolar haemorrhage
• Interstitial oedema or interstitial infiltration (e.g. fibrosis)
• Silent aspiration of gastric contents
Hypoxaemia due to ventilation-perfusion mismatch
• Pulmonary embolism
• Acute exacerbation of asthma
• COPD (with high minute volume)
Hypoxaemia from hypoventilation
• Effects of opiates
• Severe COPD (with low minute volume)
• Neuromuscular disease/general weakness from other illness
(COPD = chronic obstructive pulmonary disease)
ventricular dysrhythmias) are less common in the general inpatient
population than secondary causes of tachycardia.
A cardiac monitor or 1 2-lead ECG early in the examination will
help both determine severity (heart rate >160 beats/min should
prompt urgent escalation to a higher level of care) and narrow
the differential diagnosis. AF with a rapid ventricular response
should usually be regarded as secondary to another insult (mostly
commonly, infection) until other diagnoses have been excluded.
Hypovolaemia should not be missed. Concealed bleeding (e.g.
into the pleura, gastrointestinal tract or retroperitoneum) may not
be apparent initially and assessment of haemoglobin in an acute
haemorrhage, when <30 mLVkg of fluid has been administered,
can be misleadingly high. Sepsis and other hyper-metabolic
conditions may present with a tachycardia that is accompanied by
tachypnoea, peripheral vasodilatation and a raised temperature.
Other organ dysfunction should be noted from a brief general
examination and salient points from the history.
Assessment and management
The management of a tachycardic patient should focus on
treating the cause. Treating the rate alone with beta-blockade
in an unwell or deteriorating patient should be done only under
specialist guidance, in controlled conditions, and when a clear
evaluation of the risk-benefit ratio has been undertaken.
The recognition and management of primary cardiac
dysrhythmias are discussed on page 468. The most appropriate
method of rate control in AF depends primarily on the degree
of haemodynamic compromise. An intravenous loading dose of
amiodarone is well tolerated and efficacious in the majority of
critically ill patients with AF and a very rapid ventricular rate. There
are thromboembolic concerns regarding chemical cardioversion
of AF of unknown duration. However, in deteriorating patients,
the low incidence of embolic events makes this concern of
secondary importance to achieving haemodynamic stability.
Digoxin continues to have a role in the treatment of AF in
critically unwell but haemodynamically stable patients, when
Common presentations of deterioration • 193
its inotropic properties can be helpful. Electrical cardioversion
is reserved for dysrhythmias with extremely high heart rates,
following failure of pharmacological management, and/or for
those of ventricular origin. It is rarely successful in dysrhythmias
secondary to systemic illness.
Hypotension
Pathophysiology
Low BP (hypotension) should always be defined in relation to
a patient’s usual BP. The calculation of mean arterial pressure
(MAP) is shown in Box 10.21 ; it unifies the systolic and diastolic
BPs into a single reference value. A MAP of >65 mmHg will
maintain renal perfusion in the majority of patients, although
a MAP of up to 80 mmHg may be required in patients with
chronic hypertension.
Assessment and management
The first stage of assessment is to decide if the hypotension
is physiological or pathological. The MAP is useful as, despite
low systolic pressures, it is rare to see a physiological MAP of
<65 mmHg. Urine output is particularly useful in the determination
of the desirable MAP for an individual patient; oliguria suggests
that measures to increase the MAP should be sought (p. 204).
If the hypotension is pathological, an assessment of severity
should look at whether it is causing physiological harm to the
patient (i.e. the patient is shocked).
Shock
Shock means ‘circulatory failure’. It can be defined as a level of
oxygen delivery (D02) that fails to meet the metabolic requirements
of the tissues (Box 1 0.22). Hypotension is a common presentation
of shock but the terms are not synonymous. Patients can be
hypotensive but not shocked, and oxygen delivery can be
critically low in the context of a ‘normal’ BP. Along with the
signs of low cardiac output (Box 10.23), objective markers of
inadequate tissue oxygen delivery, such as increasing base
deficit, elevated blood lactate and reduced urine output, can aid
10.21 Calculation of mean arterial pressure (MAP)
MAP = Diastolic blood pressure +
(systolic -diastolic)
3
At normal heart rates, the heart, on average, spends two-thirds of the
cycle in diastole. The MAP reflects this by weighting the value towards
the diastolic blood pressure
10.22 Oxygen content and delivery
• Oxygen content of blood = Haemoglobin level x oxygen saturation
x constant
• Cardiac output = Heart rate x stroke volume
• Stroke volume is dependent on cardiac filling (preload) and
contractility
• In shock, the most productive measures to improve oxygen delivery
are optimising the haemoglobin level and the cardiac output
*0xygen is almost exclusively bound to haemoglobin; only tiny amounts are
dissolved in blood at atmospheric pressure.
i
10.23 Hypotension in relation to cardiac output:
clinical signs and possible causes
High cardiac output
Low cardiac output
Signs
Warm hands
Cold/clammy peripheries
Pulsatile head movement
Peripheral cyanosis
High-volume/strong pulse
Low venous pressure
Raised venous pressure
Causes Sepsis
Bleeding
Allergy
Aortic stenosis and failed
Drug overdose (e.g.
compensation
antihypertensive)
Dysrhythmia
Acidosis (e.g. diabetic
Obstructive (pulmonary
ketoacidosis)
embolism/tamponade/
Thyrotoxicosis
dynamic hyperinflation as
Beri-beri
in severe asthma)
Chronic heart failure
early identification. If shock is suspected, resuscitation should be
commenced (p. 204).
Hypotensive patients who do not have any evidence of shock
are still at significant risk of organ dysfunction. Hypotension
should serve as a ‘red flag’ that there may be serious underlying
pathology. Organ failure occurs despite normal or elevated
oxygen delivery, so a full assessment of the patient is indicated.
A review of the drug chart is essential, as many inpatients
will be on antihypertensive medications that are contributing
to hypotension. Non-cardiac medications may also have a
negative influence on BP; for example, some drugs used for
urine outflow tract obstruction, such as tamsulosin, have an
a-adrenoceptor-blocking effect.
Hypertension
Pathophysiology
High BP (hypertension) is common and is usually benign in a
critical care context. However, it can be the presenting feature
of a number of serious disease processes. Furthermore, acute
hypertension can result in an acute rise in vascular tone that
increases left ventricular end-systolic pressure (afterload). The
left ventricle may be unable to eject blood against the increased
aortic pressure, and acute pulmonary oedema can result (referred
to as ‘flash’ pulmonary oedema.)
Assessment and management
Before treating an acute rise in BP, it is worth considering a
few important diagnoses that may impact on the immediate
management:
• Intracranial event. Ischaemia of the brainstem (commonly
via a pressure effect) will cause acute increases in BP. A
neurological examination and CT scan of the head should
be considered.
• Fluid overload. Once the capacity of the venous blood
reservoir becomes saturated, increases in fluid volume will
lead to increases in BP. This can occur in younger
patients without the onset of peripheral oedema and
originate from myocardial dysfunction or impaired renal
clearance.
• Underlying medical problems. A brief search for a history
of renal disease, spinal injury and less common metabolic
causes such as phaeochromocytoma can be worthwhile.
In women of child-bearing age, pregnancy-induced
194 • ACUTE MEDICINE AND CRITICAL ILLNESS
hypertension and pre-eclampsia must always be
considered.
• Primary cardiac problems. Myocardial ischaemia, acute
heart failure and aortic dissection can all present with
hypertension.
• Drug-related problems. Most commonly, these involve a
missed antihypertensive medication, but sympathomimetic
drugs such as cocaine and amphetamines can be
implicated.
The management of hypertension is discussed further on
page 510.
Decreased conscious level
Assessment
A reduction in conscious level should prompt an urgent
assessment of the patient, a search for the likely cause and an
evaluation of the risk of airway loss. The GCS was developed
to risk-stratify head injury, but it has become the most widely
recognised assessment tool for conscious level (see Box 10.24
for breakdown of GCS assessment, Box 10.25 for how to
communicate the findings and Fig. 10.5 for how to assess
GCS). While disorders that affect language or limb function
(e.g. left hemisphere stroke, locked-in syndrome) may reduce
its usefulness, evaluation of the GCS usually provides helpful
prognostic information, and serial recordings can plot improvement
or deterioration. It is not possible to define a total score below
which a patient is unlikely to be able to protect the airway (from
10.24 Glasgow Coma Scale (GCS)
Eye-opening (E)
• Spontaneous
4
• To speech
3
• To pain
2
• Nil
1
Best motor response (M)
• Obeys commands
6
• Localises to painful stimulus
5
• Flexion to painful stimulus or withdraws
4
hand from pain
• Abnormal flexion (internal rotation of
3
shoulder, flexion of wrist)
• Extensor response (external rotation of
2
shoulder, extension of wrist)
• Nil
1
Verbal response (V)
• Orientated
5
• Confused conversation
4
• Inappropriate words
3
• Incomprehensible sounds
2
• Nil
1
Coma score = E + M + V
Always present GCS as breakdown, not a sum score (unless
3 or 15)
• Minimum sum
3
• Maximum sum
15
*Record the best score observed. When the patient is intubated, there can be no
verbal response. The suffix T should replace the verbal component of the score,
and the remainder of the score is therefore a maximum of 10.
aspiration or obstruction), but a motor score of less than 5 would
suggest significant risk.
Coma is defined as a persisting state of deep unconsciousness.
In practice, this means a sustained GCS of 8 or less. There
are many causes of coma (Box 10.26), including neurological
(structural or non-structural brain disease) and non-neurological
(e.g. type II respiratory failure) ones. The mode of onset of coma
and any precipitating event is crucial to establishing the cause,
and should be obtained from witnesses. Failure to obtain an
adequate history for patients in coma is a common cause of
diagnostic delay.
Once the patient is stable from a cardiorespiratory perspective,
examination should include accurate assessment of conscious
level and a thorough general medical examination, looking for
clues such as needle tracks indicating drug abuse, rashes, fever
and focal signs of infection, including neck stiffness or evidence
of head injury. Focal neurological signs may suggest a structural
explanation (stroke or tumour) or may be falsely localising (for
example, 6th nerve palsy can occur as a consequence of raised
intracerebral pressure). It is vital to exclude non-neurological
causes of coma. Sodium and glucose should be measured
urgently as part of the initial assessment, as acute hyponatraemia
(p. 358) and hypoglycaemia (p. 738) are easily corrected and
can cause irreversible brain injury if missed.
10.25 How to communicate conscious level to other
health-care professionals
• It is best to state the physical response along with the numerical
score
• For example, ‘a patient who doesn’t open his eyes, withdraws to
pain and makes groaning noises, having a GCS of El , M4, V2,
making a total of 7’ is preferable to ‘a male with a GCS of T
I 10.26 Causes of coma
Metabolic disturbance
• Drug overdose
•
Inborn errors of metabolism
• Diabetes mellitus:
causing hyperammonaemia
Hypoglycaemia
•
Hyperammonaemia on
Ketoacidosis
refeeding following profound
Hyperosmolar coma
anorexia
• Hyponatraemia
•
Respiratory failure
• Uraemia
•
Hypothermia
• Hepatic failure
•
Hypothyroidism
(hyperammonaemia)
Trauma
• Cerebral contusion
•
Subdural haematoma
• Extradural haematoma
•
Diffuse axonal injury
Vascular disease
• Subarachnoid haemorrhage
•
Intracerebral haemorrhage
• Brainstem infarction/
•
Cerebral venous sinus
haemorrhage
thrombosis
Infections
• Meningitis
•
Cerebral abscess
• Encephalitis
•
Systemic sepsis
Others
• Epilepsy
•
Functional (‘pseudo-coma’)
• Brain tumour
Common presentations of deterioration • 195
0
0
Fig. 10.11 Hyperacute changes in conscious state are commonly of
vascular origin. CT of the brain is unlikely to identify many vascular
causes but a CT angiogram of the circle of Willis is a high-yield
investigation in this context. [A] Non-contrast CT of the head showing
hyperdense thrombus in the basilar artery (arrow). This is a specific, but
not sensitive, sign. [§] CT angiogram of the circle of Willis demonstrating
thrombosis in the basilar artery (arrow). This has better sensitivity for acute
vascular occlusion.
Further investigations should be guided by the clinical
presentation and examination findings; a sudden onset suggests
a vascular cause. An early CT scan of the brain may demonstrate
any gross pathology but if a brainstem stroke is suspected
(Fig. 10.11), a CT angiogram of the circle of Willis will provide
more useful information, as a non-contrast CT is frequently
negative in this context. If there are features suggestive of cerebral
venous thrombosis, such as thrombophilia or sinus infection, a
CT venogram should be performed. Meningitis or encephalitis
may be suggested by the history, signs of infection or subtle
radiological findings. If these diagnoses are considered, it is best
to commence treatment with broad-spectrum antibiotics and
antivirals while awaiting more definitive diagnostic information.
Other drug, metabolic and hepatic causes of reduced conscious
level are dealt with in the relevant chapters. An ammonia level
(sent on ice) can narrow the differential diagnosis to a metabolic
or hepatic cause if there is diagnostic doubt; levels >100 |imol/L
(140 jig/d L) are significantly abnormal. Psychiatric conditions
such as catatonic depression or neurological conditions such
as the autoimmune encephalitides can cause a reduced level
of consciousness, but they are diagnoses of exclusion and will
require specialist input.
Management
Moving an unconscious patient into the recovery position is best
for airway protection while preparations are made for escalation
to a higher level of care. The decision regarding intubation for
airway protection is always difficult. Length of stay in intensive
care is significantly reduced if there is no secondary organ
dysfunction. Therefore, early intubation and the prevention
of lung injury constitute the safer option if there is any doubt
about a patient’s ability to protect the airway from obstruction
or aspiration.
Decreased urine output/deteriorating
renal function
Assessment
A urine output of 0.5 mL/kg/hr is a commonly quoted, though
admittedly arbitrary target. Although some patients can produce
urine volumes below this level with no change in their renal
biochemistry, such low volumes should alert the clinician to the
possibility of suboptimal renal perfusion.
Oliguria in association with hypotension or an increase in serum
creatinine level (even if small) should prompt examination for the
underlying cause. Pre-renal causes predominate in the general
inpatient population, so optimising the MAP by administration of
intravenous fluids (and possibly vasopressors) is the first priority.
In the majority of inpatients there is no role for high volumes (i.e.
>30 mLVkg) of intravenous fluid if the MAP is normal. Exceptions
to this rule include patients with clinical dehydration or high fluid
losses such as in burns, diabetes emergencies (pp. 735 and
738) and diabetes insipidus (p. 687), where fluid management
should be guided by local protocols.
Diagnosis and management
Further assessment and management of oliguria are explained
on page 391 . Two other important causes of renal failure in the
inpatient population are abdominal compartment syndrome and
rhabdomyolysis.
Abdominal compartment syndrome
Abdominal compartment syndrome occurs when raised pressure
within the abdomen reduces perfusion to the abdominal organs.
It is most commonly seen in surgical patients, but can occur
in medical conditions with extreme fluid retention such as liver
cirrhosis. When it is suspected, intra-abdominal pressure can
be monitored via a pressure transducer connected to a urinary
catheter (following instillation of 25 mL of 0.9% saline into the
bladder). Values over 20 mmHg suggest abdominal compartment
syndrome is present. Urgent measures should be taken to reduce
the pressure, such as decompression of the stomach, bladder
and peritoneum if ascites is present. If conservative measures
fail, a laparostomy should be considered.
Rhabdomyolysis
Rhabdomyolysis occurs when there is an injury to a large volume
of skeletal muscle, usually because a single limb or muscle
compartment has been ischaemic for a prolonged period.
It can also occur following trauma and crush injury or after
over-exertion of muscles. Over-exertion can occur after intense
physical exercise or as part of a medical condition that causes
widespread muscular activity, such as malignant hyperpyrexia
or neuroleptic malignant syndrome. A creatine kinase (CK)
level of > 1 000 U/L is highly suggestive, although it can rise to
tens of thousands in severe cases. Management should focus
on identification and correction of the underlying cause and
support for multi-organ dysfunction. Forced alkaline diuresis
(using intravenous bicarbonate infusion and furosemide) can be
used to maintain a good flow of less acidic fluid within the renal
tubules and reduce myoglobin precipitation.
196 • ACUTE MEDICINE AND CRITICAL ILLNESS
Disorders causing critical illness
Sepsis and the systemic
inflammatory response
Sepsis is one of the most common causes of multi-organ failure.
Sepsis requires the presence of infection with a resultant systemic
inflammatory state; organ dysfunction occurs from a combination
of the two processes. The definition of sepsis has undergone
various iterations and there is still a lack of consensus as to
the exact wording that best reflects this complex, multisystem
process (Box 10.27).
Aetiology and pathogenesis
To understand how an infection can lead to progressive multi¬
organ failure, it is essential to have a grasp of the pathophysiology.
Initiation of the inflammatory response
The process begins with infection in one part of the body that
triggers a localised inflammatory response. Appropriate source
control and a competent immune system will, in most cases,
contain the infection at this stage. However, if certain factors
are present, the infection may become systemic. The causative
factors are not fully elucidated but probably include:
• a genetic predisposition to sepsis
• a large microbiological load
• high virulence of the organism
• delay in source control (either surgical or antimicrobial)
• resistance of the organism to treatment
• patient factors (immune status, nutrition, frailty).
Mediators are released from damaged cells (called ‘alarmins’)
and these, coupled with direct stimulation of immune cells
by the molecular patterns of the microorganism, trigger the
inflammatory response. An example of such direct stimulation
is that of lipopolysaccharide, which is found on the surface
of Gram-negative bacteria. It strongly stimulates an immune
response and is commonly used in research settings to initiate
a septic cascade.
Viral and fungal infections can cause a syndrome that is clinically
indistinguishable from bacterial sepsis. Likewise, numerous
i
Sepsis
Patients with suspected infection who have 2 or more of:
• Hypotension - systolic blood pressure <100 mmHg
• Altered mental status - Glasgow Coma Scale score < 1 4
• Tachypnoea - respiratory rate >22 breaths/min
Sepsis can also be diagnosed by suspected infection and an increase
of >2 points on the Sequential Organ Failure Assessment (SOFA) score
(p. 214)
Septic shock
A subset of sepsis with underlying circulatory or cellular/metabolic
abnormalities associated with a substantially increased mortality:
• Sepsis and both of (after fluid resuscitation):
1. Persistent hypotension requiring vasopressors to maintain a MAP
>65 mmPIg
2. Serum lactate >2 mmol/L (18 mg/dL)
*From the Third International Consensus Definitions for Sepsis and Septic Shock
(Sepsis-3).
non-infective processes, such as pancreatitis, burns, trauma,
major surgery and drug reactions, can cause alarmins to be
released and initiate the process of systemic inflammation.
Propagation of the inflammatory response
Once activated, immune cells such as macrophages release
the inflammatory cytokines interleukin-2 (IL-2), IL-6 and tumour
necrosis factor alpha, which, in turn, activate neutrophils.
Activated neutrophils express adhesion factors and release
various other inflammatory and toxic substances; the net effects
are vasodilatation (via activation of inducible nitric oxide synthase
enzymes) and damage to the endothelium. Neutrophils migrate
into the interstitial space; fluid and plasma proteins will also leak
through the damaged endothelium, leading to oedema and
intravascular fluid depletion.
Activation of the coagulation system
Damaged endothelium triggers the coagulation cascade (via tissue
factor, factor VII, and reduced activity of proteins C and S) and
thrombus forms within the microvasculature. A vicious circle of
endothelial injury, intravascular coagulation and microvascular
occlusion develops, causing more tissue damage and further
release of inflammatory mediators. In severe sepsis, intravascular
coagulation can become widespread. This is referred to as
disseminated intravascular coagulation (DIC) and usually heralds
the onset of multi-organ failure. Specific aspects of the diagnosis
and management of DIC are discussed on page 978.
Organ damage from sepsis
Any and all organs may be injured by severe sepsis. The
pathological mechanisms are shown in Figure 10.12.
Lactate physiology
Lactate is an excellent biomarker for the severity of sepsis.
Hyperlactataemia (serum lactate >2.4 mmol/L or 22 mg/dL)
is used as a marker of severity. Figure 10.13 explains the
physiology of hyperlactataemia; it is caused by all types of
shock and therefore is not specific to sepsis. A lactate level of
>8 mmol/L (>73 mg/dL) is associated with an extremely high
mortality and should trigger immediate escalation. Measures to
optimise oxygen delivery should be sought, and the adequacy
of resuscitation measured by lactate clearance.
The anti-inflammatory cascade
As the inflammatory state develops, a compensatory anti¬
inflammatory system is activated involving the release of anti¬
inflammatory cytokines such as IL-4 and IL-10 from immune
cells. While such mechanisms are necessary to keep the
inflammatory response in check, they may lead to a period
of immunosuppression after the initial septic episode. Patients
recovering from severe sepsis are prone to developing secondary
infections due to a combination of this immunosuppression and
the presence of indwelling devices.
Management
The most important action is to consider sepsis as the cause
of a patient’s deterioration. Aligned to this is the requirement to
consider other diagnoses that could be causing the presentation,
such as haemorrhage, PE, anaphylaxis or a low cardiac
output state.
Resuscitation in sepsis
General resuscitative measures are discussed on page 204. Early
resuscitation can be aided by following the requirements of the
10.27 Definitions of sepsis and septic shock
Disorders causing critical illness • 197
‘Sepsis Six’ (Box 10.28). Red cell transfusion should be used
to target a haemoglobin concentration of 70-90 g/L (7-9 g/dL).
Albumin 4% can be used as colloid solution and has the theoretical
benefit of remaining in the intravascular space for longer than
^CROVASCO^
CELLULAR 4//cEOVASCUvt^
Fig. 10.12 Pathophysiology of organ damage in sepsis. Macrovascular.
Severe hypovolaemia, vasodilatation or septic cardiomyopathy can reduce
oxygen delivery, causing tissue hypoxia. Paradoxically, most patients with
sepsis have an increased cardiac output and oxygen delivery. Microvascular.
Tissue injury can occur from hypoxia secondary to microvascular injury and
thrombosis. Damaged epithelium permits neutrophils, proteins and fluid to
leak out. Shunting. Organs fail in sepsis despite supranormal blood flow. It is
likely that arteriovenous shunt pathways exist within vascular beds; these
shunts open up in septic shock. Cellular. Cells are damaged by a number of
mechanisms in sepsis: (1) direct injury by microorganisms; (2) injury from
toxins produced by immune cells, e.g. oxygen free radicals; (3)
mitochondrial injury causing cytopathic hypoxia - cells are unable to
metabolise oxygen; (4) apoptosis - if the cell injury is sufficient, capsase
enzymes are activated within the nucleus and programmed cell death
occurs; (5) hypoxia from micro- and macrovascular pathology.
crystalloid. Early intubation is recommended in severe cases
to facilitate further management and reduce oxygen demand.
Appropriate antibiotics should be administered as early as
possible (Box 10.29). The antibiotic choice will depend on local
patterns of resistance, patient risk factors and the likely source
of infection. Information on likely organisms and appropriate
antibiotics can be found on pages 1 1 7 and 226. Microbiological
samples (such as blood cultures, urine or CSF) should be taken,
but this should not delay antibiotic administration, if obtaining
samples is difficult.
Early source control
Source control requires an accurate diagnosis; urgent
investigations should be performed as soon as physiological
stability has been established. A CT scan of the chest and
abdomen with contrast is a high-yield test in this context. Specific
points in the history should be reviewed, such as risk factors for
human immunodeficiency virus (HIV), contacts with tuberculosis
and underlying immune status. Immunocompromised patients
will be susceptible to a far broader spectrum of infectious
microorganisms (p. 223).
10.28 The ‘Sepsis Six’
1 . Deliver high-flow oxygen
2. Take blood cultures
3. Administer intravenous antibiotics
4. Measure serum lactate and send full blood count
5. Start intravenous fluid replacement
6. Commence accurate measurement of urine output
International recommendations for the immediate management of suspected
sepsis from the Surviving Sepsis Campaign (all to be delivered within 1 hr of the
initial diagnosis of sepsis).
10.29 Early administration of antibiotics in
suspected sepsis
Broad-spectrum antibiotics should be administered as soon as
possible after sepsis is suspected
Every hour of delayed treatment is associated with a 5-10%
increase in mortality
Inadequate
Tissue hypoxia
Shock
Drugs
Excess muscle
Other causes:
oxygen
e.g. Ischaemic
(from any cause)
e.g. Adrenaline
activity
Metformin
delivery
gut
(epinephrine)
e.g. Extreme
Thiamin deficiency
Salbutamol
exercise
Haematological malignancy
Seizure
Drugs, e.g. antiretrovirals
Excess
production
Anaerobic
(32-adrenoceptor
Excess tissue
metabolism
stimulation
production
Inadequate
Hepatic
clearance
failure
i.
High
lactate
Congenital enzyme
deficiencies (rare)
Fig. 10.13 Physiology of hyperlactataemia.
198 • ACUTE MEDICINE AND CRITICAL ILLNESS
10.30 Central and mixed venous oxygen saturations
• Saturation of venous blood sampled from the right atrium or
superior vena cava (central) or pulmonary artery (mixed venous)
• Both values reflect the balance of supply and demand of oxygen to
the tissues
• Mixed venous oxygen saturation is a measure of whole-body supply
and demand of oxygen; central venous oxygen saturation measures
the supply and demand of oxygen from the upper body. Normal
mixed venous oxygen saturation is 70%. Lower values than this
suggest inadequate oxygen delivery
• Central venous oxygen saturation is more variable, depending on
whether the patient is awake or anaesthetised, but a value of 70%
is considered normal
• Where cytopathic hypoxia occurs, oxygen extraction is impaired and
the central and mixed venous oxygen saturations may be >80%.
This is often a poor prognostic sign
Noradrenaline (norepinephrine) for refractory hypotension
Central venous access should be established early in the
resuscitation process and a noradrenaline infusion commenced.
If there is severe hypotension, it is not necessary to wait until
30 mLykg of fluid has been administered before commencing
noradrenaline; early vasopressor use may improve the outcome
from acute kidney injury. Measurement of central and mixed
venous oxygen saturations may provide additional prognostic
information (Box 10.30).
Other therapies for refractory hypotension
Refractory hypotension is due to either inadequate cardiac output
or inadequate systemic vascular resistance (vasoplegia). When
vasoplegia is suspected, it may be necessary to add vasopressin
(antidiuretic hormone, ADH). This is a potent vasoconstrictor
that may be used to augment noradrenaline (norepinephrine) in
achieving an acceptable MAP. Intravenous glucocorticoids are
also commonly used in refractory hypotension. There is little
evidence that they improve the overall outcome, but they do lead
to a more rapid reversal of the shocked state. There is a small
increased risk of secondary infection following glucocorticoid use.
Septic cardiomyopathy
The myocardium can be affected by the septic process, presenting
as either acute left or right ventricular dysfunction. A bedside
echocardiogram is particularly useful to confirm the diagnosis, as
ECG changes are usually non-specific. Dobutamine or adrenaline
(epinephrine) can be used to augment cardiac output, and
intravenous calcium should be replaced if ionised calcium is low.
Other interventions such as intravenous bicarbonate in profound
metabolic acidosis, high-volume haemofiltration/haemodialysis
and extracorporeal support are sometimes used, but currently
lack evidence of benefit.
Review of the underlying pathology
While sepsis is the most common cause of acute systemic
inflammation, up to 20% of patients initially treated for sepsis
will have a non-infectious cause: that is, a sepsis mimic (Box
10.31). These conditions should be considered where the clinical
picture is not typical, no source of sepsis can be found, or the
inflammatory response seems excessive in the context of local
infection. Early reconsideration of the diagnosis of sepsis is
crucial, as many of the ‘sepsis mimics’ offer a finite time window
for specific intervention, after which irreversible organ damage
will have occurred.
10.31 Sepsis mimics
• Pancreatitis
• Drug reactions
• Widespread vasculitis - catastrophic antiphospholipid syndrome,
Goodpasture’s syndrome
• Autoimmune diseases - inflammatory bowel disease, rheumatoid
arthritis, systemic lupus erythematosus
• Malignancy - carcinoid syndrome
• Haematological conditions - haemophagocytic syndrome, diffuse
lymphoma, thrombotic thrombocytopenic purpura
Acute respiratory distress syndrome
Aetiology and pathogenesis
Acute respiratory distress syndrome (ARDS) is a diffuse
neutrophilic alveolitis caused by a range of conditions and
characterised by bilateral radiographic infiltrates and hypoxaemia
(Box 10.32). Activated neutrophils are sequestered into the lungs
and capillary permeability is increased, with damage to cells
within the alveoli. The pathophysiology is part of the inflammatory
spectrum described in ‘Sepsis’ above, and the triggers are
similar: infective and non-infective inflammatory processes. These
processes result in exudation and accumulation of protein-rich
cellular fluid within alveoli and the formation of characteristic
‘hyaline membranes’. Local release of cytokines and chemokines
by activated macrophages and neutrophils results in progressive
recruitment of inflammatory cells. Secondary effects include loss
of surfactant and impaired surfactant production. The net effect is
alveolar collapse and reduced lung compliance, most marked in
dependent regions of the lung (mainly dorsal in supine patients).
The affected airspaces become fluid-filled and can no longer
contribute to ventilation, resulting in hypoxaemia (due to increased
pulmonary shunt) and hypercapnia (due to inadequate ventilation
in some areas of the lung): that is, ventilation-perfusion mismatch.
Diagnosis and management
ARDS can be difficult to distinguish from fluid overload or cardiac
failure. Classic chest X-ray and CT appearances are shown in
Figures 10.14 and 10.15, respectively. Occasionally, conditions
may present in a similar way to ARDS but respond to alternative
treatments; an example of this might be a glucocorticoid-
responsive interstitial pneumonia (p. 605). Management of ARDS is
supportive, including use of lung-protective mechanical ventilation,
inducing a negative fluid balance and treating the underlying
cause. Establishing the severity of ARDS (Box 10.33) is useful,
as severe disease will require more proactive management such
as prone positioning or extracorporeal membrane oxygenation
(ECMO; p. 204).
10.32 Berlin definition of ARDS
• Onset within 1 week of a known clinical insult, or new or worsening
respiratory symptoms
• Bilateral opacities on chest X-ray, not fully explained by effusions,
lobar/lung collapse or nodules
• Respiratory failure not fully explained by cardiac failure or fluid
overload. Objective assessment (e.g. by echocardiography) must
exclude hydrostatic oedema if no risk factor is present
• Impaired oxygenation (see Box 10.33)
Disorders causing critical illness • 199
Fig. 10.14 Chest X-ray in acute respiratory distress syndrome
(ARDS). Note bilateral lung infiltrates, pneumomediastinum,
pneumothoraces with bilateral chest drains, surgical emphysema, and
fractures of the ribs, right clavicle and left scapula.
10.33 Determining the severity of ARDS
Severity of hypoxaemia is calculated using a Pa/Fi 02 ratio. This is a
number calculated by using the Pa02 from an arterial blood gas
measurement divided by the fraction of inspired oxygen (/702,
expressed as a fraction).
For example, a patient with a Pa02 of 10 kPa (75 mmFIg) on 50%
oxygen, i.e. Fi02 of 0.5, would have a Pa/Fi02 ratio of 20 kPa
(150 mmFIg). This would be defined as moderately severe ARDS, if the
other Berlin criteria were met (see Box 10.32). All measurements
should be taken on a minimum of 5 cmH20 of PEEP or CPAP.
• Mild: 40-26.6 kPa (300-200 mmHg)
• Moderate: 26.6-13.3 kPa (200-100 mmFIg)
• Severe: <13.3 kPa (<100 mmFIg)
(CPAP = continuous positive airway pressure; PEEP = positive end-expiratory
pressure)
Acute circulatory failure
(cardiogenic shock)
Definition and aetioiogy
Cardiogenic shock is defined as hypoperfusion due to inadequate
cardiac output or, more technically, a cardiac index of <2.2 L7min/
m2 (see Box 10.42). While cardiogenic shock is the final common
pathway of many disease processes (e.g. sepsis, anaphylaxis,
haemorrhage), the important primary causes of acute heart failure
or cardiogenic shock (Fig. 10.16) are described here.
Myocardial infarction
In the majority of cases, cardiogenic shock following acute Ml
is due to left ventricular dysfunction. However, it may also be
due to infarction of the right ventricle, or a variety of mechanical
complications, including tamponade (due to infarction and rupture
of the free wall), an acquired ventricular septal defect (due to
Fig. 10.15 CT scan of the thorax in a patient with severe ARDS. Note
the pathology is mainly in the dorsal (dependent) parts of the lung.
*1
10.34 Acute myocardial infarction:
haemodynamic subsets
Cardiac
Pulmonary oedema
output
No
Yes
Normal
Good prognosis and
requires no treatment for
heart failure
Due to moderate left
ventricular dysfunction.
Treat with vasodilators
and diuretics
Low
Due to right ventricular
dysfunction or concomitant
hypovolaemia. Give fluid
challenge and consider
pulmonary artery catheter
to guide therapy
Extensive myocardial
infarction and poor
prognosis. Consider
intra-aortic balloon pump,
vasodilators, diuretics and
i notropes
infarction and rupture of the septum) and acute mitral regurgitation
(due to infarction or rupture of the papillary muscles).
Severe myocardial systolic dysfunction causes a fall in cardiac
output, BP and coronary perfusion pressure. Diastolic dysfunction
causes a rise in left ventricular end-diastolic pressure, pulmonary
congestion and oedema, leading to hypoxaemia that worsens
myocardial ischaemia. This is further exacerbated by peripheral
vasoconstriction. These factors combine to create the ‘downward
spiral’ of cardiogenic shock (Fig. 10.17). Hypotension, oliguria,
delirium and cold, clammy peripheries are the manifestations
of a low cardiac output, whereas breathlessness, hypoxaemia,
cyanosis and inspiratory crackles at the lung bases are typical
features of pulmonary oedema. If necessary, a Swan-Ganz
catheter can be used to measure the pulmonary artery pressures
and cardiac output (p. 206). These findings can be used to
categorise patients with acute Ml into four haemodynamic
subsets (Box 10.34) and titrate therapy accordingly.
In cardiogenic shock associated with acute Ml, immediate
percutaneous coronary intervention should be performed (p. 491).
The viable myocardium surrounding a fresh infarct may contract
poorly for a few days and then recover. This phenomenon is
known as myocardial stunning and means that acute heart failure
200 • ACUTE MEDICINE AND CRITICAL ILLNESS
Left ventricular
infarct
Right ventricular
infarct
tamponade
Endocarditis
of mitral valve
Left ventricular damage
Myocardial infarction
Myocarditis
Fig. 10.16 Some common causes of cardiogenic shock.
i Cardiac T Left ventricular
output diastolic pressure
i Blood T Pulmonary
pressure congestion
st
i Coronary Hypoxaemia
perfusion
Fig. 10.17 The downward spiral of cardiogenic shock.
should be treated intensively because overall cardiac function
may subsequently improve.
Acute massive pulmonary embolism
Massive PE may complicate leg or pelvic vein thrombosis and
usually presents with sudden collapse. The clinical features and
treatment are discussed on page 619. Bedside echocardiography
may demonstrate a small, under-filled, vigorous left ventricle with
a dilated right ventricle; it is sometimes possible to see thrombus
in the right ventricular outflow tract or main pulmonary artery.
In practice, it can be difficult to distinguish massive PE from a
right ventricular infarct on transthoracic echocardiogram. CT
pulmonary angiography usually provides a definitive diagnosis.
Acute valvular pathology, aortic dissection and
cardiac tamponade
These conditions should be considered in an undifferentiated
presentation of shock. The diagnosis and management of these
conditions is discussed on pages 514, 506 and 544.
Post cardiac arrest
The initial management of cardiac arrest is discussed on
page 456. Following the return of spontaneous circulation (ROSC),
the majority of cardiac arrest survivors will need a period of
time in intensive care to achieve physiological stability, identify
Critical care medicine • 201
and manage the underlying cause of the arrest, and optimise
neurological recovery.
Acute management
A MAP of >70 mmHg should be maintained to optimise cerebral
perfusion. Shock is common following ROSC and is caused by
a combination of the underlying condition leading to the arrest,
myocardial stunning and a post-arrest vasodilated state. Support
with inotropes, vasopressors and occasionally mechanical support
from an intra-aortic balloon pump or venous-arterial ECMO
(p. 207) may be required. Specific cardiac interventions and their
indications are described in Chapter 16. Other physiological
targets are listed in Box 10.35.
Prognosis
Predicting which patients will not recover from the brain injury
sustained at the time of cardiac arrest is very difficult. Certain
features suggest that the outcome will be poor: for example, the
absence of pupillary and corneal reflexes, absence of a motor
response and persistent myoclonic jerking.
Tools to assist prognostication following cardiac arrest are
shown in Box 10.36. The clinician should, where feasible, delay
prognostication until a period of 72 hours of targeted temperature
management has been completed. The bilateral absence of
the ‘N20’ spike on the somato-sensory evoked potential is
10.35 Physiological targets following a return of
spontaneous circulation (ROSC)
the most specific test to predict irrecoverable brain injury. This
test is performed by administering an electrical impulse over a
peripheral nerve and recording the electrical impulses measured
by the scalp electrodes overlying the part of the brain expected
to receive the impulse. Where this is not available, prognostication
based on all other available information, along with the perceived
wishes relating to the level of disability the individual would be
prepared to accept, should allow a decision regarding ongoing
treatment to be made. Where there is doubt, more time should
be given to allow assessment of neurological recovery.
Other causes of multi-organ failure
As previously discussed, sepsis is the most common cause
of multi-organ failure. However, multi-organ failure secondary
to single organ dysfunction, such as cardiac failure, liver
failure, renal failure or respiratory failure, is also common. The
multisystem insult in these disease processes goes beyond
the direct biochemical damage and tissue hypoxia caused by
the primary organ dysfunction. It probably reflects cellular signalling
pathways and the release of other systemic toxins by the failing
organ, referred to as organ ‘crosstalk’.
Multi-organ failure can also be caused by a physiological
insult that damages a wide variety of cells in different organs,
including toxins from extrinsic sources such as envenomation
and intrinsic sources such as myoglobin in rhabdomyolysis
(p. 195). Multi-organ failure can also be caused by profound
physical injury to cells from processes such as nuclear radiation,
heat exposure or blast trauma.
Critical care medicine
Decisions around intensive care admission
Being a patient in intensive care is seldom a pleasant experience.
The interventions are usually painful and the loss of liberties that
are normally taken for granted can be devastating. While much of
the unpleasant sensory and emotional experience can be modified
with high-quality care and analgesia, there is a strong case that
it can only be morally ‘right’ to admit a patient to intensive care
if the end justifies the means. There must be a realistic hope
that the patient will regain a quality of life that would be worth
the pain and suffering that he or she will experience in intensive
care. Few patients are able to comprehend fully what it means
to be critically ill, so the physician should guide the process of
determining who should be admitted to intensive care.
Selecting the appropriate level of intervention for an individual
patient can be very difficult. The decision-making process
should involve an assessment of the likelihood of reversibility
of the disease, the magnitude of the interventions required, the
underlying level of frailty, and the personal beliefs and wishes
of the patient (commonly expressed through their next of kin).
As technology and science have improved, conditions that
were previously regarded as terminal can now be supported and
life can be considerably prolonged (Box 10.37). There have been
several prominent examples of individuals who have received
intensive care, but where an onlooker might have considered
treatment to be futile owing to frailty, comorbidity or profound
neurological injury. Such cases will, in part, shape the views and
expectations of society, and it is unlikely that making decisions
in this area will become any easier. Some suggested techniques
I to aid decision-making are listed in Box 10.38.
• Temperature management. Facilitate maintenance of temperature at
36°C and avoidance of pyrexia by the use of a cooling blanket. This
should be continued for 72 hrs. Muscle relaxants may be required
to prevent shivering
• Blood pressure management. Aim for a MAP of at least 70 mmHg
and a systolic blood pressure of >120 mmHg
• Glucose control. Control the glucose to 6-1 0 mmol/L (1 08-
180 mg/dL)
• Normal C02 (4.5-6 kPa, 33-45 mmHg) and oxygen saturation
(94-98%). Avoid both hypoxaemia and hyperoxia
10.36 Prognostication after cardiac arrest: predictors
of poor neurological recovery
Coexisting problems
• Multi-organ failure
• Significant comorbidities
Clinical
• Persisting and generalised myoclonus
• Absence of pupillary or corneal reflexes
• Poor motor response (absent or extensor response)
Biochemical
• A neuron-specific enolase >33 pig/L
Imaging
• CT showing loss of grey-white differentiation
• Focal cause or consequence of cardiac arrest, e.g. subarachnoid
haemorrhage
Electrophysiology
• EEG patterns may suggest brain injury, e.g. burst suppression
• Somato-sensory evoked potentials - bilateral absence of the N20
spike (recorded from scalp electrodes from cutaneous electrical
impulse over the median nerve)
202 • ACUTE MEDICINE AND CRITICAL ILLNESS
10.37 Critical illness in the context of
congenital conditions
• Longer survival: there are many congenital conditions that would,
in the past, have been fatal in childhood, but now patients survive
into adulthood. Decision-making can be difficult when the
adolescent has impaired decision-making capacity.
• Parental views: in such circumstances, the views of the parent or
legal guardian become paramount.
• Goals of care: often a detailed explanation of what is, and is not,
achievable in intensive care allows the direction of care to be
switched to palliative when life expectancy is poor and quality of life
is severely impaired.
• Decision-making: such conversations may require input from
experts in the patient’s congenital condition(s), and advanced
decision-making regarding ICU admission should be encouraged
whenever patients and families feel able to discuss such issues.
10.38 Techniques to improve admission
decision-making
• Always act in the best interests of the patient, external influences
are commonly present but these should be of only secondary
importance
• Maximise patient capacity, wherever possible, the patient should be
involved in discussions of escalation and resuscitation status
• Communicate openly and honestly with the next of kin : when
communicating potential outcomes, it is best to use natural
frequencies rather than percentages. For example, ‘If we had 100
patients with the same illness as your mother, only 10 would
survive’ is easier for most people to understand than ‘there is a
90% chance of death’
• Reach mutual agreement with the next of kin: it is rare for there to
be discord between clinicians and family, and in most cases the
most appropriate course of action is clear
• Seek additional opinions: other clinicians involved in the care of the
patient will provide useful input. The premise should be to err on
the side of escalation where the most appropriate course of action
is unclear. Where there is an unresolvable difference in opinion, a
mediation process or court ruling may be required to make the final
decision. Thankfully, this is a very infrequent occurrence
• Plan ahead: advance planning in chronic, progressive disease can
make the decision easier. Some health facilities use an escalation
form, which specifies the interventions that should be offered or are
acceptable to the patient. This can be useful as the binary decision
of for/not for resuscitation fails to account for the array of
interventions that can be performed before cardiac arrest occurs
Stabilisation and institution of
organ support
In order to stabilise a critically unwell patient, the primary problem
should be corrected as quickly as possible: for example, source
control in sepsis and control of the bleeding point in haemorrhage.
Immediate resuscitation and prioritisation of the safety of the
patient are clearly important, but there is only a limited role for
‘optimising’ the patient if such measures may significantly delay a
definitive treatment, such as laparotomy for a perforated viscus.
In some cases, the definitive treatment is not readily apparent
or treatments take time to have their full effect. In these cases,
adequate organ support to stabilise the patient while the treatment
is given becomes the main goal of care.
Respiratory support
|jlon-invasive respiratory support
Non-invasive respiratory support provides a bridge between
simple oxygen delivery devices and invasive ventilation. It can
be used in patients who are in respiratory distress but do not
have an indication for invasive ventilation, or in those who are
not suitable for intubation and ventilation for chronic health
reasons. Patients must be cooperative, able to protect their
airway, and have the strength to breathe spontaneously and
cough effectively. Clinicians should avoid using non-invasive
respiratory support to prolong the dying process in irreversible
conditions such as end-stage lung disease. Likewise, a failure
to respond to treatment or further deterioration should trigger
a decision regarding intubation, as delayed invasive ventilation
in this context is associated with worse outcome.
High-flow nasal cannulae
High-flow nasal cannulae (HFNCs) are devices that provide very
high gas flows of fully humidified oxygen and air. They offer
distinct advantages over non-invasive ventilation (NIV) in selected
patients, mainly those with type I respiratory failure (particularly
pneumonia) who have not reached an indication for invasive
ventilation. They allow patient comfort and increased expectoration
while providing some degree of positive end-expiratory pressure
(PEEP) and a high oxygen concentration that can be titrated to
the S02.
Continuous positive pressure ventilation
Continuous positive pressure ventilation therapy involves the
application of a continuous positive airway pressure (CPAP)
throughout the patient’s breathing cycle, typically 5-10 cmH20.
It helps to recruit collapsed alveoli and can enhance clearance
of alveolar fluid. It is particularly effective at treating pulmonary
atelectasis (which may be post-operative) and pulmonary oedema.
It uses a simpler device than NIV but otherwise offers no direct
benefit over it.
Non-invasive ventilation or bi-level ventilation
NIV provides ventilatory support via a tight-fitting nasal or facial
mask. It can be delivered by using a simple bi-level ventilation
(BiPAP) turbine ventilator, or an intensive care ventilator. These
machines can deliver pressure at a higher level (approximately
15-25 cmH20) for inspiration and a lower pressure (usually
4-10 cmH20) to allow expiration. Ventilation can be spontaneous
(triggered by a patient’s breaths) or timed (occurring at a set
frequency). Systems that synchronise with a patient’s efforts
are better tolerated and tend to be more effective in respiratory
failure. Timed breaths are used for patients with central apnoea.
NIV is the first-line therapy in patients with type II respiratory
failure secondary to an acute exacerbation of COPD because
it reduces the work of breathing and offloads the diaphragm,
allowing it to recover strength. It is also useful in pulmonary
oedema, obesity hypoventilation syndromes and some
neuromuscular disorders. It should be initiated early, especially
when severe respiratory acidosis secondary to hypercapnia is
present. NIV can also be used to support selected patients
with hypercapnia secondary to pneumonia, or during weaning
from invasive ventilation, but its effectiveness in these contexts
is less certain; early intubation or re-intubation is probably
more beneficial.
Stabilisation and institution of organ support • 203
I Intubation and intermittent positive
pressure ventilation
Taking control of the respiratory system in a critically ill patient
is one of the most significant and risky periods in a patient’s
journey. Critical incidents are common because the patient is
often deteriorating rapidly and is exhausted. The potential for
cardiovascular collapse is further exacerbated by the negatively
inotropic and vasodilating drugs used to induce anaesthesia, and
the period of apnoea invoked to facilitate intubation (Box 10.39).
The main aims of intermittent positive pressure ventilation
(IPPV) are to avoid critical hypoxaemia and hypercapnia while
minimising damage to the alveoli and encouraging the patient to
10.39 Optimising safety during intubation
• Intervene early in the disease process (once it has become clear
that the disease trajectory is downward)
• Use a stable anaesthetic technique: low doses of sedative agents
and rapidly acting paralytic agents
• Remember that intubation should be performed by the most
experienced operator available
• Use techniques to optimise oxygenation and ventilation in the period
around intubation, e.g. keeping non-invasive ventilation in situ for
pre-oxygenation, leaving high-flow nasal cannulae on for the
intubation process, and using a video-laryngoscope in an
anticipated difficult intubation
breathe spontaneously once it is safe to do so. The determination
of what constitutes critical will depend on the status of each
patient. For example, a patient with raised ICP will have a strong
indication for normocapnia (because hypercapnia increases ICP).
Unfortunately, achieving the minute volumes required to maintain
normocapnia can, in itself, be harmful to the lungs (p. 204).
Ventilator modes
Following intubation, most patients have a period of paralysis
from the muscle relaxation. Mandatory ventilation is, therefore,
required for a variable period, depending on the severity of the lung
injury, the underlying disease process and the general condition
of the patient. Mandatory ventilation means that the ventilator
will deliver set parameters (either a set tidal volume or a set
inspiratory pressure), regardless of patient effort. A physician can
choose to support additional patient effort in between mandatory
breaths with pressure support. This requires sufficient patient
effort to ‘trigger’ the ventilator to deliver a synchronised breath,
in time with the patient’s own ventilation. Other parameters that
should be considered when using mechanical ventilation are
shown in Figure 10.18.
As a patient’s illness resolves, or if the lung injury necessitating
intubation is not severe, periods of spontaneous breathing with
pressure support are commenced. While spontaneous breathing
is preferable to mandatory ventilation modes, the shearing
forces of patient effort can exacerbate lung injury in patients
with severely damaged lungs. It is, therefore, important that a
patient is permitted to breathe in a planned and controlled way.
Plateau pressure
Airway pressure during an
inspiratory hold. Keeping plateau
pressure as low as possible above
PEEP is the most protective
strategy for the lungs
Respiratory rate and minute volume
Depend on the minute volume required to
achieve the desired PCO2, and whether the
patient is breathing spontaneously. Rates are
commonly 20-30 breaths/min
- 1
Ventilator mode
Mandatory, spontaneous,
or mandatory with the ability
to take spontaneous breaths
(as shown here)
Pressure-time ►
graph
Volume-time ►
graph
Flow-time
graph
F/02
Fraction of inspired
oxygen. This is usually
titrated to oxygen
saturations targeting
92-95%
Tidal volume
Usual target is 6 ml_/kg
of predicted body
weight (PBW)
Positive end-expiratory pressure (PEEP)
The pressure within the respiratory system during expiration,
commonly 5-15 CIT1H2O. Higher levels of PEEP often improve
oxygenation but put strain on the right heart (as it makes it
harder to pump blood through the pulmonary circulation)
Fig. 10.18 Settings to be considered when commencing mechanical ventilation.
204 • ACUTE MEDICINE AND CRITICAL ILLNESS
Ventilator-induced lung injury
Every positive-pressure breath causes cyclical inflation of alveoli
followed by deflation. The resultant damage to alveoli occurs via
several possible mechanisms:
• distending forces from the tidal volume, termed
‘volutrauma’
• the pressure used to inflate the lung, referred to as
‘barotrauma’
• alveoli collapsing at the end of expiration, called
‘atelectotrauma’
• the release of inflammatory cytokines in response to
cyclical distension, called ‘biotrauma’.
The threshold of injurious ventilation is unique to each patient.
Moderate ventilator pressures and volumes used to ventilate
healthy lungs may not cause ventilator- induced lung injury (VILI),
but the same settings may cause significant VILI if delivered to
a patient with lungs that are already damaged from another
disease process.
Strategies that may reduce the incidence and severity of
VILI include:
• Permissive hypercapnia. In the majority of patients who
are ventilated for respiratory failure, it is preferable to
tolerate moderate degrees of hypercapnia rather than
strive for normal blood gases at the expense of VILI. For
example, in a patient with isolated respiratory failure,
a physician may choose to tolerate a PaC02 of up
to 10 kPa (75 mmHg), provided the H+ is <63 nmol/L
(pH >7.2).
• ‘Open lung’ ventilation. Maintaining a positive pressure
within the airways at the end of expiration prevents
atelectotrauma. Use of low tidal volumes, higher levels of
PEEP (Fig. 10.18) and recruitment manoeuvres (occasional
short periods of sustained high airway pressures to open
up alveoli that have collapsed) can reduce the incidence
of VILI.
• Paralysis. When respiratory failure is severe, patient effort
may worsen VILI. An infusion of muscle relaxant can be
used to moderate dyssynchrony with the ventilator.
Advanced respiratory support
Airway pressure release ventilation
Airway pressure release ventilation (APRV) is a mode of ventilation
that lengthens the inspiratory time to the extreme, with a very
short period of time for expiration. It relies on spontaneous
movement of the diaphragm from patient effort to facilitate
the mixing of gas within the respiratory system during the long
period in full inspiration, followed by a very short period of low
pressure to allow passive expiration. It has not, however, been
demonstrated to be superior to conventional modes of ventilation,
but may have a role in moderate to severe ARDS.
Prone positioning
In ARDS, the posterior parts of the lung lose airspaces due
to atelectasis and inflammatory exudate. By placing patients
on their front, the pattern of fluid distribution within the lung
changes, and ventilation-perfusion matching is improved. This
is used to enhance oxygenation in moderate to severe ARDS,
and may have some disease-modifying effects as the dependent
areas of the lung are changed periodically. Although there are
risks associated with nursing a patient in the prone position, it
is becoming a widespread therapy. Patients are usually placed
in the prone position for 12-24 hours and then rotated back
to the supine position for a similar period. This cycle continues
until there is evidence of resolving lung injury.
Extracorporeal respiratory support
Sometimes, despite optimal invasive ventilation, it is not possible
to maintain adequate oxygenation or prevent a profound
respiratory acidosis. When a patient has a reversible cause of
respiratory failure (or is a potential lung transplant recipient) and
facilities are available, extracorporeal respiratory support should
be considered.
Venous-venous extracorporeal
membrane oxygenation
In venous-venous extracorporeal membrane oxygenation (VV
ECMO), large-bore central venous cannulae are inserted into the
superior vena cava (SVC) and/or the inferior vena cava (IVC) via
the femoral or jugular veins, and advanced under ultrasound or
fluoroscopic guidance (Fig. 10.19). Venous blood is then pumped
through a membrane oxygenator. This device has thousands
of tiny silicone tubes with air/oxygen gas on the other side
of the tubes (the membrane). This facilitates the passage of
oxygen into the blood and diffusion of carbon dioxide across
the membrane, where it is removed by a constant flow of gas
(sweep gas). The oxygenated blood is then returned to the
right atrium, from where it flows through the lungs as it would
in the physiological state. This means that even if the lungs are
contributing no oxygenation or carbon dioxide removal, a patient
can remain well oxygenated and normocapnic.
Extracorporeal carbon dioxide removal
In some patients it is possible to maintain oxygenation but
there is refractory hypercapnia. There are devices available
that can remove carbon dioxide using a much lower blood flow
rate than VV ECMO. Consequently, smaller venous cannulae,
similar to those used in renal dialysis, can be sufficient to have
a ‘C02 dialysis’ effect. This can be useful in patients in whom
normocapnia is essential (such as those with a raised ICP), or
those with refractory hypercapnia and adequate oxygenation. In
addition, extracorporeal carbon dioxide removal can be used to
reduce the required minute volume, which is a beneficial strategy
for protecting the lungs against VILI or facilitating early extubation.
Cardiovascular support
| Initial resuscitation
A brief assessment can usually yield enough information to
determine whether a patient is at significant risk of an imminent
cardiac arrest. If the patient is obtunded and there is no palpable
radial or brachial pulse, then treatment should proceed as
described on page 457.
In anaphylactic shock, or undifferentiated shock in a peri-arrest
situation, a single dose of intramuscular adrenaline (epinephrine)
0.5 mg (0.5 mL of 1 :1000) can be life-saving. If expertise is
available, a small dose of intravenous adrenaline can delay
cardiac arrest long enough to identify the cause of shock and
institute other supportive measures; a suggested dose would
be 50 jig (0.5 mL of 1 : 10000). If haemorrhage is considered
a possibility, a ‘major haemorrhage’ alert should be activated,
facilitating rapid access to large volumes of blood and blood
products. A classification of shock is shown in Box 10.40.
Stabilisation and institution of organ support
205
Centrifugal pump
m
Venous ‘return’ cannula
Superior vena cava
Right atrium now full
of oxygenated blood
Tricuspid valve
Right ventricle
Inguinal ligament
Femoral artery
Access ECMO cannula
Skin puncture site
in proximal thigh
Femoral vein
From ECMO
i
Pulmonary vein (left)
Proximal aorta
Right atrium
Pulmonary vein (right)
Aortic valve
Mitral valve
Left ventricle
Oxygenated blood at
high pressure will flow
proximally up the aorta
to perfuse organs
Blood will also
flow distally to
perfuse the legs
Arterial ‘return’ cannula
Fig. 10.19 Principles of extracorporeal membrane oxygenation (ECMO). [A] Basic ECMO circuit: venous-arterial (VA) and venous-venous (VV).
[§] Example of a VV ECMO circuit. [C] Example of a VA ECMO circuit.
206 • ACUTE MEDICINE AND CRITICAL ILLNESS
10.40 Categories of shock
Category
Description
Hypovolaemic
Can be haemorrhagic or non-haemorrhagic in
conditions such as hyperglycaemic hyperosmolar
state (p. 738) and burns
Cardiogenic
See page 1 99
Obstructive
Obstruction to blood flow around the circulation,
e.g. major pulmonary embolism, cardiac
tamponade, tension pneumothorax
Septic
See page 1 96
Anaphylactic
Inappropriate vasodilatation triggered by an allergen
(e.g. bee sting), often associated with endothelial
disruption and capillary leak (p. 75)
Neurogenic
Caused by major brain or spinal injury, which
disrupts brainstem and neurogenic vasomotor
control. High cervical cord trauma may result in
disruption of the sympathetic outflow tracts, leading
to inappropriate bradycardia and hypotension.
Guillain— Barre syndrome (p. 1140) can involve the
autonomic nervous system, resulting in periods of
severe hypo- or hypertension
Others
e.g. Drug-related such as calcium channel blocker
overdose; Addisonian crisis
Venous access for the administration of drugs and fluids is
vital but often difficult in critically unwell patients. Wide-bore
cannulae are required for rapid fluid administration. In extremis,
the external jugular vein can be cannulated; it is often prominent
in low cardiac output states and readily visible on the lateral
aspect of the neck. Occluding the vein distally with finger pressure
makes it easier to cannulate, but care must be taken to remain
high in the neck to avoid causing a pneumothorax. Intra-osseous
or central venous access can be established if there are no
visible peripheral veins. Ultrasound can provide assistance for
rapid and safe venous cannulation. Rapid infusion devices are
widely available and should be used for the delivery of warmed,
air-free fluid and blood products.
Fluid and vasopressor use
Resuscitation of the shocked patient should include a 10 ml_/
kg fluid challenge. Using colloid or crystalloid is acceptable;
starch solutions are associated with additional renal
dysfunction and should be avoided. The fluid challenge can
be repeated if shock persists, to a maximum total of 30 ml_/
kg of fluid. However, commencing vasopressor therapy early
in resuscitation is better than delaying until a large volume
of fluid has been given. Amongst other beneficial effects,
vasopressors induce venoconstriction, reducing the capacitance
of the circulation and effectively mobilising more fluid into the
circulation.
If a patient remains shocked after 30 mLVkg of fluid has been
administered, a re-evaluation of the likely cause is required,
looking particularly for concealed haemorrhage or an obstructive
pathology. A bedside echocardiogram is especially useful at
this stage to evaluate cardiac output and exclude tamponade.
Noradrenaline (norepinephrine) should be commenced as
the first-line vasoactive agent in most cases, unless there is
a strong indication to use a pure inotropic or chronotropic
I 10.41 Actions of commonly used vasoactive agents
Action
Drug Vasoconstrictor
Inotrope
Chronotrope
Adrenaline ++
(epinephrine)
+++
++
Noradrenaline ++++
(norepinephrine)
+
+
Dobutamine
++++
+++
Vasopressin +++++
No action
- (reflex
bradycardia)
agent: for example, in cardiogenic shock or shock associated
with bradycardia. If there is evidence of low cardiac output,
adrenaline (epinephrine) or dobutamine should be commenced.
Both agents are equally effective, but dobutamine causes more
vasodilatation and additional noradrenaline may be required to
maintain an adequate MAP. Vasopressin is added if hypotension
persists despite high doses of noradrenaline and cardiac output
is thought to be adequate.
In extreme situations it is acceptable to start infusions of
inotropes through a well-sited, large-bore peripheral cannula,
although central venous access and an arterial line (for monitoring)
should be inserted as soon as possible. The actions of commonly
used vasoactive drugs are summarised in Box 10.41 .
Advanced haemodynamic monitoring
There are many different devices available to estimate cardiac
output. Such devices employ a variety of mechanisms, including
the Doppler effect of moving blood, changes in electrical
impedance of the thorax, or the dilution of either an indicator
substance or heat (thermodilution). The information is processed
within the equipment, and often integrated with additional data,
such as the arterial pressure waveform, to give an estimate of
cardiac output and stroke volume.
When the aetiology of shock is straightforward and the patient
is responding as predicted to treatment, the value of devices that
estimate cardiac output is limited. Portable echocardiography
has the advantage of giving qualitative information - for example,
demonstrating aortic stenosis or a regional wall motion abnormality
- as well as quantitative information on stroke volume, but it
requires technical expertise.
Pulmonary artery (PA) catheters, sometimes referred to as
Swan-Ganz catheters (Fig. 10.20), are invasive but provide useful
information on pulmonary pressures, cardiac output, mixed venous
oxygen saturations (see Box 10.30) and, by extrapolation, whether
the cause of the shock is vasodilatation or pump failure. They
can be helpful in complex cases, such as shock after cardiac
surgery, or in patients with suspected pulmonary hypertension
(Box 1 0.42). However, PA catheters are associated with some rare
but serious complications, including lung infarction, PA rupture
and thrombosis of the catheter itself. Such complications occur
infrequently in centres that use PA catheters regularly; it should
be stressed that a lack of familiarity within the wider clinical team
is a relative contraindication to their use.
Mechanical cardiovascular support
When shock is so severe that it is not possible to maintain
sufficient organ perfusion with fluids and inotropic support, it is
Stabilisation and institution of organ support • 207
0
mmHg
Fig. 10.20 A pulmonary artery (Swan-Ganz) catheter. {K\ There is a small balloon at the tip of the catheter and pressure can be measured through
the central lumen. The catheter is inserted via an internal jugular, subclavian or femoral vein and advanced through the right heart until the tip lies in the
pulmonary artery. When the balloon is deflated, the pulmonary artery pressure can be recorded. [1] Advancing the catheter with the balloon inflated will
‘wedge’ the catheter in the pulmonary artery. Blood cannot then flow past the balloon, so the tip of the catheter will now record the pressure transmitted
from the pulmonary veins and left atrium (known as the pulmonary artery capillary wedge pressure), which provides an indirect measure of the left atrial
pressure. (LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle)
10.42 Interpreting haemodynamic data
Variable
Units
Reference range
Interpretation
Cardiac output (CO)
litres/minute (L7min)
4-8 IVmin
Low cardiac output suggests pump failure
Cardiac index (Cl)
Cardiac output referenced to the
size of the patient
litres/minute/metre2
(IVmin/m2)
2.5-4 L/min/m2
More useful than raw cardiac output alone, especially in
smaller patients
Central venous pressure (CVP)
mmHg
0-6 mmHg
Reflects right atrial pressure - a non-specific measurement of
right ventricular (RV) function and volume status
Low levels suggest good RV function or hypovolaemia
Pulmonary artery systolic
pressure (PA systolic)
mmHg
15-30 mmHg
Difficult to interpret in isolation
Low levels suggest vasodilatation, hypovolaemia or right heart
failure
High levels are seen in many pathologies, e.g. left heart failure,
primary pulmonary arterial hypertension (PAH), fluid overload
Pulmonary artery diastolic
pressure (PA diastolic)
mmHg
5-15 mmHg
As with PA systolic pressure, difficult to interpret in isolation
Pulmonary artery capillary
wedge pressure (PACWP)
mmHg
2-10 mmHg (should
be within a few mmHg
of PA diastolic)
Reasonable indication of left atrial pressure - raised in left
heart failure and fluid overload
Measurement is associated with injury to PA so should only be
taken occasionally
Transpulmonary gradient
(PA diastolic - PACWP)
mmHg
1-5 mmHg
A high gradient suggests the pathology is in the pulmonary
arteries, e.g. primary PAH
sometimes necessary to use an internal device to augment or
replace the inadequate native cardiac output.
Intra-aortic balloon pump
An intra-aortic balloon counter-pulsation device is a long tube
that is usually inserted into the femoral artery and fed proximally
into the thoracic aorta. The basic principle is that a helium-filled
balloon is able to inflate and deflate rapidly in time with the
cardiac cycle. It is inflated in diastole, thus augmenting forward
flow of blood to the abdominal organs and improving diastolic
pressure proximal to the balloon, thereby optimising coronary
perfusion. While the principle is appealing, and an intra-aortic
balloon pump (IABP) is often effective in achieving predetermined
physiological goals, this does not translate into improved survival
in cardiogenic shock. There are risks associated with thrombosis
formation on the balloon, mesenteric ischaemia and femoral artery
pseudo-aneurysm following removal of the device.
Venous-arterial extracorporeal
membrane oxygenation
Venous-arterial extracorporeal membrane oxygenation (VA
ECMO) can be life-saving in profound cardiogenic shock and
has even been used effectively in refractory cardiac arrest. The
circuit and principles are very similar to those described in ‘VV
ECMO’ above (see p. 204 and Fig. 10.19) with one important
difference: oxygenated blood is returned to the arterial system
(rather than into the right atrium). This means that the pump
needs to generate sufficient pressure to allow blood to flow
208 • ACUTE MEDICINE AND CRITICAL ILLNESS
through the systemic circulation. The sites of venous and arterial
access can be either central (via a thoracotomy or sternotomy)
or peripheral via cannulae in the IVC/SVC and the femoral/
subclavian artery. If the return cannula is peripherally sited (e.g.
in the femoral artery), blood will flow back up the aorta from
distal to proximal and perfuse the organs.
The outcome depends on the avoidance of complications
(primarily, bleeding at the cannula site, intracranial haematoma,
air embolism, infection and thrombosis) and improvement of
the underlying condition. Most causes of profound cardiogenic
shock are unlikely to resolve, and the potential availability of a
longer-term solution, such as cardiac transplantation or insertion
of a ventricular assist device, is a prerequisite for commencing
VA ECMO in most centres.
Renal support
Renal replacement therapy (RRT) is explained in detail on
page 420. The key points relating to RRT in an intensive care
context are:
• Haemodynamic instability is common. Continuous
therapies are widely believed to cause less haemodynamic
instability than intermittent dialysis. However, many units
use intermittent dialysis without significant problems.
• Haemodialysis and haemofiltration are equally good.
Although there are theoretical benefits to removing
inflammatory cytokines with haemofiltration, this does not
translate into improved survival.
• Anticoagulation is usually achieved using citrate or heparin.
Citrate has a better profile for anticoagulating the
extracorporeal circuit without inducing an increased
bleeding risk, but may accumulate in patients with
profound multi-organ failure and should be avoided in very
unstable individuals.
• Most patients who survive intensive care will regain
adequate renal function to live without long-term renal
support.
• A thorough investigation for reversible causes of renal
dysfunction should always be undertaken in conjunction
with instigation of renal support (see Fig. 15.18, p. 411).
• Shock appears to reverse more rapidly when renal support
is instituted. Commencing renal support soon after a
patient develops renal ‘injury’ (when serum creatinine is
more than two times higher than baseline) is probably
beneficial in the context of septic shock.
Neurological support
A diverse range of neurological conditions require management in
intensive care. These include the various causes of coma, spinal
cord injury, peripheral neuromuscular disease and prolonged
seizures.
The goals of care in such cases are to:
• Protect the airway, if necessary by endotracheal
intubation.
• Provide respiratory support to correct hypoxaemia and
hypercapnia.
• Treat circulatory problems, e.g. neurogenic pulmonary
oedema in subarachnoid haemorrhage, autonomic
disturbances in Guillain-Barre syndrome, and spinal shock
following high spinal cord injuries.
• Manage acute brain injury with control of ICP.
• Manage status epilepticus using antiepileptic agents such
as levetiracetam, phenytoin and benzodiazepines. In
refractory cases an infusion of sodium thiopental or
ketamine may be required.
The aim of management in acute brain injury is to optimise
cerebral oxygen delivery by maintaining normal arterial oxygen
content and a cerebral perfusion pressure (CPP) of >60 mmHg.
Secondary insults to the brain, such as hypoxaemia, hyper-/
hypoglycaemia and prolonged seizures, must be avoided. ICP
rises in acute brain injury as a result of haematoma, contusions,
oedema or ischaemic swelling. Raised ICP causes damage to
the brain in two ways: direct damage to the brainstem and
motor tracts as a result of downward pressure and herniation
through the tentorium cerebelli and foramen magnum, and indirect
damage by reducing CPP. Cerebral blood flow is dependent
on an adequate CPP. The CPP is determined by the formula:
CPP = MAP -ICP
ICP can be measured by pressure transducers that are inserted
directly into the brain tissue. The normal upper limit for ICP is
15 mmHg and an upper acceptable limit of 20 mmHg is usually
adopted in intensive care. Sustained pressures of >30 mmHg are
associated with a poor prognosis. Various strategies are used to
control ICP: maintaining normocapnia, preventing any impedance
to venous drainage from the head, giving osmotic agents such
as mannitol and hypertonic saline, and using hypothermia and
decompressive craniectomy. No single technique has been
shown to improve outcome in severe intracranial hypertension.
CPP should be maintained above 60 mmHg by ensuring
adequate fluid replacement and, if necessary, by treating
hypotension with a vasopressor such as noradrenaline
(norepinephrine). Complex neurological monitoring must be
combined with frequent clinical assessment of GCS, pupillary
response to light, and focal neurological signs.
Daily clinical management in
intensive care
Clinical review
In intensive care, detailed clinical examination should be performed
daily to identify changes to a patient’s condition and review the
latest diagnostic information. Further focused clinical reviews are
usually incorporated into twice-daily ward rounds. Each ward
round offers an ideal opportunity to monitor and document
compliance with relevant care bundles. A care bundle is a group of
interventions that, when implemented concurrently, have provided
evidence of clinical benefit. The mnemonic ‘FAST HUG’ provides
a useful checklist of interventions that reduce intensive care
complications: feeding, analgesia, sedation, thromboprophylaxis,
he ad of bed elevation (to reduce the incidence of passive
aspiration), ulcer prophylaxis and glucose control.
Other key aspects of the daily review are outlined on page 174.
The overarching aim of the review is to identify the issues that
are impeding recovery from critical illness, and make alterations
to address them. In addition, specific and realistic goals for
each relevant organ system should be defined, facilitating the
autonomous titration of therapy by the bedside critical care nurse.
An example of daily goals may be: ‘Titrate the noradrenaline
(norepinephrine) to achieve a MAP of 65 mmHg, aim for a
negative fluid balance, titrate Fi02 to achieve oxygen saturations
Daily clinical management in intensive care • 209
10.43 Properties of sedative and analgesic agents used in ICU
Drug
Mode of action
Advantages
Disadvantages
Propofol
Intravenous anaesthetic
Rapid onset and offset
Large cumulative doses can cause multi-organ failure,
especially in children - the ‘propofol infusion syndrome’
Alfentanil
Potent opiate analgesic
Rapid onset and offset
High doses may be required
Agitation may persist
Morphine
Opioid
Analgesia
Active metabolites and accumulation cause slow offset
Midazolam
Benzodiazepine sedative
Can be used in children
Active metabolites and accumulation cause slow offset
Remifentanil
Very potent opiate
Analgesia and tube tolerance
Respiratory depression - extreme caution in non-intubated
patients
Dexmedetomidine
a2-adrenergic agonist
Excellent tube tolerance
Less delirium
Can be used in awake patients
Cost and availability
of 92-95% and titrate sedation to a RASS score of 0 to -1 ’
(Box 10.44).
Sedation and analgesia
Most patients require sedation and analgesia to ensure comfort,
relieve anxiety and tolerate mechanical ventilation. Some
conditions, such as critically high ICP or critical hypoxaemia,
require deep sedation to reduce tissue oxygen requirements
and protect the brain from the peaks in ICP associated with
coughing or gagging. For the majority of patients, however, optimal
sedation is an awake and lucid patient who is comfortable and
able to tolerate an endotracheal tube (termed ‘tube tolerance’).
Over-sedation is associated with longer ICU stays, a higher
prevalence of delirium, prolonged requirement for mechanical
ventilation, and an increased incidence of ICU-acquired infection.
Box 10.43 compares the various agents used for sedation in
intensive care. The key principles are that the patient should
primarily receive analgesia, rather than anaesthesia, and caution
should be used with drugs that accumulate in hepatic and renal
dysfunction. Often a combination of drugs is used to achieve
the optimal balance of sedation and analgesia.
Sedation is monitored via clinical sedation scales that record
responses to voice and physical stimulation. The Richmond
Agitation-Sedation Scale (RASS) is the best-recognised tool
(see Box 10.44 for details). Regular use of a scoring system
to adjust sedation is associated with a shorter ICU stay. Many
ICUs also have a daily ‘sedation break’, when all sedation is
stopped in appropriate cases for a short period. This is commonly
combined with a trial of spontaneous breathing aiming to shorten
the duration of mechanical ventilation.
Delirium in intensive care
Delirium is discussed on page 183. It is extremely common in
critically ill patients and often becomes apparent as sedation
is reduced. Hypoactive delirium is far more common than
hyperactive delirium, but is easily missed unless routine screening
is undertaken. A widely used bedside assessment is the CAM-ICU
score. The patient is requested to squeeze the examiner’s hand
in response to instruction and questions, aiming to ascertain
whether disordered thought or sensory inattention is present.
Delirium of any type is associated with poorer outcome.
Management is focused on non-pharmacological interventions
such as early mobilisation, reinstatement of day-night routine,
i
10.44 Richmond Agitation-Sedation Scale (RASS)
Score
Term
Description
+4
Combative
Overtly combative, violent or
immediate danger to staff
+3
Very agitated
Pulls on/removes tubes or catheters,
or aggressive to staff
+2
Agitated
Frequent non-purposeful movement
or patient-ventilator dyssynchrony
+1
Restless
Anxious or apprehensive but no
aggressive or vigorous movements
0
Alert and calm
-1
Drowsy
Not fully alert but sustained
awakening (>10 secs) with eye
opening/contact to voice
-2
Light sedation
Brief awakening (<10 secs) with eye
contact to voice
-3
Moderate sedation
Movement but no eye contact to voice
-4
Deep sedation
Movement to physical stimulation but
no response to voice
-5
Unrousable
No response to voice or physical
stimulation
noise reduction, cessation of drugs known to precipitate delirium,
and treatment of potential underlying causes such as thiamin
replacement in patients at risk of Wernicke’s encephalopathy.
Patients with agitated delirium that is refractory to verbal
de-escalation should initially be managed with small doses
of intramuscular antipsychotics, changed to the enteral route
once control is established. Atypical antipsychotics such as
olanzapine and quetiapine are more efficacious than traditional
drugs such as haloperidol. Pharmacological interventions are
not useful as prophylaxis or in hypoactive delirium. Additional
information on diagnosis and management of delirium can be
found on page 1 84.
Weaning from respiratory support
As the condition that necessitated ventilation resolves, respiratory
support is gradually reduced: the process of ‘weaning’ from
ventilation. Some approaches to weaning are described below.
210 • ACUTE MEDICINE AND CRITICAL ILLNESS
i
10.45 Advantages and disadvantages
of tracheostomy
Advantages
• Patient comfort
•
Reduced equipment ‘dead
• Improved oral hygiene
space’ (the volume of tubing)
• Access for tracheal toilet
•
Earlier weaning and ICU
• Ability to speak with cuff
discharge
deflated and a speaking valve
•
Reduced sedation requirement
attached
•
Reduced vocal cord damage
Disadvantages
• Immediate complications:
•
Tracheal damage; late
hypoxaemia, haemorrhage
stenosis
• Tracheostomy site infection
^ Spontaneous breathing trials
A spontaneous breathing trial involves the removal of all respiratory
support followed by close observation of how long the patient
is able to breathe unassisted. The technique is particularly
effective when linked to a reduction in sedation. PEEP and
pressure support are reduced to low levels, or patients are
disconnected from the ventilator and breathe oxygen or humidified
air through the endotracheal tube. Signs of failure include rapid
shallow breathing, hypoxaemia, rising PaC02, sweating and
agitation. Patients who pass a spontaneous breathing trial
are assessed for suitability of extubation (endotracheal tube
removal).
I Progressive reduction in pressure
support ventilation
Progressive reduction in pressure support ventilation (PSV) is
applied to each breath over a period of hours or days, according
to patient response. Some ICU ventilators have software that
allows the facility to wean the support provided automatically.
A useful tool to guide the weaning process is the rapid shallow
breathing index (RSBI). This composite score of a patient’s
spontaneous respiratory rate and tidal volume (respiratory rate
divided by tidal volume in litres) gives a numerical indication of
how difficult the patient is finding breathing at that particular
level of support. A RSBI value of >100 suggests that a
patient is working at a level that would be unsustainable for
longer periods.
Extubation
It is not possible to predict whether a patient is ready to
be extubated accurately; the timing relies heavily on clinical
judgement. There are, however, some simple rules that can
aid decision-making. Patients must have stable ABGs with
resolution of hypoxaemia and hypercapnia despite minimal
ventilator pressure support and a low F/02. Conscious level must
be adequate to protect the airway, comply with physiotherapy,
and cough. Furthermore, an assessment must be made as to
whether the patient can sustain the required minute volume
without ventilator support. This depends on the condition of
patients’ lungs, their strength and other factors affecting the
PaC02, such as temperature and metabolic rate. The need
for re-intubation following extubation is associated with poorer
outcome, but patients who are not given the opportunity to
breathe without a ventilator will also be at increased risk of
ventilator-associated complications such as pneumonia and
myopathy.
Tracheostomy
A tracheostomy is a percutaneous tube passed into the trachea
(usually between the first and second, or second and third tracheal
rings) to facilitate longer-term ventilation. The advantages and
disadvantages of tracheostomy insertion are listed in Box 10.45.
When ventilation weaning has been unsuccessful, a tracheostomy
provides a bridge between intubation and extubation; the
patient can have increasing periods free of ventilator support
but easily have support reinstated. A tracheostomy can be
inserted percutaneously, using a bronchoscope in the trachea for
guidance, or surgically under direct vision. Occasionally, a patient
will have a tracheostomy in situ following a laryngectomy. Such
patients are important to identify, as emergency management in
the event of a tracheostomy problem (blockage or displacement)
must be through the tracheostomy site; access will not be
possible via the upper airway.
Nutrition
It is crucial that critically ill patients receive adequate calories,
protein and essential vitamins and minerals. Calculation of exact
requirements is complex and requires the expertise of a dietitian.
It is, however, useful to make a rough estimation of requirements
(p. 705). Under-feeding leads to muscle wasting and delayed
recovery, while over-feeding can lead to biliary stasis, jaundice
and steatosis. Enteral feeding is preferred where possible because
it avoids the infective complications of total parenteral nutrition
(TPN) and helps to maintain gut integrity. However, TPN is
recommended for patients who are likely to have a sustained
period without effective enteral feeding, or who are already
malnourished. Caution must be taken to avoid the consequences
of refeeding syndrome (p. 706).
Other essential components of
intensive care
Survival after critical illness depends, to a large extent, on the
prevention of medical complications during recovery from the
primary insult.
Thromboprophylaxis
DVT, venous catheter- related thrombosis and PE are common in
critically ill patients. Low-molecular-weight heparin (LMWH) should
be administered to all patients, unless there is a contraindication.
Often patients at highest risk of thrombosis, such as those
with hepatic dysfunction or those who have suffered major
trauma, have a relative contraindication to heparin. Such
cases mandate daily evaluation of the risk-benefit ratio, and
LMWH should be administered as soon as it is deemed safe
to do so. Mechanical thromboprophylaxis, such as intermittent
calf compression devices, are useful adjuvants in high-risk
patients.
Glucose control
Hyperglycaemia is harmful in critical illness and may occur in
people with pre-existing diabetes or undiagnosed diabetes,
following administration of high-dose glucocorticoids, or as
Complications and outcomes of critical illness • 211
a consequence of ‘stress hyperglycaemia’. Hyperglycaemia
is commonly managed by infusion of intravenous insulin
titrated against a ‘sliding scale’. Intensive management of
hyperglycaemia with insulin can result in hypoglycaemia, which
may also be harmful in critical illness. Therefore, a compromise
is to titrate insulin to a blood glucose level of 6-10 mmol/L
(108-180 mg/dL).
Blood transfusion
Many critically ill patients become anaemic due to reduced red
cell production and red cell loss through bleeding and blood
sampling. However, red cell transfusion carries inherent risks
of immunosuppression, fluid overload, organ dysfunction from
microemboli, and transfusion reactions. In stable patients, a
haemoglobin level of 70 g/L (7 g/dL) is a safe compromise between
optimisation of oxygen delivery and the risks of transfusion. This
transfusion threshold should be adjusted upwards for situations
where oxygen delivery is critical, such as in patients with active
myocardial ischaemia.
Peptic ulcer prophylaxis
Stress ulceration during critical illness is a serious complication.
Proton pump inhibitors or histamine-2 receptor antagonists
are effective at reducing the incidence of ulceration. There is,
however, a suggestion that the use of these agents, particularly
in conjunction with antibiotics, may increase the incidence of
nosocomial infection, especially with Clostridium difficile (p. 264).
It is therefore common practice to stop ulcer prophylaxis once
consistent absorption of enteral feed is established.
Complications and outcomes
of critical illness
The majority of patients will survive their episode of critical illness.
While some will return to full, active lives, there are many who
have ongoing physical, emotional and psychological problems.
Adverse neurological outcomes
Brain injury
Head injury, hypoxic-ischaemic injury and infective, inflammatory
and vascular pathologies can all irreversibly injure the brain.
If treatment is unsuccessful, patients will either die or be left
with a degree of disability. In the latter situation, the provision
of ongoing organ support will depend on the severity of the
injury, the prognosis, and the wishes of the patient (usually
expressed via relatives). Brain death is a state in which cortical
and brainstem function is irreversibly lost. Diagnostic criteria
for brain death vary between countries (Box 10.46); if satisfied,
these criteria allow physicians to withdraw active treatment
and discuss the potential for organ donation. Diagnosing brain
death is complex and should be done only by physicians with
appropriate expertise, as clinical differentiation from reduced
consciousness can be challenging (Box 10.47). Where there is
doubt - for example, in patients with coexisting spinal injury or
localised brainstem pathology - additional investigations should
be performed.
The ‘locked-in’ syndrome, in which the patient is paralysed
except for eye movements, requires preserved hemispheric
i
Preconditions for considering a diagnosis of brain death
• The patient is deeply comatose:
a. There must be no suspicion that coma is due to depressant
drugs, such as narcotics, hypnotics, tranquillisers
b. Hypothermia has been excluded - rectal temperature must
exceed 35°C
c. There is no profound abnormality of serum electrolytes,
acid-base balance or blood glucose concentrations, and any
metabolic or endocrine cause of coma has been excluded
• The patient is maintained on a ventilator because spontaneous
respiration has been inadequate or has ceased. Drugs, including
neuromuscular blocking agents, must have been excluded as a
cause of the respiratory failure
• The diagnosis of the disorder leading to brain death has been firmly
established. There must be no doubt that the patient is suffering
from irremediable structural brain damage
Tests for confirming brain death
• All brainstem reflexes are absent:
a. The pupils are fixed and unreactive to light
b. The corneal reflexes are absent
c. The vestibulo-ocular reflexes are absent - there is no eye
movement following the injection of 20 mL of ice-cold water into
each external auditory meatus in turn
d. There are no motor responses to adequate stimulation within the
cranial nerve distribution
e. There is no gag reflex and no reflex response to a suction
catheter in the trachea
• No respiratory movement occurs when the patient is disconnected
from the ventilator for long enough to allow the carbon dioxide
tension to rise above the threshold for stimulating respiration
(PaC02 must reach 6.7 kPa/50 mmHg)
The diagnosis of brain death should be made by two doctors of a
specified status and experience. The tests are usually repeated after
a short interval to allow blood gases to normalise before brain death
is finally confirmed
function (and thus consciousness), but a lesion in the ventral
pons (usually caused by infarction) results in complete paralysis.
The term ‘vegetative state’ implies some retention of brainstem
function and minimal cortical function, with loss of awareness of
the environment. In contrast, ‘minimally conscious state’ implies
that there is some degree of awareness and intact brainstem
function. Confident distinction between these states is important
and requires careful assessment, often over a period of time.
Brain death is, by definition, irreversible but other states may
offer hope for improvement.
| ICU-acquired weakness
Weakness is common among survivors of critical illness. It is
usually symmetrical, proximal and most marked in the lower
limbs. Critical illness polyneuropathy and myopathy can occur
simultaneously and, within the constraints of an altered sensorium,
it can be impossible to distinguish the two conditions clinically.
Risk factors for both processes include the severity of multi-organ
failure, poor glycaemic control and the use of muscle relaxants
and glucocorticoids.
Critical illness polyneuropathy
This is due to peripheral nerve axonal loss and characteristically
presents as proximal muscle weakness with preserved sensation.
10.46 UK criteria for the diagnosis of brain death
212 • ACUTE MEDICINE AND CRITICAL ILLNESS
10.47 Classification of brain death and reduced conscious states
Diagnosis
Features
Investigation
Prognosis
Brain death
See Box 10.46
Often not required if cranial imaging
shows compatible cause and patient
meets clinical criteria
In diagnostic doubt: four-vessel
angiogram (fluoroscopic or CT) of
cerebral vessels or isotope scan of
brain to demonstrate absence of
cerebral blood flow
Time of confirmed brain death
is recorded as time of death
Potential to donate organs
- donation after brain death
(DBD) donor
Vegetative state (VS)
‘Persistent VS’ >1
month
‘Permanent VS’ >1 year
No reaction to verbal stimuli
Some reaction to noxious stimuli
Sleep-wake cycles (periods of eye opening)
Maintained respiratory drive
Intact brainstem reflexes
Occasional automatic movements (yawning,
swallowing)
Cranial imaging for primary cause
Maintained cortical blood flow
Poor. May be better with
traumatic aetiology
Minimally conscious
state
Some reaction to verbal stimuli
Some reaction to noxious stimuli
Spontaneous movements
Intact brainstem reflexes
EEG demonstrates reactivity
Variable. Recovery of function
more likely than in VS
Locked-in syndrome
Cortex is intact but bilateral motor tracts
are damaged
Can be partial or complete, i.e. some
response to verbal stimuli (e.g. vertical eye
movements to communicate)
Variable brainstem reflexes
No limb movement to noxious stimuli
Imaging for primary cause -
commonly MRI or CT will show
brainstem or pontine infarction
Variable and depends on cause
- progress can continue over
months to years
It may also manifest as failure to wean from the ventilator secondary
to respiratory muscle weakness. Electrophysiological studies of
the affected nerves can be helpful, especially to rule out other
potential causes such as Guillain-Barre syndrome. Conduction
studies typically show reduced amplitude of transmitted voltage
action potential with preserved velocity (compare with findings
in Guillain-Barre syndrome; pp. 1076 and 1140). There are
no specific treatments aside from resolution of the underlying
cause and rehabilitation. Weakness may persist long into the
convalescence stage of illness. In some cases, the clinical picture
may be more in keeping with individual nerve involvement. This
may be due to local pressure effects or part of a generalised
picture. Great care must be taken to avoid pressure on high-risk
areas such as the neck of the fibula where the common peroneal
nerve navigates a superficial course. Nerve palsies such as foot
drop can be permanent.
Critical illness myopathy
Although loss of muscle bulk is related to immobility and the
catabolic state of critical illness, it is likely that microvascular and
intracellular pathophysiological processes are also involved in
critical illness myopathy. These processes result in loss of actin
myofibrils and muscle weakness. Typically, the CK is normal or
only mildly elevated. Like critical illness polyneuropathy, critical
illness myopathy is usually a clinical diagnosis. Nerve conduction
studies and electromyography may be suggestive of critical
illness myopathy, and helpful in ruling out other pathology, but
a muscle biopsy is required to confirm the diagnosis (p. 1076).
It characteristically shows selective loss of the thick myofibrils
and muscle necrosis. Management is conservative and the
prognosis is good in ICU survivors.
Other long-term problems
The experience of critical illness and the necessary invasive
management can leave patients with profound psychological
sequelae akin to the post-traumatic stress syndrome seen in
many survivors of conflict. Specialist help is required in managing
these issues. Sometimes recovering patients benefit from returning
to the ICU to see the environment in a different way and gain
a better understanding of the processes and procedures that
haunt them.
Long-term physical consequences are also common. Many
diseases are not completely cured but follow a relapsing-remitting
course; patients who have been critically ill with sepsis are far
more likely than others in the general population to suffer from it
again. Organ damage often persists and iatrogenic complications
are common (e.g. damage to the vocal cords or tracheal stenosis
from mucosal pressure caused by the cuff of the endotracheal
tube). Intensive care follow-up clinics provide an excellent forum
for addressing such issues, and for coordinating care involving
a variety of medical specialties.
The older patient
Critically ill older patients present additional challenges following
intensive care discharge (Box 10.48). As the ability to make a
full recovery depends on frailty rather than chronological age, it
can be helpful to use a validated frailty scoring system (p. 1306)
to inform admission decision-making.
Rehabilitation medicine has much to offer survivors of critical
illness, and an early referral is beneficial when it is clear that a
patient is likely to survive with significant morbidity.
Complications and outcomes of critical illness • 213
£
Withdrawal of active treatment and death
in intensive care
Futility
The idea of futility is not new: Hippocrates stated that physicians
should ‘refuse to treat those who are overmastered by their
disease, realising that in such cases medicine is powerless’. In
intensive care, where the concept of futility is often used as a
criterion to limit or withdraw life-sustaining treatment, it is helpful
to have a working definition on which families and physicians
can agree. It is, therefore, reasonable to define futility in such
circumstances as the point at which recovery to a quality of life
that the patient would find acceptable has passed. The primary
insult may be neurological (irreversible brain injury not meeting
criteria for brain death), or multi-organ failure that is refractory
to treatment.
| Death
Whilst most patients prefer to die at home, many spend their
final days in hospital. Chapter 34 details the medical, legal
and ethical priorities that should guide patient management
once the decision to withdraw active treatment has been made
(p. 1354). The decision to shift the focus of care to palliation
should not change its intensity; it is the over-arching objective
that changes. Only interventions that will improve the quality of
a patient’s remaining life should be offered. In the ICU, it is often
appropriate to continue infusions of sedatives and analgesics,
as reducing or stopping them may cause unnecessary pain
and agitation. Measures that were instituted to prolong life
should be withdrawn (usually including cessation of inotropes
and extubation) to allow the patient to die peacefully with their
family and friends present.
Organ donation
Donation after brain death
The diagnosis of brain death is discussed on page 21 1 . Once
brain death has been confirmed, consideration should be given
to organ donation, termed ‘donation after brain death’ (DBD).
Time of death is recorded as the time when the first series
of brain death tests are undertaken, although the deceased
patient continues to be ventilated. The practice of organ
donation varies throughout the world but the principles remain
the same.
Organ donation specialists are contacted and they begin
the process of establishing the suitability of any organs for
transplantation and matching potential recipients. Many patients
will have expressed their wishes through an organ donor
registration scheme but agreement of family and next of kin
is a moral (and sometimes legal) prerequisite. Once the organ
retrieval theatre team have been assembled and all preliminary
tests have been completed, the deceased patient is transferred
to the operating theatre and the organs are sequentially removed.
Donation after cardiac death
If a patient does not meet brain death criteria but withdrawal of
treatment has been agreed, donation of organs with residual
function may be appropriate. This is termed ‘donation after
cardiac death’ (DCD). If the patient dies within a short period
following the commencement of ‘warm ischaemic time’ (the time
to asystole following the onset of physiological derangement
after the withdrawal of active treatment), then DCD can proceed.
The deceased patient is transferred to an operating theatre and
the agreed organs (often lungs, liver, kidney and pancreas) are
retrieved. As heart valves and corneas can be retrieved later (within
a longer time frame), tissue retrieval may occur in the mortuary.
Postmortem examination or autopsy
There are several indications to request a postmortem examination.
A coroner (or legal equivalent) may initiate the process if a death
is unexpected or violent, or has occurred under suspicious
circumstances. The treating physician(s) may request one if they
are unable to establish a cause of death or there is agreement
that it may yield information of interest to the family or clinical
team. The postmortem diagnosis is frequently at odds with the
antemortem diagnosis and it is a very useful learning exercise
to review the results with all those involved in the patient’s care.
Discharge from intensive care
Discharge is appropriate when the original indication for admission
has resolved and the patient has sufficient physiological reserve
to continue to recover without the facilities of intensive care.
Many ICUs and HDUs function as combined units, allowing
‘step-down’ of patients to HDU care without changing the clinical
team involved. Discharge from ICU is stressful for patients and
families, and clear communication with the clinical team accepting
responsibility is vital. Nursing ratios change from 1 : 1 (one nurse
per patient) or 1 : 2 to much lower staffing levels. Discharges from
ICU or HDU to standard wards should take place within normal
working hours to ensure adequate medical and nursing support
and detailed handover. Discharge outside normal working hours
is associated with higher ICU re-admission rates and increased
mortality. The receiving team should be provided with a written
summary, including the information listed in Box 10.49. The
ICU team should remain available for advice; many ICU teams
provide an outreach service to supply advice and facilitate
continuity of care.
Critical care scoring systems
Admission and discharge criteria vary between ICUs, so it is
important to define the characteristics of the patients admitted in
10.48 The critically ill older patient
• ICU demography: increasing numbers of critically ill older patients
are admitted to the ICU; more than 50% of patients in many
general ICUs are over 65 years old.
• Outcome: affected to some extent by age, as reflected in APACHE
II (see Box 10.50), but age should not be used as the sole criterion
for withholding or withdrawing ICU support.
• Cardiopulmonary resuscitation (CPR): successful hospital
discharge following in-hospital CPR is rare in patients over 70 years
old in the presence of significant chronic disease.
• Functional independence: tends to be lost during an ICU stay and
prolonged rehabilitation may subsequently be necessary.
• Specific problems:
Skin fragility and ulceration
Poor muscle strength: difficulty weaning from ventilator and
mobilising
Delirium: compounded by sedatives and analgesics
High prevalence of underlying nutritional deficiency.
214 • ACUTE MEDICINE AND CRITICAL ILLNESS
10.49 How to write an ICU discharge summary:
information to be included
• Summary of diagnosis and progress in intensive care
• Current medications and changes to regular medications with
justifications
• Antibiotic regime and suggested review dates
• Results of positive microbiological tests
• Positions of invasive devices and insertion dates
• Escalation plan in the event of deterioration
• Pending investigations and specialty consultations
• If the physiology remains abnormal due to chronic disease, rapid
response triggers should be adjusted accordingly
order to assess the effects of the care provided on the outcomes
achieved. Two systems are widely used to measure severity of
illness (see Box 10.50 for further details):
• APACHE //: Acute Physiology Assessment and Chronic
Health Evaluation
• SOFA score: Sequential Organ Failure Assessment tool.
When combined with the admission diagnosis, scoring systems
have been shown to correlate well with the risk of death in hospital.
Such outcome predictions are useful at a population level but
lack the specificity to be of use in decision-making for individual
patients. This is in contrast to well-validated, disease-specific
tools, such as the CURB-65 tool for pneumonia, which can be
helpful in guiding individual management (see Fig. 17.32, p. 583).
Predicted mortality figures by diagnosis have been calculated
from large databases generated from a range of ICUs. These
allow a particular unit to evaluate its performance compared to
the reference ICUs by calculating standardised mortality ratios
(SMRs) for each diagnostic group. A value of unity indicates the
same performance as the reference ICUs, while a value below 1
indicates a better than predicted outcome. If a unit has a high SMR
in a certain diagnostic category, it should prompt investigation
10.50 Comparison of APACHE II and SOFA scores
APACHE II score
• An assessment of admission characteristics (e.g. age and
pre-existing organ dysfunction) and the maximum/minimum values
of 12 routine physiological measurements during the first 24 hours
of admission (e.g. temperature, blood pressure, GCS) that reflect
the physiological impact of the illness
• Composite score out of 71
• Higher scores are given to patients with more serious underlying
diagnoses, medical history or physiological instability; higher
mortality correlates with higher scores
SOFA score
• A score of 1-4 is allocated to six organ systems (respiratory,
cardiovascular, liver, renal, coagulation and neurological) to
represent the degree of organ dysfunction, e.g. platelet count
>150x109/L scores 1 point, <25x109/L scores 4 points
• Composite score out of 24
• Higher scores are associated with increased mortality
into the management of patients with that diagnosis, in order
to identify aspects of care that could be improved.
Further information
Websites
criticalcarereviews.com Reviews and appraisal of ICU topics.
emcrit.org Online podcasts and general information on emergency
medicine and critical care.
esicm.org European Society of Intensive Care Medicine: guidelines,
recommendations, consensus conference reports.
Iifeinthefastlane.com Information on a range of intensive care and
emergency medicine topics.
survivingsepsis.org Surviving Sepsis website.
DH Dockrell
S Sundar
BJ Angus
Infectious disease
Clinical examination of patients with infectious disease 216
Protozoal infections 273
Presenting problems in infectious diseases 218
Systemic protozoal infections 273
Fever 21 8
Leishmaniasis 281
Positive blood culture 225
Gastrointestinal protozoal infections 286
Sepsis 226
Infections caused by helminths 288
Acute diarrhoea and vomiting 227
Intestinal human nematodes 288
Infections acquired in the tropics 230
Tissue-dwelling human nematodes 290
Infections in adolescence 234
Zoonotic nematodes 293
Infections in pregnancy 234
Trematodes (flukes) 294
Viral infections 236
Cestodes (tapeworms) 297
Systemic viral infections with exanthem 236
Ectoparasites 299
Systemic viral infections without exanthem 240
Fungal infections 300
Viral infections of the skin 247
Qi inprfiml m\/rnQPQ *300
Gastrointestinal viral infections 249
OUptJIIIUIal 1 1 lyUUoCo ouu
Subcutaneous mycoses 300
Respiratory viral infections 249
Systemic mycoses 301
Viral infections with neurological involvement 249
Viral infections with rheumatological involvement 250
Prion diseases 250
Bacterial infections 250
Bacterial infections of the skin, soft tissues and bones 250
Systemic bacterial infections 254
Gastrointestinal bacterial infections 262
Respiratory bacterial infections 265
Bacterial infections with neurological involvement 267
Mycobacterial infections 267
Rickettsial and related intracellular bacterial infections 270
Chlamydial infections 272
216 • INFECTIOUS DISEASE
Clinical examination of patients with infectious disease
5 Eyes
Conjunctival petechiae
Painful red eye in uveitis
Loss of red reflex in endophthalmitis
Roth’s spots in infective endocarditis
Haemorrhages and exudates
of cytomegalovirus retinitis
Choroidal lesions of tuberculosis
4 Head and neck
Lymphadenopathy
Parotidomegaly 5
Abnormal tympanic membranes
3 Oropharynx
Dental caries
Tonsillar enlargement or exudate
Candidiasis
A Streptococcal tonsillitis
2 Hands and nails
Finger clubbing
Splinter haemorrhages
Janeway lesions
Signs of chronic liver disease
Vasculitis lesions
A Splinter haemorrhages
in endocarditis
1 Skin
Generalised erythema
Rash (see opposite)
IV injection track marks
Surgical scars
Prosthetic devices, e.g. central
venous catheters
Tattoos
Observation
• Temperature
• Sweating
• Weight loss
• Respiratory distress
• Altered consciousness
• Pallor
• Jaundice
6 Neurological
Neck stiffness
Photophobia
Delirium
Focal neurological signs
7 Heart and lungs
Tachycardia, hypotension
Murmurs or prosthetic heart
sounds
Pericardial rub
Signs of consolidation
Pleural or pericardial effusion
A Chest X-ray consolidation
in pneumonia
8 Abdomen
Hepatosplenomegaly
Ascites
Renal angle tenderness
Localised tenderness or
guarding with decreased bowel
sounds, e.g. in left iliac fossa
with diverticulitis
Mass lesions
Surgical drains
9 Musculoskeletal
Joint swelling, erythema or
tenderness
Localised tender spine suggestive
of epidural abscesses or discitis
Draining sinus of
chronic osteomyelitis
10 Genitalia and rectum
Ulceration or discharge
Testicular swelling or nodules
Inguinal lymphadenopathy
Prostatic tenderness
Rectal fluctuance
ATesticular swelling
in adult mumps
Insets (splinter haemorrhages) Courtesy of Dr Nick Beeching, Royal Liverpool University Hospital; (Roth’s spots) Courtesy of Prof Ian Rennie, Royal
Hallamshire Hospital, Sheffield.
Figs A-C opposite Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield.
Clinical examination of patients with infectious disease • 217
Fever
Documentation of fever
• ‘Feeling hot’ or sweaty does not
necessarily signify fever - diagnosed only
when a body temperature of over 38.0°C
is recorded
• Axillary and aural measurement is less
accurate than oral or rectal
• Outpatients may be trained to keep a
temperature chart
Rigors
• Shivering (followed by excessive sweating)
occurs with a rapid rise in body
temperature from any cause
Night sweats
• Associated with particular infections (e.g.
TB, infective endocarditis); sweating from
any cause is worse at night
Excessive sweating
• Alcohol, anxiety, thyrotoxicosis, diabetes
mellitus, acromegaly, lymphoma and
excessive environmental heat all cause
sweating without temperature elevation
Recurrent fever
• There are various causes, e.g. Borrelia
recurrentis , bacterial abscess
Accompanying features
• Severe headache and photophobia,
although characteristic of meningitis, may
accompany other infections.
• Delirium during fever is more common in
young children or the elderly
• Myalgia may occur with viral infections,
such as influenza, and with sepsis
including meningococcal sepsis
• Shock may accompany severe infections
and sepsis (p. 196)
History-taking in suspected infectious disease
Presenting complaint
• Diverse manifestations of infectious
disease make accurate assessment of
features and duration critical; e.g. fever
and cough lasting 2 days imply an acute
respiratory tract infection but suggest TB
if they last 2 months
Review of systems
• Must be comprehensive
Past medical history
• Define the ‘host’ and likelihood of
infection(s)
• Include surgical and dental procedures
involving prosthetic materials
• Document previous infections
Medication history
• Include non-prescription drugs, use of
antimicrobials and immunosuppressants
• Identify medicines that interact with
antimicrobials or that may cause fever
Allergy history
• Esp. to antimicrobials, noting allergic
manifestation (e.g. rash versus anaphylaxis)
Family and contact history
• Note infections and their duration
• Sensitively explore exposure to key
infections, e.g. TB and HIV
Travel history
• Include countries visited and where
previously resident (relevant to exposure
and likely vaccination history, e.g.
likelihood of BCG vaccination in childhood)
Occupation
• e.g. Anthrax in leather tannery workers
Recreational pursuits
• e.g. Leptospirosis in canoeists and windsurfers
Animal exposures
• Include pets, e.g. dogs/hydatid disease
Dietary history
• Consider under-cooked meats, shellfish,
unpasteurised dairy products or well water
• Establish who else was exposed, e.g. to
food-borne pathogens
History of intravenous drug injection or
receipt of blood products
• Risks for blood-borne viruses, e.g. HIV-1 ,
HBV and HCV
Sexual history
• Explore in a confidential manner (Ch. 13);
remember that the most common mode of
HIV-1 transmission is heterosexual (Ch. 12)
Vaccination history and use of
prophylactic medicines
• Consider occupation- or age-related
vaccines
• In a traveller or infection-predisposed
patient, establish adherence to prophylaxis
*Always consider non-infectious aetiologies in the differential diagnosis. (HBV/HCV = hepatitis B/C virus; HIV-1 = human immunodeficiency virus-1 ; TB = tuberculosis)
i Skin lesions in infectious diseases
Diffuse erythema, e.g. [A]
Migrating erythema, e.g.
enlarging rash of erythema
migrans in Lyme disease
(see Fig. 11.21, p. 256)
3 ■
Purpuric or petechial rashes,
e.g. [B]
Macular or papular rashes,
e.g. primary infection with HIV
(see Box 12.8, p. 312)
Vesicular or blistering rash,
e.g. [JD
Erythema multiforme (see
Fig. 29.53 and Box 29.32,
pp. 1264 and 1265)
Nodules or plaques, e.g.
Kaposi’s sarcoma (p. 315)
Erythema nodosum ([5] and
Box 29.33, p. 1265)
Streptococcal toxic shock syndrome. Meningococcal sepsis. Shingles.
Erythema nodosum.
218 • INFECTIOUS DISEASE
The principles of infection and its investigation and therapy are
described in Chapter 6. This chapter and the following ones
on human immunodeficiency virus/acquired immunodeficiency
syndrome (HIV/AIDS) and sexually transmitted infection (STI)
describe the approach to patients with potential infectious
disease, the individual infections and the resulting syndromes.
Presenting problems in
infectious diseases
Infectious diseases present with myriad clinical manifestations.
Many of these are described in other chapters or below.
Fever
‘Fever’ implies an elevated core body temperature of more than
38.0°C (p. 138). Fever is a response to cytokines and acute
phase proteins (pp. 65 and 70), and occurs in infections and in
non-infectious conditions.
Clinical assessment
The differential diagnosis is very broad so clinical features are
used to guide the most appropriate investigations. The systematic
approach described on page 21 6 should be followed. Box 11.1
describes the assessment of elderly patients.
Investigations
If the clinical features do not suggest a specific infection, then
initial investigations should include:
• a full blood count (FBC) with differential, including
eosinophil count
• urea and electrolytes, liver function tests (LFTs), blood
glucose and muscle enzymes
• inflammatory markers, erythrocyte sedimentation rate
(ESR) and C-reactive protein (CRP)
• a test for antibodies to HIV-1 (p. 310)
• autoantibodies, including antinuclear antibodies (ANA)
• chest X-ray and electrocardiogram (ECG)
• urinalysis and urine culture
• blood culture (p. 1 06)
• throat swab for culture or polymerase chain reaction (PCR)
• Temperature measurement: fever may be missed because oral
temperatures are unreliable. Rectal measurement may be needed
but core temperature is increasingly measured using eardrum
reflectance.
• Delirium: common with fever, especially in those with underlying
cerebrovascular disease or dementia.
• Prominent causes of pyrexia of unknown origin: include
tuberculosis and intra-abdominal abscesses, complicated urinary
tract infection and infective endocarditis. Non-infective causes
include polymyalgia rheumatica/temporal arteritis and tumours. A
smaller fraction of cases remain undiagnosed than in young people.
• Pitfalls in the elderly: conditions such as stroke or thromboembolic
disease can cause fever but every effort must be made to exclude
concomitant infection.
• Common infectious diseases in the very frail (e g. nursing home
residents): pneumonia, urinary tract infection, soft tissue infection
and gastroenteritis.
• other specimens, as indicated by history and examination,
e.g. wound swab; sputum culture; stool culture,
microscopy for ova and parasites, and Clostridium difficile
toxin assay
• specific tests and their priority, indicated by geographical
location: malaria films on 3 consecutive days or a malaria
rapid diagnostic test (antigen detection, p. 276), a test
for non-structural protein 1 (NS1) in dengue (antigen
detection) and blood cultures for Salmonella Typhi, as well
as abdominal ultrasound, would be standard initial tests in
many regions in Africa, Asia, Oceania, and Central and
South America.
Subsequent investigations in patients with HIV-related (p. 313),
immune-deficient (p. 223), nosocomial or travel -related (p. 230)
pyrexia and in individuals with associated symptoms or signs of
involvement of the respiratory, gastrointestinal or neurological
systems are described elsewhere.
Management
Fever and its associated systemic symptoms can be treated with
paracetamol, and by tepid sponging to cool the skin. Replacement
of salt and water is important in patients with drenching sweats.
Further management is focused on the underlying cause.
Fever with localising symptoms or signs
In most patients, the site of infection is apparent after clinical
evaluation (p. 216), and the likelihood of infection is reinforced by
investigation results (e.g. neutrophilia with raised ESR and CRP
in bacterial infections). Not all apparently localising symptoms
are reliable, however; headache, breathlessness and diarrhoea
can occur in sepsis or malaria without localised infection in the
central nervous system (CNS), respiratory tract or gastrointestinal
tract, and abdominal pain may be a feature of basal pneumonia.
Careful interpretation of the clinical features is vital (e.g. severe
headache associated with photophobia, rash and neck stiffness
suggests meningitis, whereas moderate headache with cough
and rhinorrhoea is consistent with a viral upper respiratory tract
infection).
Common infections that present with fever are shown in Figure
11.1. Further investigation and management are specific to the
cause, but may include empirical antimicrobial therapy (p. 116)
pending confirmation of the microbiological diagnosis.
| Pyrexia of unknown origin
Pyrexia of unknown origin (PUO) was classically defined as
a temperature above 38.0°C on multiple occasions for more
than 3 weeks, without diagnosis, despite initial investigation in
hospital for 1 week. The definition has been relaxed to allow for
investigation over 3 days of inpatient care, three outpatient visits
or 1 week of intensive ambulatory investigation. Subsets of PUO
are described as HIV-1 related, immune-deficient or nosocomial.
Up to one-third of cases of PUO remain undiagnosed.
Clinical assessment
Major causes of PUO are outlined in Box 1 1 .2. Rare causes,
such as periodic fever syndromes (p. 81), should be considered
in those with a family history. Children and younger adults
are more likely to have infectious causes - in particular, viral
infections. Older adults are more likely to have certain infectious
and non-infectious causes (see Box 11.1). Detailed history and
examination should be repeated at regular intervals to detect
emerging features (e.g. rashes, signs of infective endocarditis
11.1 Fever in old age
Presenting problems in infectious diseases • 219
CT abdomen
showing a
pyogenic
liver abscess
CT abdomen
showing a
diverticular
abscess
Liver abscess
Hepatitis
Biliary infection
Pyelonephritis
Colitis
Peritonitis
Tubulo-ovarian
abscess
Appendiceal
abscess
Diverticulitis
Pancreatic
abscess
Impetigo-El
Erysipelas— ED
Cellulitis
Necrotising
fasciitis
Pyomyositis
Osteomyelitis
Epidermis — ^
Dermis
Subcutaneous fat -
Deeper fascial planes
Bone
Muscle
Cellulitis of the leg
Tuberculous
osteomyelitis of
the lower tibia
Brain abscess
Encephalitis
Neurosurgical
infection
Endophthalmitis
Meningitis
Chest X-ray
from a patient
with pulmonary
tuberculosis
CT thorax in
empyema
Fig. 11.1 Common infectious syndromes presenting with fever and localised features. Major causes are grouped by approximate anatomical
location and include central nervous system infection; respiratory tract infections; abdominal, pelvic or urinary tract infections; and skin and soft tissue
infections (SSTIs) or osteomyelitis. For each site of infection, particular syndromes and their common causes are described elsewhere in the book. The
causative organisms vary, depending on host factors, which include whether the patient has lived in or visited a tropical country or particular geographical
location, has acquired the infection in a health-care environment or is immunocompromised. Insets (cellulitis of the leg) Courtesy of Dr Ravi Gowda, Royal
Hallamshire Hospital, Sheffield; (pulmonary tuberculosis) Courtesy of Dr Ann Chapman, Royal Hallamshire Hospital, Sheffield; (empyema, pyogenic liver
abscess, diverticular abscess, tuberculous osteomyelitis) Courtesy of Dr Robert Peck, Royal Hallamshire Hospital, Sheffield.
(p. 527) or features of vasculitis). In men, the prostate should
be considered as a potential source of infection.
Clinicians should be alert to the possibility of factitious fever,
in which high temperature recordings are engineered by the
patient (Box 1 1 .3).
Investigations
If initial investigation of fever is negative, further microbiological
and non-microbiological investigations should be considered
(Boxes 1 1 .4 and 1 1 .5). As with initial investigation of fever
described above, the selection and prioritisation of tests will be
influenced by the geographical location of potential exposure to
pathogens (Box 1 1 .4). These will usually include:
• induced sputum or other specimens for mycobacterial
stains and culture
• serological tests, including an HIV test, and ferritin
estimation
• imaging of the abdomen by ultrasonography or computed
tomography (CT)
• echocardiography.
Lesions identified on imaging should usually be biopsied in order
to seek evidence of relevant pathogens by culture, histopathology
or nucleic acid detection. Particularly in patients who have received
prior antimicrobials, 16S rRNA analysis (Box 6.2, p. 101) may
aid diagnosis if a microorganism is not cultured. The chance of
a successful diagnosis is greatest if procedures for obtaining
220 • INFECTIOUS DISEASE
11.2 Aetiology of pyrexia of unknown origin (PUO)
Infections (-30%)
Connective tissue disorders (-15%)
Specific locations
• Abscesses: hepatobiliary, diverticular, urinary tract (including
prostate), pulmonary, CNS
• Infections of oral cavity (including dental), head and neck (including
sinuses)
• Bone and joint infections
• Infective endocarditis*
Specific organisms
• TB (particularly extrapul monary)*
• HIV-1 infection
• Other viral infections: cytomegalovirus (CM V), Epstein— Barr virus
(EBV)
• Fungal infections (e.g. Aspergillus spp., Candida spp. or dimorphic
fungi)
• Infections with fastidious organisms (e.g. Bartonella spp.,
Tropheryma whipplei)
Specific patient groups
• Recently spent time in a region with geographically restricted
infection:
Malaria*, dengue, rickettsial infections, Brucella spp., amoebic
liver abscess, enteric fevers (Africa, Asia, Oceania, Central and
South America), Leishmania spp. (southern Europe, India, Africa
and Latin America), Burkholderia pseudomallei (South-east Asia),
Middle East respiratory syndrome coronavirus (MERS-CoV;
Arabian Peninsula)
• Residence in or travel to a region with endemic infection:
TB* (Africa, Asia, Central and South America), extensively
drug-resistant TB (XDR-TB; South Africa), Brucella spp. (Africa,
Asia, Central and South America), HIV-1 (Africa, Asia),
Trypanosoma cruzi (Central and South America)
• Nosocomial infections:
Pneumonia*, infections related to prosthetic materials and
surgical procedures, urinary tract infections, central venous
catheter infections
• HIV-positive individuals:
Acute retroviral syndrome
AIDS-defining infections (disseminated Mycobacterium avium
complex (DMAC), Pneumocystis jirovecii pneumonia, CMV and
others)
Malignancy (-20%)
Haematological malignancy
• Lymphoma*, leukaemia and myeloma
Solid tumours
• Renal, liver, colon, stomach, pancreas
Younger adults
• Still’s disease (juvenile rheumatoid arthritis)*
• Systemic lupus erythematosus (SLE)
• Vasculitic disorders, including polyarteritis nodosa, rheumatoid disease
with vasculitis and granulomatosis with polyangiitis (formerly known as
Wegener’s granulomatosis)
• Polymyositis
• Behget’s disease
• Rheumatic fever (in regions where still endemic, e.g. Asia, Oceania
and parts of Africa)
Miscellaneous (-20%)
Cardiovascular
• Atrial myxoma, aortitis, aortic dissection
Respiratory
• Sarcoidosis, pulmonary embolism and other thromboembolic disease,
extrinsic allergic alveolitis
Gastrointestinal
• Inflammatory bowel disease, granulomatous hepatitis, alcoholic liver
disease, pancreatitis
Endocrine/metabolic
• Thyrotoxicosis, thyroiditis, hypothalamic lesions, phaeochromocytoma,
adrenal insufficiency, hypertriglyceridaemia
Haematological
• Haemolytic anaemia, paroxysmal nocturnal haemoglobinuria,
thrombotic thrombocytopenic purpura, myeloproliferative disorders,
Castleman’s disease, graft-versus-host disease (after allogeneic
haematopoietic stem cell transplantation)
Inherited
• Familial Mediterranean fever and periodic fever syndromes
Drug reactions*
• e.g. Antibiotic fever, drug hypersensitivity reactions etc.
Factitious fever
Idiopathic (-15%)
Older adults
• Temporal arteritis/polymyalgia rheumatica*
*Most common causes within each group.
1 1 .3 Clues to the diagnosis of factitious fever
• A patient who looks well
• Bizarre temperature chart with absence of diurnal variation and/or
temperature-related changes in pulse rate
• Temperature >41 °C
• Absence of sweating during defervescence
• Normal erythrocyte sedimentation rate and C-reactive protein
despite high fever
• Evidence of self-injection or self-harm
• Normal temperature during supervised (observed)
measurement
• Infection with multiple commensal organisms (e.g. enteric or mouth
flora)
and transporting the correct samples in the appropriate media
are carefully planned between the clinical team, the radiologist or
surgeon performing the procedure, and the local microbiologist
and histopathologist. Positron emission tomography (PET) scans
may aid diagnosis of vasculitis or help selection of biopsy sites.
Liver biopsy may be justified - for example, to identify idiopathic
granulomatous hepatitis - if there are biochemical or radiological
abnormalities. Bone marrow biopsies have a diagnostic yield of
up to 15%, most often revealing haematological malignancy,
myelodysplasia or tuberculosis, and also identifying brucellosis,
typhoid fever or visceral leishmaniasis. Bone marrow should
be sent for culture, as well as microscopy. Laparoscopy is
occasionally undertaken with biopsy of abnormal tissues. Splenic
aspiration in specialist centres is the diagnostic test of choice for
Presenting problems in infectious diseases • 221
11.4 Microbiological investigation of pyrexia of unknown origin
Location-independent investigations
Microscopy
• Blood for atypical lymphocytes (EBV, CMV, HIV-1 , hepatitis viruses
or Toxoplasma gondii)
• Respiratory samples for mycobacteria and fungi
• Stool for ova, cysts and parasites
• Biopsy for light microscopy (bacteria, mycobacteria, fungi)
and/or electron microscopy (viruses, protozoa (e.g.
microsporidia) and other fastidious organisms (e.g. Tropheryma
whipplei ))
• Urine for white or red blood cells and mycobacteria (early morning
urine x3)
Culture
• Aspirates and biopsies (e.g. joint, deep abscess, debrided
tissues)
• Blood, including prolonged culture and special media
conditions
• Sputum for mycobacteria
• CSF
• Gastric aspirate for mycobacteria
• Stool
• Swabs
• Urine ± prostatic massage in older men
Antigen detection
• Blood, e.g. HIV p24 antigen, cryptococcal antigen, Aspergillus
galactomannan ELISA and for Aspergillus and other causes of
invasive, fungal infection (1 ,3)-p-D-glucan
• CSF for cryptococcal antigen
• Bronchoalveolar lavage fluid for Aspergillus galactomannan
• Nasopharyngeal aspirate/throat swab for respiratory viruses, e.g. IAV
or RSV
• Urine, e.g. for Legionella antigen
Nucleic acid detection
• Blood for Bartonella spp. and viruses
• CSF for viruses and key bacteria (meningococcus, pneumococcus,
Listeria monocytogenes)
• Nasopharyngeal aspirate/throat swab for respiratory viruses
• Sputum for Mycobacterium tuberculosis (MTB) and rifampicin (RIF)
resistance with geneXpert MTB/RIF cartridge-based nucleic acid
amplification test
• Bronchoalveolar lavage fluid, e.g. for respiratory viruses
• Tissue specimens, e.g. for T. whipplei
• Urine, e.g. for Chlamydia trachomatis , Neisseria gonorrhoeae
• Stool, e.g. for norovirus, rotavirus
Immunological tests
• Serology (antibody detection) for viruses, including HIV-1 , and some
bacteria
• Interferon-gamma release assay for diagnosis of exposure to
tuberculosis (but note this will not distinguish latent from active
disease and can only be used to trigger further investigations of active
disease)
Geographically restricted tests2
Microscopy
• Blood for trypanosomiasis, malaria and Borrelia spp.
• Stool for geographically restricted ova, cysts and parasites
• Biopsy for light microscopy (dimorphic fungi, Leishmania spp. and
other parasites)
• Urine for red blood cells and schistosome ova
Antigen detection
• Blood, e.g. dengue virus NS1 antigen, Histoplasma antigen (restricted
availability) and malaria antigen (e.g. HRP-2 for Plasmodium
falciparum or parasite-specific LDH for P. falciparum and P. viva. x)
Nucleic acid detection
• Blood for causes of viral haemorrhagic fever
• CSF for geographically restricted viruses, e.g. Japanese encephalitis
virus
• Nasopharyngeal aspirate/throat swab or bronchoalveolar lavage fluid
for geographically restricted respiratory viruses, e.g. MERS-CoV
Immunological tests
• Serology (antibody detection) for viruses, dimorphic fungi and protozoa
^his list does not apply to every patient with a pyrexia of unknown origin. Appropriate tests should be selected in a stepwise manner, according to specific predisposing
factors, epidemiological exposures and local availability, and should be discussed with a microbiologist. Addition of these tests should be guided by the location of
presentation or travel history.
(CMV = cytomegalovirus; CSF = cerebrospinal fluid; EBV = Epstein— Barr virus; ELISA = enzyme-linked immunosorbent assay; HIV-1 = human immunodeficiency virus-1 ;
HRP-2 = histidine-rich protein 2; IAV = influenza A virus; LDH = lactate dehydrogenase; MERS-CoV = Middle East respiratory syndrome coronavirus; NS1 = non-structural 1 ;
RSV = respiratory syncytial virus)
1 11.5 Additional investigations in PUO
• Serological tests for connective tissue disorders:
• Labelled white cell scan
Autoantibody screen
• Positron emission tomography (PET)/single-photon emission computed
Complement levels
tomography (SPECT)
Immunoglobulins
• Biopsy:
Cryoglobulins
Bronchoscopy and lavage ± transbronchial biopsy
• Ferritin
Lymph node aspirate or biopsy
• Echocardiography
Biopsy of radiological lesion
• Ultrasound of abdomen
Biopsy of liver
• CT/MRI of thorax, abdomen and/or brain
Bone marrow aspirate and biopsy
• Imaging of the skeletal system:
Lumbar puncture
Plain X-rays
Laparoscopy and biopsy
CT/MRI spine
Temporal artery biopsy
Isotope bone scan
222 • INFECTIOUS DISEASE
suspected visceral leishmaniasis. Temporal artery biopsy should
be considered in patients over the age of 50 years, even in the
absence of physical signs or a raised ESR. ‘Blind’ biopsy of
other structures in the absence of localising signs or laboratory
or radiology results is unhelpful.
Prognosis
No cause is found in approximately 10% of PUO cases, but as
long as there is no significant weight loss or signs of another
disease, the long-term mortality is low.
Fever in the injection drug-user
Intravenous injection of recreational drugs is widespread in many
parts of the world (p. 1184). Infective organisms are introduced
by non-sterile (often shared) injection equipment (Fig. 11.2).
The risks increase with prolonged drug use and injection into
large veins of the groin and neck necessitated by progressive
thrombosis of superficial peripheral veins. The most common
causes of fever are soft tissue or respiratory infections.
Clinical assessment
The history should address the following risk factors:
• Site of injection. Femoral vein injection is associated with
vascular complications such as deep venous thrombosis
(50% of which are septic) and accidental arterial injection
with false aneurysm formation or a compartment
syndrome due to swelling within the fascial sheath. Local
complications include ilio-psoas abscess, and septic
arthritis of the hip joint or sacroiliac joint. Injection of the
jugular vein can be associated with cerebrovascular
complications. Subcutaneous and intramuscular injection
has been related to infection by clostridial species, the
spores of which contaminate heroin. Clostridium novyi
6 Cardiovascular system
Systolic ‘V’ waves in JVP of
tricuspid regurgitation (p. XXX)
Regurgitant murmurs in
endocarditis
5 Nervous system
Signs of drug intoxication
Encephalopathy
Signs of meningitis
Focal neurological features or
seizures in septic embolism/
mycotic aneurysm/abscess
Cranial nerve palsies of botulism
Trismus, muscle rigidity or
spasms in tetanus
Localised pain over vertebrae with
epidural abscess
4 Optic fundi
Roth’s spots
Candidal cotton wool spots
3 Oropharynx
Dental infections
Oropharyngeal candidiasis or
other signs of HIV-1 infection
2 Hands and nails
Splinter haemorrhages
Signs of chronic liver disease
1 Skin and soft tissues (any site)
Cellulitis
Purulent drainage
Abscesses
Ulcers
Bullae or extreme pain suggestive
of necrotising fasciitis
^ Skin abscesses in an
injection drug-user
Observation
equipment may transmit
blood-borne viruses
7 Respiratory system
Consolidation in pneumonia
Upper lobe signs in tuberculosis
Pleural rub with septic
pulmonary emboli
8 Abdomen
Jaundice ± tender liver edge
with hepatitis
Pain in left upper quadrant with
splenic abscess
9 Bone and joints
Osteomyelitis
Septic arthritis
10 Injection sites
Abscesses
Fistula
Haematoma
Pseudoaneurysm
1 1 Femoral stretch test
Passive extension of the hip
joint causes pain and reflex
muscle spasm in ilio-psoas
abscess
A Hip flexor spasm in an
injection drug-user with
ilio-psoas abscess
12 Legs
Signs of DVT
Vasculitis or ischaemic signs of
septic emboli, endocarditis or
vasospasm
Compartment syndrome
Fig. 11.2 Fever in the injection drug-user: key features of clinical examination. Full examination (p. 216) is required but features most common
amongst injection drug-users are shown here. (DVT = deep venous thrombosis; JVP = jugular venous pulse)
Presenting problems in infectious diseases • 223
causes a local lesion with significant toxin production,
leading to shock and multi-organ failure. Tetanus, wound
botulism, anthrax and gas gangrene also occur.
• Technical details of injection. Sharing of needles and other
injecting paraphernalia (including spoons and filters) increases
the risk of blood-borne virus infection (e.g. HIV-1 , hepatitis B
or C virus). Some users lubricate their needles by licking them
prior to injection, thus introducing mouth organisms (e.g.
anaerobic streptococci, Fusobacterium spp. and Prevotella
spp.). Contamination of commercially available lemon juice,
used to dissolve heroin before injection, has been associated
with blood -stream infection with Candida spp.
• Substances injected. Injection of cocaine is associated
with a variety of vascular complications. Certain
formulations of heroin have been linked with particular
infections, e.g. wound botulism with black tar heroin.
Drugs are often mixed with other substances, e.g. talc.
• Blood -borne virus status. Results of previous HIV-1 and
hepatitis virus tests or vaccinations for hepatitis viruses
should be recorded.
• Surreptitious use of antimicrobials. Addicts may use
antimicrobials to self-treat infections, masking initial blood
culture results.
Key findings on clinical examination are shown in Figure 1 1 .2.
It can be difficult to distinguish the effects of infection from the
effects of drugs or drug withdrawal (excitement, tachycardia,
sweating, marked myalgia, delirium). Stupor and delirium may
result from drug administration but may also indicate meningitis
or encephalitis. Non-infected venous thromboembolism is also
common in this group.
Investigations
The initial investigations are as for any fever (see above), including
a chest X-ray and blood cultures. Since blood sampling may
be difficult, contamination is often a problem. Echocardiography
to detect infective endocarditis should be performed in all
injection drug-users with bacteraemia due to Staphylococcus
aureus or other organisms associated with endocarditis (Fig.
1 1 .3A); thromboembolic phenomena; or a new or previously
undocumented murmur. Endovascular infection should also be
suspected if lung abscesses or pneumatoceles are detected
radiologically. Infected thrombus at injection sites, such as
the groin, is common, and may lead to abscess formation.
Additional imaging should be focused on sites of injection or of
localising symptoms and signs (Fig. 1 1 .3B). Any pathological
fluid collections should be sampled.
Urinary toxicology tests may suggest a non-infectious cause
of the presenting complaint. While being investigated, all injection
drug-users should be offered testing for infection with hepatitis
B and C virus and HIV-1 .
Injection drug-users may have more than one infection.
Skin and soft tissue infections are most often due to Staph,
aureus or streptococci, and sometimes to Clostridium spp.
or anaerobes. Pulmonary infections are most often due to the
common pathogens causing community-acquired pneumonia,
tuberculosis or septic emboli (Fig. 1 1 .3C). Endocarditis with
septic emboli commonly involves Staph, aureus and viridans
streptococci, but Pseudomonas aeruginosa and Candida spp.
are also encountered.
Management
Empirical therapy of fever in the injection drug-user includes an
antistaphylococcal penicillin (e.g. flucloxacillin) or, if meticillin-
resistant Staph, aureus (MRSA) is prevalent in the community, a
Fig. 11.3 Causes of fever in injection drug-users. {k\ Endocarditis:
large vegetation on the tricuspid valve (arrowlM Septic arthritis of the
left sternoclavicular joint (arrow A) (note the erosion of the bony surfaces
at the sternoclavicular joint) with overlying soft tissue collection (arrow B).
[C Tricuspid valve endocarditis caused by Staphylococcus aureus.
Thoracic CT scan shows multiple embolic lesions with cavitation (arrows).
The patient presented with haemoptysis. C, Courtesy of Dr Julia Greig,
Royal Hallamshire Hospital, Sheffield.
glycopeptide (e.g. vancomycin) or lipopeptide (e.g.daptomycin).
Once microbiological results are available, therapy can be
narrowed to focus on the microorganism identified. In injection
drug-users, meticillin-sensitive Staph, aureus is customarily
treated with high-dose intravenous flucloxacillin, with shorter
durations for uncomplicated right-sided endocarditis. Right-sided
endocarditis caused by MRSA is usually treated with 4 weeks of
vancomycin plus gentamicin for the first week. Specialist advice
should be sought.
For localised infections of the skin and soft tissues, oral
therapy with agents active against staphylococci, streptococci
and anaerobes is appropriate (e.g. flucloxacillin plus co-amoxiclav
or clindamycin). Non-adherence to prescribed antimicrobial
regimens leads to a high rate of complications.
Fever in the immunocompromised host
Immunocompromised hosts include those with congenital
immunodeficiency (p. 77), HIV infection (Ch. 12) and iatrogenic
224 • INFECTIOUS DISEASE
immunosuppression induced by chemotherapy (p. 1330),
transplantation (p. 88) or immunosuppressant medicines,
including high-dose glucocorticoids. Metabolic abnormalities,
such as under-nutrition or hyperglycaemia, may also contribute.
Multiple elements of the immune system are potentially
compromised. A patient may have impaired neutrophil function
from chemotherapy, impaired T-cell and/or B-cell responses
due to underlying malignancy, T-cell and phagocytosis defects
due to glucocorticoids, mucositis from chemotherapy and an
impaired skin barrier due to insertion of a central venous catheter.
Fever may result from infectious or non-infectious causes,
including drugs, vasculitis, neoplasm, lymphoprol iterative disease,
graft-versus-host disease (in recipients of haematopoietic stem
cell transplants (HSCT); p. 936), organising pneumonitis or
Sweet’s syndrome (reddish nodules or plaques with fever and
leucocytosis, in association with haematological malignancy).
Clinical assessment
The following should be addressed in the history:
• Identification of the immunosuppressant factors and nature
of the immune defect.
• Any past infections and their treatment. Infections may
recur and antimicrobial resistance may have been acquired
in response to prior therapy.
• Exposure to infections, including opportunistic infections
that would not cause disease in an immunocompetent host.
• Prophylactic medicines and vaccinations administered.
Examination should include inspection of the normal physical
barriers provided by skin and mucosal surfaces and, in particular,
central venous catheters, the mouth, sinuses, ears and perianal
area (digital rectal examination should be avoided). Disseminated
infections can manifest as cutaneous lesions. The areas around
fingernails and toenails should also be inspected closely.
Investigations
Initial screening tests are as described above (p. 218).
Immunocompromised hosts often have decreased inflammatory
responses leading to attenuation of physical signs, such as
neck stiffness with meningitis, radiological features and
laboratory findings, such as leucocytosis. Chest CT scan
should be considered in addition to chest X-ray when respiratory
symptoms occur. Abdominal imaging may also be warranted,
particularly if there is right lower quadrant pain, which may
indicate typhlitis (inflammation of the caecum) in neutropenic
patients. Blood cultures from a central venous catheter, urine
cultures, and stool cultures if diarrhoea is present are also
recommended.
Nasopharyngeal aspirates are sometimes diagnostic, as
immunocompromised hosts may shed respiratory viruses for
prolonged periods. Skin lesions should be biopsied if nodules
are present, and investigation should include fungal stains.
Useful molecular techniques include PCR for cytomegalovirus
(CMV) and Aspergillus spp. DNA, and antigen assays (e.g.
cryptococcal antigen (CrAg) for Cryptococcus neoformans,
galactomannan tor Aspergillus spp. in blood, and (1 ,3)-p-D-glucan
for Aspergillus spp. and other causes of invasive fungal infection
(though this will not identify mucoraceous moulds) or Legionella
pneumophila type 1 in urine). Antibody detection is rarely useful
in immunocompromised patients. Patients with respiratory signs
or symptoms should be considered for bronchoalveolar lavage
to detect Pneumocystis jirovecii, other fungi, bacteria and
Neutropenic fever
Neutropenic fever is defined as a neutrophil count of less than
0.5x1 09/L (p. 925) and a single axillary temperature above 38.5°C
or three recordings above 38.0°C over a 1 2-hour period, although
the infection risk increases progressively as the neutrophil count
drops below 1 .0x109/L. Patients with neutropenia are particularly
prone to bacterial and fungal infection. Gram-positive organisms
are the most common pathogens, particularly in association with
in-dwelling catheters.
Empirical broad -spectrum antimicrobial therapy is commenced
as soon as neutropenic fever occurs and cultures have been
obtained. The most common regimens for neutropenic sepsis
are broad -spectrum penicillins, such as piperacillin-tazobactam
IV. The routine addition of aminoglycosides to these agents is
not supported by trial data. If fever has not resolved after 3-5
days, empirical antifungal therapy (e.g. caspofungin) is added
(p. 125). An alternative antifungal strategy is to use azole
prophylaxis in high-risk patients and markers of early fungal
infection, such as galactomannan and/or fungal PCR, to guide
initiation of antifungal treatment (a ‘pre-emptive approach’).
|j>ost-transplantation fever
Fever in transplant recipients may be due to infection, episodes
of graft rejection in solid organ transplant recipients, or graft-
versus-host disease following HSCT (p. 936).
Infections in solid organ transplant recipients are grouped
according to the time of onset (Box 1 1 .6). Those in the first
month are mostly related to the underlying condition or surgical
complications. Those occurring 1-6 months after transplantation
are characteristic of impaired T-cell function. Risk factors for CMV
infection have been identified; patients commonly receive either
prophylaxis or intensive monitoring involving regular testing for
CMV DNA by PCR and early initiation of anti-CMV therapy using
intravenous ganciclovir or oral valganciclovir if tests become
positive.
Following HSCT, infections in the first 4 weeks are more
common in patients receiving a myeloablative-conditioning
i
11.6 Infections in transplant recipients
Time post transplantation
Infections
Solid organ transplant recipients
0-1 month
Bacterial or fungal infections related to
the underlying condition or surgical
complications
1-6 months
CMV, other opportunistic infections
(e.g. Pneumocystis jirovecii pneumonia)
>6 months
Bacterial pneumonia, other bacterial
community-acquired infections,
shingles, cryptococcal infection, PTLD
Myeloablative haematopoietic stem cell transplant recipients
Pre-engraftment (typically
Bacterial and fungal infections,
0-4 weeks)
respiratory viruses or HSV reactivation
Post-engraftment:
Early (< 1 00 days)
CMV, Pneumocystis jirovecii
pneumonia, moulds or other
opportunistic infections
Late (>100 days)
Community-acquired bacterial
infections, shingles, CMV, PTLD
(CMV =
= cytomegalovirus; HSV =
herpes simplex virus; PTLD = post-transplant
lymphoproliferative disorder)
viruses.
Presenting problems in infectious diseases • 225
regimen (Box 1 1 .6). Later infections are more common if an
allogeneic procedure is performed.
Post-transplant lymphoproliferative disorder (PTLD) is an
Epstein-Barr virus (EBV)-associated lymphoma that can
complicate transplantation, particularly when primary EBV infection
occurs after transplantation.
Positive blood culture
Blood-stream infection (BSI) is a frequent presentation of
infection. This can be community-acquired or hospital-acquired
(‘nosocomial’). The most common causes are shown in Box 1 1 .7.
In immunocompromised hosts, a wider range of microorganisms
may be isolated, e.g. fungi in neutropenic hosts.
Primary BSI describes the situation in which there is no known
extravascular source of infection (e.g. pneumonia or urinary
tract infection), and is more common in Staph, aureus BSI. In
community-acquired Staph, aureus bacteraemia, 20-30% of
cases are associated with infectious endocarditis and up to
10% are due to osteomyelitis. Peripheral and central venous
catheters are an important source of nosocomial BSI.
BSI has an associated mortality of 15-40%, depending on
the setting, host and microbial factors.
Clinical assessment
The history should determine the setting in which BSI has
occurred. Host factors predisposing to infection include skin
disease, diabetes mellitus, injection drug use, the presence
of a central venous, urinary or haemodialysis catheter, and
surgical procedures, especially those involving the implantation
of prosthetic materials (in particular, endovascular prostheses).
Physical examination should focus on signs of endocarditis
(p. 527), evidence of bone or joint infection (tenderness or
restriction of movement), and abdominal or flank tenderness.
Central venous catheters should be examined for erythema or
purulence at the exit site. Particularly in cases with Candida spp.
infection or suspected infectious endocarditis, fundoscopy after
pupil dilatation should be performed.
Investigations
Positive blood cultures may be caused by contaminants.
When isolated from only one bottle, or from all bottles from
one venesection, coagulase-negative staphylococci often
represent contamination. Repeated isolation of this organism,
however, should raise suspicion of infective endocarditis or, in a
patient with any form of prosthetic material, prosthesis infection.
Viridans streptococci occasionally cause transient non-significant
i
11.7 Common causes of blood-stream infection
Community-acquired
• Escherichia coli
•
Streptococcus pneumoniae
• Staphylococcus aureus,
including MRSA
Nosocomial
•
Other streptococci
• Staph, aureus, including
•
Enterococci, including VRE
MRSA
•
Gram-negative bacteria
• Coagulase-negative
staphylococci
•
Candida spp.
(MRSA = meticillin-resistant Staphylococcus aureus, VRE = vancomycin-resistant
enterococci)
bacteraemia or blood culture contamination but, in view of their
association with infective endocarditis, significant infection must
always be excluded. Bacillus spp. (‘aerobic spore bearers’) and
Clostridium spp. often represent incidental transient bacteraemia
or contamination, but certain species (e.g. C. septicum) are more
likely to be genuine pathogens.
Further investigations are influenced by the causative organism
and setting. Initial screening tests are similar to those for fever
(p. 218) and should include chest X-ray, urine culture and, in
many cases, ultrasound or other imaging of the abdomen.
Imaging should also include any areas of bone or joint pain and
any prosthetic material, e.g. a prosthetic joint or an aortic graft.
Echocardiography should be considered for those patients
with BSI who have valvular heart disease or clinical features of
endocarditis (p. 527), those whose cultures reveal an organism
that is a common cause of endocarditis (e.g. Staph, aureus,
viridans streptococci or enterococci), those in whom multiple
blood cultures are positive for the same organism, and those with
a rapid positive result on culture. The sensitivities of transthoracic
echocardiography (TTE) and transoesophageal echocardiography
(TOE) for the detection of vegetations are 50-90% and over
95%, respectively. Therefore, if TTE is negative, TOE should
be performed.
Certain rare causes of BSI have specific associations that warrant
further investigation. Endocarditis caused by Streptococcus
gallolyticus subsp. gallolyticus (formerly Strep, bovis biotype I)
and BSI with C. septicum are both associated with colonic
carcinoma and their isolation is an indication for colonoscopy.
Management
BSI requires antimicrobial therapy and attention to the source of
infection, including surgical drainage if appropriate. Two weeks
of therapy may be sufficient for Staph, aureus BSI from central
and peripheral venous catheter infections when the source is
identified and removed, for uncomplicated skin and soft tissue
infections, and for uncomplicated right-sided infective endocarditis.
Other Staph, aureus BSIs are usually treated for 4-6 weeks.
Central venous catheter infections
Infections of central venous catheters typically involve the catheter
lumen and are associated with fever, positive blood cultures
and, in some cases, signs of purulence or exudate at the site
of insertion. Infection is more common in temporary catheters
inserted into the groin or jugular vein than in those in the subclavian
vein. Tunnelled catheters, e.g. Hickman catheters, may also
develop tunnel site infections.
Staphylococci account for 70-90% of catheter infections, with
coagulase-negative staphylococci more common than Staph,
aureus. Other causes include enterococci and Gram-negative
bacilli. Unusual Gram-negative organisms, such as Citrobacter
freundii and Pseudomonas fluorescens, raise the possibility of
non-sterile infusion equipment or infusate. Candida spp. are a
common cause of line infections, particularly in association with
total parenteral nutrition. Non-tuberculous mycobacteria may
cause tunnel infections.
Investigations and management
In bacteraemic patients with fever and no other obvious source
of infection, a catheter infection is likely. Local evidence of
erythema, purulence or thrombophlebitis supports the diagnosis.
However, microbiological confirmation is essential (p. 106).
Catheter-related infection is suggested by higher colony counts
226 • INFECTIOUS DISEASE
or shorter time to positivity in blood cultures obtained through the
catheter than in peripheral blood cultures. If the line is removed,
a semi-quantitative culture of the tip may confirm the presence
of 1 5 or more colony-forming units, but this is retrospective and
does not detect luminal infection.
For coagulase-negative staphylococcal line infections, the
options are to remove the line and provide 5-7 days’ therapy or,
particularly in the case of tunnelled catheters, to treat empirically
with a glycopeptide antibiotic, e.g. vancomycin, with or without
the use of antibiotic-containing lock therapy to the catheter
for approximately 14 days. For Staph, aureus infection, the
chance of curing an infection with the catheter in situ is low
and the risks from infection are high. Therefore, unless the risks
of catheter removal outweigh the benefits, treatment involves
catheter removal, followed by 14 days of antimicrobial therapy;
the same applies to infections with Pseudomonas aeruginosa,
Candida spp., atypical mycobacteria or Bacillus spp. Infections
complicated by endocarditis, thrombophlebitis, metastatic infection
or tunnel infection also require catheter removal.
Infection prevention is a key component of the management
of vascular catheters. Measures include strict attention to hand
hygiene, optimal siting, full aseptic technique on insertion and
subsequent interventions, skin antisepsis with chlorhexidine
and isopropyl alcohol, daily assessment of catheter sites
(e.g. with visual infusion phlebitis (VIP) score; see Box 1 1 .37,
p. 251), and daily consideration of the continuing requirement
for catheterisation. The use of catheters impregnated with
antimicrobials, such as chlorhexidine or silver, is advocated in
some settings.
Sepsis
Sepsis is discussed on page 1 96 and there are many causes (Box
1 1 .8). The results of blood cultures and pre-existing host factors
guide initial investigations. Patients who are immunocompromised
may have a broader range of causal pathogens that may be
harder to culture, including mycobacteria and fungi. In many
regions, malaria and dengue must also be excluded.
Severe skin and soft tissue infections
Skin and soft tissue infections (SSTIs) are an important cause
of sepsis. Cases can be classified as in Box 1 1 .9, according
to the clinical features and microbiological findings. In some
cases, severe systemic features may be out of keeping with
mild local features.
Necrotising fasciitis
In necrotising fasciitis, cutaneous erythema and oedema progress
to bullae or areas of necrosis. Unlike in cellulitis, pain may be
disproportionately intense in relation to the visible cutaneous
features or may spread beyond the zone of erythema. The
infection spreads quickly along the fascial plane. Type 1
necrotising fasciitis is a mixed infection with Gram-negative
bacteria and anaerobes, often seen post-operatively in diabetic
or immunocompromised hosts. Subcutaneous gas may be
present. Type 2 necrotising fasciitis is caused by group A or other
streptococci. Approximately 60% of cases are associated with
streptococcal toxic shock syndrome (p. 253). Type 3 infection
i
11.8 Causes of sepsis
Infection
Setting
Bacterial
Staphylococcus aureus, coagulase-negative staphylococci
Streptococcus pneumoniae
Other streptococci
Staphylococcal or streptococcal toxic shock syndrome
Enterococci
Neisseria meningitidis
Escherichia coli, other Gram- negative bacteria
Pseudomonas aeruginosa, multidrug-resistant
Gram-negative bacteraemia
Salmonella Typhi or Paratyphi
Yersinia pestis
Burkholderia pseudomallei
Capnocytophaga canimorsus
Clostridium difficile
Polymicrobial infection with Gram-negatives and
anaerobes
Mycobacterium tuberculosis, M. avium complex (MAC)
Bacteraemia may be associated with endocarditis, intravascular cannula infection, or skin
or bone foci
Invasive pneumococcal disease, usually with pneumonia or meningitis; asplenia
Invasive streptococcal disease, especially necrotising fasciitis
Viridans streptococci in neutropenic host with severe mucositis
Toxin-mediated, blood cultures negative; clues include erythrodermic rash and
epidemiological setting
Most often with abdominal focus
Sepsis in children or young adults with petechial rash and/or meningitis
Urinary or biliary tract infection, or other abdominal infections
Nosocomial infection
In countries with a high incidence of enteric fever
In plague
Endemic in areas of Thailand; more likely to involve patients with diabetes mellitus or
immunocompromised
Associated with dog bites and asplenic individuals
Severe colitis, particularly in the elderly
Bowel perforation, bowel ischaemia
HIV-positive or immunocompromised with miliary tuberculosis or disseminated MAC
Fungal
Candida spp.
Histoplasma capsulatum, other dimorphic fungi
Parasitic
Falciparum malaria
Babesia microti
Strongyloides stercoralis hyperinfection syndrome
Line infection or post-operative complication, nosocomial or immunocompromised host
Immunocompromised host
Malaria with high-level parasitaemia and multi-organ failure or as a complication of
bacterial superinfection
Asplenic individual
Gram-negative infection complicating Strongyloides infection in immunocompromised host
Presenting problems in infectious diseases • 227
11.9 Severe necrotising soft tissue infections
• Necrotising fasciitis (primarily confined to subcutaneous fascia
and fat)
• Clostridial anaerobic cellulitis (confined to skin and subcutaneous
tissue)
• Non-clostridial anaerobic cellulitis
• Progressive bacterial synergistic gangrene ( Staphylococcus aureus
+ micro-aerophilic streptococcus) (‘Meleney’s gangrene’, primarily
confined to skin)
• Pyomyositis (discrete abscesses within individual muscle groups)
• Clostridial myonecrosis (gas gangrene)
• Anaerobic streptococcal myonecrosis (non-clostridial infection
mimicking gas gangrene)
• Group A streptococcal necrotising myositis
Fig. 11.4 Excision following necrotising fasciitis in an injection
drug-user.
involves organisms such as Aeromonas hydrophila and Vibrio
vulnificus, which is found in tropical to subtropical regions and
is associated with marine exposure. Type 4 is caused by fungi
such as mucoraceous moulds and may also vary geographically
in incidence with recent reports of increased cases in India and
other regions.
Necrotising fasciitis is a medical emergency, requiring immediate
surgical debridement with inspection of the involved muscle
groups, in addition to antimicrobial therapy (Fig. 1 1 .4). Empirical
treatment is with broad-spectrum agents (e.g. piperacillin—
tazobactam plus clindamycin; meropenem with clindamycin).
Ceftazidime or ciprofloxacin with doxycycline may be used
where marine exposure is a factor, and antifungals for suspected
fungal necrotising fasciitis, but it is important to combine these
with effective coverage against streptococcal infection. MRSA-
associated necrotising fasciitis has emerged in some regions
and in these places appropriate therapy for MRSA, such as a
glycopeptide or linezolid, should be added to the empirical regimen
until microbiological results allow narrowing of the antimicrobial
spectrum. Hyperbaric oxygen therapy may be considered for
polymicrobial infection. Group A streptococcal infection is treated
with benzylpenicillin plus clindamycin, and often immunoglobulin,
though to date clinical trials have not provided clear evidence
of the benefit of immunoglobulin.
Gas gangrene
Although Clostridium spp. may colonise or contaminate wounds,
no action is required unless there is evidence of spreading
infection. Infection may be limited to tissue that is already damaged
(anaerobic cellulitis) or may involve healthy muscle (gas gangrene).
In anaerobic cellulitis, usually due to C. perfringens or other
Clostridia infecting devitalised tissue following a wound, gas forms
locally and extends along tissue planes but bacteraemia does
not occur. Prompt surgical debridement of devitalised tissue
and therapy with penicillin or clindamycin is usually effective.
Gas gangrene (clostridial myonecrosis) is defined as acute
invasion of healthy living muscle undamaged by previous trauma,
and is most commonly caused by C. perfringens. In at least
70% of cases, it follows deep penetrating injury sufficient to
create an anaerobic (ischaemic) environment and allow clostridial
introduction and proliferation. Severe pain at the site of the
injury progresses rapidly over 1 8-24 hours. Skin colour changes
from pallor to bronze/purple discoloration and the skin is tense,
swollen, oedematous and exquisitely tender. Gas in tissues may
be obvious, with crepitus on clinical examination, or visible on
X-ray, CT or ultrasound. Signs of systemic toxicity develop
rapidly, with high leucocytosis, multi-organ dysfunction, raised
creatine kinase and evidence of disseminated intravascular
coagulation and haemolysis. Antibiotic therapy with high-dose
intravenous penicillin and clindamycin is recommended, coupled
with aggressive surgical debridement of the affected tissues.
Alternative agents include cephalosporins and metronidazole.
Hyperbaric oxygen has a putative but controversial role.
Other SSTIs
‘Synergistic gangrene’ is a polymicrobial infection with anaerobes
and other bacteria (Staph, aureus or Gram-negatives). When
this affects the genital/perineal area, it is known as ‘Fournier’s
gangrene’. Severe gangrenous cellulitis in immunocompromised
hosts may involve Gram-negative bacteria or fungi. Entamoeba
histolytica can cause soft tissue necrosis following abdominal
surgery in areas of the world where infection is common. Contact
with sea water or shellfish consumption in tropical to subtropical
regions worldwide, such as the Gulf of Mexico, can lead to
infection with Vibrio vulnificus. This infection causes soft tissue
necrosis and bullae, and may lead to necrotising fasciitis. Patients
with chronic liver disease are particularly susceptible to this
infection and can develop sepsis.
Acute diarrhoea and vomiting
Acute diarrhoea (p. 783), sometimes with vomiting, is the
predominant symptom in infective gastroenteritis (Box 11.10).
Acute diarrhoea may also be a symptom of other infectious and
non-infectious diseases (Box 11.11). Stress, whether psychological
or physical, can also produce loose stools.
The World Health Organisation (WHO) estimates that there are
more than 1 .7 billion cases of acute diarrhoea annually globally,
with 760000 deaths in children under 5. In developed countries,
diarrhoea remains an important problem, with the elderly being
most vulnerable (Box 11.12). The majority of episodes are due to
infections spread by the faecal-oral route and transmitted either
on fomites, on contaminated hands, or in food or water. Measures
such as the provision of clean drinking water, appropriate disposal
of human and animal sewage, and the application of simple
principles of food hygiene can all limit gastroenteritis.
The clinical features of food-borne gastroenteritis vary. Some
organisms (Bacillus cereus, Staph, aureus and Vibrio cholerae)
elute exotoxins that cause vomiting and/or so-called ‘secretory’
diarrhoea (watery diarrhoea without blood or faecal leucocytes,
228 • INFECTIOUS DISEASE
11.10 Causes of infectious gastroenteritis
Toxin in food: <6 hrs incubation
• Bacillus cereus (p. 262)
•
Clostridium spp. enterotoxin
• Staphylococcus aureus (p. 262)
(p. 262)
Bacterial: 12-72 hrs incubation
• Enterotoxigenic Escherichia
•
Vibrio cholerae (p. 264)
coli (ETEC, p. 263)
•
Salmonella (p. 262)
• Shiga toxin-producing E. coli
•
Shigella * (p. 265)
(EHEC, p. 263)*
•
Campylobacter * (p. 262)
• Enteroinvasive E. coli (El EC,
•
Clostridium difficile * (p. 264)
p. 263)*
Viral: short incubation
• Rotavirus (p. 249)
•
Norovirus (p. 249)
Protozoal: long incubation
• Giardiasis (p. 287)
•
Microsporidiosis (p. 317)
• Cryptosporidiosis (pp. 287
•
Amoebic dysentery (p. 286)*
and 317)
•
Cystoisosporiasis (p. 233)
*Associated with bloody diarrhoea.
VS 11.11 Differential diagnosis of acute diarrhoea
and vomiting
Infectious causes
• Gastroenteritis
•
Meningococcaemia (p. 1119)
• Clostridium difficile infection
•
Pneumonia (especially
(p. 264)
‘atypical disease’, p. 582)
• Acute diverticulitis (p. 833)
• Sepsis (p. 196)
• Pelvic inflammatory disease
•
Malaria (p. 273)
(p. 336)
Non-infectious causes
Gastrointestinal
• Inflammatory bowel disease
•
Overflow from constipation
(p. 813)
(p. 834)
• Bowel malignancy (p. 827)
•
Enteral tube feeding
Metabolic
• Diabetic ketoacidosis (p. 735)
•
Neuro-endocrine tumours
• Thyrotoxicosis (p. 635)
• Uraemia (p. 414)
releasing (e.g.) VIP or 5-HT
Drugs and toxins
• NSAIDs
•
Heavy metals
• Cytotoxic agents
•
Ciguatera fish poisoning
• Antibiotics
(p. 149)
• Proton pump inhibitors
•
Scombrotoxic fish poisoning
• Dinoflagellates (p. 149)
• Plant toxins (p. 150)
(P- 150)
(5-HT = 5-hydroxytryptamine, serotonin; NSAIDs = non-steroidal anti¬
inflammatory drugs; VIP = vasoactive intestinal peptide)
11.12 Infectious diarrhoea in old age
• Incidence: not increased but the impact is greater.
• Mortality: most deaths due to gastroenteritis in the developed world
are in adults aged over 70. Most are presumed to be caused by
dehydration leading to organ failure.
• Clostridium difficile infection (CDI): more common, especially in
hospital and nursing home settings, usually following antibiotic
exposure.
reflecting small bowel dysfunction). In general, the time from
ingestion to the onset of symptoms is short and, other than
dehydration, little systemic upset occurs. Other organisms, such
as Shigella spp., Campylobacter spp. and enterohaemorrhagic
Escherichia coli (EHEC), may directly invade the mucosa of
the small bowel or produce cytotoxins that cause mucosal
ulceration, typically affecting the terminal small bowel and colon.
The incubation period is longer and more systemic upset occurs,
with prolonged bloody diarrhoea. Salmonella spp. are capable of
invading enterocytes and of causing both a secretory response
and invasive disease with systemic features. This is seen with
Salmonella Typhi and Salmonella Paratyphi (enteric fever), but
may occasionally be seen with other non-typhoidal Salmonella
spp., particularly in the immunocompromised host and the elderly.
Clinical assessment
The history should address foods ingested (Box 11.13), duration
and frequency of diarrhoea, presence of blood or steatorrhoea,
abdominal pain and tenesmus, and whether other people have
been affected. Fever and bloody diarrhoea suggest an invasive,
colitic, dysenteric process. An incubation period of less than 1 8
hours suggests toxin-mediated food poisoning, and longer than
5 days suggests diarrhoea caused by protozoa or helminths.
Person-to-person spread suggests certain infections, such as
shigellosis or cholera.
Examination includes assessment of the degree of dehydration.
Assessment for early signs of hypotension, such as thirst,
headache, altered skin turgor, dry mucous membranes and
postural hypotension, is important, particularly in tropical regions
where dehydration progresses rapidly. Signs of more marked
dehydration include supine hypotension and tachycardia,
decreased urinary output, delirium and sunken eyes. The blood
pressure, pulse rate, urine output and ongoing stool losses
should be monitored closely.
11.13 Foods associated with infectious illness,
including gastroenteritis
Raw seafood
• Norovirus • Hepatitis A
• Vibrio spp.
Raw eggs
• Salmonella serova rs
Undercooked meat or poultry
• Salmonella serovars • Hepatitis E (pork products)
• Campylobacter spp. • Clostridium perfringens
• EHEC
Unpasteurised milk or juice
• Salmonella serovars. • EHEC
• Campylobacter spp. • Yersinia enterocolitica
Unpasteurised soft cheeses
• Salmonella serovars • Yersinia enterocolitica
• Campylobacter spp. • Listeria monocytogenes
• ETEC
Home-made canned goods
• Clostridium botulinum
Raw hot dogs, pate
• Listeria monocytogenes
(EHEC = enterohaemorrhagic Escherichia coli ; ETEC = enterotoxigenic E coli)
Presenting problems in infectious diseases • 229
Type 1
Separate hard
lumps, like nuts
(hard to pass)
Sausage-shaped
but lumpy
Type 3
Like a sausage but
with cracks on its
surface
Type 4
Like a sausage or
snake, smooth
and soft
Type 5
Soft blobs with
clear-cut edges
(passed easily)
Type 6
Fluffy pieces with
ragged edges, a
mushy stool
Type 7
Watery, no solid
pieces
Entirely liquid
Fig. 11.5 Bristol stool chart. The stool is given a ‘score’ of 1-7 by
reference to the verbal and visual description. This is recorded on a chart
(usually known as a ‘Bristol stool chart’) or in a patient monitoring
database. Adapted from Lewis SJ, Heaton KW. Stool form scale as a
useful guide to intestinal transit time. Scand J Gastroenterol 1997;
32:920-924.
The severity of diarrhoea may be assessed by reference to
the Bristol stool form scale (Bristol stool chart), which allows
an objective assessment of stool consistency by providing a
verbal and visual reference scale (Fig. 11.5). The Bristol stool
form scale was developed in the 1990s to monitor patients
with irritable bowel syndrome, but its main use (at least in UK
hospitals) is to monitor hospital inpatients with loose stool to
assist in decisions on stool sampling and infection prevention
precautions, especially in relation to C. difficile.
Investigations
These include stool inspection for blood and microscopy for
leucocytes, and also an examination for ova, cysts and parasites
if the history indicates residence or travel to areas where these
infections are prevalent. Stool culture should be performed and
C. difficile toxin sought. FBC and serum electrolytes indicate
the degree of inflammation and dehydration. Where cholera is
prevalent, examination of a wet film with dark-field microscopy
for darting motility may provide a diagnosis. In a malarious area,
a blood film for malaria parasites should be obtained. Blood and
urine cultures and a chest X-ray may identify alternative sites of
infection, particularly if the clinical features suggest a syndrome
other than gastroenteritis.
Management
All patients with acute, potentially infective diarrhoea should be
appropriately isolated to minimise person-to-person spread of
infection. If the history suggests a food-borne source, public
health measures must be implemented to identify the source
and to establish whether other linked cases exist (p. 114).
Fluid replacement
Replacement of fluid losses in diarrhoeal illness is crucial and
may be life-saving.
Although normal daily fluid intake in an adult is only 1-2 L,
there is considerable additional fluid movement in and out of the
gut in secretions (see Fig. 21.7, p. 769). Altered gut resorption
with diarrhoea can result in substantial fluid loss; for example,
1 0-20 L of fluid may be lost in 24 hours in cholera. The fluid
lost in diarrhoea is isotonic, so both water and electrolytes need
to be replaced. Absorption of electrolytes from the gut is an
active process requiring energy. Infected mucosa is capable
of very rapid fluid and electrolyte transport if carbohydrate is
available as an energy source. Oral rehydration solutions (ORS)
therefore contain sugars, as well as water and electrolytes (Box
11.14). ORS can be just as effective as intravenous replacement
fluid, even in the management of cholera. In mild to moderate
gastroenteritis, adults should be encouraged to drink fluids
and, if possible, continue normal dietary food intake. If this is
impossible - due to vomiting, for example - intravenous fluid
administration will be required. In very sick patients or those with
cardiac or renal disease, monitoring of urine output and central
venous pressure may be necessary.
The volume of fluid replacement required should be estimated
based on the following considerations:
• Replacement of established deficit. After 48 hours of
moderate diarrhoea (6-10 stools per 24 hrs), the average
adult will be 2-4 L depleted from diarrhoea alone.
Associated vomiting will compound this. Adults with this
symptomatology should therefore be given rapid
replacement of 1-1 .5 L, either orally (ORS) or by
intravenous infusion (normal saline), within the first 2-4
hours of presentation. Longer symptomatology or more
persistent/severe diarrhoea rapidly produces fluid losses
comparable to diabetic ketoacidosis and is a metabolic
emergency requiring active intervention.
KM 11.14 Composition of oral rehydration solution and
other replacement fluids
Fluid
Na
K
Cl
Energy
WHO
90
20
80
54
Dioralyte
60
20
60
71
Pepsi
6.5
0.8
-
400
7UP
7.5
0.2
-
320
Apple juice
0.4
26
-
480
Orange juice
0.2
49
-
400
Breast milk
22
36
28
670
*Values given in mmol/L for electrolyte and kcal/L for energy components.
(WHO = World Health Organisation)
230 • INFECTIOUS DISEASE
• Replacement of ongoing losses. The average adult’s
diarrhoeal stool accounts for a loss of 200 ml_ of isotonic
fluid. Stool losses should be carefully charted and an
estimate of ongoing replacement fluid calculated.
Commercially available rehydration sachets are
conveniently produced to provide 200 ml_ of ORS; one
sachet per diarrhoea stool is an appropriate estimate of
supplementary replacement requirements.
• Replacement of normal daily requirement. The average
adult has a daily requirement of 1-1.5 L of fluid in addition
to the calculations above. This will be increased
substantially in fever or a hot environment.
Antimicrobial agents
In non-specific gastroenteritis, routine use of antimicrobials does
not improve outcome and may lead to antimicrobial resistance
or side-effects. They are usually used where there is systemic
involvement, a host with immunocompromise or significant
comorbidity.
Evidence suggests that, in EHEC infections, the use of
antibiotics may make the complication of haemolytic uraemic
syndrome (HUS; p. 408) more likely due to increased toxin
release. Antibiotics should therefore not be used in this condition.
Conversely, antibiotics are indicated in Shigella dysenteriae
infection and in invasive salmonellosis - in particular, typhoid
fever. Antibiotics may also be advantageous in cholera epidemics,
reducing infectivity and controlling the spread of infection.
Antidiarrhoeal, antimotility and antisecretory agents
These agents are not usually recommended in acute infective
diarrhoea. Loperamide, diphenoxylate and opiates are potentially
dangerous in dysentery in childhood, causing intussusception.
Antisecretory agents, such as bismuth and chlorpromazine, may
make the stools appear more bulky but do not reduce stool fluid
losses and may cause significant sedation. Adsorbents, such
as kaolin or charcoal, have little effect.
Non-infectious causes of food poisoning
While acute food poisoning and gastroenteritis are most frequently
caused by infections, non-infectious causes must also be
considered in the differential diagnosis. These are discussed
on page 149.
| Antimicrobial-associated diarrhoea
Antimicrobial-associated diarrhoea (AAD) is a common
complication of antimicrobial therapy, especially with broad-
spectrum agents. It is most common in the elderly but can
occur at all ages. Although the specific mechanism is unknown
in most cases of AAD, C. difficile (p. 264) is implicated in 20-25%
of cases and is the most common cause among patients with
evidence of colitis. C. perfringens is a rarer cause that usually
remains undiagnosed, and Klebsiella oxytoca may also cause
antibiotic-associated haemorrhagic colitis.
Infections acquired in the tropics
Recent decades have seen unprecedented increases in long¬
distance business and holiday travel, as well as extensive
migration. Although certain diseases retain their relatively fixed
geographical distribution, being dependent on specific vectors
or weather conditions, many travel with their human hosts and
some may then be transmitted to other people. This means
11.15 How to assess health needs in travellers
before departure
• Destination
• Personal details, including previous travel experience
• Dates of trip
• Itinerary and purpose of trip
• Personal medical history, including pregnancy, medication and
allergies (e.g. to eggs, vaccines, antibiotics)
• Past vaccinations:
Childhood schedule followed? Diphtheria, tetanus, pertussis,
polio, Neisseria meningitidis types B/C, Haemophilus influenzae
B (HiB)
Travel-related? Typhoid, yellow fever, hepatitis A, hepatitis B,
meningococcal ACW135Y, rabies, Japanese B encephalitis,
tick-borne encephalitis
• Malaria prophylaxis: questions influencing the choice of antimalarial
drugs are destination, past experience with antimalarials, history of
epilepsy or psychiatric illness
*Further information is available at fitfortravel.nhs.uk.
that the pattern of infectious diseases seen in each country
changes constantly, and travel history and information on countries
previously lived in, particularly during childhood, are crucial.
In general, the diversity of infectious diseases is greater in
tropical than in temperate countries, and people in temperate
countries have immunity to a narrower range of infections,
reflecting less exposure in childhood and less ongoing boosting of
immunity later in life, so that the most common travel-associated
infections are those that are acquired by residents of temperate
countries during visits to the tropics. In addition, those who
have lived in tropical areas may lose immunity when they move
to temperate countries and become susceptible when visiting
their homeland.
Most travel-associated infections can be prevented. Pre¬
travel advice is tailored to the destination and the traveller (Box
11.15). It includes avoidance of insect bites (using at least 20%
diethyltoluamide (DEET)), sun protection (sunscreen with a sun
protection factor (SPF) of at least 15), food and water hygiene
(‘Boil it, cook it, peel it or forget it!’), how to respond to travellers’
diarrhoea (seek medical advice if bloody or if it lasts more than
48 hrs) and, if relevant, safe sex (condom use).
Fever acquired in the tropics
Presentation with unexplained fever is common in travellers
who are visiting or have recently travelled to tropical areas.
Fever may also occur in those living in tropical regions if they
have not developed immunity to the endemic pathogen or if
this immunity is compromised by factors such as pregnancy.
Frequent final diagnoses in such patients are malaria, typhoid
fever, viral hepatitis and dengue fever. Travellers to affected areas
may have viral haemorrhagic fevers (VHFs) such as Ebola, Lassa,
Crimean-Congo and Marburg (see Box 1 1 .36, p. 245), avian
influenza (H5N1) or Middle East respiratory syndrome (MERS),
which require special isolation precautions.
Clinical assessment
The approach to unexplained fever is as described above and
key questions relating to infections acquired in tropical regions
are listed in Box 1 1 .16. Medicines purchased in some countries
may have reduced efficacy, e.g. for malaria prophylaxis. Consult
reliable up-to-date sources about resistance to antimalarial drugs
Presenting problems in infectious diseases • 231
in the country visited. Vaccinations against yellow fever and
hepatitis A and B are sufficiently effective to virtually exclude
these infections. Oral and injectable typhoid vaccinations are
70-90% effective.
The differential diagnosis is guided by the clinical scenario,
presence of specific exposures (Box 11.17) and incubation period
(Box 11.18). Falciparum malaria tends to present between 7
and 28 days after exposure in an endemic area. VHF, dengue
and rickettsial infection can usually be excluded if more than 21
days have passed between leaving the area and onset of illness.
11.16 How to obtain a history from travellers to the
tropics with fever
Questions
Factors to ascertain
Countries visited and
dates of travel
Relate travel to known outbreaks of
infection or antimicrobial resistance
Determine the
environment visited
Travel to rural environments, forests,
rivers or lakes
Clarify where the person
slept
Sleeping in huts, use of bed nets,
sleeping on the ground
Establish what he/she
was doing
Exposure to people with medical illness,
animals, soil, lakes and rivers
History of insect bites
Type of insect responsible,
circumstances (location, time of day
etc.), preventive measures
Dietary history
Ingestion of uncooked foods, salads
and vegetables, meats (especially if
under-cooked), shellfish, molluscs,
unpasteurised dairy products, unbottled
water and sites at which food prepared
Sexual history
History of sexual intercourse with
commercial sex workers, local
population or travellers from other
countries
Malaria prophylaxis
Type of prophylaxis
Vaccination history
Receipt of pre-travel vaccines and
appropriateness to area visited
History of any treatments
received while abroad
Receipt of medicines, local remedies,
blood transfusions or surgical
procedures
11.17 Specific exposures and causes of fever
in the tropics
Exposure
Infection or disease
Mosquito bite
Malaria, dengue fever, Chikungunya, filariasis,
tularaemia
Tsetse fly
bite
African trypanosomiasis
Tick bite
Rickettsial infections including typhus, Lyme
disease, tularaemia, Crimean-Congo haemorrhagic
fever, Kyasanur forest disease, babesiosis,
tick-borne encephalitis
Louse bite
Typhus
Flea bite
Plague
Sandfly bite
Leishmaniasis, arbovirus infection
Reduviid bug
Chagas’ disease
Animal
contact
Q fever, brucellosis, anthrax, plague, tularaemia,
viral haemorrhagic fevers, rabies
Fresh-water
swimming
Schistosomiasis, leptospirosis, Naegleria fowleri
Exposure to
soil
Inhalation: dimorphic fungi
inhalation or inoculation: Burkholderia
pseudomallei
Inoculation (most often when barefoot):
hookworms, Strongyloides stercoralis
Raw or
under-cooked
fruit and
vegetables
Enteric bacterial infections, hepatitis A or E virus,
Fasciola hepatica, Toxocara spp., Echinococcus
granulosus (hydatid disease), Entamoeba histolytica
Under-cooked
pork
Taenia solium (cysticercosis)
Crustaceans
or molluscs
Paragonimiasis, gnathostomiasis, Angiostrongylus
cantonensis infection, hepatitis A virus,
cholera
Unpasteurised
dairy products
Brucellosis, salmonellosis, abdominal tuberculosis,
listeriosis
Untreated
water
Enteric bacterial infections, giardiasis,
Cryptosporidium spp. (chronic in
immunocompromised), hepatitis A or E
virus
Patient has travelled
within 7-21 days to an
area endemic for VHF
and has a fever
Signs of organ failure
or
epidemiological
risk factors*
Isolation with full
barrier protection
Discuss with regional
level 4 biosafety
specialist unit
PCR
positive
Proceed to standard
investigation, isolation
and treatment of
traveller with fever
or malaria
Ma'ana Isolation with full
positive barrier protection
Take blood film for
malaria test
Malaria
negative Send PCR to
regional laboratory
for VHF
PCR negative
Fig. 11.6 Approach to the patient with suspected viral haemorrhagic fever (VHF). See page 245. ^Epidemiological risk factors: staying with a febrile
individual, caring for a sick individual, or contact with body fluids from a suspected human or animal case of VHF. (PCR = polymerase chain reaction)
232 • INFECTIOUS DISEASE
11.18 Incubation times and illnesses in travellers
<2 weeks
Non-specific fever
• Malaria
•
Salmonellosis
• Chikungunya
•
Shigellosis
• Dengue
•
East African trypanosomiasis
• Scrub typhus
•
Leptospirosis
• Spotted group rickettsiae
•
Relapsing fever
• Acute HIV
•
Influenza
• Acute hepatitis C virus
•
Yellow fever
• Campylobacter
Fever and coagulopathy (usually thrombocytopenia)
• Malaria
•
Leptospirosis and other
• VHF
bacterial pathogens associated
• Meningococcaemia
with coagulopathy
• Enteroviruses
Fever and central nervous system involvement
• Malaria
•
East African trypanosomiasis
• Typhoid fever
•
Other causes of encephalitis
• Rickettsial typhus (epidemic
or meningitis
caused by Rickettsia
•
Angiostrongyliasis
prowazekii)
•
Rabies
• Meningococcal meningitis
• Arboviral encephalitis
Fever and pulmonary involvement
• Influenza
•
Acute coccidioidomycosis
• Pneumonia, including
•
Q fever
Legionella pneumonia
•
SARS
• Acute histoplasmosis
Fever and rash
• Viral exanthems (rubella,
•
Spotted or typhus group
measles, varicella, mumps,
rickettsiosis
HHV-6, enteroviruses
•
Typhoid fever
• Chikungunya
•
Parvovirus B19
• Dengue
•
HIV-1
2-6 weeks
• Malaria
•
African trypanosomiasis
• Tuberculosis
•
VHF
• Hepatitis A, B, C and E viruses
•
Q fever
• Visceral leishmaniasis
•
Acute American
• Acute schistosomiasis
trypanosomiasis
• Amoebic liver abscess
•
Viral causes of mononucleosis
• Leptospirosis
syndromes
>6 weeks
• Non -falciparum malaria
•
Schistosomiasis
• Tuberculosis
•
Amoebic liver abscess
• Hepatitis B and E viruses
•
Chronic mycoses
• HIV-1
•
African trypanosomiasis
• Visceral leishmaniasis
•
Rabies
• Filariasis
•
Typhoid fever
• Onchocerciasis
(HHV-6 = human herpesvirus-6; SARS = severe acute respiratory syndrome; VHF
= viral haemorrhagic fever)
Adapted from Traveller’s Health Yellow Book, CDC Health Information for
International Travel 2008.
Clinical examination is summarised on page 216. Particular
attention should be paid to the skin, throat, eyes, nail beds,
lymph nodes, abdomen and heart. Patients may be unaware
of tick bites or eschars (p. 270). Body temperature should be
measured at least twice daily.
1 1 .19 Investigation of tropically acquired acute fever
without localising signs
Features on full blood count
Further investigations
Neutrophil leucocytosis
Bacterial sepsis
Blood culture
Leptospirosis
Culture of blood and urine,
serology
Borreliosis (tick- or louse-borne
Blood film
relapsing fever)
Amoebic liver abscess
Ultrasound
Normal white cell count and differential
Malaria (may have low platelets or
Blood film, antigen test
anaemia)
Typhoid fever
Blood and stool culture
Typhus
Serology
Lymphocytosis
Viral fevers, including VHF
Serology, PCR
Infectious mononucleosis
Monospot test, serology
Malaria
Blood film, antigen test
Rickettsial fevers
Serology
Atypical lymphocytes
Dengue and other VHF
Serology, antigen, PCR
Infectious mononucleosis-like
Serology, PCR
syndromes
HIV (acute retroviral syndrome)
Serology, antigen
Hepatitis viruses
Serology, antigen, PCR
Parasitic, malaria, trypanosomiasis
Blood film, antigen test, PCR
(PCR = polymerase chain reaction; VHF =
viral haemorrhagic fever)
Investigations and management
Initial investigations should start with blood films for malaria
parasites, FBC, urinalysis and chest X-ray if indicated. Box 11.19
lists diagnoses and investigations to consider in unexplained
acute fever.
Management is directed at the underlying cause. In patients
with suspected VHF (p. 245), strict infection control measures
with isolation and barrier nursing are implemented to prevent
contact with the patient’s body fluids. The risk of VHF should be
determined using epidemiological risk factors and clinical signs
(Fig. 1 1 .6), and further management undertaken as described
on page 246.
Diarrhoea acquired in the tropics
Gastrointestinal illness is the most common infection amongst
visitors to the tropics, with Salmonella spp., Campylobacter spp.
and Cryptosporidium spp. infections prevalent worldwide (Box
1 1 .20). Shigella spp. and Entamoeba histolytica (amoebiasis)
are usually encountered in visitors to or residents of the Indian
subcontinent or sub-Saharan and southern Africa.
The approach to patients with acute diarrhoea is described
on page 227. The benefits of treating travellers’ diarrhoea
with antimicrobials are marginal, with slight reductions in stool
1 1 1 .20 Most common causes of travellers’ diarrhoea
• Enterotoxigenic E coli
• Salmonella serovars
(ETEC)
• Plesiomonas shigelloides
• Shigella spp.
• Non-cholera Vibrio spp.
• Campylobacter jejuni
• Aeromonas spp.
Presenting problems in infectious diseases • 233
frequency and likelihood of cure at 72 hours offset by increased
side-effects. The differential diagnosis of diarrhoea persisting for
more than 14 days is wide (see Box 21.18, p. 784). Parasitic
and bacterial causes, tropical malabsorption, inflammatory bowel
disease and neoplasia should all be considered. Box 1 1 .21 lists
causes encountered particularly in visitors to or residents of the
tropics. The workup should include tests for parasitic causes of
chronic diarrhoea, such as examination of stool and duodenal
aspirates for ova and parasites, and serological investigation.
Tropical sprue is a malabsorption syndrome (p. 807) with
no defined aetiology. It was typically associated with a long
period of residence in the tropics or with overland travel but
is now rarely seen. Giardia lamblia infection may progress to a
malabsorption syndrome that mimics tropical sprue. If no cause
is found, empirical treatment for Giardia lamblia infection with
metronidazole is often helpful.
HIV-1 has now emerged as a major cause of chronic diarrhoea.
This may be due to HIV enteropathy or infection with agents
such as Cryptosporidium spp., Cystoisospora belli (syn. Isospora
belli) or microsporidia (p. 316). However, many other causes of
chronic AIDS-associated diarrhoea seen in the developed world
are less common in tropical settings, e.g. CMV or disseminated
Mycobacterium avium complex infections.
Bl 1 1 .21 Causes of chronic diarrhoea acquired
1 in the tropics
• Giardia lamblia
• Chronic intestinal
• Strongyloidiasis
schistosomiasis
• Enteropathic Escherichia coli
• Chronic calcific pancreatitis
• HIV enteropathy
• Hypolactasia (primary and
• Intestinal flukes
secondary)
• Tropical sprue
Eosinophilia acquired in the tropics
Eosinophilia occurs in a variety of haematological, allergic and
inflammatory conditions discussed on page 927. It may also arise
in HIV-1 and human T-cell lymphotropic virus (HTLV)-1 infection.
However, eosinophils are important in the immune response to
parasitic infections, in particular those involving parasites with a
tissue migration phase. In the context of travel to or residence
in the tropics, a patient with an eosinophil count of more than
0.4x109/L should be investigated for both non-parasitic (see
Box 23.9, p. 926) and parasitic causes (Box 1 1 .22).
The response to parasite infections is often different when
travellers to and residents of endemic areas are compared.
Travellers often have recent and light infections associated with
eosinophilia. Residents have often been infected for a long time,
have evidence of chronic pathology and no longer have eosinophilia.
Clinical assessment
A history of travel to known endemic areas for schistosomiasis,
onchocerciasis and the filariases will indicate possible causes.
Assessment should establish how long patients have spent in
endemic areas and the history should address all the elements
in Box 11.16.
Physical signs or symptoms that suggest a parasitic cause
for eosinophilia include transient rashes (schistosomiasis or
strongyloidiasis), fever (Katayama syndrome; p. 295), pruritus
(onchocerciasis) or migrating subcutaneous swellings (loiasis,
gnathostomiasis) (see Box 11.22). Paragonimiasis can give
rise to haemoptysis, and the migratory phase of intestinal
nematodes or lymphatic filariasis may cause cough, wheezing and
transient pulmonary infiltrates. Schistosomiasis, strongyloidiasis
and gnathostomiasis induce transient respiratory symptoms
with infiltrates in the acute stages and, when eggs reach the
pulmonary vasculature in chronic schistosomiasis infection, can
1 1 1 .22 Parasite infections that cause eosinophilia
Infestation
Pathogen
Clinical syndrome with eosinophilia
Strongyloidiasis
Strongyloides stercoralis
Larva currens
Soil-transmitted helminthiases
Hookworm
Necator americanus
Anaemia
Ancylostoma duodenale
Anaemia
Ascariasis
Ascaris lumbricoides
Loffler’s syndrome
Toxocariasis
Toxocara cam's
Visceral larva migrans
Schistosomiasis
Schistosoma haematobium
Katayama fever
S. mansoni , S. japonicum
Chronic infection
Filariases
Loiasis
Loa loa
Skin nodules
Wuchereria bancrofti
W. bancrofti
Lymphangitis, lymphadenopathy, orchitis, intermittent bouts of cellulitis, lymphoedema
and elephantiasis
Brugia malayi
B. malayi
Brugian elephantiasis similar but typically less severe than that caused by W. bancrofti
Mansonella perstans
M. perstans
Asymptomatic infection, occasionally subconjunctival nodules
Onchocerciasis
Onchocerca volvulus
Visual disturbance, dermatitis
Other nematode infections
Trichinella spiralis
Myositis
Gnathostoma spinigerum
Pruritus, migratory nodules, eosinophilic meningitis
Cestode infections
Taenia saginata , T. solium
Usually asymptomatic; eosinophilia associated with migratory phase
Echinococcus granulosus
Lesions in liver or other organ; eosinophilia associated with leakage from cyst
Liver flukes
Fasciola hepatica
Hepatic symptoms; eosinophilia associated with migratory phase
Clonorchis sinensis
As for fascioliasis
Opisthorchis felineus
As for fascioliasis
Lung fluke
Paragonimus westermani
Lung lesions
234 • INFECTIOUS DISEASE
1 1 1 .24 Rash in tropical travellers/residents
Maculopapular rash
• Dengue
•
Spirillum minus
• HIV-1
•
Rickettsial infections
• Typhoid
•
Measles
Petechial or purpuric rash
• Viral haemorrhagic fevers
•
Leptospirosis
• Yellow fever
•
Rickettsial spotted fevers
• Meningococcal sepsis
•
Malaria
Vesicular rash
• Monkeypox
• Insect bites
•
Rickettsial pox
Urticarial rash
• Katayama fever
•
Strongyloides stercoralis
(schistosomiasis)
• Toxocara spp.
•
Fascioliasis
Ulcers
• Leishmaniasis
•
Tropical ulcer ( Fusobacterium
• Mycobacterium ulcerans
ulcerans and Treponema
(Buruli ulcer)
vincentii)
• Dracunculosis
•
Ecthyma (staphylococci,
• Anthrax
• Rickettsial eschar
streptococci)
Papules
• Scabies
•
Ringworm
• Insect bites
• Prickly heat
•
Onchocerciasis
Nodules or plaques
• Leprosy
•
Onchocerciasis
• Chromoblastomycosis
•
Myiasis (larvae of tumbu fly or
• Dimorphic fungi
botfly)
• Trypanosomiasis
Migratory linear rash
•
Tungiasis ( Tunga penetrans)
• Cutaneous larva migrans
•
Strongyloides stercoralis (larva
(CLM; dog hookworms)
currens, more rapid than CLM)
Migratory papules/nodules
• Loa loa
• Gnathostomiasis
•
Schistosomiasis
Thickened skin
• Mycetoma (acti nomycetoma/
•
Elephantiasis (filariasis)
eumycetoma)
11.23 Initial investigation of eosinophilia
Investigation
Pathogens sought
Stool microscopy
Ova, cysts and parasites
Terminal urine
Ova of Schistosoma haematobium
Duodenal aspirate
Filariform larvae of Strongyloides, liver
fluke ova
Day bloods
Microfilariae Brugia malayi, Loa loa
Night bloods
Microfilariae Wuchereria bancrofti
Skin snips
Onchocerca volvulus
Slit-lamp examination
Onchocerca volvulus
Serology
Schistosomiasis, filariasis, strongyloidiasis,
hydatid, trichinosis, gnathostomiasis etc.
result in shortness of breath with features of right heart failure
due to pulmonary hypertension. Fever and hepatosplenomegaly
are seen in schistosomiasis, Fasciola hepatica infection and
toxocariasis (visceral larva migrans). Intestinal worms, such
as Ascaris lumbricoides and Strongyloides stercoral is, can
cause abdominal symptoms, including intestinal obstruction
and diarrhoea. In the case of heavy infestation with Ascaris, this
may be due to fat malabsorption and there may be associated
nutritional deficits. Schistosoma haematobium can cause
haematuria or haematospermia. Toxocara spp. can give rise
to choroidal lesions with visual field defects. Angiostrongyius
cantonensis and gnathostomiasis induce eosinophilic meningitis,
and the hyperinfection syndrome caused by S. stercoralis in
immunocompromised hosts induces meningitis due to Gram¬
negative bacteria. Myositis is a feature of trichinosis (trichinellosis)
and cysticercosis, while periorbital oedema is found in trichinosis.
Investigations
The diagnosis of a parasitic infestation requires direct visualisation
of adult worms, larvae or ova. Serum antibody detection may not
distinguish between active and past infection and is often unhelpful
in those born in endemic areas. Radiological investigations may
provide circumstantial evidence of parasite infestation. Box 1 1 .23
describes initial investigations for eosinophilia.
Management
A specific diagnosis guides therapy. In the absence of a specific
diagnosis, many clinicians will give an empirical course of
praziquantel if the individual has potentially been exposed to
schistosomiasis, or with albendazole/ivermectin if strongyloidiasis
or intestinal nematodes are likely causes.
| Skin conditions acquired in the tropics
Community-based studies in the tropics consistently show that
skin infections (bacterial and fungal), scabies and eczema are the
most common skin problems (Box 1 1 .24). Scabies and eczema
are discussed on pages 1241 and 1244. Cutaneous leishmaniasis
and onchocerciasis have defined geographical distributions
(pp. 284 and 292). In travellers, secondarily infected insect bites,
pyoderma, cutaneous larva migrans and non-specific dermatitis
are common.
During the investigation of skin lesions, enquiry should be
made about habitation, activities undertaken and regions visited
(see Box 11.16). Examples of skin lesions in tropical disease
are shown in Figure 1 1 .7.
Skin biopsies are helpful in diagnosing aetiology. Culture of
biopsy material may be needed to diagnose bacterial, fungal,
parasitic and mycobacterial infections.
Infections in adolescence
Particular issues of relevance in adolescent patients are shown
in Box 1 1 .25.
Infections in pregnancy
Box 1 1 .26 shows some of the infections encountered in
pregnancy.
Presenting problems in infectious diseases • 235
Fig. 11.7 Examples of skin lesions in patients with fever
in the tropics. [A] Subcutaneous nodule due to botfly infection.
Ill Emerging larva after treatment with petroleum jelly. [C] Eschar
of scrub typhus. [D] Rat bite fever. A, B and D, Courtesy of
Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield.
C, Courtesy of Dr Rattanaphone Phetsouvanh, Mahosot
Hospital, Vientiane, PDR Laos.
11.25 Key issues in infectious diseases
in adolescence
• Common infectious syndromes: infectious mononucleosis,
bacterial pharyngitis, whooping cough, pneumonia, staphylococcal
skin/soft tissue infections, urinary tract infections, acute
gastroenteritis.
• Life-threatening infections: meningococcal infection (sepsis and /
or meningitis).
• Sexually transmitted infections: human papillomavirus (HP V),
HIV-1 , hepatitis B virus and chlamydia. These may reflect either
voluntary sexual activity or sexual coercion/abuse.
• Travel-related infections: diarrhoea, malaria etc. are relatively
common.
• Infections in susceptible groups: patients with cystic fibrosis,
congenital immunodeficiency, acute leukaemia and other adolescent
malignancies are vulnerable to specific groups of infections.
• Infections requiring prolonged antimicrobial use: adherence to
chronic therapy is challenging, for both oral (antituberculous or
antiretroviral) and systemic (osteomyelitis, septic arthritis or
post-operative infections) treatments. Outpatient antimicrobial
therapy is preferred to minimise hospitalisation.
• Vaccination: engagement with age-specific vaccine programmes
should be ensured, e.g. HPV, childhood booster vaccines and
meningococcal vaccine.
• Risk reduction: education relating to sexual health and alcohol and
recreational drug usage is important.
1 1 .26 Infections in pregnancy
Infection
Consequence
Prevention and management
Rubella
Congenital malformation
Childhood vaccination and vaccination of non-immune mothers
post-delivery
Cytomegalovirus
Neonatal infection, congenital malformation
Limited prevention strategies
Zika virus
Congenital malformation
Avoidance of travel, delay in pregnancy if infected
Varicella zoster virus
Neonatal infection, congenital malformation,
severe infection in mother
VZ immunoglobulin (see Box 11.31)
Herpes simplex virus (HSV)
Congenital or neonatal infection
Aciclovir and consideration of caesarean section for mothers
who shed HSV from genital tract at time of delivery. Aciclovir
for infected neonates
Hepatitis B virus
Chronic infection of neonate
Hepatitis B immunoglobulin and active vaccination of newborn
Hepatitis E virus
Fulminant hepatitis, pre-term delivery, fetal loss
Maintenance of standard food hygiene practices
HIV-1
Chronic infection of neonate
Antiretroviral drugs for mother and infant and consideration of
caesarean section if HIV-1 viral load detectable. Avoidance of
breastfeeding
Parvovirus B19
Congenital infection
Avoidance of individuals with acute infection if pregnant
Measles
More severe infection in mother and neonate,
fetal loss
Childhood vaccination, human normal immunoglobulin in
non-immune pregnant contacts and vaccination post-delivery
Dengue
Neonatal dengue if mother has infection <5
weeks prior to delivery
Vector (mosquito) control
Syphilis
Congenital malformation
Serological testing in pregnancy with prompt treatment of
infected mothers
Neisseria gonorrhoeae and
Chlamydia trachomatis
Neonatal conjunctivitis (ophthalmia neonatorum,
p. 340)
Treatment of infection in mother and neonate
Listeriosis
Neonatal meningitis or bacteraemia, bacteraemia
or pyrexia of unknown origin in mother
Avoidance of unpasteurised cheeses and other dietary sources
Brucellosis
Possibly increased incidence of fetal loss
Avoidance of unpasteurised dairy products
Group B streptococcal
infection
Neonatal meningitis and sepsis. Sepsis in
mother after delivery
Risk- or screening-based antimicrobial prophylaxis in labour
(recommendations vary between countries)
Toxoplasmosis
Congenital malformation
Diagnosis and prompt treatment of cases, avoidance of
under-cooked meat while pregnant
Malaria
Fetal loss, intrauterine growth retardation, severe
malaria in mother
Avoidance of insect bites. Intermittent preventative treatment
during pregnancy to decrease incidence in high-risk countries
236 • INFECTIOUS DISEASE
Viral infections
Systemic viral infections with exanthem
Childhood exanthems are characterised by fever and widespread
rash. Maternal antibody usually gives protection for the first 6-12
months of life. Comprehensive immunisation programmes have
dramatically reduced the number of paediatric infections but
incomplete uptake results in infections in later life.
|Measles
The WHO has set the objective of eradicating measles globally
using the live attenuated vaccine. However, vaccination of more
than 95% of the population is required to prevent outbreaks.
Natural illness produces life-long immunity.
Clinical features
Infection is by respiratory droplets with an incubation period of
6-19 days. A prodromal illness occurs, 1-3 days before the
rash, with upper respiratory symptoms, conjunctivitis and the
presence of the pathognomonic Koplik’s spots: small white
spots surrounded by erythema on the buccal mucosa (Fig.
1 1 .8A). As natural antibody develops, the maculopapular rash
appears, spreading from the face to the extremities (Fig. 1 1 .8B).
Generalised lymphadenopathy and diarrhoea are common.
Complications are more common in older children and adults,
and include otitis media, bacterial pneumonia, transient hepatitis,
pancreatitis and clinical encephalitis (approximately 0.1 % of cases).
A rare late complication is subacute sclerosing panencephalitis
(SSPE), which occurs up to 7 years after infection. Diagnosis
is clinical (although this has become unreliable in areas where
measles is no longer common) and by detection of antibody
(serum immunoglobulin M (IgM), seroconversion or salivary IgM).
Measles is a serious disease in the malnourished, vitamin-
deficient or immunocompromised, in whom the typical rash may
be missing and persistent infection with a giant cell pneumonitis
or encephalitis may occur. In tuberculosis infection, measles
suppresses cell-mediated immunity and may exacerbate disease;
for this reason, measles vaccination should be deferred until
after commencing antituberculous treatment. Measles does
not cause congenital malformation but may be more severe in
pregnant women.
Mortality clusters at the extremes of age, averaging 1 : 1000
in developed countries and up to 1 :4 in developing countries.
Death usually results from a bacterial superinfection, occurring
as a complication of measles: most often pneumonia, diarrhoeal
disease or noma/cancrum oris, a gangrenous stomatitis. Death
may also result from complications of measles encephalitis.
Management and prevention
Normal immunoglobulin attenuates the disease in the
immunocompromised (regardless of vaccination status) and in
non-immune pregnant women, but must be given within 6 days
of exposure. Vaccination can be used in outbreaks and vitamin
A may improve the outcome in uncomplicated disease. Antibiotic
therapy is reserved for bacterial complications. All children aged
1 2-1 5 months should receive measles vaccination (as combined
measles, mumps and rubella (MMR), a live attenuated vaccine),
and a further MMR dose at age 4 years.
| Rubella (German measles)
Rubella causes exanthem in the non-immunised.
Clinical features
Rubella is spread by respiratory droplet, with infectivity from up to 1 0
days before to 2 weeks after the onset of the rash. The incubation
period is 15-20 days. In childhood, most cases are subclinical,
although clinical features may include fever, maculopapular rash
spreading from the face, and lymphadenopathy. Complications
are rare but include thrombocytopenia and hepatitis. Encephalitis
and haemorrhage are occasionally reported. In adults, arthritis
involving hands or knees is relatively common, especially in
women.
If transplacental infection takes place in the first trimester
or later, persistence of the virus is likely and severe congenital
disease may result (Box 1 1 .27). Even if normal at birth, the infant
has an increased incidence of other diseases developing later,
e.g. diabetes mellitus.
Diagnosis
Laboratory confirmation of rubella is required if there has been
contact with a pregnant woman. This is achieved either by
detection of rubella IgM in serum or by IgG seroconversion. In
the exposed pregnant woman, absence of rubella-specific IgG
confirms the potential for congenital infection.
Prevention
All children should be immunised with MMR vaccine. Congenital
rubella syndrome may be controlled by testing women of child¬
bearing age for rubella antibodies and offering vaccination if
seronegative. Antenatal rubella screening was offered to pregnant
mothers in the UK for many years for this reason. However, this
Fig. 11.8 Measles. [A] Koplik’s spots (arrows) seen on buccal mucosa in the early stages of clinical measles. [B] Typical measles rash.
Viral infections • 237
I?tjj 11.27 Rubella infection: risk of
congenital malformation
Stage of
gestation
Likelihood of malformations
1-2
months
65-85% chance of illness, multiple defects/
spontaneous abortion
3 months
30-35% chance of illness, usually a single congenital
defect (most frequently deafness, cataract, glaucoma,
mental retardation or congenital heart disease,
especially pulmonary stenosis or patent ductus
arteriosus)
4 months
10% risk of congenital defects, most commonly
deafness
>20 weeks
Occasional deafness
practice ceased in 201 6 because: rubella is so rare in the UK as
to be considered eliminated; pre-pregnancy MMR vaccination is
considered to be a more effective method of protecting pregnant
women; and the screening test may give inaccurate results,
causing unnecessary stress to pregnant women.
Parvovirus B19
Parvovirus B1 9 causes exanthem and other clinical syndromes.
Some 50% of children and 60-90% of adults are seropositive.
Most infections are spread by the respiratory route, although
spread via contaminated blood is also possible. The virus has
particular tropism for red cell precursors.
Clinical features
Many infections are subclinical. Clinical manifestations result
after an incubation period of 14-21 days (Box 11.28). The
classic exanthem (erythema infectiosum) is preceded by a
prodromal fever and coryzal symptoms. A ‘slapped cheek’
rash is characteristic but the rash is very variable (Fig. 1 1 .9). In
adults, polyarthropathy is common. Infected individuals have a
transient block in erythropoiesis for a few days, which is of no
clinical consequence, except in individuals with increased red
cell turnover due to haemoglobinopathy or haemolytic anaemia.
These individuals develop an acute anaemia that may be severe
(transient aplastic crisis; p. 968). Erythropoiesis usually recovers
spontaneously after 1 0-1 4 days. Immunocompromised individuals,
including those with congenital immunodeficiency or AIDS, can
develop a more sustained block in erythropoiesis in response to
the chronic viraemia that results from their inability to clear the
infection. Infection during the first two trimesters of pregnancy
can result in intrauterine infection and impact on fetal bone
marrow; it causes 10-15% of non-immune (non-Rhesus-related)
hydrops fetalis, a rare complication of pregnancy.
Diagnosis
IgM to parvovirus B19 suggests recent infection but may persist
for months and false positives occur. Seroconversion to IgG
positivity confirms infection but in isolation a positive IgG is of
little diagnostic utility. Detection of parvovirus B19 DNA in blood
is particularly useful in immunocompromised patients. Giant
pronormoblasts or haemophagocytosis may be demonstrable
in the bone marrow.
Management
Infection is usually self-limiting. Symptomatic relief for arthritic
symptoms may be required. Severe anaemia requires transfusion.
1 1 .28 Clinical features of parvovirus B19 infection
Affected age group Clinical manifestations
Fifth disease (erythema infectiosum)
Small children Three clinical stages: a ‘slapped cheek’
appearance, followed by a maculopapular
rash progressing to a reticulate eruption on
the body and limbs, then a final stage of
resolution. Often the child is quite well
throughout
Gloves and socks syndrome
Young adults Fever and an acral purpuric eruption with a
clear margin at the wrists and ankles.
Mucosal involvement also occurs
Arthropathies
Adults and occasionally Symmetrical small-joint polyarthropathy. In
children children it tends to involve the larger joints
in an asymmetrical distribution
Impaired erythropoiesis
Adults, those with Mild anaemia; in an individual with an
haematological disease, underlying haematological abnormality it
the immunosuppressed can precipitate transient aplastic crisis, or
in the immunocompromised a more
sustained but often milder pure red cell
aplasia
Hydrops fetalis
Transplacental fetal Asymptomatic or symptomatic maternal
infection infection that can cause fetal anaemia with
an aplastic crisis, leading to non-immune
hydrops fetalis and spontaneous abortion
Fig. 11.9 Slapped cheek syndrome. The typical facial rash of parvovirus
B19 infection.
Persistent viraemia in immunocompromised hosts may require
immunoglobulin therapy to clear the virus.
Pregnant women should avoid contact with cases of parvovirus
B19 infection; if they are exposed, serology should be performed
to establish whether they are non-immune.
Passive prophylaxis with normal immunoglobulin has been
suggested for non-immune pregnant women exposed to infection
but there are limited data to support this recommendation.
The pregnancy should be closely monitored by ultrasound
scanning, so that hydrops fetalis can be treated by fetal
transfusion.
238 • INFECTIOUS DISEASE
Human herpesvirus 6 and 7
Human herpesvirus 6 (HHV-6) is a lymphotropic virus that causes
a childhood viral exanthem (exanthem subitum), rare cases of
an infectious mononucleosis-like syndrome and infection in the
immunocompromised host. Infection is almost universal, with
approximately 95% of children acquiring this virus by 2 years
of age. Transmission is via saliva.
11.29 Herpesvirus infections
Virus
Infection
Herpes simplex virus (HSV)
HSV-1 (p. 247)
HSV-2 (p. 247)
Herpes labialis (‘cold sores’)
Stomatitis, pharyngitis
Corneal ulceration
Finger infections (‘whitlows’)
Eczema herpeticum
Encephalitis
Genital ulceration and neonatal infection
(acquired during vaginal delivery)
Acute meningitis or transverse myelitis;
rarely, encephalitis
Varicella zoster virus
(VZV)
Chickenpox (varicella)
Shingles (herpes zoster)
Cytomegalovirus (CMV)
(p. 242)
Congenital infection
Infectious mononucleosis (heterophile
antibody- negative)
Hepatitis
Disease in immunocompromised patients:
retinitis, encephalitis, pneumonitis,
hepatitis, enteritis
Fever with abnormalities in
haematological parameters
Epstein— Barr virus
(EBV) (p. 241)
Infectious mononucleosis
Burkitt’s and other lymphomas
Nasopharyngeal carcinoma
Oral hairy leucoplakia (AIDS patients)
Other lymphomas, post-transplant
lymphoproliferative disorder (p. 225)
Human herpesvirus 6
and 7 (HHV-6, HHV-7)
Exanthem subitum
Disease in immunocompromised patients
Human herpesvirus 8
(HHV-8) (p. 248)
Kaposi’s sarcoma, primary effusion
lymphoma, multicentric Castleman’s
disease
HHV-7 is very closely related to HHV-6 and is believed to be
responsible for a proportion of cases of exanthem subitum. Like
HHV-6, HHV-7 causes an almost universal infection in childhood,
with subsequent latent infection and occasional infection in the
immunocompromised host.
Clinical features
Exanthem subitum is also known as roseola infantum or sixth
disease (Box 1 1 .29). A high fever is followed by a maculopapular
rash as the fever resolves. Fever and/or febrile convulsions may
also occur without a rash. Rarely, older children or adults may
develop an infectious mononucleosis-like illness, hepatitis or
rash. In the immunocompromised, infection is rare but can cause
fever, rash, hepatitis, pneumonitis, cytopenia or encephalitis.
Diagnosis and management
Exanthem subitum is usually a clinical diagnosis but can be
confirmed by antibody and/or DNA detection. The disease is
self-limiting. Treatment with ganciclovir or foscarnet is used in
immunocompromised hosts infected with HHV-6.
Chickenpox (varicella)
Varicella zoster virus (VZV) is a dermotropic and neurotropic
virus that produces primary infection, usually in childhood, which
may reactivate in later life. VZV is spread by aerosol and direct
contact. It is highly infectious to non-immune individuals. Disease
in children is usually well tolerated. Manifestations are more
severe in adults, pregnant women and the immunocompromised.
Clinical features
The incubation period is 11-20 days, after which a vesicular
eruption begins (Fig. 11.10), often on mucosal surfaces first,
followed by rapid dissemination in a centripetal distribution
(most dense on trunk and sparse on limbs). New lesions occur
every 2-4 days and each crop is associated with fever. The rash
progresses from small pink macules to vesicles and pustules
within 24 hours. Infectivity lasts from up to 4 days (but usually
48 hours) before the lesions appear until the last vesicles crust
over. Due to intense itching, secondary bacterial infection
from scratching is the most common complication of primary
chickenpox. Self-limiting cerebellar ataxia and encephalitis are
rare complications.
Adults, pregnant women and the immunocompromised are
at increased risk of visceral involvement, which presents as
pneumonitis, hepatitis or encephalitis. Pneumonitis can be fatal
and is more likely to occur in smokers. Maternal infection in
Fig. 11.10 Varicella zoster virus infection. [A] Chickenpox. |W] Shingles in a thoracic dermatome.
Viral infections • 239
early pregnancy carries a 3% risk of neonatal damage with
developmental abnormalities of eyes, CNS and limbs. Chickenpox
within 5 days of delivery leads to severe neonatal varicella with
visceral involvement and haemorrhage.
Diagnosis
Diagnosis is primarily clinical, by recognition of the rash. If
necessary, this can be confirmed by detection of antigen (direct
immunofluorescence) or DNA (PCR) of aspirated vesicular fluid.
Serology is used to identify seronegative individuals at risk of
infection.
Management and prevention
The benefits of antivirals for uncomplicated primary VZV infection
in children are marginal, shortening the duration of rash by
only 1 day, and treatment is not normally required. Antivirals
are, however, used for uncomplicated chickenpox in adults
when the patient presents within 24-48 hours of onset of
vesicles, in all patients with complications, and in those who are
immunocompromised, including pregnant women, regardless of
duration of vesicles (Box 1 1 .30). More severe disease, particularly
in immunocompromised hosts, requires initial parenteral therapy.
Immunocompromised patients may have prolonged viral shedding
and may require prolonged treatment until all lesions crust over.
Human VZ immunoglobulin (VZIG) is used to attenuate
infection in people who have had significant contact with VZV,
are susceptible to infection (i.e. have no history of chickenpox or
shingles and are seronegative for VZV IgG) and are at risk of severe
disease (e.g. immunocompromised or pregnant) (Box 11.31).
Ideally, VZIG should be given within 7 days of exposure, but it
may attenuate disease even if given up to 10 days afterwards.
Susceptible contacts who develop severe chickenpox after
receiving VZIG should be treated with aciclovir.
A live, attenuated VZV vaccine is available and in routine use
in the USA and other countries, but in the UK its use has been
restricted to non-immune health-care workers and household
contacts of immunocompromised individuals. Children receive
one dose after 1 year of age and a second dose at 4-6 years
of age; seronegative adults receive two doses at least 1 month
apart. The vaccine may also be used prior to planned iatrogenic
immunosuppression, e.g. before transplant and for the elderly
aged over 70 to prevent shingles.
| Shingles (herpes zoster)
After initial infection, VZV persists in latent form in the dorsal
root ganglion of sensory nerves and can reactivate in later life.
Clinical features
Burning discomfort occurs in the affected dermatome following
reactivation and discrete vesicles appear 3-4 days later. This
is associated with a brief viraemia, which can produce distant
satellite ‘chickenpox’ lesions. Occasionally, paraesthesia occurs
without rash (‘zoster sine herpete’). Severe disease, a prolonged
duration of rash, multiple dermatomal involvement or recurrence
suggests underlying immune deficiency, including HIV. Chickenpox
may be contracted from a case of shingles but not vice versa.
Although thoracic dermatomes are most commonly involved
(Fig. 1 1 .10B), the ophthalmic division of the trigeminal nerve is
also frequently affected; vesicles may appear on the cornea
and lead to ulceration. This condition can lead to blindness and
urgent ophthalmology review is required. Geniculate ganglion
involvement causes the Ramsay Hunt syndrome of facial palsy,
^9 11.30 Therapy for herpes simplex and
varicella zoster virus infection
Disease state
Treatment options
Primary genital HSV
Famciclovir 250 mg 3 times daily for
7-1 0 days
Valaciclovir 1 g twice daily for 7-10 days
Oral aciclovir 200 mg 5 times daily or
400 mg 3 times daily for 7-1 0 days
Severe and preventing
oral intake
Aciclovir 5 mg/kg 3 times daily IV until
patient can tolerate oral therapy
Recurrent genital
HSV-1 or 2
Oral aciclovir 200 mg 5 times daily or
400 mg 3 times daily for 5 days
Famciclovir 125 mg twice daily for
5 days
Valaciclovir 500 mg twice daily for
3-5 days or 2 g twice daily for 1 day.
Shorter durations increasingly favoured
Primary or recurrent
oral HSV
Usually no treatment
If required, usually short duration, e.g.
valaciclovir 2 g twice daily for 1 day
Mucocutaneous
HSV infection in
immunocompromised
host
Aciclovir 5 mg/kg 3 times daily IV for
7-1 0 days
Oral aciclovir 400 mg 4 times daily for
7-1 0 days
Famciclovir 500 mg 3 times daily for
7-1 0 days
Valaciclovir 1 g twice daily for 7-1 0 days
Chickenpox in adult or
child
Oral aciclovir 800 mg 5 times daily for
5 days
Famciclovir 500 mg 3 times daily for
5 days
Valaciclovir 1 g 3 times daily for 5 days
Immunocompromised
host/pregnant woman
Aciclovir 5 mg/kg 3 times daily IV until
patient is improving, then complete
therapy with oral therapy until all lesions
are crusting over
Shingles
Treatment and doses as for chickenpox
but duration typically 7-1 0 days
Visceral involvement
(non-CNS) in HSV
Aciclovir IV 5 mg/kg 3 times daily for
1 4 days
Visceral involvement
(non-CNS) in VZV
Aciclovir IV 5 mg/kg 3 times daily for
7 days
Severe complications
(encephalitis,
disseminated infection)
Aciclovir IV 1 0 mg/kg 3 times daily (up to
20 mg/kg in neonates) for 14-21 days
HSV disease
suppression
Aciclovir 400 mg twice daily
Famciclovir 250 mg twice daily
Valaciclovir 500 mg daily
(CNS = central nervous system; HSV = herpes simplex virus; VZV = varicella
zoster virus)
ipsilateral loss of taste and buccal ulceration, plus a rash in
the external auditory canal. This may be mistaken for Bell’s
palsy (p. 1082). Bowel and bladder dysfunction occur with
sacral nerve root involvement. The virus occasionally causes
cranial nerve palsy, myelitis or encephalitis. Granulomatous
cerebral angiitis is a cerebrovascular complication that leads to
a stroke-like syndrome in association with shingles, especially
in an ophthalmic distribution.
Post-herpetic neuralgia causes troublesome persistence of
pain for 1-6 months or longer, following healing of the rash. It
is more common with advanced age.
240 • INFECTIOUS DISEASE
1 1 .31 Indications for varicella zoster immunoglobulin
(VZIG) in adults
An adult should satisfy all three of the following conditions:
1. Significant contact
Contact with chickenpox (any time from 48 hrs before the rash until
crusting of lesions) or zoster (exposed, disseminated or, with
immunocompromised contacts, localised zoster; between development
of the rash until crusting) defined as:
• Prolonged household contact, sharing a room for >15 mins or
face-to-face contact (includes direct contact with zoster lesions)
• Hospital contact with chickenpox in another patient, health-care
worker or visitor
• Intimate contact (e.g. touching) with person with shingles lesions
• Newborn whose mother develops chickenpox no more than 5 days
before delivery or 2 days after delivery
2. Susceptible contact
• Individual with no history of chickenpox, ideally confirmed by
negative test for VZV IgG
3. Predisposition to severe chickenpox
• Immunocompromised due to disease (e.g. acute leukaemia, HIV,
other primary or secondary immunodeficiency)
• Medically immunosuppressed (e.g. following solid organ transplant;
current or recent (<6 months) cytotoxic chemotherapy or
radiotherapy; current or recent (<3 months) high-dose
glucocorticoids; haematopoietic stem cell transplant)
• Pregnant (any stage)
• Infants: newborn whose mother has had chickenpox as above;
premature infants <28 weeks
Management
Early therapy with aciclovir or related agents has been shown
to reduce both early- and late-onset pain, especially in patients
over 65 years. Post-herpetic neuralgia requires aggressive
analgesia, along with agents such as amitriptyline 25-100 mg
daily, gabapentin (commencing at 300 mg daily and building
slowly to 300 mg twice daily or more) or pregabalin (commencing
at 75 mg twice daily and building up to 100 mg or 200 mg
3 times daily if tolerated). Capsaicin cream (0.075%) may be
helpful. Although controversial, glucocorticoids have not been
demonstrated to reduce post-herpetic neuralgia to date.
Enteroviral exanthems
Coxsackie or echovirus infections can lead to a maculopapular
eruption or roseola-like rash that occurs after fever falls. Enteroviral
infections are discussed further under viral infections of the skin
(see below).
Systemic viral infections without exanthem
Other systemic viral infections present with features other than
a rash suggestive of exanthem. Rashes may occur in these
conditions but differ from those seen in exanthems or are not
the primary presenting feature.
| Mumps
Mumps is a systemic viral infection characterised by swelling of
the parotid glands. Infection is endemic worldwide and peaks
at 5-9 years of age. Vaccination has reduced the incidence in
children but incomplete coverage and waning immunity with
Fig. 11.11 Typical unilateral mumps, [ft] Note the loss of angle of the
jaw on the affected (right) side. [8] Comparison showing normal (left) side.
time have led to outbreaks in young adults. Infection is spread
by respiratory droplets.
Clinical features
The median incubation period is 1 9 days, with a range of 1 5-24
days. Classical tender parotid enlargement, which is bilateral
in 75%, follows a prodrome of pyrexia and headache (Fig.
11.11). Meningitis complicates up to 10% of cases. The CSF
reveals a lymphocytic pleocytosis or, less commonly, neutrophils.
Rare complications include encephalitis, transient hearing loss,
labyrinthitis, electrocardiographic abnormalities, pancreatitis
and arthritis.
Approximately 25% of post-pubertal males with mumps
develop epididymo-orchitis but, although testicular atrophy occurs,
sterility is unlikely. Oophoritis is less common. Abortion may
occur if infection takes place in the first trimester of pregnancy.
Complications may occur in the absence of parotitis.
Diagnosis
The diagnosis is usually clinical. In atypical presentations without
parotitis, serology for mumps-specific IgM or IgG seroconversion
(fourfold rise in IgG convalescent titre) confirms the diagnosis.
Virus can also be cultured from urine in the first week of infection
or detected by PCR in urine, saliva or CSF.
Management and prevention
Treatment is with analgesia. There is no evidence that
glucocorticoids are of value for orchitis. Mumps vaccine is one
of the components of the combined MMR vaccine.
Influenza
Influenza is an acute systemic viral infection that primarily affects
the respiratory tract and carries a significant mortality. It is
caused by influenza A virus or, in milder form, influenza B virus.
Infection is seasonal, and variation in the haemagglutinin (H)
and neuraminidase (N) glycoproteins on the surface of the
virus leads to disease of variable intensity each year. Minor
changes in haemagglutinin are known as ‘genetic drift’, whereas
a switch in the haemagglutinin or neuraminidase antigen is termed
‘genetic shift’. Nomenclature of influenza strains is based on
these glycoproteins, e.g. HI N1 , H3N2 etc. Genetic shift results
in the circulation of a new influenza strain within a community to
Viral infections • 241
which few people are immune, potentially initiating an influenza
epidemic or pandemic in which there is a high attack rate and
there may be increased disease severity.
Clinical features
After an incubation period of 1-3 days, uncomplicated disease
leads to fever, malaise and cough. Viral pneumonia may occur,
although pulmonary complications are most often due to
superinfection with Strep, pneumoniae, Staph, aureus or other
bacteria. Rare extrapulmonary manifestations include myositis,
myocarditis, pericarditis and neurological complications (Reye’s
syndrome in children, encephalitis or transverse myelitis). Mortality
is greatest in the elderly, those with medical comorbidities and
pregnant women. Polymorphisms in the gene encoding an
antiviral protein, interferon-induced transmembrane protein 3
(IFITM3), are associated with more severe influenza.
Diagnosis
Acute infection is diagnosed by viral antigen or RNA detection in
a nasopharyngeal sample. The disease may also be diagnosed
retrospectively by serology.
Management and prevention
Management involves early microbiological identification of
cases and good infection control, with an emphasis on hand
hygiene and preventing dissemination of infection by coughing
and sneezing. Administration of neuraminidase inhibitor, oral
oseltamivir (75 mg twice daily) or inhaled zanamivir (10 mg
twice daily) for 5 days, can reduce the severity of symptoms if
started within 48 hours of symptom onset (or possibly later in
immunocompromised individuals). These agents have superseded
routine use of amantadine and rimantadine. Antiviral drugs can
also be used as prophylaxis in high-risk individuals during the
‘flu’ season. Resistance can emerge to all of these agents and
so updated local advice should be followed with regard to the
sensitivity to antivirals of the circulating strain.
Prevention relies on seasonal vaccination of the elderly, children
2-7 years of age and individuals with chronic medical illnesses that
place them at increased risk of the complications of influenza, such
as chronic cardiopulmonary diseases or immune compromise,
as well as their health-care workers. The vaccine composition
changes each year to cover the ‘predicted’ seasonal strains
but vaccination may fail when a new pandemic strain emerges.
Avian influenza
Avian influenza is caused by transmission of avian influenza
A viruses to humans. Avian viruses, such as H5N1, possess
alternative haemagglutinin antigens to seasonal influenza strains.
Most cases have had contact with sick poultry, predominantly in
South-east Asia, and person-to-person spread has been limited
to date. Infections with H5N1 viruses have been severe, with
enteric features and respiratory failure. Treatment depends on
the resistance pattern but often involves oseltamivir. Vaccination
against seasonal ‘flu’ does not adequately protect against avian
influenza. There is a concern that adaptation of an avian strain
to allow effective person-to-person transmission is likely to lead
to a global pandemic of life-threatening influenza.
Swine influenza
Re-assortment of swine, avian and human influenza strains can
occur in pigs and lead to outbreaks of swine ‘flu’ in humans, as
occurred in 2009, when an outbreak of HI N1 pdm2009 influenza
spread around the world from Mexico. Cases were still occurring
in the Indian subcontinent in 2014-16. Symptoms included more
gastrointestinal symptoms than with seasonal influenza, respiratory
failure and seizures or encephalitis. Severe disease was a feature
of infants, adults less than 50 years, those with chronic lung
or neurological disease, obese patients and pregnant women,
but with time the clinical features have become indistinguishable
from those of seasonal influenza.
I Infectious mononucleosis and
Epstein-Barr virus
Infectious mononucleosis (IM) is a clinical syndrome characterised
by pharyngitis, cervical lymphadenopathy, fever and lymphocytosis
(known colloquially as glandular fever). It is most often caused
by Epstein-Barr virus (EBV) but other infections can produce a
similar clinical syndrome (Box 1 1 .32).
EBV is a gamma herpesvirus. In developing countries,
subclinical infection in childhood is virtually universal. In developed
countries, primary infection may be delayed until adolescence
or early adult life. Under these circumstances, about 50% of
infections result in typical IM. The virus is usually acquired from
asymptomatic excreters via saliva, either by droplet infection or
environmental contamination in childhood, or by kissing among
adolescents and adults. EBV is not highly contagious and isolation
of cases is unnecessary.
Clinical features
EBV infection has a prolonged but undetermined incubation
period, followed in some cases by a prodrome of fever, headache
and malaise. This is followed by IM with severe pharyngitis, which
may include tonsillar exudates and non-tender anterior and
posterior cervical lymphadenopathy. Palatal petechiae, periorbital
oedema, splenomegaly, inguinal or axillary lymphadenopathy, and
macular, petechial or erythema multiforme rashes may occur. In
most cases, fever resolves over 2 weeks, and fatigue and other
abnormalities settle over a further few weeks. Complications
are listed in Box 1 1 .33. Death is rare but can occur due to
respiratory obstruction, haemorrhage from splenic rupture,
thrombocytopenia or encephalitis.
The diagnosis of EBV infection outside the usual age in
adolescence and young adulthood is more challenging. In
children under 10 years the illness is mild and short-lived, but
in adults over 30 years of age it can be severe and prolonged.
In both groups, pharyngeal symptoms are often absent. EBV
may present with jaundice, as a PUO or with a complication.
Long-term complications of EBV infection
Lymphoma complicates EBV infection in immunocompromised
hosts, and some forms of Hodgkin lymphoma are EBV-associated
(p. 961). The endemic form of Burkitt’s lymphoma complicates
EBV infection in areas of sub-Saharan Africa where falciparum
malaria is endemic. Nasopharyngeal carcinoma is a geographically
restricted tumour seen in China and Alaska that is associated with
EBV infection. X-linked lymphoproliferative (Duncan’s) syndrome
is a familial lymphoproliferative disorder that follows primary EBV
infection in boys without any other history of immunodeficiency;
i
• Epstein-Barr virus infection • HIV-1 primary infection (p. 311)
• Cytomegalovirus • Toxoplasmosis
• Human herpesvirus-6 or 7
1 1 .32 Causes of infectious mononucleosis syndrome
242 • INFECTIOUS DISEASE
it is due to mutation of the SAP gene, causing failure of T-cell
and NK-cell activation and inability to contain EBV infection.
Investigations
Atypical lymphocytes are common in EBV infection but also occur
in other causes of IM, acute retroviral syndrome with HIV infection,
viral hepatitis, mumps and rubella (Fig. 1 1 .12A). They are also a
feature of dengue, malaria and other geographically restricted
infections (see Box 11.19). A ‘heterophile’ antibody is present
during the acute illness and convalescence, which is detected by
the Paul-Bunnell or ‘Monospot’ test. (A heterophile antibody is
an antibody that has affinity for antigens other than the specific
one, in this case animal immunoglobulins; the Paul-Bunnell
and Monospot tests exploit this feature by detecting the ability
1 1 .33 Complications of Epstein-Barr virus infection
Common
• Severe pharyngeal oedema
• Prolonged post-viral fatigue
• Antibiotic-induced rash
(10%)
(80-90% with ampicillin)
• Jaundice (< 10%)
• Hepatitis (80%)
Uncommon
Neurological
• Cranial nerve palsies
• Transverse myelitis
• Polyneuritis
• Meningoencephalitis
Haematological
• Haemolytic anaemia
• Thrombocytopenia
Renal
• Abnormalities on urinalysis
• Interstitial nephritis
Cardiac
• Myocarditis
• Pericarditis
• ECG abnormalities
Rare
• Ruptured spleen
• X-linked lymphoproliferative
• Respiratory obstruction
syndrome
• Agranulocytosis
EBV-associated malignancy
• Nasopharyngeal carcinoma
• Primary CNS lymphoma
• Burkitt’s lymphoma
• Lymphoproliferative disease in
• Hodgkin lymphoma (certain
immunocompromised
subtypes only)
of test serum to agglutinate sheep and horse red blood cells,
respectively.). Sometimes antibody production is delayed, so an
initially negative test should be repeated. However, many children
and 10% of adolescents with IM do not produce heterophile
antibody at any stage.
Specific EBV serology confirms the diagnosis. Acute infection is
characterised by IgM antibodies against the viral capsid, antibodies
to EBV early antigen and the initial absence of antibodies to EBV
nuclear antigen (anti-EBNA). Seroconversion of anti-EBNA at
approximately 1 month after the initial illness may confirm the
diagnosis in retrospect. CNS infections may be diagnosed by
detection of viral DNA in CSF.
Management
Treatment is largely symptomatic. If a throat culture yields
a p-haemolytic streptococcus, penicillin should be given.
Administration of ampicillin or amoxicillin in this condition
commonly causes an itchy macular rash and should be avoided
(Fig. 1 1 .12B). When pharyngeal oedema is severe, a short course
of glucocorticoids, e.g. prednisolone 30 mg daily for 5 days,
may help. Current antiviral drugs are not active against EBV.
Return to work or school is governed by physical fitness rather
than laboratory tests; contact sports should be avoided until
splenomegaly has resolved because of the danger of splenic
rupture. Unfortunately, about 10% of patients with IM suffer a
chronic relapsing syndrome.
Cytomegalovirus
Cytomegalovirus (CMV), like EBV, circulates readily among
children. A second period of virus acquisition occurs among
teenagers and young adults, peaking between the ages of 25
and 35 years, rather later than with EBV infection. CMV infection
is persistent, and is characterised by subclinical cycles of active
virus replication and by persistent low-level virus shedding.
Most post-childhood infections are therefore acquired from
asymptomatic excreters who shed virus in saliva, urine, semen
and genital secretions. Sexual transmission and oral spread are
common among adults but infection may also be acquired by
women caring for children with asymptomatic infections.
Clinical features
Most post-childhood CMV infections are subclinical, although
some young adults develop an IM-like syndrome and some have
a prolonged influenza-like illness lasting 2 weeks or more. Physical
signs resemble those of IM but in CMV infections hepatomegaly is
Fig. 11.12 Features of infectious mononucleosis. [A] Atypical lymphocytes in peripheral blood. [§] Skin reaction to ampicillin.
Viral infections • 243
more common, while lymphadenopathy, splenomegaly, pharyngitis
and tonsillitis occur less often. Jaundice is uncommon and usually
mild. Complications include meningoencephalitis, Guillain-Barre
syndrome, autoimmune haemolytic anaemia, thrombocytopenia,
myocarditis and skin eruptions, such as ampicillin-induced rash.
Immunocompromised patients can develop hepatitis, oesophagitis,
colitis, pneumonitis, retinitis, encephalitis and polyradiculitis.
Women who develop a primary CMV infection during pregnancy
have about a 40% chance of passing CMV to the fetus, causing
congenital infection and disease at any stage of gestation. Features
include petechial rashes, hepatosplenomegaly and jaundice; 1 0%
of infected infants will have long-term CNS sequelae, such as
microcephaly, cerebral calcifications, chorioretinitis and deafness.
Infections in the newborn usually are asymptomatic or have
features of an IM-like illness, although some studies suggest
that subtle sequelae affecting hearing or mental development
may occur.
Investigations
Atypical lymphocytosis is not as prominent as in EBV infection
and heterophile antibody tests are usually negative. LFTs are
often abnormal, with an alkaline phosphatase level raised out of
proportion to transaminases. Serological diagnosis depends on
the detection of CMV-specific IgM antibody plus a fourfold rise
or seroconversion of IgG. In the immunocompromised, antibody
detection is unreliable and detection of CMV in an involved organ
by PCR, antigen detection, culture or histopathology establishes
the diagnosis. Detection of CMV in the blood may be useful in
transplant populations but not in HIV-positive individuals, since
in HIV infection CMV reactivates at regular intervals, but these
episodes do not correlate well with episodes of clinical disease.
Detection of CMV in urine is not helpful in diagnosing infection,
except in neonates, since CMV is intermittently shed in the urine
throughout life following infection.
Management
Only symptomatic treatment is required in the immunocompetent
patient. Immunocompromised individuals are treated with
ganciclovir 5 mg/kg IV twice daily or with oral valganciclovir
900 mg twice daily for at least 1 4 days. Foscarnet or cidofovir
is also used in CMV treatment of immunocompromised patients
who are resistant to or intolerant of ganciclovir-based therapy.
They can be given intravitreally if required.
|j)engue
Dengue is a febrile illness caused by a flavivirus transmitted by
mosquitoes. It is endemic in Asia, the Pacific, Africa and the
Americas (Fig. 11.13). Approximately 400 million infections and
100 million clinically apparent infections occur annually, and
dengue is the most rapidly spreading mosquito-borne viral illness.
The principal vector is the mosquito Aedes aegypti, which breeds
Fig. 11.13 Endemic zones of yellow fever and dengue.
in standing water; collections of water in containers, water-based
air coolers and tyre dumps are a good environment for the vector
in large cities. Aedes albopictus is a vector in some South-east
Asian countries. There are four serotypes of dengue virus, all
producing a similar clinical syndrome; type-specific immunity is
life-long but immunity against the other serotypes lasts only a few
months. Dengue haemorrhagic fever (DHF) and dengue shock
syndrome (DSS) occur in individuals who are immune to one
dengue virus serotype and are then infected with another. Prior
immunity results in increased uptake of virus by cells expressing
the antibody Fc receptor and increased T-cell activation with
resultant cytokine release, causing capillary leak and disseminated
intravascular coagulation (DIC; p. 978). Previously, dengue was
seen in small children and DHF/DSS in children 2-15 years old,
but these conditions are now being seen in children less than 2
yearsold, and most frequently in those 16-45 years of age or
older, in whom severe organ dysfunction is more common. Other
epidemiological changes include the spread of dengue into rural
communities and greater case fatality in women.
Clinical features
Many cases of dengue infection are asymptomatic in children.
Clinical disease presents with undifferentiated fever termed
dengue-like illness. When dengue infection occurs with
characteristic symptoms or signs it is termed ‘dengue’ (Box
1 1 .34). A rash frequently follows the initial febrile phase as the
fever settles. Laboratory features include leucopenia, neutropenia,
i
Incubation period
• 2-7 days
Prodrome
• 2 days of malaise and headache
Acute onset
• Fever, backache, arthralgias, headache, generalised pains
(‘break-bone fever’), pain on eye movement, lacrimation, scleral
injection, anorexia, nausea, vomiting, pharyngitis, upper respiratory
tract symptoms, relative bradycardia, prostration, depression,
hyperaesthesia, dysgeusia, lymphadenopathy
Fever
• Continuous or ‘saddle-back’, with break on 4th or 5th day and then
recrudescence; usually lasts 7-8 days
Rash
• Initial flushing faint macular rash in first 1-2 days. Maculopapular,
scarlet morbilliform blanching rash from days 3-5 on trunk,
spreading centrifugally and sparing palms and soles; onset often
with fever defervescence. May desquamate on resolution or give
rise to petechiae on extensor surfaces
Convalescence
• Slow and may be associated with prolonged fatigue syndrome,
arthralgia or depression
Complications
• Dengue haemorrhagic fever and disseminated intravascular
coagulation
• Dengue shock syndrome
• Severe organ involvement
• Vertical transmission if infection within 5 weeks of delivery
1 1 .34 Clinical features of dengue fever
244 • INFECTIOUS DISEASE
thrombocytopenia and elevated alanine aminotransferase (ALT) or
aspartate aminotransferase (AST). Many symptomatic infections
run an uncomplicated course but complications or a protracted
convalescence may ensue. Warning signs justify intense medical
management and monitoring for progression to severe dengue.
Atypical clinical features of dengue are increasingly common,
especially in infants or older patients (Box 1 1 .35). These, along
with DHF or DSS, are recognised as features of severe dengue
in the 2015 case definition.
The period 3-7 days after onset of fever is termed the ‘critical’
phase, during which signs of DHF or DSS may develop. In
mild forms, petechiae occur in the arm when a blood pressure
cuff is inflated to a point between systolic and diastolic blood
pressure and left for 5 minutes (the positive ‘tourniquet test’) - a
non-specific test of capillary fragility and thrombocytopenia.
As the extent of capillary leak increases, DSS develops, with
a raised haematocrit, tachycardia and hypotension, pleural
i
Probable dengue fever
• Exposure in an endemic area
• Fever
• Two of:
Nausea/vomiting
Rash
Aches/pains
Positive tourniquet test
Leucopenia
Any warning sign
Laboratory confirmation important
Needs regular medical observation and instruction in the warning signs
If there are no warning signs, need for hospitalisation is influenced by
age, comorbidities, pregnancy and social factors
Dengue with warning signs
• Probable dengue plus one of:
Abdominal pain or tenderness
Persistent vomiting
Signs of fluid accumulation, e.g. pleural effusion or ascites
Mucosal bleed
Hepatomegaly >2 cm
Rapid increase in haematocrit with fall in platelet count
Needs medical intervention, e.g. intravenous fluid
Severe dengue
• Severe plasma leakage leading to:
Shock (dengue shock syndrome)
Fluid accumulation with respiratory distress
• Severe haemorrhagic manifestations, e.g. gastrointestinal
haemorrhage
• Severe organ involvement (atypical features):
Liver AST or ALT >1000 U/L
CNS: impaired consciousness, meningoencephalitis, seizures
Cardiomyopathy, conduction defects, arrhythmias
Other organs, e.g. acute kidney injury, pancreatitis, acute lung
injury, disseminated intravascular coagulopathy, rhabdomyolysis
Needs emergency medical treatment and specialist care with intensive
care input
(ALT = alanine aminotransferase; AST = aspartate aminotransferase)
Adapted from https://wwwn. cdc. gov/nndss/conditions/dengue- virus-infections/
case-definition/20 1 5/
effusions and ascites. This may progress to metabolic acidosis
and multi-organ failure, including acute respiratory distress
syndrome (ARDS; p. 198). Minor (petechiae, ecchymoses,
epistaxis) or major (gastrointestinal or vaginal) haemorrhage, a
feature of DHF, may occur. Cerebrovascular bleeding may be
a complication of severe dengue.
Diagnosis
In endemic areas, mild dengue must be distinguished from other
viral infections. The diagnosis can be confirmed by seroconversion
of IgM or a fourfold rise in IgG antibody titres. Serological tests
may detect cross- reacting antibodies from infection or vaccination
against other flaviviruses, including yellow fever virus, Japanese
encephalitis virus and West Nile virus. Isolation of dengue virus
or detection of dengue virus RNA by PCR (p. 106) in blood or
CSF is available in specialist laboratories. Commercial enzyme-
linked immunosorbent assay (ELISA) kits to detect the NS1
viral antigen, although less sensitive than PCR, are available in
many endemic areas.
Management and prevention
Treatment is supportive, emphasising fluid replacement and
appropriate management of shock and organ dysfunction, which
is a major determinant of morbidity and mortality. With intensive
care support, mortality rates are 1 % or less. Aspirin should be
avoided due to bleeding risk. Glucocorticoids have not been
shown to help. No existing antivirals are effective.
Breeding places of Aedes mosquitoes should be abolished
and the adults destroyed by insecticides. A recently licensed
vaccine is available.
Yellow fever
Yellow fever is a haemorrhagic fever of the tropics, caused by a
flavivirus. It is a zoonosis of monkeys in West and Central African,
and South and Central American tropical rainforests, where it
may cause devastating epidemics (Fig. 11.13). Transmission is by
tree-top mosquitoes, Aedes africanus (Africa) and Haemagogus
spp. (America). The infection is introduced to humans either by
infected mosquitoes when trees are felled, or by monkeys raiding
human settlements. In towns, yellow fever may be transmitted
between humans by Aedes aegypti, which breeds efficiently in
small collections of water. The distribution of this mosquito is far
wider than that of yellow fever, and more widespread infection
is a continued threat.
Yellow fever causes approximately 200 000 infections each
year, mainly in sub-Saharan Africa, and the number is increasing.
Overall mortality is around 15%, although this varies widely.
Humans are infectious during the viraemic phase, which starts
3- 6 days after the bite of the infected mosquito and lasts for
4- 5 days.
Clinical features
After an incubation period of 3-6 days, yellow fever is often
a mild febrile illness lasting less than 1 week, with headache,
myalgia, conjunctival erythema and bradycardia. This is followed
by fever resolution (defervescence) but, in some cases, fever
recurs after a few hours to days. In more severe disease, fever
recrudescence is associated with lower back pain, abdominal pain
and somnolence, prominent nausea and vomiting, bradycardia and
jaundice. Liver damage and DIC lead to bleeding with petechiae,
mucosal haemorrhages and gastrointestinal bleeding. Shock,
hepatic failure, renal failure, seizures and coma may ensue.
1 1 .35 WHO case definitions of dengue, 2015
Viral infections • 245
Diagnosis
The differential diagnosis includes malaria, typhoid, viral hepatitis,
leptospirosis, haemorrhagic fevers and aflatoxin poisoning.
Diagnosis of yellow fever can be confirmed by detection of
virus in the blood in the first 3-4 days of illness (e.g. by culture
or reverse transcription polymerase chain reaction (RT-PCR)),
the presence of IgM or a fourfold rise in IgG antibody titre.
Leucopenia is characteristic. Liver biopsy should be avoided
in life due to the risk of fatal bleeding. Postmortem features,
such as acute mid-zonal necrosis and Councilman bodies with
minimal inflammation in the liver, are suggestive but not specific.
Immunohistochemistry for viral antigens improves specificity.
Management and prevention
Treatment is supportive, with meticulous attention to fluid and
electrolyte balance, urine output and blood pressure. Blood
transfusions, plasma expanders and peritoneal dialysis may be
necessary. Patients should be isolated, as their blood and body
products may contain virus particles.
A single vaccination with a live attenuated vaccine gives
full protection for at least 10 years and many travellers do not
require a booster unless specified by individual countries’ travel
requirements. Potential side-effects include hypersensitivity,
encephalitis and systemic features of yellow fever (viscerotropic
disease) caused by the attenuated virus. Vaccination is not
recommended in people who are significantly immunosuppressed.
The risk of vaccine side-effects must be balanced against the
risk of infection for less immunocompromised hosts, pregnant
women and older patients. An internationally recognised
certificate of vaccination is sometimes necessary when crossing
borders.
Viral haemorrhagic fevers
Viral haemorrhagic fevers (VHFs) are zoonoses caused by several
different viruses (Box 1 1 .36). They are geographically restricted
and previously occurred in rural settings or in health-care facilities.
The largest outbreak of VHF to date started in 201 4, with Ebola
11.36 Viral haemorrhagic fevers
Disease
Reservoir
Transmission
Incubation
period
Geography
Mortality
rate
Clinical features of severe
disease
Lassa fever
Multimammate
rats ( Mastomys
natalensis)
Urine from rat
Body fluids from
patients
6-21 days
West Africa
15%
Flaemorrhage, shock,
encephalopathy, ARDS (responds
to ribavirin), deafness in survivors
Ebola fever
Fruit bats
[Pteropodidae
family) and
bush meat
Body fluids from
patients
Handling infected
primates
2-21 days
Central Africa
Outbreaks as far
north as Sudan
25-90%
Flaemorrhage and/or diarrhoea,
hepatic failure and acute kidney
injury
Marburg fever
Undefined
Body fluids from
patients
Handling infected
primates
3-9 days
Central Africa
Outbreak in
Angola
25-90%
Flaemorrhage, diarrhoea,
encephalopathy, orchitis
Yellow fever
Monkeys
Mosquitoes
3-6 days
See Figure 11.13
-15%
Hepatic failure, acute kidney
injury, haemorrhage
Dengue
Flumans
Aedes aegypti
2-7 days
See Figure 11.13
<10%2
Flaemorrhage, shock
Crimean-Congo
haemorrhagic
fever
Small
vertebrates
Domestic and
wild animals
Ixodes tick
Body fluids
1-3 days up
to 9 days
3-6 days up
to 1 3 days
Africa, Asia,
Eastern Europe
30%
Encephalopathy, early
haemorrhage, hepatic failure,
acute kidney injury, ARDS
Rift Valley
fever
Domestic
livestock
Contact with
animals, mosquito
or other insect bites
2-6 days
Africa, Arabian
peninsula
1%
Flaemorrhage, blindness,
meningoencephalitis
(complications only in a minority)
Kyasanur fever
Monkeys
Ticks
3-8 days
Karnataka State,
India
5-10%
Flaemorrhage, pulmonary
oedema, neurological features,
iridokeratitis in survivors
Bolivian and
Argentinian
haemorrhagic
fever (Junin
and Machupo
viruses)
Rodents
( Calomys spp.)
Urine, aerosols
Body fluids from
case (rare)
5-1 9 days
(3-6 days
for
parenteral)
South America
15-30%
Flaemorrhage, shock, cerebellar
signs (may respond to ribavirin)
Haemorrhagic
fever with
renal syndrome
(Hantaan fever)
Rodents
Aerosols from
faeces
5-42 days
(typically 14
days)
Northern Asia,
northern Europe,
Balkans
5%
Acute kidney injury,
cerebrovascular accidents,
pulmonary oedema, shock
(hepatic failure and haemorrhagic
features only in some variants)
*AII potentially have circulatory failure. Mortality of uncomplicated and haemorrhagic dengue fever, respectively.
(ARDS = acute respiratory distress syndrome)
246 • INFECTIOUS DISEASE
circulating in Guinea, Liberia and Sierra Leone. The outbreak
resulted in over 28 000 cases by 201 6.
Serological surveys have shown that Lassa fever is widespread
in West Africa and may lead to up to 500000 infections annually.
Mortality overall may be low, as 80% of cases are asymptomatic,
but in hospitalised cases mortality averages 15%. Ebola outbreaks
have occurred at a rate of approximately one per year in Africa,
involving up to a few hundred cases prior to the 2014 outbreak.
Marburg has been documented less frequently, with outbreaks in
the Democratic Republic of Congo and Uganda, but the largest
outbreak to date involved 163 cases in Angola in 2005. Mortality
rates of Ebola and Marburg are high.
VHFs have extended into Europe, with an outbreak of Congo-
Crimean haemorrhagic fever (CCHF) in Turkey in 2006, and cases
of haemorrhagic fever with renal syndrome in the Balkans and
Russia. An outbreak of CCHF in 201 1 in Gujarat, India, involved
several health-care workers and emphasised the importance of
maintaining a high index of suspicion for VHF and implementing
appropriate infection control measures at the first opportunity.
Kyasanur forest disease is a tick-borne VHF currently confined
to a small focus in Karnataka, India; there are about 500 cases
annually. Monkeys are the principal hosts but, with forest felling,
there are fears that this disease will increase.
New outbreaks and new agents are identified sporadically.
Details on recent disease outbreaks can be found at the WHO
website (see ‘Further information’).
Clinical features
VHFs present with non-specific fever, malaise, body pains, sore
throat and headache. On examination, conjunctivitis, throat
injection, an erythematous or petechial rash, haemorrhage,
lymphadenopathy and bradycardia may be noted. The
viruses cause endothelial dysfunction with the development
of capillary leak. Bleeding is due to endothelial damage and
platelet dysfunction. Hypovolaemic shock and ARDS may
develop (p. 198).
Haemorrhage is a late feature of most VHFs and most patients
present with earlier features. In Lassa fever, joint and abdominal
pain is prominent. A macular blanching rash may be present
but bleeding is unusual, occurring in only 20% of hospitalised
patients. Encephalopathy may develop and deafness affects 30%
of survivors. In CCHF, bleeding, manifest by haematemesis or
bleeding per rectum, may be an early feature, accompanied by
derangement of LFTs.
The clue to the viral aetiology comes from the travel and
exposure history. Travel to an outbreak area, activity in a rural
environment and contact with sick individuals or animals within
21 days all increase the risk of VHF. Enquiry should be made
about insect bites, hospital visits and attendance at ritual
funerals (Ebola virus infection). For Lassa fever, retrosternal pain,
pharyngitis and proteinuria have a positive predictive value of 80%
in West Africa.
Investigations and management
Non-specific findings include leucopenia, thrombocytopenia and
proteinuria. In Lassa fever, an AST of >150 U/L is associated
with a 50% mortality. It is important to exclude other causes of
fever, especially malaria, typhoid and respiratory tract infections.
Most patients suspected of having a VHF in the UK turn out
to have malaria.
A febrile patient from an endemic area within the 21 -day
incubation period, who has specific epidemiological risk factors
(see Fig. 11.6) or signs of organ failure or haemorrhage, should be
treated as being at high risk of VHF; appropriate infection control
measures must be implemented and the patient transferred to
a centre with biosafety level (BSL) 4 facilities if testing positive.
Individuals with a history of travel within 21 days and fever,
but without the relevant epidemiological features or signs of
VHF, are classified as medium-risk and should have an initial
blood sample tested to exclude malaria. If this is negative,
relevant specimens (blood, throat swab, urine and pleural fluid,
if available) are collected and sent to an appropriate reference
laboratory for nucleic acid detection (PCR), virus isolation and
serology. If patients are still felt to be at significant risk of VHF or if
infection is confirmed, they should be transferred to a specialised
high-security infectious disease unit. All further laboratory tests
should be performed at BSL 4. Transport requires an ambulance
with BSL 3 facilities.
In addition to general supportive measures, ribavirin is given
intravenously (100 mg/kg, then 25 mg/kg daily for 3 days and
12.5 mg/kg daily for 4 days) when Lassa fever or South American
haemorrhagic fevers are suspected.
Prevention
Ribavirin has been used as prophylaxis in close contacts in Lassa
fever but there are no formal trials of its efficacy.
Ebola virus disease (EVD)
Ebola virus disease (EVD) is thought to spread to human
populations from fruit bats, sometimes indirectly via contact
with infected primates or other animals. Person-to-person spread,
via contact with blood, secretions or body parts, establishes
EVD in populations. Family members, health-care workers and
people performing traditional burials are at particular risk. The
2014 outbreak involved the Zaire strain of Ebola virus.
Clinical features
The incubation period is 2-21 days but typically 8-10 days. Fever
and non-specific signs are accompanied by abdominal pain,
diarrhoea, vomiting and hiccups. A maculopapular rash occurs
after 5-7 days in some. Although bleeding from the gums or
venepuncture sites or in the stool occurs, haemorrhage may be
less prominent than in other VHFs and is often a terminal event,
as observed in the 2014 epidemic. In contrast, fluid losses from
diarrhoea are more marked and reach 10 L a day. Complications
include meningoencephalitis, uveitis and miscarriages in pregnant
women.
Investigations
Lymphopenia occurs, followed by neutrophilia, atypical
lymphocytes, thrombocytopenia and coagulation abnormalities.
Elevations of AST/ALT, features of acute kidney injury, electrolyte
disturbances and proteinuria are also observed. The virus is
detected by a PCR in blood or body fluids, but may need
retesting if the duration of symptoms is less than 3 days. Serology
provides a retrospective diagnosis.
Management
Treatment is supportive and aimed at fluid replacement. Bacterial
super-infections should be promptly treated. A cocktail of
monoclonal antibodies against Ebola virus, ZMapp, has been
used in a few cases, but efficacy requires further studies. Mortality
is approximately 40%. Survivors recover from the second week
of illness but experience late sequelae, including arthritis (76%),
uveitis (60%) and deafness (24%), while skin sloughing is common.
Relapse with meningitis is reported months after recovery.
Viral infections • 247
Prevention
Ebola virus may be detected in the semen months after recovery.
Male survivors are therefore encouraged to practise safe sex for
1 2 months after symptom onset or until semen tests negative
on two occasions, but recommendations are evolving. Public
health measures are essential for outbreak control and involve
contact surveillance and monitoring through the incubation period,
separating healthy from sick individuals, practising safe burial
methods and ensuring appropriate infection control measures to
protect health-care and laboratory workers, including provision
of personal protective equipment such as gloves, gowns and
full-face protection (face shield or masks combined with goggles).
An Ebola glycoprotein vaccine, rVZV-ZEBOV, was shown to be
effective in 201 6 after a trial in West Africa.
| Zika virus
Zika virus is a flavivirus spread from primate hosts by Aedes
aegypti and Aedes albopictus, which bite during the day.
Described in Africa and Asia since 2015, it has been epidemic
in the Caribbean and Central and South America, where a
mosquito-man-mosquito transmission cycle is established. It
also can be transmitted in semen.
Clinical features
The incubation period is 3-12 days. Infection is asymptomatic or
mild, resembling dengue with fever, arthralgia, conjunctivitis and
maculopapular rash. Complications include increased reports of
Guillain-Barre syndrome. The major concern has been a marked
increase in microcephaly in pregnant women infected with Zika
virus, as well as increased rates of cerebral calcification, deafness,
visual problems such as chorioretinal scarring, joint contractures
(arthrogryposis), hydrops fetalis and growth retardation. Zika
virus appears to infect neural progenitor cells.
Investigations
Routine blood tests are usually normal but may show leucopenia,
thrombocytopenia or increased transaminases. PCR detects
virus in the first week of illness or in urine up to 14 days.
Serology provides a retrospective diagnosis but cross-reacts
with other flaviruses. Plaque-reduction neutralisation testing
can be used to detect virus-specific neutralising antibodies and
distinguish between cross- reacting antibodies in primary flavivirus
infections.
Prevention
Prevention focuses on avoiding mosquito bites. Since Zika virus
may be found in the semen or genital secretions for prolonged
periods, infected individuals should practise safe sex for at least
6 months and planned pregnancy should be postponed for at
least 6 months. Individuals who have travelled to an endemic
area but are asymptomatic should practise safe sex and avoid
pregnancy for at least 2 months. As this is an evolving area,
updated guidance should be sought. There is currently no vaccine.
Viral infections of the skin
Herpes simplex virus 1 and 2
Herpes simplex viruses (HSVs) cause recurrent mucocutaneous
infection; HSV-1 typically involves the mucocutaneous surfaces
of the head and neck (Fig. 11.14), while HSV-2 predominantly
involves the genital mucosa (pp. 333 and 336), although there
is overlap (see Box 11.29). The seroprevalence of HSV-1 is
30-100%, varying by socioeconomic status, while that of HSV-2
is 20-60%. Infection is acquired by inoculation of viruses shed by
an infected individual on to a mucosal surface in a susceptible
person. The virus infects sensory and autonomic neurons and
establishes latent infection in the nerve ganglia. Primary infection
is followed by episodes of reactivation throughout life.
Clinical features
Primary HSV-1 or 2 infection is more likely to be symptomatic
later in life, causing gingivostomatitis, pharyngitis or painful genital
tract lesions. The primary attack may be associated with fever
and regional lymphadenopathy.
Recurrence
Recurrent attacks occur throughout life, most often in association
with concomitant medical illness, menstruation, mechanical
trauma, immunosuppression, psychological stress or, for oral
lesions, ultraviolet light exposure. HSV reactivation in the oral
mucosa produces the classical ‘cold sore’ or ‘herpes labialis’.
Prodromal hyperaesthesia is followed by rapid vesiculation,
pustulation and crusting. Recurrent HSV genital disease is a
common cause of recurrent painful ulceration (pp. 333 and 336).
An inoculation lesion on the finger gives rise to a paronychia,
termed a ‘whitlow’, in contacts of patients with herpetic lesions
(Fig. 11.14B).
Fig. 11.14 Cutaneous manifestations of herpes simplex virus 1 (HSV-1). [A] Acute HSV-1 . There were also vesicles in the mouth - herpetic
stomatitis. J] Herpetic whitlow. [C] Eczema herpeticum. HSV-1 infection spreads rapidly in eczematous skin.
248 • INFECTIOUS DISEASE
Complications
Disseminated cutaneous lesions can occur in individuals with
underlying dermatological diseases, such as eczema (eczema
herpeticum) (Fig. 11.14C). Herpes keratitis presents with pain
and blurring of vision; characteristic dendritic ulcers are visible
on slit-lamp examination and may produce corneal scarring and
permanent visual impairment.
Primary HSV-2 can cause meningitis or transverse myelitis.
HSV is the leading cause of sporadic viral encephalitis (p. 1121);
this follows either primary or secondary disease, usually with
HSV-1 . A haemorrhagic necrotising temporal lobe cerebritis
produces temporal lobe epilepsy and altered consciousness/
coma. Without treatment, mortality is 80%. HSV is also implicated
in the pathogenesis of Bell’s palsy with a lower motor neuron
7th nerve palsy, although antivirals have not been demonstrated
to improve outcome.
Neonatal HSV disease is usually associated with primary
infection of the mother at term (see Box 1 1 .26). In excess of
two-thirds of cases develop disseminated disease with cutaneous
lesions, hepatitis, pneumonitis and frequently encephalitis.
Immunocompromised hosts can develop visceral disease with
oesophagitis, hepatitis, pneumonitis, encephalitis or retinitis.
Diagnosis
Differentiation from other vesicular eruptions is achieved by
demonstration of virus in vesicular fluid, usually by direct
immunofluorescence or PCR. HSV encephalitis is diagnosed
by a positive PCR for HSV in CSF. Serology is of limited value.
Management
Therapy of localised disease must commence in the first 48 hours
of clinical disease (primary or recurrent); thereafter it is unlikely to
influence clinical outcome. Oral lesions in an immunocompetent
individual may be treated with topical aciclovir. All severe
manifestations should be treated, regardless of the time of
presentation (see Box 1 1 .30). Suspicion of HSV encephalopathy
requires immediate empirical antiviral therapy. Aciclovir resistance
is encountered occasionally in immunocompromised hosts, in
which case foscarnet is the treatment of choice.
Human herpesvirus 8
Human herpesvirus 8 (HHV-8) (see Box 1 1 .29) causes Kaposi’s
sarcoma in both AIDS-related and endemic non-AIDS-related
forms (p. 314). HHV-8 is spread via saliva, and men who have sex
with men have an increased incidence of infection. Seroprevalence
varies widely, being highest in sub-Saharan Africa. HHV-8 also
causes two rare haematological malignancies: primary effusion
lymphoma and multicentric Castleman’s disease. Current antivirals
are not effective.
Enterovirus infections
Hand, foot and mouth disease
This systemic infection is caused by Coxsackie viruses usually, or
occasionally by echoviruses. It affects children and occasionally
adults, resulting in local or household outbreaks, particularly
in the summer months. A relatively mild illness with fever
and lymphadenopathy develops after an incubation period of
approximately 10 days; 2-3 days later, a painful papular or
vesicular rash appears on palmoplantar surfaces of hands and
feet, with associated oral lesions on the buccal mucosa and
tongue that ulcerate rapidly. A papular erythematous rash may
appear on buttocks and thighs. Antiviral treatment is not available
and management consists of symptom relief with analgesics.
Herpangina
This infection, caused by Coxsackie viruses, primarily affects
children and teenagers in the summer months. It is characterised
by a small number of vesicles at the soft/hard palate junction,
often associated with high fever, an extremely sore throat and
headache. The lesions are short-lived, rupturing after 2-3 days
and rarely persisting for more than 1 week. Treatment is with
analgesics if required. Culture of the virus from vesicles or DNA
detection by PCR differentiates herpangina from HSV.
| Poxviruses
These DNA viruses are rare but potentially important pathogens.
Smallpox (variola)
Smallpox, which has high mortality, was eradicated worldwide
by a global vaccination programme but interest has re-emerged
due to its potential as a bioweapon. The virus is spread by
the respiratory route or contact with lesions, and is highly
infectious.
The incubation period is 7-17 days. A prodrome with fever,
headache and prostration leads, in 1-2 days, to the rash, which
develops through macules and papules to vesicles and pustules,
worst on the face and distal extremities. Lesions in one area
are all at the same stage of development with no cropping
(unlike chickenpox). Vaccination can lead to a modified course
of disease with milder rash and lower mortality.
If a case of smallpox is suspected, national public health
authorities must be contacted. Electron micrography (like Fig.
11.15) and DNA detection tests (PCR) are used to confirm
diagnosis.
Monkeypox
Despite the name, the animal reservoirs for this virus are
probably small squirrels and rodents. It causes a rare zoonotic
infection in communities in the rainforest belt of Central Africa,
producing a vesicular rash that is indistinguishable from smallpox,
but differentiated by the presence of lymphadenopathy. Little
person-to-person transmission occurs. Outbreaks outside
Fig. 11.15 Electron micrograph of molluscum contagiosum, a
poxvirus. Courtesy of Prof. Goura Kudesia, Northern General Hospital,
Sheffield.
Viral infections • 249
Africa have been linked to importation of African animals as
exotic pets. Diagnosis is by electron micrography or DNA
detection (PCR).
Cowpox
Humans in contact with infected cows develop large vesicles,
usually on the hands or arms and associated with fever and
regional lymphadenitis. The reservoir is thought to be wild rodents.
Vaccinia vims
This laboratory strain is the basis of the existing vaccine to prevent
smallpox. Widespread vaccination is no longer recommended
due to the likelihood of local spread from the vaccination site
(potentially life-threatening in those with eczema (eczema
vaccinatum) or immune deficiency) and of encephalitis. However,
vaccination may still be recommended for key medical staff.
Other poxviruses: orf and molluscum contagiosum
See page 1239 and Figure 11.15.
Gastrointestinal viral infections
Norovirus (Norwalk agent)
Norovirus is the most common cause of infectious gastroenteritis
in the UK and leads to outbreaks in hospital wards, cruise ships
and military camps. Food handlers may transmit this virus,
which is relatively resistant to decontamination procedures.
The incubation period is 24-48 hours. High attack rates and
prominent vomiting are characteristic. Diagnosis may be achieved
by electron microscopy, antigen or DNA detection (PCR) in stool
samples, although the characteristic clinical and epidemiological
features mean that microbiological confirmation is not always
necessary. The virus is highly infectious and cases should be
isolated and environmental surfaces cleaned with detergents
and disinfected with bleach.
Astrovirus
Astroviruses cause diarrhoea in small children and occasionally
in immunocompromised adults.
Rotavirus
Rotaviruses infect enterocytes and are a major cause of diarrhoeal
illness in young children worldwide. There are winter epidemics
in developed countries, particularly in nurseries. Adults in close
contact with cases may develop disease. The incubation period
is 48 hours and patients present with watery diarrhoea, vomiting,
fever and abdominal pain. Dehydration is prominent. Diagnosis is
aided by commercially available enzyme immunoassay kits, which
require fresh or refrigerated stool samples. Immunity develops
to natural infection. Monovalent and multivalent vaccines have
been licensed in many countries and have now demonstrated
efficacy in large trials in Africa and the Americas.
Hepatitis viruses (A-E)
See Chapter 22.
Other viruses
Adenoviruses are frequently identified from stool culture and
implicated as a cause of diarrhoea in children. They have also
been linked to cases of intussusception.
Respiratory viral infections
These infections are described on page 581 .
Adenoviruses, rhinoviruses and enteroviruses (Coxsackie viruses
and echoviruses) often produce non-specific upper respiratory
tract symptoms but may cause viral pneumonia. Parainfluenza
and respiratory syncytial viruses cause upper respiratory tract
disease, croup and bronchiolitis in small children and pneumonia in
the immunocompromised. Respiratory syncytial virus also causes
pneumonia in nursing home residents and may be associated
with nosocomial pneumonia. Metapneumovirus and bocavirus
cause upper and occasionally lower respiratory tract infection,
especially in immunosuppressed individuals. The severe acute
respiratory syndrome (SARS), caused by the SARS coronavirus,
emerged as a major respiratory pathogen during an outbreak
in 2002-2003, with 8000 cases and 10% mortality (p. 582).
I Middle East respiratory syndrome
coronavirus (MERS-CoV)
In 2012, a novel coronavirus, distantly related to the SARS
coronavirus, caused several deaths connected with pneumonia
in patients originating from the Middle East. The Middle East
respiratory syndrome coronavirus (MERS-CoV) appears to be a
zoonosis, involving transmission from bats to camels and then
to humans. Over 20 countries have reported cases, although
most cases have a history of travel to Saudi Arabia or other
countries in the Arabian Peninsula. By 2016 there had been
over 1 700 reported cases.
Clinical features
The incubation period in person-to-person transmission is 2-1 4
(average 5) days. Any age may be infected but the severe form
of MERS-CoV mainly occurs in patients over 50 with medical
comorbidities. Initial symptoms are fever, chills, headache, myalgia,
dry cough and dyspnoea. Abdominal pain and diarrhoea may be
prominent. The mean period from symptom onset to hospitalisation
is 4 days, and 5 days to intensive care unit admission. Illness
is complicated by rapid development of respiratory failure and
features of ARDS and multi-organ failure. Mortality is 35%.
Diagnosis and management
Laboratory features include lymphopenia, thrombocytopenia and
raised lactate dehydrogenase (LDH). Diagnosis is confirmed by
PCR of serum, nasopharyngeal or other respiratory samples.
Serology may also be useful. Treatment is supportive. Strict
infection control measures should be implemented for anyone with
fever, severe respiratory illness and epidemiological risk factors.
Patients should be managed in an airborne infection isolation
room with contact and airborne infection control measures,
including personal protective equipment for health-care workers.
Viral infections with
neurological involvement
See also page 1121.
| Japanese B encephalitis
This flavivirus is an important cause of endemic encephalitis
in Japan, China, Russia, South-east Asia, India and Pakistan;
outbreaks also occur elsewhere. There are 1 0 000-20 000 cases
reported to the WHO annually. Pigs and aquatic birds are the
250 • INFECTIOUS DISEASE
virus reservoirs and transmission is by mosquitoes. Exposure
to rice paddies is a recognised risk factor.
Clinical features
The incubation period is 4-21 days. Most infections are subclinical
in childhood and 1 % or less of infections lead to encephalitis.
Initial systemic illness with fever, malaise and anorexia is
followed by headache, photophobia, vomiting and changes in
brainstem function. Other neurological features include meningism,
seizures, cranial nerve palsies, flaccid or spastic paralysis and
extrapyramidal syndromes. Mortality with neurological disease
is 25%. Most children die from respiratory failure. Some 50%
of survivors have neurological sequelae.
Investigations, management and prevention
Other infectious causes of encephalitis should be excluded
(p. 1121). There is neutrophilia and often hyponatraemia. CSF
analysis reveals lymphocytosis and elevated protein. Serological
testing of serum and CSF aids diagnosis but may cross-react
with dengue and other flaviviruses.
Treatment is supportive. Vaccination is recommended for
travellers to endemic areas during the monsoon. Some endemic
countries include vaccination in their childhood schedules.
West Nile virus
This flavivirus is an important cause of neurological disease in
an area that extends from Australia, India and Russia through
Africa and Southern Europe and across to North America. The
disease has an avian reservoir and a mosquito vector. Older
people are at increased risk of neurological disease.
Clinical features
Most infections are asymptomatic. After 2-6 days’ incubation,
a mild febrile illness and arthralgia may occur. A prolonged
incubation may be seen in immunocompromised individuals.
Children may develop a maculopapular rash. Neurological disease
is seen in 1 % and is characterised by encephalitis, meningitis or
asymmetric flaccid paralysis with 1 0% mortality.
Diagnosis and management
Diagnosis is by serology or detection of viral RNA in blood or
CSF. Serological tests may show cross-reactivity with other
flaviviruses, including vaccine strains. Treatment is supportive.
Enterovirus 71
Enterovirus 71 has caused outbreaks around the globe of
enteroviral disease with hand, foot and mouth disease (p. 248)
and aseptic meningitis. Some cases have been complicated by
encephalitis with flaccid paralysis or by brainstem involvement
and death. The virus can be isolated from vesicle fluid, stool
or CSF, and viral RNA can be detected in CSF by RT-PCR.
Nipah virus encephalitis
Nipah virus is a paramyxovirus in the Henipavirus genus, which
caused an epidemic of encephalitis amongst Malaysian pig farmers
in 1999 and subsequently caused outbreaks in Bangladesh and
India. Mortality is around 30%. Diagnosis is by PCR or serology.
Human T-cell lymphotropic virus type I
Human T-cell lymphotropic virus type I (HTLV-1) is a retrovirus
that causes chronic infection with development of adult T-cell
leukaemia/lymphoma (ATL) or HTLV-1 -associated myelopathy
(HAM) in a subset of those infected (see Box 23.57, p. 964). It is
found mainly in Japan, the Caribbean, Central and South America,
and the Seychelles. HAM or tropical spastic paraparesis occurs
in less than 5% of those with chronic infection, and presents
with gait disturbance, spasticity of the lower extremities, urinary
incontinence, impotence and sensory disturbance. Myositis
and uveitis may also occur with HTLV-1 infection. Serology,
sometimes confirmed with PCR, establishes the diagnosis.
Treatment is usually supportive.
Viral infections with
rheumatological involvement
Rheumatological syndromes characterise a variety of viral
infections ranging from exanthems, such as rubella and parvovirus
B19 (p. 237), to blood-borne viruses, such as HBV and HIV-1
and the sequelae of EVD.
Chikungunya virus
Chikungunya is an alphavirus that causes fever, rash and
arthropathy. It is found principally in Africa and Asia, including
India. Humans and non-human primates are the main reservoir
and the main vector is the Aedes aegypti mosquito. Cases occur
in epidemics on a background of sporadic cases. In 2007, an
outbreak extended as far north as Italy.
The incubation period is 2-12 days. A period of fever may
be followed by an afebrile phase and then recrudescence of
fever. Children may develop a maculopapular rash. Adults are
susceptible to arthritis, which causes early morning pain and
swelling, most often in the small joints. Arthritis can persist for
months and may become chronic in individuals who are positive
for human leucocyte antigen (HLA)-B27. Related alphaviruses
causing similar syndromes include Sindbis virus (Scandinavia and
Africa), O’nyong-nyong virus (Central Africa), Ross River virus
(Australia) and Mayaro virus (Caribbean and South America).
Diagnosis is by serology but cross-reactivity between
alphaviruses occurs. Treatment is symptomatic.
Prion diseases
Prions cause transmissible spongiform encephalopathies and
are discussed on page 1 1 26.
Bacterial infections
Bacterial infections of the skin, soft tissues
and bones
Most infections of the skin, soft tissues and bone are caused by
either Staph, aureus or streptococci (mainly Strep, pyogenes)
(see pp. 1019 and 1237).
Staphylococcal infections
Staphylococci are usually found colonising the anterior nares and
skin. Some staphylococci produce coagulase, an enzyme that
converts fibrinogen to fibrin in rabbit plasma, causing it to clot.
Staph, aureus is coagulase-positive, and most other species are
coagulase-negative. In modern laboratory practice, however, the
identification of Staph, aureus rarely involves the coagulase test.
Bacterial infections • 251
Staph, aureus is the main cause of staphylococcal infections.
Staph, intermedius is another coagulase-positive staphylococcus,
which causes infection following dog bites. Among coagulase-
negative organisms, Staph, epidermidis is the predominant
commensal organism of the skin, and can cause severe infections
in those with central venous catheters or implanted prosthetic
materials. Staph, saprophyticus is part of the normal vaginal
flora and causes urinary tract infections in sexually active young
women. Others implicated in human infections include Staph,
tugdunensis, Staph, schleiferi, Staph, haemolyticus and Staph,
caprae. Coagulase-negative staphylococci are not usually
identified to species level.
Staphylococci are particularly dangerous if they gain access
to the blood stream, having the potential to disseminate widely
(Fig. 11.16). In any patient with staphylococcal bacteraemia,
especially injection drug-users, the possibility of endocarditis
must be considered (p. 527). Growth of Staph, aureus in blood
cultures should not be dismissed as a ‘contaminant’ unless all
possible underlying sources have been excluded and repeated
blood culture is negative. Any evidence of spreading cellulitis
indicates the urgent need for an antistaphylococcal antibiotic,
such as flucloxacillin (unless there is a likely risk of MRSA). This
is particularly true for mid-facial cellulitis, which can result in
cavernous sinus thrombophlebitis.
In addition, Staph, aureus can cause severe systemic disease
due to the effects of toxin produced at superficial sites in the
absence of tissue invasion by bacteria.
Skin infections
Staphylococcal infections cause ecthyma, folliculitis, furuncles,
carbuncles, bullous impetigo and the scalded skin syndrome
(pp. 1235-1237). They may also be involved in necrotising
infections of the skin and subcutaneous tissues (p. 226).
Wound infections
Many wound infections are caused by staphylococci, which
may significantly prolong post-operative hospital stays
Intestinal
Enterocolitis
Respiratory
Pneumonia
Lung abscess
Empyema
CNS
Meningitis
Brain abscess
(neurosurgical
infections in
particular)
Cardiac
Endocarditis
Pericarditis
Bone and joint
Osteomyelitis
Septic arthritis
Blood stream
Blood-stream
Multisystem
Toxic shock
syndrome
infection
Metastatic
abscesses
Skin
Wound
infections
Boils, styes,
carbuncles,
abscesses
Fig. 11.16 Infections caused by Staphylococcus aureus.
(Fig. 11.17A). Prevention involves careful attention to hand
hygiene, skin preparation and aseptic technique, and the use
of topical and systemic antibiotic prophylaxis.
Treatment is by drainage of any abscesses plus adequate
dosage of antistaphylococcal antibiotics, done early, particularly
if prosthetic implants have been inserted.
Cannula-related infection
Staphylococcal infection associated with cannula sepsis (Fig.
11.17B and p. 196) and thrombophlebitis is an important and
common reason for morbidity following hospital admission. The
Visual Infusion Phlebitis (V IP) score aids cannula evaluation (Box
1 1 .37). Staphylococci have a predilection for plastic, rapidly
Fig. 11.17 Manifestations of skin infection with Staphylococcus
aureus. [A] Wound infection. [§] Cannula-related infection.
1 1 .37 How to assess an intravenous cannula using
the Visual Infusion Phlebitis (VIP) score
Clinical features
Score
Assessment and
management
IV site appears healthy
0
No signs of phlebitis
Observe cannula
One of the following is evident:
Slight pain near IV site
Slight redness near IV site
1
Possible first signs
of phlebitis
Observe cannula
Two of the following are evident:
Pain near IV site
Erythema
Swelling
2
Early stage of
phlebitis
Resite cannula
ALL of the following are evident
and extensive:
Pain along path of cannula
Erythema
Induration
3
Medium stage of
phlebitis
Resite cannula
Consider treatment
ALL of the following are evident
and extensive:
Pain along path of cannula
Erythema
Induration
Palpable venous cord
4
Advanced stage of
phlebitis or start of
thrombophlebitis
Resite cannula
Consider treatment
ALL of the following are evident:
Pain along path of cannula
Erythema
Induration
Palpable venous cord
Pyrexia
5
Advanced stage of
thrombophlebitis
Initiate treatment
Resite cannula
Adapted from Jackson A. Nursing Times 1997; 94:68-71.
252 • INFECTIOUS DISEASE
forming a biofilm on cannulae, which remains as a source of
bacteraemia. Local poultice application may relieve symptoms
but cannula removal and antibiotic treatment with flucloxacillin
(or a glycopeptide if MRSA is suspected) are necessary if there
is any suggestion of spreading infection.
Meticillin-resistant Staph, aureus
Resistance to meticillin is due to a penicillin-binding protein
mutation in Staph, aureus. Resistance to vancomycin/teicoplanin
(glycopeptides) in either glycopeptide intermediate Staph, aureus
(GISA) or, rarely, vancomycin-resistant (VRSA) strains threatens
the ability to manage serious infections produced by such
organisms. Meticillin-resistant Staph, aureus (MRSA) is now a
major worldwide health care-acquired pathogen, accounting for
up to 40% of staphylococcal bacteraemia in developed countries.
Community-acquired MRSA (c-MRSA) currently accounts for
50% of all MRSA infections in the USA. These organisms have
also acquired other toxins, such as Panton-Valentine leukocidin
(PVL), and cause rapidly fatal infection in young people. Clinicians
must be aware of the potential danger of these infections and
be prepared to take whatever appropriate infection control
measures are locally advised (p. 111).
Treatment options for MRSA are shown in Box 6.16
(p. 117). Treatment should always be based on the results of
antimicrobial susceptibility testing, since resistance to all these
agents occurs. Milder MRSA infections may be treated with
clindamycin, tetracyclines or co-trimoxazole. Glycopeptides,
linezolid and daptomycin are reserved for treatment of more
severe infections. Toxin-producing MRSA infections should
be treated with protein-inhibiting antibiotics (clindamycin,
linezolid).
Staphylococcal toxic shock syndrome
Staphylococcal toxic shock syndrome (TSS) is a serious and
life-threatening disease associated with infection by Staph,
aureus, which produces a specific toxin (toxic shock syndrome
toxin 1, TSST1). It was formerly seen in young women in
association with the use of highly absorbent intravaginal tampons
but can occur with any Staph, aureus infection involving a
relevant toxin-producing strain. The toxin acts as a ‘super¬
antigen’, triggering significant T-cell activation and massive
cytokine release.
TSS has an abrupt onset with high fever, generalised systemic
upset (myalgia, headache, sore throat and vomiting), a widespread
erythematous blanching rash resembling scarlet fever, and
hypotension. It rapidly progresses over a few hours to multi-organ
failure, leading to death in 10-20%. Recovery is accompanied
at 7-10 days by desquamation (Fig. 1 1 .18).
The diagnosis is clinical and may be confirmed in menstrual
cases by finding a retained tampon with staphylococci on Gram
stain. Subsequent culture and demonstration of toxin production
are confirmatory.
Management
Treatment is with immediate and aggressive fluid resuscitation
and an intravenous antistaphylococcal antimicrobial (flucloxacillin
or vancomycin), usually with the addition of a protein synthesis
inhibitor (e.g. clindamycin) to inhibit toxin production. Intravenous
immunoglobulin is occasionally added in the most severe cases.
Women who recover from tampon-associated TSS should avoid
tampons for at least 1 year and be advised that the condition
can recur.
Fig. 11.18 Full-thickness desquamation after staphylococcal toxic
shock syndrome.
Streptococcal infections
Streptococci are oropharyngeal and gut commensals, which
appear as Gram-positive cocci in chains (see Fig. 6.3, p. 102).
They are classified by the pattern of haemolysis they produce
on blood agar (see Fig. 6.4, p. 102), by their ‘Lancefield groups’
(Box 1 1 .38) and more recently by speciation on matrix-assisted
laser desorption/ionisation time-of-flight (MALDI-TOF) mass
spectometry. Some streptococci (e.g. Strep, milleri group) defy
simple classification.
Group A streptococci (GAS) are the leading cause of bacterial
pharyngitis. Although the presence of fever, tender anterior
lymphadenopathy and purulent tonsillar exudate and the absence
of cough make streptococcal pharyngitis more likely than viral
infection, clinical features alone are unreliable for diagnosing
streptococcal pharyngitis. GAS are also the major cause of
cellulitis, erysipelas and impetigo (pp. 1237 and 1235). Groups
C and G streptococci cause cellulitis, particularly in elderly,
diabetic or immunocompromised patients. Group B streptococci
(GBS) colonise the gut and vagina. They cause post-partum
and neonatal sepsis, as well as other deep infections (infective
endocarditis, septic arthritis, osteomyelitis etc.), especially in
the elderly.
Streptococcal scarlet fever
Group A (or occasionally groups C and G) streptococci causing
pharyngitis, tonsillitis or other infection may lead to scarlet
fever, if the infecting strain produces a streptococcal pyrogenic
exotoxin. Scarlet fever is most common in school-age children,
but can also occur in young adults who have contact with young
children. A diffuse erythematous rash occurs, which blanches
on pressure (Fig. 1 1 .19A), classically with circumoral pallor. The
tongue, initially coated, becomes red and swollen (‘strawberry
tongue’, Fig. 1 1 .19B). The disease lasts about 7 days, the rash
disappearing in 7-10 days, followed by a fine desquamation.
Residual petechial lesions in the antecubital fossa may be seen
(‘Pastia’s sign’, Fig. 11.19C).
Treatment involves intravenous benzylpenicillin or an oral
penicillin plus symptomatic measures.
Bacterial infections • 253
11.38 Streptococcal and related infections
p-haemolytic group A {Strep, pyogenes)
• Skin and soft tissue infection
(including erysipelas, impetigo,
necrotising fasciitis)
• Streptococcal toxic shock
syndrome
• Puerperal sepsis
• Scarlet fever
• Glomerulonephritis
• Rheumatic fever
• Bone and joint infection
• Tonsillitis
p-haemolytic group B {Strep, agalactiae)
• Neonatal infections, including • Female pelvic infections
meningitis • Cellulitis
p-haemolytic group C (various zoonotic streptococci)
• Cellulitis • Pharyngitis
• Endocarditis • Septic arthritis
a-, p- or non-haemolytic group D {Enterococcus faecalis,
E. faecium)
• Endocarditis • Urinary tract infection
• Intra-abdominal infections
a- or non-haemolytic group D {Strep, gallolyticus subsp.
gallolyticus/S. bovis biotype I)
• Bacteraemia/endocarditis associated with large bowel malignancy
p-haemolytic group G streptococci
• Cellulitis • Liver abscess
• Endocarditis • Septic arthritis
a-haemolytic optochin-resistant (viridans streptococci -
Strep, mitis, Strep, sanguis, Strep, mutans, Strep, salivarius)
• Sepsis in immunosuppressed • Endocarditis
a-haemolytic optochin-sensitive {Strep, pneumoniae)
• Pneumonia
• Meningitis
• Endocarditis
• Otitis media
• Sepsis
• Spontaneous bacterial
peritonitis
• Sinusitis
Variable haemolysis {Strep, milieri group - Strep, anginosus,
Strep, intermedius, Strep, constellatus)
• Endocarditis • Urinary tract infection
• Intra-abdominal infections
Anaerobic streptococci {Peptostreptococcus spp.)
• Sepsis in immunosuppressed • Endocarditis
N.B. All streptococci can cause sepsis.
Streptococcal toxic shock syndrome
Group A (or occasionally group C or G) streptococci can produce
one of a variety of toxins, such as pyogenic exotoxin A. Like
staphylococcal TSST1 (see above), these act as super-antigens.
Initially, an influenza-like illness occurs, with signs of localised
infection in 50% of cases, most often involving the skin and soft
tissues. A faint erythematous rash, mainly on the chest, rapidly
progresses to circulatory shock. Without aggressive management,
multi-organ failure will develop.
Fluid resuscitation must be undertaken, along with parenteral
antistreptococcal antibiotic therapy, usually with benzylpenicillin
and clindamycin, to inhibit toxin production. Intravenous
immunoglobulin is often administered. If necrotising fasciitis is
present, it should be treated as described on page 227 with
urgent debridement.
iJTreponematoses
Syphilis
This disease is described on page 337.
Endemic treponematoses
Yaws
Yaws is a granulomatous disease, mainly involving the skin and
bones; it is caused by Treponema pertenue, morphologically and
serologically indistinguishable from the causative organisms of
syphilis and pinta. It is important to establish the geographical
origin and sexual history of patients to exclude false-positive
syphilis serology due to endemic treponemal infections. Between
1 950 and 1 960, WHO campaigns treated over 60 million people
and eradicated yaws from many areas, but the disease has
persisted patchily throughout the tropics; there was a resurgence
in the 1980s and 1990s in West and Central Africa and the
South Pacific.
Organisms are transmitted by bodily contact from a patient
with infectious yaws through minor abrasions of the skin of
another patient, usually a child. After an incubation period of
3-4 weeks, a proliferative granuloma containing numerous
treponemes develops at the site of inoculation. This primary lesion
is followed by secondary eruptions. In addition, there may be
hypertrophic periosteal lesions of many bones, with underlying
cortical rarefaction. Lesions of late yaws are characterised
Fig. 11.19 Clinical features of scarlet fever. [A] Characteristic rash with blanching on pressure. \W\ ‘Strawberry tongue’. [C] Pastia’s sign: a petechial
rash in the cubital fossa.
254 • INFECTIOUS DISEASE
1 1 .39 Diagnosis and treatment of yaws, pinta
and bejel
by destructive changes that closely resemble the osteitis and
gummas of tertiary syphilis and that heal with scarring and
deformity. Investigations and management are outlined in Box
1 1 .39. Improved housing and hygiene, combined with mass
chemotherapy programmes, have achieved dramatic success
in the control of yaws.
Pinta and bejel
These two treponemal infections occur in poor rural populations
with low standards of domestic hygiene but are found in separate
parts of the world. They have features in common, notably that
they are transmitted by contact, usually within the family and
not sexually, and in the case of bejel, through common eating
and drinking utensils. Their diagnosis and management are as
for yaws (Box 1 1 .39).
• Pinta. Pinta is found only in South and Central America,
where its incidence is declining. The infection is confined
to the skin. The early lesions are scaly papules or
dyschromic patches on the skin. The late lesions are often
depigmented and disfiguring.
• Bejel. Bejel is the Middle Eastern name for non-venereal
syphilis, which has a patchy distribution across sub-
Saharan Africa, the Middle East, Central Asia and
Australia. It has been eradicated from Eastern Europe.
Transmission is most commonly from the mouth of the
mother or child and the primary mucosal lesion is seldom
seen. The early and late lesions resemble those of
secondary and tertiary syphilis (p. 337) but cardiovascular
and neurological disease is rare.
Tropical ulcer
Tropical ulcer is due to a synergistic bacterial infection caused
by a fusobacterium (F. ulcerans, an anaerobe) and Treponema
vincentii. It is common in hot, humid regions. The ulcer is most
common on the lower legs and develops as a papule that rapidly
breaks down to a sharply defined, painful ulcer. The base of the
ulcer has a foul slough. Penicillin and metronidazole are useful
in the early stages but rest, elevation and dressings are the
mainstays of treatment.
Buruli ulcer
This ulcer is caused by Mycobacterium ulcerans and occurs
widely in tropical rainforests. In 1999, a survey in Ghana found
6500 cases; there are an estimated 10 000 cases in West Africa
as a whole.
The initial lesion is a small subcutaneous nodule on the arm or
leg. This breaks down to form a shallow, necrotic ulcer with deeply
undermined edges, which extends rapidly. Healing may occur
after 6 months but granuloma formation and the accompanying
fibrosis cause contractures and deformity. Clumps of acid-fast
bacilli can be detected in the ulcer floor.
A combination of rifampicin and streptomycin can cure the
infection. Infected tissue should be removed surgically. Health
campaigns in Ghana have successfully focused on early removal
of the small, pre-ulcerative nodules.
Systemic bacterial infections
Brucellosis
Brucellosis is an enzootic infection (i.e. endemic in animals)
caused by Gram-negative bacilli. The four species causing human
disease and their animal hosts are: Brucella melitensis (goats,
sheep and camels in Europe, especially the Mediterranean basin,
the Middle East, Africa, India, Central Asia and South America),
B. abortus (cattle, mainly in Africa, Asia and South America),
B. suis (pigs in South Asia) and B. canis (dogs). B. melitensis
causes the most severe disease; B. suis is often associated
with abscess formation.
Infected animals may excrete Brucella spp. in their milk for
prolonged periods and human infection is acquired by ingesting
contaminated dairy products (especially unpasteurised milk),
uncooked meat or offal. Animal urine, faeces, vaginal discharge
and uterine products may transmit infection through abraded
skin or via splashes and aerosols to the respiratory tract and
conjunctiva.
Clinical features
Brucella spp. are intracellular organisms that survive for long
periods within the reticulo-endothelial system. This explains
the disease chronicity and tendency to relapse, even after
antimicrobial therapy.
Acute illness is characterised by a high swinging temperature,
rigors, lethargy, headache, joint and muscle pains, and scrotal
pain. Occasionally, there is delirium, abdominal pain and
constipation. Physical signs are non-specific, e.g. enlarged
lymph nodes. Splenomegaly may cause thrombocytopenia.
Localised infection (Fig. 11.20), which occurs in about
30% of patients, is more likely if diagnosis and treatment are
delayed.
Diagnosis
Definitive diagnosis depends on culture of the organism. Blood
cultures are positive in 75-80% of B. melitensis and 50% of
B. abortus infections. Bone marrow culture is not routine but
may increase the diagnostic yield if antibiotics have been used
prior to culture. CSF culture in neurobrucellosis is positive in
about 30% of cases. The laboratory should be alerted to a
suspected diagnosis of brucellosis, as the organism may infect
laboratory workers and must be cultured at the appropriate
biosafety level.
Serology may also aid diagnosis. In endemic areas, a single
high antibody titre of more than 1/320 or a fourfold rise in titre
is needed to support a diagnosis of acute infection. The test
usually takes several weeks to become positive but should
eventually detect 95% of acute infections.
Management
Aminoglycosides show synergistic activity with tetracyclines
against brucellae. Treatment regimens for different forms of
brucellosis are outlined in Box 1 1 .40.
Diagnosis of early stages
• Detection of spirochaetes in exudate of lesions by dark ground
microscopy
Diagnosis of latent and early stages
• Positive serological tests, as for syphilis (see Box 13.8, p. 339)
Treatment of all stages
• Single intramuscular injection of 1.2 g long-acting penicillin, e.g.
benzathine benzylpenicillin
Bacterial infections • 255
Meningitis
Intracranial or subarachnoid
haemorrhage
Stroke
Myelopathy
Radiculopathy
Malodorous perspiration
Myocarditis
Endocarditis
Splenic abscesses
or calcification
Hepatitis
Epididymo-orchitis
Fig. 11.20 Clinical features of brucellosis.
1 1 .40 Treatment of brucellosis
Adults with non-localised disease
• Doxycycline 1 00 mg twice daily orally for 6 weeks plus gentamicin
5 mg/kg IV once daily for 7 days
or
• Doxycycline 1 00 mg twice daily plus rifampicin 600-900 mg orally
once daily for 6 weeks
Bone disease
• Doxycycline 100 mg twice daily plus rifampicin 600-900 mg once
daily orally for 6 weeks plus gentamicin 5 mg/kg IV once daily for
7 days
or
• Ciprofloxacin 750 mg twice daily orally plus rifampicin 600-900 mg
orally once daily for 3 months
Neurobrucellosis
• Doxycycline 1 00 mg twice daily plus rifampicin 600-900 mg orally
once daily for 6 weeks plus ceftriaxone 2vg IV twice daily until the
cerebrospinal fluid is clear (though susceptibility should be
confirmed because sensitivity to third-generation cephalosporins
varies among strains)
Endocarditis
• Almost always needs surgical intervention
plus
• Doxycycline 100 mg twice daily, rifampicin 600-900 mg orally once
daily and co-trimoxazole 5 mg/kg of trimethoprim component for
6 months plus gentamicin 5 mg/kg IV once daily for 2-4 weeks
Pregnancy
• Rifampicin 600-900 mg orally once daily and co-trimoxazole 5 mg/
kg of trimethoprim component for 4 weeks, but caution in last week
of pregnancy due to displacement of bilirubin from albumin by
drugs and risk of kernicterus to the fetus
Borrelia infections
Borrelia are flagellated spirochaetal bacteria that infect humans
after bites from ticks or lice. They cause a variety of human
infections worldwide (Box 1 1 .41).
Lyme disease
Lyme disease (named after the town of Old Lyme in Connecticut,
USA) is caused by B. burgdorferi, which occurs in the USA,
Europe, Russia, China, Japan and Australia. In Europe, two
additional genospecies are also encountered, B. afzelii and B.
garinii. The reservoir of infection is ixodid (hard) ticks that feed
on a variety of large mammals, particularly deer. Birds may
spread ticks over a wide area. The organism is transmitted to
humans via the bite of infected ticks; larval, nymphal and adult
forms are all capable of spreading infection.
Ehrlichiosis is a common co-infection with Lyme disease. Two
forms occur: Anaplasma phagocytophilum , human granulocytic
anaplasmosis (HGA); and Ehrlichia chaffeensis, human monocytic
ehrlichiosis (HME).
Clinical features
There are three stages of disease. Progression may be arrested
at any stage.
• Early localised disease. The characteristic feature is a
skin reaction around the site of the tick bite, known as
erythema migrans (Fig. 11.21). Initially, a red ‘bull’s eye’
macule or papule appears 2-30 days after the bite. It then
enlarges peripherally with central clearing and may persist
for months. Atypical forms are common. The lesion is not
pathognomonic of Lyme disease since similar lesions can
occur after tick bites. Acute manifestations, such as fever,
headache and regional lymphadenopathy, may develop
with or without the rash.
256 • INFECTIOUS DISEASE
Clinical diseases caused by Borrelia spp.
Species
Vector
Geographical distribution
Lyme disease
B. burgdorferi
Tick: Ixodes
Northern and eastern USA
sensu stricto
scapularis
1. pacificus
Western USA
B. afzelii
1. ricinus
Europe
1. persulcatus
Asia
B. garinii
1. ricinus
Europe
1. persulcatus
Asia
Louse-borne relapsing fever
B. recurrent is
Human louse:
Pediculus humanus
corporis
Worldwide
Tick-borne relapsing fever
B. hermsii
Tick: Ornithodoros
hermsii
Western North America
B. turicatae
0. turicatae
South-western North
America and northern
Mexico
B. venezuelensis 0. rudis
Central America and
northern South America
B. hispanica
0. erraticus
Iberian peninsula and
north-western Africa
B. crocidurae
0. erraticus
North Africa and
Mediterranean region
B. duttonii
0. moubata
Central, eastern and
southern Africa
B. persica
0. tholozani
Western China, India,
Central Asia, Middle East
B. latyschewii
0. tartakovskyi
Tajikistan, Uzbekistan
after initial infection. Carditis, sometimes accompanied by
atrioventricular conduction defects, occurs in the USA but
is rare in Europe.
• Late disease. Late manifestations include arthritis,
polyneuritis and encephalopathy. Prolonged arthritis,
particularly affecting large joints, and brain parenchymal
involvement, causing neuropsychiatric abnormalities, may
occur but are rare in the UK. Acrodermatitis chronica
atrophicans is an uncommon late complication seen
more frequently in Europe than North America. Doughy,
patchy discoloration occurs on the peripheries, eventually
leading to shiny atrophic skin. The lesions are easily
mistaken for those of peripheral vascular disease. In
patients coming from an endemic area or having risk
factors, who have facial nerve palsy, Lyme disease should
be considered.
Diagnosis
The diagnosis of early Lyme borreliosis is often clinical. Culture
from biopsy material is not generally available, has a low
yield and may take longer than 6 weeks. Antibody detection
is frequently negative early in the course of the disease but
sensitivity increases to 90-100% in disseminated or late disease.
Immunofluorescence or ELISA can give false-positive reactions in
a number of conditions, including other spirochaetal infections,
infectious mononucleosis, rheumatoid arthritis and systemic lupus
erythematosus (SLE). Immunoblot (Western blot) techniques are
more specific and, although technically demanding, should be
used to confirm the diagnosis. Microorganism DNA detection
by PCR has been applied to blood, urine, CSF and biopsies of
skin and synovium.
Fig. 11.21 Rash of erythema migrans in Lyme disease with
metastatic secondary lesions. Courtesy of Dr Ravi Gowda, Royal
Hallamshire Hospital, Sheffield.
Management
Recent evidence suggests that asymptomatic patients with
positive antibody tests should not be treated. However, erythema
migrans always requires therapy because organisms may persist
and cause progressive disease, even if the skin lesions resolve.
Standard therapy consists of a 14-day course of doxycycline
(200 mg daily) or amoxicillin (500 mg 3 times daily). Some 15% of
patients with early disease will develop a mild Jarisch-Herxheimer
reaction (JHR) during the first 24 hours of therapy (p. 339). In
pregnant women and small children with penicillin allergy, or in
those allergic to amoxicillin and doxycycline, 14-day treatment
with cefuroxime axetil (500 mg twice daily) or erythromycin
(250 mg 4 times daily) may be used.
Disseminated disease and arthritis require therapy for a
minimum of 28 days. Arthritis may respond poorly and prolonged
or repeated courses may be necessary. Neuroborreliosis is
treated with parenteral (3-lactam antibiotics for 3-4 weeks; third-
generation cephalosporins such as ceftriaxone are the preferred
therapy.
• Early disseminated disease. Dissemination occurs via the
blood stream and lymphatics. There may be a systemic
reaction with malaise, arthralgia and, occasionally,
metastatic areas of erythema migrans (Fig. 1 1 .21).
Neurological involvement may follow weeks or months
after infection. Common features include lymphocytic
meningitis, cranial nerve palsies (especially unilateral or
bilateral facial nerve palsy) and peripheral neuropathy.
Radiculopathy, often painful, may present a year or more
Prevention
Protective clothing and insect repellents should be used in
tick-infested areas. Since the risk of borrelial transmission is
lower in the first few hours of a blood feed, prompt removal
of ticks is advisable. Unfortunately, larval and nymphal ticks
are tiny and may not be noticed. Where risk of transmission
is high, a single 200 mg dose of doxycycline, given within
72 hours of exposure, has been shown to prevent erythema
migrans.
Bacterial infections • 257
Louse-borne relapsing fever
The human body louse, Pediculus humanus, causes itching.
Borreliae (B. recurrentis) are liberated from infected lice when
they are crushed during scratching, which also inoculates the
borreliae into the skin. The disease occurs worldwide, with
epidemic relapsing fever most often seen in Central/East Africa
and South America.
The borreliae multiply in the blood, where they are abundant
in the febrile phases, and invade most tissues, especially the
liver, spleen and meninges.
Clinical features
Onset is sudden with fever. The temperature rises to 39.5^0.5°C,
accompanied by a tachycardia, headache, generalised
aching, injected conjunctivae (Fig. 1 1 .22) and herpes labialis.
Thrombocytopenia is associated with a petechial rash and
epistaxis. As the disease progresses tender hepatosplenomegaly,
accompanied by jaundice and elevated transaminases, is common.
There may be severe serosal and intestinal haemorrhage, delirium
and meningism. The fever ends in crisis between the fourth and
tenth days, often associated with profuse sweating, hypotension
and circulatory and cardiac failure. There may be no further fever
but, in a proportion of patients, after an afebrile period of about
7 days, there are one or more relapses, which are usually milder
and less prolonged. In the absence of specific treatment, the
mortality rate is up to 40%, especially among the elderly and
malnourished.
Investigations and management
Dark ground microscopy of a wet film or Wright-Giemsa stained
thick and thin films demonstrate the organism in blood from a
febrile patient.
Treatment aims to eradicate the organism and prevent
relapses, while minimising the severe JHR that inevitably follows
successful chemotherapy. The safest treatment is procaine
penicillin 300 mg IM, followed the next day by 0.5 g tetracycline.
Tetracycline alone is effective and prevents relapse, but may
give rise to a worse reaction. Doxycycline 200 mg once orally in
place of tetracycline has the advantage of also being curative for
typhus, which often accompanies epidemics of relapsing fever.
JHR is best managed in a high-dependency unit with expert
nursing and medical care.
The patient, clothing and all contacts must be freed from lice,
as in epidemic typhus.
Fig. 11.22 Louse-borne relapsing fever. Injected conjunctivae.
Tick-borne relapsing fever
Soft ticks (Ornithodoros spp.) transmit B. duttonii (and other
Borrelia species) through saliva while feeding on their host. People
sleeping in mud houses are at risk, as the tick hides in crevices
during the day and feeds on humans during the night. Rodents
are the reservoir in all parts of the world except East Africa, where
humans are the reservoir. Clinical manifestations are similar to
those seen with the louse-borne disease but microorganisms
are detected in fewer patients on dark field microscopy. A
7-day course (due to a higher relapse rate than in louse-borne
relapsing fever) of treatment with either tetracycline (500 mg 4
times daily) or erythromycin (500 mg 4 times daily) is needed.
Leptospirosis
Microbiology and epidemiology
Leptospirosis is one of the most common zoonotic diseases,
favoured by a tropical climate and flooding during the monsoon
but occurring worldwide. Leptospires are tightly coiled, thread-like
organisms about 5-7 |im in length, which are actively motile; each
end is bent into a hook. Leptospira interrogans is pathogenic
for humans. The genus can be separated into more than 200
serovars (subtypes) belonging to 23 serogroups.
Leptospirosis appears to be ubiquitous in wildlife and in
many domestic animals. The organisms persist indefinitely in
the convoluted tubules of the kidney and are shed into the urine
in massive numbers, but infection is asymptomatic in the host.
The most frequent hosts are rodents, especially the common
rat (Rattus norvegicus). Particular leptospiral serogroups are
associated with characteristic animal hosts; for example, L.
ictero-haemorrhagiae is the classical parasite of rats and L.
canicola of dogs. There is nevertheless considerable overlap in
host-serogroup associations.
Leptospires can enter their human hosts through intact skin
or mucous membranes but entry is facilitated by cuts and
abrasions. Prolonged immersion in contaminated water will
also favour invasion, as the spirochaete can survive in water
for months. Leptospirosis is common in the tropics and also in
freshwater sports enthusiasts.
Clinical features
After a relatively brief bacteraemia, invading organisms are
distributed throughout the body, mainly in kidneys, liver, meninges
and brain. The incubation period averages 1-2 weeks. Four main
clinical syndromes can be discerned and clinical features can
involve multiple different organ systems (Fig. 1 1 .23).
Bacteraemic leptospirosis
Bacteraemia with any serogroup can produce a non-specific illness
with high fever, weakness, muscle pain and tenderness (especially
of the calf and back), intense headache and photophobia, and
sometimes diarrhoea and vomiting. Conjunctival congestion
is the only notable physical sign. The illness comes to an end
after about 1 week, or else merges into one of the other forms
of infection.
Aseptic meningitis
Classically associated with L. canicola infection, this illness is
very difficult to distinguish from viral meningitis. The conjunctivae
may be congested but there are no other differentiating signs.
Laboratory clues include a neutrophil leucocytosis, abnormal LFTs,
and the occasional presence of albumin and casts in the urine.
258 • INFECTIOUS DISEASE
Uveitis
Jaundice
Epistaxis
Haematemesis
Pericarditis/
myocarditis/
vasculiitis
Hepatomegaly
Renal failure
Transient
macular rash
Purpura
Bruising
Fig. 11.23 Clinical syndromes of leptospirosis.
(ARDS = acute respiratory distress syndrome)
Icteric leptospirosis (Weil’s disease)
Fewer than 10% of symptomatic infections result in severe
icteric illness. Weil’s disease is a dramatic life-threatening event,
characterised by fever, haemorrhages, jaundice and acute
kidney injury. Conjunctival hyperaemia is a frequent feature. The
patient may have a transient macular erythematous rash but
the characteristic skin changes are purpura and large areas of
bruising. In severe cases there may be epistaxis, haematemesis
and melaena, or bleeding into the pleural, pericardial or
subarachnoid spaces. Thrombocytopenia, probably related
to activation of endothelial cells with platelet adhesion and
aggregation, is present in 50% of cases. Jaundice is deep and
the liver is enlarged but there is usually little evidence of hepatic
failure or encephalopathy. Acute kidney injury, primarily caused by
impaired renal perfusion and acute tubular necrosis, manifests as
oliguria or anuria, with the presence of albumin, blood and casts
in the urine.
Weil’s disease may also be associated with myocarditis,
encephalitis and aseptic meningitis. Uveitis and iritis may appear
months after apparent clinical recovery.
Pulmonary syndrome
This syndrome has long been recognised in the Far East and has
been described during an outbreak of leptospirosis in Nicaragua.
It is characterised by haemoptysis, patchy lung infiltrates on chest
X-ray, and respiratory failure. Total bilateral lung consolidation
and ARDS (p. 324) with multi-organ dysfunction may develop,
with a high mortality (over 50%).
Diagnosis
A polymorphonuclear leucocytosis is accompanied in severe
infection by thrombocytopenia and elevated blood levels of
creatine kinase. In jaundiced patients, there is hepatitis and the
prothrombin time may be prolonged. The CSF in leptospiral
meningitis shows a variable cellular response, a moderately
elevated protein level and normal glucose content. Acute kidney
injury due to interstitial nephritis is common.
In the tropics, dengue, malaria, typhoid fever, scrub typhus
and hantavirus infection are important differential diagnoses.
Definitive diagnosis of leptospirosis depends on isolation of
the organism, serological tests or detection of specific DNA. In
general, however, it is probably under-diagnosed.
• Blood cultures are most likely to be positive if taken before
the 10th day of illness. Special media are required and
cultures may have to be incubated for several weeks.
• Leptospires appear in the urine during the second week of
illness, and in untreated patients may be recovered on
culture for several months.
• Serological tests are diagnostic if seroconversion or a
fourfold increase in titre is demonstrated. The microscopic
agglutination test (MAT) is the investigation of choice and
can become positive by the end of the first week. IgM
ELISA and immunofluorescent techniques are easier to
perform, however, while rapid immunochromatographic
tests are specific but of only moderate sensitivity in the
first week of illness.
• Detection of leptospiral DNA by PCR is possible in blood
in early symptomatic disease, and in urine from the eighth
day of illness and for many months thereafter.
Management and prevention
The general care of the patient is critically important. Blood
transfusion for haemorrhage and careful attention to renal function,
the usual cause of death, are especially important. Acute kidney
injury is potentially reversible with adequate support, such as
dialysis. Most infections are self-limiting. Therapy with either
oral doxycycline (1 00 mg twice daily for 1 week) or intravenous
penicillin (900 mg 4 times daily for 1 week) is effective but may
not prevent the development of renal failure. Parenteral ceftriaxone
(1 g daily) is as effective as penicillin. JHR may occur but is usually
Bacterial infections • 259
mild. Uveitis is treated with a combination of systemic antibiotics
and local glucocorticoids. There is no role for the routine use of
glucocorticoids in the management of leptospirosis.
Trials in military personnel have shown that infection with L.
interrogans can be prevented by taking prophylactic doxycycline
200 mg weekly.
Plague
Plague is caused by Yersinia pestis, a small Gram-negative
bacillus that is spread between rodents by their fleas. If
domestic rats become infected, infected fleas may bite humans.
Hunters and trappers can contract plague from handling
rodents. In the late stages of human plague, /. pestis may be
expectorated and spread between humans by droplets, causing
‘pneumonic plague’.
Epidemics of plague, such as the ‘Black Death’, have occurred
since ancient times. It is often said that the first sign of plague is
the appearance of dead rats. Plague foci are widely distributed
throughout the world, including the USA; human cases are
reported from about 10 countries per year (Fig. 1 1 .24).
Y. pestis is a potential bioweapon because of the possibility
of person-to-person spread and the high fatality rate associated
with pneumonic plague.
Clinical features
Organisms inoculated through the skin are transported rapidly to
the draining lymph nodes, where they elicit a severe inflammatory
response that may be haemorrhagic. If the infection is not
contained, sepsis ensues and necrotic, purulent or haemorrhagic
lesions develop in many organs. Oliguria and shock follow,
and disseminated intravascular coagulation may result in
widespread haemorrhage. Inhalation of Y. pestis causes alveolitis.
The incubation period is 3-6 days but shorter in pneumonic
plague.
Bubonic plague
In this, the most common form of the disease, onset is usually
sudden, with a rigor, high fever, dry skin and severe headache.
Soon, aching and swelling at the site of the affected lymph
nodes begin. The groin is the most common site of this ‘bubo’,
made up of the swollen lymph nodes and surrounding tissue.
Some infections are relatively mild but, in the majority of patients,
toxaemia quickly increases, with a rapid pulse, hypotension and
delirium. The spleen is usually palpable.
Septicaemic plague
Those not exhibiting a bubo usually deteriorate rapidly and have
a high mortality. The elderly are more prone to this form of illness.
Fig. 11.24 Foci of the transmission of plague. Reproduced by
permission of the World Health Organisation.
The patient is toxic and may have gastrointestinal symptoms, such
as nausea, vomiting, abdominal pain and diarrhoea. DIC may
occur, manifested by bleeding from various orifices or puncture
sites, along with ecchymoses. Hypotension, shock, renal failure
and ARDS may lead to further deterioration. Meningitis, pneumonia
and expectoration of blood-stained sputum containing Y. pestis
may complicate septicaemic, or occasionally bubonic, plague.
Pneumonic plague
Following primary infection in the lung, the onset of disease
is very sudden, with cough and dyspnoea. The patient soon
expectorates copious blood-stained, frothy, highly infective
sputum, becomes cyanosed and dies. Chest radiology reveals
bilateral infiltrates, which may be nodular and progress to an
ARDS-like picture.
Investigations
The organism may be cultured from blood, sputum and bubo
aspirates. For rapid diagnosis, Gram, Giemsa and Wayson’s
stains (the latter containing methylene blue) are applied to
smears from these sites. Y. pestis is seen as bipolar staining
coccobacilli, sometimes referred to as having a ‘safety pin’
appearance. Smears are also subjected to antigen detection
by immunofluorescence, using Y. pestis FI antigen-specific
antibodies. The diagnosis may be confirmed by seroconversion
or a single high titre (>128) of anti-FI antibodies in serum. DNA
detection by PCR is under evaluation.
Plague is a notifiable disease under international health
regulations (p. 114).
Management
If the diagnosis is suspected on clinical and epidemiological
grounds, treatment must be started as soon as, or even
before, samples have been collected for laboratory diagnosis.
Streptomycin (1 g twice daily) or gentamicin (1 mg/kg 3 times
daily) is the drug of choice. Tetracycline (500 mg 4 times daily)
and chloramphenicol (12.5 mg/kg 4 times daily) are alternatives.
Fluoroquinolones (ciprofloxacin and levofloxacin) may be as
effective but there is less clinical experience. Treatment may
also be needed for acute circulatory failure, DIC and hypoxia.
Prevention and infection control
Rats and fleas should be controlled. In endemic areas, people
should avoid handling and skinning wild animals. The patient
should be isolated for the first 48 hours or until clinical improvement
begins. Attendants must wear gowns, masks and gloves. Exposed
symptomatic or asymptomatic people who have been in close
contact with a patient with pneumonic plague should receive
post-exposure antibiotic prophylaxis (doxycycline 100 mg or
ciprofloxacin 500 mg twice daily) for 7 days.
A recombinant subunit vaccine (protein antigens FI + V) is
in development.
Listeriosis
Listeria monocytogenes is an environmental Gram-positive bacillus
that can contaminate food. Outbreaks have been associated
with raw vegetables, soft cheeses, under-cooked chicken, fish,
meat and pates. The bacterium demonstrates ‘cold enrichment’,
outgrowing other contaminating bacteria during refrigeration.
Although food-borne outbreaks of gastroenteritis have been
reported in immunocompetent individuals, Listeria causes more
significant invasive infection, especially in pregnant women, older
adults (over 55 years) and the immunocompromised.
260 • INFECTIOUS DISEASE
In pregnancy, in addition to systemic symptoms of fever and
myalgia, listeriosis causes chorioamnionitis, fetal deaths, abortions
and neonatal infection. In other susceptible individuals, it causes
systemic illness due to bacteraemia without focal symptoms.
Meningitis, similar to other bacterial meningitis but with normal
CSF glucose, is the next most common presentation; CSF
usually shows increased neutrophils but occasionally only the
mononuclear cells are increased (see Box 25.6, p. 1078).
Investigations and management
Diagnosis is made by blood and CSF culture. The organism
grows readily in culture media.
The most effective regimen consists of a combination of
intravenous amoxicillin or ampicillin plus an aminoglycoside.
A sulfamethoxazole/trimethoprim combination can be used in
those with penicillin allergy. Cephalosporins are of no use in this
infection, as the organism is inherently resistant, an important
consideration when treating meningitis empirically.
Proper treatment of foods before eating is the key to preventing
listeriosis. Pregnant women are advised to avoid high-risk
products, including soft cheeses.
| Typhoid and paratyphoid (enteric) fevers
Typhoid and paratyphoid fevers, which are transmitted by the
faecal-oral route, are important causes of fever in the Indian
subcontinent, sub-Saharan Africa and Latin America. Elsewhere,
they are relatively rare. Enteric fevers are caused by infection
with Salmonella Typhi and Salmonella Paratyphi A and B. After
a few days of bacteraemia, the bacilli localise, mainly in the
lymphoid tissue of the small intestine, resulting in typical lesions
in the Peyer’s patches and follicles. These swell at first, then
ulcerate and usually heal. After clinical recovery, about 5% of
patients become chronic carriers (i.e. continue to excrete the
bacteria after 1 year); the bacilli may live in the gallbladder for
months or years and pass intermittently in the stool and, less
commonly, in the urine.
Clinical features
Typhoid fever
Clinical features are outlined in Box 1 1 .42. The incubation period
is typically about 1 0-1 4 days but can be longer, and the onset
may be insidious. The temperature rises in a stepladder fashion
for 4 or 5 days with malaise, increasing headache, drowsiness
and aching in the limbs. Constipation may be caused by swelling
of lymphoid tissue around the ileocaecal junction, although in
1 1 .42 Clinical features of typhoid fever
First week
• Fever
• Constipation
• Headache
• Diarrhoea and vomiting in
• Myalgia
• Relative bradycardia
children
End of first week
• Rose spots on trunk
• Abdominal distension
• Splenomegaly
• Cough
• Diarrhoea
End of second week
• Delirium, complications, then coma and death (if untreated)
children diarrhoea and vomiting may be prominent early in the
illness. The pulse is often slower than would be expected from
the height of the temperature, i.e. a relative bradycardia.
At the end of the first week, a rash may appear on the upper
abdomen and on the back as sparse, slightly raised, rose-red
spots, which fade on pressure. It is usually visible only on white
skin. Cough and epistaxis occur. Around the 7th-10thday, the
spleen becomes palpable. Constipation is followed by diarrhoea
and abdominal distension with tenderness. Bronchitis and delirium
may develop. If untreated, by the end of the second week the
patient may be profoundly ill.
Paratyphoid fever
The course tends to be shorter and milder than that of typhoid
fever and the onset is often more abrupt with acute enteritis.
The rash may be more abundant and the intestinal complications
less frequent.
Complications
These are given in Box 1 1 .43. Haemorrhage from, or a perforation
of, the ulcerated Peyer’s patches may occur at the end of the
second week or during the third week of the illness. A drop
in temperature to normal or subnormal levels may be falsely
reassuring in patients with intestinal haemorrhage. Additional
complications may involve almost any viscus or system because
of the bacteraemia present during the first week. Bone and joint
infection is common in children with sickle-cell disease.
Investigations
In the first week, diagnosis may be difficult because, in this
invasive stage with bacteraemia, the symptoms are those of
a generalised infection without localising features. Typically,
there is a leucopenia. Blood culture establishes the diagnosis
and multiple cultures increase the yield. Stool cultures are often
positive in the second and third weeks. The Widal test detects
antibodies to the O and H antigens but is not specific.
Management
Antibiotic therapy must be guided by in vitro sensitivity testing.
Chloramphenicol (500 mg 4 times daily), ampicillin (750 mg 4
times daily) and co-trimoxazole (2 tablets or IV equivalent twice
daily) are losing their effect due to resistance in many areas of
the world, especially India and South-east Asia. Fluoroquinolones
are the drugs of choice (e.g. ciprofloxacin 500 mg twice daily),
if nalidixic acid screening predicts susceptibility, but resistance
is common, especially in the Indian subcontinent and also in
the UK. Extended-spectrum cephalosporins (ceftriaxone and
cefotaxime) are useful alternatives but have a slightly increased
Bacterial infections • 261
treatment failure rate. Azithromycin (500 mg once daily) is an
alternative when fluoroquinolone resistance is present but has not
been validated in severe disease. Treatment should be continued
for 1 4 days. Pyrexia may persist for up to 5 days after the start
of specific therapy. Even with effective chemotherapy, there is
still a danger of complications, recrudescence of the disease
and the development of a carrier state.
Chronic carriers were formerly treated for 4 weeks with
ciprofloxacin but may require an alternative agent and duration,
as guided by antimicrobial sensitivity testing. Cholecystectomy
may be necessary.
Prevention
Improved sanitation and living conditions reduce the incidence
of typhoid. Travellers to countries where enteric infections are
endemic should be inoculated with one of the three available
typhoid vaccines (two inactivated injectable and one oral live
attenuated).
| Tularaemia
Tularaemia is primarily a zoonotic disease of the northern
hemisphere. It is caused by a highly infectious Gram-negative
bacillus, Francisella tularensis. F. tularensis is passed transovarially
(ensuring transmission from parent to progeny) in ticks, which
allows persistence in nature without the absolute requirement
for an infected animal reservoir. It is a potential weapon for
bioterrorism. Wild rabbits, rodents and domestic dogs or cats
are potential reservoirs, and ticks, mosquitoes or other biting
flies are the vectors.
Infection is introduced either through an arthropod or animal
bite or via contact with infected animals, soil or water through
skin abrasions. The most common ‘ulceroglandular’ variety of
the disease (70-80%) is characterised by skin ulceration with
regional lymphadenopathy. There is also a purely ‘glandular’
form. Alternatively, inhalation of the infected aerosols may result
in pulmonary tularaemia, presenting as pneumonia. Rarely, the
portal of entry of infection may be the conjunctiva, leading to a
nodular, ulcerated conjunctivitis with regional lymphadenopathy
(an ‘oculoglandular’ form). Typhoidal tularaemia is a rare
and serious form of tularaemia with vomiting, diarrhoea and
hepatosplenomegaly, which may be complicated by pneumonia
and meningitis.
Investigations and management
Demonstration of a single high titre (>1 : 1 60) or a fourfold rise in
2-3 weeks in the tularaemia tube agglutination test confirms the
diagnosis. Bacterial yield from the lesions is extremely poor. DNA
detection methods to enable rapid diagnosis are in development.
Treatment consists of a 10-21 -day course of parenteral
aminoglycosides, streptomycin (7.5-10 mg/kg twice daily)
or gentamicin (1.7 mg/kg 3 times daily), with doxycycline or
ciprofloxacin offered as alternatives.
| Melioidosis
Melioidosis is caused by Burkholderia pseudomallei, a saprophyte
found in soil and water (rice paddy fields). Infection is by inoculation
or inhalation, leading to bacteraemia, which is followed by the
formation of abscesses in the lungs, liver and spleen. Patients
with diabetes, renal stones, thalassaemia or severe burns are
particularly susceptible. The disease is most common in South¬
east Asia and northern Australia, and carries a significant mortality.
Disease may present years or decades after the initial exposure.
Clinical features
Pneumonia is the most common feature but localised skin
nodules and abscesses, or sepsis, especially in diabetics, may
occur. Diarrhoea and hepatosplenomegaly may be observed.
The chest X-ray can resemble cavitatory tuberculosis. In
chronic forms, multiple abscesses occur in subcutaneous
tissue, liver, spleen and bone, accompanied by profound
weight loss.
Investigations and management
Culture of blood, sputum or pus on selective media, e.g. Ashdown
agar, may yield B. pseudomallei. Latex agglutination has been
developed as a rapid diagnostic test in Thailand and PCR-based
tests are also available. Indirect haemagglutination testing can
be helpful in travellers; however, most people in endemic areas
are seropositive.
In the acute illness, prompt initiation of empirical therapy is life¬
saving. Ceftazidime 100 mg/kg (2 g 3 times daily) or meropenem
(0.5-1 g 3 times daily) is given for 2-3 weeks, followed by
maintenance therapy of co-trimoxazole (sulfamethoxazole
1600 mg plus trimethoprim 320 mg twice daily) or doxycycline
200 mg daily for 3-6 months. Abscesses should be drained
surgically.
Actinomycete infections
Nocardiosis
Nocardiosis is an uncommon infection caused by aerobic
Actinomycetes of the genus Nocardia, which are found in the soil.
Infection occurs most frequently by direct traumatic inoculation
or occasionally via inhalation or ingestion. Nocardiosis can
result in localised cutaneous ulcers or nodules, most often
in the lower limbs. Chronic destructive infection in tropical
countries can result in acti nomycetoma, involving soft tissues
with occasional penetration to the bone. Actinomycetoma may
also be caused by other aerobic Actinomycetes, and a similar
clinical syndrome, eumycetoma, is caused by filamentous
fungi. Both conditions are discussed on page 301 . Systemic
Nocardia infection, most commonly in immunocompromised
individuals, results in suppurative disease with lung and brain
abscesses.
On microscopy, Nocardia spp. appear as long, filamentous,
branching Gram-positive rods, which are also weakly acid-
fast. They are easily grown in culture but require prolonged
incubation.
Treatment of systemic infection is guided by sensitivity testing
and typically requires combinations of imipenem with ceftriaxone,
amikacin or co-trimoxazole, often for 6-1 2 months or longer.
Meropenem, tigecycline, linezolid and minocycline may also be
used with severe disease or with allergy, or when intolerance
prevents use of the preferred agents. Abscesses are drained
surgically when this is feasible. Localised cutaneous infection is
usually treated with a single agent for 1-3 months. Treatment
of actinomycetoma is discussed on page 301 .
Actinomyces spp.
Actinomyces are anaerobic Actinomycetes, which are
predominantly commensals of the oral cavity. They are
capable of causing deep, suppurating infection in the head
and neck (cervicofacial actinomycosis) and the lungs (thoracic
actinomycosis). They also cause suppurating disease in the
pelvis, associated with intrauterine contraceptive devices (lUCDs).
Modern diagnostic techniques demonstrate that actinomycosis
262 • INFECTIOUS DISEASE
is caused by many different Actinomyces species, the most
common of which is Actinomyces israelii. Treatment of established
disease requires prolonged (about 6-12 months) of penicillin or
doxycycline. Early disease may respond to shorter antibiotic
courses.
Gastrointestinal bacterial infections
The approach to patients presenting with acute gastroenteritis
is described on page 227.
Staphylococcal food poisoning
Staph, aureus is transmitted via the hands of food handlers to
foodstuffs such as dairy products, including cheese, and cooked
meats. Inappropriate storage of these foods allows growth of the
organism and production of one or more heat-stable enterotoxins
that cause the symptoms.
Nausea and profuse vomiting develop within 1-6 hours.
Diarrhoea may not be marked. The toxins that cause the
syndrome act as ‘super-antigens’ and induce a significant
neutrophil leucocytosis that may be clinically misleading. Most
cases settle rapidly but severe dehydration can occasionally
be life-threatening.
Antiemetics and appropriate fluid replacement are the
mainstays of treatment. Suspect food should be cultured
for staphylococci and demonstration of toxin production. The
public health authorities should be notified if food vending is
involved.
Bacillus cereus food poisoning
Ingestion of the pre-formed heat-stable exotoxins of B. cereus
causes rapid onset of vomiting and some diarrhoea within hours
of food consumption, which resolves within 24 hours. Fried rice
and freshly made sauces are frequent sources; the organism
grows and produces enterotoxin during storage (Fig. 11.25).
If viable bacteria are ingested and toxin formation takes place
within the gut lumen, then the incubation period is longer (12-24
hours) and watery diarrhoea and cramps are the predominant
symptoms. The disease is self-limiting but can be quite severe.
Rapid and judicious fluid replacement and appropriate
notification of the public health authorities are all that is required.
Clostridium perfringens food poisoning
Spores of C. perfringens are widespread in the guts of large
animals and in soil. If contaminated meat products are incompletely
cooked and stored in anaerobic conditions, C. perfringens spores
germinate and viable organisms multiply. Subsequent reheating
of the food causes release of enterotoxin. Symptoms (diarrhoea
and cramps) occur some 6-12 hours following ingestion. The
illness is usually self-limiting.
Clostridial enterotoxins are potent and most people who ingest
them will be symptomatic. ‘Point source’ outbreaks, in which a
number of cases all become symptomatic following ingestion,
classically occur after school or canteen lunches where meat
stews are served.
Clostridial necrotising enteritis (CNE) or pigbel is an often-fatal
type of food poisoning caused by a (3-toxin of C. perfringens,
type C. The toxin is normally inactivated by certain proteases or
by normal cooking. Pigbel is more likely in protein malnutrition
or in the presence of trypsin inhibitors, either in foods such as
sweet potatoes or during infection with Ascaris sp. roundworms.
r
Rapid deep-fry kills
bacteria not toxins
t
Inadequate reheating
Viable bacteria remain
Ingestion
of toxin
Acute vomiting ± diarrhoea
2-4 hours after ingestion
Ingestion of spores
or viable bacteria
i
Bacteria multiply in gut
and elute toxin
i
Enterocolitis12-24 hours
after ingestion
Fig. 11.25 Bacillus cereus food poisoning.
Campylobacter jejuni infection
This infection is essentially a zoonosis, although contaminated
water may be implicated, as the organism can survive for many
weeks in fresh water. The most common sources of the infection
are chicken, beef and contaminated milk products. Pet puppies
have also been sources. Campylobacter infection is now the
most common cause of bacterial gastroenteritis in the UK,
accounting for some 100000 cases per annum, most of which
are sporadic.
The incubation period is 2-5 days. Colicky abdominal
pain may be severe and mimic acute appendicitis or other
surgical pathology. Nausea, vomiting and significant diarrhoea,
frequently containing blood, are common features. The majority
of Campylobacter infections affect fit young adults and are
self-limiting after 5-7 days. About 10-20% will have prolonged
symptomatology, occasionally meriting treatment with a macrolide,
most often azithromycin, as many organisms are resistant to
ciprofloxacin.
Approximately 1 % of cases will develop bacteraemia and
possible distant foci of infection. Campylobacter spp. have been
linked to Guillain-Barre syndrome and post-infectious reactive
arthritis (pp. 1140 and 1031).
Salmonella spp. infection
Salmonella enterica serovars other than Salmonella Typhi and
Paratyphi (p. 260), of which there are more than 2000, can cause
gastroenteritis. They are widely distributed throughout the animal
kingdom. Two serovars are most important worldwide: Salmonella
Enteritidis phage type 4 and Salmonella Typhimurium dt.104. The
Bacterial infections • 263
latter may be resistant to commonly used antibiotics such as
ciprofloxacin. Some strains have a clear relationship to particular
animal species, e.g. Salmonella Arizonae and pet reptiles.
Transmission is by contaminated water or food, particularly
poultry, egg products and minced beef, direct person-to-person
spread or the handling of exotic pets such as salamanders,
lizards or turtles. The incidence of Salmonella enteritis is falling
in the UK due to an aggressive culling policy in broiler chicken
stocks, coupled with vaccination.
The incubation period of Salmonella gastroenteritis is 12-72
hours and the predominant feature is diarrhoea, sometimes
with passage of blood. Vomiting may be present at the outset.
Approximately 5% of cases are bacteraemic and invasive non-
typhoidal salmonellosis is a leading cause of bacteraemia in
sub-Saharan Africa. Reactive (post- infective) arthritis occurs in
approximately 2%.
Antibiotics are not indicated for uncomplicated Salmonella
gastroenteritis but are prescribed for bacteraemia. Salmonellae
are notorious for persistent infection and can seed endothelial
surfaces such as an atherosclerotic aorta. Mortality, as with
other forms of gastroenteritis, is higher in the elderly (see Box
11.12, p. 228).
Escherichia coli infection
Many serotypes of E. coli constitute part of the human gut
microbiome. Clinical disease requires either colonisation with
a new or previously unrecognised strain, or the acquisition by
current colonising bacteria of a particular pathogenicity factor for
mucosal attachment or toxin production. Travel to unfamiliar areas
of the world allows contact with different strains of endemic E coli
and the development of travellers’ diarrhoea. Enteropathogenic
strains may be found in the gut of healthy individuals and, if
these people move to a new environment, close contacts may
develop symptoms.
At least five different clinico-pathological patterns of diarrhoea
are associated with specific strains of E coli with characteristic
virulence factors.
Enterotoxigenic E. coli
Enterotoxigenic E. coli (ETEC) is the most common cause of
travellers’ diarrhoea, although there are other causes (see Box
1 1 .20, p. 232). The organisms produce either a heat-labile or a
heat-stable enterotoxin, causing marked secretory diarrhoea and
vomiting after 1-2 days’ incubation. The illness is usually mild
and self-limiting after 3-4 days. Antibiotics are of questionable
value (p. 232).
Entero-invasive E. coli
Illness caused by entero-invasive E. coli (EEC) is very similar
to Shigella dysentery (p. 265) and is caused by invasion and
destruction of colonic mucosal cells. No enterotoxin is produced.
Acute watery diarrhoea, abdominal cramps and some scanty
blood-staining of the stool are common. The symptoms are
rarely severe and are usually self-limiting.
Enteropathogenic E. coli
Enteropathogenic E. coli (EPEC) organisms are very important
in infant diarrhoea. They are able to attach to the gut mucosa,
inducing a specific ‘attachment and effacement’ lesion and
causing destruction of microvilli and disruption of normal
absorptive capacity. The symptoms vary from mild non-bloody
diarrhoea to quite severe illness, but without bacteraemia.
Entero-aggregative E. coli
Entero-aggregative E. coli (EAEC) strains adhere to the mucosa
but also produce a locally active enterotoxin and demonstrate
a particular ‘stacked brick’ aggregation to tissue culture cells
when viewed by microscopy. They have been associated with
prolonged diarrhoea in children in South America, South-east
Asia and India.
Enterohaemorrhagic E coli
A number of distinct ‘O’ serotypes of E. coli possess both the
genes necessary for adherence (see ‘EPEC’ above) and plasmids
encoding two distinct enterotoxins (verotoxins), which are identical
to the toxins produced by Shigella (‘shiga toxins 1 and 2’). E. coli
01 57: H7 is perhaps the best known of these verotoxin-producing
E. coli (VTEC) but others, including types 0126 and Oil, are
also implicated. In 201 1 , an outbreak of food-borne illness linked
to fenugreek seeds occurred in Germany and was due to E. coli
O104:H4, an EAEC strain that had acquired genes encoding
shiga toxin 2a. Although the incidence of enterohaemorrhagic
E. coli (EH EC) is considerably lower than that of Campylobacter
and Salmonella infection, it is increasing in the developing world.
The reservoir of infection is in the gut of herbivores. The
organism has an extremely low infecting dose (1 0-1 00 organisms).
Runoff water from pasture lands where cattle have grazed, which
is used to irrigate vegetable crops, as well as contaminated
milk, meat products (especially hamburgers that have been
incompletely cooked), lettuce, radish shoots and apple juice
have all been implicated as sources (Fig. 1 1 .26).
The incubation period is between 1 and 7 days. Initial watery
diarrhoea becomes uniformly blood-stained in 70% of cases and
2.5% British cattle
excrete VTEC
Normal reservoir
Meat products
surface
contamination
r*
Farm contacts/
visits
Children camping/
playing on soiled
pasture
Water supplies
(runoff)
contaminated
lT
Contaminated
milk
Very low infecting dose
< 100 organisms/g food
Poor kitchen
hygiene
Mincing/
processing
Poor hand
hygiene
Lack of washing
facilities
Irrigation of
vegetables
h
Eaten unwashed
or uncooked
J
Inadequate
pasteurisation
- :>
A
Disease
Fig. 11.26 Verocytotoxigenic Escherichia coli (VTEC) infections.
264 • INFECTIOUS DISEASE
is associated with severe abdominal pain. There is little systemic
upset, vomiting or fever.
Enterotoxins have both a local effect on the bowel and a distant
effect on particular body tissues, such as glomerular apparatus,
heart and brain. The potentially life-threatening haemolytic uraemic
syndrome (HUS, p. 408) occurs in 10-15% of sufferers from
this infection, arising 5-7 days after the onset of symptoms.
It is most likely at the extremes of age, is heralded by a high
peripheral leucocyte count, and may be induced, particularly in
children, by antibiotic therapy.
HUS is treated by dialysis if necessary and may be averted
by plasma exchange. Antibiotics should be avoided since they
can stimulate toxin release.
Clostridium difficile infection
C. difficile is the most commonly diagnosed cause of antibiotic-
associated diarrhoea (p. 230), and is an occasional constituent
of the gut microbiome. C. difficile can produce two toxins (A
and B). C. difficile infection (CDI) usually follows antimicrobial
therapy, which alters the composition of the gastrointestinal
flora and may result in colonisation with toxigenic C. difficile, if
the patient is exposed to C. difficile spores. The combination
of toxin production and the ability to produce environmentally
stable spores accounts for the clinical features and transmissibility
of CDI. A hypervirulent strain of C. difficile, ribotype 027, has
emerged, which produces more toxin and more severe disease
than other C. difficile strains.
Clinical features
Disease manifestations range from diarrhoea to life-threatening
pseudomembranous colitis. Around 80% of cases occur in people
over 65 years of age, many of whom are frail with comorbid
diseases. Symptoms usually begin in the first week of antibiotic
therapy but can occur at any time up to 6 weeks after treatment
has finished. The onset is often insidious, with lower abdominal
pain and diarrhoea that may become profuse and watery. The
presentation may resemble acute ulcerative colitis with bloody
diarrhoea, fever and even toxic dilatation and perforation. Ileus
is also seen in pseudomembranous colitis.
Investigations
C. difficile can be isolated from stool culture in 30% of patients
with antibiotic-associated diarrhoea and over 90% of those
with pseudomembranous colitis, but also from 5% of healthy
adults and up to 20% of elderly patients in residential care. The
diagnosis of CDI therefore rests on detection of toxins A or B
in the stool. Current practice in the UK is to screen stool from
patients with a compatible clinical syndrome by detection either
of glutamate dehydrogenase (GDH), an enzyme produced by C.
difficile, or of C. difficile nucleic acid (e.g. by PCR); if screening is
positive, a C. difficile toxin ELISA or a tissue culture cytotoxicity
assay is performed.
The rectal appearances at sigmoidoscopy may be characteristic,
with erythema, white plaques or an adherent pseudomembrane
(Fig. 1 1 .27), or may resemble ulcerative colitis. In some cases,
the rectum is spared and abnormalities are observed in the
proximal colon. Patients who are ill require abdominal and erect
chest X-rays to exclude perforation or toxic dilatation. CT may
be useful when the diagnosis is in doubt.
Management
The precipitating antibiotic should be stopped and the patient
should be isolated. Supportive therapy includes intravenous
Fig. 11.27 Clostridium difficile infection. Colonoscopic view showing
numerous adherent ‘pseudomembranes’ on the mucosa.
fluids and bowel rest. First-line antimicrobial therapy involves
metronidazole (500 mg orally 3 times daily for 10 days)
or vancomycin (125 mg orally 4 times daily for 7-10 days).
Although vancomycin is more effective than metronidazole
against hypervirulent C. difficile strains (e.g. ribotype 027), it is
more expensive and may drive the emergence of vancomycin
resistance in other organisms (e.g. enterococci, Staph, aureus).
For these reasons, some authorities reserve its use for relapse
(1 5-30% of patients), failure of initial response or severe infection.
Fidaxomicin is associated with a lower relapse rate than
vancomycin but is more expensive. Intravenous immunoglobulin
and/or glucocorticoids are sometimes given in the most severe
or refractory cases, and faecal transplantation from a healthy
donor is increasingly used to manage relapses by restoring a
more advantageous gut microbiome profile. Surgical intervention
needs to be considered early in severe cases.
\Yersinia enterocolitica infection
Yersinia enterocolitica, commonly found in pork, causes mild to
moderate gastroenteritis and can produce significant mesenteric
adenitis after an incubation period of 3-7 days. It predominantly
causes disease in children but adults may also be affected. The
illness resolves slowly. Complications include reactive arthritis
(p. 1031; 10-13% of cases), which may be persistent, and
anterior uveitis.
Cholera
Cholera, caused by Vibrio cholerae serotype 01 , is the archetypal
toxin -mediated bacterial cause of acute watery diarrhoea. The
enterotoxin activates adenylate cyclase in the intestinal epithelium,
inducing net secretion of chloride and water. V. cholerae 01
has two biotypes, classical and El Tor, and each of these has
two distinct serotypes, Inaba and Ogawa. Following its origin
in the Ganges valley, devastating epidemics have occurred,
often in association with large religious festivals, and pandemics
have spread worldwide. The seventh pandemic, due to the El
Tor biotype, began in 1961 and spread via the Middle East to
become endemic in Africa, subsequently spreading throughout
South and Central America. Numbers of cases of cholera have
been increasing, with outbreaks in Ghana in 2014 and Tanzania
in 2015. El Tor is more resistant to commonly used antimicrobials
than classical Vibrio, and causes prolonged carriage in 5% of
Bacterial infections • 265
infections. An atypical serotype, 0139, has been responsible
for localised outbreaks in Bangladesh.
Infection spreads via the stools or vomit of symptomatic patients
or of the much larger number of subclinical cases. Organisms
survive for up to 2 weeks in fresh water and 8 weeks in salt water.
Transmission is normally through infected drinking water, shellfish
and food contaminated by flies, or on the hands of carriers.
Clinical features
Severe diarrhoea without pain or colic begins suddenly and is
followed by vomiting. Following the evacuation of normal gut faecal
contents, typical ‘rice water’ material is passed, consisting of clear
fluid with flecks of mucus. Classical cholera produces enormous
loss of fluid and electrolytes, leading to intense dehydration with
muscular cramps. Shock and oliguria develop but mental clarity
remains. Death from acute circulatory failure may occur rapidly
unless fluid and electrolytes are replaced. Improvement is rapid
with proper treatment.
The majority of infections, however, cause mild illness with
slight diarrhoea. Occasionally, a very intense illness, ‘cholera
sicca’, occurs, with loss of fluid into dilated bowel, killing the
patient before typical gastrointestinal symptoms appear. The
disease is more dangerous in children.
Diagnosis and management
Clinical diagnosis is easy during an epidemic. Otherwise, the
diagnosis should be confirmed bacteriologically. Stool dark-
field microscopy shows the typical ‘shooting star’ motility of
V. cholerae. Rectal swab or stool cultures allow identification.
Cholera is notifiable under international health regulations.
Maintenance of circulation by replacement of water and
electrolytes is paramount (p. 229). Ringer-Lactate is the best
fluid for intravenous replacement. Vomiting usually stops once
the patient is rehydrated, and fluid should then be given orally
up to 500 mL hourly. Early intervention with oral rehydration
solutions that include resistant starch, based on either rice or
cereal, shortens the duration of diarrhoea and improves prognosis.
Severe dehydration, as indicated by altered consciousness, skin
tenting, very dry tongue, decreased pulses, low blood pressure
or minimal urine output, mandates intravenous replacement. Total
fluid requirements may exceed 50 L over a period of 2-5 days.
Accurate records are greatly facilitated by the use of a ‘cholera
cot’, which has a reinforced hole under the patient’s buttocks,
beneath which a graded bucket is placed.
Three days’ treatment with tetracycline 250 mg 4 times daily, a
single dose of doxycycline 300 mg or ciprofloxacin 1 g in adults
reduces the duration of excretion of V. cholerae and the total
volume of fluid needed for replacement.
Prevention
Strict personal hygiene is vital and drinking water should come
from a clean piped supply or be boiled. Flies must be denied
access to food. Oral vaccines containing killed V. cholerae with or
without the B subunit of cholera toxin are used in specific settings.
In epidemics, improvements in sanitation and access to clean
water, public education and control of population movement are
vital. Mass single-dose vaccination and treatment with tetracycline
are valuable. Disinfection of discharges and soiled clothing, and
scrupulous hand-washing by medical attendants reduce spread.
Vibrio parahaemolyticus infection
This marine organism produces a disease similar to enterotoxigenic
E coli (see above). It is very common where ingestion of raw
seafood is widespread (e.g. Japan). After an incubation period
of approximately 20 hours, explosive diarrhoea, abdominal
cramps and vomiting occur. Systemic symptoms of headache
and fever are frequent but the illness is self-limiting after 4-7
days. Rarely, a severe septic illness arises; in this case, V.
parahaemolyticus can be isolated using specific halophilic
culture.
Bacillary dysentery (shigellosis)
Shigellae are Gram-negative rods, closely related to E. coli, that
invade the colonic mucosa. There are four main groups: Sh.
dysenteriae, flexneri, boydii and sonnei. In the tropics, bacillary
dysentery is usually caused by Sh. flexneri, while in the UK most
cases are caused by Sh. sonnei. Shigellae are often resistant to
multiple antibiotics, especially in tropical countries. The organism
only infects humans and its spread is facilitated by its low infecting
dose of around 10 organisms.
Spread may occur via contaminated food or flies, but person-
to-person transmission by unwashed hands after defaecation
is the most important factor. Outbreaks occur in psychiatric
hospitals, residential schools and other closed institutions, and
dysentery is a constant accompaniment of wars and natural
catastrophes, which bring crowding and poor sanitation in their
wake. Shigella infection may spread rapidly among men who
have sex with men.
Clinical features
Disease severity varies from mild Sh. sonnei infections that may
escape detection to more severe Sh. flexneri infections, while
those due to Sh. dysenteriae may be fulminating and cause
death within 48 hours.
In a moderately severe illness, the patient complains of
diarrhoea, colicky abdominal pain and tenesmus. Stools are small,
and after a few evacuations contain blood and purulent exudate
with little faecal material. Fever, dehydration and weakness occur,
with tenderness over the colon. Reactive arthritis or iritis may
occasionally complicate bacillary dysentery (p. 1031).
Management and prevention
Oral rehydration therapy or, if diarrhoea is severe, intravenous
replacement of water and electrolyte loss is necessary. Antibiotic
therapy is with ciprofloxacin (500 mg twice daily for 3 days)
Azithromycin and ceftriaxone are alternatives but resistance
occurs to all agents, especially in Asia. The use of antidiarrhoeal
medication should be avoided.
The prevention of faecal contamination of food and milk and
the isolation of cases may be difficult, except in limited outbreaks.
Hand-washing is very important.
Respiratory bacterial infections
Most of these infections are described in Chapter 17.
| Diphtheria
Infection with Corynebacterium diphtheriae occurs most commonly
in the upper respiratory tract and is usually spread by droplet
infection. Infection may also complicate skin lesions, especially
in alcoholics. The organisms remain localised at the site of
infection but release of a soluble exotoxin damages the heart
muscle and the nervous system.
Diphtheria has been eradicated from many parts of the world
by mass vaccination using a modified exotoxin but remains
266 • INFECTIOUS DISEASE
i
important in areas where vaccination has been incomplete,
e.g. in Russia and South-east Asia. The disease is notifiable
in all countries of Europe and North America, and international
guidelines have been issued by the WHO for the management
of infection.
Clinical features
The average incubation period is 2-4 days. The disease begins
insidiously with a sore throat (Box 1 1 .44). Despite modest fever,
there is usually marked tachycardia. The diagnostic feature is
the ‘wash-leather’ elevated, greyish-green membrane on the
tonsils. It has a well-defined edge, is firm and adherent, and is
surrounded by a zone of inflammation. There may be swelling
of the neck (‘bull neck’) and tender enlargement of the lymph
nodes. In the mildest infections, especially where there is a
high degree of immunity, a membrane may not appear and
inflammation is minimal.
With anterior nasal infection there is nasal discharge, frequently
blood-stained. In laryngeal diphtheria, a husky voice and high-
pitched cough signal potential respiratory obstruction requiring
urgent tracheostomy. If infection spreads to the uvula, fauces
and nasopharynx, the patient is gravely ill.
Death from acute circulatory failure may occur within the first
1 0 days. Late complications arise as a result of toxin action on
the heart or nervous system. About 25% of survivors of the
early toxaemia may later develop myocarditis with arrhythmias or
cardiac failure. These are usually reversible, with no permanent
damage other than heart block in survivors.
Neurological involvement occurs in 75% of cases. After tonsillar
or pharyngeal diphtheria, it usually starts after 10 days with
palatal palsy. Paralysis of accommodation often follows, manifest
by difficulty in reading small print. Generalised polyneuritis with
weakness and paraesthesia may follow in the next 1 0-1 4 days.
Recovery from such neuritis is always ultimately complete.
Management
A clinical diagnosis of diphtheria must be notified to the public
health authorities and the patient sent urgently to a specialist
infectious diseases unit. Empirical treatment should commence
after collection of appropriate swabs.
Diphtheria antitoxin is produced from hyperimmune horse
serum. It neutralises circulating toxin but has no effect on toxin
already fixed to tissues, so it must be injected intramuscularly
without awaiting the result of a throat swab. However, reactions
to this foreign protein include a potentially lethal immediate
anaphylactic reaction (p. 75) and a ‘serum sickness’ with fever,
urticaria and joint pains, which occurs 7-12 days after injection.
A careful history of previous horse serum injections or allergic
reactions should be taken and a small test injection of serum
should be given half an hour before the full dose in every patient.
Adrenaline (epinephrine) solution must be available to deal with
any immediate type of reaction (0.5-1 .0 mL of 1/1000 solution
IM). An antihistamine is also given. In a severely ill patient, the
risk of anaphylactic shock is outweighed by the mortal danger
of diphtheritic toxaemia. A dose of up to 100000 IU of antitoxin
is injected intravenously if the test dose is tolerated. For disease
of moderate severity, 16000-40000 IU IM will suffice, and for
mild cases 4000-8000 IU.
Penicillin (1200 mg 4 times daily IV) or amoxicillin (500 mg 3
times daily) should be administered for 2 weeks to eliminate C.
diphtheriae. Patients allergic to penicillin can be given erythromycin.
Due to poor immunogenicity of primary infection, all sufferers
should be immunised with diphtheria toxoid following recovery.
Patients must be managed in strict isolation and attended by
staff with a clearly documented immunisation history until three
swabs 24 hours apart are culture-negative.
Prevention
Active immunisation should be given to all children. If diphtheria
occurs in a closed community, contacts should be given
erythromycin, which is more effective than penicillin in eradicating
the organism in carriers.
All contacts should also be immunised or given a booster
dose of toxoid. Booster doses are required every 10 years to
maintain immunity.
| Pneumococcal infection
Strep, pneumoniae (the pneumococcus) is the leading cause
of community-acquired pneumonia globally (p. 582) and one of
the leading causes of infection-related mortality. Otitis media,
meningitis and sinusitis are also frequently caused by Strep,
pneumoniae. Occasional patients present with bacteraemia
without obvious focus. Asplenic individuals are at risk of fulminant
pneumococcal disease with purpuric rash.
Increasing rates of penicillin resistance have been reported
around the world for Strep, pneumoniae, although they remain
low in the UK. Strains with cephalosporin resistance causing
meningitis require treatment with a combination of cephalosporins,
glycopeptides and rifampicin. Macrolide resistance is also
increasing. Newer quinolones are also used (e.g. levofloxacin)
but rates of resistance are rising.
Vaccination of infants with the protein conjugate pneumococcal
vaccine decreases Strep, pneumoniae infection in infants and in
their relatives. The polysaccharide pneumococcal vaccine is used
in individuals predisposed to Strep, pneumoniae infection and the
elderly, but only modestly reduces pneumococcal bacteraemia
and does not prevent pneumonia. All asplenic individuals should
receive vaccination against Strep, pneumoniae.
Anthrax
Anthrax is an endemic zoonosis in many countries; it causes
human disease following inoculation of the spores of Bacillus
anthracis. B. anthracis was the first bacterial pathogen described
by Koch and the model pathogen for ‘Koch’s postulates’ (see Box
6.1 , p. 100). It is a Gram-positive organism with a central spore.
The spores can survive for years in soil. Infection is commonly
acquired from contact with animals, particularly herbivores. The
ease of production of B. anthracis spores makes this infection
a candidate for biological warfare or bioterrorism. B. anthracis
produces a number of toxins that mediate the clinical features
of disease.
1 1 .44 Clinical features of diphtheria
Acute infection
• Membranous tonsillitis
• or Nasal infection
• or Laryngeal infection
• or Skin/wound/conjunctival infection (rare)
Complications
• Laryngeal obstruction or paralysis
• Myocarditis
• Peripheral neuropathy
Bacterial infections • 267
Clinical features
These depend on the route of entry of the anthrax spores.
Cutaneous anthrax
This skin lesion is associated with occupational exposure to
anthrax spores during processing of hides and bone products. It
accounts for the vast majority of clinical cases. Animal infection is
a serious problem in Africa, India, Pakistan and the Middle East.
Spores are inoculated into exposed skin. A single lesion
develops as an irritable papule on an oedematous haemorrhagic
base. This progresses to a depressed black eschar. Despite
extensive oedema, pain is infrequent.
Gastrointestinal anthrax
This is associated with the ingestion of contaminated meat. The
caecum becomes infected, which produces nausea, vomiting,
anorexia and fever, followed in 2-3 days by severe abdominal
pain and bloody diarrhoea. Toxaemia and death can develop
rapidly thereafter.
Inhalational anthrax
This form of the disease is extremely rare but has been associated
with bioterrorism. Without rapid and aggressive therapy at the
onset of symptoms, the mortality is 50-90%. Fever, dyspnoea,
cough, headache and sepsis develop 3-14 days following
exposure. Typically, the chest X-ray shows only widening of
the mediastinum and pleural effusions, which are haemorrhagic.
Meningitis may occur.
Management
B. anthracis can be cultured from skin swabs from lesions.
Skin lesions are readily curable with early antibiotic therapy.
Treatment is with ciprofloxacin (500 mg twice daily) until penicillin
susceptibility is confirmed; the regimen can then be changed
to benzylpenicillin with doses up to 2.4 g IV given 6 times
daily or phenoxymethylpenicillin 500-1000 mg 4 times daily
administered for 10 days. The addition of an aminoglycoside
may improve the outlook in severe disease. In view of concerns
about concomitant inhalational exposure, particularly in the era of
bioterrorism, a further 2-month course of ciprofloxacin 500 mg
twice daily or doxycycline 100 mg twice daily orally is added
to eradicate inhaled spores. Inhalational anthrax is treated with
ciprofloxacin and clindamycin for at least 1 4 days, followed by
therapy to eradicate spores. Monoclonal antibodies against B.
anthracis protective antigen can be added for systemic infection.
Prophylaxis with ciprofloxacin (500 mg twice daily for 2 months)
is recommended for anyone at high risk of inhalational exposure
to anthrax spores and should be combined with three doses of
anthrax vaccine adsorbed (AVA).
Bacterial infections with
neurological involvement
Infections affecting the CNS, including bacterial meningitis,
botulism and tetanus, are described on page 1117.
Mycobacterial infections
| Tuberculosis
Tuberculosis is predominantly, although by no means exclusively,
a respiratory disease and is described on page 588.
Leprosy
Leprosy (Hansen’s disease) is a chronic granulomatous disease
affecting skin and nerves and caused by Mycobacterium leprae,
a slow-growing mycobacterium that cannot be cultured in vitro.
The clinical manifestations are determined by the degree of the
patient’s cell-mediated immunity (CMI; p. 69) towards M. leprae
(Fig. 1 1 .28). High levels of CMI with elimination of leprosy bacilli
produces tuberculoid leprosy, whereas absent CMI results in
lepromatous leprosy. Complications arise due to nerve damage,
immunological reactions and bacillary infiltration. People with
leprosy are frequently stigmatised and using the word ‘leper’
is inappropriate.
Epidemiology and transmission
Some 4 million people have leprosy and around 750000 new
cases are detected annually. About 70% of the world’s leprosy
patients live in India, with the disease endemic in Brazil, Indonesia,
Mozambique, Madagascar, Tanzania and Nepal.
Untreated lepromatous patients discharge bacilli from the nose.
Infection occurs through the nose, followed by haematogenous
spread to skin and nerve. The incubation period is 2-5 years
for tuberculoid cases and 8-12 years for lepromatous cases.
Leprosy incidence peaks at 10-14 years, and is more common
in males and in household contacts of leprosy cases.
Pathogenesis
M. leprae has tropism for Schwann cells and skin macrophages.
In tuberculoid leprosy, effective CMI controls bacillary multiplication
(‘paucibacillary’) and organised epithelioid granulomata form. In
lepromatous leprosy, there is abundant bacillary multiplication
(‘multibacillary’), e.g. in Schwann cells and perineurium. Between
these two extremes is a continuum, varying from patients with
6 - - „
High
Bacillary \
invasion
Nerves, skin,
muscle, bone,
mucosae, eye, testis
Immune complexes
(type 2 lepra
reactions)
Nerves, skin,
eye, testis,
kidney
Chronic
exaggerated
cellular
hypersensitivity
Nerves, skin
Acute
changes \
in cellullar \
hypersensitivity
(type 1 lepra reactions)
Nerves, skin
Complications of nerve damage
Zero
(anaesthesia, dryness, paralysis, contracture,
misuse, tissue destruction)
Face, hands, feet
Lepromatous
Borderline Tuberculoid
LL BL
BT TT
Fig. 11.28 Leprosy: mechanisms of damage and tissue affected.
Mechanisms under the broken line are characteristic of disease near the
lepromatous end of the spectrum, and those under the solid line are
characteristic of the tuberculoid end. They overlap in the centre where, in
addition, instability predisposes to type 1 lepra reactions. At the peak in
the centre, neither bacillary growth nor cell-mediated immunity has the
upper hand. (BL = borderline lepromatous; BT = borderline tuberculoid)
Adapted from Bryceson ADM, Ptaltzgraff RE. Leprosy, 3rd edn. Churchill
Livingstone, Elsevier Ltd; 1990.
268 • INFECTIOUS DISEASE
moderate CMI (borderline tuberculoid) to patients with little
cellular response (borderline lepromatous).
Immunological reactions evolve as the immune response
develops and the bacillary antigenic stimulus varies, particularly
in borderline patients. Delayed hypersensitivity reactions produce
type 1 (reversal) reactions, while immune complexes contribute
to type 2 (erythema nodosum leprosum) reactions.
HIV/leprosy co-infected patients have typical lepromatous and
tuberculoid leprosy skin lesions and typical leprosy histology and
granuloma formation. Surprisingly, even with low circulating CD4
counts, tuberculoid leprosy may be observed and there is not
an obvious shift to lepromatous leprosy.
Clinical features
Box 1 1 .45 gives the cardinal features of leprosy. Types of leprosy
are compared in Box 1 1 .46.
• Skin. The most common skin lesions are macules or
plaques. Tuberculoid patients have few, hypopigmented
lesions (Fig. 11.29A). In lepromatous leprosy, papules,
nodules or diffuse infiltration of the skin occur. The earliest
lesions are ill defined; gradually, the skin becomes
infiltrated and thickened. Facial skin thickening leads to the
characteristic leonine facies (Fig. 1 1 .29B).
1 1 .45 Cardinal features of leprosy
• Skin lesions, typically anaesthetic at tuberculoid end of spectrum
• Thickened peripheral nerves
• Acid-fast bacilli on skin smears or biopsy
1 1 .46 Clinical characteristics of the polar forms
1 of leprosy
Clinical and
tissue-specific
features
Lepromatous
Tuberculoid
Skin and nerves
Number and
Widely disseminated
One or a few sites,
distribution
asymmetrical
Skin lesions
Definition:
Clarity of margin
Poor
Good
Elevation of margin
Colour:
Never
Common
Dark skin
Slight
Marked
hypopigmentation
hypopigmentation
Light skin
Slight erythema
Coppery or red
Surface
Smooth, shiny
Dry, scaly
Central healing
None
Common
Sweat and hair growth
Impaired late
Impaired early
Loss of sensation
Late
Early and marked
Nerve enlargement
and damage
Late
Early and marked
Bacilli (bacterial
index)
Many (5 or 6+)
Absent (0)
Natural history
Progressive
Self-healing
Other tissues
Upper respiratory
mucosa, eye, testes,
bones, muscle
None
Reactions
Immune complexes
Cell-mediated
(type 2)
(type 1)
• Anaesthesia. In skin lesions, the small dermal sensory and
autonomic nerve fibres are damaged, causing localised
sensory loss and loss of sweating. Anaesthesia can occur
in the distribution of a damaged large peripheral nerve. A
‘glove and stocking’ sensory neuropathy is also common
in lepromatous leprosy.
• Nerve damage. Peripheral nerve trunks are affected at
‘sites of predilection’. These are the ulnar (elbow), median
(wrist), radial (humerus), radial cutaneous (wrist), common
peroneal (knee), posterior tibial and sural nerves (ankle),
facial nerve (zygomatic arch) and great auricular nerve
(posterior triangle of the neck). Damage to peripheral nerve
trunks produces characteristic signs with regional sensory
loss and muscle dysfunction (Fig. 1 1 .29C). All these
nerves should be examined for enlargement and
tenderness, and tested for motor and sensory function.
The CNS is not affected.
• Eye involvement. Blindness is a devastating complication
for a patient with anaesthetic hands and feet. Eyelid
closure is impaired when the facial nerve is affected.
Damage to the trigeminal nerve causes anaesthesia of the
cornea and conjunctiva. The cornea is then susceptible to
trauma and ulceration.
• Other features. Many organs can be affected. Nasal
collapse occurs secondary to bacillary destruction of the
nasal cartilage and bone. Diffuse infiltration of the testes
causes testicular atrophy and the acute orchitis that
occurs with type 2 reactions. This results in azoospermia
and hypogonadism.
Leprosy reactions
Leprosy reactions (Box 1 1 .47) are events superimposed on the
cardinal features shown in Box 1 1 .45.
• Type 1 (reversal) reactions. These occur in 30% of
borderline patients (BT, BB or BL - see below) and are
delayed hypersensitivity reactions. Skin lesions become
11.47
Reactions in leprosy
Lepra reaction
type 1 (reversal)
Lepra reaction type 2
(erythema nodosum
leprosum)
Mechanism
Cell-mediated
hypersensitivity
Immune complexes
Clinical
features
Painful tender
nerves, loss of
function
Swollen skin
lesions
New skin lesions
Tender papules and nodules;
may ulcerate
Painful tender nerves, loss of
function
Iritis, orchitis, myositis,
lymphadenitis
Fever, oedema
Management
Prednisolone
40 mg, reducing
over 3-6
months1
Moderate: prednisolone
40 mg daily
Severe: thalidomide2 or
prednisolone 40-80 mg daily,
reducing over 1-6 months;
local if eye involved3
Indicated for any new impairment of nerve or eye function. Contraindicated in
women who may become pregnant. 31 % hydrocortisone drops or ointment and
1 % atropine drops.
Bacterial infections • 269
0
Fig. 11.29 Clinical features of leprosy.
[A] Tuberculoid leprosy. Single lesion with a
well-defined active edge and anaesthesia within
the lesion. Bl Lepromatous leprosy. Widespread
nodules and infiltration, with loss of the eyebrows.
This man also has early collapse of the nose.
[Cl Borderline tuberculoid leprosy with severe
nerve damage. This boy has several well-defined,
hypopigmented, macular, anaesthetic lesions. He
has severe nerve damage affecting both ulnar and
median nerves bilaterally and has sustained
severe burns to his hands. [D] Reversal (type 1)
reactions. Erythematous, oedematous lesions.
erythematous (Fig. 11.29D). Peripheral nerves become
tender and painful, with sudden loss of nerve function.
These reactions may occur spontaneously, after starting
treatment and also after completion of multidrug
therapy (MDT).
• Type 2 (erythema nodosum leprosum, ENL) reactions.
These are partly due to immune complex deposition and
occur in BL and LL patients who produce antibodies and
have a high antigen load. They manifest with malaise, fever
and crops of small pink nodules on the face and limbs.
Iritis and episcleritis are common. Other signs are acute
neuritis, lymphadenitis, orchitis, bone pain, dactylitis,
arthritis and proteinuria. ENL may continue intermittently
for several years.
Borderline cases
In borderline tuberculoid (BT) cases, skin lesions are more
numerous than in tuberculoid (TT) cases, and there is more
severe nerve damage and a risk of type 1 reactions. In borderline
leprosy (BB) cases, skin lesions are numerous and vary in
size, shape and distribution; annular lesions are characteristic
and nerve damage is variable. In borderline lepromatous
(BL) cases, there are widespread small macules in the skin
and widespread nerve involvement; both type 1 and type 2
reactions occur.
Pure neural leprosy (i.e. without skin lesions) occurs principally
in India and accounts for 10% of patients. There is asymmetrical
involvement of peripheral nerve trunks and no visible skin lesions.
On nerve biopsy, all types of leprosy have been found.
Investigations
The diagnosis is clinical, made by finding a cardinal sign of
leprosy and supported by detecting acid-fast bacilli in slit-skin
smears or typical histology in a skin biopsy. Slit-skin smears
i
• Stop the infection with chemotherapy
• Treat reactions
• Educate the patient about leprosy
• Prevent disability
• Support the patient socially and psychologically
are obtained by scraping dermal material on to a glass slide.
The smears are then stained for acid-fast bacilli, the number
counted per high-power field and a score derived on a
logarithmic scale (0-6): the bacterial index (Bl). Smears are
useful for confirming the diagnosis and monitoring response to
treatment. Neither serology nor PCR is sensitive or specific enough
for diagnosis.
Management
The principles of treatment are outlined in Box 1 1 .48. All
leprosy patients require MDT with an approved first-line regimen
(Box 1 1 .49).
Rifampicin is a potent bactericidal for M. leprae but should
always be given in combination with other antileprotics, since
a single-step mutation can confer resistance. Dapsone is
bacteriostatic. It commonly causes mild haemolysis and rarely
anaemia. Clofazimine is a red, fat-soluble crystalline dye, weakly
bactericidal for M. leprae. Skin discoloration (red to purple-black)
and ichthyosis are troublesome side-effects, particularly on pale
skins. New bactericidal drugs against M. leprae have been
identified, notably fluoroquinolones (pefloxacin and ofloxacin).
Minocycline and clarithromycin may also be used. These agents
are now established second-line drugs. Minocycline causes a
grey pigmentation of skin lesions.
1 1 .48 Principles of leprosy treatment
270 • INFECTIOUS DISEASE
11.49 Modified WHO-recommended multidrug
therapy (MDT) regimens in leprosy
Type of
leprosy
Monthly
supervised
treatment
Daily self-
administered
treatment
Duration of
treatment2
Paucibacillary
Rifampicin
600 mg
Dapsone 1 00 mg
6 months
Multi bacillary
Rifampicin
600 mg
Clofazimine
300 mg
Clofazimine
50 mg
Dapsone 1 00 mg
12 months
Paucibacillary
single-lesion
Ofloxacin
400 mg
Rifampicin
600 mg
Minocycline
100 mg
Single dose
Classification uses the bacillary index (Bl) in slit-skin smears or, if Bl is not
available, the number of skin lesions:
• paucibacillary single-lesion leprosy (1 skin lesion)
• paucibacillary (2-5 skin lesions)
• multibacillary (>5 skin lesions).
Studies from India have shown that multibacillary patients with an initial Bl of
>4 need longer treatment, for at least 24 months.
Although single-dose treatment is less effective than the
conventional 6-month treatment for paucibacillary leprosy, it is an
operationally attractive field regimen recommended by the WHO.
Lepra reactions are treated as shown in Box 1 1 .47. Chloroquine
can also be used.
Patient education
This is essential and should patients should be informed that, after
3 days of chemotherapy, they are not infectious and can lead
a normal social life. It should emphasise that gross deformities
are not inevitable.
Patients with anaesthetic hands or feet need to avoid and
treat burns or other minor injuries. Good footwear is important.
Physiotherapy helps maintain range of movement of affected
muscles and neighbouring joints.
Prognosis
Untreated, tuberculoid leprosy has a good prognosis; it may
self-heal and peripheral nerve damage is limited. Lepromatous
leprosy (LL) is a progressive condition with high morbidity if
untreated.
After treatment, the majority of patients, especially those
who have no nerve damage at the time of diagnosis, do well,
with resolution of skin lesions. Borderline patients are at risk of
developing type 1 reactions, which may result in devastating
nerve damage.
Prevention and control
The previous strategy of centralised leprosy control campaigns
has been superseded by integrated programmes, with primary
health-care workers in many countries now responsible for
case detection and provision of MDT. It is not yet clear how
successful this will be, especially in the time-consuming area
of disability prevention.
BCG vaccination has been shown to give good but variable
protection against leprosy; adding killed M. leprae to BCG does
not enhance protection.
Rickettsial and related intracellular
bacterial infections
| Rickettsial fevers
The rickettsial fevers are the most common tick-borne infections.
It is important to ask potentially infected patients about contact
with ticks, lice or fleas. There are two main groups of rickettsial
fevers: spotted fevers and typhus (Box 1 1 .50).
Pathogenesis
The rickettsiae are intracellular Gram-negative organisms that
parasitise the intestinal canal of arthropods. Infection of humans
through the skin occurs from the excreta of arthropods, but the
saliva of some biting vectors is infected. The organisms multiply
in capillary endothelial cells, producing lesions in the skin, CNS,
heart, lungs, liver, kidneys and skeletal muscles. Endothelial
proliferation, associated with a perivascular reaction, may cause
thrombosis and purpura. In epidemic typhus, the brain is the target
organ; in scrub typhus, the cardiovascular system and lungs in
particular are attacked. An eschar, a black necrotic crusted sore,
is often found in tick- and mite-borne typhus (see Fig. 1 1 .7C,
p. 235). This is due to vasculitis following immunological
recognition of the inoculated organism. Regional lymph nodes
often enlarge.
Spotted fever group
Rocky Mountain spotted fever
Rickettsia rickettsii is transmitted by tick bites. It is widely
distributed and increasing in western and south-eastern states
of the USA and also in Central and South America. The incubation
period is about 7 days. The rash appears on about the third
or fourth day of illness, looking at first like measles, but in a
few hours a typical maculopapular eruption develops. The rash
spreads in 24-48 hours from wrists, forearms and ankles to
the back, limbs and chest, and then to the abdomen, where
it is least pronounced. Larger cutaneous and subcutaneous
haemorrhages may appear in severe cases. The liver and spleen
become palpable. At the extremes of life, the mortality is 2-12%.
Other spotted fevers
R. conorii (boutonneuse fever) and R. africae (African tick bite
fever) cause Mediterranean and African tick typhus, which also
occurs on the Indian subcontinent. The incubation period is
approximately 7 days. Infected ticks may be picked up by
walking on grasslands, or dogs may bring ticks into the house.
Careful examination might reveal a diagnostic eschar, and the
maculopapular rash on the trunk, limbs, palms and soles. There
may be delirium and meningeal signs in severe infections but
recovery is usual. R. africae can be associated with multiple
eschars. Some cases, particularly those with R. africae, present
without rash (‘spotless spotted fever’). Other spotted fevers are
shown in Box 1 1 .50.
Typhus group
Scrub typhus fever
Scrub typhus is caused by Orientia tsutsugamushi (formerly
Rickettsia tsutsugamushi), transmitted by mites. It occurs in the
Far East, Myanmar, Pakistan, Bangladesh, India, Indonesia, the
South Pacific islands and Queensland, particularly where patches
of forest cleared for plantations have attracted rats and mites.
In many patients, one eschar or more develops,
surrounded by an area of cellulitis (see Fig. 1 1 .7C, p. 235) and
Bacterial infections • 271
11.50 Features of rickettsial infections
Geographical
Disease
Organism
Reservoir
Vector
area
Rash
Gangrene
Target organs
Mortality
Spotted fever group
Rocky Mountain
R. rickettsii
Rodents, dogs,
Ixodes tick
North, Central and
Morbilliform
Often
Bronchi,
2-1 2%2
spotted fever
ticks
South America
Haemorrhagic
myocardium,
brain, skin
Boutonneuse
R. conorii
Rodents, dogs,
Ixodes tick
Mediterranean,
Maculopapular
-
Skin, meninges
2.5%3
fever
ticks
Africa, South-west
Asia, India
Siberian tick
R. sibirica
Rodents, birds,
Various
Siberia, Mongolia,
Maculopapular
-
Skin, meninges
Rare3
typhus
domestic
animals, ticks
ticks
northern China
Australian tick
R. australis
Rodents, ticks
Ticks
Australia
Maculopapular
-
Skin, meninges
Rare3
typhus
Oriental spotted
R. japonica
Rodents, dogs,
Ticks
Japan
Maculopapular
_
Skin, meninges
Rare3
fever
ticks
African tick bite
R. africae
Cattle, game,
Ixodes tick
South Africa
Can be
-
Skin, meninges
Rare3
fever1
ticks
spotless
Typhus group
Scrub typhus
Orientia
Rodents
Trombicula
South-east Asia
Maculopapular
Unusual
Bronchi,
Rare3
tsutsugamushi
mite
myocardium,
brain, skin
Epidemic
R. prowazekii
Humans
Louse
Worldwide
Morbilliform
Often
Brain, skin,
Up to
typhus
Haemorrhagic
bronchi,
myocardium
40%
Endemic typhus
R. typhi
Rats
Flea
Worldwide
Slight
-
-
Rare3
Eschar at bite site and local lymphadenopathy. highest in adult males. 3Except in infants, older people and the debilitated.
enlargement of regional lymph nodes. The incubation period is
about 9 days.
Mild or subclinical cases are common. The onset of symptoms
is usually sudden, with headache (often retro-orbital), fever,
malaise, weakness and cough. In severe illness, the general
symptoms increase, with apathy and prostration. An erythematous
maculopapular rash often appears on about the 5th-7th day and
spreads to the trunk, face and limbs, including the palms and
soles, with generalised painless lymphadenopathy. The rash fades
by the 14th day. The temperature rises rapidly and continues
as a remittent fever (i.e. the difference between maximum and
minimum temperature exceeds 1 °C), remaining above normal with
sweating until it falls on the 1 2th— 1 8th day. In severe infection,
the patient is prostrate with cough, pneumonia, delirium and
deafness. Cardiac failure, renal failure and haemorrhage may
develop. Convalescence is often slow and tachycardia may
persist for some weeks.
Epidemic (louse-borne) typhus
Epidemic typhus is caused by R. prowazekii and is transmitted
by infected faeces of the human body louse, usually through
scratching the skin. Patients suffering from epidemic typhus
infect lice, which leave when the patient is febrile. In conditions
of overcrowding, the disease spreads rapidly. It is prevalent
in parts of Africa, especially Ethiopia and Rwanda, and in the
South American Andes and Afghanistan. Large epidemics have
occurred in Europe, usually as a sequel to war. The incubation
period is usually 1 2-1 4 days.
There may be a few days of malaise but the onset is more
often sudden, with rigors, fever, frontal headaches, pains in the
back and limbs, constipation and bronchitis. The face is flushed
and cyanotic, the eyes are congested and the patient becomes
confused. The rash appears on the 4th-6th day. In its early
stages, it disappears on pressure but soon becomes petechial
with subcutaneous mottling. It appears first on the anterior folds
of the axillae, sides of the abdomen or backs of hands, then on
the trunk and forearms. The neck and face are seldom affected.
During the second week, symptoms increase in severity. Sores
develop on the lips. The tongue becomes dry, brown, shrunken
and tremulous. The spleen is palpable, the pulse feeble and the
patient stuporous and delirious. The temperature falls rapidly at
the end of the second week and the patient recovers gradually.
In fatal cases, the patient usually dies in the second week from
toxaemia, cardiac or renal failure, or pneumonia.
Endemic (flea-borne) typhus
Flea-borne or ‘endemic’ typhus caused by R. typhi is endemic
worldwide. Humans are infected when the faeces or contents of
a crushed flea, which has fed on an infected rat, are introduced
into the skin. The incubation period is 8-14 days. The symptoms
resemble those of a mild louse-borne typhus. The rash may be
scanty and transient.
Investigation of rickettsial infection
Routine blood investigations are not diagnostic. There is usually
hepatitis and thrombocytopenia. Diagnosis is made on clinical
grounds and response to treatment, and may be confirmed by
antibody detection or PCR in specialised laboratories. Differential
diagnoses include malaria, which should be excluded, typhoid,
meningococcal sepsis and leptospirosis.
Management of rickettsial fevers
The different rickettsial fevers vary in severity but all respond
to tetracycline 500 mg 4 times daily, doxycycline 200 mg daily
272 • INFECTIOUS DISEASE
or chloramphenicol 500 mg 4 times daily for 7 days. Louse-
borne typhus and scrub typhus can be treated with a single
dose of 200 mg doxycycline, repeated for 2-3 days to prevent
relapse. Chloramphenicol- and doxycycline-resistant strains of O.
tsutsugamushi have been reported from Thailand and patients
here may need treatment with rifampicin.
Nursing care is important, especially in epidemic typhus.
Sedation may be required for delirium and blood transfusion
for haemorrhage. Relapsing fever and typhoid are common
intercurrent infections in epidemic typhus, and pneumonia in scrub
typhus, which require diagnosis and treatment. Convalescence
is usually protracted, especially in older people.
To prevent rickettsial infection, lice, fleas, ticks and mites need
to be controlled with insecticides.
Q fever
Q fever occurs worldwide and is caused by the rickettsia-like
organism Coxiella burnetii, an obligate intracellular organism
that survives in the extracellular environment. Cattle, sheep and
goats are important reservoirs and the organism is transmitted
by inhalation of aerosolised particles. An important characteristic
of C. burnetii is its antigenic variation, called phase variation,
due to a change of lipopolysaccharide (LPS). When isolated
from animals or humans, C. burnetii expresses phase I antigen
and is very infectious (a single bacterium is sufficient to infect
a human). In culture, there is an antigenic shift to the phase II
form, which is not infectious. Measurement of antigenic shift
helps differentiate acute and chronic Q fever.
Clinical features
The incubation period is 3-4 weeks. The initial symptoms are
non-specific with fever, headache and chills; in 20% of cases,
a maculopapular rash occurs. Other presentations include
pneumonia and hepatitis. Chronic Q fever may present with
osteomyelitis, encephalitis and endocarditis.
Investigations and management
Diagnosis is usually serological and the stage of the infection can
be distinguished by isotype tests and phase-specific antigens.
Phase I and II IgM titres peak at 4-6 weeks. In chronic infections,
IgG titres to phase I and II antigens may be raised.
Prompt treatment of acute Q fever with doxycycline
reduces fever duration. Treatment of Q fever endocarditis is
problematic, requiring prolonged therapy with doxycycline and
rifampicin or ciprofloxacin with hydroxychloroquine; even then,
organisms are not always eradicated. Valve surgery is often
required (p. 526).
Bartonellosis
This group of diseases is caused by intracellular Gram-negative
bacilli closely related to the rickettsiae, which have been discovered
to be important causes of ‘culture-negative’ endocarditis. They are
found in many domestic pets, such as cats, although for several
the host is undefined (Box 1 1 .51). The principal human pathogens
are Bartonella quintana, B. henselae and B. bacilliformis. Bartonella
infections are associated with the following:
• Trench fever. This is a relapsing fever with severe leg pain
and is caused by B. quintana. The disease is not fatal but
is very debilitating.
• Bacteraemia and endocarditis in the homeless.
Endocarditis due to B. quintana or B. henselae is
associated with severe damage to the heart valves.
i
11.51
Clinical diseases caused by Bartonella spp.
Reservoir
Vector
Organism
Disease
Cats
Flea
B. henselae
Cat scratch disease,
bacillary angiomatosis,
endocarditis
Undefined
Lice
B. quintana
Trench fever, bacillary
angiomatosis,
endocarditis
Undefined
Sandfly
B. bacilliformis
Carrion’s disease:
Oroya fever and
verruga peruana
Undefined
Flea
B. rochalimae
Fever, rash, anaemia,
splenomegaly
• Cat scratch disease. B. henselae causes this common
benign lymphadenopathy in children and young adults.
A vesicle or papule develops on the head, neck or arms
after a cat scratch. The lesion resolves spontaneously but
there may be regional lymphadenopathy that persists for
up to 4 months before also resolving spontaneously. Rare
complications include retinitis and encephalopathy.
• Bacillary angiomatosis. This is an HIV-associated disease
caused by B. quintana or B. henselae (p. 316).
• Oroya fever and verruga peruana (Carrion’s disease). This
is endemic in areas of Peru. It is a biphasic disease
caused by B. bacilliformis, transmitted by sandflies of the
genus Phlebotomus. Fever, haemolytic anaemia and
microvascular thrombosis with end-organ ischaemia are
features. It is frequently fatal if untreated.
Investigations and management
Bartonellae can be cultured in specialised laboratories but PCR
is often used to diagnose infection. Serum antibody detection
is possible but cross-reactions occur with Chlamydia and
Coxiella spp.
Bartonella spp. are typically treated with macrolides or
tetracyclines. Antibiotic use is guided by clinical need. Cat
scratch disease usually resolves spontaneously but Bartonella
endocarditis requires valve replacement and combination antibiotic
therapy with doxycycline and gentamicin.
Chlamydial infections
These are listed in Box 1 1 .52 and are also described on pages
340 and 582.
i
11.52 Chlamydialinfections
Organism
Disease caused
Chlamydia trachomatis
Trachoma
Lymphogranuloma venereum
(see Box 13.12, p. 341)
Cervicitis, urethritis, proctitis
(p. 334)
Chlamydia psittaci
Psittacosis (see Box 17.36, p. 582)
Chlamydophila (Chlamydia)
Atypical pneumonia (see Box 17.36,
pneumoniae
p. 582)
Acute/chronic sinusitis
Protozoal infections • 273
| Trachoma
Trachoma is a chronic keratoconjunctivitis caused by Chlamydia
trachomatis and is the most common cause of avoidable
blindness. The classic trachoma environment is dry and dirty,
causing children to have eye and nose discharges. Transmission
occurs through flies, on fingers and within families. In endemic
areas, the disease is most common in children.
Pathology and clinical features
The onset is usually insidious. Infection may be asymptomatic,
lasts for years, may be latent over long periods and may
recrudesce. The conjunctiva of the upper lid is first affected
with vascularisation and cellular infiltration. Early symptoms
include conjunctival irritation and blepharospasm. The early
follicles are characteristic (Fig. 11.30) but clinical differentiation
from conjunctivitis due to other causes may be difficult. Scarring
causes inversion of the lids (entropion) so that the lashes rub
against the cornea (trichiasis). The cornea becomes vascularised
and opaque. The problem may not be detected until vision
begins to fail.
Investigations and management
Intracellular inclusions may be demonstrated in conjunctival
scrapings by staining with iodine or immunofluorescence. Although
chlamydiae may, in theory, be isolated in chick embryo or cell
culture or detected by nucleic acid amplification tests, these
methods are rarely available in the areas where trachoma is
encountered, and in any case their sensitivity and specificity are
poorly established. Diagnosis of trachoma is therefore based on
clinical and epidemiological features.
A single dose of azithromycin (20 mg/kg) has been shown
to be superior to 6 weeks of tetracycline eye ointment twice
daily for individuals in mass treatment programmes. Deformity
and scarring of the lids, and corneal opacities, ulceration and
scarring require surgical treatment after control of local infection.
Prevention
Personal and family hygiene should be improved. Proper care
of the eyes of newborn and young children is essential. Family
contacts should be examined. The WHO is promoting the
SAFE strategy for trachoma control (surgery, antibiotics, facial
cleanliness and environmental improvement).
Fig. 11.30 Trachoma. Trachoma is characterised by hyperaemia and
numerous pale follicles. Courtesy of Institute of Ophthalmology, Moorfields
Eye Hospital, London.
Protozoal infections
Protozoa are responsible for many important infectious diseases.
They can be categorised according to whether they cause
systemic or local infection. Trichomoniasis is described on
page 335.
Systemic protozoal infections
|Malaria
Malaria in humans is caused by Plasmodium falciparum, P. vivax,
P. ovale (subspecies curtisi and wallikeri), P. malariae and the
predominantly simian parasite P. knowlesi. It is transmitted by
the bite of female anopheline mosquitoes and occurs throughout
the tropics and subtropics at altitudes below 1500 metres (Fig.
11.31). The WHO estimates that 214 million cases of clinical
malaria occurred in 2015, 88% of these in Africa, especially among
children and pregnant women. WHO prevention and treatment
campaigns reduced the incidence of malaria between 1950 and
1960, but since 1970 there has been resurgence. Furthermore,
P. falciparum has now become resistant to chloroquine and
sulfadoxine-pyrimethamine, initially in South-east Asia and now
throughout Africa. The WHO’s Millennium Development Goal
malaria target aimed to halt the spread of the disease by 2015
and this has been achieved. The ‘Roll Back Malaria’ campaign
was designed to halve mortality by 2010 by utilising the ‘best
evidence’ vector and disease control methods, such as artemisinin
combination therapy (ACT).
Travellers are susceptible to malaria (p. 230). Most cases are
due to P. falciparum, usually from Africa, and of these 1 % die
because of late diagnosis. Migrants from endemic countries
who spend long periods of time in non-endemic countries are
particularly at risk if they visit friends and family in their country
of origin. They have lost their partial immunity and frequently do
not take malaria prophylaxis. A few people living near airports
in Europe have acquired malaria from accidentally imported
mosquitoes.
Pathogenesis
Life cycle of the malarial parasite
The female anopheline mosquito becomes infected when it
feeds on human blood containing gametocytes, the sexual forms
of the malarial parasite (Figs 1 1 .32 and 1 1 .33). Development
in the mosquito takes 7-20 days, and results in sporozoites
accumulating in the salivary glands and being inoculated into
the human blood stream. Sporozoites disappear from human
blood within half an hour and enter the liver. After some days,
merozoites leave the liver and invade red blood cells, where further
asexual cycles of multiplication take place, producing schizonts.
Fig. 11.31 Distribution of malaria. (For up-to-date information see the
Malaria Atlas Project (MAP): map.ox.ac.uk.)
274 • INFECTIOUS DISEASE
Rupture of the schizont releases more merozoites into the blood
and causes fever, the periodicity of which depends on the
species of parasite.
P. vivax and P. ovale may persist in liver cells as dormant
forms, hypnozoites, capable of developing into merozoites
months or years later. Thus the first attack of clinical malaria
may occur long after the patient has left the endemic area, and
the disease may relapse after treatment with drugs that only kill
the erythrocytic stage of the parasite.
P. falciparum, P. knowlesi and P. malariae have no persistent
exo-erythrocytic phase but recrudescence of fever may result
Fig. 11.32 Scanning electron micrograph of Plasmodium falciparum
oocysts lining an anopheline mosquito’s stomach.
from multiplication of parasites in red cells that have not been
eliminated by treatment and immune processes (Box 1 1 .53).
Pathology
Red cells infected with malaria are prone to haemolysis. This is
most severe with P. falciparum, which invades red cells of all
ages but especially young cells; P. vivax and P. ovale invade
reticulocytes, and P. malariae normoblasts, so that infections
Bl 1 1 .53 Relationships between life cycle of parasite
and clinical features of malaria
Cycle/
feature
Plasmodium
vivax, P. ovale
P. malariae
P. falciparum
Pre-patent
period
(minimum
incubation)
8-25 days
1 5-30 days
8-25 days
Exo-
erythrocytic
cycle
Persistent as
hypnozoites
Pre-erythrocytic
only
Pre-erythrocytic
only
Asexual
cycle
48 hrs
synchronous
72 hrs
synchronous
<48 hrs
asynchronous
Fever
periodicity
Alternate days
Every third day
None
Delayed
onset
Common
Rare
Rare
Relapses
Common up to
2 years
Recrudescence
many years
later
Recrudescence
up to 1 year
Fig. 11.33 Malarial parasites: life cycle. Hypnozoitesf) are present only in Plasmodium vivax and P. ovale infections. (RBC = red blood cell)
Protozoal infections • 275
remain lighter. Anaemia may be profound and is worsened by
dyserythropoiesis, splenomegaly and depletion of folate stores.
In P. falciparum malaria, red cells containing trophozoites
adhere to vascular endothelium in post-capillary venules in
brain, kidney, liver, lungs and gut by the formation of ‘knob’
proteins. They also form ‘rosettes’ and rouleaux with uninfected
red cells. Vessel congestion results in organ damage, which is
exacerbated by rupture of schizonts, liberating toxic and antigenic
substances (Fig. 11.33).
P. falciparum has influenced human evolution, with the
appearance of protective mutations such as sickle-cell (HbS;
p. 951), thalassaemia (p. 953), glucose-6-phosphate
dehydrogenase (G6PD) deficiency (p. 948) and HLA-B53. P.
falciparum does not grow well in red cells that contain haemoglobin
F, C or especially S. Flaemoglobin S heterozygotes (AS) are
protected against the lethal complications of malaria. P. vivax
cannot enter red cells that lack the Duffy blood group; therefore
many West Africans and African Americans are protected.
Clinical features
The clinical features of malaria are non-specific and the diagnosis
must be suspected in anyone returning from an endemic area
who has features of infection.
P. falciparum infection
This is the most dangerous of the malarias. The onset is often
insidious, with malaise, headache and vomiting. Cough and mild
diarrhoea are also common. The fever has no particular pattern.
Jaundice is common due to haemolysis and hepatic dysfunction.
The liver and spleen enlarge and may become tender. Anaemia
develops rapidly, as does thrombocytopenia.
A patient with falciparum malaria, apparently not seriously ill,
may rapidly develop dangerous complications (Fig. 11.34 and
Box 1 1 .54). Cerebral malaria is manifested by delirium, seizures
or coma, usually without localising signs. Children die rapidly
without any specific symptoms other than fever. Immunity is
impaired in pregnancy and the parasite can preferentially bind
to the placental protein chondroitin sulphate A. Abortion and
intrauterine growth retardation from parasitisation of the maternal
side of the placenta are frequent. Previous splenectomy increases
the risk of severe malaria.
P. vivax and P. ovale infection
In many cases, the illness starts with several days of continued
fever before the development of classical bouts of fever on
alternate days. Fever starts with a rigor. The patient feels cold
and the temperature rises to about 40°C. After half an hour to
Neurological
Coma
Hypoglycaemia
Seizures
Cranial nerve palsies
Opisthotonus
^ Disconjugate gaze due
to cranial nerve palsy
Optic fundi
A Malaria retinopathy
with Roth’s spots
Respiratory
Pulmonary oedema
Secondary bacterial pneumonia
Cardiovascular -
Shock
Cardiac failure (‘algid malaria’)
Dysrhythmias with quinine
Renal -
Acute kidney injury
Severe haemolysis resulting
in haemoglobinuria (‘blackwater
Abdomen -
Jaundice
Tender liver edge with hepatitis
Pain in left upper quadrant
with splenomegaly
fever’
Blood
Parasitaemia
Anaemia
Thrombocytopenia
Coagulopathy
Blood film showing
parasitaemia
Ring form in RBCs
T P. vivax in RBCs
Ring form
Trophozoite
Schizont
Fig. 11.34 Features of Plasmodium falciparum infection. (RBC = red blood cell) Insets (malaria retinopathy) Courtesy of Dr Nicholas Beare, Royal
Liverpool University Hospital; (blood films of P. vivax and P. falciparum^ Courtesy of Dr Kamolrat Silamut, Mahidol Oxford Research Unit, Bangkok, Thailand.
276 • INFECTIOUS DISEASE
*
11.54 Severe manifestations/complications of falciparum malaria and their immediate management
Coma (cerebral malaria)
Spontaneous bleeding and coagulopathy
• Maintain airway
• Transfuse screened fresh whole blood (cryoprecipitate/fresh frozen
• Nurse on side
plasma and platelets if available)
• Exclude other treatable causes of coma (e.g. hypoglycaemia,
• Vitamin K injection
bacterial meningitis)
Metabolic acidosis
• Avoid harmful ancillary treatments such as glucocorticoids, heparin
and adrenaline (epinephrine)
• Exclude or treat hypoglycaemia, hypovolaemia and Gram-negative
• Intubate if necessary
sepsis
• Fluid resuscitation
Hyperpyrexia
• Give oxygen
• Tepid sponging, fanning, cooling blanket
Shock (‘algid malaria’)
• Antipyretic drug (paracetamol)
• Suspect Gram-negative sepsis
uonvuisions
• Take blood cultures
• Maintain airway
• Give parenteral antimicrobials
• Treat promptly with diazepam or paraldehyde injection
• Correct haemodynamic disturbances
Hypoglycaemia
Aspiration pneumonia
• Measure blood glucose
• Give parenteral antimicrobial drugs
• Give 50% dextrose injection followed by 10% dextrose infusion
• Change position
(glucagon may be ineffective)
• Physiotherapy
Severe anaemia (packed cell volume <15%)
• Give oxygen
• Transfuse fresh whole blood or packed cells if pathogen screening
Hyperparasitaemia
of donor blood is available
• Consider exchange transfusion (e.g. >10% of circulating erythrocytes
Acute pulmonary oedema
parasitised in non-immune patient with severe disease)
• Nurse at 45°, give oxygen, venesect 250 mL of blood, give diuretic,
Specific therapy
stop intravenous fluids
• Intravenous artesunate
• Intubate and add PEEP/CPAP (p. 202) in life-threatening hypoxaemia
• Mefloquine should be avoided due to increased risk of post-malaria
• Haemofilter
neurological syndrome
Acute kidney injury
• Exclude pre-renal causes
• Fluid resuscitation if appropriate
• Peritoneal dialysis (haemofiltration or haemodialysis if available)
(CPAP ;
= continuous positive airway pressure; PEEP = positive end-expiratory pressure)
From WHO. Severe falciparum malaria. In: Severe and complicated malaria, 3rd edn. Trans Roy Soc Trop Med Hyg 2000; 94 (suppl. 1):S1-41.
an hour, the hot or flush phase begins. It lasts several hours
and gives way to profuse perspiration and a gradual fall in
temperature. The cycle is repeated 48 hours later. Gradually,
the spleen and liver enlarge and may become tender. Anaemia
develops slowly. Relapses are frequent in the first 2 years after
leaving the malarious area and infection may be acquired from
blood transfusion.
P. malariae and P. knowlesi infection
This is usually associated with mild symptoms and bouts
of fever every third day. Parasitaemia may persist for many
years, with the occasional recrudescence of fever or without
producing any symptoms. Chronic P. malariae infection causes
glomerulonephritis and long-term nephrotic syndrome in children.
P. knowlesi is usually mild but can deteriorate rapidly.
Investigations
Giemsa-stained thick and thin blood films should be examined
whenever malaria is suspected. In the thick film, erythrocytes
are lysed, releasing all blood stages of the parasite. This, as well
as the fact that more blood is used in thick films, facilitates the
diagnosis of low-level parasitaemia. A thin film is essential to
confirm the diagnosis, species and, in P. falciparum infections,
to quantify the parasite load (by counting the percentage of
infected erythrocytes). P. falciparum parasites may be very scanty,
especially in patients who have been partially treated. With P.
falciparum, only ring forms are normally seen in the early stages
(Fig. 1 1 .34); with the other species, all stages of the erythrocytic
cycle may be found. Gametocytes appear after about 2 weeks,
persist after treatment and are harmless, except that they are
the source by which more mosquitoes become infected.
Immunochromatographic rapid diagnostic tests (RDTs) for
malaria antigens, such as OptiMAL (which detects the Plasmodium
LDH of P. falciparum and vivax) and Parasight-F (which detects
the P. falciparum histidine-rich protein 2), are extremely sensitive
and specific for falciparum malaria but less so for other species.
They should be used in parallel with blood film examination but
are especially useful where the microscopist is less experienced
in examining blood films (e.g. in the UK). They are less sensitive
for low-level parasitaemia and positivity may persist for a
month or more in some individuals. The QBC Malaria Test is a
fluorescence microscopy-based malaria diagnostic test that is also
widely used.
DNA detection (PCR) is used mainly in research and is useful
for determining whether a patient has a recrudescence of the
same malaria parasite or a reinfection with a new parasite.
Protozoal infections • 277
Management
Mild P. falciparum malaria
Since P. falciparum is now resistant to chloroquine and
sulfadoxine-pyrimethamine (Fansidar) almost worldwide, an
artemisinin-based treatment is recommended (Box 1 1 .55)
and WHO policy in Africa recommends always using ACT,
e.g. co-artemether or artesunate-amodiaquine. Unfortunately,
artemisinin resistance has now been reported in South-east Asia.
i
Mild malaria
Preferred therapy
• Co-artemether (CoArtem or Riamet); contains artemether and
lumefantrine (4 tablets orally at 0, 8, 24, 36, 48 and 60 hrs)
Alternative therapy
• Quinine (600 mg of quinine salt 3 times daily orally for 5-7 days),
together with or followed by doxycycline (200 mg once daily orally
for 7 days)
Use clindamycin not doxycycline if the patient is a pregnant
woman or young child
or
• Atovaquone-proguanil (Malarone, 4 tablets orally once daily for 3
days)
Pregnancy
• Co-artemether but avoid in early pregnancy.
• If not using co-artemether, use quinine plus clindamycin (450 mg 3
times daily orally for 7 days)
Other regimens
• Artesunate (200 mg orally daily for 3 days) and mefloquine (1 g
orally on day 2 and 500 mg orally on day 3)
Severe malaria
Preferred therapy
• Artesunate 2.4 mg/kg IV at 0, 12 and 24 hrs and then once daily
for 7 days. Once the patient is able to recommence oral intake,
switch to 2 mg/kg orally once daily, to complete a total cumulative
dose of 1 7-1 8 mg/kg
Alternative therapy
• Quinine, loading dose 20 mg/kg IV over 4 hrs, up to a maximum of
1 .4 g, then maintenance doses of 10 mg/kg quinine salt given as
4-hr infusions 3 times daily for the first 48 hrs then twice a day, up
to a maximum of 700 mg per dose or until the patient can take
drugs orally. Combine with doxycycline (or clindamycin if there are
contraindications to doxycycline)
• Note the loading dose should not be given if quinine, quinidine or
mefloquine has been administered in the previous 24 hrs
• Patients should be monitored by ECG while receiving quinine, with
special attention to QRS duration and QT interval
Non-falciparum malaria
Preferred therapy
• Chloroquine: 600 mg chloroquine base orally, followed by 300 mg
base in 6 hrs, then 150 mg base twice daily for 2 more days plus
primaquine (30 mg orally daily (for P. viva. x) or 15 mg orally daily
(for P. ovale) for 14 days) after confirming G6PD-negative
Patients with mild to moderate G6PD deficiency and P. vivax or
P. ovale
• Chloroquine plus primaquine 0.75 mg/kg weekly orally for 8 weeks
Chloroquine-resistant P. vivax
• Co-artemether as for P. falciparum
(G6PD = glucose-6-phosphate dehydrogenase)
Complicated P. falciparum malaria
Severe malaria should be considered in any non-immune patient
with a parasite count greater than 2% or with complications, and
is a medical emergency (see Box 1 1 .54). Management includes
early and appropriate antimalarial chemotherapy, active treatment
of complications, correction of fluid, electrolyte and acid-base
balance, and avoidance of harmful ancillary treatments.
The treatment of choice is intravenous artesunate. Late
haemolysis is a treatment side-effect in some patients. Rectal
administration of artesunate is also being developed to allow
administration in remote rural areas. Quinine salt is the alternative.
Exchange transfusion has not been tested in randomised
controlled trials but may be beneficial for non-immune patients
with persisting high parasitaemias (>10% circulating erythrocytes).
Non -falciparum malaria
P. vivax, P. ovale, P. knowlesi and P. malariae infections should
be treated with oral chloroquine but some chloroquine resistance
has been reported from Indonesia. ‘Radical cure’ is achieved
in patients with P. vivax or P. ovale malaria using a course of
primaquine, which destroys the hypnozoite phase in the liver.
Haemolysis may develop in those who are G6PD-deficient.
Cyanosis due to the formation of methaemoglobin in the red
cells is more common but not dangerous (see Fig. 7.1 , p. 135).
All are sensitive to ACTs.
Prevention
Clinical attacks of malaria may be preventable with
chemoprophylaxis using chloroquine, atovaquone plus proguanil
(Malarone), doxycycline or mefloquine. Box 1 1 .56 gives the
recommended doses for protection of the non-immune. The risk
of malaria in the area to be visited and the degree of chloroquine
resistance guide the recommendations for prophylaxis. Updated
recommendations are summarised at fitfortravel.nhs.uk. Fansidar
should not be used for chemoprophylaxis, as deaths have
occurred from agranulocytosis or Stevens-Johnson syndrome
(pp. 1224 and 1254). Mefloquine is useful in areas of multiple
drug resistance, such as East and Central Africa and Papua
New Guinea. Experience shows it to be safe for at least 2 years
but there are several contraindications to its use (Box 1 1 .56).
Expert advice is required for individuals unable to tolerate
the first-line agents listed or in whom they are contraindicated.
Mefloquine should be started 2-3 weeks before travel to give
time for assessment of side-effects. Chloroquine should not be
taken continuously as a prophylactic for more than 5 years without
regular ophthalmic examination, as it may cause irreversible
retinopathy. Pregnant and lactating women may take proguanil
or chloroquine safely.
Prevention also involves advice about the use of high-
percentage diethyltoluamide (DEET), covering up extremities
when out after dark, and sleeping under permethrin-impregnated
mosquito nets.
Malaria control in endemic areas
There are major initiatives to reduce and eliminate malaria
in endemic areas. Successful programmes combine vector
control, including indoor residual spraying, use of long-lasting
insecticide-treated bed nets (ITNs) and intermittent preventative
therapy (IPT; repeated dose of prophylactic drugs in high-risk
groups, such as children and pregnant women, which reduces
malaria and anaemia).
Research to produce a fully protective malaria vaccine is
ongoing.
11.55 Malaria treatment
278 • INFECTIOUS DISEASE
11.56 Chemoprophylaxis of malaria
Antimalarial tablets
Adult prophylactic dose
Regimen
Chloroquine resistance high
Mefloquine2
orDoxycycline3'4
or Malarone4
250 mg weekly
100 mg daily
1 tablet daily
Started 2-3 weeks before travel and continued until 4 weeks after
Started 1 week before and continued until 4 weeks after travel
From 1-2 days before travel until 1 week after return
Chloroquine resistance absent
Chloroquine5 and proguanil
300 mg base weekly ->
100-200 mg daily J
Started 1 week before and continued until 4 weeks after travel
1 Choice of regimen is determined by area to be visited, length of stay, level of malaria transmission, level of drug resistance, presence of underlying disease in the traveller
and concomitant medication taken. Contraindicated in the first trimester of pregnancy, lactation, cardiac conduction disorders, epilepsy, psychiatric disorders; may cause
neuropsychiatric disorders. Causes photosensitisation and sunburn if high-protection sunblock is not used. 4Avoid in pregnancy. 5British preparations of chloroquine usually
contain 150 mg base, French preparations 100 mg base and American preparations 300 mg base.
Babesiosis
Babesiosis is a tick-borne intra-erythrocytic protozoon parasite.
There are more than 100 species of Babesia, all of which have
an animal reservoir, typically either rodents or cattle, and are
transmitted to humans via the tick vector Ixodes scapularis.
Most American cases of babesiosis are due to B. microti and
most European cases to B. divergens. Patients present with
fever and malaise 1-4 weeks after a tick bite. Illness may be
complicated by haemolytic anaemia. Severe illness is seen in
splenectomised patients. The diagnosis is made by blood-film
examination. Treatment is with quinine and clindamycin.
African trypanosomiasis (sleeping sickness)
African sleeping sickness is caused by trypanosomes (Fig. 1 1 .35)
conveyed to humans by the bites of infected tsetse flies, and
is unique to sub-Saharan Africa (Fig. 1 1 .36). The incidence of
sleeping sickness across Africa has declined by over 60% since
1990 due to better control measures. Trypanosoma brucei
gambiense trypanosomiasis has a wide distribution in West
and Central Africa and accounts for 90% of human African
trypanosomiasis (HAT). T. brucei rhodesiense trypanosomiasis
is found in parts of East and Central Africa. In West Africa,
transmission is mainly at the riverside, where the fly rests in the
shade of trees; no animal reservoir has been identified for T.
gambiense. T. rhodesiense has a large reservoir in numerous
wild animals and transmission takes place in the shade of woods
bordering grasslands. Rural populations employed in agriculture,
fishing and animal husbandry are susceptible. Local people
and tourists visiting forests infested with tsetse flies and animal
reservoirs may become infected.
Clinical features
A bite by a tsetse fly is painful and commonly becomes inflamed;
if trypanosomes are introduced, the site may again become
painful and swollen about 10 days later (‘trypanosomal chancre’),
associated with regional lymphadenopathy. Within 2-3 weeks of
infection, the trypanosomes invade the blood stream. The disease
is characterised by an early haematolymphatic (stage 1) and a
late encephalitic phase (stage 2), in which the parasite crosses
the blood-brain barrier and chronic encephalopathy develops.
Rhodesiense infections
In these infections, the disease is more acute and severe than
in gambiense infections, so that, within days or a few weeks,
Fig. 11.35 Trypanosomiasis. Scanning electron micrograph showing
trypanosomes swimming among erythrocytes.
Fig. 11.36 Distribution of human African trypanosomiasis. Data are
from 2009. From Simarro PP, Diarra A, Ruiz Postigo JA, et al. The human
African trypanosomiasis control and surveillance programme of the World
Health Organization 2000-2009: the way forward. PLoS Negl Prop Dis
2011; 5(2):e1 007.
the patient is usually severely ill and may have developed pleural
effusions and signs of myocarditis or hepatitis. There may be
a petechial rash. The patient may die before there are signs of
involvement of the CNS. If the illness is less acute, drowsiness,
tremors and coma develop.
Protozoal infections • 279
Gambiense infections
The distinction between early and late stages may not be
apparent in gambiense infections. The disease usually runs a
slow course over months or years, with irregular bouts of fever
and enlargement of lymph nodes. These are characteristically
firm, discrete, rubbery and painless, and are particularly prominent
in the posterior triangle of the neck (‘Winterbottom’s sign’). The
spleen and liver may become palpable. After some months without
treatment, the CNS is invaded. Patients develop headache,
altered behaviour, blunting of higher mental functions, insomnia
by night and sleepiness by day, delirium and eventually tremors,
pareses, wasting, coma and death.
Investigations
Trypanosomiasis should be considered in any febrile patient from
an endemic area. In rhodesiense infections, thick and thin malaria
blood films will reveal trypanosomes. The trypanosomes may be
seen in the blood or from puncture of the primary lesion in the
earliest stages of gambiense infections, but it is usually easier to
demonstrate them by aspiration of a lymph node. Concentration
methods include buffy coat microscopy and miniature anion
exchange chromatography.
Due to the cyclical nature of parasitaemia, the diagnosis
is often made by demonstration of antibodies using a
simple, rapid screening card agglutination trypanosomiasis
test (CATT) for gambiense HAT, followed by parasitological
confirmation. No reliable serological test is available for
rhodesiense HAT. PCR diagnosis is available, although technical
requirements limit its availability in endemic regions. If the
CNS is affected, the cell count (>20x109 leucocytes/L) and
protein content of the CSF are increased and the glucose is
diminished. A very high level of serum IgM or the presence of
IgM in the CSF is suggestive of trypanosomiasis. Recognition
of CNS involvement is critical, as failure to treat it might
be fatal.
Management
Therapeutic options for African trypanosomiasis are limited and
most antitrypanosomal drugs are toxic and expensive. The
prognosis is good if treatment is begun early, before the brain
has been invaded. At this stage, intravenous suramin, after a
test dose of 100-200 mg, should be given for rhodesiense
infections, followed by five injections of 20 mg/kg every 7 days.
For gambiense infections, deep intramuscular or intravenous
pentamidine 4 mg/kg for 7 days is given.
For the treatment of stage 2 (nervous system) infection
caused by gambiense HAT, patients were previously treated
with melarsoprol (an arsenical). Treatment-related mortality
with melarsoprol is 4-12% due to reactive encephalopathy.
Now eflornithine (DFMO), an irreversible inhibitor of ornithine
decarboxylase (100 and 150 mg/kg IV 4 times daily for 14 days
for adults and children, respectively), is a safer and cost-effective
option. Combinations of eflornithine (400 mg daily for 7 days)
with oral nifurtimox (15 mg/kg daily for 15 days) have been
shown to decrease relapses, deaths and drug toxicity. Stage 2
rhodesiense infection is treated with melarsoprol 2.2 mg/kg IV for
1 0 days.
Prevention
In endemic gambiense areas, various measures are taken against
tsetse flies, and field teams help detect and treat early HAT. In
rhodesiense endemic areas, control is difficult.
American trypanosomiasis (Chagas’ disease)
Chagas’ disease occurs widely in South and Central America.
The cause is Trypanosoma cruzi, transmitted to humans from the
faeces of a reduviid (triatomine) bug, in which the trypanosomes
develop before infecting humans. These bugs live in wild forests
in crevices, burrows and palm trees. The Triatoma infestans
bug has become domesticated in the Southern Cone countries
(Argentina, Brazil, Chile, Paraguay and Uruguay). It lives in
the mud and wattle walls and thatched roofs of simple rural
houses and emerges at night to feed and defaecate on the
sleeping occupants. Infected faeces are rubbed in through
the conjunctiva, mucosa of mouth or nose, or abrasions of the
skin. Over 100 species of mammal - domestic, peridomestic
and wild - may serve as reservoirs of infection. In some areas,
blood transfusion accounts for about 5% of cases. Congenital
transmission occasionally occurs.
Pathology
The trypanosomes migrate via the blood stream, develop into
amastigote forms in the tissues and multiply intracellularly by binary
fission. In the acute phase (primarily cell-mediated), inflammation
of parasitised, as well as non-parasitised, cardiac muscles
and capillaries occurs, resulting in acute myocarditis. In the
chronic phase, focal myocardial atrophy, signs of chronic passive
congestion and thromboembolic phenomena, cardiomegaly and
apical cardiac aneurysm are salient findings. In the digestive
form of disease, focal myositis and discontinuous lesions of
the intramural myenteric plexus are seen, predominantly in the
oesophagus and colon.
Clinical features
Acute phase
Clinical manifestations of the acute phase are seen in only 1-2%
of individuals infected before the age of 1 5 years. Young children
(1-5 years) are most commonly affected. The entrance of T.
cruzi through an abrasion produces a dusky- red, firm swelling
and enlargement of regional lymph nodes. A conjunctival lesion,
although less common, is characteristic; the unilateral firm, reddish
swelling of the lids may close the eye and constitutes ‘Romana’s
sign’. In a few patients, an acute generalised infection soon
appears, with a transient morbilliform or urticarial rash, fever,
lymphadenopathy and enlargement of the spleen and liver. In a
small minority of patients, acute myocarditis and heart failure or
neurological features, including personality changes and signs
of meningoencephalitis, may be seen. The acute infection may
be fatal to infants.
Chronic phase
About 50-70% of infected patients become seropositive and
develop an indeterminate form when no parasitaemia is detectable.
They have a normal lifespan with no symptoms but are a natural
reservoir for the disease and maintain the life cycle of parasites.
After a latent period of several years, 1 0-30% of chronic cases
develop low-grade myocarditis and damage to conducting fibres,
which causes cardiomyopathy characterised by cardiac dilatation,
arrhythmias, partial or complete heart block and sudden death.
In nearly 10% of patients, damage to Auerbach’s plexus results
in dilatation of various parts of the alimentary canal, especially
the colon and oesophagus, so-called ‘mega’ disease. Dilatation
of the bile ducts and bronchi are also recognised sequelae.
Autoimmune processes may be responsible for much of the
damage. There are geographical variations of the basic pattern
280 • INFECTIOUS DISEASE
of disease. Reactivation of Chagas’ disease can occur in patients
with HIV if the CD4 count falls lower than 200 cells/mm3; this
can cause space-occupying lesions with a presentation similar to
Toxoplasma gondii, encephalitis, encephalitis, meningoencephalitis
or myocarditis.
Investigations
T. cruzi is easily detectable in a blood film in the acute illness. In
chronic disease, it may be recovered in up to 50% of cases by
xenodiagnosis, in which infection -free, laboratory-bred reduviid
bugs feed on the patient; subsequently, the hindgut or faeces
of the bug are examined for parasites. Parasite DNA detection
by PCR in the patient’s blood is a highly sensitive method for
documentation of infection and, in addition, can be employed in
faeces of bugs used in xenodiagnosis tests to improve sensitivity.
Antibody detection is also highly sensitive.
Management and prevention
Parasiticidal agents are used to treat the acute phase, congenital
disease and early chronic phase (within 10 years of infection).
Nifurtimox is given orally. The dose, which has to be carefully
supervised to minimise toxicity while preserving parasiticidal
activity, is 10 mg/kg daily orally, divided into three equal doses
for 90 days. The paediatric dose is 15 mg/kg daily. Cure rates of
80% in acute disease are obtained. Benznidazole is an alternative,
given at a dose of 5 mg/kg daily orally, in two divided doses for
60 days; children receive 1 0 mg/kg daily. Both nifurtimox and
benznidazole are toxic, with adverse reaction rates of 30-55%.
Parasiticidal treatment of the chronic phase is usually performed
but, in the cardiac or digestive ‘mega’ diseases, does not reverse
tissue damage. Surgery may be needed.
Preventative measures include improvement of housing
and destruction of reduviid bugs by spraying of houses with
insecticides. Blood and organ donors should be screened.
|joxoplasmosis
Toxoplasma gondii is an intracellular parasite. The sexual phase of
the parasite’s life cycle (Fig. 1 1 .37) occurs in the small intestinal
epithelium of the domestic cat. Oocysts are shed in cat faeces
and are spread to intermediate hosts (pigs, sheep and also
humans) through widespread contamination of soil. Oocysts may
survive in moist conditions for weeks or months. Once they are
ingested, the parasite transforms into rapidly dividing tachyzoites
through cycles of asexual multiplication. Microscopic tissue cysts
develop containing bradyzoites, which persist for the lifetime of
the host. Cats become infected or reinfected by ingesting tissue
cysts in prey such as rodents and birds.
Human infection occurs via oocyst-contaminated soil, salads
and vegetables, or by ingestion of raw or under-cooked meats
containing tissue cysts. Sheep, pigs and rabbits are the most
common meat sources. Outbreaks of toxoplasmosis have been
linked to the consumption of unfiltered water. In developed
countries, toxoplasmosis is the most common protozoal infection;
around 22% of adults in the UK are seropositive. Most primary
infections are subclinical; however, toxoplasmosis is thought to
account for about 1 5% of heterophile antibody-negative infectious
mononucleosis (p. 241). In India or Brazil, approximately 40-60%
of pregnant females are seropositive for T. gondii. In HIV-1
infection (p. 320), toxoplasmosis is an important opportunistic
infection with considerable morbidity and mortality. Generalised
toxoplasmosis has been described after accidental laboratory
infection with highly virulent strains.
Congenital
infection
Fig. 1 1 .37 Life cycle of Toxoplasma gondii.
Clinical features
In most immunocompetent individuals, including children and
pregnant women, the infection goes unnoticed. In approximately
1 0% of patients, it causes a self-limiting illness, most common in
adults aged 25-35 years. The presenting feature is usually localised
or generalised painless lymphadenopathy. The cervical nodes are
primarily involved but mediastinal, mesenteric or retroperitoneal
groups may be affected. The spleen is seldom palpable. Most
patients have no systemic symptoms but some complain of
malaise, fever, fatigue, muscle pain, sore throat and headache.
Complete resolution usually occurs within a few months, although
symptoms and lymphadenopathy tend to fluctuate unpredictably
and some patients do not recover completely for a year or more.
Encephalitis, myocarditis, polymyositis, pneumonitis or hepatitis
occasionally occur in immunocompetent patients but are more
frequent in immunocompromised hosts. Retinochoroiditis (Fig.
1 1 .38) is usually the result of congenital infection but has also
been reported in acquired disease.
Congenital toxoplasmosis
Acute toxoplasmosis, mostly subclinical, affects 0.3-1% of
pregnant women, with an approximately 60% transmission rate
to the fetus, which rises with increasing gestation. Seropositive
females infected 6 months before conception have no risk of
fetal transmission. Congenital disease affects approximately 40%
of infected fetuses, and is more likely and more severe with
infection early in gestation (see Box 1 1 .26, p. 235). Many fetal
infections are subclinical at birth but long-term sequelae include
retinochoroiditis, microcephaly and hydrocephalus.
Protozoal infections • 281
Fig. 11.38 Retinochoroiditis due to toxoplasmosis.
Investigations
In contrast to immunocompromised patients, in whom the
diagnosis often requires direct detection of parasites, serology is
often used in immunocompetent individuals. The Sabin-Feldman
dye test (indirect fluorescent antibody test), which detects IgG
antibody, is most commonly used. Recent infection induces a
fourfold or greater increase in titre when paired sera are tested
in parallel. Peaktitres of 1/1000 or more are reached within 1-2
months of the onset of infection, and serology then becomes
an unreliable indicator of recent infection. The detection of
significant levels of Toxoplasma- specific IgM antibody may be
useful in confirming acute infection. A false-positive result or
persistence of IgM antibodies for years after infection makes
interpretation difficult; however, negative IgM antibodies virtually
rule out acute infection.
During pregnancy, it is critical to differentiate recent from past
infection; the presence of high-avidity IgG antibodies excludes
infection acquired in the preceding 3-4 months.
If necessary, the presence of Toxoplasma organisms in a lymph
node biopsy or other tissue can be detected histochemically with
T. gondii antiserum, or by the use of PCR to detect Toxoplasma-
specific DNA.
Management
In immunocompetent subjects, uncomplicated toxoplasmosis
is self-limiting and responds poorly to antimicrobial therapy.
Treatment with sulfadiazine, pyrimethamine and folinic acid
is usually reserved for severe or progressive disease, and for
infection in immunocompromised patients.
In pregnant women with established recent infection, spiramycin
(3 g daily in divided doses) is given until term. Once fetal infection
is established, treatment with sulfadiazine and pyrimethamine
plus calcium folinate is recommended (spiramycin does not cross
the placental barrier). The cost/benefit of routine Toxoplasma
screening and treatment in pregnancy is being debated in many
countries. There is insufficient evidence to determine the effects
on mother or baby of current antiparasitic treatment for women
who seroconvert in pregnancy.
Leishmaniasis
Leishmaniasis is caused by unicellular, flagellate, intracellular
protozoa belonging to the genus Leishmania (order Kineto-
Fig. 11.39 Transmission of leishmaniasis. [A] Zoonotic transmission.
[B] Anthroponotic transmission. [C] Anthroponotic transmission in the
injection drug-user. (CL = cutaneous leishmaniasis; VL = visceral
leishmaniasis)
plastidae). There are 21 leishmanial species that cause diverse
clinical syndromes, which can be placed into three broad groups:
• visceral leishmaniasis (VL, kala-azar)
• cutaneous leishmaniasis (CL)
• mucosal leishmaniasis (ML).
Epidemiology and transmission
Although most clinical syndromes are caused by zoonotic
transmission of parasites from animals (chiefly canine and rodent
reservoirs) to humans through phlebotomine sandfly vectors (Fig.
1 1 .39A), humans are the only known reservoir (anthroponotic
person-to-person transmission) in major VL foci in the Indian
subcontinent and in injection drug-users (Fig. 1 1 .39B and C).
Leishmaniasis occurs in approximately 100 countries around
the world, with an estimated annual incidence of 0.9-1 .3 million
new cases (25% VL).
The life cycle of Leishmania is shown in Figure 1 1 .40. Flagellar
promastigotes (1 0-20 |im) are introduced by the feeding female
sandfly. The promastigotes are taken up by neutrophils, which
undergo apoptosis and are then engulfed by macrophages,
in which the parasites transform into amastigotes (2-4 jam;
Leishman-Donovan body). These multiply, causing macrophage
282 • INFECTIOUS DISEASE
Sandfly
(Phlebotomus in eastern hemisphere,
Lutzomyia and Psychodopygus
in western hemisphere)
Dermis only Dermis and
L. tropica mucosae
L. mexicana etc. (sometimes)
L. brasiliensis
Viscera and
dermis
(sometimes)
L. do novan i
Fig. 1 1 .40 Life cycle of Leishmania. From Knight R. Parasitic disease
in man. Churchill Livingstone, Elsevier Ltd; 1982.
Fig. 11.41 World distribution of visceral leishmaniasis.
Fig. 11.42 Splenic smear showing numerous intracellular, and a few
extracellular, amastigotes. Courtesy of Dr S. Sundar and Dr H.W. Murray.
lysis and infection of other cells. Sandflies pick up amastigotes
when feeding on infected patients or animal reservoirs. In the
sandfly, the parasite transforms into a flagellar promastigote,
which multiplies by binary fission in the gut of the vector and
migrates to the proboscis to infect a new host.
Sandflies live in hot and humid climates in the cracks and
crevices of mud or straw houses and lay eggs in organic matter.
People living in such conditions are more prone to leishmaniasis.
Female sandflies bite during the night and preferentially feed on
animals; humans are incidental hosts.
| Visceral leishmaniasis (kala-azar)
VL is caused by the protozoon Leishmania donovani complex
(comprising L. donovani, L. infantum and L. chagasi). India,
Sudan, Bangladesh and Brazil account for 90% of cases of VL.
Other affected regions include the Mediterranean, East Africa,
China, Arabia, Israel and other South American countries (Fig.
11.41). In addition to sandfly transmission, VL has also been
reported to follow blood transfusion, and disease can present
unexpectedly in immunosuppressed patients - for example, after
renal transplantation and in HIV infection.
The majority of people infected remain asymptomatic. In
visceral disease, the spleen, liver, bone marrow and lymph
nodes are primarily involved.
Clinical features
In the Indian subcontinent, adults and children are equally affected;
elsewhere, VL is mainly a disease of small children and infants,
except in adults with HIV co-infection. The incubation period
ranges from weeks to months (occasionally, several years).
The first sign of infection is high fever, usually accompanied by
rigor and chills. Fever intensity decreases over time and patients
may become afebrile for intervening periods ranging from weeks
to months. This is followed by a relapse of fever, often of lesser
intensity. Splenomegaly develops quickly in the first few weeks
and becomes massive as the disease progresses. Moderate
hepatomegaly occurs later. Lymphadenopathy is common in
Africa, the Mediterranean and South America but is rare in the
Indian subcontinent. Blackish discoloration of the skin, from which
the disease derived its name, kala-azar (the Hindi word for ‘black
fever’), is a feature of advanced illness but is now rarely seen.
Pancytopenia is common. Moderate to severe anaemia develops
rapidly and can cause cardiac failure. Thrombocytopenia, often
compounded by hepatic dysfunction, may result in bleeding from
the retina, gastrointestinal tract and nose. In advanced illness,
hypoalbuminaemia may manifest as pedal oedema, ascites and
anasarca (gross generalised oedema and swelling).
As disease progresses, there is profound immunosuppression
and secondary infections are very common. These include
tuberculosis, pneumonia, gastroenteritis, severe amoebic
or bacillary dysentery, boils, cellulitis, chickenpox, shingles
and scabies. Without adequate treatment, most patients with
clinical VL die.
Investigations
Pancytopenia is the dominant feature, with granulocytopenia and
monocytosis. Polyclonal hypergammaglobulinaemia, chiefly IgG
followed by IgM, and hypoalbuminaemia are seen later.
Demonstration of amastigotes (Leishman-Donovan bodies)
in splenic smears is the most efficient means of diagnosis, with
98% sensitivity (Fig. 1 1 .42); however, it carries a risk of serious
haemorrhage in inexperienced hands. Safer methods, such as
bone marrow or lymph node smears, are not as sensitive but
Protozoal infections • 283
are frequently employed. Parasites may be demonstrated in
buffy coat smears, especially in immunosuppressed patients.
Sensitivity is improved by culturing the aspirate material or by
using PCR for DNA detection and species identification, but
these tests can only be performed in specialised laboratories.
Serodiagnosis, by ELISA or immunofluorescence antibody test,
is employed in developed countries. In endemic regions, a highly
sensitive direct agglutination test using stained promastigotes and
an equally efficient rapid immunochromatographic k39 strip test
have become popular. These tests remain positive for several
months after cure has been achieved, so do not predict response
to treatment or relapse. The vast majority of people exposed to
the parasite do not develop clinical illness but may have positive
serological tests thereafter. Formal gel (aldehyde) or other similar
tests based on the detection of raised globulin have limited value
and should not be employed for the diagnosis of VL.
Differential diagnosis
This includes malaria, typhoid, tuberculosis, schistosomiasis and
many other infectious and neoplastic conditions, some of which
may coexist with VL. Fever, splenomegaly, pancytopenia and
non-response to antimalarial therapy may provide clues before
specific laboratory diagnosis is made.
Management
Pentavalent antimonials
Antimony (Sb) compounds were the first drugs to be used
for the treatment of leishmaniasis and remain the mainstay of
treatment in most parts of the world. The exception is the Indian
subcontinent, especially Bihar state, where almost two-thirds of
cases are refractory to Sb treatment. Traditionally, pentavalent
antimony is available as sodium stibogluconate (100 mg/mL)
in English-speaking countries and meglumine antimoniate
(85 mg/mL) in French-speaking ones. The daily dose is 20 mg/
kg body weight, intravenously or intramuscularly, for 28-30
days. Side-effects are common and include arthralgia, myalgia,
raised hepatic transaminases, pancreatitis (especially in patients
co-infected with HI V) and ECG changes (T-wave inversion and
reduced amplitude). Severe cardiotoxicity, manifest by concave
ST segment elevation, prolongation of QTC greater than 0.5 msec
and ventricular dysrhythmias, is not uncommon. The incidence
of cardiotoxicity and death is particularly high with improperly
manufactured Sb.
Amphotericin B
Amphotericin B deoxycholate, given once daily or on alternate
days at a dose of 0.75-1.00 mg/kg for 15-20 doses, is used
as the first-line drug in many regions where there is a significant
level of Sb unresponsiveness. It has a cure rate of nearly
100%. Infusion-related side-effects, such as high fever with
rigor, thrombophlebitis, diarrhoea and vomiting, are extremely
common. Serious side-effects, including renal or hepatic toxicity,
hypokalaemia and thrombocytopenia, are observed frequently.
Lipid formulations of amphotericin B (p. 126) are less
toxic. AmBisome is first-line therapy in Europe for VL. Dosing
recommendations vary according to geographical region.
In the Indian subcontinent, a total dose of 10 or 15 mg/kg,
administered in a single dose or as multiple doses over several
days, respectively, is considered adequate, whereas in Africa
14-18 mg/kg, and in South America and Europe 21-24 mg/kg,
in divided doses, typically spread over 10 days, is recommended
for immunocompetent patients. High daily doses of the lipid
formulations are well tolerated, and in one study a single dose
of 10 mg/kg of AmBisome cured 96% of Indian patients. The
manufacturer of AmBisome has donated a large quantity of the
drug for use in the Kala-azar Elimination Programme in India,
Nepal and Bangladesh, leading to its adoption as the first-line
drug in treatment.
Other drugs
The oral drug miltefosine, an alkyl phospholipid, has been
approved in several countries for the treatment of VL. A daily dose
of 50 mg (patient’s body weight <25 kg) to 100 mg (>25 kg), or
2.5 mg/kg for children, for 28 days cures over 90% of patients.
Side-effects include mild to moderate vomiting and diarrhoea,
and rarely skin allergy or renal or liver toxicity. Since it is a
teratogenic drug, it cannot be used in pregnancy; female patients
are advised not to become pregnant for the duration of treatment
and 3 months thereafter because of its half-life of nearly 1 week.
Paromomycin is an aminoglycoside that has undergone trials in
India and Africa, and is highly effective if given intramuscularly at
1 1 mg/kg of paromomycin base, daily for 3 weeks. No significant
auditory or renal toxicity is seen. The drug is approved in India
for VL treatment.
Pentamidine isethionate was used to treat Sb-refractory patients
with VL. However, declining efficacy and serious side-effects,
such as type 1 diabetes mellitus, hypoglycaemia and hypotension,
have led to it being abandoned.
Multidrug therapy of VL is likely to be used increasingly to
prevent emergence of drug resistance, and in India short-course
combinations (a single dose of AmBisome 5 mg/kg with either 7
days of miltefosine or 10 days of paromomycin, or 10 days each
of miltefosine and paromomycin) were as effective as standard
therapy. In India, in treatment centres where the cold chain (a
temperature-controlled supply chain) is not maintained, 10 days
of paromomycin combined with miltefosine is an alternative
treatment regimen.
Response to treatment
A good response results in fever resolution, improved well-being,
reduction in splenomegaly, weight gain and recovery of blood
counts. Patients should be followed regularly for 6-1 2 months,
as some may experience relapse irrespective of the treatment
regimen.
HIV-visceral leishmaniasis co-infection
HIV-induced immunosuppression (Ch. 12) increases the risk
of contracting VL 100-1000 times. Most cases of HIV-VL
co-infection have been reported from Spain, France, Italy and
Portugal. Antiretroviral therapy (ART) has led to a remarkable
decline in the incidence of VL co-infection in Europe. However,
numbers are increasing in Africa (mainly Ethiopia), Brazil and
the Indian subcontinent.
Although the clinical triad of fever, splenomegaly and
hepatomegaly is found in the majority of co-infected patients,
those with low CD4 count may have atypical clinical presentations.
VL may present with gastrointestinal involvement (stomach,
duodenum or colon), ascites, pleural or pericardial effusion, or
involvement of lungs, tonsil, oral mucosa or skin. Diagnostic
principles remain the same as those in non-HIV patients. Parasites
are numerous and easily demonstrable, even in buffy coat
preparations. Sometimes amastigotes are found in unusual sites,
such as bronchoalveolar lavage fluid, pleural fluid or biopsies of
the gastrointestinal tract. Serological tests have low sensitivity.
DNA detection by PCR of the blood or its buffy coat is at least
95% sensitive and accurately tracks recovery and relapse.
284 • INFECTIOUS DISEASE
Treatment of VL with HIV co-infection is essentially the same
as in immunocompetent patients but there are some differences
in outcome. Conventional amphotericin B (0.7 mg/kg/day for
28 days) may be more effective in achieving initial cure than
Sb (20 mg/kg/day for 28 days). Using high-dose liposomal
amphotericin B (4 mg/kg on days 1-5, 10, 17, 24, 31 and 38), a
high cure rate is possible. However, co-infected patients have a
tendency to relapse within 1 year and maintenance chemotherapy
with monthly liposomal amphotericin B is useful.
Post-kala-azar dermal leishmaniasis
After treatment and apparent recovery from VL in India and
Sudan, some patients develop dermatological manifestations
due to local parasitic infection.
Clinical features
In India, dermatological changes occur in a small minority of
patients 6 months to at least 3 years after the initial infection.
They are seen as macules, papules, nodules (most frequently)
and plaques, which have a predilection for the face, especially
the area around the chin. The face often appears erythematous
(Fig. 1 1 .43A). Hypopigmented macules can occur over all parts of
the body and are highly variable in extent. There are no systemic
symptoms and little spontaneous healing occurs.
In Sudan, approximately 50% of patients with VL develop
post-kala-azar dermal leishmaniasis (PKDL), experiencing skin
manifestations concurrently with VL or within the following 6
months. In addition to the dermatological features, a measles-like
micropapular rash (Fig. 1 1 .43B) may be seen all over the body.
In Sudan, children are more frequently affected than in India.
Spontaneous healing occurs in about three-quarters of cases
within 1 year.
Investigations and management
The diagnosis is clinical, supported by demonstration of
scanty parasites in lesions by slit-skin smear and culture.
Immunofluorescence and immunohistochemistry may demonstrate
the parasite in skin tissues. In the majority of patients, serological
tests (direct agglutination test or k39 strip tests) are positive.
Treatment of PKDL is difficult. In India, Sb for 120 days,
several courses of amphotericin B infusions, or miltefosine for
12 weeks is required. In Sudan, Sb for 2 months is considered
adequate. In the absence of a physical handicap, most patients
are reluctant to complete the treatment. PKDL patients are a
human reservoir, and focal outbreaks have been linked to patients
with PKDL in areas previously free of VL.
Prevention and control
Sandfly control through insecticide spray is very important.
Mosquito nets or curtains treated with insecticides will keep out
the tiny sandflies. In endemic areas with zoonotic transmission,
infected or stray dogs should be destroyed.
In areas with anthroponotic transmission, early diagnosis
and treatment of human infections, to reduce the reservoir and
control epidemics of VL, is extremely important. Serology is
useful in diagnosis of suspected cases in the field. No vaccine
is currently available.
Cutaneous and mucosal leishmaniasis
Cutaneous leishmaniasis
CL (oriental sore) occurs in both the Old World (Asia, Africa
and Europe) and the New World (the Americas). Transmission
is described on page 281 .
In the Old World, CL is mild. It is found around the Mediterranean
basin, throughout the Middle East and Central Asia as far as
Pakistan, and in sub-Saharan West Africa and Sudan (Fig. 1 1 .44).
The causative organisms for Old World zoonotic CL are L major,
L. tropica and L. aethiopica (Box 1 1 .57). Anthroponotic CL is
caused by L tropica, and is confined to urban or suburban areas
of the Old World. Afghanistan is currently the biggest focus but
infection is endemic in Pakistan, the western deserts of India,
Iran, Iraq, Syria and other areas of the Middle East. In recent
years, there has been an increase in the incidence of zoonotic
CL in both the Old and the New Worlds due to urbanisation
and deforestation, which led to peridomestic transmission (in
and around human dwellings).
Fig. 11.43 Post-kala-azar dermal leishmaniasis. [A] In India, with macules, papules, nodules and plaques. [§] In Sudan, with micronodular rash.
A, From Sundar S, Kumar K, Chakravarty J, et al. Cure of antimony-unresponsive Indian post-kala-azar dermal leishmaniasis with oral miltefosine. Trans R
Soc Trop Med Hyg 2006; 100(7):698-700. B, Courtesy of Dr E.E. Zijistra.
Protozoal infections • 285
New World CL is a more significant disease, which may
disfigure the nose, ears and mouth, and is caused by the
L. mexicana complex (comprising L. mexicana, L amazonensis
and L. venezuelensis) and by the Viannia subgenus L. (V.)
brasiliensis complex (comprising L. (V.) guyanensis, L. (V.)
panamensis, L. (V.) brasiliensis and L. (V.) peruviana).
CL is commonly imported and should be considered in the
differential diagnosis of an ulcerating skin lesion, especially in
travellers who have visited endemic areas of the Old World or
forests in Central and South America.
Pathogenesis
Inoculated parasites are taken up by dermal macrophages, in
which they multiply and form a focus for lymphocytes, epithelioid
cells and plasma cells. Self-healing may occur with necrosis
of infected macrophages, or the lesion may become chronic
with ulceration of the overlying epidermis, depending on the
aetiological pathogen.
Clinical features
The incubation period is typically 2-3 months (range 2 weeks
to 5 years). In all types of CL a papule develops at the site of
1 1 1 .57 Types of Old World cutaneous leishmaniasis
Leishmania spp.
Host
Clinical features
L. tropica
Dogs
Slow evolution, less severe
L. major
Gerbils, desert
rodents
Rapid necrosis, wet sores
L aethiopica
Hyraxes
Solitary facial lesions with
satellites
L. mexicana L. infantum L. major
■ L. brasiliensis L. tropica b. aethiopica
Fig. 11.44 World distribution of cutaneous leishmaniasis.
the vector bite. The small, red papules may be single or multiple
and increase gradually in size, reaching 2-10 cm in diameter.
A crust forms, overlying an ulcer with a granular base and
with raised borders (Fig. 11.45). These ulcers develop a few
weeks or months after the bite. There can be satellite lesions,
especially in L. major and occasionally in L. tropica infections.
Regional lymphadenopathy, pain, pruritus and secondary bacterial
infections may occur.
Lesions of L. mexicana and L. peruviana closely resemble
those seen in the Old World, but lesions on the pinna of the ear
are common and are chronic and destructive. L. mexicana is
responsible for chiclero ulcers, the self-healing sores of Mexico.
If immunity is effective, there is usually spontaneous healing
in L tropica, L major and L mexicana lesions. In some patients
with anergy to Leishmania, the skin lesions of L. aethiopica,
L. mexicana and L. amazonensis infections progress to the
development of diffuse CL; this is characterised by spread of
the infection from the initial ulcer, usually on the face, to involve
the whole body in the form of non-ulcerative nodules. Occasionally,
in L tropica infections, sores that have apparently healed relapse
persistently (recidivans or lupoid leishmaniasis).
Mucosal leishmaniasis
The Viannia subgenus extends widely from the Amazon basin
as far as Paraguay and Costa Rica, and is responsible for deep
sores and ML. In L (V.) brasiliensis complex infections, cutaneous
lesions may be followed by mucosal spread of the disease
simultaneously or even years later. Young men with chronic
lesions are particularly at risk, and 2-40% of infected persons
develop ‘espundia’, metastatic lesions in the mucosa of the nose
or mouth. This is characterised by thickening and erythema of
the nasal mucosa, typically starting at the junction of the nose
and upper lip. Later, ulceration develops. The lips, soft palate,
fauces and larynx may also be invaded and destroyed, leading
to considerable suffering and deformity. There is no spontaneous
healing, and death may result from severe respiratory tract
infections due to massive destruction of the pharynx.
Investigations in CL and ML
CL is often diagnosed on the basis of the lesions’ clinical
characteristics. Parasitological confirmation is important, however,
because clinical manifestations may be mimicked by other
infections. Amastigotes can be demonstrated on a slit-skin smear
with Giemsa staining; alternatively, they can be cultured from the
sores early during the infection. Parasites seem to be particularly
Fig. 11.45 Cutaneous leishmaniasis. [A] Papule. J] Ulcer. B, Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital, Sheffield.
286 • INFECTIOUS DISEASE
difficult to isolate from sores caused by L brasiliensis, responsible
for the vast majority of cases in Brazil. Touch preparations from
biopsies and histopathology usually have a low sensitivity. Culture
of fine needle aspiration material has been reported to be the
most sensitive method.
ML is more difficult to diagnose parasitologically. The leishmanin
skin test measures delayed-type hypersensitivity to killed
Leishmania organisms. A positive test is defined as induration
of more than 5 mm, 48 hours after intradermal injection. The
test is positive, except in diffuse CL and during active VL. PCR
is used increasingly for diagnosis and speciation, which is useful
in selecting therapy.
Management of CL and ML
Small lesions may self-heal or are treated by freezing with liquid
nitrogen or curettage. There is no ideal antimicrobial therapy.
Treatment should be individualised on the basis of the causative
organism, severity of the lesions, availability of drugs, tolerance
of the patient for toxicity, and local resistance patterns.
In CL, topical application of paromomycin 15% plus
methylbenzethonium chloride 12% is beneficial. Intralesional
antimony (Sb 0.2-0. 8 mMesion) up to 2 g seems to be rapidly
effective in suitable cases; it is well tolerated and economic, and
is safe in patients with cardiac, liver or renal diseases.
In ML, and in CL when the lesions are multiple or in a disfiguring
site, it is better to treat with parenteral Sb in a dose of 20 mg/
kg/day (usually given for 20 days for CL and 28 days for ML), or
with conventional or liposomal amphotericin B (see treatment of
VL above). Sb is also indicated to prevent the development of
mucosal disease, if there is any chance that a lesion acquired
in South America is due to an L brasiliensis strain. Refractory
CL or ML should be treated with an amphotericin B preparation.
Other regimens may be effective. Two to four doses of
pentamidine (2-4 mg/kg), administered on alternate days, are
effective in New World CL caused by L. guyanensis. In ML, 8
injections of pentamidine (4 mg/kg on alternate days) cure the
majority of patients. Ketoconazole (600 mg daily for 4 weeks)
has shown some potential against L. mexicana infection. In
Saudi Arabia, fluconazole (200 mg daily for 6 weeks) reduced
healing times and cured 79% of patients with CL caused by L.
major. In India, itraconazole (200 mg daily for 6 weeks) produced
good results in CL.
Prevention of CL and ML
Personal protection against sandfly bites is important. No effective
vaccine is yet available.
Gastrointestinal protozoal infections
Amoebiasis
Amoebiasis is caused by Entamoeba histolytica, which is
spread between humans by its cysts. It is one of the leading
parasitic causes of morbidity and mortality in the tropics and
is occasionally acquired in non-tropical countries. Two non¬
pathogen ic Entamoeba species (E dispar and E moshkovskii) are
morphologically identical to E histolytica, and are distinguishable
only by molecular techniques, isoenzyme studies or monoclonal
antibody typing. However, only E. histolytica causes amoebic
dysentery or liver abscess. The life cycle of the amoeba is shown
in Figure 1 1 .46A.
Pathology
Cysts of E. histolytica are ingested in water or uncooked foods
contaminated by human faeces. Infection may also be acquired
through anal/oral sexual practices. In the colon, trophozoite
forms emerge from the cysts. The parasite invades the mucous
membrane of the large bowel, producing lesions that are maximal
0
Ingested
mature cyst
Cyst maturation
in distal colon
and faeces c;
Excystment in
ij) small bowel
Amoeboma
Amoebic
abscess
AAA^/v^^^yvvvi/wi ;
Ingested
erythrocytes
Tissue
trophozoite
Fig. 11.46 Amoebiasis. [A] The life cycle of Entamoeba histolytica. [§] The chocolate-brown appearance of aspirated material from an amoebic liver
abscess. A, From Knight R. Parasitic disease in man. Churchill Livingstone, Elsevier Ltd; 1982. B, Courtesy of Dr Ravi Gowda, Royal Hallamshire Hospital,
Sheffield.
Protozoal infections • 287
in the caecum but extend to the anal canal. These are flask¬
shaped ulcers, varying greatly in size and surrounded by healthy
mucosa. A localised granuloma (amoeboma), presenting as a
palpable mass in the rectum or a filling defect in the colon on
radiography, is a rare complication that should be differentiated
from carcinoma. Amoebic ulcers may cause severe haemorrhage
but rarely perforate the bowel wall.
Amoebic trophozoites can emerge from the vegetative cyst
from the bowel and be carried to the liver in a portal venule.
They can multiply rapidly and destroy the liver parenchyma,
causing an abscess (see also p. 879). The liquid contents at first
have a characteristic pinkish colour, which may later change to
chocolate-brown (said to resemble anchovy sauce).
Cutaneous amoebiasis, though rare, causes progressive
genital, perianal or peri-abdominal surgical wound ulceration.
Clinical features
Intestinal amoebiasis - amoebic dysentery
Most amoebic infections are asymptomatic. The incubation
period of amoebiasis ranges from 2 weeks to many years,
followed by a chronic course with abdominal pains and two or
more unformed stools a day. Offensive diarrhoea, alternating
with constipation, and blood or mucus in the stool are common.
There may be abdominal pain, especially in the right lower
quadrant (which may mimic acute appendicitis). A dysenteric
presentation with passage of blood, simulating bacillary dysentery
or ulcerative colitis, occurs particularly in older people, in
the puerperium and with super-added pyogenic infection of
the ulcers.
Amoebic liver abscess
The abscess is usually found in the right hepatic lobe. There
may not be associated diarrhoea. Early symptoms may be only
local discomfort and malaise; later, a swinging temperature
and sweating may develop, usually without marked systemic
symptoms or signs. An enlarged, tender liver, cough and pain in
the right shoulder are characteristic but symptoms may remain
vague and signs minimal. A large abscess may penetrate the
diaphragm, rupturing into the lung, and may be coughed up
through a hepatobronchial fistula. Rupture into the pleural or
peritoneal cavity, or rupture of a left lobe abscess in the pericardial
sac, is less common but more serious.
Investigations
The stool and any exudate should undergo prompt microscopic
examination for motile trophozoites containing red blood cells.
Movements cease rapidly as the stool preparation cools. Several
stools may need to be examined in chronic amoebiasis before
cysts are found. Sigmoidoscopy may reveal typical flask-shaped
ulcers, which should be scraped and examined immediately for
E histolytica. In endemic areas, one-third of the population are
symptomless passers of amoebic cysts.
An amoebic abscess of the liver is suspected on clinical
grounds; there is often a neutrophil leucocytosis and a raised
right hemidiaphragm on chest X-ray. Confirmation is by ultrasonic
scanning. Aspirated pus from an amoebic abscess has the
characteristic chocolate-brown appearance but only rarely
contains free amoebae (Fig. 1 1 .46B).
Serum antibodies are detectable by immunofluorescence in
over 95% of patients with hepatic amoebiasis and intestinal
amoeboma, but in only about 60% of dysenteric amoebiasis.
DNA detection by PCR has been shown to be useful in diagnosis
of E. histolytica infections but is not generally available.
Management
Intestinal and early hepatic amoebiasis responds quickly to oral
metronidazole (800 mg 3 times daily for 5-10 days) or other
long-acting nitroimidazoles like tinidazole or ornidazole (both
in doses of 2 g daily for 3 days). Nitazoxanide (500 mg twice
daily for 3 days) is an alternative drug. Either diloxanide furoate
or paromomycin, in doses of 500 mg orally 3 times daily for 10
days after treatment, should be given to eliminate luminal cysts.
If a liver abscess is large or threatens to burst, or if the response
to chemotherapy is not prompt, aspiration is required and is
repeated if necessary. Rupture of an abscess into the pleural
cavity, pericardial sac or peritoneal cavity necessitates immediate
aspiration or surgical drainage. Small serous effusions resolve
without drainage.
Prevention
Personal precautions against contracting amoebiasis include not
eating fresh, uncooked vegetables or drinking unclean water.
Giardiasis
Infection with Giardia lamblia is found worldwide and is
common in the tropics. It particularly affects children, tourists
and immunosuppressed individuals, and is the parasite most
commonly imported into the UK. In cystic form, it remains viable in
water for up to 3 months and infection usually occurs by ingesting
contaminated water. Its flagellar trophozoite form attaches to the
duodenal and jejunal mucosa, causing inflammation.
Clinical features and investigations
After an incubation period of 1-3 weeks, there is diarrhoea,
abdominal pain, weakness, anorexia, nausea and vomiting. On
examination, there may be abdominal distension and tenderness.
Chronic diarrhoea and malabsorption may occur, with bulky
stools that float.
Stools obtained at 2-3-day intervals should be examined
for cysts. Duodenal or jejunal aspiration by endoscopy gives a
higher diagnostic yield. The ‘string test’ may be used, in which
one end of a piece of string is passed into the duodenum by
swallowing and retrieved after an overnight fast; expressed fluid
is then examined for the presence of G. lamblia trophozoites.
A number of stool antigen detection tests are available. Jejunal
biopsy specimens may show G. lamblia on the epithelial surface.
Management
Treatment is with a single dose of tinidazole 2 g, metronidazole
400 mg 3 times daily for 1 0 days, or nitazoxanide 500 mg orally
twice daily for 3 days.
Cryptosporidiosis
Cryptosporidium spp. are coccidian protozoal parasites of humans
and domestic animals. Infection is acquired by the faecal-oral
route through contaminated water supplies. The incubation period
is approximately 7-10 days and is followed by watery diarrhoea
and abdominal cramps. The illness is usually self-limiting but in
immunocompromised patients, especially those with HIV, the
illness can be devastating, with persistent severe diarrhoea and
substantial weight loss (p. 317).
Cyclosporiasis
Cyclospora cayetanensis is a globally distributed coccidian
protozoal parasite of humans. Infection is acquired by ingestion
288 • INFECTIOUS DISEASE
of contaminated water and recent food-borne outbreaks have
been associated with raspberries and coriander (cilantro). The
incubation period of approximately 2-1 1 days is followed by
diarrhoea with abdominal cramps, which may remit and relapse.
Although usually self-limiting, the illness may last as long as 6
weeks, with significant weight loss and malabsorption, and is
more severe in immunocompromised individuals. Diagnosis is
by detection of oocysts on faecal microscopy or PCR of stool.
Treatment may be necessary in a few cases, using co-trimoxazole
960 mg twice daily for 7 days.
Infections caused by helminths
Helminths (from the Greek helmins, meaning worm) include
three groups of parasitic worm (Box 1 1 .58), large multicellular
organisms with complex tissues and organs.
Intestinal human nematodes
Adult nematodes living in the human gut can cause disease.
There are two types:
• the hookworms, which have a soil stage in which they
develop into larvae that then penetrate the host
• a group of nematodes that survive in the soil merely as
eggs, which have to be ingested for their life cycle to
continue.
The geographical distribution of hookworms is limited by the
larval requirement for warmth and humidity. Soil-transmitted
nematode infections can be prevented by avoidance of faecal
soil contamination (adequate sewerage disposal) or skin contact
(wearing shoes), and by strict personal hygiene.
Ancylostomiasis (hookworm)
Ancylostomiasis is caused by Ancylostoma duodenale or Necator
americanus. The complex life cycle is shown in Figure 1 1 .47. The
i
Nematodes or roundworms
• Intestinal human nematodes: Ancylostoma duodenale, Necator
americanus, Strongyloides stercoralis, Ascaris lumbricoides,
Enterobius vermicularis, Trichuris trichiura
• Tissue-dwelling human nematodes: Wuchereria bancrofti, Brugia
malayi, Loa loa, Onchocerca volvulus, Dracunculus medinensis,
Mansonella perstans, Dirofilaria immitis
• Zoonotic nematodes: Trichinella spiralis
Trematodes or flukes
• Blood flukes: Schistosoma haematobium, S. mansoni, S. japonicum,
S. mekongi, S. intercalatum
• Lung flukes: Paragonimus spp.
• Hepatobiliary flukes: Clonorchis sinensis, Fasciola hepatica,
Opisthorchis felineus
• Intestinal flukes: Fasciolopsis buski
Cestodes or tapeworms
• Intestinal tapeworms: Taenia saginata, T. solium, Diphyllobothrium
latum, Hymenolepis nana
• Tissue-dwelling cysts or worms: Taenia solium, Echinococcus
granulosus
adult hookworm is 1 cm long and lives in the duodenum and
upper jejunum. Eggs are passed in the faeces. In warm, moist,
shady soil, the larvae develop into rhabditiform and then the
infective filariform stages; they then penetrate human skin and
are carried to the lungs. After entering the alveoli, they ascend
the bronchi, are swallowed and mature in the small intestine,
reaching maturity 4-7 weeks after infection. The worms attach
to the mucosa of the small intestine by their buccal capsule (Fig.
1 1 .48) and withdraw blood. The mean daily blood loss from one
A. duodenale is 0.15 mL and that from N. americanus 0.03 ml_.
Hookworm infection is a leading cause of anaemia in the
tropics and subtropics. A. duodenale is endemic in the Far East
and Mediterranean coastal regions, and is also present in Africa,
while N. americanus is endemic in West, East and Central Africa,
and Central and South America, as well as in the Far East.
Fig. 11.48 Ancylostoma duodenale. Electron micrograph showing the
ventral teeth. From Gibbons LM. SEM guide to the morphology of nematode
parasites of vertebrates. Farnham Royal, Slough: Commonwealth
Agricultural Bureau International; 1986.
11.58 Classes of helminth that parasitise humans
Infections caused by helminths • 289
Clinical features
An allergic dermatitis, usually on the feet (ground itch), may be
experienced at the time of infection. The passage of the larvae
through the lungs in a heavy infection causes a paroxysmal cough
with blood-stained sputum, associated with patchy pulmonary
consolidation and eosinophilia. When the worms reach the
small intestine, vomiting and epigastric pain resembling peptic
ulcer disease may occur. Sometimes, frequent loose stools are
passed. The degree of iron and protein deficiency depends not
only on the worm burden but also on patient nutrition and iron
stores. Anaemia with high-output cardiac failure may result. The
mental and physical development of children may be delayed
in severe infection.
Investigations
There is eosinophilia. The characteristic ovum can be recognised
in the stool. If hookworms are present in numbers sufficient
to cause anaemia, faecal occult blood testing will be positive.
Management
A single dose of albendazole (400 mg) is the treatment of choice.
Alternatively, mebendazole 1 00 mg twice daily for 3 days may
be used. Anaemia and heart failure associated with hookworm
infection respond well to oral iron, even when severe; blood
transfusion is rarely required.
manifestations, either urticaria or larva currens (a highly
characteristic pruritic, elevated, erythematous lesion, rapidly
advancing along the course of larval migration), are characteristic
and occur in 66% of patients.
Systemic strongyloidiasis (the Strongyloides hyperinfection
syndrome), with dissemination of larvae throughout the body,
occurs with immune suppression (HIV or HTLV-1 infection,
immunosuppressant treatment). Patients present with severe,
generalised abdominal pain, abdominal distension and shock.
Massive larval invasion of the lungs causes cough, wheeze and
dyspnoea; cerebral involvement has manifestations ranging
from subtle neurological signs to coma. Gram-negative sepsis
frequently complicates the picture.
Investigations
There is eosinophilia. Serology (ELISA) is helpful but definitive
diagnosis depends on finding the larvae. The faeces should
be examined microscopically for motile larvae; excretion is
intermittent and so repeated examinations are necessary. Larvae
may be found in jejunal aspirates or detected using the string test
(p. 287). Larvae may also be cultured from faeces.
Management
A course of two doses of ivermectin (200 jig/kg), administered
on successive days, is effective. Alternatively, albendazole is
given orally (15 mg/kg twice daily for 3 days). A second course
may be required. For the Strongyloides hyperinfection syndrome,
ivermectin is given at 200 jug/kg for 5-7 days.
Ascaris lumbricoides (roundworm)
This pale yellow nematode is 20-35 cm long. Humans are infected
by eating food contaminated with mature ova. Ascaris larvae hatch
in the duodenum, migrate through the lungs, ascend the bronchial
tree, are swallowed and mature in the small intestine. This tissue
migration can provoke both local and general hypersensitivity
reactions, with pneumonitis, eosinophilic granulomas, wheezing
and urticaria.
Clinical features
Intestinal ascariasis causes symptoms ranging from vague
abdominal pain to malnutrition. The large size of the adult worm
and its tendency to aggregate and migrate cause obstructive
complications. Tropical and subtropical areas are endemic
for ascariasis, and here it causes up to 35% of all intestinal
obstructions, most commonly in the terminal ileum. Obstruction
can be complicated further by intussusception, volvulus,
haemorrhagic infarction and perforation. Other complications
include blockage of the bile or pancreatic duct and obstruction
of the appendix by adult worms. Ascariasis in non-endemic areas
has been associated with pig husbandry and may be caused
by Ascaris suum, which is indistinguishable from (and possibly
the same species as) Ascaris lumbricoides.
Investigations
The diagnosis is made microscopically by finding ova in the
faeces. Adult worms are frequently expelled rectally or orally.
Occasionally, the worms are demonstrated radiographically by
a barium examination. There is eosinophilia.
Management
A single dose of albendazole (400 mg), pyrantel pamoate
(11 mg/kg; maximum 1 g), or ivermectin (150-200 (ig/kg),
or alternatively mebendazole (100 mg twice daily for 3 days)
| Strongyloidiasis (threadworm)
Strongyloides stercoralis is a small nematode (2 mm x 0.4 mm) that
parasitises the mucosa of the upper part of the small intestine,
often in large numbers, causing persistent eosinophilia. The eggs
hatch in the bowel but only larvae are passed in the faeces. In
moist soil, they moult and become the infective filariform larvae.
After penetrating human skin, they undergo a development cycle
similar to that of hookworms, except that the female worms
burrow into the intestinal mucosa and submucosa. Some larvae
in the intestine may develop into filariform larvae, which may
then penetrate the mucosa or the perianal skin and lead to
autoinfection and persistent infection. Patients with Strongyloides
infection persisting for more than 35 years have been described.
Strongyloidiasis occurs in the tropics and subtropics, and is
especially prevalent in the Far East.
Clinical features
These are shown in Box 1 1 .59. The classic triad of symptoms
consists of abdominal pain, diarrhoea and urticaria. Cutaneous
1 1 .59 Clinical features of strongyloidiasis
Penetration of skin by infective larvae
• Itchy rash
Presence of worms in gut
• Abdominal pain, diarrhoea, steatorrhoea, weight loss
Allergic phenomena
• Urticarial plaques and papules, wheezing, arthralgia
Autoinfection
• Transient itchy, linear, urticarial weals across abdomen and
buttocks (larva currens)
Systemic (super-)infection
• Diarrhoea, pneumonia, meningoencephalitis, death
290 • INFECTIOUS DISEASE
treats intestinal ascariasis. Patients should be warned that they
might expel numerous whole, large worms. Obstruction due to
ascariasis should be treated with nasogastric suction, piperazine
and intravenous fluids. Complete intestinal obstruction and its
complications require urgent surgical intervention.
Prevention
Community chemotherapy programmes reduce Ascaris infection.
The whole community can be treated every 3 months for several
years. Alternatively, schoolchildren are targeted; treating them
lowers the prevalence of ascariasis in the community.
Enterobius vermicularis (threadworm)
This helminth is common worldwide and affects mainly children.
After the ova are swallowed, development takes place in the
small intestine but the adult worms are found chiefly in the colon.
Clinical features
The female lays ova around the anus, causing intense itching,
especially at night. The ova are often carried to the mouth on the
fingers and so reinfection or human-to-human infection occurs
(Fig. 1 1 .49). In females, the genitalia may be involved. The adult
worms may be seen moving on the buttocks or in the stool.
Investigations
Ova are detected in stool samples or by applying the adhesive
surface of cellophane tape to the perianal skin in the morning.
This is then examined on a glass slide under the microscope.
A perianal swab, moistened with saline, also allows diagnosis.
Management
A single dose of mebendazole (100 mg), albendazole (400 mg),
pyrantel pamoate (1 1 mg/kg) or piperazine (4 g) treats infection
and is repeated after 2 weeks to control auto-reinfection. If
infection recurs in a family, each member should be treated.
All nightclothes and bed linen are laundered during treatment.
Fingernails must be kept short and hands washed carefully before
meals. Subsequent therapy is reserved for family members with
recurrent infection.
Trichuris trichiura (whipworm)
Whipworm infections are common worldwide with poor hygiene.
Infection follows ingestion of earth or food contaminated with
ova, which have become infective after lying for 3 weeks or
more in moist soil. The adult worm is 3-5 cm long and has a
coiled anterior end resembling a whip. Whipworms inhabit the
caecum, lower ileum, appendix, colon and anal canal. There
are usually no symptoms, but intense infections in children
may cause persistent diarrhoea or rectal prolapse, and growth
retardation. The diagnosis is readily made by identifying ova in
faeces. Treatment is with mebendazole in doses of 100 mg twice
daily or albendazole 400 mg daily for 3 days for patients with
light infections, and for 5-7 days for those with heavy infections.
Tissue-dwelling human nematodes
Filarial worms are tissue-dwelling nematodes. The larval stages
are inoculated by biting mosquitoes or flies, each specific
to a particular filarial species. The larvae develop into adult
worms (2-50 cm long), which, after mating, produce millions of
microfilariae (1 70-320 jim long) that migrate in blood or skin. The
life cycle is completed when the vector takes up microfilariae by
biting humans. In the insect, ingested microfilariae develop into
infective larvae for inoculation in humans, normally the only host.
Disease is due to the host’s immune response to the worms
(both adult and microfilariae), particularly dying worms, and its
pattern and severity vary with the site and stage of each species
(Box 1 1 .60). The worms are long-lived: microfilariae survive 2-3
years and adult worms 10-15 years. The infections are chronic
and worst in individuals constantly reinfected.
| Lymphatic filariasis
The filarial worms Wuchereria bancrofti and Brugia malayi infect
approximately 120 million people globally and cause clinical
outcomes ranging from subclinical infection to hydrocele and
elephantiasis.
1/1/. bancrofti is usually transmitted by night-biting culicine or
anopheline mosquitoes (Fig. 1 1 .50). The adult worms, 4-10 cm in
length, live in the lymphatics, and the females produce microfilariae
that circulate in large numbers in the peripheral blood, usually at
night. The infection is widespread in tropical Africa, on the North
African coast, in coastal areas of Asia, Indonesia and northern
Australia, the South Pacific islands, the West Indies and also in
North and South America.
Bl 1 1 .60 Pathogenicity of filarial infections depending
on site and stage of worms
Worm species
Adult worm
Microfilariae
Wuchereria bancrofti
and Brugia malayi
Lymphatic
vessels^
Blood-
Pulmonary capillaries^
Loa loa
Subcutaneous+
Blood+
Onchocerca volvulus
Subcutaneous+
Skin+++
Eye^
Mansonella perstans
Retroperitoneal-
Blood-
Mansonella
Skin+
Skin4^
streptocerca
Fig. 11.49 Threadworm. Life cycle of Enterobius vermicularis.
(+++ severe; ++ moderate; + mild; - rarely pathogenic)
Infections caused by helminths • 291
Infective larva Microfilariae in
Fig. 1 1 .50 Wuchereria bancrofti and Brugia malayi. Life cycle of
organisms and pathogenesis of lymphatic filariasis.
B. malayi usually causes less severe disease than 1/1/. bancrofti
and is transmitted by Mansonia or Anopheles mosquitoes in
Indonesia, Borneo, Malaysia, Vietnam, South China, South
India and Sri Lanka.
Pathology
Several factors contribute to the pathogenesis of lymphatic
filariasis. Toxins released by adult worms cause lymphangiectasia;
this dilatation of the lymphatic vessels leads to lymphatic
dysfunction and the chronic clinical manifestations of lymphatic
filariasis, lymphoedema and hydrocele. Death of the adult worm
results in acute filarial lymphangitis. The filariae are symbiotically
infected with rickettsia-like bacteria ( Wolbachia spp.), and
lipopolysaccharide released from Wolbachia triggers inflammation.
Lymphatic obstruction persists after death of the adult worm.
Secondary bacterial infections cause tissue destruction. The
host response to microfilariae is central to the pathogenesis of
tropical pulmonary eosinophilia.
Clinical features
Acute filarial lymphangitis presents with fever, pain, tenderness
and erythema along the course of inflamed lymphatic vessels.
Inflammation of the spermatic cord, epididymis and testis is
common. Episodes last a few days but may recur several times a
year. Temporary oedema becomes more persistent and regional
lymph nodes enlarge. Progressive enlargement, coarsening,
corrugation, Assuring and bacterial infection of the skin and
subcutaneous tissue develop gradually, causing irreversible
‘elephantiasis’. The scrotum may reach an enormous size.
Chyluria and chylous effusions are milky and opalescent; on
standing, fat globules rise to the top.
Acute lymphatic manifestations of filariasis must be differentiated
from thrombophlebitis and infection. Oedema and lymphatic
obstructive changes must be distinguished from congestive
cardiac failure, malignancy, trauma and idiopathic abnormalities
of the lymphatic system. Silicates absorbed from volcanic soil
can also cause non-filarial elephantiasis.
Tropical pulmonary eosinophilia is a complication, seen mainly
in India, due to microfilariae trapped in the pulmonary capillaries
that are destroyed by allergic inflammation. Patients present with
paroxysmal cough, wheeze and fever. If untreated, this may
progress to debilitating chronic interstitial lung disease.
Investigations
In the earliest stages of lymphangitis, the diagnosis is made
on clinical grounds, supported by eosinophilia and sometimes
by positive filarial serology. Filarial infections cause the highest
eosinophil counts of all helminthic infections.
Microfilariae can be found in the peripheral blood at night,
and either are seen moving in a wet blood film or are detected
by microfiltration of a sample of lysed blood. They are usually
present in hydrocele fluid, which may occasionally yield an adult
filaria. By the time elephantiasis develops, microfilariae become
difficult to find. Calcified filariae may sometimes be demonstrable
by radiography. Movement of adult worms can be seen on scrotal
ultrasound. PCR-based tests for detection of 1/1/. bancrofti and
B. malayi DNA from blood have been developed.
Indirect fluorescence and ELISA detect antibodies in over 95%
of active cases and 70% of established elephantiasis. The test
becomes negative 1-2 years after cure. Serological tests cannot
distinguish the different filarial infections. Highly sensitive and
specific, commercially available, immunochromatographic card
tests detect circulating 1/1/. bancrofti antigen using fingerprick
blood samples taken at any time of the day.
In tropical pulmonary eosinophilia, serology is strongly positive
and IgE levels are massively elevated but circulating microfilariae
are not found. The chest X-ray shows miliary changes or mottled
opacities. Pulmonary function tests show a restrictive picture.
Management
Treatment is aimed at halting and reversing disease progression.
Diethylcarbamazine (DEC, 2 mg/kg orally 3 times daily for 12
days, or 6 mg/kg as a single dose) kills microfilariae and adult
worms. Most adverse effects seen with DEC treatment are due
to the host response to dying microfilariae, which is directly
proportional to the microfilarial load. The main symptoms are
fever, headache, nausea, vomiting, arthralgia and prostration.
These usually occur within 24-36 hours of the first dose of DEC.
Antihistamines or glucocorticoids treat these allergic phenomena.
Combining albendazole (400 mg) with ivermectin (200 jig/kg)
in a single dose, with or without DEC (300 mg), is also highly
effective in clearing the parasites. Treatment of Wolbachia with
doxycycline (200 mg/day) for 4-8 weeks provides additional
benefit by eliminating the bacteria; this leads to interruption of
parasite embryogenesis. For tropical pulmonary eosinophilia,
DEC for 1 4 days is the treatment of choice.
Chronic lymphatic pathology
Experience in India and Brazil shows that active management
of chronic lymphatic pathology can alleviate symptoms. Patients
should be taught meticulous skin care of their lymphoedematous
limbs to prevent secondary bacterial and fungal infections. Tight
bandaging, massage and bed rest with elevation of the affected
limb help to control the lymphoedema. Prompt diagnosis and
antibiotic therapy of bacterial cellulitis prevent further lymphatic
damage and worsening of existing elephantiasis. Plastic surgery
may be indicated in established elephantiasis. Relief can be
obtained by removal of excess tissue but recurrences are probable
292 • INFECTIOUS DISEASE
unless new lymphatic drainage is established. Hydroceles and
chyluria can be repaired surgically.
Prevention
Treatment of the whole population in endemic areas with annual
single-dose DEC (6 mg/kg), either alone or in combination
with albendazole or ivermectin, can reduce filarial transmission.
Mass treatment should be combined with mosquito control
programmes.
Loiasis
Loiasis is caused by infection with the filaria Loa loa. The disease
is endemic in forested and swampy parts of Western and Central
Africa. The adult worms, 3-7 cmx4 mm, chiefly parasitise the
subcutaneous tissue of humans, releasing larval microfilariae into
the peripheral blood in the daytime. The vector is Chrysops, a
forest-dwelling, day-biting fly.
The host response to Loa loa is usually absent or mild, so
that the infection may be harmless. From time to time a short¬
lived, inflammatory, oedematous swelling (a Calabar swelling) is
produced around an adult worm. Heavy infections, especially
when treated, may cause encephalitis.
Clinical features
The infection is often symptomless. The incubation period is
commonly over a year but may be just 3 months. The first sign
is usually a Calabar swelling: an irritating, tense, localised swelling
that may be painful, especially if it is near a joint. The swelling is
generally on a limb; it measures a few centimetres in diameter
but may be diffuse and extensive. It usually disappears after a
few days but may persist for 2-3 weeks. Several swellings may
appear at irregular intervals, often in adjacent sites. Sometimes,
there is urticaria and pruritus elsewhere. Occasionally, a worm
may be seen wriggling under the skin, especially that of an
eyelid, and may cross the eye under the conjunctiva, taking
many minutes to do so.
Investigations
Diagnosis is by demonstrating microfilariae in blood taken during
the day, but they may not always be found in patients with
Calabar swellings. Antifilarial antibodies are positive in 95%
of patients and there is massive eosinophilia. Occasionally, a
calcified worm may be seen on X-ray.
Management
DEC (see above) is curative, in a dose of 9-12 mg/kg daily,
continued for 21 days. Treatment may precipitate a severe
reaction in patients with a heavy microfilaraemia, characterised
by fever, joint and muscle pain, and encephalitis; microfilaraemic
patients should be given glucocorticoid cover.
Prevention
Building houses away from trees and having dwellings wire-
screened reduce infections. Protective clothing and insect
repellents are also useful. DEC in a dose of 5 mg/kg daily for 3
days each month is partially protective.
Onchocerciasis (river blindness)
Onchocerciasis results from infection by the filarial Onchocerca
volvulus. The infection is conveyed by flies of the genus Simulium,
which breed in rapidly flowing, well-aerated water. Adult flies inflict
painful bites during the day, both inside and outside houses. While
Fig. 11.51 Onchocerca volvulus. Life cycle of organism and
pathogenesis of onchocerciasis.
feeding, they pick up the microfilariae, which mature into the
infective larva and are transmitted to a new host in subsequent
bites. Humans are the only known hosts (Fig. 1 1 .51).
Onchocerciasis is endemic in sub-Saharan Africa, Yemen and
a few foci in Central and South America. It is estimated that
26 million people are infected, of whom 500 000 are visually
impaired and 270000 blind. Due to onchocerciasis, huge tracts
of fertile land lie virtually untilled and individuals and communities
are impoverished.
Pathology
After inoculation of larvae by a bite, the worms mature in
2-4 months and live for up to 17 years in subcutaneous and
connective tissues. At sites of trauma, over bony prominences
and around joints, fibrosis may form nodules around adult
worms, which otherwise cause no direct damage. Innumerable
microfilariae, discharged by the female O. volvulus, move actively
in these nodules and in the adjacent tissues. The microfilariae
are widely distributed in the skin and may invade the eye. Live
microfilariae elicit little tissue reaction but dead ones may cause
severe allergic inflammation, leading to hyaline necrosis and loss
of collagen and elastin. Death of microfilariae in the eye causes
inflammation and may lead to blindness.
Clinical features
The infection may remain symptomless for months or years.
The first symptom is usually itching, localised to one quadrant
of the body and later becoming generalised and involving the
eyes. Transient oedema of part or all of a limb is an early sign,
followed by papular urticaria spreading gradually from the site
of infection. This is difficult to see on dark skins, in which the
most common signs are papules excoriated by scratching, spotty
hyperpigmentation from resolving inflammation, and chronic
changes of a rough, thickened or inelastic, wrinkled skin. Both
infected and uninfected superficial lymph nodes enlarge and may
hang down in folds of loose skin in the groin. Hydrocele, femoral
hernias and scrotal elephantiasis can occur. Firm subcutaneous
nodules of more than 1 cm in diameter (onchocercomas) occur
in chronic infection.
Infections caused by helminths • 293
Eye disease is most common in highly endemic areas and
is associated with chronic heavy infections and nodules on
the head. Early manifestations include itching, lacrimation and
conjunctival injection. These cause conjunctivitis; sclerosing
keratitis with pannus formation; uveitis, which may lead to
glaucoma and cataract; and, less commonly, choroiditis and
optic neuritis. Classically, ‘snowflake’ deposits are seen in the
edges of the cornea.
Investigations
The finding of nodules or characteristic lesions of the skin or eyes
in a patient from an endemic area, associated with eosinophilia,
is suggestive. Skin snips or shavings, taken with a corneoscleral
punch or scalpel blade from calf, buttock and shoulder, are
placed in saline under a cover slip on a microscope slide and
examined after 4 hours. Microfilariae are seen wriggling free in
all but the lightest infections. Slit-lamp examination may reveal
microfilariae moving in the anterior chamber of the eye or trapped
in the cornea. A nodule may be removed and incised, showing
the coiled, thread-like adult worm.
Filarial antibodies are positive in up to 95% of patients.
Rapid strip tests to detect antibody or antigen are under clinical
evaluation. When there is a strong suspicion of onchocerciasis
but tests are negative, a provocative Mazzotti test, in which
administration of 0.5-1 .0 mg/kg of DEC exacerbates pruritus
or dermatitis, strongly suggests onchocerciasis.
Management
Ivermectin is recommended, in a single dose of 100-200 jug/kg ,
repeated several times at 3-monthly intervals to prevent relapses.
It kills microfilariae and has minimal toxicity. In the rare event
of a severe reaction causing oedema or postural hypotension,
prednisolone 20-30 mg may be given daily for 2 or 3 days.
Ivermectin has little macrofilaricidal effect so that, 1 year after
ivermectin treatment, skin microfilarial densities regain at least
20% of pre-treatment levels; repeated treatments are required
for the lifespan of the adult worm. Eradication of Wolbachia
with doxycycline (100 mg daily for 6 weeks) prevents worm
reproduction.
Prevention
Mass treatment with ivermectin reduces community morbidity
and slows the progression of eye disease but it does not clear
worm infection. Simulium can be destroyed in its larval stage by
the application of insecticide to streams. Long trousers, skirts
and sleeves discourage the fly from biting.
|j)racunculiasis (Guinea worm)
Infestation with the Guinea worm Dracunculus medinensis
manifests when the female worm, over a metre long, emerges
from the skin. Humans are infected by ingesting a small
crustacean, Cyclops, which inhabits wells and ponds, and
contains the infective larval stage of the worm. The worm was
widely distributed across Africa and the Middle East but successful
global eradication programmes have limited the infection to a
few countries in sub-Saharan Africa. However, recent findings
of dog dracunculiasis in Chad and Ethiopia pose a new threat
to eradication efforts.
Management and prevention
Traditionally, the protruding worm is extracted by winding it out
gently over several days on a matchstick. The worm must never
be broken. Antibiotics for secondary infection and prophylaxis
of tetanus are also required.
A global eradication campaign aims to provide clean drinking
water and eradicate water fleas from drinking water by simple
filtration of water through a plastic mesh filter and chemical
treatment of water supplies.
Other filariases
Mansonella perstans
This filarial worm is transmitted by the midges Culicoides austeni
and C. grahami. It is common throughout equatorial Africa, as
far south as Zambia, and also in Trinidad and parts of northern
and eastern South America.
M. perstans has never been proven to cause disease but it
may be responsible for a persistent eosinophilia and occasional
allergic manifestations. M. perstans is resistant to ivermectin and
DEC, and the infection may persist for many years.
Dirofilaria immitis
This dog heartworm infects humans, causing skin and lung
lesions. It is not uncommon in the USA, Japan and Australia.
Zoonotic nematodes
| Trichinosis (trichinellosis)
Trichinella spiralis is a nematode that parasitises rats and pigs,
and is transmitted to humans by ingestion of partially cooked
infected pork, particularly sausage or ham, or occasionally by bear
meat. Symptoms result from invasion of intestinal submucosa
by ingested larvae, which develop into adult worms, and the
secondary invasion of striated muscle by fresh larvae produced
by these adult worms. Outbreaks have occurred in countries
where pork is eaten.
Clinical features
The clinical features of trichinosis are determined by the larval
numbers. A light infection with a few worms may be asymptomatic;
a heavy infection causes nausea and diarrhoea 24-48 hours after
the infected meal. A few days later, the symptoms associated
with larval invasion predominate: there is fever and oedema of
the face, eyelids and conjunctivae; invasion of the diaphragm
may cause pain, cough and dyspnoea; and involvement of the
muscles of the limbs, chest and mouth causes stiffness, pain
and tenderness in affected muscles. Larval migration may cause
acute myocarditis and encephalitis. Eosinophilia is observed after
the second week. An intense infection may prove fatal but those
who survive recover completely.
Investigations
Frequently, people who have eaten infected pork from a common
source develop symptoms at about the same time. Biopsy
from the deltoid or gastrocnemius muscle after the third week
of symptoms may reveal encysted larvae. Serological tests are
also helpful.
Management
Treatment is with albendazole (400 mg twice daily for 8-14
days) or mebendazole (200-400 mg three times daily for 3 days,
followed by 400-500 mg three times daily for 1 0 days). Treatment
commenced early in infection kills newly formed adult worms in
the submucosa and reduces the number of larvae reaching the
294 • INFECTIOUS DISEASE
muscles. Glucocorticoids are necessary to control the serious
effects of acute inflammation.
| Anisakiasis (herring worm)
This infection is caused by the larvae of a fish nematode (/■ \nisakis
simplex or Pseudoterranova decipiens ) and is associated with
consumption of under-cooked fish or squid. The parasite cannot
complete its life cycle in humans but larval ingestion is associated
with pharyngeal tingling, abdominal pain, diarrhoea and vomiting.
Diagnosis is made by identification of the larva by patients or
endoscopists, and albendazole (400 mg twice a day for 5 days)
can be used in treatment if larvae are not removed.
|j)utaneous larva migrans
Cutaneous larva migrans (CLM) is the most common linear
lesion seen in travellers (Fig. 11.52). Intensely pruritic, linear,
serpiginous lesions result from the larval migration of the dog
hookworm {/■ \ncylostoma caninum). The track moves across the
skin at a rate of 2-3 cm/day. This contrasts with the fast-moving
transient rash of Strongyloides (p. 289). Although the larvae of
dog hookworms frequently infect humans, they do not usually
develop into the adult form. The most common site for CLM
is the foot but elbows, breasts and buttocks may be affected.
Most patients with CLM have recently visited a beach where the
affected part was exposed. The diagnosis is clinical. Treatment
may be local with 1 2-hourly application of 1 5% thiabendazole
cream, or systemic with a single dose of albendazole (400 mg)
or ivermectin (150-200 jig/kg).
Angiostrongylus cantonensis
The rat lungworm infects humans in Asia and the Pacific basin,
via infected snails or contaminated water. It causes eosinophilic
meningitis. The role of combination therapy with glucocorticoids
and albendazole remains controversial.
A.
Fig. 11.52 Cutaneous larva migrans. Courtesy of Dr Ravi Gowda, Royal
Hallamshire Hospital, Sheffield.
Gnathostomiasis
Gnathostomiasis is a nematode infection that occurs predominantly
in South-east Asia and is due to Gnathostoma spinigerum. It also
occurs in other parts of Asia, Central and South America, and
Africa. Humans are infected by the larvae from intermediate hosts
(raw or under-cooked freshwater fish, shrimps and frogs) and
are not definitive hosts, so the life cycle is incomplete. Pruritic,
painful, migratory nodules appear 3-4 weeks after ingestion due to
larval migration. Complications include cough, visual disturbance,
eosinophilic meningitis or encephalitis. Serology confirms diagnosis
and the preferred treatment is albendazole (400 mg twice daily)
for 21 days, but its role in visual or neurological disease is
uncertain as it may increase larval migration.
Trematodes (flukes)
These leaf-shaped worms are parasitic to humans and animals.
Their complex life cycles may involve one or more intermediate
hosts, often freshwater molluscs.
Schistosomiasis
Schistosomiasis is a major cause of morbidity in the tropics. The
species commonly causing disease in humans are: Schistosoma
haematobium, S. mansoni, S. japonicum, S. mekongi and S.
intercalatum. S. haematobium is sometimes called bilharzia or
bilharziasis. Schistosome eggs have been found in Egyptian
mummies.
The life cycle is shown in Figure 1 1 .53A. The ovum is passed
in the urine or faeces of infected individuals and gains access to
fresh water, where the ciliated miracidium inside it is liberated;
it enters its intermediate host, a species of freshwater snail,
and multiplies. Large numbers of fork-tailed cercariae are then
liberated into the water, where they may survive for 2-3 days.
Cercariae can penetrate the skin or the mucous membrane of
the mouth of humans. They transform into schistosomulae and
moult as they pass through the lungs; then they are carried by
the blood stream to the liver, and so to the portal vein, where
they mature. The male worm is up to 20 mm in length and the
more slender cylindrical female, usually enfolded longitudinally by
the male, is longer (Fig. 1 1 .53B). Within 4-6 weeks of infection,
they migrate to the venules draining the pelvic viscera, where
the females deposit ova.
Pathology
Disease is usually due to passage of eggs through mucosa and
to the granulomatous reaction to eggs deposited in tissues.
The eggs of S. haematobium pass mainly through the bladder
wall but may also involve the rectum, seminal vesicles, vagina,
cervix and uterine tubes. S. mansoni and S. japonicum eggs
pass mainly through the wall of the lower bowel or are carried
to the liver. The most serious, although rare, site of ectopic
egg deposition is the CNS. Granulomas are composed of
macrophages, eosinophils, and epithelioid and giant cells around
an ovum. Later, there is fibrosis and eggs calcify, which is often
visible radiologically. Eggs of S. haematobium may leave the
vesical plexus and be carried directly to the lung. Those of S.
mansoni and S. japonicum may also reach the lungs after the
development of portal hypertension and consequent portasystemic
collateral circulation. Egg deposition in the pulmonary vasculature,
and the resultant host response, can lead to pulmonary
hypertension.
Infections caused by helminths • 295
Fig. 11.53 Schistosoma. 5] Life cycle.fjj] Scanning electron micrograph of adult schistosome worms, showing the larger male worm embracing the
thinner female.
Clinical features
Recent travellers, especially those overlanding through Africa, may
present with allergic manifestations and eosinophilia; residents of
schistosomiasis-endemic areas are more likely to present with
chronic urinary tract pathology or portal hypertension.
During the early stages of infection, there may be itching lasting
1-2 days at the site of cercarial penetration (‘swimmer’s itch’).
After a symptom-free period of 3-5 weeks, acute schistosomiasis
(Katayama syndrome) may present with allergic manifestations,
such as urticaria, fever, muscle aches, abdominal pain,
headaches, cough and sweating. On examination, hepatomegaly,
splenomegaly, lymphadenopathy and pneumonia may be present.
These allergic phenomena may be severe in infections with S.
mansoni and S. japonicum, but are rare with S. haematobium.
The features subside after 1-2 weeks.
Chronic schistosomiasis is due to egg deposition and occurs
months to years after infection. The symptoms and signs
depend on the intensity of infection and the species of infecting
schistosome (Box 1 1 .61).
Schistosoma haematobium
Humans are the only natural hosts of S. haematobium, which is
highly endemic in Egypt and East Africa, and occurs throughout
Africa and the Middle East (Fig. 1 1 .54). Infection can be acquired
after a brief exposure, such as swimming in freshwater lakes
in Africa.
Painless terminal haematuria is usually the first and most
common symptom. Frequency of micturition follows, due to
bladder neck obstruction. Later, frequent urinary tract infections,
bladder or ureteric stones, hydronephrosis, and ultimately renal
failure with a contracted calcified bladder may occur. Pain is
often felt in the iliac fossa or in the loin, and radiates to the
groin. In several endemic areas, there is a strong epidemiological
i
S. mansoni and
Time Schistosoma haematobium S. japonicum
Cercarial penetration
Days Papular dermatitis at site of
As for S. haematobium
penetration
Larval migration and maturation
Weeks Pneumonitis, myositis, hepatitis,
As for S. haematobium
fever, ‘serum sickness’,
eosinophilia, seroconversion
Early egg deposition
Months Cystitis, haematuria
Colitis, granulomatous
hepatitis, acute portal
hypertension
Ectopic granulomatous lesions:
skin, CNS etc.
Immune complex
glomerulonephritis
As for S. haematobium
Late egg deposition
Years Fibrosis and calcification of
Colonic polyposis and
ureters, bladder: bacterial
strictures, periportal
infection, calculi,
fibrosis, portal
hydronephrosis, carcinoma
hypertension
Pulmonary granulomas and
pulmonary hypertension
As for S. haematobium
association of S. haematobium infection with squamous cell
carcinoma of the bladder. Disease of the seminal vesicles may
lead to haematospermia. Females may develop schistosomal
papillomas of the vulva, and schistosomal lesions of the cervix
may be mistaken for cancer. Intestinal symptoms may follow
1 1 .61 Pathogenesis of schistosomiasis
296 • INFECTIOUS DISEASE
Fig. 11.54 Geographical distribution of schistosomiasis. From Cook
GC, ed. Manson’s tropical diseases, 20th edn. Saunders, Elsevier Inc.;
1995.
involvement of the bowel wall. Ectopic worms cause skin or
spinal cord lesions.
The severity of S. haematobium infection varies greatly and
many with a light infection are asymptomatic. However, as adult
worms can live for 20 years or more and lesions may progress,
these patients should always be treated.
Schistosoma mansoni
S. mansoni is endemic throughout Africa, the Middle East,
Venezuela, Brazil and the Caribbean (Fig. 1 1 .54).
Characteristic symptoms begin 2 months or more after
infection. They may be slight - no more than malaise - or
consist of abdominal pain and frequent stools that contain
blood-stained mucus. With severe advanced disease, increased
discomfort from rectal polyps may be experienced. The early
hepatomegaly is reversible but portal hypertension may cause
massive splenomegaly, fatal haematemesis from oesophageal
varices, or progressive ascites (p. 868). Liver function is initially
preserved because the pathology is fibrotic rather than cirrhotic.
S. mansoni and other schistosome infections predispose to the
carriage of Salmonella, in part because Salmonella may attach
to the schistosomes and in part because shared antigens on
schistosomes may induce immunological tolerance to Salmonella.
Schistosoma japonicum, S. mekongi and S. intercalatum
In addition to humans, the adult worm of S. japonicum infects
the dog, rat, field mouse, water buffalo, ox, cat, pig, horse and
sheep. Although other Schistosoma spp. can infect species other
than humans, the non-human reservoir seems to be particularly
important only in transmission for S. japonicum. S. japonicum is
prevalent in the Yellow River and Yangtze-Jiang basins in China,
where the infection is a major public health problem. It also has
a focal distribution in the Philippines, Indonesia and Thailand
(Fig. 1 1 .54). The related S. mekongi occurs in Laos, Thailand
and Myanmar, and S. intercalatum in West and Central Africa.
The pathology of S. japonicum is similar to that of S. mansoni,
but as this worm produces more eggs, the lesions tend to be
more extensive and widespread. The clinical features resemble
those of severe infection with S. mansoni, with added neurological
features. The small and large bowel may be affected, and hepatic
Fig. 11.55 Ova of Schistosoma haematobium in urine. Note the
terminal spike.
fibrosis with splenic enlargement is usual. Deposition of eggs or
worms in the CNS, especially in the brain or spinal cord, causes
symptoms in about 5% of infections, notably epilepsy, blindness,
hemiplegia or paraplegia.
Investigations
There is marked eosinophilia. Serological tests (ELISA) are useful
as screening tests but remain positive after treatment.
In S. haematobium infection, dipstick urine testing shows
blood and albumin. The eggs can be found by microscopic
examination of the centrifuged deposit of terminal stream urine
(Fig. 1 1 .55). Ultrasound assesses the urinary tract; bladder
wall thickening, hydronephrosis and bladder calcification can
be detected. Cystoscopy reveals ‘sandy’ patches, bleeding
mucosa and later distortion.
In a heavy infection with S. mansoni or S. japonicum, the
characteristic egg with its lateral spine can usually be found in
the stool. When the infection is light or of long duration, a rectal
biopsy can be examined. Sigmoidoscopy may show inflammation
or bleeding. Biopsies should be examined for ova.
Management
The object of therapy is to kill the adult schistosomes and stop
egg-laying. Praziquantel (20 mg/kg orally twice daily for 1 day)
is the drug of choice for all forms of schistosomiasis except
S. japonicum and S. mekongi, for which 60 mg/kg (20 mg for
3 doses) is recommended. The drug produces parasitological
cure in 80% of treated individuals and over 90% reduction in
egg counts in the remainder. Side-effects are uncommon but
include nausea and abdominal pain. Praziquantel therapy in
early infection reverses hepatomegaly, bladder wall thickening
and granulomas.
Surgery may be required to deal with residual lesions such as
ureteric stricture, small fibrotic urinary bladders, or granulomatous
masses in the brain or spinal cord. Removal of rectal papillomas
by diathermy or by other means may provide symptomatic relief.
Prevention
No single means of controlling schistosomiasis has been
established to date. The life cycle is terminated if fresh water
containing the snail host is not contaminated by ova-containing
urine or faeces. The provision of latrines and of a safe water supply,
however, remains a major problem in rural areas throughout the
Infections caused by helminths • 297
1 1 .62 Diseases caused by flukes in the bile duct
Clonorchiasis
Opisthorchiasis
Fascioliasis
Parasite
Clonorchis sinensis
Opisthorchis felineus
Fasciola hepatica
Other mammalian hosts
Dogs, cats, pigs
Dogs, cats, foxes, pigs
Sheep, cattle
Mode of spread
Ova in faeces, water
As for C. sinensis
Ova in faeces on to wet pasture
1st intermediate host
Snails
Snails
Snails
2nd intermediate host
Freshwater fish
Freshwater fish
Encysts on vegetation
Geographical distribution
Far East, especially South China
Far East, especially North-east Thailand
Cosmopolitan, including UK
Pathology
Escherichia coli cholangitis,
abscesses, biliary carcinoma
As for C. sinensis
Toxaemia, cholangitis, eosinophilia
Symptoms
Often symptom-free, recurrent
jaundice
As for C. sinensis
Unexplained fever, tender liver, may be
ectopic, e.g. subcutaneous fluke
Diagnosis
Ova in stool or duodenal aspirate
As for C. sinensis
As for C. sinensis , also serology
Prevention
Cook fish
Cook fish
Avoid contaminated watercress
Treatment
Praziquantel 25 mg/kg 3 times
daily for 2 days
As for C. sinensis but for 1 day only
Triclabendazole 10 mg/kg single dose;
repeat treatment may be required*
*ln the UK, available from the Hospital for Tropical Diseases, London.
tropics. Furthermore, S. japonicum has so many hosts besides
humans that latrines would have little impact. Population mass
treatment annually helps prevent S. haematobium and S. mansoni
infection but so far has had little success with S. japonicum.
Targeting the intermediate host, the snail, is problematic and
has not, on its own, proved successful. For personal protection,
contact with infected water must be avoided.
| Liver flukes
Liver flukes infect at least 20 million people and remain an
important public health problem in endemic areas. They are
associated with abdominal pain, hepatomegaly and relapsing
cholangitis. Clonorchis sinensis and Opisthorchis felineus are
major aetiological agents of bile duct cancer. The three major
liver flukes have similar life cycles and pathologies, as outlined
in Box 1 1 .62.
Other flukes of medical importance include lung and intestinal
flukes (see Box 1 1 .58).
Cestodes (tapeworms)
Cestodes are ribbon-shaped worms that inhabit the intestinal
tract. They have no alimentary system and absorb nutrients
through the tegumental surface. The anterior end, or scolex,
has suckers for attaching to the host. From the scolex, a series
of progressively developing segments arise, the proglottides,
which may continue to show active movements when shed.
Cross-fertilisation takes place between segments. Ova, present
in large numbers in mature proglottides, remain viable for weeks,
and during this period they may be consumed by the intermediate
host. Larvae liberated from the ingested ova pass into the tissues
of the intermediate host, forming larval cysticerci.
Tapeworms cause two distinct patterns of disease: either
intestinal infection or systemic cysticercosis (Fig. 1 1 .56). Taenia
saginata (beef tapeworm), Taenia asiatica and Diphyllobothrium
latum (fish tapeworm) cause only intestinal infection in humans,
following ingestion of intermediate hosts. Taenia solium causes
intestinal infection if a cysticerci-containing intermediate host
If eggs are swallowed
by humans they develop
to cysticerci in various
sites, e.g. brain, muscle
If cysticerci
are swallowed
they develop to
adult tapeworms
in the human
intestine
Faecal-oral
route
Human pork tapeworm
infection results from
eating undercooked
pork containing cysticerci
Human cysticercosis
results from ingestion of
the tapeworm eggs as
a result of faecal
contamination of food
Fig. 1 1 .56 Cysticercosis. Life cycle of Taenia solium.
is ingested, and cysticercosis (systemic infection from larval
migration) if ova are ingested. Echinococcus granulosus (dog
tapeworm) does not cause human intestinal infection, but causes
hydatid disease (which is analogous to cysticercosis) following
ingestion of ova and subsequent larval migration.
298 • INFECTIOUS DISEASE
|jntestinal tapeworm
Humans acquire tapeworm by eating under-cooked beef
infected with the larval stage of T. saginata, under-cooked
pork containing the larval stage of T. solium or T. asiatica, or
under-cooked freshwater fish containing larvae of D. latum.
Usually, only one adult tapeworm is present in the gut but
up to 10 have been reported. The ova of all the three Taenia
are indistinguishable microscopically. However, examination
of scolex and proglottides can differentiate them: T. solium
has a rostellum and two rows of hooklets on the scolex, and
discharges multiple proglottides (3-5) attached together with
lower degrees of uterine branching (approximately 10); T.
saginata has only four suckers in its scolex, and discharges single
proglottids with greater uterine branching (up to 30); T. asiatica
has a rostellum without hooks on its scolex and is difficult to
differentiate from T. saginata, except that there are fewer uterine
branches (16-21).
Taenia solium
T. solium, the pork tapeworm, is common in central Europe,
South Africa, South America and parts of Asia. It is not
as large as T. saginata. The adult worm is found only in
humans following the ingestion of pork containing cysticerci.
Intestinal infection is treated with praziquantel (5-10 mg/kg)
or niclosamide (2 g), both as a single dose, or alternatively
with nitazoxanide (500 mg twice daily for 3 days). These
are followed by a mild laxative (after 1-2 hours) to prevent
retrograde intestinal autoinfection. Cooking pork well prevents
intestinal infection. Great care must be taken while attending a
patient harbouring an adult worm to avoid ingestion of ova or
segments.
Taenia saginata
Infection with T. saginata occurs in all parts of the world. The
adult worm may be several metres long and produces little
or no intestinal upset in human beings, but identification of
segments in the faeces or on underclothing may distress the
patient. Ova may be found in the stool. Praziquantel is the
drug of choice; niclosamide or nitazoxanide is an alternative.
Prevention depends on efficient meat inspection and the thorough
cooking of beef.
Taenia asiatica
T. asiatica is a newly recognised species of Taenia, restricted
to Asia. It is acquired by eating uncooked meat or viscera of
pigs. Clinical features and treatment are similar to those of
T. saginata.
j Cysticercosis
Human cysticercosis is acquired by ingesting T. solium tapeworm
ova, from either contaminated fingers or food (Fig. 1 1 .56). The
larvae are liberated from eggs in the stomach, penetrate the
intestinal mucosa and are carried to many parts of the body,
where they develop and form cysticerci, 0.5-1 cm cysts that
contain the head of a young worm. They do not grow further
or migrate. Common locations are the subcutaneous tissue,
skeletal muscles and brain (Fig. 11.57).
Clinical features
Superficial cysts can be palpated under the skin or mucosa as
pea-like ovoid bodies, but cause few or no symptoms and will
eventually die and become calcified.
Fig. 11.57 Neurocysticercosis. T2-weighted axial image of the brain
showing multiple lesions of neurocysticercosis (large arrows show the
largest lesions).
Heavy brain infections, especially in children, may cause
features of encephalitis. More commonly, however, cerebral
signs do not occur until the larvae die, 5-20 years later. Epilepsy,
including new-onset focal seizures, personality changes,
staggering gait and signs of hydrocephalus are the most common
features.
Investigations
Calcified cysts in muscles can be recognised radiologically. In
the brain, however, less calcification takes place and larvae
are only occasionally visible by plain X-ray; CT or magnetic
resonance imaging (MRI) will usually show them. Epileptic fits
starting in adult life suggest the possibility of cysticercosis if
the patient has lived in or travelled to an endemic area. The
subcutaneous tissue should be palpated and any nodule
excised for histology. Radiological examination of the skeletal
muscles may be helpful. Antibody detection is available for
serodiagnosis.
Management and prevention
Albendazole (15 mg/kg daily for a minimum of 8 days) has now
become the drug of choice for parenchymal neurocysticercosis.
Praziquantel (50 mg/kg in 3 divided doses daily for 10 days)
is another option. Prednisolone (10 mg 3 times daily) is also
given for 1 4 days, starting 1 day before the albendazole or
praziquantel. In addition, antiepileptic drugs should be given until
the reaction in the brain has subsided. Operative intervention
is indicated for hydrocephalus. Studies from India and Peru
suggest that most small, solitary cerebral cysts will resolve
without treatment.
I Echinococcus granulosus ( Taenia
echinococcus) and hydatid disease
Dogs are the definitive hosts of the tiny tapeworm E granulosus.
The larval stage, a hydatid cyst, normally occurs in sheep, cattle,
Ectoparasites • 299
Fig. 11 .58 Hydatid disease. [A] Life cycle of Echinococcus granulosus. |J] Daughter cysts removed at surgery, [c] Within the daughter cysts are the
protoscolices.
camels and other animals that are infected from contaminated
pastures or water. By handling a dog or drinking contaminated
water, humans may ingest eggs (Fig. 11.58). The embryo is
liberated from the ovum in the small intestine and invades
the blood stream, spreading to the liver. The resultant cyst
grows very slowly, sometimes intermittently. It is composed of
an enveloping fibrous pericyst, laminated hyaline membrane
(ectocyst) and inner germinal layers (endocyst) that give rise to
daughter cysts, or a germinating cystic brood capsule in which
larvae (protoscolices) develop. Over time, some cysts calcify and
become non-viable. The disease is common in the Middle East,
North and East Africa, Australia and Argentina. Foci of infection
persist in the UK in rural Wales and Scotland. E. multilocularis,
which has a cycle between foxes and voles, causes a similar but
more severe infection, ‘alveolar hydatid disease’, which invades
the liver like cancer.
Clinical features
A hydatid cyst is typically acquired in childhood and, after
growing for years, may cause pressure symptoms. These vary,
depending on the site involved. In nearly 75% of patients with
hydatid disease, the right lobe of the liver is invaded and contains
a single cyst. In others, a cyst may be found in lung, bone,
brain or elsewhere.
Investigations
The diagnosis depends on the clinical, radiological and ultrasound
findings in a patient that has close contact with dogs in an
endemic area. Complement fixation and ELISA are positive in
70-90% of patients.
Management and prevention
Hydatid cysts should be excised wherever possible. Great
care is taken to avoid spillage and cavities are sterilised with
0.5% silver nitrate or 2.7% sodium chloride. Albendazole
(400 mg twice daily for 3 months) should also be used and is
often combined with PAIR (percutaneous puncture, aspiration,
injection of scolicidal agent and re-aspiration). Praziquantel
(20 mg/kg twice daily for 14 days) also kills protoscolices
perioperatively.
Prevention is difficult when there is a close association with dogs.
Personal hygiene, satisfactory disposal of carcasses, meat inspection
and deworming of dogs reduces the prevalence of disease.
Other tapeworms
Other cestodes’ adult or larval stages may infect humans.
Sparganosis is a condition in which an immature worm develops
in humans, usually subcutaneously, as a result of eating or
applying to the skin the secondary or tertiary intermediate host,
such as frogs or snakes.
Ectoparasites
Ectoparasites only interact with the outermost surfaces of the
host; see also page 1241 .
| Jiggers (tungiasis)
This is widespread in tropical America and Africa, and is caused
by the sand flea Tunga penetrans. The pregnant flea burrows
into the skin around toes and produces large numbers of eggs.
300 • INFECTIOUS DISEASE
The burrows are intensely irritating and the whole inflammatory
nodule should be removed with a sterile needle. Secondary
infection of lesions is common.
| Myiasis
Myiasis is due to skin infestation with larvae of the South American
botfly, Dermatobia hominis, or the African tumbu fly, Cordylobia
anthropophaga. The larvae develop in a subcutaneous space
with a central sinus. This orifice is the air source for the larvae,
and periodically the larval respiratory spiracles protrude through
the sinus. Patients with myiasis feel movement within the larval
burrow and can experience intermittent sharp, lancinating pains.
Myiasis is diagnosed clinically and should be suspected with
any furuncular lesion accompanied by pain and a crawling
sensation in the skin. The larva may be suffocated by blocking
the respiratory orifice with petroleum jelly and gently removing it
with tweezers. Secondary infection of myiasis is rare and rapid
healing follows removal of intact larvae.
Fungal infections
Fungal infections, or mycoses, are classified as superficial,
subcutaneous or systemic (deep), depending on the degree of
tissue invasion. They are caused by filamentous fungi (moulds), by
yeasts or by fungi that vary between these two forms, depending
on environmental conditions (dimorphic fungi; Fig. 11.59).
Superficial mycoses
Superficial cutaneous fungal infections caused by dermatophyte
fungi are described in Chapter 29.
Candidiasis (thrush)
Superficial candidiasis is caused by Candida spp., mainly C.
albicans. Manifestations include oropharyngeal (pp. 790 and 1 240)
and vaginal candidiasis (‘thrush’), intertrigo and chronic paronychia.
Superficial candidiasis often follows antibiotic therapy. Intertrigo
is characterised by inflammation in skin folds with surrounding
‘satellite lesions’. Chronic paronychia is associated with frequent
wetting of the hands. Superficial candidiasis is treated mainly with
topical azoles (p. 126), oral azoles being reserved for refractory
or recurrent disease. Severe oropharyngeal and oesophageal
candidiasis is a consequence of CD4+ T-lymphocyte depletion/
dysfunction, as in HIV infection (p. 316). Recurrent vaginal or
penile candidiasis may be a manifestation of diabetes mellitus.
Rarely, mutations in the autoimmune regulator gene (AIRE)
or signal transducer and activator of transcription 1 (STAT1)
cause a syndrome of chronic mucocutaneous candidiasis
(p. 689). This is characterised by Candida infections of skin,
mucosa and nails, with hyperkeratotic nails and erythematous
periungual skin. Patients have cell-mediated immune defects
against Candida and may have polyendocrinopathy and
autoimmune features.
Subcutaneous mycoses
Chromoblastomycosis
Chromoblastomycosis is a predominantly tropical or subtropical
disease caused by environmental dematiaceous (dark- pigmented)
fungi, most commonly Fonsecaea pedrosoi. Other causes
include F. compacta, Cladophialophora carrionii and Phialophora
verrucosa. The disease is a cutaneous/subcutaneous mycosis
acquired by traumatic inoculation. Commonly affected areas
Filamentous fungi (moulds)
Dimorphic fungi
Characterised by the production of
elongated, cylindrical, often septate
cells (hyphae) and conidia (spores)
Exist in filamentous (top) or yeast
(bottom) form, depending on
environmental conditions
Characterised by the production of
oval or round cells, which reproduce
by binary fission (budding)
Examples:
• Aspergillus spp. (A. fumigatus
shown here)
• Fusarium spp.
• Dermatophyte fungi (Tricophyton spp.,
Microsporum spp. etc.)
• Mucorales
Examples:
• Histopiasma capsulatum,
Coccidioides immitis, Paracoccidioides
brasiliensis (shown here), Blastomyces
dermatidis
• Sporothrix schenkii
• Talaromyces marneffei
• Malassezia spp.
Examples:
• Candida spp.*
• Cryptococcus spp. (C. neoformans
shown here)
Fig. 11.59 Classification of medically important fungi. Fungal classification is based on simple morphological characteristics. Pneumocystis jirovecii
is morphologically distinct from other fungi and does not fit into this classification. ^Although Candida albicans exists in a number of forms, including
filamentous (hyphae and pseudohyphae), it is generally encountered in its yeast form so is classified in this category. Insets (dimorphic fungi) Courtesy of
Beatriz Gomez and Angela Restrepo, CIB, Medellin, Colombia.
Fungal infections • 301
include the foot, ankle and lower leg. Lesions may start several
months after the initial injury, and medical attention is often
sought several years later. The initial lesion is a papule. Further
papules develop and coalesce to form irregular plaques. Nodular
lesions may produce a characteristic ‘cauliflower’ appearance.
Diagnosis is by histopathological examination of infected
material, which shows dematiaceous, rounded, thick-walled
‘sclerotic bodies’ with septa at right angles to each other. The
aetiological agent is confirmed by culture. Therapeutic approaches
include antifungal agents, cryosurgery and surgical excision,
alone or in combination, but the optimal therapy is unknown.
Itraconazole and terbinafine are the most effective antifungal
agents. However, posaconazole has also been used with a
good outcome.
Mycetoma (eumycetoma and actinomycetoma)
Mycetoma is a chronic suppurative infection of the deep soft
tissues and bones, most commonly of the limbs but also of the
abdominal or chest wall or head. It is caused by either filamentous
fungi, Eumyces (eumycetoma - 40%) or aerobic Actinomycetes
(actinomycetoma - 60%). Many fungi cause eumycetomas,
the most common being Madurella mycetomatis, M. grisea,
Leptosphaeria senegalensis and Scedosporium apiospermum-,
causes of actinomycetoma include Nocardia, Streptomyces
and Actinomadura spp. Both groups produce characteristically
coloured ‘grains’ (microcolonies), the colour depending on
the organism (black grains - eumycetoma, red and yellow
grains - actinomycetoma, white grains - either). The disease
occurs mostly in the tropics and subtropics.
Clinical features
The disease is acquired by inoculation (e.g. from a thorn) and
most commonly affects the foot (Madura foot). Mycetoma begins
as a painless swelling at the implantation site, which becomes
chronic and progressive, grows and spreads steadily within the
soft tissues, eventually extending into bone. Nodules develop
under the epidermis and these rupture, revealing sinuses through
which grains may be discharged. Sinuses heal with scarring,
while fresh sinuses appear elsewhere. Deeper tissue invasion and
bone involvement are less rapid and extensive in eumycetoma
than actinomycetoma. There is little pain and usually no fever or
lymphadenopathy, but there is progressive disability.
Investigations
Diagnosis of mycetoma involves identification of grains in pus, and/
or histopathological examination of tissue. Culture is necessary
for species identification and susceptibility testing. Serological
tests are not available.
Management
Eumycetoma is usually treated with a combination of surgery and
antifungal therapy. Antifungal susceptibility testing, if available, is
recommended, although clinical outcome does not necessarily
correspond to in vitro test results. Itraconazole and ketoconazole
(both 200-400 mg/day) are used most commonly. Success
has also been reported with terbinafine monotherapy, and
refractory cases have responded to voriconazole or posaconazole.
Amphotericin B is not usually effective. Therapy is continued for
6-12 months or longer. In extreme cases, amputation may be
required. Actinomycetoma is treated with prolonged antibiotic
combinations, most commonly streptomycin and dapsone.
Dapsone is replaced by co-trimoxazole in intolerance or refractory
disease. Success has also been reported wth co-trimoxazole
plus amikacin, with rifampicin added in difficult cases and to
prevent recurrence.
Phaeohyphomycosis
Phaeohyphomycoses are a heterogeneous group of fungal
diseases caused by a large number (more than 70) of
dematiaceous fungi. In phaeohyphomycosis, the tissue form of
the fungus is predominantly mycelial (filamentous), as opposed
to eumycetoma (grain) or chromoblastomycosis (sclerotic
body). Disease may be superficial, subcutaneous or deep. The
most serious manifestation is cerebral phaeohyphomycosis,
which presents with a ring-enhancing, space-occupying
cerebral lesion. Optimal therapy for this condition has not been
established but usually consists of neurosurgical intervention
and antifungal (usually triazole) therapy. Causative agents are
Cladophialophora bantiana, Fonsecaea spp. and Rhinocladiella
mackenziei, which occurs mainly in the Middle East and is
usually fatal.
Sporotrichosis
Sporotrichosis is caused by Sporothrix schenckii, a dimorphic
fungal saprophyte of plants in tropical and subtropical regions.
Disease is caused by dermal inoculation of the fungus, usually
from a thorn (occasionally from a cat scratch). In fixed cutaneous
sporotrichosis, a subcutaneous nodule develops at the site of
infection and subsequently ulcerates, with a purulent discharge.
The disease may then spread along the cutaneous lymphatic
channels, resulting in multiple cutaneous nodules that ulcerate
and discharge (lymphocutaneous sporotrichosis). Rarer forms
include cutaneous disease presenting with arthritis. Later,
draining sinuses may form. Pulmonary sporotrichosis occurs
as a result of inhalation of the conidia (spores) and causes
chronic cavitary fibronodular disease with haemoptysis and
constitutional symptoms. Disseminated disease may occur,
especially in patients with HIV.
Investigations
Typical yeast forms detected on histology confirm diagnosis
but are rarely seen; the fungus can also be cultured from
biopsy specimen. A latex agglutination test detects S. schenckii
antibodies in serum.
Management
Cutaneous and lymphocutaneous disease is treated with
itraconazole (200-400 mg daily, prescribed as the oral solution,
which has better bioavailability than the capsule formulation)
for 3-6 months. Alternative agents include a saturated solution
of potassium iodide (SSKI, given orally), initiated with 5 drops
and increased to 40-50 drops 3 times daily, or terbinafine
(500 mg twice daily). Localised hyperthermia may be used in
pregnancy (to avoid azole use). Osteoarticular disease requires
a longer course of therapy (at least 12 months). Severe or life-
threatening disease is treated with amphotericin B (lipid formulation
preferred).
Systemic mycoses
Aspergillosis
Aspergillosis is an opportunistic systemic mycosis, which affects
the respiratory tract predominantly. It is described on page 596.
302 • INFECTIOUS DISEASE
| Candidiasis
Systemic candidiasis is an opportunistic mycosis caused
by Candida spp. The most common cause is C. albicans.
Other agents include C. dubliniensis, C. g lab rata, C. krusei, C.
parapsilosis and C. tropicalis. Candida species identification
often predicts susceptibility to fluconazole: C. krusei is
universally resistant, many C. glabrata isolates have reduced
susceptibility or are resistant, and other species are mostly
susceptible. Candidiasis is usually an endogenous disease that
originates from oropharyngeal, genitourinary or skin colonisation,
although nosocomial spread occurs. C. auris is an emerging
species, which has a particular propensity for nosocomial
transmission.
Syndromes of systemic candidiasis
Acute disseminated candidiasis
This usually presents as candidaemia (isolation of Candida
spp. from the blood). The main predisposing factor is the
presence of a central venous catheter. Other major factors
include recent abdominal surgery, total parenteral nutrition (TPN),
recent antimicrobial therapy and localised Candida colonisation.
Up to 40% of cases will have ophthalmic involvement, with
characteristic retinal ‘cotton wool’ exudates. As this is a sight-
threatening condition, candidaemic patients should have a
full ophthalmoscopy review. Skin lesions (non-tender pink/
red nodules) may be seen. Although predominantly a disease
of intensive care and surgical patients, acute disseminated
candidiasis and/or Candida endophthalmitis is seen occasionally
in injection drug-users, due to candidal contamination of citric
acid or lemon juice used to dissolve heroin.
Chronic disseminated candidiasis (hepatosplenic candidiasis)
Persistent fever in a neutropenic patient, despite antibacterial
therapy and neutrophil recovery, associated with the development
of abdominal pain, raised alkaline phosphatase and multiple
lesions in abdominal organs (e.g. liver, spleen and/or kidneys)
on radiological imaging, suggests a diagnosis of hepatosplenic
candidiasis. This represents a form of immune reconstitution
syndrome (p. 104) in patients recovering from neutropenia
and usually lasts for several months, despite appropriate
therapy.
Other manifestations
Renal tract candidiasis, osteomyelitis, septic arthritis, peritonitis,
meningitis and endocarditis are all well recognised and are usually
sequelae of acute disseminated disease. Diagnosis and treatment
of these conditions require specialist mycological advice.
Management
Blood cultures positive for Candida spp. must never be ignored.
Acute disseminated candidiasis is treated with antifungal therapy,
removal of any in-dwelling central venous catheter (whether
known to be the source of infection or not) and removal of any
documented source. Candidaemia should be treated initially with
an echinocandin (p. 126), with subsequent adjustment (usually
to intravenous or oral fluconazole) guided by clinical response,
species identification and susceptibility testing. Treatment should
continue for a minimum of 1 4 days. Alternative therapies include
voriconazole and amphotericin B formulations.
Chronic disseminated candidiasis requires prolonged treatment
over several months with fluconazole or other agents, depending
on species and clinical response. The duration of the condition may
be reduced by adjuvant therapy with systemic glucocorticoids.
Cryptococcosis
Cryptococcosis is a systemic mycosis caused by two environmental
yeast species, Cr. neof ormans and Cr. gattii. Cr. neof ormans
is distributed worldwide and is primarily an opportunistic
pathogen, most commonly associated with HIV infection (p. 321).
Cr. gattii is a primary pathogen with a widespread distribution
that includes Australasia, Africa, Canada (Vancouver Island) and
the north-western USA.
Cryptococcosis is acquired by inhalation of yeasts. These
may disseminate to any organ, most commonly the CNS and
skin. The manifestations of Cr. neoformans are most severe in
immunocompromised individuals. Conversely, Cr. gattii causes
severe disease in immunocompetent hosts. Disseminated
cryptococcosis (sepsis with cryptococci present in the blood stream
or at multiple sites) is largely restricted to immunocompromised
patients. CNS manifestations of cryptococcosis include meningitis
(p. 321) and cryptococcoma (Fig. 1 1 .60), the latter more likely with
Cr. gattii infection. Manifestations of pulmonary cryptococcosis
range from severe pneumonia (in more immunocompromised
patients) to asymptomatic disease with single or multiple
pulmonary nodules, sometimes exhibiting cavitation (in patients
with lesser immunosuppression). Cryptococcal nodules may
mimic other causes of lung pathology, such as tuberculosis
or malignancy, and diagnosis requires histopathology and/or
culture.
Treatment of severe cryptococcosis is the same as for
cryptococcal meningitis, initially with liposomal amphotericin B
(p. 321). Mild pulmonary disease is usually treated with fluconazole,
although for asymptomatic nodules resection of the lesions is
likely to be sufficient.
| Fusariosis
Fusarium spp. cause disseminated disease in patients
with prolonged neutropenia. The disease presents with
Fig. 11.60 Cryptococcal disease. A 23-year-old HIV-positive male
developed headache and left-sided weakness. {K\ MRI scan of the brain
showed a space-occupying lesion (arrow) with surrounding oedema.
[SI Histopathological examination of the lesion stained with Grocott’s silver
stain showed encapsulated yeasts. Cryptococcus neoformans ms cultured.
Fungal infections • 303
Fig. 11.61 Fusarium infection. A patient presented with fever and skin
nodules after developing neutropenia secondary to haematopoietic stem
cell transplantation and chemotherapy for relapsed leukaemia. Fusarium
solani was cultured from skin lesions and blood cultures. [A] Tender,
erythematous papules/nodules on upper arm. [§] Gram stain of Fusarium
in blood culture medium.
antibiotic-resistant fever and evidence of dissemination (e.g.
skin nodules, endophthalmitis, septic arthritis, pulmonary disease;
Fig. 11.61). In contrast to Aspergillus spp., Fusarium spp. is
often recovered from blood cultures. Treatment is challenging
because of resistance to antifungal agents; voriconazole,
posaconazole or lipid-formulated amphotericin B is most often
prescribed.
| Mucormycosis
Mucormycosis is a severe but uncommon opportunistic systemic
mycosis caused by a number of ‘mucoraceous’ moulds, most
commonly Lichtheimia (formerly Absidia) spp., Rhizomucor
spp., Mucor spp. and Rhizopus spp. Disease patterns include
rhinocerebral/craniofacial, pulmonary, cutaneous and systemic
disease. All are characterised by the rapid development
of severe tissue necrosis, which is almost always fatal if
left untreated. The most common predisposing factors are
profound immunosuppression from neutropenia and/or
haematopoietic stem cell transplantation, uncontrolled diabetes
mellitus, iron chelation therapy with desferrioxamine and severe
burns.
Definitive diagnosis is by culture but histopathological
confirmation is required, as the fungi may be environmental
contaminants. Treatment requires a combination of antifungal
therapy and surgical debridement, with correction of predisposing
factor(s) if possible. High-dose lipid-formulated amphotericin B
is most commonly used. Posaconazole is active against many
mucoraceous moulds in vitro and may be used as a second-line
agent or as oral ‘step-down’ therapy.
ITalaromyces (formerly Penicillium)
marneffei infection
T. marneffei is a thermally dimorphic pathogen (filamentous in
environmental conditions and yeast at body temperature), which
causes disease in South-east Asia, mainly in association with
HIV infection (although immunocompetent patients may also be
infected). Acquisition is usually by inhalation of environmental
spores, with primary lung infection followed by haematogenous
dissemination. A generalised papular rash, which progresses to
widespread necrosis and ulceration, is a characteristic feature.
Skin lesions may resemble molluscum contagiosum. Diagnosis is
by histopathology and/or culture of respiratory secretions, blood
or any infected clinical material (e.g. skin lesions, bone marrow,
biopsies). Treatment involves an amphotericin B formulation
followed by itraconazole (in severe infection), or itraconazole alone.
Histoplasmosis
Histoplasmosis is a primary systemic mycosis caused by the
dimorphic fungus Fiistopiasma capsulatum. FI. capsulatum
var. capsulatum is endemic to east-central USA (especially the
Mississippi and Ohio river valleys), parts of Canada, Latin America,
the Caribbean, East and South-east Asia, and Africa. It occurs
sporadically in Australia and India, and is very rare in Europe. FI.
capsulatum var. duboisii is found in West Africa and Madagascar.
The primary reservoir of FI. capsulatum is soil enriched by
bird and bat droppings, in which the fungus remains viable for
many years. Infection is by inhalation of infected dust. Natural
infections are found in bats, which represent a secondary reservoir
of infection. Histoplasmosis is a specific hazard for explorers of
caves and people who clear out bird (including chicken) roosts.
Pathology
The organism is inhaled in the form of conidia or hyphal
fragments and transforms to the yeast phase during infection.
Conidia or yeasts are phagocytosed by alveolar macrophages
and neutrophils, and this may be followed by haematogenous
dissemination to any organ. Subsequent development of a
T-lymphocyte response brings the infection under control, resulting
in a latent state in most exposed individuals.
Clinical features
Disease severity depends on the quantity of spores inhaled
and the immune status of the host. In most cases, infection is
asymptomatic. Pulmonary symptoms are the most common
presentation, with fever, non-productive cough and an influenza¬
like illness. Erythema nodosum, myalgia and joint pain frequently
occur, and chest radiography may reveal a pneumonitis with
hilar or mediastinal lymphadenopathy.
Patients with pre-existing lung disease, such as chronic
obstructive pulmonary disease (COPD) or emphysema,
may develop chronic pulmonary histoplasmosis (CPH). The
predominant features of this condition, which may easily be
mistaken for tuberculosis, are fever, cough, dyspnoea, weight
loss and night sweats. Radiological findings include fibrosis,
nodules, cavitation and hilar/mediastinal lymphadenopathy.
Disease caused by FI. capsulatum var. duboisii presents more
commonly with papulonodular and ulcerating lesions of the
skin and underlying subcutaneous tissue and bone (sometimes
referred to as ‘African histoplasmosis’). Multiple lesions of the
ribs are common and the bones of the limbs may be affected.
Lung involvement is relatively rare. Radiological examination may
show rounded foci of bone destruction, sometimes associated
304 • INFECTIOUS DISEASE
with abscess formation. Other disease patterns include a visceral
form with liver and splenic invasion, and disseminated disease.
Acute disseminated histoplasmosis is seen with immuno¬
compromise, including HIV infection. Features include fever,
pancytopenia, hepatosplenomegaly, lymphadenopathy and often
a papular skin eruption. Chronic disseminated disease presents
with fever, anorexia and weight loss. Cutaneous and mucosal
lesions, lymphadenopathy, hepatosplenomegaly and meningitis
may develop. Emergomyces africanus (formerly Emmonsia sp.)
is a dimorphic fungus recently described in South Africa, which
causes a disseminated histoplasmosis-like illness, mainly associ¬
ated with HIV infection. Histopathologically, yeast forms appear
similar to histoplasmosis and can be distinguished only by PCR.
Investigations
Histoplasmosis should be suspected in endemic areas with
every undiagnosed infection in which there are pulmonary signs,
enlarged lymph nodes, hepatosplenomegaly or characteristic
cutaneous/bony lesions. Radiological examination in long-standing
cases may show calcified lesions in the lungs, spleen or other
organs. In the more acute phases of the disease, single or
multiple soft pulmonary shadows with enlarged tracheobronchial
nodes are seen on chest X-ray.
Laboratory diagnosis is by direct detection (histopathology
or antigen detection), culture and serology; although antigen
detection is the most effective method, it is not widely available.
Serology utilises complement fixation testing or immunodiffusion;
interpretation is complex and requires a specialist. Histoplasma
antigen may be detectable in blood or urine. Culture is definitive
but slow (up to 1 2 weeks). Histopathology may show characteristic
intracellular yeasts. Diagnosis of subcutaneous or bony infection
is mainly by histopathological examination and/or culture.
Management
Mild pulmonary disease does not require treatment. However,
if prolonged, it may be treated with itraconazole. More severe
pulmonary disease is treated with an amphotericin B formulation
for 2 weeks, followed by itraconazole for 12 weeks, with
methylprednisolone added for the first 2 weeks of therapy if
there is hypoxia or ARDS. CPH is treated with itraconazole oral
solution for 12-24 months, and disseminated histoplasmosis
with an amphotericin B formulation followed by itraconazole.
Lipid formulations of amphotericin B are preferred but their use
is subject to availability. In subcutaneous and bone infection,
patterns of remission and relapse are more common than cure.
A solitary bony lesion may require local surgical treatment only.
| Coccidioidomycosis
This is a primary systemic mycosis caused by the dimorphic fungi
Coccidioides immitis and C. posadasii, found in the south-western
USA and Central and South America. The disease is acquired
by inhalation of conidia (arthrospores). In 60% of cases it is
asymptomatic but in the remainder it affects the lungs, lymph
nodes and skin. Rarely (in approximately 0.5%), it may spread
haematogenously to bones, adrenal glands, meninges and other
organs, particularly in those with immunocompromise.
Pulmonary coccidioidomycosis has two forms: primary and
progressive. If symptomatic, primary coccidioidomycosis presents
with cough, fever, chest pain, dyspnoea and (commonly) arthritis
and a rash (erythema multiforme). Progressive disease presents
with systemic upset (e.g. fever, weight loss, anorexia) and features
of lobar pneumonia, and may resemble tuberculosis.
Coccidioides meningitis (which may be associated with CSF
eosinophils) is the most severe disease manifestation; it is fatal
if untreated and requires life-long suppressive therapy with
antifungal azoles.
Investigations and management
Diagnosis is by direct histopathological detection in specimens,
culture of infected tissue or fluids, or antibody detection. IgM may
be detected after 1-3 weeks of disease by precipitin tests. IgG
appears later and is detected with the complement fixation test.
Change in IgG titre may be used to monitor clinical progress.
Treatment depends on specific disease manifestations and
ranges from regular clinical reassessment without antifungal
therapy (in mild pulmonary, asymptomatic cavitary or single
nodular disease) to high-dose treatment with an antifungal
azole, which may be continued indefinitely (e.g. in meningitis).
Amphotericin B is used in diffuse pneumonia, disseminated
disease and, intrathecal ly, in meningitis. Posaconazole has been
used successfully in refractory disease.
| Paracoccidioidomycosis
This is a primary systemic mycosis caused by inhalation of the
dimorphic fungus Paracoccidioides brasiliensis, which is restricted
to South America. The disease affects the lungs, mucous
membranes (painful destructive ulceration in 50% of cases), skin,
lymph nodes and adrenal glands (hypoadrenalism). Diagnosis is
by microscopy and culture of lesions, and antibody detection.
Oral itraconazole solution (200 mg/day) has demonstrated 98%
efficacy and is currently the treatment of choice (mean duration
6 months). Ketoconazole, fluconazole, voriconazole and 2-3-year
courses of sulphonamides are alternatives. Amphotericin B is
used in severe or refractory disease, followed by an azole or
sulphonamide.
Blastomycosis
Blastomyces dermatitidis is a dimorphic fungus endemic to
restricted parts of North America, mainly around the Mississippi
and Ohio rivers. Very occasionally, it is reported from Africa.
The disease usually presents as a chronic pneumonia similar to
pulmonary tuberculosis. Bones, skin and the genitourinary tract
may also be affected. Diagnosis is by culture of the organism
or identification of the characteristic yeast form in a clinical
specimen. Antibody detection is rarely helpful. Treatment is with
amphotericin B (severe disease) or itraconazole.
Further information
Websites
britishinfection.org British Infection Association; source of general
information on communicable diseases.
cdc.gov Centers for Disease Control, USA; source of general
information about infectious diseases.
fitfortravel.nhs.uk Scottish site with valuable information for travellers.
https://www.gov.uk/government/organisations/public-health-england
Public Health England; information on infectious diseases in the UK.
idsociety.org Infectious Diseases Society of America; source of general
information relating to infectious diseases and of authoritative
practice guidelines.
who.int. especially www.who.int/csr/don World Health Organisation;
invaluable links on travel medicine with updates on outbreaks of
infections, changing resistance patterns and vaccination
requirements.
HIV infection and AIDS
Clinical examination in HIV disease 306
Prevention of opportunistic infections 323
Epidemiology 308
Global and regional epidemics 308
Modes of transmission 308
Preventing exposure 323
Chemoprophylaxis 323
Immunisation 324
Virology and immunology 309
Diagnosis and investigations 10
Diagnosing HIV infection 31 0
Viral load and CD4 counts 31 1
Antiretroviral therapy 324
ART complications 325
ART in special situations 326
Prevention of HIV 327
Clinical manifestations of HIV 311
Presenting problems in HIV infection 312
Lymphadenopathy 31 3
Weight loss 313
Fever 31 3
Mucocutaneous disease 31 4
Gastrointestinal disease 31 6
Hepatobiliary disease 317
Respiratory disease 31 8
Nervous system and eye disease 31 9
Rheumatological disease 321
Haematological abnormalities 322
Renal disease 322
Cardiac disease 322
HIV-related cancers 322
306 • HIV INFECTION AND AIDS
Clinical examination in HIV disease
2 Oropharynx
Mucous membranes
A Oropharyngeal candidiasis
A Oral hairy leucoplakia
Herpes simplex
Aphthous ulcers
Kaposi’s sarcoma
Teeth
A Gingivitis/periodontitis
1 Skin
Papular pruritic eruption
A Kaposi’s sarcoma
A Molluscum contagiosum
Herpes zoster
Seborrhoeic dermatitis
3 Neck
Lymph node enlargement
Tuberculosis
Lymphoma
Kaposi’s sarcoma
Persistent generalised
lymphadenopathy
Parotidomegaly
A Cervical lymphadenopathy
4 Eyes
Retina
Toxoplasmosis
HIV retinopathy
Progressive outer retinal
necrosis
A Cytomegalovirus retinitis
5 Central nervous system
Higher mental function
HIV dementia
Progressive multifocal
leucoencephalopathy
Focal signs
Toxoplasmosis
Primary CNS lymphoma
Neck stiffness
Cryptococcal meningitis
Tuberculous meningitis
Pneumococcal meningitis
6 Chest
Lungs
Pleural effusion
Tuberculosis
Kaposi’s sarcoma
Parapneumonic
7 Abdomen
Hepatosplenomegaly
8 Anogenital region
Rashes
Fevers and sweats
AAnal cancer
Condylomas
Herpes simplex
Ulcers
9 Legs
Peripheral nerve examination
Spastic paraparesis
Peripheral neuropathy
Inset (oral hairy leucoplakia) Courtesy of Audiovisual Dept, St Mary’s Hospital, London.
Clinical examination in HIV disease • 307
mm
1 HIV clinical staging classifications
World Health Organisation (WHO) clinical stage
Centers for Disease Control (CDC) clinical categories
(used in low- and middle-income countries)
(used in high-income countries)
Stage 1
Category A
Asymptomatic
Primary HIV infection
Persistent generalised lymphadenopathy
Asymptomatic
Persistent generalised lymphadenopathy
Stage 2
Category B
Unexplained moderate weight loss (<10% of body weight)
Bacillary angiomatosis
Recurrent upper respiratory tract infections
Candidiasis, oropharyngeal (thrush)
Herpes zoster
Candidiasis, vulvovaginal; persistent, frequent or poorly responsive to therapy
Angular cheilitis
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Recurrent oral ulceration
Constitutional symptoms, such as fever (38.5°C) or diarrhoea lasting >1 month
Papular pruritic eruptions
Oral hairy leucoplakia
Seborrhoeic dermatitis
Herpes zoster, involving two distinct episodes or more than one dermatome
Fungal nail infections
Idiopathic thrombocytopenic purpura
Stage 3 ubieriobib
Unexplained severe weight loss (> 1 0% of body weight) Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess
Unexplained chronic diarrhoea for >1 month Peripheral neuropathy
Unexplained persistent fever (>37.5°C for >1 month)
Persistent oral candidiasis
Oral hairy leucoplakia
Pulmonary tuberculosis
Severe bacterial infections
Acute necrotising ulcerative stomatitis, gingivitis or periodontitis
Unexplained anaemia (<80 g/L (8 g/dL)), neutropenia (<0.5x109/L)
and/or chronic thrombocytopenia (< 50 x 1 09/L)
Stage 4 Category C
Candidiasis of oesophagus, trachea, bronchi or lungs
Cervical carcinoma - invasive
Cryptococcosis - extrapulmonary
Cryptosporidiosis, chronic (>1 month)
Cytomegalovirus disease (outside liver, spleen and nodes)
Herpes simplex chronic (>1 month) ulcers or visceral
HIV encephalopathy
HIV wasting syndrome
Cystoisosporiasis (formerly known as isosporiasis), chronic (>1 month)
Kaposi’s sarcoma
Lymphoma (cerebral or B-cell non-Hodgkin)
Mycobacterial infection, non-tuberculous, extrapulmonary or disseminated
Mycosis - disseminated endemic (e.g. coccidioidomycosis, talaromycosis (formerly penicilliosis), histoplasmosis)
Pneumocystis pneumonia
Pneumonia, recurrent bacterial
Progressive multifocal leucoencephalopathy
Toxoplasmosis - cerebral
Tuberculosis - extrapulmonary (CDC includes pulmonary)
Sepsis, recurrent (including non-typhoidal Salmonella) (CDC only includes Salmonella)
Symptomatic HIV-associated nephropathy*
Symptomatic HIV-associated cardiomyopathy*
Leishmaniasis, atypical disseminated*
*These conditions are in WHO stage 4 but not in CDC category C.
308 • HIV INFECTION AND AIDS
Epidemiology
The acquired immunodeficiency syndrome (AIDS) was first
recognised in 1981, although the earliest documented case
of HIV infection has been traced to a blood sample from the
Democratic Republic of Congo in 1959. AIDS is caused by the
human immunodeficiency virus (HIV), which progressively impairs
cellular immunity. The origin of HIV is a zoonotic infection with
simian immunodeficiency viruses (SIV) from African primates,
probably first infecting local hunters. SIVs do not cause disease
in their natural primate hosts. HIV-1 was transmitted from
chimpanzees and HIV-2 from sooty mangabey monkeys. HIV-1
is the cause of the global HIV pandemic, while HIV-2, which
causes a similar illness to HIV-1 but progresses more slowly
and is less transmissible, is restricted mainly to western Africa.
It has been estimated that both HIV-1 and HIV-2 first infected
humans about 100 years ago. HIV-2 will not be discussed
further in this chapter.
There are three groups of HIV-1 , representing three separate
transmission events from chimpanzees: M (‘major’, worldwide
distribution), O (‘outlier’) and N (‘non-major and non-outlier’).
Groups O and N are restricted to West Africa. Group M consists
of nine subtypes: A-D, F-H, J and K (subtypes E and I were
subsequently shown to be recombinants of other subtypes).
Globally, subtype C (which predominates in sub-Saharan Africa
and India) accounts for half of infections and appears to be more
readily transmitted. Subtype B predominates in Western Europe,
the Americas and Australia. In Europe, the prevalence of non-B
subtypes is increasing because of migration. Subtypes A and
D are associated with slower and faster disease progression,
respectively.
Global and regional epidemics
In 2015 it was estimated that there were 36.7 million people
living with HIV/AIDS, 2.1 million new infections and 1.1 million
AIDS-related deaths. The global epidemiology of HIV has been
changed by expanding access to combination antiretroviral
therapy (ART), which reached 17 million people in 2015: the
annual number of AIDS-related deaths has almost halved since
the peak in 2005, the number of new infections has decreased
by 40% since the peak in 1 997, and the number of people living
with HIV has increased. Regions have marked differences in HIV
prevalence, incidence and dominant modes of transmission (Box
12.1). HIV has had a devastating impact in sub-Saharan Africa,
particularly in southern Africa, where average life expectancy
of the general population fell to below 40 years before the
introduction of ART.
Modes of transmission
HIV is transmitted by sexual contact, by exposure to blood
(e.g. injection drug use, occupational exposure in health-care
workers) and blood products, or to infants of HIV-infected mothers
(who may be infected in utero, perinatally or via breastfeeding).
Worldwide, the major route of transmission is heterosexual. The
risk of contracting HIV after exposure to infected body fluid is
dependent on the integrity of the exposed site, the type and
volume of fluid, and the level of viraemia in the source person.
The approximate transmission risk after exposure is given in
Box 12.2. Factors that increase the risk of transmission are
listed in Box 12.3.
A high proportion of patients with haemophilia in high-income
countries had been infected through contaminated blood products
by the time HIV antibody screening was adopted in 1 985. Routine
screening of blood and blood products for HIV infection has
virtually eliminated this as a mode of transmission. However, the
World Health Organisation (WHO) estimates that, because of the
lack of adequate screening facilities in resource-poor countries,
5-10% of blood transfusions globally are with HIV-infected blood.
KM 1 2.2 Risk of HIV transmission after single exposure
to an HIV-infected source
HIV exposure
Approximate risk
Sexual
Vaginal intercourse: female to male
0.05%
Vaginal intercourse: male to female
0.1%
Anal intercourse: insertive
0.05%
Anal intercourse: receptive
0.5%
Oral intercourse: insertive
0.005%
Oral intercourse: receptive
0.01%
Blood exposure
Blood transfusion
90%
Intravenous drug-users sharing needles
0.67%
Percutaneous needlestick injury
0.3%
Mucous membrane splash
0.09%
Mother to child
Vaginal delivery
15%
Breastfeeding (per month)
0.5%
12.1 Regional HIV prevalence in 2015, incidence trend and dominant mode of transmission
Region
People living with HIV (millions)
HIV incidence trend (2011-2015)
Dominant transmission
Sub-Saharan Africa
25.5
Decreasing
Heterosexual
Asia and Pacific
5.1
Stable
IDU, heterosexual
Latin America and Caribbean
2
Stable
MSM, heterosexual
Western and Central Europe, and
North America
2.4
Stable
MSM
Eastern Europe and Central Asia
1.5
Increasing
IDU
Middle East and North Africa
0.23
Stable
IDU, MSM
(IDU = injection drug-users; MSM = men who have sex with men)
Virology and immunology • 309
1 2.3 Factors increasing the risk of transmission
of HIV
Common to all transmission categories
• High viral load
Sexual transmission
• STIs, especially genital
• Receptive anal intercourse
ulcers
• Depot intramuscular
• Cervical ectopy
progesterone contraceptive
• Rectal or vaginal lacerations
use
• Menstruation
• Uncircumcised male
partner
Injection drug use transmission
• Sharing equipment
• Concomitant cocaine use
• Linked commercial sex
• Incarceration
• Intravenous use
Occupational transmission
• Deep injury
• Needle was in a blood vessel
• Visible blood on device
Vertical transmission
• Prolonged rupture of
• Older gestational age
membranes
(STIs = sexually transmitted infections)
Virology and immunology
HIV is an enveloped ribonucleic acid (RNA) retrovirus from the
lentivirus family. After mucosal exposure, HIV is transported via
dendritic cells to the lymph nodes, where infection becomes
established. This is followed by viraemia and dissemination to
lymphoid organs, which are the main sites of viral replication.
Each mature virion has a lipid membrane lined by a matrix
protein that is studded with glycoprotein (gp) 1 20 and gp41 spikes.
The inner cone-shaped protein core (p24) houses two copies of
the single-stranded RNA genome and viral enzymes. The HIV
genome consists of three characteristic retroviral genes - gag
(encodes a polyprotein that is processed into structural proteins,
including p24), pol (codes for the enzymes reverse transcriptase,
integrase and protease) and env (codes for envelope proteins
gp120 and gp41) - as well as six regulatory genes.
HIV infects cells bearing the CD4 receptor; these are T-helper
lymphocytes, monocyte-macrophages, dendritic cells, and
microglial cells in the central nervous system (CNS). Entry into
the cell commences with binding of gp120 to the CD4 receptor
(Fig. 12.1), which results in a conformational change in gp120
that permits binding to one of two chemokine co-receptors
(CXCR4 or CCR5). The chemokine co-receptor CCR5 is utilised
during initial infection, but later on the virus may adapt to use
CXCR4. Individuals who are homozygous for the CCR5 delta
Maturation
310 • HIV INFECTION AND AIDS
32 mutation do not express CCR5 on CD4 cells and are
immune to HIV infection. Chemokine co-receptor binding is
followed by membrane fusion and cellular entry involving gp41 .
After penetrating the cell and uncoating, a deoxyribonucleic
acid (DNA) copy is transcribed from the RNA genome by the
reverse transcriptase enzyme, which is carried by the infecting
virion. Reverse transcription is an error-prone process and
multiple mutations arise with ongoing replication, which results
in considerable viral genetic heterogeneity. Viral DNA is transported
into the nucleus and integrated within the host cell genome by
the integrase enzyme. Integrated virus is known as proviral DNA
and persists for the life of the cell. Cells infected with proviral HIV
DNA produce new virions only if they undergo cellular activation,
resulting in the transcription of viral messenger RNA (mRNA)
copies, which are then translated into viral peptide chains. The
precursor polyproteins are then cleaved by the viral protease
enzyme to form new viral structural proteins and enzymes that
migrate to the cell surface and are assembled using the host
cellular apparatus to produce infectious viral particles; these bud
from the cell surface, incorporating the host cell membrane into
the viral envelope. The mature virion then infects other CD4 cells
and the process is repeated. CD4 lymphocytes that are replicating
HIV have a very short survival time of about 1 day. It has been
estimated that in asymptomatic HIV-infected people, more than
1010 virions are produced and 109 CD4 lymphocytes destroyed
each day. The CD4 lymphocytes are destroyed primarily by the
host immune response rather than by cytopathic effects of HIV.
A small percentage of T-helper lymphocytes enter a post¬
integration latent phase. Latently infected cells are important
as sanctuary sites from antiretroviral drugs, which act only
on replicating virus. Current ART is unable to eradicate HIV
infection due to the persistence of proviral DNA in long-lived
latent CD4 cells.
The host immune response to HIV infection is both humoral,
with the development of antibodies to a wide range of antigens,
and cellular, with a dramatic expansion of HIV-specific CD8
cytotoxic T lymphocytes, resulting in a CD8 lymphocytosis and
reversal of the usual CD4:CD8 ratio. CD8 cytotoxic T lymphocytes
kill activated CD4 cells that are replicating HIV, but not latently
infected CD4 cells. HIV evades destruction despite this vigorous
immune response, in part because the highly conserved regions
of gp120 and gp41 that are necessary for viral attachment and
entry are covered by highly variable glycoprotein loops that change
over time as a result of mutations selected for by the immune
response. The initial peak of viraemia in primary infection settles
to a plateau phase of persistent chronic viraemia. With time, there
is gradual attrition of the T-helper lymphocyte population and,
as these cells are pivotal in orchestrating the immune response,
the patient becomes susceptible to opportunistic diseases.
The predominant opportunist infections in HIV-infected people
are the consequences of impaired cell-mediated rather than
antibody-mediated immunity (e.g. mycobacteria, herpesviruses).
However, there is also a B-lymphocyte defect with impaired
antibody production to new antigens and dysregulated antibody
production with a polyclonal increase in gamma globulins, resulting
in an increased risk of infection with encapsulated bacteria,
notably Streptococcus pneumoniae.
The immune activation in response to HIV infection does not
completely resolve on effective ART. This residual inflammatory
state has been implicated in the pathogenesis of several non-AIDS
morbidities that occur at a higher rate in HIV-infected people on
ART than in the general population: cardiovascular, neurological
and liver disease, chronic kidney disease and non-AIDS cancers.
Diagnosis and investigations
Diagnosing HIV infection
Globally, the trend is towards universal HIV testing, rather than
testing only those patients at high risk or those with manifestations
of HIV infection. However, in the UK, testing is still targeted to
high-risk groups (Box 12.4). HIV is diagnosed by detecting host
antibodies either with rapid point-of-care tests or in the laboratory,
where enzyme-linked immunosorbent assay (ELISA) tests are
usually done. Most tests detect antibodies to both HIV-1 and
HIV-2. A positive antibody test from two different immunoassays
is sufficient to confirm infection. Western blot assays can also be
used to confirm infection but they are expensive and sometimes
yield indeterminate results. Screening tests often include an
assay for p24 antigen in addition to antibodies, in order to detect
patients with primary infection before the antibody response
occurs. Nucleic acid amplification tests (usually polymerase
chain reaction, PCR) to detect HIV RNA are used to diagnose
infections in infants of HIV-infected mothers, who carry maternal
antibodies to HIV for up to 15 months irrespective of whether
they are infected, and to diagnose primary infection before
12.4 Patients who should be offered and
recommended HIV testing in the UK
Patients accessing specialist sexual health services (including
genitourinary medicine)
• All patients who attend for testing or treatment
Patients accessing primary care (including emergency care) and
secondary care
• All patients attending their first appointment at:
Drug dependency programmes
Pregnancy termination services
Services treating hepatitis B or C, lymphoma or tuberculosis
• All patients who:
Have symptoms that may indicate HIV or for which HIV is part of
the differential diagnosis
Are from a country or group with high rate of HIV infection
Are male, or trans women, who have sex with men
Report sexual contact with someone from a country with high
rate of HIV infection
Disclose high-risk sexual practices, e.g. ‘chemsex’ (p. 332)
Are diagnosed with, or request testing for, a sexually transmitted
infection
Report a history of injecting drug use
Are the sexual partners of people known to be HIV-positive or at
high risk of HIV
• In areas of high2 and extremely high3 prevalence:
All patients not previously diagnosed with HIV who register with a
general practice or undergo blood testing for any reason
• In areas of extremely high prevalence3:
All emergency care and secondary care patients not previously
diagnosed with HIV
At each general practice consultation consider offering
opportunistic HIV testing
Prison inmates
• All new inmates not previously diagnosed with HIV
''Adapted from National Institute for Health and Care Excellence NG60 - HIV
testing: increasing uptake among people who may have undiagnosed HIV NICE
guideline (Dec. 2016). Prevalence of diagnosed HIV is 2-5 per 1000 people
aged 15-59. Prevalence of diagnosed HIV is > 5 per 1000 people aged 15-59.
Clinical manifestations of HIV • 311
12.5 How to carry out pre-test counselling
1 12.7 Baseline investigations
• CD4 count
• Syphilis serology
• Viral load
• Cervical smear in women
• Hepatitis B surface antigen
• Serum cryptococcal antigen
• Hepatitis C antibody
(if CD4 <100)
• Liver function tests
• Tuberculin skin test
• Full blood count
• Sexually transmitted infection
• Urinalysis, serum creatinine
screen
antibodies have developed. PCR is more sensitive than p24
antigen detection for diagnosing primary infection.
The purpose of HIV testing is not simply to identify infected
individuals, but also to educate people about prevention and
transmission of the virus. Counselling in the client’s home language
is essential both before testing and after the result is obtained
(Boxes 12.5 and 12.6). There are major advantages to using
rapid point-of-care HIV tests in that pre- and post-test counselling
can be done at the same visit.
A number of baseline investigations should be done at the initial
medical evaluation (Box 12.7). The extent of these investigations
will depend on the resources available.
Viral load and CD4 counts
CD4 counts
CD4 lymphocyte counts are usually determined by flow cytometry
but cheaper methods have been developed for low-income
countries. The CD4 count is the most clinically useful laboratory
indicator of the degree of immune suppression; it is used, together
with clinical staging, in decisions to start prophylaxis against
opportunistic infections, and is of great value in the differential
diagnosis of clinical problems.
The CD4 count varies by up to 20% from day to day and is also
transiently reduced by intercurrent infections. Due to this variability,
major therapeutic decisions should not be taken on the basis of
a single count. The percentage of lymphocytes that are CD4+,
rather than the absolute count, is routinely used in paediatrics,
as the normal CD4 counts in infants and young children are
much higher than in adults. In adults, the CD4 percentage is
occasionally useful when evaluating significant reductions in an
individual’s CD4 count, which may be associated with transient
lymphopenia due to intercurrent infection or pregnancy. In this
case, the CD4 percentage will be unchanged.
The normal CD4 count is over 500 cells/mm3. The rate of
decline in CD4 count is highly variable. People with CD4 counts
between 200 and 500 cells/mm3 have a low risk of developing
major opportunistic infections. Morbidity due to inflammatory
dermatoses, herpes zoster, oral candidiasis, tuberculosis, bacterial
pneumonia and HIV-related immune disorders (e.g. immune
thrombocytopenia) becomes increasingly common as CD4 counts
decline. Once the count is below 200 cells/mm3, there is severe
immune suppression and a high risk of AIDS-defining conditions.
It is important to note that patients can be asymptomatic despite
very low CD4 counts and that major opportunistic diseases
occasionally present with high CD4 counts.
The CD4 count should be performed every 3-6 months in
patients on ART, together with measurement of the viral load.
Viral load
The level of viraemia is measured by quantitative PCR of HIV
RNA, known as the viral load. Determining the viral load is crucial
for monitoring responses to ART (p. 324). People with high viral
loads (e.g. >100000 copies/mL) experience more rapid declines
in CD4 count, while those with low viral loads (<1000 copies/mL)
usually have slow or even no decline in CD4 counts.
Transient increases in viral load occur with intercurrent
infections and immunisations, so the test should be done at
least 2 weeks afterwards. Viral loads are variable; only changes
in viral load of more than 0.5 log10 copies/mL are considered
clinically significant.
Clinical manifestations of HIV
Clinical staging of patients should be done at the initial medical
examination, as it provides prognostic information and is a key
criterion for initiating prophylaxis against opportunistic infections.
Two clinical staging systems are used internationally (p. 307).
In both, patients are staged according to the most severe
manifestation and do not improve their classification. For
example, a patient who is asymptomatic following a major
opportunistic disease (AIDS) remains at stage 4 or category C
of the WHO and CDC systems, respectively, and never reverts
to earlier stages. Finally, patients do not always progress steadily
through all stages and may present with AIDS, having been
asymptomatic.
Primary HIV infection
Primary infection is symptomatic in more than 50% of cases but
the diagnosis is often missed. The incubation period is usually
2-4 weeks after exposure. The duration of symptoms is variable
but is seldom longer than 2 weeks. The clinical manifestations
(Box 12.8) resemble those of infectious mononucleosis/glandular
fever (p. 241), but the presence of maculopapular rash or
mucosal ulceration strongly suggests primary HIV infection
Discuss meaning of positive and negative test results
Realise importance of maintaining confidentiality
Identify person to whom positive result could be disclosed
Explore knowledge and explain natural history of HIV
Discuss transmission and risk reduction
Assess coping strategy
Explain test procedure
Obtain informed consent
12.6 How to carry out post-test counselling
Test result negative
• Discuss transmission and need for behaviour modification
• Advise second test 3 months after last exposure
Test result positive
• Explain meaning of result
• Organise medical follow-up
• Assess coping strategy
• Stress importance of disclosure
• Explain value of antiretroviral therapy
• Provide written information and useful Internet resources
• Discuss confidentiality issues
• Organise emotional and practical support (names/phone numbers)
• Facilitate notification of sexual partners
312 • HIV INFECTION AND AIDS
Acute HIV syndrome
Wide dissemination of virus Opportunistic
Seeding of lymphoid organs diseases
Fig. 12.2 Virological and immunological
progression of untreated HIV infection.
12.8 Clinical features of primary infection
• Fever
• Diarrhoea
• Maculopapular rash
• Headache
• Pharyngitis
• Oral and genital ulceration
• Lymphadenopathy
• Meningo-encephalitis
• Myalgia/arthralgia
• Bell’s palsy
rather than the other viral causes of infectious mononucleosis.
In infectious mononucleosis due to Epstein-Barr virus (EBV)
or in cytomegalovirus (CMV), rashes generally occur only if
aminopenicillins are given. Atypical lymphocytosis occurs less
frequently than in EBV infection. Transient lymphopenia, including
CD4 lymphocytes, is found in most cases (Fig. 12.2), which
may result in opportunistic infections, notably oropharyngeal
candidiasis. Major opportunistic infections like Pneumocystis
jirovecii pneumonia (PJP) may rarely occur. Thrombocytopenia
and moderate elevation of liver enzymes are commonly present.
The differential diagnosis of primary HIV includes acute EBV,
primary CMV infection, rubella, primary toxoplasmosis and
secondary syphilis.
Early diagnosis is made by detecting HIV RNA by PCR or p24
antigenaemia. The appearance of specific anti-HIV antibodies in
serum (seroconversion) occurs 2-1 2 weeks after the development
of symptoms. The window period during which antibody tests may
be false negative is prolonged when post-exposure prophylaxis
has been used.
Asymptomatic infection
A prolonged period of clinical latency follows primary infection,
during which infected individuals are asymptomatic. Persistent
generalised lymphadenopathy with nodes typically <2 cm
diameter is a common finding. Eventually, the lymph nodes
regress, with destruction of node architecture as disease
advances.
Viraemia peaks during primary infection and then drops as the
immune response develops, to reach a plateau about 3 months
later. The level of viraemia post seroconversion is a predictor
of the rate of decline in CD4 counts, which is highly variable
and explained in part by genetic factors affecting the immune
response. The median time from infection to the development of
AIDS in adults is about 9 years (see Fig. 12.2). A small proportion
of untreated HIV-infected people are long-term non-progressors,
with CD4 counts in the reference range for 1 0 years or more.
Some long-term non-progressors have undetectable viral loads
and are known as ‘elite controllers’.
Minor HIV-associated disorders
A wide range of disorders indicating some impairment of cellular
immunity occur in most patients before they develop AIDS (CDC
category B or WHO stages 2 and 3). Careful examination of the
mouth is important when patients are being followed up, as oral
candidiasis and oral hairy leucoplakia are common conditions that
require initiation of prophylaxis against opportunistic infections,
irrespective of the CD4 count.
Acquired immunodeficiency syndrome
AIDS is defined by the development of specified opportunistic
infections, cancers and severe manifestations of HIV itself
(p. 307). CDC category C is the most widely used definition of
AIDS. WHO updated its classification more recently and added
a few conditions of similar prognosis to its stage 4 disease.
Presenting problems in HIV infection
HIV itself is associated with a wide variety of clinical manifestations,
and opportunistic diseases add many more. All body systems
can be affected by HIV. The CD4 count is useful in differential
diagnosis (Box 12.9): opportunistic diseases that may
present at higher CD4 counts become increasingly common
as CD4 counts decline, so the CD4 count helps to rule out certain
disorders. For example, in a patient with a pulmonary infiltrate
and a CD4 count of 350 cells/mm3, pulmonary tuberculosis is
a likely diagnosis and PJP is very unlikely, but if the patient’s
CD4 count is 50 cells/mm3, both PJP and tuberculosis are likely.
Globally, tuberculosis is the most common cause of morbidity
and mortality in HIV-infected patients. Tuberculosis should
be considered in the differential diagnosis of most presenting
problems in patients from communities where tuberculosis is
common.
Presenting problems in HIV infection • 313
12.9 CD4 count and risk of common
HIV-associated diseases
<500 cells/mm3
• Tuberculosis
• Bacterial pneumonia
• Herpes zoster
• Oropharyngeal candidiasis
• Non-typhoid salmonellosis
<200 cells/mm3
• Pneumocystis jirovecii
pneumonia
• Chronic herpes simplex ulcers
• Oesophageal candidiasis
• Cystoisospora belli (syn.
Isospora belli) diarrhoea
<100 cells/mm
• Cerebral toxoplasmosis
• Cryptococcal meningitis
• Cryptosporidiosis and
microsporidiosis
• Primary CNS lymphoma
Lymphadenopathy
Persistent generalised lymphadenopathy due to HIV is described
above under asymptomatic infection. Lymphadenopathy may
also be due to malignancy (Kaposi’s sarcoma or lymphoma) or
infections, especially tuberculosis, which is an extremely common
cause in low- and middle-income countries. Tuberculous lymph
nodes are often matted and may become fluctuant due to
extensive caseous necrosis; inexperienced clinicians often perform
incision and drainage inappropriately when simple aspiration is all
that is required. Symmetrical generalised lymphadenopathy may
occur in disseminated tuberculosis. Lymphoma typically presents
with large, firm, asymmetric nodes. Rapid enlargement of a node,
asymmetric enlargement or lymphadenopathy associated with
constitutional symptoms (even if the nodes are symmetrical)
warrants further investigation. Lymph node needle aspiration (using
a wide-bore needle such as 1 9G if tuberculosis is suspected)
should be performed. One slide should be air-dried and sent
for staining for acid-fast bacilli, which has about a 70% yield
in tuberculosis. The other slide should be fixed and sent for
cytology. If caseous liquid is aspirated, this should be sent for
mycobacterial culture or PCR. If needle aspiration is unhelpful, or
if lymphoma or Kaposi’s sarcoma is suspected, excision biopsy
should be performed.
Weight loss
Weight loss is a very common finding in advanced HIV infection.
The HIV wasting syndrome is an AIDS-defining condition and is
defined as weight loss of more than 1 0% of body weight, plus
either unexplained chronic diarrhoea (lasting over 1 month) or
chronic weakness and unexplained prolonged fever (lasting over 1
month). This is a diagnosis of exclusion. If the weight loss is rapid
(more than 1 kg a month), then major opportunistic infections or
cancers become more likely. Painful oral conditions and nausea
from drugs contribute by limiting intake. Depression is very
common and can cause significant weight loss. Measurement
of C-reactive protein is helpful in the work-up of weight loss, as
this is markedly raised with most opportunistic diseases but not
with HIV itself. Erythrocyte sedimentation rate (ESR) is elevated
by HIV infection and is therefore not useful. The presence of
fever or diarrhoea is helpful in the differential diagnosis of weight
loss (Fig. 12.3).
Fever
Fever is a very common presenting feature. Common causes
of prolonged fever with weight loss are listed in Figure 12.3.
Non-typhoid Salmonella bacteraemia, which commonly presents
with fever in low-income countries, is accompanied by diarrhoea
in only about 50% of patients. Pyrexia of unknown origin (PUO)
in HIV infection is defined as temperature over 38°C with no
cause found after 4 weeks in outpatients or 3 days in inpatients,
and initial investigations such as chest X-rays, urinalysis and
• Kaposi’s sarcoma
• Non-Hodgkin lymphoma
• HIV-associated idiopathic
thrombocytopenic purpura
• HIV wasting syndrome
• HIV-associated dementia
• Peripheral neuropathy
• Endemic mycoses
• Cytomegalovirus
• Disseminated Mycobacterium
avium complex (MAC)
• Progressive multifocal
leucoencephalopathy
r
Fever
Tuberculosis
MAC
Disseminated mycoses
NHL
CMV
HIV wasting
Loss of weight
Depression
HIV wasting
Painful oral/oesophageal disorder
Lipoatrophy (d4T and AZT)
Symptomatic hyperlactataemia
Gl side-effects of ART
i
Diarrhoea
r
Small bowel
(large-volume,
watery)
Large bowel
(small-volume, blood/mucus,
tenesmus)
Cryptosporidiosis
Microsporidiosis
Cystoisosporiasis
HIV enteropathy
Pl-induced
MAC
CMV
Salmonella
Shigella
Campylobacter
Clostridium difficile
Fig. 12.3 Presentation and differential diagnosis of weight loss. (ART = antiretroviral therapy; AZT = zidovudine; CMV = cytomegalovirus; d4T =
stavudine; KS = Kaposi’s sarcoma; MAC = Mycobacterium avium complex; NHL = non-Hodgkin lymphoma; PI = protease inhibitor)
314 • HIV INFECTION AND AIDS
Fig. 12.4. Disseminated histoplasmosis presenting with diffuse
papular rash and fever. Skin biopsy was diagnostic. Courtesy of
Professor Graeme Meintjes.
blood cultures have failed to identify the cause. HIV itself
can present with prolonged fever but this is a diagnosis of
exclusion, as a treatable cause will be found in most patients.
Abdominal imaging, preferably by computed tomography (CT),
should be requested. Abdominal nodes (especially if they are
hypodense in the centre) or splenic microabscesses strongly
suggest tuberculosis. Mycobacterial blood cultures, which can
also detect fungi, should be performed. Bone marrow aspirate
and trephine biopsy are helpful if the full blood count shows
cytopenias. Liver biopsy may be helpful if the liver enzymes are
elevated but is invasive and seldom necessary. Mycobacterial and
fungal stains and cultures should be done on all biopsies. Chest
X-rays should be repeated after about a week, as micronodular
or interstitial infiltrates may have become apparent (see p. 319
for differential diagnosis).
Tuberculosis is by far the most common cause of PUO in
low- and middle-income countries, and in these settings a trial
of empirical therapy is warranted after cultures have been sent.
In high-income countries, disseminated Mycobacterium avium
complex (MAC) infection is an important cause of PUO, often
also presenting with diarrhoea and splenomegaly. Disseminated
endemic mycoses (e.g. histoplasmosis, coccidioidomycosis,
talaromycosis) present with PUO, often with papular skin eruptions
or mucosal ulcerations (Fig. 12.4). Skin biopsy for histology and
fungal culture is often diagnostic.
Mucocutaneous disease
The skin and mouth must be carefully examined, as
mucocutaneous manifestations are extremely common in HIV
and many prognostically important conditions can be diagnosed
by simple inspection. The differential diagnosis of dermatological
conditions is simplified by categorising disorders according to the
lesion type (Box 12.10). Some common dermatological diseases,
notably psoriasis, are exacerbated by HIV. The risk of many drug
rashes is increased in HIV-infected patients. Skin biopsy should
12.10 Differential diagnosis of skin conditions by
lesion type
Scaly rashes
• Seborrhoeic dermatitis
• Psoriasis* (exacerbated by HI V)
• Tinea corporis*
• Dry skin/ichthyosis
• Norwegian scabies*
• Drug rashes*
Pruritic papules
• Pruritic papular eruption (‘itchy
• Eosinophilic folliculitis
red bump disease’)
• Scabies*
Papules and nodules (non-pruritic)
• Molluscum contagiosum*
• Warts*
• Secondary syphilis
• Disseminated endemic
• Kaposi’s sarcoma
mycoses (histoplasmosis,
• Bacillary angiomatosis
coccidioidomycosis and
• Cryptococcosis
talaromycosis)
Blisters
• Herpes simplex
• Drug rashes (especially toxic
• Herpes zoster
epidermal necrolysis)
• Fixed drug eruptions
Mucocutaneous ulcers
• Ecthyma
• Histoplasmosis
• Herpes simplex
• Drug rashes (Stevens-
• Aphthous ulcers (minor and
Johnson syndrome)
major)
Hyperpigmentation
• Post-inflammatory (especially
• Emtricitabine (palms and
pruritic papular eruption)
soles)
• Zidovudine
*See Chapter 29 for more information.
be taken, and sent for histology and culture for mycobacteria and
fungi, in patients with papular rashes or if there are constitutional
symptoms coinciding with the development of the rash.
Seborrhoeic dermatitis
Seborrhoeic dermatitis is very common in HIV. The severity
increases as the CD4 count falls. It presents as scaly red patches,
typically in the nasolabial folds and in hairy areas. Fungal infections
are thought to play a role in the pathogenesis of this condition.
It responds well to a combined topical antifungal and
glucocorticoid. Selenium sulphide shampoo is helpful for scalp
involvement.
Fig. 12.5 Severe mucocutaneous herpes simplex. Chronic anogenital
or perioral ulcers are very common in advanced HIV infection.
Presenting problems in HIV infection • 315
12.11 Treatment of common opportunistic infections in adults with AIDS
Opportunistic infection
Treatment
Alternative treatment
Secondary prophylaxis*
Pneumocystis jirovecii
pneumonia
Co-trimoxazole 20/100 mg/kg/day
(in 4 divided doses) for 21 days;
maximum per dose 320/1600 mg
Early adjunctive prednisone 40 mg
twice daily, if hypoxic
Clindamycin 900 mg 3 times daily
IV (switch to 600 mg 3 times daily
PO once improving) plus primaquine
30 mg daily for 21 days
Co-trimoxazole 160/800 mg daily
Cerebral toxoplasmosis
Sulfadiazine 15 mg/kg 4 times daily
plus pyrimethamine 200 mg stat,
then 75 mg daily plus folinic acid
1 5-25 mg daily for 6 weeks
Co-trimoxazole 320/1600 mg twice
daily for 4 weeks, then
160/800 mg twice daily for
3 months
Co-trimoxazole 160/800 mg daily
Cryptococcosis
Liposomal amphotericin B 4 mg/kg/
day IV plus flucytosine 25 mg/kg
4 times daily for 14 days, followed
by fluconazole 400 mg daily for
8 weeks
Amphotericin B 1 mg/kg/day IV plus
fluconazole 800 mg daily for
14 days, followed by fluconazole
400 mg daily for 8 weeks
Fluconazole 200 mg daily (for
minimum of 1 year)
Oesophageal candidiasis
Fluconazole 200 mg daily for
1 4 days
Itraconazole 200 mg daily for
14-21 days
Not usually recommended
Disseminated Mycobacterium
avium complex
Clarithromycin 500 mg twice daily
plus ethambutol 15 mg/kg daily
Azithromycin 500 mg daily plus
ethambutol 15 mg/kg daily
Continue treatment for minimum
of 1 year
Herpes simplex ulcers
Aciclovir 400 mg 3 times daily for
5-1 0 days
Valaciclovir 500 mg or famciclovir
125 mg twice daily for 5-10 days
Aciclovir 400 mg twice daily only
if recurrences are frequent/severe
Cystoisospora belli diarrhoea
Co-trimoxazole 160/800 mg 4 times
daily for 1 0 days
Ciprofloxacin 500 mg twice daily for
1 0 days
Co-trimoxazole 160/800 mg daily
*Secondary prophylaxis may be discontinued once CD4 counts have increased to >200 cells/mm3 on antiretroviral therapy for at least 3 months.
Herpes simplex infections
Recurrences of herpes simplex infection are very common and
primarily affect the nasolabial and anogenital areas (Fig. 12.5).
As immune suppression worsens, the ulcers take longer to heal
and become more extensive. Ulcers that persist for more than
4 weeks are AIDS-defining. The diagnosis is clinical, but PCR of
vesicle fluid or from ulcer swabs may be diagnostic with unusual
presentations. Response to a course of antiviral drug such as
aciclovir is good but relapses are common. Frequent relapses
that persist despite ART should be treated with aciclovir 400 mg
twice daily for 6-12 months (Box 12.1 1).
Herpes zoster
This usually presents with a pathognomonic vesicular rash
on an erythematous base in a dermatomal distribution
(p. 239). The median CD4 count at the first episode of zoster is
350 cells/mm3. In patients with advanced HIV disease, the rash
may be multidermatomal and recurrent episodes may occur.
Disseminated zoster is rare. In HIV-infected patients, zoster is
generally more extensive and has a longer duration, and there is
a higher risk of developing post-herpetic neuralgia. High doses
of aciclovir or its congeners should be given for all cases with
active disease, irrespective of the time since the onset of the rash.
Post-herpetic neuralgia is difficult to manage. Analgesic adjuvants,
e.g. amitriptyline and pregabalin, should be commenced in all
patients with prolonged pain. Topical capsaicin has modest
efficacy.
Kaposi’s sarcoma
Kaposi’s sarcoma (KS) is a spindle-cell tumour of lympho-
endothelial origin. All forms of KS are due to sexually transmitted
human herpesvirus 8, also known as KS-associated herpesvirus.
KS occurs in four patterns:
• classic KS: rare, indolent and restricted largely to elderly
Mediterranean or Jewish men
• endemic KS: occurs in sub-Saharan Africa, is more
aggressive, presents at earlier ages than classic KS, and
affects men more than women
• KS in patients on immunosuppressant drugs: usually
transplant recipients, who experience disseminated disease
• AIDS-associated KS.
In Africa, the male-to-female ratio of AIDS-associated KS is
much lower than is seen with endemic KS, but men are still more
affected than women, despite the fact that the seroprevalence
of human herpesvirus 8 is the same in both sexes.
AIDS-associated KS is always a multicentric disease. Early
mucocutaneous lesions are macular and may be difficult to
diagnose. Subsequently, lesions become papular or nodular,
and may ulcerate. KS lesions typically have a red-purple colour
(Fig. 12.6 and p. 306) but may become hyperpigmented,
especially in dark-skinned patients. As the disease progresses,
the skin lesions become more numerous and larger.
Lymphoedema is common, as lymphatic vessels are infiltrated.
KS also commonly spreads to lymph nodes and viscerally,
especially to the lungs and gastrointestinal tract. Visceral
disease occasionally occurs in the absence of mucocutaneous
involvement. B symptoms of fever, night sweats and weight
loss may occur.
KS may respond to ART. Chemotherapy should be reserved
for those patients who fail to remit on ART, or be given together
with ART if there are poor prognostic features such as visceral
involvement, oedema, ulcerated lesions and B symptoms.
Bacillary angiomatosis
Bacillary angiomatosis is a bacterial infection caused by Bartonella
henselae or B. quintana. Skin lesions range from solitary superficial
red-purple lesions resembling KS or pyogenic granuloma, to
316 • HIV INFECTION AND AIDS
Fig. 12.6 Oral Kaposi’s sarcoma. A full examination is important to
detect disease that may affect the palate, gums, fauces or tongue.
multiple subcutaneous nodules or plaques. Lesions are painful and
may bleed or ulcerate. The infection may become disseminated
with fevers, lymphadenopathy and hepatosplenomegaly. Diagnosis
is made by biopsy of a lesion and Warth in-Starry silver staining,
which reveals aggregates of bacilli. Treatment with doxycycline
or azithromycin is effective.
Papular pruritic eruption
Papular pruritic eruption (‘itchy red bump disease’) is an intensely
itchy, symmetrical rash affecting the trunk and extremities. It
is thought to be due to an allergic reaction to insect bites. In
sub-Saharan Africa, it is the most common skin manifestation of
HIV. Post- inflammatory hyperpigmentation is common. Topical
glucocorticoids, emollients and antihistamines are useful but
response is variable. Measures to reduce insect bites are logical
but difficult to implement in low-income settings.
|j)rug rashes
Cutaneous hypersensitivity to drugs is said to occur 100 times
more frequently in HIV infection. The most common type is an
erythematous maculopapular rash, which may be scaly. The
drugs most commonly associated with rashes are sulphonamides
and non-nucleoside reverse transcriptase inhibitors (NNRTIs
- see below). Severe, life-threatening features of drug rashes
include blistering (when this affects more than 30% of surface
area it is known as toxic epidermal necrolysis), involvement of
mucous membranes (Stevens-Johnson syndrome, pp. 1 224 and
1254), or systemic involvement with fever or organ dysfunction
(especially hepatitis, which is often delayed for a week or two
after the rash develops). Because sulphonamides are important
in the treatment and prophylaxis of opportunistic infections,
rechallenge or desensitisation is often attempted in patients
who have previously experienced rashes, provided the reaction
was not life-threatening. Details of rashes caused by ART are
given below.
Oral conditions
Oropharyngeal candidiasis is very common. It is nearly always
caused by C. albicans (p. 300), but azole-resistant Candida
species may be selected for if there have been repeated courses
of azole drugs. Pseudomembranous candidiasis is the most
common manifestation, with white patches on the buccal mucosa
(p. 306) that can be scraped off to reveal a red raw surface.
Erythematous candidiasis is more difficult to diagnose and
presents with a reddened mucosa and a smooth shiny tongue.
Angular cheilitis due to Candida is a common manifestation.
Topical antifungals are usually effective. Antifungal lozenges are
more effective than antifungal solutions. Systemic azole therapy,
usually fluconazole, should be given if topical therapy fails or if
there are oesophageal symptoms.
Oral hairy leucoplakia (p. 306) appears as corrugated white
plaques running vertically on the side of the tongue and is virtually
pathognomonic of HIV disease. It is usually asymptomatic and
is due to EBV.
Oral ulcers are common. Herpetiform oral ulcers occur in
primary infection. Herpes simplex typically affects the nasolabial
area but may cause oral ulcers. In early disease, minor aphthous
ulcers are common. In advanced disease, giant aphthous
ulcers occur. These destroy tissue, are painful and need to be
differentiated from herpes simplex and CMV ulcers by biopsy.
They respond to systemic glucocorticoids and ART. A number
of disseminated endemic mycoses, notably histoplasmosis
(p. 303), may cause oral ulcers, usually associated with constitutional
symptoms. Finally, superficial oral ulcers may occur as part of the
Stevens-Johnson syndrome, usually caused by sulphonamides
or NNRTIs.
KS often involves the mouth, especially the hard palate (see
above and Fig. 12.6). Nodular oral lesions are associated with
a worse prognosis.
Gingivitis is very common. Good oral hygiene and regular
dental check-ups are important. Acute necrotising ulcerative
gingivitis and periostitis (p. 306) can result in loss of teeth; they
should be treated with a course of metronidazole and a dental
referral should be made.
Nail disorders
Fungal infections (onychomycosis, p. 1240) are very common
and often involve multiple nails. Blue-black discoloration of
nails is common and may be due to HIV or to the antiretroviral
drug zidovudine.
Gastrointestinal disease
Oesophageal diseases
Oesophageal candidiasis (Fig. 12.7) is the most common cause
of pain on swallowing (odynophagia), dysphagia and regurgitation.
Concomitant oral candidiasis is present in about 70% of patients.
Systemic azole therapy, e.g. fluconazole 200 mg daily for 14
days, is usually curative but relapses are common (Box 12.1 1).
Patients whose oesophageal symptoms fail to respond to azoles
should be investigated with oesophagoscopy. Major aphthous
ulceration and CMV ulcers are the most likely causes and need
to be differentiated by biopsy. Occasionally, herpes simplex
oesophagitis or KS is responsible.
Diarrhoea
Chronic diarrhoea is a very common presenting problem in
patients with advanced HIV, especially in areas where there is
no access to safe water. It is a major cause of wasting. The
differential diagnosis of diarrhoea depends on whether the
presentation is with large- or small-bowel symptoms (see Fig.
12.3). The presentation and aetiology of acute diarrhoea are
similar to those in HIV-uninfected patients.
Presenting problems in HIV infection • 317
1 1 2.1 2 Common causes of chronic watery diarrhoea
Cryptosporidiosis
Microsporidiosis
Cystoisosporiasis (formerly isosporiasis)
Organism
Protozoan
Fungus
Protozoan
Species
Cryptosporidium parvum
C. hominis
Enterozoon bieneusi
Encephalitozoon intestinal is etc.
Cystoisospora belli
Animal host
Multiple
Multiple
No
Distribution
Global
Global
Tropics
Stool examination
Acid -fast stain
Trichrome stain
Polymerase chain reaction
Acid-fast stain
Specific treatment
No established therapy
Albendazole (some species)
Co-trimoxazole
Fig. 12.7 Oesophageal candidiasis. Endoscopy showing typical
pseudomembranous candidiasis.
Large-bowel diarrhoea
Acute diarrhoea caused by the bacterial enteric pathogens
Campylobacter, Shigella and Salmonella occurs more frequently
than in HIV-uninfected people and the illness is more severe.
Bacteraemia is much more common, notably due to non-typhoid
Salmonella (p. 262). Diarrhoea caused by Clostridium difficile
should be considered if there has been prior exposure to
antibiotics, as is often the case in patients with symptomatic HIV.
CMV colitis presents with chronic large-bowel symptoms
and fever in patients with CD4 counts below 100 cells/mm3.
On colonoscopy, ulcers are seen, mostly involving the left
side of the colon. Biopsy of ulcers shows typical ‘owl’s-eye’
inclusion bodies.
Small-bowel diarrhoea
Chronic small-bowel diarrhoea may be due to HIV enteropathy
but this is a diagnosis of exclusion. It typically presents with
chronic watery diarrhoea and wasting without fever. Infection
with one of three unicellular organisms is responsible for most
cases: cryptosporidiosis, microsporidiosis and cystoisosporiasis
(formerly known as isosporiasis) (Box 12.12). All three organisms
are intracellular parasites that invade enterocytes. If the diagnosis
is not made by stool microscopy on at least two specimens,
a duodenal biopsy should be performed (Fig. 12.8). Electron
microscopy is essential for speciation of microsporidia.
About 40% of patients with disseminated MAC infections
have watery diarrhoea. Fever is a prominent feature of MAC
infection, which helps differentiate it from cryptosporidiosis,
microsporidiosis and cystoisosporiasis. Intestinal tuberculosis
typically involves the ileocaecal area and may present with
Fig. 12.8 Cryptosporidiosis. Duodenal biopsy may be necessary to
confirm cryptosporidiosis or microsporidiosis. The arrow indicates an
oocyst.
fever, weight loss and diarrhoea, but the diarrhoea is seldom
profuse.
Hepatobiliary disease
| Chronic viral hepatitis
Hepatitis B and/or C (HBV and HCV) co-infection is common in
HIV-infected people due to shared risk factors for transmission.
The natural history of both HBV and HCV is altered by HIV
co-infection. In the ART era, chronic liver disease from viral
hepatitis has emerged as a major cause of morbidity and mortality.
HBV and HCV are further described on pages 873 and 877.
Hepatitis B
HBV infection is common in several groups of people at risk of HIV
infection: residents of low- and middle-income countries, injection
drug-users, haemophiliacs and MSM. HIV co-infection increases
HBV viraemia, is associated with less elevation of transaminase
(presumably due to immune suppression), and increases the risk
of liver fibrosis and hepatocellular carcinoma. Several nucleoside
reverse transcriptase inhibitors (NRTIs; lamivudine, emtricitabine
and tenofovir) are also effective against HBV. HBV status should
be checked at baseline in all HIV-infected patients. Treatment with
anti-HBV drugs should be considered for all patients who have
active HBV replication (HBeAg-positive or HBV DNA >2000 IU/
ml_) and/or evidence of inflammation or fibrosis on liver biopsy
(see also p. 876). A flare of hepatitis may be associated with
improved immune function after starting ART or discontinuing
318 • HIV INFECTION AND AIDS
antiretrovirals that have anti-HBV activity. HBV co-infection
increases the risk of antiretroviral hepatotoxicity.
Hepatitis C
HCV infection is extremely common in injection drug-users and
haemophiliacs. HIV co-infection increases HCV viraemia and
increases the risk of liver fibrosis and hepatocellular carcinoma.
Treatment for HCV should preferably be deferred in patients
with CD4 counts <200 cells/mm3 until they are stable on
ART. As with HBV co-infection, a flare of hepatitis may be
associated with improved immune function after starting ART,
and there is an increased risk of antiretroviral hepatotoxicity.
Response to anti-HCV therapy is similar to that seen in HIV-
uninfected people, but there are important drug-drug interactions
between several antiretrovirals and the newer HCV protease
inhibitors.
HIV cholangiopathy
HIV cholangiopathy, a form of secondary sclerosing cholangitis
(p. 888), may occur in patients with severe immune suppression.
In some patients, coexisting intestinal infection with CMV,
cryptosporidiosis or microsporidiosis is present, but it is uncertain
if these organisms play an aetiological role. Papillary stenosis is
common and is amenable to cautery via endoscopic retrograde
cholangiopancreatography (ERCP), which provides symptomatic
relief. Acalculous cholecystitis is a common complication of
cholangiopathy. ART may improve the condition.
Respiratory disease
Pulmonary disease is very common and is the major reason
for hospital admission. Most patients who are admitted for
respiratory diseases will have either bacterial pneumonia,
pulmonary tuberculosis or PJP. PJP is more common in high-
income countries, while tuberculosis is more common in low- and
middle-income countries. An approach to the differential diagnosis
of all three conditions is given in Box 12.13.
Pneumocystis jirovecii pneumonia
The key presenting feature of Pneumocystis jirovecii pneumonia
(PJP) is progressive dyspnoea with a duration of less than 12
weeks. Dry cough and fever are common. The chest X-ray typically
shows a bilateral interstitial infiltrate spreading out from the hilar
12.13 Comparative features of bacterial
pneumonia, Pneumocystis jirovecii pneumonia and
pulmonary tuberculosis
Pneumocystis
Bacterial
jirovecii
Pulmonary
pneumonia
pneumonia
tuberculosis
Duration
Acute
Subacute
Variable
Dyspnoea
Common
Prominent
Occasional
White cell count
Increased
Normal
Variable
Chest X-ray
Infiltrate
Consolidation
Interstitial
Variable
Bilateral infiltrate
Occasional
Usual
Common
Effusion
Occasional
No
Common
Nodes
Rare
No
Common
C-reactive
Markedly
Variable
Increased
protein
increased
Fig. 12.9 Pneumocystis pneumonia: typical chest X-ray appearance.
Note the interstitial bilateral infiltrate.
regions (Fig. 12.9) but may be normal initially. High-resolution CT
scan is more sensitive than chest X-ray, usually showing typical
‘ground-glass’ interstitial infiltrates. Pneumatoceles may occur and
may rupture, resulting in a pneumothorax. The diagnosis is made
with silver stains, PCR or immunofluorescence of broncho-alveolar
lavage or induced sputum (note that spontaneously produced
sputum should not be sent, as the yield is low). Treatment is
with high-dose co-trimoxazole, together with adjunctive systemic
glucocorticoids if the patient is hypoxic (see Box 12.1 1).
| Pulmonary tuberculosis
Tuberculosis is the most common cause of admission in countries
with a high tuberculosis incidence. Pulmonary tuberculosis in
patients with mild immune suppression typically presents as
in HIV-uninfected patients, with a chronic illness and apical
pulmonary cavities (p. 588). However, in patients with CD4 counts
below 200 cells/mm3, there are four important differences in the
clinical presentation of pulmonary tuberculosis:
• Tuberculosis progresses more rapidly, with a subacute or
even acute presentation. The diagnosis therefore needs to
be made and therapy commenced promptly. A trial of
empirical therapy is often started while awaiting the results
of mycobacterial cultures.
• The chest X-ray appearance alters: cavities are rarely
seen, pulmonary infiltrates are no longer predominantly in
apical areas, and pleural effusions and hilar or mediastinal
lymphadenopathy are common (Fig. 12.10). A normal
chest X-ray is not unusual in symptomatic patients with
tuberculosis confirmed on sputum culture. These atypical
findings can result in a delayed or missed diagnosis.
• Sputum smears, which are positive in most HIV- uninfected
adults with pulmonary tuberculosis, are negative in more
than half of patients. The main reason for this is the
absence of pulmonary cavities.
• Many patients have disseminated tuberculosis, sometimes
with a classic miliary pattern on chest X-ray, but more
Presenting problems in HIV infection • 319
Fig. 12.10 Chest X-ray of pulmonary tuberculosis in advanced HIV
infection. Lower-zone infiltrates and hilar or mediastinal nodes in a patient
with a CD4 count of <200 cells/mm3.
commonly presenting with pulmonary infiltrates together
with extrapulmonary tuberculosis. The most common sites
of concomitant extrapulmonary tuberculosis are the pleura
and lymph nodes. Acid-fast bacilli are more often found on
wide-needle aspirate of nodes than on sputum (p. 313).
Pleural aspirate showing a lymphocytic exudate suggests
tuberculosis as a likely cause and pleural biopsy will
usually confirm the diagnosis.
Tuberculosis in HIV-infected patients responds well to standard
short-course therapy (p. 592).
Bacterial pneumonia
The incidence of bacterial pneumonia is increased about 100-fold
by HIV infection. The severity, likelihood of bacteraemia, risk of
recurrent pneumonia, and mortality are all increased compared
with HIV-uninfected patients. The aetiology is similar to that of
community-acquired pneumonia in HIV-uninfected patients with
co-morbidity: S. pneumoniae is the most common cause, followed
by Haemophilus influenzae, Enterobacteriaceae (e.g. Klebsiella
pneumoniae) and Staphylococcus aureus. The prevalence of
atypical bacteria in HIV-infected patients with pneumonia is similar
to that in the general population. Treatment is with a broad-
spectrum (3-lactam (e.g. ceftriaxone, amoxicillin-clavulanate),
with the addition of a macrolide if the pneumonia is severe.
Uncommon bacteria causing pneumonia include Pseudomonas
aeruginosa, Nocardia (which mimics tuberculosis) and
Rhodococcus equi (which can cause pulmonary cavities).
| Miscellaneous causes of pulmonary infiltrates
Pulmonary cryptococcosis may present as a component of
disseminated disease or be limited to the lungs. The chest
X-ray appearances are variable. Cryptococcomas occur less
commonly than in HIV-uninfected people. The most common
radiographic pattern seen in HIV infection is patchy consolidation,
often with small areas of cavitation resembling tuberculosis.
Pleural involvement is rare. The disseminated endemic mycoses
(histoplasmosis, coccidioidomycosis and talaromycosis) often
cause diffuse pulmonary infiltrates, mimicking miliary tuberculosis.
Lymphoid interstitial pneumonitis is a slowly progressive disorder
causing a diffuse reticulonodular infiltrate. It is caused by a benign
polyclonal lymphocytic interstitial infiltrate and is part of the diffuse
infiltrative lymphocytosis syndrome (DILS - see p. 321). Patients
may have other features of DILS, notably parotidomegaly.
KS often spreads to the lungs. Typical chest X-ray appearances
are large, irregular nodules, linear reticular patterns and pleural
effusions. Bronchoscopy is diagnostic.
Nervous system and eye disease
The central and peripheral nervous systems are commonly
involved in HIV, either as a direct consequence of HIV infection
or due to opportunistic diseases. An approach to common
presentations is outlined in Figure 12.11.
Cognitive impairment
HIV-associated neurocognitive disorders
HIV is a neurotropic virus and invades the CNS early during
infection. Meningo-encephalitis may occur at seroconversion.
About 50% of HIV-infected people have abnormal neuropsychiatric
testing. The term HIV-associated neurocognitive disorder (HAND)
describes a spectrum of disorders: asymptomatic neurocognitive
impairment (which is the most common), minor neurocognitive
disorder and HIV-associated dementia (also called HIV
encephalopathy). The proportion of patients with symptomatic
HAND increases with declining CD4 counts. HIV-associated
dementia is a subcortical dementia characterised by impairment
of executive function, psychomotor retardation and impaired
memory. There is no diagnostic test for HIV-associated dementia.
CT or magnetic resonance imaging (MRI) shows diffuse cerebral
atrophy out of keeping with age. It is important to exclude
depression, cryptococcal meningitis and neurosyphilis. ART
usually improves HIV-associated dementia but milder forms of
HAND often persist.
Progressive multifocal leucoencephalopathy
Progressive multifocal leucoencephalopathy (PML) is a progressive
disease that presents with stroke-like episodes and cognitive
Neurological presentation
Cognitive
impairment
Space-occupying
lesion
Meningitis
i
i
HAND
Toxoplasmosis
Cryptococcal
Depression
PCNSL
Tuberculous
Neurosyphilis
Tuberculoma
Pneumococcal
Cryptococcal
meningitis
PML
CMV
encephalitis
Cryptococcoma
HIV
Fig. 12.11 Presentation and differential diagnosis of HIV-related
neurological disorders. (CMV = cytomegalovirus; HAND = HIV-associated
neurocognitive disorder; PCNSL = primary CNS lymphoma; PML =
progressive multifocal leucoencephalopathy)
320 • HIV INFECTION AND AIDS
Fig. 12.12 Progressive multifocal leucoencephalopathy. Non¬
enhancing white-matter lesions without surrounding oedema are seen.
impairment. Vision is often impaired due to involvement of the
occipital cortex. PML is caused by the JC virus. A combination
of characteristic appearances on MRI (Fig. 12.12) and detection
of JC virus DNA in the cerebrospinal fluid (CSF) by PCR is
diagnostic. No specific treatment exists and prognosis remains
poor despite ART.
CMV encephalitis
This presents with behavioural disturbance, cognitive impairment
and a reduced level of consciousness. Focal signs may also
occur. Detection of CMV DNA in the CSF supports the diagnosis.
Response to anti-CMV therapy is usually poor.
Space-occupying lesions
Space-occupying lesions in AIDS patients typically present over
days to weeks. The most common cause is toxoplasmosis.
As toxoplasmosis responds rapidly to therapy, a trial of anti¬
toxoplasmosis therapy should be given to all patients presenting
with space-occupying lesions while the results of diagnostic
tests are being awaited.
Cerebral toxoplasmosis
Cerebral toxoplasmosis is caused by reactivation of residual
Toxoplasma gondii cysts from past infection, which results in
the development of space-occupying lesions. The characteristic
findings on imaging are multiple space-occupying lesions with ring
enhancement on contrast and surrounding oedema (Fig. 12.13).
Toxoplasma serology shows evidence of previous exposure
(positive immunoglobulin (lg)G antibodies); a negative serological
test effectively rules out toxoplasmosis but a positive test is not
specific. The standard therapy for toxoplasmosis is sulfadiazine
with pyrimethamine, together with folinic acid, to reduce the
risk of bone marrow suppression (see Box 12.11). However,
co-trimoxazole has been shown to be as effective and less toxic,
and is also more widely available. Response to a trial of therapy
is usually diagnostic, with clinical improvement in 1-2 weeks and
shrinkage of lesions on imaging in 2-4 weeks. Definitive diagnosis
is by brain biopsy but this is seldom necessary.
Fig. 12.13 Cerebral toxoplasmosis. Multiple ring-enhancing lesions with
surrounding oedema are characteristic.
Fig. 12.14 Primary CNS lymphoma. A single enhancing periventricular
lesion with moderate oedema is typical.
Primary CNS lymphoma
Primary CNS lymphomas (PCNSLs) are high-grade B-cell
lymphomas associated with EBV infection. Characteristically,
imaging demonstrates a single homogeneously enhancing,
periventricular lesion with surrounding oedema (Fig. 12.14). If it
is considered safe to perform a lumbar puncture, PCR for EBV
DNA in the CSF has a high sensitivity and specificity for PCNSL.
Brain biopsy is definitive but carries a risk of morbidity and may
be non-diagnostic in up to one-third. The prognosis is poor.
Tuberculoma
Lesions resemble toxoplasmosis on imaging, except that oedema
tends to be less marked and single lesions occur more commonly.
Presenting problems in HIV infection • 321
There may be evidence of tuberculosis elsewhere. The CSF may
show features consistent with tuberculous meningitis. Response
to antituberculosis therapy is slow and paradoxical expansion
of lesions despite therapy is not uncommon.
Stroke
There is a higher incidence of stroke in patients with HIV disease.
Atherosclerosis is accelerated by the presence of inflammation
due to the immune response to HIV, which is not completely
suppressed by ART, and by dyslipidaemia caused by some
antiretroviral drugs. HIV vasculopathy, which is thought to be
a vasculitis, can also cause a stroke. It is important to exclude
tuberculous meningitis and meningovascular syphilis in all patients
who present with a stroke.
| Meningitis
Cryptococcal meningitis
Cryptococcus neoformans is the most common cause of
meningitis in AIDS patients. Patients usually present subacutely
with headache, vomiting and decreased level of consciousness.
Neck stiffness is present in less than half. CSF pleocytosis is often
mild or even absent, and protein and glucose concentrations
are variable. It is important to request CSF cryptococcal antigen
tests in all HIV-infected patients undergoing lumbar puncture, as
this test has a high sensitivity and specificity. Treatment is with
amphotericin B (plus flucytosine if available) for 2 weeks, followed
by fluconazole (see Box 12.11). Raised intracranial pressure is
common and should be treated with repeated therapeutic lumbar
punctures, removing sufficient CSF to reduce pressure to less
than 20 cmH20. (Most experts are reluctant to withdraw more
than 30 ml_ at a time.)
Tuberculous meningitis
The presentation and CSF findings of tuberculous meningitis
are similar to those in HIV-uninfected patients (p. 1120), except
that concomitant tuberculosis at other sites is more common
in HIV infection.
Peripheral nerve disease
HIV infection causes axonal degeneration, resulting in a
sensorimotor peripheral neuropathy in about one-third of AIDS
patients. The incidence increases with lower CD4 counts, older
age and increased height. Sensory symptoms predominate.
Treatment involves foot care, analgesia and analgesic adjuvants.
ART has minimal effect on halting or reversing the process. The
NRTIs stavudine and didanosine, now largely abandoned due
to their toxicity, can cause drug-induced peripheral neuropathy,
which is typically more painful and more rapidly progressive
than HIV neuropathy.
Acute inflammatory demyelinating polyneuropathy is an
uncommon manifestation, usually occurring in primary infection.
It resembles Guillain-Barre syndrome (p. 1140), except that CSF
pleocytosis is more prominent. Mononeuritis may also occur,
commonly involving the facial nerve.
| Myelopathy and radiculopathy
The most common cause of myelopathy in HIV infection is cord
compression from tuberculous spondylitis. Vacuolar myelopathy is
seen in advanced disease and is due to HIV. It typically presents
with a slowly progressive paraparesis with no sensory level. MRI
of the spine is normal but is an important investigation to exclude
other causes. Most patients have concomitant HIV-associated
dementia.
CMV polyradiculitis presents with painful legs, progressive
flaccid paraparesis, saddle anaesthesia, absent reflexes and
sphincter dysfunction. CSF shows a neutrophil pleocytosis (which
is unusual for a viral infection), and the detection of CMV DNA
by PCR confirms the diagnosis. Functional recovery is poor
despite treatment with ganciclovir or valganciclovir.
Psychiatric disease
Significant psychiatric morbidity is very common and is a major
risk factor for poor adherence. Reactive depression is the most
common disorder. Diagnosis is often difficult, as many patients
have concomitant HAND. Substance misuse is common in
many groups of people at risk of HIV. Some antiretroviral drugs
can cause psychiatric adverse effects and these are detailed
on page 326.
Retinopathy
CMV retinitis presents with painless, progressive visual loss in
patients with severe immune suppression. On fundoscopy, the
vitreous is clear. Haemorrhages and exudates are seen in the
retina (p. 306), often with sheathing of vessels (‘frosted branch
angiitis’). The disease usually starts unilaterally but progressive
bilateral involvement occurs in most untreated patients. Diagnosis
is usually clinical, but if there is doubt, demonstrating CMV DNA
by PCR of vitreous fluid is diagnostic. Treatment with ganciclovir
or valganciclovir stops progression of the disease but lost vision
does not recover. Some patients may develop immune recovery
uveitis in response to ART, with intraocular inflammation, macular
oedema and cataract formation that require prompt treatment with
oral and intraocular glucocorticoids to prevent further visual loss.
Three other conditions may mimic CMV retinitis: ocular
toxoplasmosis, which typically presents with a vitritis and retinitis
without retinal haemorrhages; HIV retinopathy, a microangiopathy
that causes cotton wool spots, which are not sight-threatening;
and varicella zoster virus, which can cause rapidly progressive
outer retinal necrosis.
Rheumatological disease
The immune dysregulation associated with HIV infection may result
in autoantibody formation, usually in lowtitres. Mild arthralgias and
a fibromyalgia-like syndrome are common in HIV-infected people.
Arthritis
HIV can cause a seronegative arthritis, which resembles
rheumatoid arthritis. A more benign oligoarthritis may also occur.
Reactive arthritis is more severe in HIV infection (p. 1031).
| Diffuse infiltrative lymphocytosis syndrome
Diffuse infiltrative lymphocytosis syndrome (DILS) is a benign
disorder involving polyclonal CD8 lymphocytic infiltration of tissues,
which has some features in common with Sjogren’s syndrome
(p. 1038). It is linked to human leucocyte antigen (HLA)-DRB1 .
Most patients have a marked CD8 lymphocytosis. DILS usually
presents in patients with mild immune suppression. The most
common manifestation is bilateral parotid gland enlargement;
the glands are often massive, with lymphoepithelial cysts
322 • HIV INFECTION AND AIDS
Fig. 12.15 CT scan of parotid glands showing multiple cysts
(arrows) in a patient with the diffuse infiltrative lymphocytosis
syndrome.
on histology (Fig. 12.15). Sicca symptoms are common but
usually mild. Lymphocytic interstitial pneumonitis is the most
common manifestation outside the salivary glands. Generalised
lymphadenopathy may occur, with nodes larger than those seen
with persistent generalised lymphadenopathy of HIV. Hepatitis,
mononeuritis, polyarthritis and polymyositis may also occur.
The manifestations outside the salivary glands usually respond
to systemic glucocorticoids. Parotid gland enlargement may
be treated by aspiration of parotid cysts and instillation of a
sclerosant for cosmetic reasons, and surgery is best avoided.
DILS may regress on ART but response is variable.
Haematological abnormalities
Disorders of all three major cell lines may occur in HIV. In advanced
disease, haematopoiesis is impaired due to the direct effect of HIV
and by cytokines. Pancytopenia may occur as a consequence of
HIV but it is important to exclude a disorder infiltrating the bone
marrow, such as mycobacterial or fungal infections, or lymphoma.
| Anaemia
Normochromic, normocytic anaemia is very common in advanced
HIV disease. Opportunistic diseases may cause anaemia of
chronic disease (e.g. tuberculosis) or marrow infiltration (e.g.
MAC, tuberculosis, lymphoma, fungi). Anaemia is a common
adverse effect of zidovudine, which also causes a macrocytosis.
Red cell aplasia is rare and may be caused either by parvovirus
B19 infection or by lamivudine.
Neutropenia
Isolated neutropenia is occasionally due to HIV but is nearly
always caused by drug toxicity (e.g. zidovudine, co-trimoxazole,
ganciclovir).
| Thrombocytopenia
Mild thrombocytopenia is common in HIV-infected people.
Transient thrombocytopenia is frequently found in primary infection.
The most common disorder causing severe thrombocytopenia
is immune-mediated platelet destruction resembling idiopathic
thrombocytopenic purpura (p. 971). This responds to
glucocorticoids or intravenous immunoglobulin, together with
ART. Splenectomy should be avoided if possible because it
further increases the risk of infection with encapsulated bacteria.
Severe thrombocytopenia with a microangiopathic anaemia also
occurs in a thrombotic thrombocytopenic purpura-like illness
(p. 979), which has a better prognosis and fewer relapses than
the classical disease.
Renal disease
Acute kidney injury is common, usually due to acute infection
or nephrotoxicity of drugs (e.g. tenofovir (p. 412), amphotericin
B (p. 126)) HIV-associated nephropathy (HIVAN) is the most
important cause of chronic kidney disease (CKD) and is seen
most frequently in patients of African descent and those with
low CD4 counts. Progression to end-stage disease is more
rapid than with most other causes of CKD, and renal size is
usually preserved. HIVAN presents with nephrotic syndrome,
CKD or a combination of both. ART has some effect in slowing
progression of HIVAN. Other important HIV-associated renal
diseases include HIV immune complex kidney diseases and
thrombotic microangiopathy. With the overall improvement
in life expectancy from ART, conditions such as diabetes
mellitus, hypertension and vascular disease add to the burden
of CKD. Outcomes of renal transplantation are good in patients
on ART.
Cardiac disease
HIV-associated cardiomyopathy resembles idiopathic dilated
cardiomyopathy (p. 539) but progresses more rapidly. ART
may improve cardiac failure but does not reverse established
cardiomyopathy. Pericardial disease due to opportunistic
diseases is not uncommon. Globally, the most common cause
is tuberculous pericardial effusions. Tuberculous constrictive
pericarditis is less common than in HIV-uninfected people. KS
and lymphoma may cause pericardial effusions. Septic pericarditis,
usually due to S. pneumoniae, is uncommon.
HIV is associated with an increased risk of myocardial infarction
due to accelerated atherogenesis caused by the inflammatory
state, which is not completely suppressed by ART, and by
dyslipidaemia caused by some antiretroviral drugs.
HIV-related cancers
The AIDS-defining cancers are KS (see above), cervical cancer
and non-Hodgkin lymphoma (NHL, p. 964). NHL may occur at
any CD4 count but is more commonly seen with counts below
200 cells/mm3. Almost all NHLs are B-cell tumours and most
are stage 3 or 4. Long-term remission rates similar to those in
patients without HIV can be achieved with NHL in AIDS patients
using ART and chemotherapy (including the anti-B-cell monoclonal
antibody rituximab if it is a B-cell tumour).
The incidence of a number of other cancers induced by
viruses is also increased in HIV-infected people (Box 12.14).
Regular cytological examination of the cervix, and of the anus
in people who practise anal sex, should be performed to detect
pre-malignant lesions, which are easier to treat. In general, the
incidence of cancers that are not induced by viruses is similar
to that in the general population.
Prevention of opportunistic infections • 323
^9 1 2.1 4 Approximate incidence ratio of virus-related
cancers compared to the general population
Viral cancers
Incidence ratio
Human herpesvirus 8-related
Kaposi’s sarcoma
3600
Epstein-Barr virus-related
Non-Hodgkin lymphoma
80
Hodgkin lymphoma
10
Human papillomavirus-related
Cervical cancer
6
Vulval cancer
6
Anal cancer
30
Penile cancer
4
Hepatitis B/C virus-related
Hepatocellular carcinoma
5
Prevention of opportunistic infections
The best way to prevent opportunistic infections is to improve
the CD4 count with ART. However, infections continue to occur
in the ART era as CD4 counts take time to improve if ART is
initiated in patients with profound immune suppression, immune
reconstitution on ART is often suboptimal, and CD4 counts may
decline because antiretroviral resistance develops.
Preventing exposure
The best method for avoiding infection is to prevent exposure to
the infectious agent. This is possible only for a few opportunistic
infections, however. Furthermore, many opportunistic infections
occur after reactivation of latent/dormant infection after prior
exposure; examples include herpes simplex virus, zoster (shingles),
CMV, toxoplasmosis, cryptococcosis and the endemic mycoses.
Safe water and food
Cryptosporidiosis, microsporidiosis and cystoisosporiasis may
be water-borne. If there is no access to safe water, then water
should be boiled before drinking. Food-borne illnesses are also
important in HIV infection, notably Salmonella species. Toxoplasma
exposure is related to eating raw or undercooked meat. People
living with HIV infection need to be informed about food hygiene
and the importance of adequately cooked meat.
| Tuberculosis
Preventing exposure to tuberculosis is important when there is
an infectious case in the household, in clinics and in hospitals.
Adequate ventilation, masks and safe coughing procedures
reduce the risk of exposure.
| Malaria vector control
All HIV-infected individuals living in malarious areas should
practise vector control, as malaria occurs more frequently and
is more severe in HIV-infected people. The most cost-effective
way to achieve this is by using insecticide-impregnated bed
nets. Other modalities of vector control that are of benefit
to the community, such as reducing standing water and
spraying with residual insecticides and larvicides, should also
be implemented.
Safer sex
HIV-infected individuals should practise safer sex in order to
reduce the transmission of HIV. Even if their partners are HIV-
infected, condoms should be used, as HIV mutants that have
developed antiretroviral drug resistance can be transmitted. Safer
sex will also lower the risk of acquiring herpes simplex virus and
human herpesvirus 8.
Pets
Toxoplasma gondii can be acquired from kittens or cat litter,
and people living with HIV infection should avoid handling either.
Cryptosporidiosis can be transmitted from animals, and patients
should be advised to wash their hands after handling animals.
Chemoprophylaxis
Chemoprophylaxis is the use of antimicrobial agents to prevent
infections. Primary prophylaxis is used to prevent opportunistic
infections that have not yet occurred. Secondary prophylaxis is
used to prevent recurrence of opportunistic infections because
many may recur after an initial response to therapy (see Box
12.11). Secondary prophylaxis can be discontinued when ART
results in immune reconstitution, with CD4 counts increasing to
over 200 cells/mm3, but for CMV and MAC, prophylaxis can be
stopped if CD4 counts increase to more than 1 00 cells/mm3.
| Co-trimoxazole primary prophylaxis
Co-trimoxazole reduces the incidence of a number of opportunistic
infections (Box 12.15), resulting in lower hospitalisation and
mortality rates. The indications for initiating co-trimoxazole are
either clinical evidence of immune suppression (WHO clinical
stages 3 or 4) or laboratory evidence of immune suppression
(CD4 count <200 cells/mm3). In low-income countries where
malaria and/or severe bacterial infections are highly prevalent,
the WHO recommends initiating co-trimoxazole regardless
of CD4 counts or clinical stage. The recommended dose of
co-trimoxazole is 960 mg daily, but trials have shown that
half this dose is as effective and may be associated with
less toxicity. Co-trimoxazole prophylaxis can be discontinued
when CD4 counts increase to more than 200 cells/mm3 on
ART, except in low-income countries where it should be
continued life-long.
Co-trimoxazole prophylaxis is well tolerated. The most common
side-effect is hypersensitivity, causing a maculo-papular rash.
If therapy is discontinued, desensitisation or rechallenge under
antihistamine cover should be attempted, unless the rash was
accompanied by systemic symptoms or mucosal involvement.
Prophylactic doses of co-trimoxazole can also cause neutropenia,
but this is very uncommon and routine monitoring of blood counts
is not necessary. If co-trimoxazole cannot be tolerated, then
12.15 Opportunistic infections reduced by
co-trimoxazole
• Pneumocystis jirovecii pneumonia
• Cerebral toxoplasmosis
• Bacterial pneumonia
• Bacteraemia
• Cystoisosporiasis
• Malaria
324 • HIV INFECTION AND AIDS
dapsone 100 mg daily should be substituted. Dapsone is equally
effective at reducing the incidence of P. jirovecii pneumonia,
but has little or no effect on reducing the other opportunistic
infections prevented by co-trimoxazole.
Tuberculosis preventive therapy
Trials in patients not on ART showed that preventive therapy,
either with isoniazid or combinations of rifamycins with isoniazid,
reduces the risk of tuberculosis only in HIV-infected patients
with a positive tuberculin skin test. In HIV infection, induration
of 5 mm or more on a Mantoux test is regarded as positive.
Recent evidence indicates that tuberculin skin tests do not
predict benefit in patients starting ART or established on ART
in high tuberculosis prevalence settings.
There is no CD4 count or clinical threshold for starting or
stopping tuberculosis preventive therapy. It is important to rule
out active tuberculosis before starting preventive therapy, and
symptom screening has been shown to be adequate to achieve
this (Box 1 2.16). The usual duration of isoniazid preventive therapy
is 6 months but this does not provide long-term reduction in the
risk of tuberculosis. Isoniazid for 36 months has been shown
to be much more effective in people with a positive tuberculin
skin test. Rifampicin or rifapentine combined with isoniazid for
1 2 weeks has been shown to be at least as effective as 6-1 2
months of isoniazid.
Mycobacterium avium complex prophylaxis
In high-income countries, a macrolide (azithromycin or
clarithromycin) is recommended to prevent MAC in patients with
a CD4 count below 50 cells/mm3, which can be discontinued
once the CD4 count has risen to over 100 cells/mm3 on ART.
MAC is uncommon in low- and middle-income countries and
primary prophylaxis is thus not warranted.
Preventing cryptococcosis
Serum cryptococcal antigen test should be done in patients with
a CD4 count below 100 cells/mm3. If this is positive, pre-emptive
therapy with fluconazole should be commenced.
Immunisation
There are significant problems associated with vaccination in HIV
infection. Firstly, vaccination with live organisms is contraindicated
in patients with severe immune suppression, as this may result
in disease from the attenuated organisms. Secondly, immune
responses to vaccination are impaired in HIV-infected patients. If
the CD4 count is below 200 cells/mm3, then immune responses
to immunisation are very poor. Therefore it is preferable to wait
until the CD4 count has increased to more than 200 cells/mm3
on ART before immunisation is given, and essential if live virus
vaccines are used. All patients should be given a conjugate
pneumococcal vaccine and annual influenza vaccination.
Hepatitis B vaccination should be given to those who are not
12.16 Symptom screen for tuberculosis before
isoniazid preventive therapy
All of the following must be absent:
• Active cough • Night sweats
• Weight loss • Fever
immune. In the UK, the following additional vaccines are also
recommended:
• hepatitis A: in those at risk
• human papillomavirus: in people <40 years old
• measles, mumps and rubella (MMR): in those with
negative measles serology
• meningococcus: in people <25 years old, those with
asplenia or complement deficiency, during outbreaks
• diphtheria/tetanus/acellular pertussis (dTaP)/inactivated
poliovirus vaccine (IPV): meeting general indications
• chickenpox: if seronegative; those who are seropositive
should receive the shingles vaccine.
Bacille Calmette-Guerin (BCG) is contraindicated in all HIV-infected
people.
Antiretroviral therapy
ART has transformed HIV from a progressive illness with a fatal
outcome into a chronic manageable disease with a near-normal
life expectancy.
The goals of ART are to:
• reduce the viral load to an undetectable level for as long
as possible
• improve the CD4 count to over 200 cells/mm3 so that
severe HIV-related disease is unlikely
• improve the quantity and quality of life without
unacceptable drug toxicity
• reduce HIV transmission.
Many of the antiretroviral drugs that were initially used have
largely been abandoned because of toxicity or poor efficacy. The
drugs that are currently recommended are shown in Box 12.1 7,
and their targets in the HIV life cycle in Figure 12.1 .
Selecting antiretroviral regimens
The standard combination antiretroviral regimens are two NRTIs
together with an NNRTI, protease inhibitor (PI) or integrase
inhibitor. Dual NRTI combinations are usually emtricitabine or
lamivudine (they have the same mechanism of action and so
are never combined), together with one of abacavir, tenofovir or
zidovudine. It is possible to construct effective regimens without
NRTIs if there is intolerance or resistance to the NRTIs. Currently
used Pis should always be administered with ritonavir, which
1 12.17 Commonly used antiretroviral drugs
Classes
Drugs
Nucleoside reverse
transcriptase inhibitors (NRTIs)
Abacavir, emtricitabine,
lamivudine, tenofovir, zidovudine*
Non-nucleoside reverse
transcriptase inhibitors
(N NRTIs)
Efavirenz*, rilpivirine (only if viral
load <100 000)
Protease inhibitors (Pis)
Atazanavir, darunavir, lopinavir*
Integrase inhibitors
Raltegravir, dolutegravir,
elvitegravir
Chemokine receptor inhibitor
Maraviroc
These drugs are no longer recommended as first-line options in high-income
countries due to their toxicity.
Antiretroviral therapy • 325
itself is a PI that is toxic in therapeutic doses. Low doses of
ritonavir dramatically increase the concentrations and elimination
half-lives of other Pis by inhibiting the efflux pump P-glycoprotein
and the cytochrome P450 isoenzyme CYP3A.
Most guidelines from high-income countries, including the
UK, allow clinicians to choose a starting regimen of dual NRTIs
combined with an NNRTI, or a PI or an integrase inhibitor, as
these three regimens have similar efficacy. Subsequent ART
regimen switches for virological failure are guided by the results
of resistance testing (see below). For low- and middle-income
countries, the WHO recommends a public health approach to
using ART with standardised first-line (NNRTI plus dual NRTIs)
and second-line (ritonavir-boosted PI plus dual NRTIs) regimens.
N NRTIs are preferred by the WHO in first-line regimens, as they
are cheaper than Pis and better tolerated. Furthermore, NNRTIs
need to be given with two fully active NRTIs because they
have a low genetic barrier to resistance (see below), whereas
Pl-containing regimens are effective even when there are some
mutations conferring resistance to the NRTIs. Pis in second-line
regimens are therefore preferable in settings where resistance
testing is not widely available. The public health approach to using
ART can be implemented by nurses and has been successfully
applied in resource-poor settings.
Criteria for starting ART
Guidelines now recommend starting ART in all people with
confirmed HIV infection, irrespective of CD4 count or clinical
status. Early initiation of ART, compared with the previous
strategy of deferring ART until CD4 thresholds or clinical
disease occurs, has been shown to reduce morbidity and
mortality, and has the additional benefit of reducing the risk of
transmission.
It is seldom necessary to start ART urgently. Several
consultations are required to give patients insight into the need
for life-long ART, to stress the importance of adherence and to
formulate a personal treatment plan. Disclosure of HIV status,
joining support groups and using patient-nominated treatment
supporters should be encouraged, as these have been shown to
improve adherence. Recognition and management of depression
and substance abuse is also important.
In patients with major opportunistic infections, ART should
generally be started within 2 weeks, with two important exceptions:
in cryptococcal meningitis, ART should be deferred for 5 weeks,
as earlier initiation increases the risk of death; and in tuberculosis,
ART should be deferred until 8 weeks (except if the CD4 count
is <50 cells/mm3), as earlier initiation increases the risk of the
immune reconstitution inflammatory syndrome (see below).
| Monitoring efficacy
The most important measure of ART efficacy is the viral load. A
baseline viral load should be measured prior to initiating treatment.
Viral load measurement should be repeated 4 weeks after starting
ART, when there should be at least a 1 0-fold decrease. The viral
load should be suppressed after 6 months. Once the viral load
is suppressed, measurement should be repeated 6-monthly.
Failure of ART is defined by the viral load becoming detectable
after suppression. In most guidelines, a viral load threshold is
used to define virological failure, e.g. more than 200 (UK) or
more than 1000 (WHO) copies/mL. Adherence support should
be enhanced if virological failure is detected, and measurement
of the viral load repeated to confirm failure before switching to
a new ART regimen.
CD4 counts are generally monitored every 6 months together
with the viral load, but there is little point in repeating the CD4
count in patients who maintain virological suppression and whose
CD4 count is >350 cells/mm3. The CD4 count increases rapidly
in the first month, followed by a more gradual increase. In the
first year, the CD4 count typically increases by 1 00-1 50 cells/
mm3, and about 80 cells/mm3 per annum thereafter until the
reference range is reached, provided the viral load is suppressed.
However, CD4 responses are highly variable: in about 1 5-30%
of patients the CD4 count does not increase despite virological
suppression, and in a similar proportion of patients the CD4
response is good despite the presence of virological failure. If
ART is stopped, the CD4 count rapidly falls to the baseline value
before ART was commenced.
| Antiretroviral resistance
Reverse transcription is error-prone, generating a large number of
mutations. If the viral load is suppressed on ART, viral replication
is suppressed and resistance mutations will not be selected.
If ART is taken and there is ongoing replication, due to either
resistant mutations or suboptimal adherence, mutations conferring
resistance to antiretroviral drugs will be selected. Antiretroviral
drugs differ in their ability to select for resistant mutations.
Some drugs (e.g. emtricitabine, lamivudine, efavirenz) have a
low genetic barrier to resistance, rapidly selecting for a single
mutation conferring high-level resistance. Pis and some NRTIs
(e.g. zidovudine) select for resistance mutations slowly, and
multiple resistant mutations often need to accumulate before
the drug’s efficacy is lost. Patients who develop antiretroviral
resistance may transmit resistant virus to others and will eventually
develop clinical failure.
Antiretroviral resistance is assessed by sequencing the
relevant viral genes to detect mutations that are known to
confer resistance. The patient must be taking ART when the test
is performed, as otherwise the wild-type virus will predominate
and resistant mutations will not be detected. The resistant
proviral DNA is archived in latent CD4 cells and will re-emerge
rapidly on re-exposure to the antiretroviral. In regions where
resistance testing is affordable, it is recommended at baseline
(to detect primary resistance) and at every confirmed virological
failure, in order to select the most appropriate antiretrovirals in
a new regimen.
ART complications
B Immune reconstitution
inflammatory syndrome
Immune reconstitution inflammatory syndrome (IRIS) is a common
early complication of ART, especially in patients who start ART
with CD4 counts below 50 cells/mm3. IRIS presents either with
paradoxical deterioration of an existing opportunistic disease
(including infections that are responding to appropriate therapy) or
with the unmasking of a new infection. The clinical presentation
of IRIS events is often characterised by an exaggerated immune
response, with pronounced inflammatory features. For example,
patients with CMV retinitis developing IRIS on ART develop a
uveitis; inflammatory haloes occur around KS lesions. Paradoxical
tuberculosis IRIS events are common but it is important to
exclude multidrug resistance, which could be responsible for the
deterioration. IRIS is associated with a mortality of around 5%
but this is higher when it complicates CNS infections.
326 • HIV INFECTION AND AIDS
The management of IRIS is to continue ART and to ensure
that the opportunistic disease is adequately treated. Symptomatic
treatments are helpful. Glucocorticoids are often used for more
severe IRIS manifestations but they should not be given to
patients with KS, as this can result in rapid progression of
KS lesions.
Fig. 12.16 Fat loss complicating long-term use of the thymidine
analogue NRTIs stavudine and zidovudine.
population. Although not yet fully resolved, the current weight
of evidence is that fat gain on ART is a return to normal by
treating HIV infection.
Hypersensitivity rashes
These are common but must be differentiated from the
other causes described on page 314. The NRTI abacavir
typically causes a systemic hypersensitivity reaction, which
is limited to people with HLA-B*5701 , about 50% of whom
will develop a hypersensitivity reaction. HLA testing should
be done before abacavir is given and the drug should not be
prescribed for people who are HLA-B*5701 -positive, which
is rare in people of African descent. Rechallenge must never
be attempted after abacavir hypersensitivity, as fatal reactions
may occur.
Drug rashes are very common with NNRTIs. When
the NNRTI rash is mild and not accompanied by systemic
involvement, the suspected drug is often continued and
antihistamines are administered. The rash usually resolves. If it
worsens or if systemic features develop, the NNRTI should be
discontinued.
Other adverse effects
The NNRTI efavirenz causes insomnia, agitation, euphoria or
dysphoria in many patients but tolerance to its neuropsychiatric
effects develops in a few weeks in most patients. The NRTI
zidovudine can cause anaemia and neutropenia, and tenofovir
may cause nephrotoxicity and loss of bone mineral density.
Some Pis are associated with dyslipidaemias and may increase
the risk of myocardial infarction.
ART in special situations
| Pregnancy
All pregnant women should have HIV testing at an early stage in
pregnancy. The CD4 count falls by about 25% during pregnancy
due to haemodilution. The course of HIV disease progression
is not altered by pregnancy. In the pre-ART era, the rate of
mother-to-child transmission was 15-40%, with rates being
influenced by several factors (see Box 12.3).
ART has dramatically reduced the risk of mother-to-child
transmission of HIV to less than 1 %. All pregnant women should
start ART at the beginning of the second trimester, unless they
have advanced disease, when ART should be started in the
first trimester.
Caesarean section is associated with a lower risk of mother-
to-child transmission than vaginal delivery, but the mode of
delivery does not affect transmission risk if the viral load is
suppressed on ART.
HIV is also transmitted by breastfeeding. In high-income
countries, exclusive formula feeding is generally recommended.
In resource-poor settings, however, formula feeding is associated
with a risk of infant morbidity and mortality, which may negate the
benefit of not transmitting HIV to the infant. There is minimal risk
of transmitting HIV by breastfeeding in women with a suppressed
viral load on ART. Furthermore, providing antiretrovirals to infants
(usually nevirapine monotherapy) while they are breastfeeding has
been shown to reduce the risk of transmission. Breastfeeding
is therefore now encouraged in resource-poor settings. Infants
should be exclusively breastfed for the first 6 months, as mixed
|Lipodystrophy
Long-term use of ART is associated with changes in body
fat distribution called lipodystrophy, which can present either
with fat accumulation (e.g. visceral fat, ‘buffalo hump’) or with
subcutaneous fat loss (‘lipoatrophy’, Fig. 12.16), or with both fat
loss and accumulation. The thymidine analogue NRTIs (stavudine
and, to a lesser extent, zidovudine) are associated with fat loss.
Switching to the non-thymidine NRTIs, abacavir or tenofovir, will
result in very gradual improvement of lipoatrophy.
Previously, Pis were thought to be the cause of fat
accumulation. However, recent studies have shown that all
classes of antiretrovirals are associated with fat gain to a similar
extent, and visceral adiposity is similar to that seen in the general
• Epidemiology: the HIV-infected population is ageing due to the
life-prolonging effects of ART.
• Immunity: age-related decline increases the risk of infections. CD4
counts decline more rapidly as age extends beyond 40 years,
resulting in faster disease progression. CD4 responses to ART
decrease with increasing age.
• Dementia: HIV causes cerebral atrophy and neurocognitive
disorders; dementia is therefore more common and more severe
than in the HIV-uninfected elderly.
• Vascular disease: HIV is associated with an increased risk,
exacerbated by some antiretrovirals that increase the risk of
vascular disease by causing dyslipidaemia or insulin resistance.
• Polypharmacy: treatment of co-morbidities is complex due to the
many drug interactions with antiretrovirals.
12.18 HIV infection in old age
Further information • 327
feeding (with formula or solids) is associated with a higher risk
of transmission.
Diagnosis of HIV in infancy requires the detection of HIV RNA
by PCR, as maternal antibodies to HIV, which persist for up to
15 months, will give a false-positive result on antibody assays.
PCR should ideally be carried out within 6 weeks of birth to
facilitate early ART initiation. If the baby is breastfed, the PCR
should be repeated 2 weeks after weaning.
Prevention of HIV
An effective HIV vaccine remains elusive due to the extensive
genetic diversity of HIV and the lack of a safe attenuated virus.
Measures for the prevention of HIV transmission are shown in
Box 12.19.
Pre-exposure prophylaxis
Pre-exposure prophylaxis (PrEP) with daily tenofovir plus
emtricitabine has been shown to reduce the risk of HIV acquisition
in people at ongoing high risk (e.g. from sex or injecting drug
use) and is well tolerated. Regular HIV testing should be done
in people on PrEP.
Post-exposure prophylaxis
Post-exposure prophylaxis (PEP) is recommended when the
risk is deemed to be significant after a careful risk assessment,
in both occupational and non-occupational settings. The first
dose should be given as soon as possible, preferably within
6-8 hours. There is no point in starting PEP after 72 hours.
Tenofovir together with emtricitabine is the most widely used
dual NRTI combination, together with either a PI or an integrase
inhibitor. PEP should not be given if the exposed person is
HIV-infected. HIV antibody testing should be performed at 3
months after exposure.
12.19 Prevention measures for HIV transmission
Sexual
• Sex education programmes in schools
• Easily accessible voluntary counselling and testing centres
• Promotion of safer sex practices (delaying sexual debut, condom
use, fewer sexual partners)
• Effective ART for HIV-infected individuals
• Pre-exposure prophylaxis for high-risk groups
• Male circumcision
• Post-exposure prophylaxis
Parenteral
• Blood product transmission: donor questionnaire, routine screening
of donated blood
• Injection drug use: education, needle/syringe exchange, avoidance
of ‘shooting galleries’, methadone maintenance programmes
Perinatal
• Routine ‘opt-out’ antenatal HIV antibody testing
• Measures to reduce vertical transmission (see text)
Occupational
• Education/training: universal precautions, needlestick injury
avoidance
• Post-exposure prophylaxis
Further information
Websites with updated clinical guidelines
aidsinfo.nih.gov AIDSinfo, a service of the US Department of Health
and Human Services (HHS).
bhiva.org British HIV Association.
who.int/hiv/pub World Health Organisation.
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Sexually transmitted infections
Clinical examination in men 330
Clinical examination in women 331
Approach to patients with a suspected STI 332
Presenting problems in men 333
Urethral discharge 333
Genital itch and/or rash 333
Genital ulceration 333
Genital lumps 334
Proctitis in men who have sex with men 334
Presenting problems in women 335
Vaginal discharge 335
Lower abdominal pain 336
Genital ulceration 336
Genital lumps 336
Chronic vulval pain and/or itch 336
Prevention of STI 336
Sexually transmitted bacterial infections 337
Syphilis 337
Gonorrhoea 339
Chlamydial infection 340
Other sexually transmitted bacterial infections 341
Sexually transmitted viral infections 341
Genital herpes simplex 341
Human papillomavirus and anogenital warts 342
Molluscum contagiosum 343
Viral hepatitis 343
330 • SEXUALLY TRANSMITTED INFECTIONS
Clinical examination in men
5 Skin of penis
(Retract prepuce if present)
Genital warts
Ulcers
Be aware of normal anatomical
features such as coronal papillae,
or prominent sebaceous or
parafrenal glands
A Coronal papillae
4 Scrotal contents
Abnormal masses or tenderness
(epididymo-orchitis)
3 Pubic area
Pthirus pubis (crab louse)
2 Skin around groin
and scrotum
Warts
Tinea cruris
1 Inguinal glands
Significant enlargement
Urethral meatus
5
©
©
A Discharge
©■
► Mouth
► Eyes
► Joints
► Skin:
Rash of secondary syphilis
Scabies
Manifestations of HIV
infection (Ch. 12)
7 Perianal area
(Men who have sex with men,
and heterosexual men)
A Warts
8 Rectum
(Men who have sex with men
practising receptive anal
intercourse)
8
A Proctitis
Insets (Perianal warts) From McMillan A, Scott GR. Sexually transmitted infections: a colour guide. Churchill Livingstone, Elsevier Ltd; 2000. (Coronal
papillae, mucopus) From McMillan A, Young H, Ogilvie MM, Scott GR. Clinical practice in sexually transmissible infections. Saunders, Elsevier Inc.; 2002.
Investigations for STIs in
heterosexual males
• First-void urine (FVU)* is the specimen of
choice for the combined nucleic acid
amplification test (NAAT) for gonorrhoea
and chlamydia
• Alternatively, for gonorrhoea, a urethral
swab plated directly on a selective
medium such as modified New York City
(MNYC), or sent in an appropriate
transport medium, can be cultured to
allow for assessment of antimicrobial
sensitivities
• Serological test for syphilis (STS), e.g.
enzyme immunoassay (EIA) for
antitreponemal immunoglobulin G (IgG)
antibody
• Fluman immunodeficiency virus (HIV) test
(see note)
*A urethral swab can be submitted if the patient is
unable to pass urine.
Investigations for STIs in men
who have sex with men
• FVU*, and pharyngeal and rectal swabs
for combined NAAT for gonorrhoea and
chlamydia
• STS (repeat testing may be necessary in
the event of negative test results in the
first few weeks following exposure)
• Serological tests for hepatitis A/B (with a
view to vaccination if seronegative)
• HIV test (see note)
*A urethral swab can be submitted if the patient is
unable to pass urine.
HIV testing
It should always be standard practice
to offer HIV testing as part of screening
for sexually transmitted infection (STI)
because the benefits of early diagnosis
outweigh other considerations. Extensive
pre-test counselling is not required in most
instances, but it is important to establish
efficient pathways for referral of patients
at high risk for whom the clinician wishes
specialist support, and for those diagnosed
as HIV-positive.
Clinical examination in women • 331
Clinical examination in women
A Warts
3 Pubic area
Lpthirus pubis (crab louse)
2 Inguinal glands
Significant enlargement
1 Abdomen
Abnormal masses or tenderness
Observation
• Mouth
• Eyes
• Joints
• Skin:
Rash of secondary syphilis
Scabies
Manifestations of HIV
infection (Ch. 12)
and perianal skin
5
A Inflammation
6 Vagina and cervix
Abnormal discharge
Warts
Ulcers
Inflammation
In women with lower abdominal
pain, bimanual examination for
adnexal tenderness
(pelvic inflammatory disease)
5 Perineum
Warts
Ulcers
Inset (Inflammation) From McMillan A, Young H, Ogilvie MM, Scott GR. Clinical practice in sexually transmissible infections. Saunders, Elsevier Inc.; 2002.
Investigations for STIs
in women
• Self-taken vaginal swab, or clinician-
obtained cervical or vaginal swab, for
combined NAAT for gonorrhoea and
chlamydia
• Alternatively, for gonorrhoea, cervical and
urethral swabs plated directly on a
selective medium such as MNYC, or sent
in appropriate transport medium, can be
cultured to allow for assessment of
antimicrobial sensitivities
• Wet mount for microscopy or high vaginal
swab (HVS) for culture of Trichomonas
• STS, e.g. EIA for antitreponemal IgG
antibody
• HIV test (see note)
Management goals in
suspected STI
• Relief of any symptoms
• Screening for treatable STI that may not
be causing symptoms
• Tracing and treatment of sexual contacts
who may also be infected
• Advice to reduce risk of infection in the
future
Those at particular risk
from STIs
• Sex workers, male and female
• Clients of sex workers
• Men who have sex with men
• Injecting drug users (sex for money or
drugs) and their partners
• Frequent travellers
* Adapted from WHO/UNAIDS, 1997.
332 • SEXUALLY TRANSMITTED INFECTIONS
Sexually transmitted infections (STIs) are a group of contagious
conditions whose principal mode of transmission is by intimate
sexual activity involving the moist mucous membranes of the
penis, vulva, vagina, cervix, anus, rectum, mouth and pharynx,
along with their adjacent skin surfaces. A wide range of infections
may be sexually transmitted, including syphilis, gonorrhoea,
human immunodeficiency virus (HI V), genital herpes, genital
warts, chlamydia and trichomoniasis. Bacterial vaginosis and
genital candidiasis are not regarded as STIs, although they are
common causes of vaginal discharge in sexually active women.
Chancroid, lymphogranuloma venereum (LGV) and granuloma
inguinale are usually seen in tropical countries. Hepatitis viruses
A, B, C and D (p. 871) may be acquired sexually, as well as by
other routes. Although primarily transmitted by mosquito bite,
cases of male-to-female sexual transmission of Zika virus have
been described and the virus is known to persist in semen for
several months (p. 247).
The World Health Organization (WHO) estimates that 357 million
curable STIs ( Trichomonas vaginalis, Chlamydia trachomatis,
gonorrhoea and syphilis) occur worldwide each year. In the
UK in 2014, the most common treatable STIs diagnosed were
chlamydia (220000 cases) and gonorrhoea (nearly 40000 cases).
Genital warts are the second most common complaint seen in
genitourinary medicine (GUM) departments. In addition to causing
morbidity themselves, STIs may increase the risk of transmitting
or acquiring HIV infection (Ch. 12).
As coincident infection with more than one STI is seen
frequently, GUM clinics routinely offer a full set of investigations
at the patient’s first visit (pp. 330-331), regardless of the reason
for attendance. In other settings, less comprehensive investigation
may be appropriate.
The extent of the examination largely reflects the likelihood
of HIV infection or syphilis. Most heterosexuals in the UK are
at such low risk of these infections that routine extragenital
examination is unnecessary. This is not the case in parts of the
world where HIV is endemic, or for men who have sex with men
(MSM) in the UK. In other words, the extent of the examination
is determined by the sexual history (Box 13.1).
Approach to patients with a
suspected STI
Patients concerned about the possible acquisition of an STI
are often anxious. Staff must be friendly, sympathetic and
reassuring; they should have the ability to put patients at ease,
while emphasising that clinic attendance is confidential. The history
focuses on genital symptoms, with reference to genital ulceration,
rash, irritation, pain, swelling and urinary symptoms, especially
dysuria. In men, the clinician should ask about urethral discharge,
and in women, vaginal discharge, pelvic pain or dyspareunia.
Enquiry about general health should include menstrual and
obstetric history, cervical cytology, recent medication, especially
with antimicrobial or antiviral agents, previous STI and allergy.
Immunisation status for hepatitis A and B should be noted, as
should information about alcohol intake and recreational drug
use. Some MSM use new psychoactive substances (NPS),
formerly referred to in the UK as ‘legal highs’, to enhance their
sexual experience. Often described as ‘chemsex’, this has been
associated with outbreaks of infections including syphilis, LGV
and hepatitis C.
A detailed sexual history is imperative (Box 13.1), as this informs
the clinician of the degree of risk for certain infections, as well
as specific sites that should be sampled; for example, rectal
samples should be taken from men who have had unprotected
anal sex with other men. Sexual partners, whether male or
female, and casual or regular, should be recorded. Sexual
practices - insertive or receptive vaginal, anal, orogenital or
oroanal - should be noted, as should choice of contraception
for women, and condom use for both sexes.
| STI during pregnancy
Many STIs can be transmitted from mother to child in pregnancy,
either transplacentally or during delivery. Possible outcomes are
highlighted in Box 13.2.
STI in children
The presence of an STI in a child may be indicative of sexual abuse,
although vertical transmission may explain some presentations in
the first 2 years. In an older child and in adolescents, STI may
13.1 How to take a sexual history
• In your lifetime, have your sexual partners been male, female or
both?
• Do you have a regular sexual partner at present?
• If yes:
How long have you been together?
When did you last have sex with anyone else?
• If no:
When did you last have sex?
Was this a regular or a casual partner?
• Do/did you use a condom?
13.2 Possible outcomes of STI in pregnancy
Organism
Mode of transmission
Outcome for fetus/neonate
Outcome for mother
Treponema pallidum
Transplacental
Ranges from no effect to severe
stigmata or miscarriage/stillbirth
None directly relating to the pregnancy
Neisseria gonorrhoeae
Intrapartum
Severe conjunctivitis
Possibility of ascending infection postpartum
Chlamydia trachomatis
Intrapartum
Conjunctivitis, pneumonia
Possibility of ascending infection postpartum
Herpes simplex
Usually intrapartum, but
transplacental infection may
occur rarely
Ranges from no effect to severe
disseminated infection
Rarely, primary infection during 2nd/3rd trimesters
becomes disseminated, with high maternal mortality
Human papillomaviruses
Intrapartum
Anogenital warts or laryngeal
papillomas are very rare
Warts may become more florid during pregnancy,
but usually regress postpartum
Presenting problems in men • 333
be the result of voluntary sexual activity. Specific issues regarding
the management of STI and other infections in adolescence are
discussed in Box 1 1 .25 (p. 235).
Presenting problems in men
Urethral discharge
In the UK the most important causes of urethral discharge are
gonorrhoea and chlamydia. In a significant minority of cases,
tests for both of these infections are negative, a scenario often
referred to as non-specific urethritis (NSU). Some of these cases
may be caused by Trichomonas vaginalis, herpes simplex virus
(HSV), mycoplasmas, ureaplasmas or adenoviruses. A small
minority seem not to have an infectious aetiology.
Gonococcal urethritis usually causes symptoms within 7 days
of exposure. The discharge is typically profuse and purulent.
Chlamydial urethritis has an incubation period of 1-4 weeks,
and tends to result in milder symptoms than gonorrhoea; there
is overlap, however, and microbiological confirmation should
always be sought.
Investigations
A presumptive diagnosis of urethritis can be made from a
Gram-stained smear of the urethral exudate (Fig. 13.1), which
will demonstrate significant numbers of polymorphonuclear
leucocytes (>5 per high-power field). A working diagnosis of
gonococcal urethritis is made if Gram-negative intracellular
diplococci (GNDC) are seen; if no GNDC are seen, a label of
NSU is applied.
If microscopy is not available, urine samples and/or swabs
should be taken and empirical antimicrobials prescribed. A
first-void urine (FVU) sample should be submitted for a combined
nucleic acid amplification test (NAAT) for gonorrhoea and
chlamydia; a urethral swab is an alternative if the patient cannot
pass urine. When gonorrhoea is suspected, a urethral swab should
be sent for culture and antimicrobial sensitivities of Neisseria
gonorrhoeae. Tests for other potential causes of urethritis are
not performed routinely.
A swab should also be taken from the pharynx because
gonococcal infection here is not reliably eradicated by single-dose
therapy. In MSM, swabs for gonorrhoea and chlamydia should
be taken from the rectum.
Fig. 13.1 A Gram-stained urethral smear from a man with
gonococcal urethritis. Gram-negative diplococci are seen within
polymorphonuclear leucocytes.
Management
This depends on local epidemiology and the availability of
diagnostic resources. Treatment is often presumptive, with
prescription of multiple antimicrobials to cover the possibility of
gonorrhoea and/or chlamydia. This is likely to include a single¬
dose treatment for gonorrhoea, which is desirable because it
eliminates the risk of non-adherence. The recommended agents
for treating gonorrhoea vary according to local antimicrobial
resistance patterns (p. 340). Appropriate treatment for chlamydia
(p. 340) should also be prescribed because concurrent
infection is present in up to 50% of men with gonorrhoea.
Non-gonococcal, non-chlamydial urethritis is treated as for
chlamydia.
Patients should be advised to avoid sexual contact until it is
confirmed that any infection has resolved and, whenever possible,
recent sexual contacts should be traced. The task of contact
tracing - also called partner notification - is best performed by
trained nurses based in GUM clinics; it is standard practice in
the UK to treat current sexual partners of men with gonococcal
or non-specific urethritis without waiting for microbiological
confirmation.
If symptoms clear, a routine test of cure is not necessary,
but patients should be re- interviewed to confirm that there was
no immediate vomiting or diarrhoea after treatment, that there
has been no risk of reinfection, and that traceable partners have
sought medical advice.
Genital itch and/or rash
Patients may present with many combinations of penile/genital
symptoms, which may be acute or chronic, and infectious or
non-infectious. Box 13.3 provides a guide to diagnosis.
Balanitis refers to inflammation of the glans penis, often
extending to the under-surface of the prepuce, in which case it
is called balanoposthitis. Tight prepuce and poor hygiene may
be aggravating factors. Candidiasis is sometimes associated
with immune deficiency, diabetes mellitus, and the use of
broad-spectrum antimicrobials, glucocorticoids or antimitotic
drugs. Local saline bathing is usually helpful, especially when
no cause is found.
Genital ulceration
The most common cause of ulceration is genital herpes.
Classically, multiple painful ulcers affect the glans, coronal sulcus
or shaft of penis (Fig. 13.2), but solitary lesions occur rarely.
Perianal ulcers may be seen in MSM. The diagnosis is made
by gently scraping material from lesions and sending this in an
appropriate transport medium for culture or detection of HSV DNA
by polymerase chain reaction (PCR). Increasingly, laboratories
will also test for Treponema pallidum by PCR.
In the UK, the possibility of syphilis or any other ulcerating
STI is much less likely unless the patient is an MSM and/or
has had a sexual partner from a region where tropical STIs are
more common. The classic lesion of primary syphilis (chancre)
is single, painless and indurated; however, multiple lesions are
seen rarely and anal chancres are often painful. Diagnosis is
made in GUM clinics by dark-ground microscopy and/or PCR
on a swab from a chancre, but in other settings by serological
tests for syphilis (p. 338). Other rare infective causes seen
in the UK include varicella zoster virus (p. 238) and trauma
with secondary infection. Tropical STIs, such as chancroid,
334 • SEXUALLY TRANSMITTED INFECTIONS
13.3 Differential diagnosis of genital itch and/or rash in men
Likely diagnosis
Acute or
chronic
Itch
Pain
Discharge
(non-urethral)
Specific characteristics
Diagnostic
test
Treatment
Subclinical
urethritis
Either
±
-
±
Often intermittent
Gram stain and
urethral swabs
As for urethral discharge
Candidiasis
Acute
y
-
White
Post-coital
Microscopy
Antifungal cream, e.g.
clotrimazole
Anaerobic
(erosive) balanitis
Acute
+
-
Yellow
Offensive
Clinical
Saline bathing ±
metronidazole
Pthirus pubis
(‘crab lice’)
infection
Either
Lice and nits seen attached
to pubic hairs
Can be by
microscopy but
usually visual
According to local policy
- often permethrin
Lichen planus
(p. 1252)
Either
±
Violaceous papules ±
Wickham’s striae
Clinical
None or mild topical
glucocorticoid, e.g.
hydrocortisone
Lichen sclerosus
Chronic
±
Ivory-white plaques,
scarring
Clinical or
biopsy
Strong topical
glucocorticoid, e.g.
clobetasol
Plasma cell
balanitis of Zoon
Chronic
±
Shiny, inflamed
circumscribed areas
Clinical or
biopsy
Strong topical
glucocorticoid, e.g.
clobetasol
Dermatoses, e g.
eczema or psoriasis
Either
y
-
-
Similar to lesions elsewhere
on skin
Clinical
Mild topical glucocorticoid,
e.g. hydrocortisone
Genital herpes
Acute
±
y
-
Atypical ulcers are not
uncommon
Swab for HSV
PCR
Oral antiviral, e.g. aciclovir
Circinate balanitis
Either
Painless erosions with raised
edges; usually as part of
sexually acquired reactive
arthritis (SARA, p. 1031)
Clinical
Mild topical glucocorticoid,
e.g. hydrocortisone
(HSV PCR = herpes simplex virus polymerase chain reaction)
Fig. 13.2 Penile herpes simplex (HSV-2) infection.
LGV and granuloma inguinale, are described in Box 13.12
(p. 341). Inflammatory causes include Stevens-Johnson syndrome
(pp. 1224 and 1254), Behget’s disease (p. 1043) and fixed
drug reactions. In older patients, malignant and pre-malignant
conditions, such as squamous cell carcinoma and erythroplasia
of Queyrat (intra-epidermal carcinoma), should be considered.
Genital lumps
The most common cause of genital ‘lumps’ is warts (p. 342).
These are classically found in areas of friction during sex, such
as the parafrenal skin and prepuce of the penis. Warts may also
be seen in the urethral meatus, and less commonly on the shaft
or around the base of the penis. Perianal warts are surprisingly
common in men who do not have anal sex.
The differential diagnosis includes molluscum contagiosum
and skin tags. Adolescent boys may confuse normal anatomical
features such as coronal papillae (p. 330), parafrenal glands or
sebaceous glands (Fordyce spots) with warts.
Proctitis in men who have sex with men
STIs that may cause proctitis in MSM include gonorrhoea,
chlamydia, herpes and syphilis. The substrains of Chlamydia
trachomatis that cause LGV (LI -3) have been associated with
outbreaks of severe proctitis in Northern Europe, including the
UK. Symptoms include mucopurulent anal discharge, rectal
bleeding, pain and tenesmus.
Presenting problems in women • 335
Examination may show mucopus and erythema with contact
bleeding (p. 330). In addition to the diagnostic tests listed on
page 330, a PCR test for HSV and a request for identification
of the LGV substrain should be arranged if chlamydial infection
is detected. Treatment is directed at the individual infections.
MSM may also present with gastrointestinal symptoms
from infection with organisms such as Entamoeba histolytica
(p. 286), Shigella spp. (p. 265), Campylobacter spp. (p. 262)
and Cryptosporidium spp. (pp. 287 and 317).
Presenting problems in women
Vaginal discharge
The natural vaginal discharge may vary considerably, especially
under differing hormonal influences such as puberty, pregnancy
or prescribed contraception. A sudden or recent change in
discharge, especially if associated with alteration of colour and/
or smell, or vulval itch/irritation, is more likely than a gradual or
long-standing change to indicate an infective cause.
Local epidemiology is particularly important when assessing
possible causes. In the UK, most cases of vaginal discharge are
not sexually transmitted, being due to either candidal infection or
bacterial vaginosis (B V). Worldwide, the most common treatable
STI causing vaginal discharge is trichomoniasis; other possibilities
include gonorrhoea and chlamydia. HSV may cause increased
discharge, although vulval pain and dysuria are usually the
predominant symptoms. Non-infective causes include retained
tampons, malignancy and/or fistulae.
Speculum examination often allows a relatively accurate
diagnosis, with appropriate treatment to follow (Box 13.4). If the
discharge is homogeneous and off-white in colour, vaginal pH
is greater than 4.5, and Gram stain microscopy reveals scanty
or absent lactobacilli with significant numbers of Gram-variable
organisms, some of which may be coating vaginal squamous
cells (so-called Clue cells, Fig. 13.3), the likely diagnosis is BV.
If there is vulval and vaginal erythema, the discharge is curdy in
nature, vaginal pH is less than 4.5, and Gram stain microscopy
reveals fungal spores and pseudohyphae, the diagnosis is
candidiasis. Trichomoniasis tends to cause a profuse yellow
or green discharge and is usually associated with significant
vulvovaginal inflammation. Diagnosis is made by observing motile
flagellate protozoa on a wet-mount microscopy slide of vaginal
material and/or by culture.
If examination reveals the discharge to be cervical in origin,
the possibility of chlamydial or gonococcal infection is increased
and appropriate cervical or vaginal swabs should be taken
(p. 331). In addition, Gram stain of cervical and urethral material
may reveal GNDC, allowing presumptive treatment for gonorrhoea
to be given. If gonococcal cervicitis is suspected, swabs should
also be taken from the pharynx and rectum; infections at these
sites are not reliably eradicated by single-dose therapy and a
test of cure will therefore be required.
GUM clinics in the UK may offer sexually active women
presenting with vaginal discharge an STI screen (p. 331). In
other settings, such as primary care or gynaecology, testing for
chlamydia and gonorrhoea may be considered in young women
(<25 years old), those who have changed partner recently, and
those not using a barrier method of contraception, even if a
non-STI cause of discharge is suspected clinically.
Treatment of infections causing vaginal discharge is shown
in Box 13.4.
Fig. 13.3 Gram stain of a Clue cell from a patient with bacterial
vaginosis. The margin of this vaginal epithelial cell is obscured by a
coating of anaerobic organisms. From McMillan A, Young H, Ogiivie MM,
Scott GR. Clinical practice in sexually transmissible infections. Saunders,
Elsevier Inc.; 2002.
13.4 Infections that cause vaginal discharge
Cause
Clinical features
Treatment (in pregnancy seek specialist advice)
Candidiasis
Vulval and vaginal inflammation
Curdy white discharge adherent
to walls of vagina
Low vaginal pH
Clotrimazole1 500 mg pessary once at night and clotrimazole cream twice
daily or
Econazole1 pessary 150 mg for 3 nights and econazole cream twice daily
(topical creams for 7 days) or
Fluconazole2 150 mg orally stat
Trichomoniasis
Vulval and vaginal inflammation
Frothy yellow/green discharge
Metronidazole3 400 mg twice daily orally for 5-7 days or
Metronidazole3 2 g orally as a single dose
Bacterial vaginosis
No inflammation
White homogeneous discharge
High vaginal pH
Metronidazole3 2 g stat or 400 mg twice daily orally for 5-7 days
Metronidazole3 vaginal gel 0.75% daily for 5 days
Clindamycin1’4 vaginal cream 2% daily for 7 days
Streptococcal/staphylococcal
infection
Purulent vaginal discharge
Choice of antibiotic depends on sensitivity tests
1 Clotrimazole, econazole and clindamycin damage latex condoms and diaphragms. 2Avoid in pregnancy and breastfeeding. 3Avoid alcoholic drinks until 48 hours after
finishing treatment. Avoid high-dose regimens in pregnancy or breastfeeding. 4 Clostridium difficile colitis has been reported with the use of clindamycin cream.
336 • SEXUALLY TRANSMITTED INFECTIONS
Lower abdominal pain
Pelvic inflammatory disease (PID, infection or inflammation of
the Fallopian tubes and surrounding structures) is part of the
extensive differential diagnosis of lower abdominal pain in women,
especially those who are sexually active. The possibility of PID
is increased if, in addition to acute/subacute pain, there is
dyspareunia, abnormal vaginal discharge and/or bleeding. There
may also be systemic features, such as fever and malaise. On
examination, lower abdominal pain is usually bilateral, and vaginal
examination reveals adnexal tenderness with or without cervical
excitation. Unfortunately, a definitive diagnosis can only be made
by laparoscopy. A pregnancy test should be performed (as
well as the diagnostic tests on p. 331) because the differential
diagnosis includes ectopic pregnancy.
Broad-spectrum antibiotics, including those active against
gonorrhoea and chlamydia, such as ofloxacin and metronidazole,
should be prescribed if PID is suspected, along with appropriate
analgesia. Delaying treatment increases the likelihood of adverse
sequelae, such as abscess formation, and tubal scarring that
may lead to ectopic pregnancy or infertility. Hospital admission
may be indicated for severe symptoms.
Genital ulceration
The most common cause of ulceration is genital herpes. Classically,
multiple painful ulcers affect the introitus, labia and perineum,
but solitary lesions occur rarely. Inguinal lymphadenopathy and
systemic features, such as fever and malaise, are more common
than in men. Diagnosis is made by gently scraping material from
lesions and sending this in an appropriate transport medium
for culture or detection of HSV DNA by PCR. Increasingly,
laboratories will also test such samples for Treponema pallidum
by PCR. In the UK, the possibility of any other ulcerating STI
is unlikely unless the patient has had a sexual partner from a
region where tropical STIs are more common (see Box 13.12).
Inflammatory causes include lichen sclerosus, Stevens-Johnson
syndrome (pp. 1224 and 1254), Behget’s disease (p. 1043)
and fixed drug reactions. In older patients, malignant and pre-
malignant conditions, such as squamous cell carcinoma, should
be considered.
Genital lumps
The most common cause of genital ‘lumps’ is warts. These
are classically found in areas of friction during sex, such as the
fourchette and perineum. Perianal warts are surprisingly common
in women who do not have anal sex.
The differential diagnosis includes molluscum contagiosum,
skin tags, and normal papillae or sebaceous glands.
Chronic vulval pain and/or itch
Women may present with a range of chronic symptoms that
may be intermittent or continuous (Box 13.5).
Recurrent candidiasis may lead to hypersensitivity to candidal
antigens, with itch and erythema becoming more prominent than
increased discharge. Effective treatment may require regular
oral antifungals, e.g. fluconazole 150 g once a week, plus a
combined antifungal/glucocorticoid cream.
Early diagnosis and treatment facilitated by active case-finding
will help to reduce the spread of infection by limiting the period
of infectivity; tracing and treating sexual partners will also reduce
the risk of reinfection. Unfortunately, the majority of individuals
with an STI are asymptomatic and therefore unlikely to seek
medical attention. Improving access to diagnosis in primary
care or non-medical settings, especially through opportunistic
testing, may help. However, the impact of medical intervention
through improved access alone is likely to be small.
Changing behaviour
The prevalence of STIs is driven largely by sexual behaviour.
Primary prevention encompasses efforts to delay the onset of
sexual activity and limit the number of sexual partners thereafter.
Encouraging the use of barrier methods of contraception will also
help to reduce the risk of transmitting or acquiring STIs. This
13.5 Chronic vulval pain and/or itch
Likely diagnosis
Itch
Pain
Specific characteristics
Diagnostic test
Treatment
Candidiasis
y
+
Usually cyclical
Microscopy (culture for yeasts
other than Candida albicans in
recurrent/refractory disease)
Oral antifungal, e.g. fluconazole
150 mg
Lichen planus
±
-
Violaceous papules ± Wickham’s
striae
Clinical
No treatment, or mild topical
glucocorticoid, e.g. hydrocortisone
Lichen sclerosus
±
-
Ivory-white plaques, scarring ±
labial resorption
Clinical or biopsy
Strong topical glucocorticoid, e.g.
clobetasol
Vestibulitis
-
y
Dyspareunia common, pain on
touching erythematous area
Clinical
Refer to specialist vulva clinic
Vulvodynia
-
y
Pain usually neuropathic in nature
Clinical
Refer to specialist vulva clinic
Dermatoses, e g.
eczema or psoriasis
y
-
Similar to lesions elsewhere on skin
Clinical
Mild topical glucocorticoid, e.g.
hydrocortisone
Genital herpes
±
y
Atypical ulcers are not uncommon
Swab for HSV PCR
Oral antiviral, e.g. aciclovir
(HSV PCR = herpes simplex virus polymerase chain reaction)
Sexually transmitted bacterial infections • 337
is especially important in the setting of ‘sexual concurrency’,
where sexual relationships overlap.
Unfortunately, there is contradictory evidence as to which (if
any) interventions can reduce sexual activity. Knowledge alone
does not translate into behaviour change, and broader issues,
such as poor parental role modelling, low self-esteem, peer
group pressure in the context of the increased sexualisation
of our societies, gender power imbalance and homophobia, all
need to be addressed. Throughout the world there is a critical
need to enable women to protect themselves from undisciplined
and coercive male sexual activity. Economic collapse and the
turmoil of war regularly lead to situations where women are
raped or must turn to prostitution to feed themselves and their
children, and an inability to negotiate safe sex increases their
risk of acquiring STI, including HIV.
Sexually transmitted
bacterial infections
Syphilis
Syphilis is caused by infection, through abrasions in the skin or
mucous membranes, with the spirochaete Treponema pallidum.
In adults the infection is usually sexually acquired; however,
transmission by kissing, blood transfusion and percutaneous
injury has been reported. Transplacental infection of the fetus
can occur.
The natural history of untreated syphilis is variable. Infection
may remain latent throughout, or clinical features may develop
at any time. The classification of syphilis is shown in Box 13.6.
All infected patients should be treated. Penicillin remains the
drug of choice for all stages of infection.
Acquired syphilis
Early syphilis
Primary syphilis
The incubation period is usually between 14 and 28 days, with
a range of 9-90 days. The primary lesion or chancre (Fig. 13.4)
develops at the site of infection, usually in the genital area. A
dull red macule develops, becomes papular and then erodes to
form an indurated ulcer (chancre). The draining inguinal lymph
nodes may become moderately enlarged, mobile, discrete and
rubbery. The chancre and the lymph nodes are both painless and
non-tender, unless there is concurrent or secondary infection.
Without treatment, the chancre will resolve within 2-6 weeks to
leave a thin atrophic scar.
i
13.6 Classification of syphilis
Stage
Acquired
Congenital
Early
Primary
Secondary
Latent
Clinical and latent
Late
Latent
Benign tertiary
Cardiovascular
Neurosyphilis
Clinical and latent
Fig. 13.4 Primary syphilis. A painless ulcer (chancre) is shown in the
coronal sulcus of the penis. This is usually associated with inguinal
lymphadenopathy. Courtesy of Dr P. Hay, St George’s Hospital, London.
Chancres may develop on the vaginal wall and on the cervix.
Extragenital chancres are found in about 1 0% of patients, affecting
sites such as the finger, lip, tongue, tonsil, nipple, anus or rectum.
Anal chancres often resemble fissures and may be painful.
Secondary syphilis
This occurs 6-8 weeks after the development of the chancre,
when treponemes disseminate to produce a multisystem disease.
Constitutional features, such as mild fever, malaise and headache,
are common. Over 75% of patients present with a rash on the
trunk and limbs that may later involve the palms and soles; this
is initially macular but evolves to maculopapular or papular forms,
which are generalised, symmetrical and non-irritable. Scales
may form on the papules later. Lesions are red, changing to a
‘gun-metal’ grey as they resolve. Without treatment, the rash may
last for up to 1 2 weeks. Condylomata lata (papules coalescing
to plaques) may develop in warm, moist sites such as the vulva
or perianal area. Generalised non-tender lymphadenopathy is
present in over 50% of patients. Mucosal lesions, known as
mucous patches, may affect the genitalia, mouth, pharynx or
larynx and are essentially modified papules, which become
eroded. Rarely, confluence produces characteristic ‘snail track
ulcers’ in the mouth.
Other features, such as meningitis, cranial nerve palsies,
anterior or posterior uveitis, hepatitis, gastritis, glomerulonephritis
or periostitis, are sometimes seen. Neurological involvement
may be more common in HIV-positive patients.
The differential diagnosis of secondary syphilis can be extensive,
but in the context of a suspected STI, primary HIV infection is
the most important alternative condition to consider (Ch. 12).
Non-STI conditions that mimic the rash include psoriasis, pityriasis
rosea, scabies, allergic drug reaction, erythema multiforme and
pityriasis (tinea) versicolor.
The clinical manifestations of secondary syphilis will resolve
without treatment but relapse may occur, usually within the
first year of infection. Thereafter, the disease enters the phase
of latency.
Latent syphilis
This phase is characterised by the presence of positive syphilis
serology or the diagnostic cerebrospinal fluid (CSF) abnormalities
of neurosyphilis in an untreated patient with no evidence of
clinical disease. It is divided into early latency (within 2 years
of infection), when syphilis may be transmitted sexually, and
late latency, when the patient is no longer sexually infectious.
338 • SEXUALLY TRANSMITTED INFECTIONS
■■
1 13.7 Clinical features of congenital syphilis
Early congenital syphilis (neonatal period)
• Maculopapular rash
•
Hepatosplenomegaly
• Condylomata lata
•
Osteochondritis/periostitis
• Mucous patches
•
Generalised lymphadenopathy
• Fissures around mouth, nose
•
Choroiditis
and anus
•
Meningitis
• Rhinitis with nasal discharge
•
Anaemia/thrombocytopenia
(snuffles)
Late congenital syphilis
• Benign tertiary syphilis
•
8th nerve deafness
• Periostitis
•
Interstitial keratitis
• Paroxysmal cold
•
Clutton’s joints (painless
haemoglobinuria
effusion into knee joints)
• Neurosyphilis
Stigmata
• Hutchinson’s incisors
•
Rhagades (radiating scars
(anterior-posterior thickening
around mouth, nose and anus
with notch on narrowed
following rash)
cutting edge)
•
Salt and pepper scars on
• Mulberry molars (imperfectly
retina (from choroiditis)
formed cusps/deficient dental
•
Corneal scars (from interstitial
enamel)
keratitis)
• High arched palate
•
Sabre tibia (from periostitis)
• Maxillary hypoplasia
•
Bossing of frontal and parietal
• Saddle nose (following
bones (healed periosteal
snuffles)
nodes)
Transmission of syphilis from a pregnant woman to her fetus,
and rarely by blood transfusion, is possible for several years
following infection.
Late syphilis
Late latent syphilis
This may persist for many years or for life. Without treatment, over
60% of patients might be expected to suffer little or no ill health.
Coincidental prescription of antibiotics for other illnesses, such
as respiratory tract or skin infections, may treat latent syphilis
serendipitously and make the interpretation of serological test
results difficult (see below).
Benign tertiary syphilis
This may develop between 3 and 1 0 years after infection but
is now rarely seen in the UK. Skin, mucous membranes, bone,
muscle or viscera can be involved. The characteristic feature
is a chronic granulomatous lesion called a gumma, which may
be single or multiple. Healing with scar formation may impair
the function of the structure affected. Skin lesions may take
the form of nodules or ulcers, while subcutaneous lesions may
ulcerate with a gummy discharge. Healing occurs slowly, with
the formation of characteristic tissue-paper scars. Mucosal
lesions may occur in the mouth, pharynx, larynx or nasal septum,
appearing as punched-out ulcers. Of particular importance is
gummatous involvement of the tongue, healing of which may
lead to leucoplakia with the attendant risk of malignant change.
Gummas of the tibia, skull, clavicle and sternum have been
described, as has involvement of the brain, spinal cord, liver,
testis and, rarely, other organs. Resolution of active disease
should follow treatment, though some tissue damage may be
permanent. Paroxysmal cold haemoglobinuria (p. 950) may
be seen.
Cardiovascular syphilis
This may present many years after initial infection. Aortitis, which
may involve the aortic valve and/or the coronary ostia, is the key
feature. Clinical features include aortic incompetence, angina
and aortic aneurysm (p. 505). The condition typically affects the
ascending aorta and sometimes the aortic arch; aneurysm of the
descending aorta is rare. Treatment with penicillin will not correct
anatomical damage and surgical intervention may be required.
Neurosyphilis
This may also take years to develop. Asymptomatic infection
is associated with CSF abnormalities in the absence of clinical
signs. Meningovascular disease, tabes dorsalis and general
paralysis of the insane constitute the symptomatic forms
(p. 1125). Neurosyphilis and cardiovascular syphilis may coexist
and are sometimes referred to as quaternary syphilis.
| Congenital syphilis
Congenital syphilis is rare where antenatal serological screening
is practised. Antisyphilitic treatment in pregnancy treats the fetus,
if infected, as well as the mother.
Treponemal infection may give rise to a variety of outcomes
after 4 months of gestation, when the fetus becomes
immunocompetent:
• miscarriage or stillbirth, prematurely or at term
• birth of a syphilitic baby (a very sick baby with
hepatosplenomegaly, bullous rash and perhaps
pneumonia)
• birth of a baby who develops signs of early congenital
syphilis during the first few weeks of life (Box 13.7)
• birth of a baby with latent infection who either remains well
or develops congenital syphilis/stigmata later in life (see
Box 13.7).
Investigations in adult cases
Treponema pallidum may be identified in serum collected from
chancres, or from moist or eroded lesions in secondary syphilis
using a dark-field microscope, a direct fluorescent antibody
test or PCR.
The serological tests for syphilis (STS) are listed in Box 13.8.
These are antibody tests that almost always remain positive,
even after successful treatment. Prolonged untreated infection
results in higher titres that may not decline at all. Interpretation
of results requires knowledge of any treatment, which may
include antibiotics given coincidentally, e.g. for skin or respiratory
tract infections.
Many centres use treponemal enzyme immunoassays
(ElAs) for IgG and IgM antibodies to screen for syphilis. EIA
for antitreponemal IgM becomes positive at approximately 2
weeks, while non-treponemal tests become positive about 4
weeks after primary syphilis. All positive results in asymptomatic
patients must be confirmed by repeat tests.
Biological false- positive reactions occur occasionally; these are
most commonly seen with Venereal Diseases Research Laboratory
(VDRL) or rapid plasma reagin (RPR) tests (when treponemal tests
will be negative). Acute false- positive reactions may be associated
with infections, such as infectious mononucleosis, chickenpox
and malaria, and may also occur in pregnancy. Chronic false¬
positive reactions may be associated with autoimmune diseases.
False-negative results for non-treponemal tests may be found in
secondary syphilis because extremely high antibody levels can
Sexually transmitted bacterial infections • 339
i
prevent the formation of the antibody-antigen lattice necessary
for the visualisation of the flocculation reaction (the prozone
phenomenon).
In benign tertiary and cardiovascular syphilis, examination of
CSF should be considered because asymptomatic neurological
disease may coexist. The CSF should also be examined in patients
with clinical signs of neurosyphilis (p. 1 1 25) and in both early and
late congenital syphilis. Positive STS may be found in patients
who are being investigated for neurological disease, especially
dementia. In many instances, the serology reflects previous
infection unrelated to the presenting complaint, especially when
titres are low. Examination of CSF is occasionally necessary.
Chest X-ray, electrocardiogram (ECG) and echocardiogram
are useful in the investigation of cardiovascular syphilis. Biopsy
may be required to diagnose gumma.
Endemic treponematoses, such as yaws, endemic (non-
venereal) syphilis (bejel) and pinta (pp. 253 and 254), are caused
by treponemes that are morphologically indistinguishable from
T. pallidum and cannot be differentiated by serological tests. A
VDRL or RPR test may help to elucidate the correct diagnosis
because adults with late yaws usually have low titres.
Investigations in suspected congenital syphilis
Passively transferred maternal antibodies from an adequately
treated mother may give rise to positive serological tests in her
baby. In this situation, non-treponemal tests should become
negative within 3-6 months of birth. A positive EIA test for
antitreponemal IgM suggests early congenital syphilis. A diagnosis
of congenital syphilis mandates investigation of the mother, her
partner and any siblings.
Management
Penicillin is the drug of choice. Currently, a single dose of
2.4 megaunits of intramuscular benzathine benzylpenicillin is
recommended for early syphilis (<2 years’ duration), with three
doses at weekly intervals being recommended in late syphilis.
A 14-day course of procaine penicillin is recommended for the
treatment of neurosyphilis, supplemented by a 3-day course of
prednisolone (see below). Doxycycline is indicated for patients
allergic to penicillin, except in pregnancy (see below). Azithromycin
is less favoured due to the potential for resistance. All patients
must be followed up to ensure cure, and partner notification
is of particular importance. Resolution of clinical signs in early
syphilis with declining titres for non-treponemal tests, usually
to undetectable levels within 6 months for primary syphilis and
1 2-1 8 months for secondary syphilis, is an indicator of successful
treatment. Specific treponemal antibody tests may remain positive
for life. In patients who have had syphilis for many years there
may be little serological response following treatment.
Pregnancy
Penicillin is the treatment of choice in pregnancy. Erythromycin
stearate can be given if there is penicillin hypersensitivity, but it
crosses the placenta poorly; the newborn baby must therefore
be treated with a course of penicillin and consideration given
to retreating the mother. Some specialists recommend penicillin
desensitisation for pregnant mothers so that penicillin can be
given during temporary tolerance. A 1 0-day course of ceftriaxone
is a further alternative. Babies should be treated in hospital with
the help of a paediatrician.
Treatment reactions
• Anaphylaxis. Penicillin is a common cause; on-site facilities
should be available for management (p. 75).
• Jarisch-Herxheimer reaction. This is an acute febrile
reaction that follows treatment and is characterised by
headache, malaise and myalgia; it resolves within 24
hours. It is common in early syphilis and rare in late
syphilis. Fetal distress or premature labour can occur in
pregnancy.
The reaction may also cause worsening of neurological
(cerebral artery occlusion) or ophthalmic (uveitis, optic
neuritis) disease, myocardial ischaemia (inflammation of
the coronary ostia) and laryngeal stenosis (swelling of a
gumma). Prednisolone 40-60 mg daily for 3 days is
recommended to prevent the reaction in patients with
these forms of the disease; antisyphilitic treatment can be
started 24 hours after introducing glucocorticoids. In
high-risk situations it is wise to initiate therapy in hospital.
• Procaine reaction. Fear of impending death occurs
immediately after the accidental intravenous injection
of procaine penicillin and may be associated with
hallucinations or fits. Symptoms are short-lived, but verbal
assurance and sometimes physical restraint are needed.
The reaction can be prevented by aspiration before
intramuscular injection to ensure the needle is not in a
blood vessel.
Gonorrhoea
Gonorrhoea is caused by infection with Neisseria gonorrhoeae
and may involve columnar epithelium in the lower genital tract,
rectum, pharynx and eyes. Transmission is usually the result
of vaginal, anal or oral sex. Gonococcal conjunctivitis may
be caused by accidental infection from contaminated fingers.
Untreated mothers may infect babies during delivery, resulting in
ophthalmia neonatorum (Fig. 13.5). Infection of children beyond
the neonatal period usually indicates sexual abuse.
Clinical features
The incubation period is usually 2-10 days. In men the anterior
urethra is commonly infected, causing urethral discharge and
dysuria, but symptoms are absent in about 10% of cases.
Examination will usually show a mucopurulent or purulent urethral
discharge. Rectal infection in MSM is usually asymptomatic but
may present with anal discomfort, discharge or rectal bleeding.
Proctoscopy may reveal either no abnormality, or clinical evidence
of proctitis (p. 334) such as inflamed rectal mucosa and mucopus.
In women, the urethra, paraurethral glands/ducts, Bartholin’s
glands/ducts or endocervical canal may be infected. The rectum
may also be involved either due to contamination from a urogenital
site or as a result of anal sex. Occasionally, the rectum is the
13.8 Serological tests for syphilis
Non-treponemal (non-specific) tests
• Venereal Diseases Research Laboratory (VDRL) test
• Rapid plasma reagin (RPR) test
Treponemal (specific) antibody tests
• Treponemal antigen-based enzyme immunoassay (EIA) for IgG
and IgM
• Treponema pallidum haemagg I uti nation assay (TPHA)
• T. pallidum particle agglutination assay (TPPA)
• Fluorescent treponemal antibody-absorbed (FTA-ABS) test
340 • SEXUALLY TRANSMITTED INFECTIONS
Fig. 13.5 Gonococcal ophthalmia neonatorum. From McMillan A,
Scott GR. Sexually transmitted infections: a colour guide. Churchill
Livingstone, Elsevier Ltd; 2000.
only site infected. About 80% of women who have gonorrhoea
are asymptomatic. There may be vaginal discharge or dysuria
but these symptoms are often due to additional infections,
such as chlamydia (see below), trichomoniasis or candidiasis,
making full investigation essential (p. 331). Lower abdominal
pain, dyspareunia and intermenstrual bleeding may be indicative
of PID. Clinical examination may show no abnormality, or pus
may be expressed from urethra, paraurethral ducts or Bartholin’s
ducts. The cervix may be inflamed, with mucopurulent discharge
and contact bleeding.
Pharyngeal gonorrhoea is the result of receptive orogenital
sex and is usually symptomless. Gonococcal conjunctivitis is an
uncommon complication, presenting with purulent discharge from
the eye(s), severe inflammation of the conjunctivae and oedema
of the eyelids, pain and photophobia. Gonococcal ophthalmia
neonatorum presents similarly with purulent conjunctivitis and
oedema of the eyelids. Conjunctivitis must be treated urgently
to prevent corneal damage.
Disseminated gonococcal infection (DGI) is seen rarely, and
typically affects women with asymptomatic genital infection.
Symptoms include arthritis of one or more joints, pustular skin
lesions, tenosynovitis and fever. Gonococcal endocarditis has
been described.
Investigations
Gram-negative diplococci may be seen on microscopy of smears
from infected sites (see Fig. 13.1). Pharyngeal smears are difficult
to analyse due to the presence of other diplococci, so the
diagnosis must be confirmed by culture or NAAT.
Management of adults
Emerging resistance is making it increasingly difficult to cure
gonorrhoea with a single oral dose of antimicrobials, and
recommended treatment in the UK has changed to intramuscular
ceftriaxone 500 mg given with an oral dose of azithromycin
1 g, in the hope that combination therapy will slow down the
development of cephalosporin resistance. The alternatives listed
in Box 13.9 are less likely to be effective.
Longer courses of antibiotics are required for complicated
infection. The partner(s) of patients with gonorrhoea should
13.9 Treatment of uncomplicated
anogenital gonorrhoea
Uncomplicated infection
• Ceftriaxone 500 mg IM plus azithromycin 1 g orally or
• Cefixime 400 mg stat or
• Ciprofloxacin 500 mg orally stat1,2 or
• Ofloxacin 400 mg orally stat1,2
Pregnancy and breastfeeding
• Ceftriaxone 500 mg plus azithromycin 1 g IM stat or
• Spectinomycin 2 g IM stat3
Pharyngeal gonorrhoea
• Ceftriaxone 500 mg IM plus azithromycin 1 g stat or
• Ciprofloxacin 500 mg1'2 orally stat or
• Ofloxacin 400 mg1,2 orally stat
1 Contraindicated in pregnancy and breastfeeding. 2lf prevalence of quinolone
resistance for Neisseria gonorrhoeae is <5%. 3May be available only in specialist
clinics.
13.10 Complications of delayed therapy
in gonorrhoea
• Acute prostatitis
• Epididymo-orchitis
• Bartholin’s gland abscess
• Pelvic inflammatory disease (may lead to infertility or ectopic
pregnancy)
• Disseminated gonococcal infection
be seen as soon as possible. Delay in treatment may lead to
complications (Box 13.10).
Chlamydial infection
Chlamydial infection in men
Chlamydia is transmitted and presents in a similar way to
gonorrhoea; however, urethral symptoms are usually milder and
may be absent in over 50% of cases. Conjunctivitis is also milder
than in gonorrhoea; pharyngitis does not occur. The incubation
period varies from 1 week to a few months. Without treatment,
symptoms may resolve but the patient remains infectious for
several months. Complications, such as epididymo-orchitis and
sexually acquired reactive arthritis (SARA, p. 1031), are rare.
Sexually transmitted pathogens, such as chlamydia or gonococci,
are usually responsible for epididymo-orchitis in men aged less
than 35 years, whereas bacteria such as Gram-negative enteric
organisms are more commonly implicated in older men.
Treatments for chlamydia are listed in Box 13.11. NSU is
treated identically. The partner(s) of men with chlamydia should
be treated, even if laboratory tests for chlamydia are negative.
Investigation is not mandatory but serves a useful epidemiological
purpose; moreover, positive results encourage further attempts
at contact-tracing.
Chlamydial infection in women
The cervix and urethra are commonly involved. Infection is
asymptomatic in about 80% of patients but may cause
intermenstrual and/or post-coital bleeding, dysuria or vaginal
discharge. Lower abdominal pain and dyspareunia are features
of PID. Examination may reveal mucopurulent cervicitis, contact
Sexually transmitted viral infections • 341
i
Standard regimens
• Azithromycin 1 g orally as a single dose1 or
• Doxycycline 100 mg twice daily orally for 7 days2
Alternative regimens
• Erythromycin 500 mg four times daily orally for 7 days or 500 mg
twice daily for 2 weeks or
• Ofloxacin 200 mg twice daily orally for 7 days2
Safety in pregnancy and breastfeeding has not been fully established.
Contraindicated in pregnancy and breastfeeding.
bleeding from the cervix, evidence of PID or no obvious clinical
signs. Treatment options are listed in Box 13.1 1 . The patient’s
male partner(s) should be investigated and treated.
Many infections clear spontaneously but others persist. PID,
with the risk of tubal damage and subsequent infertility or ectopic
pregnancy, is a rare but important long-term complication.
Other complications include perihepatitis, chronic pelvic pain,
conjunctivitis and SARA (p. 1031). Perinatal transmission may
lead to ophthalmia neonatorum and/or pneumonia in the neonate.
Other sexually transmitted
bacterial infections
Chancroid, granuloma inguinale and LGV as causes of genital
ulcers in the tropics are described in Box 13.12. LGV is also a
cause of proctitis in MSM (p. 334).
Sexually transmitted viral infections
Genital herpes simplex
Infection with herpes simplex virus type 1 (HSV-1) or type
2 (HSV-2) produces a wide spectrum of clinical problems
(p. 247), and may facilitate HIV transmission. Infection is usually
acquired sexually (vaginal, anal, orogenital or oroanal), but
perinatal transmission to the neonate may also occur. Primary
infection at the site of HSV entry, which may be symptomatic
or asymptomatic, establishes latency in local sensory ganglia.
Recurrences, either symptomatic or asymptomatic viral shedding,
are a consequence of HSV reactivation. The first symptomatic
episode is usually the most severe. Although HSV-1 is classically
associated with orolabial herpes and HSV-2 with anogenital
herpes, HSV-1 now accounts for more than 50% of anogenital
infections in the UK.
Clinical features
The first symptomatic episode presents with irritable vesicles
that soon rupture to form small, tender ulcers on the external
genitalia (Fig. 13.6 and see Fig. 13.2). Lesions at other sites (e.g.
urethra, vagina, cervix, perianal area, anus or rectum) may cause
dysuria, urethral or vaginal discharge, or anal, perianal or rectal
pain. Constitutional symptoms, such as fever, headache and
malaise, are common. Inguinal lymph nodes become enlarged
and tender, and there may be nerve root pain in the 2nd and
3rd sacral dermatomes.
Extragenital lesions may develop at other sites, such as the
buttock, finger or eye, due to auto-inoculation. Oropharyngeal
infection may result from orogenital sex. Complications, such
1 3.1 1 Treatment of chlamydial infection
13.12 Salient features of lymphogranuloma venereum, chancroid and granuloma inguinale (Donovanosis)
Infection and
distribution
Organism
Incubation
period
Genital lesion
Lymph nodes
Diagnosis
Management
Lymphogranuloma venereum (LGV)
E/W Africa, India, Chlamydia
SE Asia, S America, trachomatis
Caribbean types LI , 2, 3
3-30 days
Small, transient,
painless ulcer,
vesicle, papule;
often unnoticed
Tender, usually
unilateral, matted,
suppurative bubo;
inguinal/femoral
nodes involved1
Serological tests
for LI -3
serotypes; swab
from ulcer or bubo
pus for Chlamydia
Doxycycline2 twice
daily orally for 21
days or
Erythromycin 500 mg
four times daily orally
Chancroid
Africa, Asia, Central
and S America
Haemophilus
ducreyi (short
Gram-negative
bacillus)
3-1 0 days
Single or multiple
painful ulcers with
ragged undermined
edges
As above but
unilocular,
suppurative bubo;
inguinal nodes
involved in -50%
Microscopy and
culture of
scrapings from
ulcer or pus from
bubo
Azithromycin3 1 g
orally once or
Ceftriaxone 250 mg
IM once or
Ciprofloxacin2 500 mg
twice daily orally for 3
days
Granuloma inguinale
Australia, India,
Caribbean, S Africa,
S America, Papua
New Guinea
Klebsiella
granulomatis
(Donovan bodies)
3-40 days
Ulcers or
hypertrophic
granulomatous
lesions; usually
painless4
Initial swelling of
inguinal nodes,
then spread of
infection to form
abscess or
ulceration through
adjacent skin
Microscopy of
cellular material
for intracellular
bipolar-staining
Donovan bodies
Azithromycin3 1 g
weekly orally or
500 mg daily orally or
Doxycycline2 100 mg
twice daily orally or
Ceftriaxone 1 g IM
daily
N.B. Partners of patients with LGV, chancroid and granuloma inguinale should be investigated and treated, even if asymptomatic.
The genito-ano-rectal syndrome is a late manifestation of LGV. 2Doxycycline and ciprofloxacin are contraindicated in pregnancy and breastfeeding. The safety of
azithromycin in pregnancy and breastfeeding has not been fully assessed. 4Mother-to-baby transmission of granuloma inguinale may rarely occur.
342 • SEXUALLY TRANSMITTED INFECTIONS
Fig. 13.6 Herpetic ulceration of the vulva. From McMillan A, Scott GR.
Sexually transmitted infections: a colour guide. Churchill Livingstone,
Elsevier Ltd; 2000.
as urinary retention due to autonomic neuropathy, and aseptic
meningitis, are occasionally seen.
First episodes usually heal within 2-4 weeks without treatment;
recurrences are usually milder and of shorter duration than the
initial attack. They occur more often in HSV-2 infection and their
frequency tends to decrease with time. Prodromal symptoms,
such as irritation or burning at the subsequent site of recurrence,
or neuralgic pain affecting buttocks, legs or hips are commonly
seen. The first symptomatic episode may be a recurrence
of a previously undiagnosed primary infection. Recurrent
episodes of asymptomatic viral shedding are important in the
transmission of HSV.
Diagnosis
Swabs are taken from vesicular fluid or ulcers for detection of
DNA by PCR, or tissue culture and typing as either HSV-1 or 2.
Electron microscopy of such material will give only a presumptive
diagnosis, as herpes group viruses appear similar. Type-specific
antibody tests are available but are not sufficiently accurate for
general use.
Management
First episode
The following 5-day oral regimens should be started within 5
days of the beginning of the episode, or while lesions are still
forming:
• aciclovir 400 mg three times daily
• valaciclovir 500 mg twice daily.
Famciclovir 250 mg three times daily or aciclovir 200 mg five
times daily is an alternative.
Analgesia may be required and saline bathing can be soothing.
Treatment may be continued for longer than 5 days if new lesions
develop. Occasionally, intravenous therapy may be indicated if
oral therapy is poorly tolerated or aseptic meningitis occurs.
Catheterisation via the suprapubic route is advisable for urinary
retention due to autonomic neuropathy because the transurethral
route may introduce HSV into the bladder.
Recurrent genital herpes
Symptomatic recurrences are usually mild and may require no
specific treatment other than saline bathing. For more severe
episodes, patient-initiated treatment at onset, with one of the
following 5-day oral regimens, should reduce the duration of
the recurrence:
• aciclovir 200 mg five times daily
• famciclovir 1 25-250 mg twice daily
• valaciclovir 500 mg twice daily.
In a few patients, treatment started at the onset of prodromal
symptoms may abort recurrence.
Suppressive therapy may be required for patients with frequent
recurrences, especially if these are experienced at intervals of
less than 4 weeks. Treatment should be given for a minimum of
1 year before stopping to assess recurrence rate. About 20%
of patients will experience reduced attack rates thereafter, but
for those whose recurrences remain unchanged, resumption of
suppressive therapy is justified. Aciclovir 400 mg twice daily is
most commonly prescribed.
Management in pregnancy
If her partner is known to be infected with HSV, a pregnant
woman with no previous anogenital herpes should be advised
to protect herself during sexual intercourse because the risk of
disseminated infection is increased in pregnancy. Consistent
condom use during pregnancy may reduce transmission of
HSV. Genital herpes acquired during the first or second trimester
of pregnancy is treated with aciclovir as clinically indicated.
Although aciclovir is not licensed for use in pregnancy in the
UK, there is considerable clinical evidence to support its safety.
Third -trimester acquisition of infection has been associated with
life-threatening haematogenous dissemination and should be
treated with aciclovir.
Vaginal delivery should be routine in women who are
symptomless in late pregnancy. Caesarean section is sometimes
considered if there is a recurrence at the beginning of labour,
although the risk of neonatal herpes through vaginal transmission
is very low. Caesarean section is often recommended if primary
infection occurs after 34 weeks because the risk of viral shedding
is very high in labour.
Human papillomavirus and
anogenital warts
Human papillomavirus (HPV) DNA typing has demonstrated over
90 genotypes (p. 1238), of which HPV-6, HPV-1 1 , HPV-16 and
HPV-18 most commonly infect the genital tract through sexual
transmission. It is important to differentiate between the benign
genotypes (HPV-6 and 11) that cause anogenital warts, and
genotypes such as 1 6 and 1 8 that are associated with dysplastic
conditions and cancers of the genital tract but are not a cause of
benign warts. All genotypes usually result in subclinical infection
of the genital tract rather than clinically obvious lesions affecting
penis, vulva, vagina, cervix, perineum or anus.
Sexually transmitted viral infections • 343
Clinical features
Anogenital warts caused by HPV may be single or multiple,
exophytic, papular or flat. Perianal warts (p. 330), while being
more common in MSM, are also found in heterosexual men and in
women. Rarely, a giant condyloma (Buschke-Lowenstein tumour)
develops, with local tissue destruction. Atypical warts should be
biopsied. In pregnancy, warts may dramatically increase in size
and number, making treatment difficult. Rarely, they are large
enough to obstruct labour and, in this case, delivery by caesarean
section will be required. Uncommonly, perinatal transmission of
HPV leads to anogenital warts, or possibly laryngeal papillomas,
in the neonate.
Management
The use of condoms can help prevent the transmission of HPV
to non-infected partners, but HPV may affect parts of the genital
area not protected by condoms. Vaccination against HPV infection
has been introduced and is in routine use in many countries.
There are three types of vaccine:
• A bivalent vaccine offers protection against HPV types 16
and 18, which account for approximately 75% of cervical
cancers in the UK.
• A quadrivalent vaccine offers additional protection against
HPV types 6 and 1 1 , which account for over 90% of
genital warts.
• A nonovalent vaccine protects against five additional
high-risk types (31 , 33, 45, 52 and 58).
All vaccines have been shown to be highly effective in the
prevention of cervical intra-epithelial neoplasia in young women,
and the quadrivalent and nonovalent vaccines have also been
demonstrated to be highly effective in protecting against HPV-
associated genital warts. It is currently recommended that HPV
vaccination should be administered prior to the onset of sexual
activity, typically at age 11-13, in a course of three injections. In
the UK, only girls are offered vaccination, but it is possible that
vaccination will be extended to MSM in whom HPV transmission
is associated with an increased risk of anal cancer. As no vaccine
protects against all oncogenic types of HPV, cervical screening
programmes will still be necessary.
A variety of treatments are available for established disease,
including the following:
• Podophyllotoxin, 0.5% solution or 0.15% cream
(contraindicated in pregnancy), applied twice daily for 3
days, followed by 4 days’ rest, for up to 4 weeks, is
suitable for home treatment of external warts.
• Imiquimod cream (contraindicated in pregnancy), applied 3
times weekly (and washed off after 6-1 0 hours) for up
to 1 6 weeks, is also suitable for home treatment of
external warts.
• Catephen (an extract of the green tea plant, Camellia
sinensis) is applied by the patient three times daily for up
to 1 6 weeks.
• Cryotherapy using liquid nitrogen to freeze warty tissue is
suitable for external and internal warts but often requires
repeated clinic visits.
• Hyf recation - electrofulgu ration that causes superficial
charring - is suitable for external and internal warts.
Hyfrecation results in smoke plume, which contains HPV
DNA and has the potential to cause respiratory infection in
the operator/patient. Masks should be worn during the
procedure and adequate extraction of fumes should be
provided.
• Surgical removal may be used to excise refractory warts,
especially pedunculated perianal lesions, under local or
general anaesthesia.
Molluscum contagiosum
Infection by molluscum contagiosum virus, both sexual and
non-sexual, produces flesh-coloured, umbilicated, hemispherical
papules usually up to 5 mm in diameter after an incubation period
of 3-12 weeks (Fig. 13.7). Larger lesions may be seen in HIV
infection (p. 306). Lesions are often multiple and, once established
in an individual, may spread by auto-inoculation. They are found
on the genitalia, lower abdomen and upper thighs when sexually
acquired. Facial lesions are highly suggestive of underlying
HIV infection. Diagnosis is made clinically or very rarely by
electron microscopy. Typically, lesions persist for several months
before spontaneous resolution occurs. Treatment regimens are
therefore cosmetic; they include cryotherapy, hyfrecation, topical
applications of 0.15% podophyllotoxin cream (contraindicated
in pregnancy) or expression of the central core.
Fig. 13.7 Molluscum contagiosum of the shaft of the penis.
From McMillan A, Scott GR. Sexually transmitted infections: a colour
guide. Churchill Livingstone, Elsevier Ltd; 2000.
Viral hepatitis
The hepatitis viruses A-D (p. 871) may be sexually transmitted:
• Hepatitis A (HAV). Insertive oroanal sex, insertive digital
sex, insertive anal sex and multiple sexual partners have
been linked with HAV transmission in MSM. HAV
transmission in heterosexual men and women is also
possible through oroanal sex.
• Hepatitis B (HBV). Insertive oroanal sex, anal sex and
multiple sexual partners are linked with HBV infection in
MSM. Heterosexual transmission of HBV is well
documented and commercial sex workers are at particular
risk. Hepatitis D (HD V) may also be sexually transmitted.
• Hepatitis C (HCV). Sexual transmission of HCV is well
documented in MSM but less so in heterosexuals. Sexual
transmission is less efficient than for HBV.
344 • SEXUALLY TRANSMITTED INFECTIONS
The sexual partner(s) of patients with HAV and HBV should
be seen as soon as possible and offered immunisation where
appropriate. Patients with HAV should abstain from all forms of
unprotected sex until non-infectious. Those with HBV should
likewise abstain from unprotected sex until they are non-infectious
or until their partners have been vaccinated successfully. No active
or passive immunisation is available for protection against HCV
but the consistent use of condoms is likely to protect susceptible
partners. Active immunisation against HAV and HBV should
be offered to susceptible people at risk of infection. Many STI
clinics offer HAV immunisation to MSM along with routine HBV
immunisation; a combined HAV and HBV vaccine is available.
Further information
Books and journal articles
Pattman R, Sankar N, Elawad B, et al. (eds). Oxford handbook of
genitourinary medicine, HIV, and sexual health. Oxford: Oxford
University Press; 201 0.
Rogstad KE (ed.). ABC of sexually transmitted infections, 6th edn.
Oxford: Wiley-Blackwell; 201 1 .
Website
bashh.org/guidelines British Association for Sexual Health and HIV;
updates on treatment of all STIs.
L Burnett
DR Sullivan
P Stewart
Clinical biochemistry and
metabolic medicine
Clinical examination in biochemical and metabolic disorders 346
Magnesium homeostasis 367
Biochemical investigations 348
Water and electrolyte homeostasis 349
Sodium homeostasis 349
Functional anatomy and physiology 367
Presenting problems in magnesium homeostasis 367
Hypomagnesaemia 368
Hypermagnesaemia 368
Functional anatomy and physiology 349
Presenting problems in sodium and water balance 352
Hypovolaemia 352
Hypervolaemia 353
Water homeostasis 355
Phosphate homeostasis 368
Functional anatomy and physiology 368
Presenting problems in phosphate homeostasis 368
Hypophosphataemia 368
Hyperphosphataemia 369
Functional anatomy and physiology 355
Presenting problems in regulation of osmolality 356
Hyponatraemia 357
Hypernatraemia 358
Disorders of amino acid metabolism 369
Disorders of carbohydrate metabolism 370
Disorders of complex lipid metabolism 370
Potassium homeostasis 360
Lipids and lipoprotein metabolism 370
Functional anatomy and physiology 360
Presenting problems in potassium homeostasis 361
Hypokalaemia 361
Hyperkalaemia 362
Acid-base homeostasis 363
Functional anatomy and physiology 363
Presenting problems in acid-base balance 364
Metabolic acidosis 364
Metabolic alkalosis 366
Respiratory acidosis 367
Respiratory alkalosis 367
Mixed acid-base disorders 367
Calcium homeostasis 367
Functional anatomy and physiology 371
Lipids and cardiovascular disease 373
Investigations 373
Presenting problems in lipid metabolism 373
Hypercholesterolaemia 373
Hypertriglyceridaemia 374
Mixed hyperlipidaemia 375
Rare dyslipidaemias 375
Principles of management 375
The porphyrias 378
346 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
Clinical examination in biochemical and metabolic disorders
Many biochemical and metabolic disorders are clinically silent or present with non-specific manifestations, and are first detected by
laboratory testing. Several abnormalities can be picked up by history and physical examination, however, as summarised below.
Hyperlipidaemia
I Atheroma
G Corneal arcus
Hypervolaemia
F Extra heart sounds
E Lung crepitations
D Raised jugular venous
pressure
C Ankle oedema
Hypovolaemia
B Low blood pressure
A Rapid pulse
Acute hypernatraemia
J Extra heart sounds
Dizziness
Delirium
Weakness
Acute hyponatraemia
J Cerebral oedema
Vomiting
Somnolence
Seizures
Coma
Observation
• General appearance
• Skin turgor
• Oedema
• Rash
• Eyes
Glycogen storage disease
L Hepatomegaly
Porphyria
M Abdominal pain
N Photosensitive rash
Hyperlipidaemia
P Eruptive xanthoma
Insets: (ankle oedema) From Huang H-W, Wong L-S, Lee C-H. Sarcoidosis with bilateral leg lymphedema as the initial presentation: a review of the
literature. Dermatologica Sinica 2016; 34:29-32; (raised jugular venous pressure) Newby D, Grubb N. Cardiology: an illustrated colour text. Edinburgh:
Churchill Livingstone, Elsevier Ltd; 2005; (cherry-red spots) Vieira de Rezende Pinto WB, Sgobbi de Souza PV, Pedroso JL, et al. Variable phenotype and
severity of sialidosis expressed in two siblings presenting with ataxia and macular cherry- red spots. J Clin Neurosci 2013; 20:1327-1328; (photosensitive
rash) Ferri FF. Ferri’s Color atlas and text of clinical medicine. Philadelphia: Saunders, Elsevier Inc.; 2009; courtesy of the Institute of Dermatology, London.
Clinical examination in biochemical and metabolic disorders • 347
Assessment of volume status and electrolyte disturbances
Check blood pressure, pulse and jugular venous pressure
Check skin turgor Check for dry mouth
Check for sacral and ankle oedema
Examine chest for pleural
effusion
Examine abdomen for
hepatomegaly and ascites
Check bloods
Review results
Check ECG
|1 U wave
Peaked
1 T wave
Ja
ST
depression
Nl/
Hypokalaemia
Hyperkalaemia
348 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
There is a worldwide trend towards increased use of laboratory-
based diagnostic investigations, and biochemical investigations
in particular. In the health-care systems of developed countries,
it has been estimated that 60-70% of all critical decisions taken
in regard to patients, and over 90% of data stored in electronic
medical records systems, involve a laboratory service or result.
This chapter covers a diverse group of disorders affecting
adults that are not considered elsewhere in this book, whose
primary manifestation is in abnormalities of biochemistry laboratory
results, or whose underlying pathophysiology involves disturbance
in specific biochemical pathways.
Biochemical investigations
There are three broad reasons why a clinician may request a
biochemical laboratory investigation:
• to screen an asymptomatic subject for the presence of
disease
• to assist in diagnosis of a patient’s presenting complaint
• to monitor changes in test results, as a marker of disease
progression or response to treatment.
Contemporary medical practice has become increasingly reliant
on laboratory investigation and, in particular, on biochemical
investigation. This has been associated with extraordinary
improvements in the analytical capacity and speed of laboratory
instrumentation and the following operational trends:
• Large central biochemistry laboratories feature extensive
use of automation and information technology. Specimens
are transported from clinical areas to the laboratory using
high-speed transport systems (such as pneumatic tubes)
and identified with machine-readable labels (such as bar
codes). Laboratory instruments have been miniaturised
and integrated with robot transport systems to enable
multiple rapid analyses of a single sample. Statistical
process control techniques are used to assure the quality
of analytical results, and increasingly to monitor other
aspects of the laboratory, such as the time taken to
complete the analysis (‘turn-around time’).
• Point-of-care testing (POCT) brings selected laboratory
analytical systems into clinical areas, to the patient’s
bedside or even connected to an individual patient. These
systems allow the clinician to receive results almost
instantaneously for immediate treatment of the patient,
although often with lesser precision or at greater cost than
using a central laboratory.
• The diversity of analyses has widened considerably with
the introduction of many techniques borrowed from the
chemical or other industries (Box 14.1).
Good medical practice involves the appropriate ordering of
laboratory investigations and correct interpretation of test results
(Box 14.2). The key principles, including the concepts of sensitivity
and specificity, are described on page 4. Reference intervals for
laboratory results are provided in Chapter 35. Many laboratory
investigations can be subject to variability arising from whether
the sample is being taken in the fed or fasted state; the timing
of sample collection, in relation to diurnal variation of analytes;
dosage intervals for therapeutic drug monitoring; sample type,
such as serum plasma; use of anticoagulants, such as EDTA,
which can interfere with some assays; or artefacts, such as
14.1 Range of analytical modalities used in the clinical biochemistry laboratory
Analytical modality
Analyte
Typical applications
Ion-selective electrodes
Blood gases, electrolytes (Na, K, Cl)
Point-of-care testing (POCT)
High-throughput analysers
Colorimetric chemical reaction or
Simple mass or concentration measurement
High-throughput analysers
coupled enzymatic reaction
(creatinine, phosphate)
Simple enzyme activity
Ligand assay
Specific proteins
Increasingly available for POCT or high-throughput analysers
(usually immunoassay)
Hormones
Drugs
Chromatography: gas
chromatography (GC), high-
performance liquid chromatography
(HPLC), thin-layer chromatography
(TLC)
Organic compounds
Therapeutic drug monitoring (TDM)
Mass spectroscopy (MS)
Drug screening (drugs of misuse)
Vitamins
Biochemical metabolites
Spectrophotometry, turbidimetry,
Haemoglobin derivatives
Xanthochromia
nephelometry, fluorimetry
Specific proteins
Lipoproteins
Immunoglobulins
Paraproteins
Electrophoresis
Proteins
Paraproteins
Some enzymes
Isoenzyme analysis
Atomic absorption (AA)
Inductively coupled plasma/mass
spectroscopy (ICP-MS)
Trace elements and metals
Quantitation of heavy metals
Molecular diagnostics
Nucleic acid quantification and/or sequence
Inherited and somatic cell mutations (Ch. 3)
Genetic polymorphisms (Ch. 3)
Variations in rates of drug metabolism (Ch. 2)
Microbial diagnosis (Ch. 6)
Sodium homeostasis • 349
14.2 How to interpret urea and electrolytes results
Sodium
• Largely reflects changes in sodium and water balance
• See ‘Hypernatraemia’ and ‘Hyponatraemia’ (pp. 358 and 357)
Potassium
• May reflect K shifts in and out of cells
• Low levels usually mean excessive losses (gastrointestinal or renal)
• High levels usually mean renal dysfunction
• See ‘Hypokalaemia’ and ‘Hyperkalaemia’ (pp. 361 and 362)
Chloride
• Generally changes in parallel with plasma Na
• Low in metabolic alkalosis
• High in some forms of metabolic acidosis
Bicarbonate
• Abnormal in acid-base disorders
• See Box 14.18 (p. 365)
Urea
• Increased with a fall in glomerular filtration rate (GFR), reduced
renal perfusion or urine flow rate, and in high protein intake or
catabolic states
• See page 386
Creatinine
• Increased with a fall in GFR, in individuals with high muscle mass,
and with some drugs
• See Fig. 15.2 (p. 387)
*The term urea and electrolytes (U&Es) refers to urea, electrolyes and creatinine.
In some countries this is abbreviated to EUC (electrolytes/urea/creatinine).
taking a venous sample proximal to the site of an intravenous
infusion. It is therefore important for clinical and laboratory staff
to communicate effectively and for clinicians to follow local
recommendations concerning collection and transport of samples
in the appropriate container and with appropriate labelling.
Water and electrolyte homeostasis
Total body water (TBW) is approximately 60% of body weight
in an adult male, although the proportion is somewhat more
for infants and less for women. In a 70 kg man TBW is
therefore about 40 L. Approximately 25 L is located inside
cells (the intracellular fluid or ICF), while the remaining 15 L is
in the extracellular fluid (ECF) compartment (Fig. 14.1). Most of
the ECF (approximately 12 L) is interstitial fluid, which is within
the tissues but outside cells, whereas the remainder (about 3 L)
is in the plasma compartment.
The ion composition between the main body fluid compartments
intracellularly and extracellularly is illustrated in Figure 14.1 . The
dominant positively charged ion (cation) within cells is potassium,
whereas phosphates and negatively charged proteins constitute
the major intracellular negatively charged ions (anions). In the
ECF the dominant cation is sodium, while chloride and, to a
lesser extent, bicarbonate are the most important ECF anions.
An important difference between the intravascular (plasma) and
interstitial compartments of the ECF is that only plasma contains
significant concentrations of protein.
The major force maintaining the difference in cation
concentrations between the ICF and ECF is the sodium-potassium
Extracellular fluid
Fig. 14.1 Normal distribution of body water and electrolytes.
Schematic representation of volume (L = litres) and composition (dominant
ionic species only shown) of the intracellular fluid (ICF) and extracellular
fluid (ECF) in a 70 kg male. The main difference in composition between
the plasma and interstitial fluid (ISF) is the presence of appreciable
concentrations of protein in the plasma but not the ISF. The Na/K
differential is maintained by the Na,K-adenosine triphosphatase (ATPase)
pump.
pump (Na,K-activated adenosine triphosphatase (ATPase)), which
is present in all cell membranes. Maintenance of these gradients
is essential for many cell processes, including the excitability of
conducting tissues such as nerve and muscle. The difference
in protein content between the plasma and the interstitial fluid
compartment is maintained by the impermeability of the capillary
wall to protein. This protein concentration gradient (the colloid
osmotic, or oncotic, pressure of the plasma) contributes to
the balance of forces across the capillary wall that favour fluid
retention within the plasma compartment.
The concentration of sodium in the ECF plays a pivotal role in
determining plasma osmolality and thereby controlling intracellular
volume through changes in water balance between the intracellular
and extracellular space. In contrast, plasma volume is largely
controlled by total body sodium, which determines volume
change. Therefore, disturbances in water homeostasis typically
present with biochemical abnormalities such as hyponatraemia
or hypernatraemia, whereas disturbances in sodium homeostasis
present with hypervolaemia or hypovolaemia as the result of
expansion or contraction of ECF volume, respectively.
Sodium homeostasis
Most of the body’s sodium is located in the ECF, where it is by
far the most abundant cation. Accordingly, total body sodium
is the principal determinant of ECF volume. Sodium intake
varies widely between individuals, ranging between 50 and
250 mmol/24 hrs. The kidneys can compensate for these wide
variations in sodium intake by increasing excretion of sodium
when there is sodium overload, and retaining sodium in the
presence of sodium depletion, to maintain normal ECF volume and
plasma volume.
Functional anatomy and physiology
The functional unit for renal excretion is the nephron (Fig. 14.2).
Blood undergoes ultrafiltration in the glomerulus, generating a
350 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
fluid that is free from cells and protein and which resembles
plasma in its electrolyte composition. This is delivered into
the renal tubules, where reabsorption of water and various
electrolytes occurs. (More detail on the structure and function of
the glomerulus is given in Ch. 15.) The glomerular filtration rate
(GFR) is approximately 1 25 mLVmin (equivalent to 1 80 L724 hrs)
in a normal adult. Over 99% of the filtered fluid is reabsorbed
into the blood in the peritubular capillaries during its passage
through successive segments of the nephron, largely as a result
of tubular reabsorption of sodium. The processes mediating
sodium reabsorption, and the factors that regulate it, are key
to understanding clinical disturbances and pharmacological
interventions of sodium and fluid balance.
The nephron can be divided into at least four different functional
segments in terms of sodium reabsorption (Fig. 14.3).
Proximal renal tubule
About 65% of the filtered sodium load is reabsorbed in the
proximal renal tubule. The cellular mechanisms are complex but
some of the key features are shown in Figure 14.3A. Filtered
sodium in the luminal fluid enters the proximal tubular cell through
transporters in the apical membrane that couple sodium transport
to the entry of glucose, amino acid, phosphate and other organic
molecules. Entry of sodium into the tubular cells at this site is
also linked to secretion of H+ ions, through the sodium-hydrogen
exchanger (NHE-3). Intracellular H+ ions are generated within
tubular cells from the breakdown of carbonic acid, which is
produced from carbon dioxide and water under the influence
of carbonic anhydrase. Large numbers of Na,K-ATPase pumps
Fig. 14.2 The nephron. Letters A-D refer to tubular segments shown in
more detail in Figure 14.3. (aa = afferent arteriole; ea = efferent arteriole;
md = macula densa)
are present on the basolateral membrane of tubular cells, which
transport sodium from the cells into the blood. In addition, a
large component of the transepithelial flux of sodium, water and
other dissolved solutes occurs through gaps between the cells
(the ‘shunt’ pathway). Overall, fluid and electrolyte reabsorption
is almost isotonic in this segment, as water reabsorption is
matched very closely to sodium fluxes, such that the osmolality
of fluid passing into the loop of Henle is very similar to that of
plasma. A component of this water flow also passes through
the cells, via aquaporin-1 (AQP-1) water channels, which are
not sensitive to hormonal regulation.
|j.oop of Henle
The thick ascending limb of the loop of Henle (Fig. 1 4.3B) reabsorbs
a further 25% of the filtered sodium but is impermeable to water,
resulting in dilution of the luminal fluid. The primary driving force
is the Na,K-ATPase on the basolateral cell membrane, but in this
segment sodium enters the cell from the lumen through a specific
carrier molecule, the Na,K,2CI co-transporter (‘triple co-transporter’,
or NKCC2), which allows electroneutral entry of these ions into
the renal tubular cell by balancing transport of anions (Na+/K+)
with cations (CL). Some of the potassium accumulated inside
the cell recirculates across the apical membrane back into the
lumen through a specific potassium channel (ROMK), providing a
continuing supply of potassium to match the high concentrations
of sodium and chloride in the lumen. A small positive transepithelial
potential difference exists in the lumen of this segment relative to
the interstitium, and this serves to drive cations such as sodium,
potassium, calcium and magnesium between the cells, forming
a reabsorptive shunt pathway.
| Early distal renal tubule
About 6% of filtered sodium is reabsorbed in the early distal tubule
(also called distal convoluted tubule) (Fig. 14.30), again driven by
the activity of the basolateral Na,K-ATPase. In this segment, entry
of sodium into the cell from the luminal fluid occurs through a
sodium-chloride co-transport carrier (NCCT). This segment is also
impermeable to water, resulting in further dilution of the luminal
fluid. There is no significant transepithelial flux of potassium in
this segment, but calcium is reabsorbed through the mechanism
shown in Figure 14.30: a basolateral sodium-calcium exchanger
leads to low intracellular concentrations of calcium, promoting
calcium entry from the luminal fluid through a calcium channel.
Late distal renal tubule and collecting ducts
The late distal tubule and cortical collecting duct are anatomically
and functionally continuous (Fig. 14. 3D). Here, sodium entry from
the luminal fluid occurs through the epithelial sodium channel
(ENaC), generating a substantial lumen-negative transepithelial
potential difference. This sodium flux into the tubular cells is
balanced by secretion of potassium and hydrogen ions into
the lumen and by reabsorption of chloride ions. Potassium is
accumulated in the cell by the basolateral Na,K-ATPase, and
passes into the luminal fluid down its electrochemical gradient,
through an apical potassium channel (ROMK). Chloride ions pass
largely between cells. Hydrogen ion secretion is mediated by an
H+-ATPase located on the luminal membrane of the intercalated
cells, which constitute approximately one-third of the epithelial
cells in this segment of the nephron. The distal tubule and
collecting duct have a variable permeability to water, depending
on circulating levels of vasopressin (antidiuretic hormone, ADH).
Sodium homeostasis • 351
Lumen
Blood
(A) Proximal
Transporter
Na reabsorption (%) Water
hormonal control permeability Diuretics
‘Shunt’
©Loop of Henle
Na+
2CI
K+
©
Na+, K+, Ca2+, Mg:
©Early distal
Na+
3Na+-
Na+-^J >NHE-3^C02+H20
<0, J, co,
-2K+
3Na+-
l
ROMK
(65%)
Angiotensin II
Sympathetic nerves
Peritubular forces
(25%)
Highly
permeable
1
Ca2+-
© Late distal
Na+-
©
cr^OT ncct
-4
3Na+ ^ >
x
2K+
3Na+
l
Urine
Principal cell
>ENaC
3Na+-
--K+
ROMK
^Y~2K+
Intercalated cell
HCO-
3 T
2-cr
(6%)
(2-3%)
Aldosterone
Impermeable
Permeability
increased by
vasopressin
SGLT2 inhibitors
Acetazolamide
Loop diuretics
Impermeable Thiazide diuretics
Amiloride
Spironolactone
Fig. 14.3 Principal transport mechanisms in segments of the nephron. The apical membrane of tubular cells is the side facing the lumen and the
basolateral membrane is the side facing the blood. Black circles indicate active transport pumps linked to ATP hydrolysis and white symbols indicate ion
channels and transporter molecules. Details of the proportion of sodium reabsorbed, influence of regulatory factors, water permeability and sites of action
for different classes of diuretics are shown. The SGLT2 inhibitors are primarily used for the treatment of diabetes but have diuretic properties by blocking
SGLT2 in the proximal tubule. At the same site, acetazolamide inhibits carbonic anhydrase (CA), which, by reducing production of hydrogen ions by
proximal tubular cells, inhibits sodium-hydrogen exchange through the NHE-3 transporter. Loop diuretics block the NKCC2 transporter in the loop of Henle,
whereas thiazide diuretics block the NCCT channel in the early distal tubule. Amiloride and spironolactone block the ENaC channel in the late distal tubule
and collecting ducts. See text for further details and abbreviations.
All ion transport processes in this segment are stimulated by
the steroid hormone aldosterone, which can increase sodium
reabsorption in this segment to a maximum of 2-3% of the
filtered sodium load.
Less than 1 % of sodium reabsorption occurs in the medullary
collecting duct, where it is inhibited by atrial natriuretic peptide
(ANP) and brain natriuretic peptide (BNP).
Regulation of sodium transport
The amount of sodium excreted by the kidney is dependent on
the filtered load of sodium (which is largely determined by GFR)
and the control of tubular sodium reabsorption. A number of
interrelated mechanisms serve to maintain whole-body sodium
balance, and hence ECF volume, by matching urinary sodium
excretion to sodium intake (Fig. 14.4), and controlling those
two processes.
Important sensing mechanisms include volume receptors in
the cardiac atria and the intrathoracic veins, as well as pressure
receptors located in the central arterial tree (aortic arch and carotid
sinus) and the afferent arterioles within the kidney. A further
afferent signal is generated within the kidney itself: the enzyme
renin is released from specialised smooth muscle cells in the
walls of the afferent and efferent arterioles, at the point where
they make contact with the early distal tubule (at the macula
densa; see Fig. 14.2) to form the juxtaglomerular apparatus.
Renin release is stimulated by:
• reduced perfusion pressure in the afferent arteriole
• increased sympathetic nerve activity
• decreased sodium chloride concentration in the distal
tubular fluid.
Renin acts on the peptide substrate, angiotensinogen (which
is produced by the liver), to produce angiotensin I, which is
cleaved by angiotensin-converting enzyme (ACE), largely in the
pulmonary capillary bed, to produce angiotensin II (see Fig.
18.18, p. 666). Angiotensin II has multiple actions: it stimulates
proximal tubular sodium reabsorption and release of aldosterone
from the zona glomerulosa of the adrenal cortex, and causes
vasoconstriction of small arterioles. Aldosterone amplifies sodium
352 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
Afferent
Efferent
• Volume receptors
Cardiac atria
Intrathoracic veins
• Pressure receptors
Aortic arch/carotids
Afferent arteriole
• Tubular fluid [NaCI]
Macula densa
T
• Neurohumoral
RAA©
SNS/catecholamines©
ANP©
BNP©
Prostaglandins©
• Haemodynamic
GFR©
Peritubular forces©©
Sensors
ECF Na content
and volume
Effectors
Fig. 14.4 Mechanisms involved in the regulation of sodium
transport. (ANP = atrial natriuretic peptide; BNP = brain natriuretic
peptide; ECF = extracellular fluid; GFR = glomerular filtration rate; RAA =
renin-angiotensin-aldosterone system; SNS = sympathetic nervous
system. © indicates an effect to stimulate Na reabsorption and hence
reduce Na excretion, while © indicates an effect to inhibit Na reabsorption
and hence increase Na excretion)
retention by its action on the cortical collecting duct. The net
effect of activation of the renin-angiotensin system is to raise
blood pressure and cause sodium and water retention, thereby
correcting hypovolaemia.
Changes in GFR alter peritubular hydrostatic pressure and
oncotic pressure in opposite directions, resulting in a change
in sodium reabsorption. In particular, with hypovolaemia, and
a reduction in hydrostatic pressure and an increase in oncotic
pressure, there is an increase in sodium reabsorption.
The sympathetic nervous system also acts to increase sodium
retention, both through haemodynamic mechanisms (afferent
arteriolar vasoconstriction and GFR reduction) and by direct
stimulation of proximal tubular sodium reabsorption. In contrast,
other humoral mediators, such as the natriuretic peptides, which
inhibit sodium reabsorption, contribute to natriuresis during
periods of sodium and volume excess.
Increases in sodium intake cause hypervolaemia, which
increases renal perfusion and GFR and suppresses renin
production through increased delivery of sodium into the macula
densa. This sets in motion a train of events opposite to those that
occur in hypovolaemia, to cause an increase in sodium excretion.
Presenting problems in sodium and
water balance
14.3 Clinical features of hypovolaemia and
hypervolaemia
Hypovolaemia
Hypervolaemia
Symptoms
Thirst
Ankle swelling
Dizziness on standing
Abdominal swelling
Weakness
Breathlessness
Signs
Postural hypotension
Peripheral oedema
Tachycardia
Raised JVP
Dry mouth
Pulmonary crepitations
Reduced skin turgor
Pleural effusion
Reduced urine output
Ascites
Weight loss
Weight gain
Delirium, stupor
Hypertension (sometimes)
(JVP = jugular venous pressure)
1 14.4 Causes of hypovolaemia
Mechanism
Examples
Inadequate sodium
intake
Environmental deprivation, inadequate
therapeutic replacement
Gastrointestinal sodium
loss
Vomiting, diarrhoea, nasogastric suction,
external fistula
Skin sodium loss
Excessive sweating, burns
Renal sodium loss
Diuretic therapy, mineralocorticoid
deficiency, tubulointerstitial disease
Internal sequestration
Bowel obstruction, peritonitis,
pancreatitis, crush injury
Reduced blood volume
Acute blood loss
*A cause of circulatory volume depletion, although total body sodium and water
may be normal or increased.
of sodium-containing fluids or acute blood loss, as summarised
in Box 14.4.
Pathogenesis
Loss of sodium-containing fluid triggers the changes in renal
sodium handling and activation of the renin-angiotensin system
that were described on page 349. Loss of whole blood, as in
acute haemorrhage, is another cause of hypovolaemia, and
elicits the same mechanisms for the conservation of sodium
and water as loss of sodium-containing fluid.
Clinical features
When the balance of sodium intake and excretion is disturbed, any
tendency for plasma sodium concentration to change is usually
corrected by the osmotic mechanisms controlling water balance
(p. 349). As a result, disorders in sodium balance present chiefly
as alterations in the ECF volume, resulting in hypovolaemia or
hypervolaemia, rather than as an alteration in plasma sodium
concentration. Clinical manifestations of altered ECF volume are
illustrated in Box 14.3.
Hypovolaemia
Hypovolaemia is defined as a reduction in circulating blood
volume. The most common causes are loss or sequestration
Hypovolaemia is primarily a clinical diagnosis, based on
characteristic symptoms such as thirst, dizziness and weakness
along with characteristic clinical signs (see Box 14.3) in the
context of a relevant precipitating illness.
Investigations
Serum sodium concentrations are usually normal in hypovolaemia.
The GFR is usually maintained unless the hypovolaemia is very
severe or prolonged, but urinary flow rate is reduced as a
consequence of activation of sodium- and water-retaining
mechanisms in the nephron. Serum creatinine, which reflects
GFR, is usually normal, but serum urea concentration is typically
elevated due to a low urine flow rate, which is accompanied
Sodium homeostasis • 353
by increased tubular reabsorption of urea. Similarly, serum uric
acid may also rise, reflecting increased reabsorption in the
proximal renal tubule. The urine osmolality increases due to
increased reabsorption of sodium and water, while the urine
sodium concentration falls and sodium excretion may fall to less
than 0.1% of the filtered sodium load.
Management
Management of sodium and water depletion has two main
components:
• treat the cause where possible, to stop ongoing salt and
water losses
• replace the salt and water deficits, and provide ongoing
maintenance requirements, usually by intravenous fluid
replacement when depletion is severe.
Intravenous fluid therapy
Intravenous fluid therapy can be used to maintain water, sodium
and potassium intake when the patient is fasting, such as during
an acute illness or post-operatively. If any deficits or continuing
pathological losses are identified, additional fluid and electrolytes
will be required. In prolonged periods of fasting (more than a few
days), attention also needs to be given to providing sufficient
caloric and nutritional intake to prevent excessive catabolism of
body energy stores (p. 704). The daily maintenance requirements
for water and electrolytes in a typical adult are shown in Box
14.5 and the composition of some widely available intravenous
fluids are given in Box 14.6. The choice of fluid and the rate of
administration depend on the clinical circumstances, as assessed
at the bedside and from laboratory data, as described in Box 1 4.7.
The choice of intravenous fluid therapy in the treatment of
significant hypovolaemia relates to the concepts in Figure 14.1 .
If fluid containing neither sodium nor protein is given, it will
distribute in the body fluid compartments in proportion to the
normal distribution of total body water. For example, administration
of 1 L of 5% dextrose contributes little (approximately 3/40 of
the infused volume) towards expansion of the plasma volume,
which makes this fluid unsuitable for restoring the circulation
and perfusion of vital organs. Intravenous infusion of an isotonic
(normal) saline solution, on the other hand, is more effective at
expanding the ECF, although only a small proportion (about 3/15)
of the infused volume actually contributes to plasma volume.
1 14.5 Basic daily water and electrolyte requirements
Requirement per kg
Typical 70 kg adult
Water
35-45 mLVkg
2.45-3.15 L/24 hrs
Sodium
1.5-2 mmol/kg
105-140 mmol/24 hrs
Potassium
1.0-1. 5 mmol/kg
70-105 mmol/24 hrs
You would expect that solutions containing plasma proteins
(colloids) would be better retained within the vascular space and
to be more effective at correcting hypovolaemia than protein-free
fluids (crystalloids). However, recent clinical studies have not
shown any advantage of giving albumin-containing infusions in
the treatment of acute hypovolaemia. Furthermore, synthetic
colloids such as dextrans have been shown to be associated
with an increased risk of acute kidney injury and mortality in
the critically ill. Therefore, crystalloids are the fluid of choice for
resuscitation in acute hypovolaemia. More studies, however,
are required to clarify the most appropriate crystalloid in this
situation, given that normal saline can cause a mild metabolic
acidosis, perhaps related to excessive chloride loading, whereas
‘balanced solutions’, such as Hartmann’s, may cause a mild
hyponatraemia, as its composition is slightly hypotonic.
Hypervolaemia
Hypervolaemia is the result of sodium and water excess and
is rare in patients with normal cardiac and renal function, since
14.7 How to assess fluid and electrolyte balance in
hospitalised patients
Step 1: assess clinical volume status
• Examine patient for signs of hypovolaemia or hypervolaemia (see
Box 14.3)
• Check daily weight change
Step 2: review fluid balance chart
• Check total volumes IN and OUT on previous day (IN-OUT is
positive by -400 mL in normal balance, reflecting insensible fluid
losses of -800 mL and metabolic water generation of -400 mL)
• Check cumulative change in daily fluid balance over previous
3-5 days
• Correlate chart figures with weight change and clinical volume
status to estimate net fluid balance
Step 3: assess ongoing pathological process
• Check losses from gastrointestinal tract and surgical drains
• Estimate increased insensible losses (e.g. in fever) and internal
sequestration (‘third space’)
Step 4: check plasma U&Es (see Box 14.2)
• Check plasma Na as marker of relative water balance
• Check plasma K as a guide to extracellular K balance
• Check HC03“ as a clue to acid-base disorder
• Check urea and creatinine to monitor renal function
Step 5: prescribe appropriate intravenous fluid
replacement therapy
• Replace basic water and electrolytes each day (see Box 14.5)
• Allow for anticipated oral intake and pathological fluid loss
• Adjust amounts of water (if IV, usually given as isotonic 5% dextrose),
sodium and potassium according to plasma electrolyte results
1 14.6 Composition of some isotonic intravenous fluids
Fluid D-glucose
Calories
Na+ (mmol/L)
Cl“ (mmol/L)
Other (mmol/L)
5% dextrose 50 g
200
0
0
0
Normal (0.9%) saline 0
0
154
154
0
Hartmann’s solution 0
0
131
111
K+ 5
Ca2+ 2
Lactate- 29
354 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
the kidney has a large capacity to increase renal excretion of
sodium and water via the homeostatic mechanisms described
on page 349.
Pathogenesis
The most common systemic disorders responsible for
hypervolaemia are outlined in Box 14.8. In cardiac failure, cirrhosis
and nephrotic syndrome, sodium retention occurs in response
to circulatory insufficiency caused by the primary disorder, as
illustrated in Figure 14.5. The pathophysiology is different in
renal failure, when the primary cause of volume expansion is
the profound reduction in GFR impairing sodium and water
excretion, while secondary tubular mechanisms are of lesser
1 14.8 Causes of sodium and water excess
Mechanism
Examples
Impaired renal function
Primary renal disease
Primary hyperaldosteronism
Conn’s syndrome
Secondary hyperaldosteronism
(see Fig. 14.5)
Congestive cardiac failure
Cirrhotic liver disease
Nephrotic syndrome
Protein-losing enteropathy
Malnutrition
Idiopathic/cyclical oedema
Renal artery stenosis*
Conditions in this box other than primary hyperaldosteronism and renal artery
stenosis are typically associated with generalised oedema.
Fig. 14.5 Secondary mechanisms causing sodium excess and
oedema in cardiac failure, cirrhosis and nephrotic syndrome. Primary
renal retention of Na and water may also contribute to oedema formation
when glomerular filtration rate is significantly reduced (see Box 14.8
and p. 395).
importance. In Conn’s syndrome (p. 674), the pathophysiology
also differs, in that increased secretion of aldosterone directly
stimulates sodium reabsorption.
Clinical features
Peripheral oedema is the most common physical sign of
hypervolaemia since the excess fluid leaks out of the capillaries to
expand the interstitial compartment of the ECF. This is particularly
the case in nephrotic syndrome and chronic liver disease, in
which hypoalbuminaemia is a prominent feature. The main
exception is primary hyperaldosteronism (Conn’s syndrome),
which presents with hypertension and often hypokalaemia, but
in which peripheral oedema is not commonly seen.
Investigations
Although hypervolaemia is accompanied by an excess of total
body sodium, serum sodium concentrations are normal due
to the accompanying water retention. Serum concentrations
of potassium are normal except in Conn’s syndrome, where
there is hypokalaemia due to the increased aldosterone
production (p. 674). Creatinine, GFR and urea are usually normal,
unless the underlying cause of hypervolaemia is renal failure.
General investigations may reveal evidence of cardiac, renal or
liver disease.
Management
The management of hypervolaemia involves a number of
components:
• specific treatment directed at the underlying cause, such
as ACE inhibitors in heart failure and glucocorticoids in
minimal change nephropathy
• restriction of dietary sodium (to 50-80 mmol/24 hrs) to
match the diminished excretory capacity
• treatment with diuretics.
Diuretic therapy
Diuretics play a pivotal role in the treatment of hypervolaemia
due to salt and water retention and in hypertension (p. 513).
They act by inhibiting sodium reabsorption at various locations
along the nephron (see Fig. 14.3). Their potency and adverse
effects relate to their mechanism and site of action.
Carbonic anhydrase inhibitors Acetazolamide is a carbonic
anhydrase inhibitor that inhibits intracellular production of H+
ions in the proximal tubule, reducing the fraction of sodium
reabsorption that is exchanged for H+ by the apical membrane
sodium-hydrogen exchanger. It is a weak diuretic but is seldom
used clinically for this purpose, since only a small fraction of
proximal sodium reabsorption uses this mechanism, and
much of the sodium that is not reabsorbed in the proximal
tubule can be reabsorbed by downstream segments
of the nephron.
Sodium-dependent glucose transporter inhibitors Inhibitors of
the sodium-dependent glucose transporter 2 (SGLT2), such as
dapagliflozin and canagliflozin, simultaneously block glucose
and sodium reabsorption in the proximal tubule. They have
mild diuretic properties but are principally used to lower blood
glucose in the treatment of diabetes (p. 745).
Loop diuretics Loop diuretics, such as furosemide, inhibit
sodium reabsorption in the thick ascending limb of the loop of
Henle, by blocking the action of the apical membrane NKCC2
co-transporter. Because this segment reabsorbs a large fraction
Water homeostasis • 355
of the filtered sodium, these drugs are potent diuretics, and are
commonly used in diseases associated with significant oedema.
Loop diuretics cause excretion not only of sodium (and with it
water) but also of potassium. This occurs largely as a result
of delivery of increased amounts of sodium to the late distal
tubule and cortical collecting ducts, where sodium reabsorption
is associated with excretion of potassium, and is amplified if
circulating aldosterone levels are high.
Thiazide diuretics Thiazide diuretics inhibit sodium reabsorption in
the early distal tubule, by blocking the NCCT co-transporter in the
apical membrane. Since this segment reabsorbs a much smaller
fraction of the filtered sodium, these are less potent than loop
diuretics, but are widely used in the treatment of hypertension
and less severe oedema. Like loop diuretics, thiazides increase
excretion of potassium through delivery of increased amounts
of sodium to the late distal tubule and collecting duct. They
are the diuretics that are most likely to be complicated by the
development of hyponatraemia, as outlined on page 357.
Potassium-sparing diuretics Potassium-sparing diuretics act on
the late distal renal tubule and cortical collecting duct segment
to inhibit sodium reabsorption. Since sodium reabsorption and
potassium secretion are linked at this site, the reduced sodium
reabsorption is accompanied by reduced potassium secretion. The
apical sodium channel (see Fig. 14.3) is blocked by amiloride and
triamterene, while spironolactone and eplerenone also act at this
site by blocking binding of aldosterone to the mineralocorticoid
receptor.
Osmotic diuretics These act independently of a specific transport
mechanism. As they are freely filtered at the glomerulus but
not reabsorbed by any part of the tubular system, they retain
fluid osmotically within the tubular lumen and limit the extent
of sodium reabsorption in multiple segments. Mannitol is the
most commonly used osmotic diuretic. It is given by intravenous
infusion to achieve short-term diuresis in conditions such as
cerebral oedema.
Clinical use of diuretics
The following principles should be observed when using diuretics:
• Use the minimum effective dose.
• Use for as short a period of time as necessary.
• Monitor regularly for adverse effects.
The choice of diuretic is determined by the potency required,
the presence of coexistent conditions, and the side-effect profile.
Adverse effects encountered with the most frequently used
classes of diuretic (loop drugs and thiazide drugs) are summarised
in Box 14.9. Volume depletion and electrolyte disorders are the
most common, as predicted from their mechanism of action. The
metabolic side-effects listed are rarely of clinical significance and
may reflect effects on K+ channels that influence insulin secretion
(p. 723). Since most drugs from these classes are sulphonamides,
there is a relatively high incidence of hypersensitivity reactions,
and occasional idiosyncratic side-effects in a variety of organ
systems.
The side-effect profile of the potassium -sparing diuretics differs
in a number of important respects from that of other diuretics.
The disturbances in potassium, magnesium and acid-base
balance are in the opposite direction, so that normal or increased
levels of potassium and magnesium are found in the blood, and
there is a tendency to metabolic acidosis, especially when renal
function is impaired.
i
14.9 Adverse effects of loop-acting and
thiazide diuretics
Renal side-effects
• Hypovolaemia
•
Hyperuricaemia
• Hyponatraemia
•
Hypomagnesaemia
• Hypokalaemia
•
Hypercalciuria (loop)
• Metabolic alkalosis
•
Hypocalciuria (thiazide)
Metabolic side-effects
• Glucose intolerance/
•
Hyperlipidaemia
hyperglycaemia
Miscellaneous side-effects
• Hypersensitivity reactions
•
Acute pancreatitis/cholecystitis
• Erectile dysfunction
(thiazides)
An important feature of the most commonly used diuretic drugs
(furosemide, thiazides and amiloride) is that they act on their
target molecules from the luminal side of the tubular epithelium.
Since they are highly protein-bound in the plasma, very little
reaches the urinary fluid by glomerular filtration, but there are
active transport mechanisms for secreting organic acids and
bases, including these drugs, across the proximal tubular wall
into the lumen, resulting in adequate drug concentrations being
delivered to later tubular segments. This secretory process may
be impaired by certain other drugs, and also by accumulated
organic anions as occurs in chronic kidney disease and chronic
liver failure, leading to resistance to diuretics.
Diuretic resistance is encountered under a variety of
circumstances, including impaired renal function, activation of
sodium-retaining mechanisms, impaired oral bioavailability (such
as in patients with gastrointestinal disease) and decreased renal
blood flow. In these circumstances, short-term intravenous therapy
with a loop-acting agent such as furosemide may be useful.
Combinations of diuretics administered orally may also increase
potency. Either a loop or a thiazide drug can be combined with
a potassium-sparing drug, and all three classes can be used
together for short periods, with carefully supervised clinical and
laboratory monitoring.
Water homeostasis
Daily water intake can vary from about 500 mL to several litres a
day. About 800 mL of water is lost daily through the stool, sweat
and the respiratory tract (insensible losses) and about 400 mL is
generated daily through oxidative metabolism (metabolic water).
The kidneys are chiefly responsible for adjusting water excretion
to balance intake, endogenous production and losses so as to
maintain total body water content and serum osmolality within
the reference range of 280-296 mOsmol/kg.
Functional anatomy and physiology
While regulation of total ECF volume is largely achieved through
renal control of sodium excretion, mechanisms exist to allow for
the excretion of urine that is hypertonic or hypotonic in relation
to plasma to maintain constant plasma osmolality.
These functions are largely achieved by the loop of Henle and the
collecting ducts (see Fig. 1 4.2). The countercurrent configuration
of flow in adjacent limbs of the loop (Fig. 14.6) involves osmotic
movement of water from the descending limbs and reabsorption of
356 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
Fig. 14.6 Mechanisms of renal water handling. (1) Filtrate from the proximal tubule is isosmotic to plasma and cortical interstitial fluid. (2) Water
moves down its osmotic gradient, concentrating the filtrate but not diluting the interstitium, as the vasa recta carries away the water. (3) The filtrate is at its
highest concentration at the bend of the loop and therefore the surrounding medulla is also concentrated. (4) NaCI is pumped out of the filtrate in the thick
ascending limb and early distal tubule, increasing the interstitial fluid osmolality. (5) The filtrate has a concentration of lOOmOsmol/kg as it leaves the early
distal tubule. [A] In the face of water deficit, vasopressin causes water permeability of the collecting ducts, resulting in osmotic reabsorption of water.
[§] In the situation of water overload, vasopressin secretion is suppressed and urine remains dilute.
solute from neighbouring ascending limbs, to set up a gradient of
osmolality from isotonic (like plasma) in the renal cortex to hypertonic
(around 1 200 mOsmol/kg) in the inner part of the medulla. At the
same time, the fluid emerging from the thick ascending limb is
hypotonic compared to plasma because it has been diluted by the
reabsorption of sodium, but not water, from the thick ascending
limb and is further diluted in the early distal tubule. As this dilute
fluid passes from the cortex through the collecting duct system
to the renal pelvis, it traverses the medullary interstitial gradient
of osmolality set up by the operation of the loop of Henle, and
water is able to be reabsorbed.
Further changes in the urine osmolality on passage through the
collecting ducts depend on the circulating level of vasopressin,
which is released by the posterior pituitary gland under conditions
of increased plasma osmolality or hypovolaemia (p. 688).
• When water intake is high and plasma osmolality is normal
or low-normal (Fig. 14.6B), vasopressin levels are
suppressed and the collecting ducts remain impermeable
to water. The luminal fluid osmolality remains low, resulting
in the excretion of a dilute urine (minimum osmolality
approximately 50 mOsmol/kg in a healthy young person).
• When water intake is restricted and plasma osmolality is
high (Fig. 14.6A), or in the presence of plasma volume
depletion, vasopressin levels rise. This causes water
permeability of the collecting ducts to increase through
binding of vasopressin to the V2 receptor, which enhances
collecting duct water permeability through the insertion of
AQP-2 channels into the luminal cell membrane. This
results in osmotic reabsorption of water along the entire
length of the collecting duct, with maximum urine
osmolality approaching that in the medullary tip (up to
1200 mOsmol/kg).
Parallel to these changes in vasopressin release are changes
in water-seeking behaviour triggered by the sensation of thirst,
which also becomes activated as plasma osmolality rises.
In summary, for adequate dilution of the urine there must be:
• adequate solute delivery to the loop of Henle and early
distal tubule
• normal function of the loop of Henle and early distal tubule
• absence of vasopressin in the circulation.
If any of these processes is faulty, water retention and
hyponatraemia may result.
Conversely, to achieve concentration of the urine there must be:
• adequate solute delivery to the loop of Henle
• normal function of the loop of Henle
• vasopressin release into the circulation
• vasopressin action on the collecting ducts.
Failure of any of these steps may result in inappropriate water
loss and hypernatraemia.
Presenting problems in regulation
of osmolality
Changes in plasma osmolality are largely determined by changes in
serum sodium concentration and its associated anions. Changes
in sodium concentration usually occur because of disturbances
in water balance either because there is a relative excess of
body water compared to total body sodium (hyponatraemia) or
Water homeostasis • 357
a relative lack of body water compared to total body sodium
(hypernatraemia). Abnormalities of water balance can result from
disturbances in urinary concentration or dilution.
If extracellular osmolality falls abruptly, water flows rapidly
across cell membranes, causing cell swelling, whereas cell
shrinkage occurs when osmolality rises. Cerebral function is
particularly sensitive to such volume changes, particularly brain
swelling during hypo-osmolality, which can lead to an increase
in intracerebral pressure and reduced cerebral perfusion.
Hyponatraemia
Hyponatraemia is defined as a serum Na < 1 35 mmol/L. It is a
common electrolyte abnormality with many potential underlying
causes, as summarised in Box 14.10.
Pathophysiology
In all cases, hyponatraemia is caused by greater retention of water
relative to sodium. The causes are best categorised according
to associated changes in the ECF volume (Box 14.10).
Hyponatraemia with hypovolaemia
In this situation there is depletion of sodium and water but the
sodium deficit exceeds the water deficit, causing hypovolaemia
and hyponatraemia (see Box 14.3). The cause of sodium loss is
usually apparent and common examples are shown in Box 14.10.
Hyponatraemia with euvolaemia
In this situation there are no major disturbances of body sodium
content and the patient is clinically euvolaemic. Excess body
water may be the result of abnormally high intake, either orally
(primary polydipsia) or as a result of medically infused fluids (as
intravenous dextrose solutions, or by absorption of sodium-free
bladder irrigation fluid after prostatectomy).
Water retention also occurs in the syndrome of inappropriate
secretion of antidiuretic hormone, or vasopressin (SIADH). In
this condition, an endogenous source of vasopressin (either
cerebral or tumour-derived) promotes water retention by the
kidney in the absence of an appropriate physiological stimulus
(Box 14.11). The clinical diagnosis requires the patient to be
1 14.10 Causes of hyponatraemia
Volume status
Examples
Hypovolaemic
Renal sodium losses:
Diuretic therapy (especially thiazides)
Adrenocortical failure
Gastrointestinal sodium losses:
Vomiting
Diarrhoea
Skin sodium losses:
Burns
Euvolaemic
Primary polydipsia
Excessive electrolyte-free water infusion
SIADH
Hypothyroidism
Hypervolaemic
Congestive cardiac failure
Cirrhosis
Nephrotic syndrome
Chronic kidney disease (during free water intake)
(SIADH = syndrome of inappropriate antidiuretic hormone (vasopressin) secretion;
see Box 14.11).
euvolaemic, with no evidence of cardiac, renal or hepatic disease
potentially associated with hyponatraemia. Other non-osmotic
stimuli that cause release of vasopressin (pain, stress, nausea)
should also be excluded. Supportive laboratory findings are
shown in Box 14.1 1 .
Hyponatraemia with hypervolaemia
In this situation, excess water retention is associated with sodium
retention and volume expansion, as in heart failure, liver disease
or kidney disease.
Clinical features
Hyponatraemia is often asymptomatic but can also be associated
with profound disturbances of cerebral function, manifesting as
anorexia, nausea, vomiting, delirium, lethargy, seizures and coma.
The likelihood of symptoms occurring is related to the speed
at which hyponatraemia develops rather than the severity of
hyponatraemia. This is because water rapidly flows into cerebral
cells when plasma osmolality falls acutely, causing them to become
swollen and ischaemic. However, when hyponatraemia develops
gradually, cerebral neurons have time to respond by reducing
intracellular osmolality, through excreting potassium and reducing
synthesis of intracellular organic osmolytes (Fig. 14.7). The
osmotic gradient favouring water movement into the cells is thus
reduced and symptoms are avoided. This process takes about
24-48 hours and hyponatraemia is therefore classified as acute
(<48 hours) and chronic (> 48 hours). Hyponatraemia can also be
defined as mild (130-135 mmol/L), moderate (125-129 mmol/L)
or severe (<124 mmol/L), based on biochemical findings or on
the degree of severity of symptoms (Box 14.12).
Investigations
An algorithm for the clinical assessment of patients with
hyponatraemia is shown in Figure 14.8. Artefactual causes of
hyponatraemia should be considered in all cases. These include
severe hyperlipidaemia or hyperproteinaemia, when the aqueous
fraction of the serum specimen is reduced because of the
volume occupied by the macromolecules (although this artefact
is dependent on the assay technology). Transient hyponatraemia
14.11 Causes and diagnosis of syndrome of
inappropriate antidiuretic hormone secretion
Causes
• Tumours
• Central nervous system disorders: stroke, trauma, infection,
psychosis, porphyria
• Pulmonary disorders: pneumonia, tuberculosis, obstructive lung
disease
• Drugs: anticonvulsants, psychotropics, antidepressants, cytotoxics,
oral hypoglycaemic agents, opiates
• Idiopathic
Diagnosis
• Low plasma sodium concentration (typically <130 mmol/L)
• Low plasma osmolality (<275 mOsmol/kg)
• Urine osmolality not minimally low (typically >100 mOsmol/kg)
• Urine sodium concentration not minimally low (>30 mmol/L)
• Low-normal plasma urea, creatinine, uric acid
• Clinical euvolaemia
• Absence of adrenal, thyroid, pituitary or renal insufficiency
• No recent use of diuretics
• Exclusion of other causes of hyponatraemia (see Box 14.10)
• Appropriate clinical context (above)
358 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
Normal Plasma
cerebral osmo
cell ' 290
Plasma
osmo falls
gradually
290^220
Slowly /
developing
hyponatraemia 1 Qsmo
Loss of cellular
osmolytes
Plasma
osmo falls
abruptly
290^220
0\Plasma|
osmo
\Osmo / 220 \ Osmo
,220 / \ 220
No change in
cerebral cell size
Cerebral swelling
— > cerebral oedema
Fig. 14.7 Hyponatraemia and the brain. Numbers represent osmolality
(osmo) in mOsmol/kg.
| 1 4.1 2 Symptoms and severity of hyponatraemia
Severity
Serum sodium
Symptoms
Mild
130-135 mmol/L
None
Moderate
125-129 mmol/L
Nausea
Delirium
Headache
Severe
<124 mmol/L
Vomiting
Somnolence
Seizures
Coma
Cardiorespiratory arrest
may also occur due to osmotic shifts of water out of cells during
hyperosmolar states caused by acute hyperglycaemia or by
mannitol infusion, but in these cases plasma osmolality is normal.
When these conditions have been excluded, serum and
urine electrolytes and osmolality (Fig. 14.8) are usually the only
tests required to clarify the underlying cause. Hypovolaemic
hyponatraemia is characterised by a low urinary sodium
concentration (<30 mmol/L) when there are extrarenal causes of
sodium loss and high urinary sodium concentration (>30 mmol/L)
in patients with excessive renal sodium loss.
Measurement of vasopressin is not generally helpful in
distinguishing between different categories of hyponatraemia.
This is because concentrations of vasopressin are raised both in
hypovolaemic states and in most chronic hypervolaemic states, as
the impaired circulation in those disorders activates vasopressin
release through non-osmotic mechanisms. Indeed, patients with
these disorders may have higher circulating vasopressin (ADH)
levels than patients with SIADH. The only disorders listed in Box
14.10 in which vasopressin is suppressed are primary polydipsia
and iatrogenic water intoxication, where the hypo-osmolar state
inhibits vasopressin release from the pituitary.
Management
The treatment of hyponatraemia is critically dependent on its rate
of development, severity, presence of symptoms and underlying
cause. If hyponatraemia has developed rapidly (<48 hours) and
there are signs of cerebral oedema, such as obtundation or
convulsions, sodium levels should be restored rapidly to normal
by infusion of hypertonic (3%) sodium chloride. A common
approach is to give an initial bolus of 150 mL over 20 minutes,
which may be repeated once or twice over the initial hours of
observation, depending on the neurological response and rise
in plasma sodium.
Rapid correction of hyponatraemia that has developed
more slowly (> 48 hours) can be hazardous, since brain cells
adapt to slowly developing hypo-osmolality by reducing the
intracellular osmolality, thus maintaining normal cell volume
(see Fig. 14.7). Under these conditions, an abrupt increase in
extracellular osmolality can lead to water shifting out of neurons,
abruptly reducing their volume and causing them to detach from
their myelin sheaths. The resulting ‘myelinolysis’ can produce
permanent structural and functional damage to mid-brain
structures, and is generally fatal. The rate of correction of the
plasma Na concentration in chronic asymptomatic hyponatraemia
should not exceed 1 0 mmol/Ly24 hrs, and an even slower rate
is generally safer.
The underlying cause should also be treated. For hypovolaemic
patients, this involves controlling the source of sodium loss, and
administering intravenous saline if clinically warranted. Patients with
euvolaemic hyponatraemia generally respond to fluid restriction
in the range of 600-1000 mL/24 hrs, accompanied where
possible by withdrawal of the precipitating stimulus (such as
drugs causing SIADH). In patients with persistent hyponatraemia
due to prolonged SIADH, oral urea therapy (30-45 g/day) can be
used, which provides a solute load to promote water excretion.
Oral vasopressin receptor antagonists such as tolvaptan may
also be used to block the vasopressin-mediated component
of water retention in a range of hyponatraemic conditions, but
concerns exist with regard to the risk of overly rapid correction
of hyponatraemia with these agents. Hypervolaemic patients
with hyponatraemia need treatment of the underlying condition,
accompanied by cautious use of diuretics in conjunction
with strict fluid restriction. Potassium-sparing diuretics may
be particularly useful in this context when there is significant
secondary hyperaldosteronism.
Hypernatraemia
Hypernatraemia is defined as existing when the serum Na is
>145 mmol/L. The causes are summarised in Box 14.13, grouped
according to any associated disturbance in total body sodium
content.
Pathophysiology
Hypernatraemia occurs due to inadequate concentration of the
urine in the face of restricted water intake. This can arise because
Water homeostasis • 359
Low serum sodium (<135mmol/L)
Check urea, glucose, lipids,
immunoglobins
J
Normal
Abnormal
*
Hypotonic hyponatraemia
(osmolality <275mOsmol/kg)
T
Check urine osmolality
Consider non-hypotonic
hyponatraemia
Investigate and treat
underlying disorder
f -
<100mOsmol/kg
Excessive water intake
i
>100mOsmol/kg
i
Measure urine sodium
Primary polydipsia
Beer potomania
Low solute intake
I -
< 30mmol/L
Low intravascular
volume
- 1
>30mmol/L
i
Evidence of kidney
disease?
Yes
Hyponatraemia
may be secondary
to kidney disease
r
of V
>leti(
J_
depletion?
Vomiting
Diarrhoea
Pancreatitis
— 1
e Signs of fluid
1
No
overload?
1
▼
Cirrhosis
Check for
evidence of
Heart failure
Nephrotic
syndrome
hypovolaemia
I -
Signs of hypovolaemia
Diuretics
Adrenal insufficiency
1
Normal ECF volume
SIADH
Hypothyroidism
Fig. 14.8 Algorithm for the diagnosis of hyponatraemia. (ECF = extracellular fluid; SIADH = syndrome of inappropriate antidiuretic hormone
(vasopressin) secretion)
i
14.13 Causes of hypernatraemia
Volume status
Examples
Hypovolaemic
Renal sodium losses:
Diuretic therapy (especially osmotic diuretic, or
loop diuretic during water restriction)
Glycosuria (hyperglycaemic hyperosmolar
state, p. 738)
Gastrointestinal sodium losses:
Colonic diarrhoea
Skin sodium losses:
Excessive sweating
Euvolaemic
Diabetes insipidus (central or nephrogenic) (p. 687)
Hypervolaemic
Enteral or parenteral feeding
Intravenous or oral salt administration
Chronic kidney disease (during water restriction)
of failure to generate an adequate medullary concentration
gradient in the kidney due to low GFR or loop diuretic therapy,
but more commonly is caused by failure of the vasopressin
system. This can occur because of pituitary damage (cranial
diabetes insipidus, p. 687) or because the collecting duct cells
are unable to respond to circulating vasopressin concentrations
in the face of restricted water intake (nephrogenic diabetes
insipidus). Whatever the underlying cause, sustained or severe
hypernatraemia generally reflects an impaired thirst mechanism
or responsiveness to thirst.
Clinical features
Patients with hypernatraemia generally have reduced cerebral
function, either as a primary problem or as a consequence
of the hypernatraemia itself, which results in dehydration of
neurons and brain shrinkage. In the presence of an intact thirst
mechanism and preserved capacity to obtain and ingest water,
360 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
• Decline in GFR: older patients are predisposed to both
hyponatraemia and hypernatraemia, mainly because, as glomerular
filtration rate declines with age, the capacity of the kidney to dilute
or concentrate the urine is impaired.
• Hyponatraemia: occurs when free water intake continues in the
presence of a low dietary salt intake and/or diuretic drugs
(particularly thiazides).
• Vasopressin release: water retention is aggravated by any
condition that stimulates vasopressin release, especially heart
failure. Moreover, the vasopressin response to non-osmotic stimuli
may be brisker in older subjects. Appropriate water restriction may
be a key part of management.
• Hypernatraemia: occurs when water intake is inadequate, due to
physical restrictions preventing access to drinks and/or blunted
thirst. Both are frequently present in patients with advanced
dementia or following a severe stroke.
• Dietary salt: hypernatraemia is aggravated if dietary supplements
or medications with a high sodium content (especially effervescent
preparations) are administered. Appropriate prescription of fluids is
a key part of management.
14.14 Hyponatraemia and hypernatraemia in old age
Tk+ intake
I
TPIasma [K+;
-►^Plasma [K+l Negative
^ L J feedback
Adrenal
cortex
(Zona glomerulosa)
_Tk+
excretion
TAIdosterone
j
Kidney
Fig. 14.9 Feedback control of plasma potassium concentration.
hypernatraemia may not progress very far. If adequate water
is not obtained, dizziness, delirium, weakness and, ultimately,
coma and death can result.
Management
Treatment of hypernatraemia depends on both the rate of
development and the underlying cause. If there is reason to think
that the condition has developed rapidly, neuronal shrinkage may
be acute and relatively rapid correction may be attempted. This
can be achieved by infusing an appropriate volume of intravenous
fluid (isotonic 5% dextrose or hypotonic 0.45% saline) at an
initial rate of 50-70 mL/hr. In older, institutionalised patients,
however, it is more likely that the disorder has developed slowly,
and extreme caution should be exercised in lowering plasma
sodium to avoid the risk of cerebral oedema. Where possible,
the underlying cause should also be addressed (Box 14.13).
Elderly patients are predisposed, in different circumstances,
to both hyponatraemia and hypernatraemia, and a high index
of suspicion of these electrolyte disturbances is appropriate
in elderly patients with recent alterations in behaviour
(Box 14.14).
Potassium homeostasis
Potassium is the major intracellular cation (see Fig. 14.1), and
the steep concentration gradient for potassium across the cell
membrane of excitable cells plays an important part in generating
the resting membrane potential and allowing the propagation
of the action potential that is crucial to normal functioning of
nerve, muscle and cardiac tissues. Control of body potassium
balance is described below.
Functional anatomy and physiology
The kidneys normally excrete some 90% of the daily intake of
potassium, typically 80-100 mmol/24 hrs. Potassium is freely
filtered at the glomerulus; around 65% is reabsorbed in the
proximal tubule and a further 25% in the thick ascending limb
of the loop of Henle. Little potassium is transported in the early
distal tubule but a significant secretory flux of potassium into
the urine occurs in the late distal tubule and cortical collecting
duct to ensure that the amount removed from the blood is
proportional to the ingested load.
The mechanism for potassium secretion in the distal parts of
the nephron is shown in Figure 14. 3D. Movement of potassium
from blood to lumen is dependent on active uptake across the
basal cell membrane by the Na,K-ATPase, followed by diffusion
of potassium through the ROMK channel into the tubular fluid.
The electrochemical gradient for potassium movement into the
lumen is contributed to both by the high intracellular potassium
concentration and by the negative luminal potential difference
relative to the blood.
A number of factors influence the rate of potassium secretion.
Luminal influences include the rate of sodium delivery and fluid
flow through the late distal tubule and cortical collecting ducts.
This is a major factor responsible for the increased potassium
loss that accompanies diuretic treatment. Agents interfering
with the generation of the negative luminal potential also impair
potassium secretion, and this is the basis of reduced potassium
secretion associated with potassium-sparing diuretics such as
amiloride. Factors acting on the blood side of this tubular segment
include plasma potassium and pH, such that hyperkalaemia and
alkalosis both enhance potassium secretion directly. However, the
most important factor in the acute and chronic adjustment of
potassium secretion to match metabolic potassium load is
aldosterone.
As shown in Figure 1 4.9, a negative feedback relationship exists
between the plasma potassium concentration and aldosterone.
In addition to its regulation by the renin-angiotensin system (see
Fig. 18.18, p. 666), aldosterone is released from the adrenal
cortex in direct response to an elevated plasma potassium.
Aldosterone then acts on the kidney to enhance potassium
secretion, hydrogen secretion and sodium reabsorption, in the
late distal tubule and cortical collecting ducts. The resulting
increased excretion of potassium maintains plasma potassium
within a narrow range (3. 6-5.0 mmol/L). Factors that reduce
angiotensin II levels may indirectly affect potassium balance
by blunting the rise in aldosterone that would otherwise be
provoked by hyperkalaemia. This accounts for the increased
risk of hyperkalaemia during therapy with ACE inhibitors and
related drugs.
Potassium homeostasis • 361
Presenting problems in
potassium homeostasis
Changes in the distribution of potassium between the ICF and
ECF compartments can alter plasma potassium concentration,
without any overall change in total body potassium content.
Potassium is driven into the cells by extracellular alkalosis and
by a number of hormones, including insulin, catecholamines
(through the p2-receptor) and aldosterone. Any of these factors
can produce hypokalaemia, whereas extracellular acidosis, lack
of insulin, and insufficiency or blockade of catecholamines or
aldosterone can cause hyperkalaemia due to efflux of potassium
from the intracellular compartment.
Hypokalaemia
Hypokalaemia is a common electrolyte disturbance and is defined
as existing when serum K+ falls below 3.5 mmol/L. The main
causes of hypokalaemia are shown in Box 14.15.
i
14.15 Causes of hypokalaemia
Cause
Other features and comment
Reduced intake
Urine K+ >20-30 mmol/24 hrs
Dietary deficiency
Potassium -free intravenous fluids
Redistribution into cells
Alkalosis 1
Insulin
Catecholamines
■ Caused by flux of K+ into cells
(3-adrenergic agonists
Hypokalaemic periodic paralysis .
Increased urinary excretion
Urine K+ >20-30 mmol/24 hrs
Activation of mineralocorticoid
receptor:
Conn’s syndrome i
Cushing’s syndrome
i Associated with hypertension
Glucocorticoid excess
1 and alkalosis
Carbenoxelone/liquorice J
Genetic disorders:
Liddle’s syndrome j
Associated with hypertension and
Bartter’s syndrome
( alkalosis
Gitelman’s syndrome J
Associated with hypertension,
Renal tubular acidosis
alkalosis and hypomagnesaemia
Type 1 (distal)
Inherited and acquired forms;
Type 2 (proximal)
associated with high serum
Acetazolamide
chloride. Type 2 associated with
glycosuria, aminoaciduria and
phosphaturia
Associated with acidosis
Diuresis:
Loop diuretics
Thiazides
Recovery from acute tubular
Increased sodium delivery to
necrosis
’ distal tubule
Recovery from renal obstruction J
Increased gastrointestinal loss
Urine K+ <20-30 mmol/L
Upper gastrointestinal tract:
Vomiting ]
Loss of gastric acid
\ Associated with metabolic
Nasogastric aspiration J
alkalosis
Lower gastrointestinal tract:
Diarrhoea 1
Laxative abuse
Associated with metabolic
Villous adenoma
acidosis
Bowel obstruction/fistula
Ureterosigmoidostomy J
Pathophysiology
Hypokalaemia is generally indicative of abnormal potassium loss
from the body, through either the kidney or the gastrointestinal
tract. Renal causes of hypokalaemia can be divided into those with
and those without hypertension. Hypokalaemia in the presence
of hypertension may be due to increased aldosterone secretion
in Conn’s syndrome (p. 674) or a genetic defect affecting sodium
channels in the distal nephron (Liddle’s syndrome). Excessive
intake of liquorice or treatment with carbenoxolone may result in
a similar clinical picture, due to inhibition of the renal 1 1 (3HSD2
enzyme, which inactivates cortisol in peripheral tissues.
If blood pressure is normal or low, hypokalaemia can be
classified according to the associated change in acid-base
balance. Inherited defects in tubular transport should be
suspected when hypokalaemia occurs in association with
alkalosis, provided that diuretic use has been excluded. One
such disease is Bartter’s syndrome, in which sodium reabsorption
in the thick ascending limb of Henle is defective, usually due
to a loss-of-function mutation of the NKCC2 transporter. The
clinical and biochemical features are similar to those in chronic
treatment with furosemide. In Gitelman’s syndrome there is a
loss-of-function mutation affecting the NCCT transporter in the
early distal tubule. The clinical and biochemical features are similar
to chronic thiazide treatment. Note that while both Bartter’s
and Gitelman’s syndromes are characterised by hypokalaemia
and hypomagnesaemia, urinary calcium excretion is increased
in Bartter’s syndrome but decreased in Gitelman’s syndrome,
analogous to the effects of the loop and thiazide diuretics,
respectively, on calcium transport (see Box 14.9).
If hypokalaemia occurs in the presence of a normal blood
pressure and metabolic acidosis, renal tubular acidosis (proximal
or ‘classical’ distal) should be suspected (p. 364).
When hypokalaemia is due to potassium wasting through
the gastrointestinal tract, the cause is usually obvious clinically.
In some cases, when there is occult induction of vomiting, the
hypokalaemia is characteristically associated with metabolic
alkalosis, due to loss of gastric acid. If, however, potassium
loss has occurred through the surreptitious use of aperients, the
hypokalaemia is generally associated with metabolic acidosis.
In both cases, urinary potassium excretion is low unless there
is significant extracellular volume depletion, which can raise
urinary potassium levels by stimulating aldosterone production.
Hypokalaemia can also be caused by redistribution of potassium
into cells as the result of insulin, p-adrenoceptor agonists and
alkalosis, or as the result of K+ flux into muscle in hypokalaemic
periodic paralysis, which is associated with mutations in several
genes that regulate transmembrane ion flow into muscle cells.
Finally, reduced dietary intake of potassium can contribute
to hypokalaemia but is seldom the only cause, except in extreme
cases.
Clinical features
Patients with mild hypokalaemia (plasma K+ 3. 0-3. 3 mmol/L) are
generally asymptomatic, but more profound reductions in plasma
potassium often lead to muscular weakness and associated
tiredness. Ventricular ectopic beats or more serious arrhythmias
may occur and the arrhythmogenic effects of digoxin may be
potentiated. Typical electrocardiogram (ECG) changes occur,
affecting the T wave in particular (p. 347). Functional bowel
obstruction may occur due to paralytic ileus. Long-standing
hypokalaemia may cause renal tubular damage (hypokalaemic
nephropathy) and can interfere with the tubular response to
vasopressin (acquired nephrogenic diabetes insipidus), resulting
in polyuria and polydipsia.
362 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
Investigations
Measurement of plasma electrolytes, bicarbonate, urine potassium
and sometimes of plasma calcium and magnesium is usually
sufficient to establish the diagnosis. If the diagnosis remains
unclear, plasma renin should be measured. Levels are low in
patients with primary hyperaldosteronism (p. 674) and other
forms of mineralocorticoid excess, but raised in other causes
of hypokalaemia. When there is no obvious clinical clue to
which pathway is involved, measurement of urinary potassium
may be helpful; if the kidney is the route of potassium loss,
the urine potassium is high (> 30 mmol/24 hrs), whereas if
potassium is being lost through the gastrointestinal tract, the
kidney retains potassium, resulting in a lower urinary potassium
(generally <20 mmol/24 hrs). It should be noted, however, that if
gastrointestinal fluid loss is also associated with hypovolaemia,
activation of the renin-angiotensin-aldosterone system may
occur, causing increased loss of potassium in the urine.
The cause of hypokalaemia may remain unclear despite the
above investigations when urinary potassium measurements are
inconclusive and the history is incomplete or unreliable. Many
such cases are associated with metabolic alkalosis, and in this
setting the measurement of urine chloride concentration can be
helpful. A low urine chloride (<30 mmol/L) is characteristic of
vomiting (spontaneous or self-induced, in which chloride is lost
in HCI in the vomit), while a urine chloride >40 mmol/L suggests
diuretic therapy (acute phase) or a tubular disorder such as
Bartter’s or Gitelman’s syndrome. Differentiation between occult
diuretic use and primary tubular disorders can be achieved by
performing a screen of urine for diuretic drugs.
Management
Treatment of hypokalaemia involves first determining the cause
and correcting this where possible. If the problem is mainly one
of redistribution of potassium into cells, reversal of the process
responsible may be sufficient to restore plasma potassium without
providing supplements. In most cases, however, some form of
potassium replacement will be required. This can generally be
achieved with slow-release potassium chloride tablets, but in
more acute circumstances intravenous potassium chloride may
be necessary. The rate of administration depends on the severity
of hypokalaemia and the presence of cardiac or neuromuscular
complications, but should generally not exceed 10 mmol of
potassium per hour. In patients with severe, life-threatening
hypokalaemia, the concentration of potassium in the infused
fluid may be increased to 40 mmol/L if a peripheral vein is used,
but higher concentrations must be infused into a large ‘central’
vein with continuous cardiac monitoring.
In the less common situation where hypokalaemia occurs in the
presence of systemic acidosis, alkaline salts of potassium, such
as potassium bicarbonate, can be given by mouth. If magnesium
depletion is also present, replacement of magnesium may also
be required, since low cell magnesium can promote tubular
potassium secretion, causing ongoing urinary losses. In some
circumstances, potassium-sparing diuretics, such as amiloride,
can assist in the correction of hypokalaemia, hypomagnesaemia
and metabolic alkalosis, especially when renal loss of potassium
is the underlying cause.
Hyperkalaemia
Hyperkalaemia is a common electrolyte disorder, which is
defined as existing when serum K+ is >5 mmol/L. The causes
of hyperkalaemia are summarised in Box 14.16.
1 14.16 Causes of hyperkalaemia
Cause
Other features and comment
Artefactual
Haemolysis during venepuncture
Haemolysis in vitro
Thrombocytosis/leucocytosis
Release of intracellular K+ during
sample collection, transit or
clotting
Increased intake
Dietary potassium
Potassium-containing intravenous
fluids
Redistribution from cells
Acidosis
Insulin deficiency
Severe hyperglycaemia
p-adrenergic blockers
(p-blockers)
Hyperkalaemic periodic paralysis
Rhabdomyolysis
Severe haemolysis
Tumour lysis syndrome
Caused by flux of intracellular K+
into plasma
Reduced urinary excretion
Reduced glomerular filtration:
Acute kidney injury
Chronic kidney disease J
Plasma creatinine typically
i >500 jimol/L (5.67 mg/dL)
Reduced mineralocorticoid
receptor activation:
Addison’s disease
Congenital adrenal hyperplasia
Isolated aldosterone deficiency
Angiotensin-converting ]
enzyme (ACE) inhibitors
Angiotensin-receptor blockers J
(ARBs)
Calcineurin inhibitors j
Spironolactone
Eplerenone J
Heparin
( ACE inhibitors and ARBs reduce
aldosterone levels
, All block the mineralocorticoid
[ receptor
Heparin inhibits aldosterone
production
Inhibitors of renin production:
Non-steroidal anti¬
inflammatory drugs (NSAIDs)
p-blockers
Tubulointerstitial disease:
Interstitial nephritis
Diabetic nephropathy
Obstructive uropathy
Other:
Amiloride
Gordon’s syndrome
Blocks K+ exchange in distal
tubule
Direct effect on K+ transport in
renal tubule
Pathophysiology
It is important to remember that hyperkalaemia can be artefactual
due to haemolysis of blood specimens during collection or in
vitro, or due to release of potassium from platelets in patients
with thrombocytosis.
True hyperkalaemia, however, can occur either because
of redistribution of potassium between the ICF and ECF, or
because potassium intake exceeds excretion. Redistribution
Acid-base homeostasis • 363
of potassium from the ICF to the ECF may take place in the
presence of systemic acidosis, or when the circulating levels of
insulin, catecholamines and aldosterone are reduced, or when
the effects of these hormones are blocked (p. 361).
High dietary potassium intake may contribute to hyperkalaemia,
but is seldom the only explanation unless renal excretion
mechanisms are impaired. The mechanism of hyperkalaemia
in acute kidney injury and chronic kidney disease is impaired
excretion of potassium into the urine as the result of a reduced
GFR. In addition, acute kidney injury can be associated with
severe hyperkalaemia when there is an increased potassium load,
such as in rhabdomyolysis or in sepsis, particularly when acidosis
is present. In chronic kidney disease, adaptation to moderately
elevated plasma potassium levels commonly occurs. However,
acute rises in potassium triggered by excessive dietary intake,
hypovolaemia or drugs (see below) may occur and destabilise
the situation.
Hyperkalaemia can also develop when tubular potassium
secretory processes are impaired, even if the GFR is normal.
This can arise in association with low levels of aldosterone, as is
found in Addison’s disease, hyporeninaemic hypoaldosteronism or
inherited disorders such as congenital isolated hypoaldosteronism,
in which there is a defect in aldosterone biosynthesis, and
pseudohypoaldosteronism type 2 (Gordon’s syndrome), caused
by mutations in the WNK2 and WNK4 genes, which causes
decreased potassium secretion in the renal tubules.
Drug-induced causes include ACE inhibitors, angiotensin-
receptor blockers (ARBs), non-steroidal anti-inflammatory drugs
(NSAIDs) and (3-adrenoceptor antagonists ((3-blockers).
In another group of conditions, tubular potassium secretion
is impaired as the result of aldosterone resistance. This can
occur in a variety of diseases in which there is inflammation of
the tubulointerstitium, such as systemic lupus erythematosus;
following renal transplantation; during treatment with potassium¬
sparing diuretics; and in a number of inherited disorders of
tubular transport.
In aldosterone deficiency or aldosterone resistance,
hyperkalaemia may be associated with acid retention, giving
rise to the pattern of hyperkalaemic distal (‘type 4’) renal tubular
acidosis (p. 364).
Clinical features
Mild to moderate hyperkalaemia (< 6.5 mmol/L) is usually
asymptomatic. More severe hyperkalaemia can present with
progressive muscular weakness, but sometimes there are no
symptoms until cardiac arrest occurs. The typical ECG changes |
are shown on page 347. Peaking of the T wave is an early ECG
sign, but widening of the QRS complex presages a dangerous
cardiac arrhythmia. However, these characteristic ECG findings
are not always present, even in severe hyperkalaemia.
Investigations
Measurement of electrolytes, creatinine and bicarbonate,
when combined with clinical assessment, usually provides
the explanation for hyperkalaemia. In aldosterone deficiency,
plasma sodium concentration is characteristically low, although
this can occur with many causes of hyperkalaemia. Addison’s
disease should be excluded unless there is an obvious alternative
diagnosis, as described on page 671 .
Management
Treatment of hyperkalaemia depends on its severity and the
rate of development, but opinions vary as to what level of
14.17 Treatment of severe hyperkalaemia
Objective Therapy
Stabilise cell membrane
IV calcium gluconate (10 mL of 10%
potential
solution)
Shift K+ into cells
Inhaled (32-adrenoceptor agonist
IV glucose (50 mL of 50% solution) and
insulin (5 IU Actrapid)
IV sodium bicarbonate2
Remove K+ from body
IV furosemide and normal saline3
Ion-exchange resin (e.g. Resonium)
orally or rectally
Dialysis
If severe hyperkalaemia (K+ typically >6.5 mmol/L). 2lf acidosis present.
3lf adequate residual renal function.
serum potassium constitutes severe hyperkalaemia and requires
urgent treatment. Patients who have potassium concentrations
<6.5 mmol/L in the absence of neuromuscular symptoms or ECG
changes can be treated with a reduction of potassium intake
and correction of predisposing factors. However, in acute and/
or severe hyperkalaemia (plasma potassium >6. 5-7.0 mmol/L),
more urgent measures must be taken (Box 14.17). The first step
should be infusion of 10 mL 10% calcium gluconate to stabilise
conductive tissue membranes (calcium has the opposite effect
to potassium on conduction of an action potential). Measures
to shift potassium from the ECF to the ICF should also be
applied, as they generally have a rapid effect and may avert
arrhythmias. Ultimately, a means of removing potassium from the
body is generally necessary. When renal function is reasonably
preserved, loop diuretics (accompanied by intravenous saline
if hypovolaemia is present) may be effective. In renal failure,
dialysis may be required. Oral ion exchange resins, such as
sodium polystyrene sulfonate (SPS), have traditionally been
used to bind and excrete gastrointestinal potassium. There
are concerns, however, with regard to SPS’s lack of proven
efficacy and safety, with a number of reports of intestinal necrosis
associated with its use. Alternative cation exchanges have
been developed and are currently being trialled, with the aim of
providing more effective and safer alternatives for the treatment
of hyperkalaemia.
Acid-base homeostasis
The pH of arterial plasma is normally 7.40, corresponding
to an H+ concentration of 40 nmol/L, and under normal
circumstances H+ concentrations do not vary outside the range
of 37-45 nmol/L (pH 7.43-7.35). Abnormalities of acid-base
balance can occur in a wide range of diseases. Increases
in H+ concentration cause acidosis with a decrease in pH,
whereas decreases in H+ concentration cause alkalosis with a
rise in pH.
Functional anatomy and physiology
A variety of physiological mechanisms maintain pH of the ECF
within narrow limits. The first is the action of blood and tissue
buffers, of which the most important involves reaction of H+
ions with bicarbonate to form carbonic acid, which, under the
364 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
influence of the enzyme carbonic anhydrase (CA), dissociates
to form C02 and water:
co2 + h2o <-> h2co3 ^ H+ + HC03-
CA
This buffer system is important because bicarbonate is present
at a relatively high concentration in ECF (21-29 mmol/L), and two
of its key components are under physiological control: C02 by the
lungs, and bicarbonate by the kidneys. These relationships are
illustrated in Figure 14.10 (a form of the Henderson-Hasselbalch
equation).
Respiratory compensation for acid-base disturbances can
occur quickly. In response to acid accumulation, pH changes
in the brainstem stimulate ventilatory drive, reduce PC02 and
increase pH (p. 555). Conversely, systemic alkalosis leads to
inhibition of ventilation, causing a rise in PC02 and reduction in
pH, although it should be noted that this mechanism has limited
capacity to change pH because hypoxia provides an alternative
stimulus to drive ventilation.
The kidneys provide a third line of defence against disturbances
of arterial pH. When acid accumulates due to chronic respiratory
or metabolic (non-renal) causes, the kidneys have the long-term
capacity to enhance urinary excretion of acid, effectively increasing
the plasma bicarbonate.
Renal control of acid-base balance
Regulation of acid-base balance occurs at several sites in
the kidney. The proximal tubule reabsorbs about 85% of the
filtered bicarbonate ions, through the mechanism for H+ secretion
illustrated in Figure 14.3A. This is dependent on the enzyme
carbonic anhydrase, both in the cytoplasm of the proximal
tubular cells and on the luminal surface of the brush border
membranes. The system has a high capacity and is required
to rescue filtered bicarbonate, but does not lead to significant
acidification of the luminal fluid.
Distal nephron segments also have an important role in acid
excretion. Hydrogen ions are secreted into the lumen by an
H+-ATPase in the intercalated cells of the cortical collecting
duct and the outer medullary collecting duct cells. The H+ ions
1 0 changes
Fig. 14.10 Relationship between pH, PC02 (in mmHg) and plasma
bicarbonate concentration (in mmol/L). *Note that changes in
HC03“ concentration are also part of the renal correction for sustained
metabolic acid-base disturbances as long as the kidney itself is not the
cause of the primary disturbance.
are generated in the tubular cell from the hydration of C02 to
form carbonic acid, which dissociates into an H+ ion secreted
luminally, and a bicarbonate ion that passes across the basolateral
membrane into the blood. The secreted H+ ions contribute to the
reabsorption of any residual bicarbonate present in the luminal
fluid, by generating intracellular OH- that reacts with C02 to form
HC03“, which exits across the basolateral membrane. However,
H+ secretion also contributes net acid for removal from the body,
bound to a variety of urinary buffers, of which phosphate and
ammonia are the most important. Urinary buffers are required
to prevent a reduction in urinary pH, which would create an
unfavourable gradient that would prevent further H+ secretion.
Filtered phosphate (HP042_) combines with H+ in the distal tubular
lumen to form dihydrogen phosphate (H2P04“), which is excreted
in the urine with sodium. Ammonia (NH3) is generated within
tubular cells by deamination of the amino acid glutamine by the
enzyme glutaminase. The NH3 then reacts with secreted H+ in
the tubular lumen to form ammonium (NH4+), which becomes
trapped in the luminal fluid and is excreted with chloride ions.
These two mechanisms remove approximately 1 mmol/kg
of hydrogen ions from the body per day, which equates to the
non-volatile acid load arising from the metabolism of dietary
protein. The slightly alkaline plasma pH of 7.4 (H+ 40 nmol/L)
that is maintained during health can be accounted for by the
kidney’s ability to generate an acidic urine (typically pH 5-6 (H+
1000-10000 nmol/L), in which the net daily excess of metabolic
acid produced by the body can be excreted.
Presenting problems in acid-base balance
Patients with disturbances of acid-base balance may present
clinically either with the effects of tissue malfunction due to
disturbed pH (such as altered cardiac and central nervous system
function), or with secondary changes in respiration that occur as a
response to the underlying metabolic change (such as Kussmaul
respiration during metabolic acidosis). The clinical picture is often
dominated by the underlying cause rather than the acid-base
abnormality itself. Frequently, acid-base disturbances only become
evident when the venous plasma bicarbonate concentration is
measured and found to be abnormal, or when blood gas analysis
shows abnormalities in pH, PC02 or bicarbonate.
The most common patterns of abnormality in blood gas
parameters are shown in Box 1 4.1 8. Note that the terms acidosis
and alkalosis strictly refer to the underlying direction of the
acid-base change, while acidaemia and alkalaemia more correctly
refer to the net change present in the blood. Interpretation of
arterial blood gases is also described on page 555.
In metabolic disturbances, respiratory compensation is almost
immediate, so that the predicted compensatory change in PC02
is achieved soon after the onset of the metabolic disturbance. In
respiratory disorders, on the other hand, a small initial change
in bicarbonate occurs as a result of chemical buffering of C02,
largely within red blood cells, but over days and weeks the
kidney achieves further compensatory changes in bicarbonate
concentration as a result of long-term adjustments in acid secretory
capacity. When the clinically obtained acid-base parameters do
not accord with the predicted compensation shown, a mixed
acid-base disturbance should be suspected (p. 367).
Metabolic acidosis
Metabolic acidosis occurs when an acid other than carbonic acid
(due to C02 retention) accumulates in the body, resulting in a
Acid-base homeostasis • 365
I 14.18 Principal patterns of acid-base disturbance
Disturbance
Blood H+
Primary change
Compensatory response
Predicted compensation
Metabolic acidosis
>40'
HC03' <24 mmol/L
PC 02 <5.33 kPa2
PC 02 fall in kPa = 0.16 x HC03' fall in mmol/L
Metabolic alkalosis
<401
HC03“ >24 mmol/L
PC 02>5.33 kPa2,3
PC 02 rise in kPa = 0.08 x HC03“ rise in mmol/L
Respiratory acidosis
>40'
PC02 >5.33 kPa2
HC03“ >24 mmol/L
Acute: HC03' rise in mmol/L = 0.75 x PC 02 rise in kPa
Chronic: HC03' rise in mmol/L = 2.62 x PC 02 rise in kPa
Respiratory alkalosis
<40'
PC02 <5.33 kPa2
HC03' <24 mmol/L
Acute: HC03' fall in mmol/L = 1 .50 x PC 02 fall in kPa
Chronic: HC03' fall in mmol/L = 3.75 x PC 02 fall in kPa
1H+ of 40 nmol/L = pH of 7.40. 2PC 02 of 5.33 kPa = 40 mmHg. 3PC02 does not rise above 7.33 kPa (55 mmHg) because hypoxia then intervenes to drive respiration.
14.19 Causes of metabolic acidosis
Disorder
Mechanism
Normal anion gap
Ingestion or infusion of
inorganic acid
Gastrointestinal HC03' loss
Renal tubular acidosis (RTA)
Therapeutic infusion of or poisoning
with NH4CI, HCI
Loss of HC03' in diarrhoea, small
bowel fistula, urinary diversion
procedure
Urinary loss of HC03“ in proximal RTA;
impaired tubular acid secretion in
distal RTA
Increased anion gap
Endogenous acid load
Diabetic ketoacidosis
Starvation ketosis 1
Alcoholic ketoacidosis 1
Lactic acidosis
Kidney disease
Accumulation of ketones1 with
hyperglycaemia (p. 735)
Accumulation of ketones without
hyperglycaemia (p. 725)
Shock, liver disease, drugs
Accumulation of organic acids
Exogenous acid load
Aspirin poisoning
Methanol poisoning
Ethylene glycol poisoning
Accumulation of salicylate2
Accumulation of formate
Accumulation of glycolate, oxalate
Tetones include acid anions acetoacetate and [3-hydroxybutyrate (p. 725).
2Salicylate poisoning is also associated with respiratory alkalosis due to direct
ventilatory stimulation.
fall in the plasma bicarbonate. The causes of metabolic acidosis
are summarised in Box 14.19, subdivided into two categories,
depending on whether the anion gap is normal or raised.
Pathophysiology
Metabolic acidosis with a normal anion gap occurs when there
is a primary loss of bicarbonate from the ECF, or when there is
poisoning with or therapeutic infusion of a mineral acid such as
hydrochloric acid or ammonium chloride. Renal tubular acidosis
(RTA) is an important cause of metabolic acidosis with a normal
anion gap. It can be caused by a defect in one of three processes:
• impaired bicarbonate reabsorption in the proximal tubule
(proximal RTA)
• impaired acid secretion in the late distal tubule or cortical
collecting duct intercalated cells (classical distal RTA)
• impaired sodium reabsorption in the late distal tubule or
cortical collecting duct, which is associated with reduced
secretion of both potassium and H+ ions (hyperkalaemic
distal RTA).
Various subtypes of RTA are recognised and the most common
causes are shown in Box 14.20. The inherited forms of RTA are
14.20 Causes of renal tubular acidosis
Proximal renal tubular acidosis (type II RTA)
• Inherited:
• Heavy metal toxicity:
Fanconi’s syndrome
Lead, cadmium and
Cystinosis
mercury poisoning
Wilson’s disease
• Drugs:
• Paraproteinaemia:
Carbonic anhydrase
Myeloma
inhibitors
• Amyloidosis
• Hyperparathyroidism
Ifosfamide
Classical distal renal tubular acidosis (type 1 RTA)
• Inherited
• Hyperglobulinaemia
• Autoimmune diseases:
• Toxins and drugs:
Systemic lupus
Toluene
erythematosus
Lithium
Sjogren’s syndrome
Amphotericin
Hyperkalaemic distal renal tubular acidosis (type IV RTA)
• Hypoaldosteronism (primary or
• Drugs:
secondary)
Amiloride
• Obstructive nephropathy
• Renal transplant rejection
Spironolactone
due to mutations in the genes that regulate acid or bicarbonate
transport in the renal tubules (see Fig. 14.3).
Acidosis with an increased anion gap is most commonly
seen in ketoacidosis, renal failure and lactic acidosis, where
there is endogenous production of anions distinct from Cl' and
HC03'. Ketoacidosis is caused by insulin deficiency and is
exacerbated by catecholamine and stress hormone excess,
which combine to cause lipolysis and the formation of acidic
ketones (acetoacetate, 3-hydroxybutyrate and acetone). The
most common cause of ketoacidosis is diabetic ketoacidosis
(DKA); its aetiology and management are discussed on page
735. Starvation ketoacidosis occurs when there is reduced
food intake in situations of high glucose demand, such as in
neonates, and in pregnant or breastfeeding women. In alcoholic
ketoacidosis, there is usually a background of chronic malnutrition
and a recent alcohol binge. Two subtypes of lactic acidosis have
been defined:
• type 1 , due to tissue hypoxia and peripheral generation of
lactate, as in patients with circulatory failure and shock
• type 2, due to impaired metabolism of lactate, as in liver
disease or by a number of drugs and toxins, including
metformin, which inhibit lactate metabolism (p. 746).
Metabolic acidosis with an increased anion gap may also be
a consequence of exogenous acid loads from poisoning with
aspirin, methanol or ethylene glycol.
366 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
Clinical features
Normal anion gap metabolic acidosis is usually due either to
bicarbonate loss in diarrhoea, where the clinical diagnosis is
generally obvious, or to RTA. Although some forms of RTA are
inherited, it may also be an acquired disorder, and in these
circumstances the discovery of metabolic acidosis may serve
as an early clue to the underlying diagnosis. The presentation
of increased anion gap acidosis is usually dominated by clinical
features of the underlying disease, such as uncontrolled diabetes
mellitus, kidney failure or shock, or may be suggested by the
clinical history of starvation, alcoholism or associated symptoms,
such as visual complaints in methanol poisoning (p. 147).
Investigations
The different types of metabolic acidosis can be distinguished by
blood gas measurements, along with measurements of creatinine,
electrolytes and bicarbonate. Under normal circumstances, the
anion gap, defined as the numerical difference between the
main measured cations (Na+ + K+) and the anions (Cl- + HC03-)
is about 5-1 1 mmol/L. This gap is normally made up of anions,
such as phosphate and sulphate, as well as albumin. RTA should
be suspected when there is a hyperchloraemic acidosis with a
normal anion gap in the absence of gastrointestinal disturbance.
The diagnosis can be confirmed by finding an inappropriately high
urine pH (>5.5) in the presence of systemic acidosis. Sometimes,
distal RTA may be incomplete, such that the plasma bicarbonate
concentration may be normal under resting conditions. In this
case, an acid challenge test can be performed by administration
of an acid load in the form of ammonium chloride to reduce
plasma bicarbonate. The diagnosis of incomplete distal RTA
can be confirmed if the urine pH fails to fall below 5.3 in the
presence of a low bicarbonate.
The different subtypes of RTA can be differentiated by various
biochemical features. Patients with proximal and distal RTA often
present with features of profound hypokalaemia, while type IV
RTA is associated with hyperkalaemia. Proximal RTA is frequently
associated with urinary wasting of amino acids, phosphate
and glucose (Fanconi’s syndrome), as well as bicarbonate and
potassium. Patients with this disorder can lower the urine pH
when the acidosis is severe and plasma bicarbonate levels have
fallen below 16 mmol/L, since distal H+ secretion mechanisms
are intact. In the classical form of distal RTA, however, acid
accumulation is relentless and progressive, resulting in mobilisation
of calcium from bone and osteomalacia with hypercalciuria, renal
stone formation and nephrocalcinosis. Potassium is also lost in
classical distal RTA, while it is retained in hyperkalaemic distal RTA.
Investigations in patients with raised anion gap metabolic
acidosis show features of the underlying cause, such as
reduced GFR in renal failure and raised urine or blood ketones
in ketoacidosis. In DKA, blood glucose is raised, while in starvation
and alcoholic acidosis blood glucose is not elevated and may be
low. Measurement of plasma lactate is helpful in the diagnosis
of lactic acidosis when values are increased over the normal
maximal level of 2 mmol/L.
Management
The first step in management of metabolic acidosis is to
identify and correct the underlying cause when possible (see
Box 14.19). This may involve controlling diarrhoea, treating
diabetes mellitus, correcting shock, stopping drugs that might
cause the condition, or using dialysis to remove toxins. Since
metabolic acidosis is frequently associated with sodium and
water depletion, resuscitation with intravenous fluids is often
needed. In alcoholism and starvation ketosis, intravenous glucose
is indicated. By stimulating endogenous insulin secretion, this
will reverse hepatic ketone production. Malnourished patients
may also require thiamin, potassium, magnesium and phosphate
supplements (p. 706). Use of intravenous bicarbonate in metabolic
acidosis is controversial. Because rapid correction of acidosis
can induce hypokalaemia or a fall in plasma ionised calcium,
the use of bicarbonate infusions is best reserved for situations
where the underlying disorder cannot be readily corrected and
acidosis is severe (H+ >100 nmol/L, pH <7.00) or associated
with evidence of tissue dysfunction.
The acidosis in RTA can sometimes be controlled by treating
the underlying cause (see Box 14.20), but usually supplements
of sodium and potassium bicarbonate are also necessary in
types I and II RTA to achieve a target plasma bicarbonate
level of >18 mmol/L and normokalaemia. In type IV RTA, loop
diuretics, thiazides or fludrocortisone (as appropriate to the
underlying diagnosis) may be effective in correcting the acidosis
and the hyperkalaemia.
Metabolic alkalosis
Metabolic alkalosis is characterised by an increase in the plasma
bicarbonate concentration and the plasma pH (see Box 14.18).
There is a compensatory rise in PC02 due to hypoventilation but
this is limited by the need to avoid hypoxia. Classical causes
include primary hyperaldosteronism (Conn’s syndrome, p. 674),
Cushing’s syndrome (p. 666) and glucocorticoid therapy (p. 670).
Occasionally, overuse of antacid salts for treatment of dyspepsia
produces a similar pattern.
Pathophysiology
Metabolic alkalosis is best classified according to the
accompanying changes in ECF volume. Hypovolaemic metabolic
alkalosis is the most common pattern. This can be caused by
sustained vomiting, in which acid-rich fluid is lost directly from
the body, or by treatment with loop diuretics or thiazides. In the
case of sustained vomiting, loss of gastric acid is the immediate
cause of the alkalosis, but several factors act to sustain or
amplify this in the context of volume depletion (Fig. 14.11).
Loss of sodium and fluid leads to hypovolaemia and secondary
hyperaldosteronism, triggering proximal sodium bicarbonate
reabsorption and additional acid secretion by the distal tubule.
Hypokalaemia occurs due to potassium loss in the vomitus and
by the kidney as the result of secondary hyperaldosteronism, and
itself is a stimulus to acid secretion. Additionally, the compensatory
rise in PC02 further enhances tubular acid secretion. The net
result is sustained metabolic alkalosis with an inappropriately acid
urine, which cannot be corrected until the deficit in circulating
volume has been replaced.
Normovolaemic (or hypervolaemic) metabolic alkalosis occurs
when bicarbonate retention and volume expansion occur
simultaneously.
Clinical features
Clinically, apart from manifestations of the underlying cause,
there may be few symptoms or signs related to alkalosis itself.
When the rise in systemic pH is abrupt, however, plasma ionised
calcium falls and signs of increased neuromuscular irritability,
such as tetany, may develop (p. 663).
Investigations
The diagnosis can be confirmed by measurement of electrolytes
and arterial blood gases.
Magnesium homeostasis • 367
Fig. 14.11 Generation and maintenance of metabolic alkalosis
during prolonged vomiting. Loss of H+cr generates metabolic alkalosis,
which is maintained by renal changes.
Management
Metabolic alkalosis with hypovolaemia can be corrected by
intravenous infusions of 0.9% saline with potassium supplements.
This reverses the secondary hyperaldosteronism and allows the
kidney to excrete the excess alkali in the urine. In metabolic
alkalosis with normal or increased volume, treatment should focus
on management of the underlying endocrine cause (Ch. 18).
Respiratory acidosis
Respiratory acidosis occurs when there is accumulation of C02
due to type II respiratory failure (p. 565). This results in a rise in
the PC02, with a compensatory increase in plasma bicarbonate
concentration, particularly when the disorder is of long duration
and the kidney has fully developed its capacity for increased
acid excretion.
This acid-base disturbance can arise from lesions anywhere
along the neuromuscular pathways from the brain to the
respiratory muscles that result in impaired ventilation. It can
also arise during intrinsic lung disease if there is significant
mismatching of ventilation and perfusion.
Clinical features are primarily those of the underlying cause of
the respiratory disorder, such as paralysis, chest wall injury or
chronic obstructive lung disease, but the C02 accumulation may
itself lead to drowsiness that further depresses respiratory drive.
Management involves correction of causative factors where
possible, but ultimately ventilatory support may be necessary.
Respiratory alkalosis
Respiratory alkalosis develops when there is a period of sustained
hyperventilation, resulting in a reduction of PC02 and increase
in plasma pH. If the condition is sustained, renal compensation
occurs, such that tubular acid secretion is reduced and the
plasma bicarbonate falls.
Respiratory alkalosis is usually of short duration, occurring in
anxiety states or as the result of over-vigorous assisted ventilation.
It can be prolonged in the context of pregnancy, pulmonary
embolism, chronic liver disease, and ingestion of certain drugs
such as salicylates that directly stimulate the respiratory centre
in the brainstem.
Clinical features are those of the underlying cause but agitation
associated with perioral and digital tingling may also occur, as
alkalosis promotes the binding of calcium to albumin, resulting in
a reduction in ionised calcium concentrations. In severe cases,
Trousseau’s sign and Chvostek’s sign may be positive, and
tetany or seizures may develop (p. 663).
Management involves correction of identifiable causes,
reduction of anxiety, and a period of rebreathing into a closed
bag to allow C02 levels to rise.
|Mixed acid-base disorders
It is not uncommon for more than one disturbance of acid-base
metabolism to be present at the same time in the same patient:
for example, a respiratory acidosis due to narcotic overdose with
metabolic alkalosis due to vomiting. In these situations, the arterial
pH will represent the net effect of all primary and compensatory
changes. Indeed, the pH may be normal, but the presence of
underlying acid-base disturbances can be gauged from concomitant
abnormalities in the PC02 and bicarbonate concentration.
In assessing these disorders, all clinical influences on the
patient’s acid-base status should be identified, and reference
should be made to the table of predicted compensation given
in Box 14.18. If the compensatory change is discrepant from
the rules of thumb provided, more than one disturbance of
acid-base metabolism may be suspected.
Calcium homeostasis
Disorders of calcium homeostasis are discussed in Chapter 18
and bone disease is discussed in Chapter 24.
Magnesium homeostasis
Magnesium is mainly an intracellular cation. It is important to
the function of many enzymes, including the Na,K-ATPase, and
can regulate both potassium and calcium channels. Its overall
effect is to stabilise excitable cell membranes.
Functional anatomy and physiology
Renal handling of magnesium involves filtration of free plasma
magnesium at the glomerulus (about 70% of the total), with
extensive reabsorption (50-70%) in the loop of Henle and
other parts of the proximal and distal renal tubule. Magnesium
reabsorption is also enhanced by parathyroid hormone (PTH).
Presenting problems in
magnesium homeostasis
Disturbances in magnesium homeostasis usually occur because
of increased loss of magnesium through the gut or kidney or
368 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
inability to excrete magnesium normally in patients with renal
impairment.
Hypomagnesaemia
Hypomagnesaemia is defined as existing when plasma magnesium
concentrations are below the reference range of 0.75-1 .0 mmol/L
(1 .5-2.0 mEq/L).
Pathophysiology
Hypomagnesaemia usually is a reflection of magnesium depletion
(Box 14.21), which can be caused by excessive magnesium loss
from the gastrointestinal tract (notably in chronic diarrhoea) or
the kidney (during prolonged use of loop diuretics). Excessive
alcohol ingestion can cause magnesium depletion through both
gut and renal losses. Some inherited tubular transport disorders,
such as Gitelman’s and Bartter’s syndromes, can also result in
urinary magnesium wasting (p. 361). Magnesium depletion has
important effects on calcium homeostasis because magnesium
is required for the normal secretion of PTH in response to a
fall in serum calcium, and because hypomagnesaemia causes
end -organ resistance to PTH.
Clinical features
Mild degrees of hypomagnesaemia may be asymptomatic but
more severe hypomagnesaemia may be associated with symptoms
of hypocalcaemia, such as tetany, cardiac arrhythmias (notably
torsades de pointes, p. 476), central nervous excitation and
seizures, vasoconstriction and hypertension. Hypomagnesaemia
and magnesium depletion are also associated (through uncertain
mechanisms) with hyponatraemia and hypokalaemia, which may
contribute to some of the clinical manifestations.
i
14.21 Causes of hypomagnesaemia
Mechanism
Examples
Inadequate intake
Starvation
Malnutrition
Alcoholism
Parenteral alimentation
Excessive losses
Gastrointestinal
Prolonged vomiting/nasogastric aspiration
Chronic diarrhoea/laxative abuse
Malabsorption
Small bowel bypass surgery
Fistulae
Urinary
Diuretic therapy
Alcohol
Tubulotoxic drugs:
Gentamicin
Cisplatin
Volume expansion
Diabetic ketoacidosis
Post-obstructive diuresis
Recovery from acute tubular necrosis
Inherited tubular transport defect:
Bartter’s syndrome
Gitelman’s syndrome
Primary renal magnesium wasting
Miscellaneous
Acute pancreatitis
Foscarnet therapy
Proton pump inhibitor therapy
Hungry bone syndrome
Diabetes mellitus
Management
The underlying cause should be identified and treated where
possible. When symptoms are present, the treatment of choice
is intravenous magnesium chloride at a rate not exceeding
0.5 mmol/kg in the first 24 hours. If intravenous access is not
feasible, magnesium sulphate can be given intramuscularly. Oral
magnesium salts have limited effectiveness due to poor absorption
and may cause diarrhoea. If hypomagnesaemia is caused by
diuretic treatment, adjunctive use of a potassium-sparing agent
can also help by reducing magnesium loss into the urine.
Hypermagnesaemia
This is a much less common abnormality than hypomagnesaemia.
Predisposing conditions include acute kidney injury, chronic
kidney disease and adrenocortical insufficiency. The condition
is generally precipitated in patients at risk from an increased
intake of magnesium, or from the use of magnesium-containing
medications, such as antacids, laxatives and enemas.
Clinical features include bradycardia, hypotension, reduced
consciousness and respiratory depression.
Management involves ceasing all magnesium-containing
drugs and reducing dietary magnesium intake, improving renal
function if possible, and promoting urinary magnesium excretion
using a loop diuretic with intravenous hydration, if residual renal
function allows. Calcium gluconate may be given intravenously to
ameliorate cardiac effects. Dialysis may be necessary in patients
with poor renal function.
Phosphate homeostasis
Inorganic phosphate (mainly present as HP042_) is intimately
involved in cell energy metabolism, intracellular signalling and
bone and mineral homeostasis (Ch. 24). The normal plasma
concentration is 0.8-1 .4 mmol/L (2.48-4.34 mg/dL).
Functional anatomy and physiology
Phosphate is freely filtered at the glomerulus and approximately
65% is reabsorbed by the proximal tubule, through an apical
sodium-phosphate co-transport carrier. A further 10-20% is
reabsorbed in the distal tubules, leaving a fractional excretion of
some 1 0% to pass into the urine, usually as H2P04~. Proximal
reabsorption is decreased by PTH, fibroblast growth factor 23
(FGF23), volume expansion, osmotic diuretics and glucose infusion.
Presenting problems in
phosphate homeostasis
The following section deals primarily with conditions that cause
acute disturbances in serum phosphate concentrations. Chronic
disorders that are accompanied by phosphate depletion, such
as osteomalacia and hypophosphataemic rickets, are discussed
in Chapter 24. Acute kidney injury and chronic kidney disease,
which are associated with hyperphosphataemia, are discussed
below and also in Chapter 15.
Hypophosphataemia
Hypophosphataemia is defined as existing when serum phosphate
values fall below 0.8 mmol/L (2.48 mg/dL). The causes are
shown in Box 14.22, subdivided into the underlying pathogenic
mechanisms.
Disorders of amino acid metabolism • 369
1 14.22 Causes of hypophosphataemia
Mechanism
Examples
Redistribution
into cells
Refeeding after starvation
Respiratory alkalosis
Treatment for diabetic ketoacidosis
Inadequate
intake or
absorption
Malnutrition
Malabsorption
Chronic diarrhoea
Phosphate binders
Antacids
Vitamin D deficiency or resistance
Increased renal
excretion
Hyperparathyroidism
Extracellular fluid volume expansion with diuresis
Osmotic diuretics
Fanconi’s syndrome
Familial hypophosphataemic rickets
Tumour-induced hypophosphataemic rickets
Pathophysiology
Phosphate may redistribute into cells during periods of increased
energy utilisation (such as refeeding after a period of starvation) and
during systemic alkalosis. However, severe hypophosphataemia
usually represents an overall body deficit due to either inadequate
intake or absorption through the gut, or excessive renal losses,
most notably in primary hyperparathyroidism (p. 663) or as the
result of acute plasma volume expansion, osmotic diuresis and
diuretics acting on the proximal renal tubule. Less common
causes include inherited defects of proximal sodium-phosphate
co-transport and tumour-induced osteomalacia due to ectopic
production of the hormone FGF23 (p. 1053).
Clinical features
The clinical features of phosphate depletion are wide-ranging,
reflecting the involvement of phosphate in many aspects of
metabolism. Defects appear in the blood (impaired function and
survival of all cell lineages), skeletal muscle (weakness, respiratory
failure), cardiac muscle (congestive cardiac failure), smooth
muscle (ileus), central nervous system (decreased consciousness,
seizures and coma) and bone (osteomalacia in severe prolonged
hypophosphataemia, p. 1053).
Investigations
Measurement of creatinine, electrolytes, phosphate, albumin,
calcium and alkaline phosphatase should be performed. In selected
cases, measurement of PTH and 25(OH)D may be helpful to exclude
osteomalacia or hypophosphataemic rickets. The combination
of hypophosphataemia and hypercalcaemia suggests primary
hyperparathyroidism, which should be further investigated by
measurements of PTH, as described on page 663. The presence
of hypocalcaemia suggests hypophosphataemic rickets, which
should be further investigated as described on page 1053.
Management
Management of hypophosphataemia due to decreased dietary
intake or excessive losses involves administering oral phosphate
supplements and high-protein/high-dairy dietary supplements
that are rich in naturally occurring phosphate. Intravenous
treatment with sodium or potassium phosphate salts can be
used in critical situations, but there is a risk of precipitating
hypocalcaemia and metastatic calcification. Management of
primary hyperparathyroidism and hypophosphataemic rickets
are described in more detail on pages 664 and 1053.
Hyperphosphataemia
Hyperphosphataemia is most commonly caused by acute kidney
injury or chronic kidney disease (pp. 413 and 419).
Pathophysiology
In acute kidney injury and chronic kidney disease, the primary
cause is reduced phosphate excretion as the result of a low GFR.
In contrast, the hyperphosphataemia in hypoparathyroidism and
pseudohypoparathyroidism is due to increased tubular phosphate
reabsorption. Redistribution of phosphate from cells into the plasma
can also be a contributing factor in the tumour lysis syndromes and
other catabolic states. Phosphate accumulation can be aggravated
in any of these conditions if the patient takes phosphate-containing
preparations or inappropriate vitamin D therapy.
Clinical features
The clinical features relate to hypocalcaemia and metastatic
calcification, particularly in chronic kidney disease with tertiary
hyperparathyroidism (when a high calcium-phosphate product
occurs).
Management
Hyperphosphataemia in patients with kidney disease should
be treated with dietary phosphate restriction and the use
of oral phosphate binders (p. 418). Hyperphosphataemia in
hypoparathyroidism and pseudohypoparathyroidism does not
usually require treatment. Hyperphosphataemia associated with
tumour lysis syndromes and catabolic states can be treated with
intravenous normal saline, which is given to promote phosphate
excretion.
Disorders of amino acid metabolism
Congenital disorders of amino acid metabolism usually present in
the neonatal period and may involve life-long treatment regimens.
However, some disorders, particularly those involved in amino
acid transport, may not present until later in life.
Phenylketonuria
Phenylketonuria (PKU) is inherited as an autosomal recessive
disorder caused by loss-of-function mutations in the PAH gene,
which encodes phenylalanine hydroxylase, an enzyme required
for degradation of phenylalanine. As a result, phenylalanine
accumulates at high levels in the neonate’s blood, causing
intellectual disability.
The diagnosis of PKU is almost always made by routine
neonatal screening (p. 56). Treatment involves life-long adherence
to a low-phenylalanine diet. Early and adequate dietary treatment
prevents major intellectual disability, although there may still be
a slight reduction in IQ.
Homocystinuria
Homocystinuria is an autosomal recessive disorder caused by
loss-of-function mutations in the CBS gene, which encodes
cystathionine |3-synthase. The enzyme deficiency causes
accumulation of homocysteine and methionine in the blood.
Many cases of homocystinuria are diagnosed through newborn
screening programmes.
370 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
Clinical manifestations are wide-ranging and involve the eyes
(ectopia lentis - displacement of the lens), central nervous
system (intellectual disability, delayed developmental milestones,
seizures, psychiatric disturbances), skeleton (resembling Marfan’s
syndrome, and also with generalised osteoporosis), vascular
system (thrombotic lesions of arteries and veins) and skin
(hypopigmentation).
Treatment is dietary, involving a methionine-restricted, cystine-
supplemented diet, as well as large doses of pyridoxine.
Disorders of carbohydrate metabolism
The most common disorder of carbohydrate metabolism is
diabetes mellitus, which is discussed in Chapter 20. There are
also some rare inherited defects, discussed below.
Galactosaemia
Galactosaemia is caused by loss-of-function mutations in the
GALT gene, which encodes galactose-1 -phosphate uridyl
transferase. It is usually inherited in an autosomal recessive
manner. The neonate is unable to metabolise galactose, one of
the hexose sugars contained in lactose. Vomiting or diarrhoea
usually begins within a few days of ingestion of milk, and the
neonate may become jaundiced. Failure to thrive is the most
common clinical presentation. The classic form of the disease
results in hepatomegaly, cataracts and intellectual disability.
Fulminant infection with Escherichia coli is a frequent complication.
Treatment involves life-long avoidance of galactose- and lactose-
containing foods.
The widespread inclusion of galactosaemia in newborn
screening programmes has resulted in the identification of a
number of milder (‘Duarte’) variants.
Glycogen storage diseases
Glycogen storage diseases (GSDs, or glycogenoses) result from
inherited defects in one of the many enzymes responsible for the
formation or breakdown of glycogen, a complex carbohydrate
that can be broken down quickly to release glucose during
exercise or between meals.
There are several major types of GSD, which are classified by
a number, by the name of the defective enzyme, or eponymously
after the physician who first described the condition (Box 1 4.23).
Most forms of GSD are inherited in an autosomal recessive manner.
The diagnosis of GSD is made on the basis of the symptoms,
physical examination and results of biochemical tests. Occasionally,
a muscle or liver biopsy is required to confirm the enzyme defect.
Different types of GSD present at different ages, and some may
require life-long modifications of diet and lifestyle.
Disorders of complex lipid metabolism
Complex lipids are key components of the cell membrane
that are normally catabolised in organelles called lysosomes.
The lysosomal storage diseases are a heterogeneous group
of disorders caused by loss-of-function mutations in various
lysosomal enzymes (Box 14.24), resulting in an inability to break
down complex glycolipids or other intracellular macromolecules.
These disorders have diverse clinical manifestations, typically
including intellectual disability. Some can be treated with enzyme
replacement therapy, while others (such as Tay-Sachs disease)
can be prevented through community participation in genetic
carrier screening programmes.
Lipids and lipoprotein metabolism
The three main biological classes of lipid are:
• cholesterol, which is composed of hydrocarbon rings
• triglycerides (TGs), which are esters composed of glycerol
linked to three long-chain fatty acids
• phospholipids, which are composed of a hydrophobic ‘tail’
consisting of two long-chain fatty acids linked through
glycerol to a hydrophilic head containing a phosphate
group.
Phospholipids are present in cell membranes and are important
signalling molecules.
Despite their poor water solubility, lipids need to be absorbed
from the gastrointestinal tract and transported throughout the
body. This is achieved by incorporating lipids within lipoproteins.
Plasma cholesterol and TGs are clinically important because
they are major treatable risk factors for cardiovascular disease,
while severe hypertriglyceridaemia also predisposes to acute
pancreatitis.
M
14.23 Glycogen storage diseases
Type
Eponym
Enzyme deficiency
Clinical features and complications
1
Von Gierke
Glucose-6-phosphatase
Childhood presentation, hypoglycaemia, hepatomegaly
II
Pompe
a-glucosidase (acid maltase)
Classical presentation in infancy, muscle weakness (may be severe)
III
Cori
Glycogen debrancher enzyme
Childhood presentation, hepatomegaly, mild hypoglycaemia
IV
Andersen
Brancher enzyme
Presentation in infancy, severe muscle weakness (may affect heart), cirrhosis
V
McArdle
Muscle glycogen phosphorylase
Exercise-induced fatigue and myalgia
VI
Hers
Liver phosphorylase
Mild hepatomegaly
VII
Tarui
Muscle phosphofructokinase
Exercise-induced fatigue and myalgia
IX1
Liver phosphorylase kinase
Mild hepatomegaly
0
Hepatic glycogen synthase
Fasting hypoglycaemia, post-prandial hyperglycaemia
X2
Muscle phosphoglycerate mutase
Exercise-induced myoglobinuria
^ote that type VIII has been merged into type IX and no longer exists as a separate entity. 2Recent progress in molecular genetics has recognised a number of additional,
rarer types of glycogen storage disease. These are not shown in this table, which stops at type X.
Lipids and lipoprotein metabolism • 371
14.24 Lysosomal storage diseases
Lysosomal storage disease
Enzyme deficiency
Clinical features
Human enzyme
replacement therapy
Fabry’s disease
a-galactosidase A
Variable age of onset
Neurological (pain in extremities)
Dermatological (hypohidrosis, angiokeratomas)
Cerebrovascular (renal, cardiac, central nervous system)
Available for clinical
use
Gaucher’s disease (various types)
Glucocerebrosidase
Splenic and liver enlargement, with variable severity
of disease
Some types also have neurological involvement
Available for clinical
use in some types
Mucopolysaccharidosis
Hurler’s syndrome
Hunter’s syndrome
Sanfilippo’s syndrome
Morquio’s syndrome + several
other types
Several enzymes involved
in breakdown of
glycosaminoglycans
Vary with syndrome: can cause intellectual disability,
skeletal and joint abnormalities, abnormal facies,
obstructive respiratory diseases and recurrent
respiratory infections
Available for clinical
use in some types;
clinical trials under
way for other types
Niemann-Pick disease
Acid sphingomyelinase
Most common presentation is as a progressive
neurological disorder, accompanied by organomegaly
Some variants do not have neurological symptoms
Clinical trials planned
for some types
GM2-gangliosidosis
Tay-Sachs disease
Hexosaminidase activator deficiency
Sandhoff’s disease
Hexosaminidase A i
Hexosaminidase activator
Hexosaminidase A and B J
Severe progressive neurological disorder
> Cherry-red spot in macula
Organomegaly in Sandhoff’s disease
Functional anatomy and physiology
Lipids are transported and metabolised by apolipoproteins, which
combine with lipids to form spherical or disc-shaped lipoproteins,
consisting of a hydrophobic core and a less hydrophobic coat
(Fig. 14.12). The structure of some apolipoproteins also enables
them to act as enzyme co-factors or cell receptor ligands.
Variations in lipid and apolipoprotein composition result in distinct
classes of lipoprotein that perform specific metabolic functions.
| Processing of dietary lipid
The intestinal absorption of dietary lipid is described on
page 768 (see also Fig. 14.13). Enterocytes lining the gut extract
monoglyceride and free fatty acids from micelles and re-esterify
them into TGs, which are combined with a truncated form
of apolipoprotein B (Apo B48) as it is synthesised. Intestinal
cholesterol derived from dietary and biliary sources is also
absorbed through a specific intestinal membrane transporter
Apolipoprotein
Free
cholesterol
Phospholipid
^^^Triglyceride
Cholesteryl
ester
Fig. 14.12 Structure of lipoproteins.
termed NPC1 LI . This produces chylomicrons containing TG and
cholesterol ester that are secreted basolaterally into lymphatic
lacteals and carried to the circulation through the thoracic duct.
On entering the blood stream, nascent chylomicrons are modified
by further addition of apolipoproteins. Chylomicron TGs are
hydrolysed by lipoprotein lipase located on the endothelium
of tissue capillary beds. This releases fatty acids that are used
locally for energy production or stored as TG in muscle or fat.
The residual ‘remnant’ chylomicron particle is avidly cleared
by low-density lipoprotein receptors (LDLRs) in the liver, which
recognise Apo E on the remnant lipoproteins. Complete absorption
of dietary lipids takes about 6-10 hours, so chylomicrons are
usually undetectable in the plasma after a 12-hour fast.
The main dietary determinants of plasma cholesterol
concentrations are the intake of saturated and trans- unsaturated
fatty acids, which reduce LDLR levels (see below), whereas dietary
cholesterol has surprisingly little effect on fasting cholesterol
levels. Plant sterols and drugs that inhibit cholesterol absorption
are effective because they also reduce the re- utilisation of biliary
cholesterol. The dietary determinants of plasma TG concentrations
are complex since excessive intake of carbohydrate, fat or
alcohol may all contribute to increased plasma TG by different
mechanisms.
Endogenous lipid synthesis
In the fasting state, the liver is the major source of plasma lipids
(Fig. 14.13). The liver may acquire lipids by uptake, synthesis or
conversion from other macronutrients. These lipids are transported
to other tissues by secretion of very low-density lipoproteins
(VLDLs), which are rich in TG but differ from chylomicrons in
that they are less massive and contain full-length Apo B100.
Following secretion into the circulation, VLDLs undergo metabolic
processing similar to that of chylomicrons. Hydrolysis of VLDL TG
releases fatty acids to tissues and converts VLDLs into ‘remnant’
particles, referred to as intermediate-density lipoproteins (IDLs).
Most IDLs are rapidly cleared by LDLRs in the liver but some are
372 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
Fig. 14.13 Absorption, transport and storage of lipids. Pathways of lipid transport are shown; in addition, cholesterol ester transfer protein exchanges
triglyceride and cholesterol ester between very low-density lipoprotein/chylomicrons and high-/low-density lipoprotein, and free fatty acids released from
peripheral lipolysis can be taken up in the liver. (ABCA1/ABCG1 = adenosine triphosphate-binding cassette A1/G1; Apo = apolipoprotein; BA = bile acids;
C = cholesterol; CE = cholesterol ester; FFA = free fatty acids; HDL = mature high-density lipoprotein; HL = hepatic lipase; HMGCoAR = hydroxy- methyl -
glutaryl-co-enzyme A reductase; IDL = intermediate-density lipoprotein; iHDL = immature high-density lipoprotein; LCAT = lecithin cholesterol acyl
transferase; LDL = low-density lipoprotein; LDLR = low-density lipoprotein receptor (Apo B100 receptor); LPL = lipoprotein lipase; PCSK9 = proprotein
convertase subtilisin kexin 9; SRB1 = scavenger receptor B1 ; TG = triglyceride; VLDL = very low-density lipoprotein)
processed by hepatic lipase, which converts the particle to an
LDL by removing TG and most materials other than Apo BIOO,
and free and esterified cholesterol. The catabolism of TG-rich
chylomicrons and VLDL by lipoprotein lipase is modulated by
Apos C2 and C3 on the surface of these particles.
The LDL particles act as a source of cholesterol for cells
and tissues (Fig. 14.13). LDL cholesterol is internalised by
receptor- mediated endocytosis through the LDLR. Delivery of
cholesterol via this pathway down-regulates expression of LDLR
and reduces the synthesis and activity of the rate-limiting enzyme
for cholesterol synthesis, hydroxy- methyl -glutary I -co-enzyme A
(HMGCoA) reductase. Another important regulator of LDLR levels
is the sterol -sensitive protease proprotein convertase subtilisin
kexin 9 (PCSK9), which degrades the LDLR. Intracellular free
cholesterol concentrations are maintained within a narrow range
by the inhibitory effects of LDL on expression of LRLR, fine-tuning
of the half-life of LDLR through PCSK9, and modulation of
cholesterol esterification.
Cholesterol transport
Peripheral tissues are further guarded against excessive cholesterol
accumulation by high-density lipoproteins (HDLs; Fig. 14.13).
Lipid-poor Apo A1 (derived from the liver, intestine and th e outer
layer of chylomicrons and VLDL) accepts cellular cholesterol and
phospholipid from a specific membrane transporter known as the
ATP-binding cassette A1 (ABCA1). This produces small FIDLs
that are able to accept more free cholesterol from cholesterol -
rich regions of the cell membrane known as ‘rafts’ via another
membrane transporter (ABCG1). The cholesterol that has been
accepted by these small HDLs is esterified by lecithin cholesterol
acyl transferase (LCAT), thus maintaining an uptake gradient and
Lipids and lipoprotein metabolism • 373
remodelling the particle into a mature spherical HDL. These HDLs
release their cholesterol to the liver and other cholesterol-requiring
tissues via the scavenger receptor B1 (SRB1).
The cholesterol ester transfer protein (CETP) in plasma
allows transfer of cholesterol from HDLs or LDLs to VLDLs or
chylomicrons in exchange for TG. When TG is elevated, the
action of CETP may reduce HDL cholesterol and remodel LDLs
into ‘small, dense’ LDL particles that may be more atherogenic
in the blood-vessel wall. Animal species that lack CETP are
resistant to atherosclerosis.
Lipids and cardiovascular disease
Plasma lipoprotein levels are major modifiable risk factors
for cardiovascular disease. Increased levels of atherogenic
lipoproteins (especially LDL, but also IDL, and possibly
chylomicron remnants) contribute to the development of
atherosclerosis (p. 484). A sub-population of LDL particles
bears an additional protein known as apolipoprotein (a), which
shares homology with plasminogen. The combination of LDL
and apolipoprotein (a) is known as lipoprotein (a) (Lp(a)). It
transports oxidised phospholipid and is regarded as atherogenic
because its plasma concentration is an independent risk factor
for cardiovascular disease. Following chemical modifications
such as oxidation, Apo B-containing lipoproteins are no longer
cleared by normal mechanisms. They trigger a self-perpetuating
inflammatory response, during which they are taken up by
macrophages to form foam cells, a hallmark of atherosclerotic
lesions. These processes also have an adverse effect on
endothelial function.
Conversely, HDL removes cholesterol from the tissues to the
liver, where it is metabolised and excreted in bile. HDL may also
counteract some components of the inflammatory response,
such as the expression of vascular adhesion molecules by the
endothelium. Consequently, low HDL cholesterol levels, which
are often associated with TG elevation, are also associated with
atherosclerosis.
Investigations
Lipid measurements are usually performed for the following
reasons:
• screening for primary or secondary prevention of
cardiovascular disease
• investigation of patients with clinical features of lipid
disorders (p. 347) and their relatives
• monitoring of response to diet, weight control and
medication.
Abnormalities of lipid metabolism most commonly come to
light following these tests. Non-fasting measurements of total
cholesterol (TC) and HDL cholesterol (HDL-C) allow estimation
of non-HDL cholesterol (non-HDLC, calculated as TC- HDL-C),
but a 12-hour fasting sample is required to standardise TG
measurement and allow calculation of LDL cholesterol (LDL-C)
according to the Friedewald formula:
LDL-C = TC - HDL-C - (TG/2.2) mmol/L
or
LDL-C = TC - HDL-C - (TG/5) mg/dL
The formula becomes unreliable when TG levels exceed
4 mmol/L (350 mg/dL). Measurements of non-HDLC or Apo
B100 may assess risk of cardiovascular disease more accurately
than LDL-C, particularly when TG levels are increased. The
use of non-fasting samples is increasing because non-fasting
TG is a more sensitive marker of the risk of cardiovascular
disease. Nevertheless, a 12-hour fast is required for formal
diagnosis of the presence of hypertriglyceridaemia or use
of the Friedewald equation. Consideration must be given
to confounding factors, such as recent illness, after which
cholesterol, LDL and HDL levels temporarily decrease in proportion
to severity. Results that will affect major decisions, such as
initiation of drug therapy, should be confirmed with a repeat
measurement.
Elevated levels of TG are common in obesity, diabetes and
insulin resistance (Chs 1 9 and 20), and are frequently associated
with low HDL and increased ‘small, dense’ LDL. Under these
circumstances, LDL-C may under-estimate risk. This is one
situation in which measurement of non-HDLC or Apo B may
provide more accurate risk assessment.
Presenting problems in lipid metabolism
Hyperlipidaemia can occur in association with various diseases
and drugs, as summarised in Box 14.25. Overt or subclinical
hypothyroidism (p. 639) may cause hypercholesterolaemia,
and so measurement of thyroid function is warranted in
most cases, even in the absence of typical symptoms
and signs.
Once secondary causes are excluded, primary lipid
abnormalities may be diagnosed. Primary lipid abnormalities
can be classified according to the predominant lipid problem:
hypercholesterolaemia, hypertriglyceridaemia or mixed
hyperlipidaemia (Box 14.26). Although single-gene disorders
are encountered in all three categories, most cases are due
to multiple-gene (polygenic) loci interacting with environmental
factors. Clinical consequences of dyslipidaemia vary somewhat
between these causes (pp. 346-347).
Hypercholesterolaemia
Hypercholesterolaemia is a polygenic disorder that is the
most common cause of a mild to moderate increase in
14.25 Causes of secondary hyperlipidaemia
Secondary hypercholesterolaemia
Moderately common
• Drugs:
•
Hypothyroidism
Diuretics
•
Pregnancy
Ciclosporin
•
Cholestatic liver disease
Glucocorticoids
Androgens
Antiretroviral agents
Less common
• Nephrotic syndrome
•
Porphyria
• Anorexia nervosa
•
Hyperparathyroidism
Secondary hypertriglyceridaemia
Common
• Type 2 diabetes mellitus
•
Drugs:
• Chronic renal disease
p-blockers
• Abdominal obesity
Retinoids
• Excess alcohol
Glucocorticoids
• Hepatocellular disease
Antiretroviral agents
374 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
i
14.26 Classification of hyperlipidaemia
Disease
Elevated lipid results
Elevated lipoprotein
CHD risk
Pancreatitis risk
Predominant hypercholesterolaemia
Polygenic (majority)
TC ± TG
LDL ± VLDL
+
Familial hypercholesterolaemia (LDLR defect,
TC ± TG
LDL ± VLDL
+++
-
defective Apo B1 00, increased function of PCSK9)
Hyperalphalipoproteinaemia
TC ± TG
HDL
-
-
Predominant hypertriglyceridaemia
Polygenic (majority)
TG
VLDL ± LDL
Variable
+
Lipoprotein lipase deficiency
TG » TC
Chylo
?
+++
Familial hypertriglyceridaemia
TG > TC
VLDL ± Chylo
?
++
Mixed hyperlipidaemia
Polygenic (majority)
TC + TG
VLDL + LDL
Variable
+
Familial combined hyperlipidaemia*
TC and/or TG
LDL and/or VLDL
++
+
Dysbetalipoproteinaemia*
TC and/or TG
IDL
+++
+
+ = slightly increased risk; ++ = increased risk; +++ = greatly increased risk; ? = risk unclear
*Familial combined hyperlipidaemia and dysbetalipoproteinaemia may also present as predominant hypercholesterolaemia or predominant hypertriglyceridaemia.
(Apo B100 = apolipoprotein B100; CHD = coronary heart disease; Chylo = chylomicrons; HDL =
high-density lipoprotein; IDL =
intermediate-density lipoprotein; LDL =
low-density lipoprotein; LDLR = low-density lipoprotein receptor; TC = total cholesterol; TG = triglycerides; VLDL = very low-density lipoprotein)
« Statin treatment: may be required from the age of about 10.
It does not compromise normal growth and maturation.
• Smoking: patients should be strongly advised not to smoke.
* Adherence to medication: critically important to the success of
treatment. Simple regimens should be used and education and
support provided.
LDL-C (Box 14.26). Physical signs, such as corneal arcus and
xanthelasma, may be found in this as well as other forms of
lipid disturbance (p. 346). The risk of cardiovascular disease is
proportional to the degree of LDL-C (or Apo B) elevation, but is
modified by other major risk factors, including low HDL-C and
high Lp(a).
Familial hypercholesterolaemia (FH) is a more severe disorder
with a prevalence of at least 0.4% in most populations. It is usually
caused by loss-of-function mutations affecting the LDLR gene,
which results in an autosomal dominant pattern of inheritance. A
similar syndrome can arise with loss-of-function mutations in the
ligand-binding domain of Apo B100 or gain-of-f unction mutations
in PCSK9, which promote LDLR degradation. Causative mutations
can be detected in one of these three genes by genetic testing
in about 70% of patients with FH. Most patients with these
types of FH have LDL-C levels that are approximately twice
as high as in normal subjects of the same age and gender.
Affected patients suffer from severe hypercholesterolaemia and
premature cardiovascular disease. FH may be accompanied
by xanthomas of the Achilles or extensor digitorum tendons
(p. 346), which are strongly suggestive of FH. The onset of
corneal arcus before age 40 is also suggestive of this condition.
Identification of an index case of FH (the first case of FH in a
family) should trigger genetic and biochemical screening of
other family members, which is a cost-effective method for case
detection. Affected individuals should be managed from childhood
(Box 14.27).
Homozygous FH may occur sporadically, especially in
populations in which there is a ‘founder’ gene effect or
consanguineous marriage. Homozygosity results in more extensive
xanthomas and precocious cardiovascular disease, often in
childhood. Hyperalphalipoproteinaemia refers to increased levels
of HDL-C. In the absence of an increase in LDL-C, this condition
rarely causes cardiovascular disease, but exceptions can occur
so it should not be regarded as universally benign.
Familial combined hyperlipidaemia, and dysbetalipoproteinaemia,
may present with the pattern of predominant hypercholesterolaemia
(see ‘Mixed hyperlipidaemia’ below).
Hypertriglyceridaemia
Hypertriglyceridaemia also usually involves polygenic factors
(see Box 14.26). Other common causes include excess alcohol
intake, medications (such as (3-blockers and retinoids), type
2 diabetes, impaired glucose tolerance, central obesity or
other manifestations of insulin resistance (p. 728) and impaired
absorption of bile acids. It is often accompanied by post-prandial
hyperlipidaemia and reduced HDL-C, both of which may contribute
to cardiovascular risk. Excessive intake of alcohol or dietary fat,
or other exacerbating factors, may precipitate a massive increase
in TG levels, which, if they exceed 10 mmol/L (880 mg/dL), may
pose a risk of acute pancreatitis.
Monogenic forms of hypertriglyceridaemia also occur due to
loss-of-function mutations in the genes encoding lipoprotein lipase,
Apo C2 or ANGPTL4, which coordinate the lipolytic breakdown
of TG-rich lipoproteins. These cause recessively inherited forms of
severe hypertriglyceridaemia that is not readily amenable to drug
treatment. They can present in childhood and may be associated
with episodes of acute abdominal pain and pancreatitis. In
common with other causes of severe hypertriglyceridaemia,
hepatomegaly, lipaemia retinalis and eruptive xanthomas may
occur (p. 346). Familial hypertriglyceridaemia may also be inherited
in a dominant manner due to mutations in the APOA5 gene, which
encodes Apo A5 - a co-factor that is essential for lipoprotein
lipase activity. These disorders may also be associated with
increased risk of cardiovascular disease.
Familial combined hyperlipidaemia, and dysbetalipoproteinaemia,
may present with the pattern of predominant hypertriglyceridaemia
(see ‘Mixed hyperlipidaemia’, below).
14.27 Familial hypercholesterolaemia in adolescence
Lipids and lipoprotein metabolism • 375
j Mixed hyperlipidaemia
It is difficult to define quantitatively the distinction between
predominant hyperlipidaemias and mixed hyperlipidaemia. The
term ‘mixed’ usually implies the presence of hypertriglyceridaemia,
as well as an increase in LDL-C or IDL. Treatment of massive
hypertriglyceridaemia may improve TG faster than cholesterol,
thus temporarily mimicking mixed hyperlipidaemia.
Primary mixed hyperlipidaemia is usually polygenic and, like
predominant hypertriglyceridaemia, often occurs in association
with type 2 diabetes, impaired glucose tolerance, central obesity
or other manifestations of insulin resistance (p. 728). Both
components of mixed hyperlipidaemia may contribute to the risk
of cardiovascular disease.
Familial combined hyperlipidaemia is a term used to identify an
inherited tendency towards the over-production of atherogenic
Apo B-containing lipoproteins. It results in elevation of cholesterol,
TG or both in different family members at different times. It is
associated with an increased risk of cardiovascular disease
but it does not produce any pathognomonic physical signs. In
practice, this relatively common condition is substantially modified
by factors such as age and weight. It may not be a monogenic
condition, but rather one end of a heterogeneous spectrum that
overlaps insulin resistance.
Dysbetalipoproteinaemia (also referred to as type 3
hyperlipidaemia, broad-beta dyslipoproteinaemia or remnant
hyperlipidaemia) involves accumulation of roughly equimolar levels
of cholesterol and TG. It is caused by homozygous inheritance of
the Apo E2 allele, which is the isoform least avidly recognised by
the LDLR. In conjunction with other exacerbating factors, such
as obesity or diabetes, it leads to accumulation of atherogenic
IDL and chylomicron remnants. Premature cardiovascular disease
is common, as is peripheral vascular disease. It may also result
in the formation of palmar xanthomas, tuberous xanthomas or
tendon xanthomas.
Rare dyslipidaemias
Several rare disturbances of lipid metabolism have been described
(Box 14.28). They provide important insights into lipid metabolism
and its impact on risk of cardiovascular disease.
BS 14.28 Miscellaneous and rare forms
of hyperlipidaemia
Condition
Lipoprotein pattern
CVD risk
Tangier disease
Very low HDL, low TC
+
Apo A1 deficiency
Very low HDL
++
ApoAl Milano
Very low HDL
-
Fish eye disease
Very low HDL, high TG
-
LCAT deficiency
Very low HDL, high TG
?
Autosomal recessive FH
Very high LDL
++
Sitosterolaemia
High plant sterols
including sitosterol
+
Cerebrotendinous
xanthomatosis
Bile acid defect
(cholestanol
accumulation)
+
+ = slightly increased risk; ++ = increased risk.
(CVD = cardiovascular disease; FH = familial hypercholesterolaemia; HDL =
high-density lipoprotein; LCAT = lecithin cholesterol acyl transferase; LDL =
low-density lipoprotein; TC = total cholesterol; TG = triglycerides)
Fish eye disease, Apo A1 Milano and lecithin cholesterol acyl
transferase (LCAT) deficiency demonstrate that very low HDL-C
levels do not necessarily cause cardiovascular disease, but Apo
A1 deficiency, and possibly Tangier disease, demonstrate that
low HDL-C can be atherogenic under some circumstances.
Autosomal recessive FH and PCSK9 gain-of-function mutations
reveal the importance of proteins that chaperone the LDLR.
Sitosterolaemia and cerebrotendinous xanthomatosis demonstrate
that sterols other than cholesterol can cause xanthomas and
cardiovascular disease, while PCSK9 loss-of-fu notion mutations,
abetalipoproteinaemia and hypobetalipoproteinaemia suggest
that low levels of Apo B-containing lipoproteins reduce the risk
of cardiovascular disease. The only adverse health outcomes
associated with extremely low plasma lipid levels in the latter
two conditions are attributable to fat-soluble vitamin deficiency,
or impaired transport of lipid from intestine or liver.
Principles of management
Lipid-lowering therapies have a key role in the secondary
and primary prevention of cardiovascular diseases (p. 487).
Assessment of absolute risk of cardiovascular disease, treatment
of all modifiable risk factors and optimisation of lifestyle, especially
diet and exercise, are central to management in all cases. Patients
with the greatest absolute risk of cardiovascular disease derive
the greatest absolute benefit from treatment. Public health
organisations recommend thresholds for the introduction of
lipid-lowering therapy based on the identification of patients
in very high-risk categories, or those calculated to be at high
absolute risk according to algorithms or tables such as the Joint
British Societies Coronary Risk Prediction Chart (see Fig. 16.77,
p. 511). These tables, which are based on large epidemiological
studies, should be recalibrated for the local population, if possible.
In general, patients who have cardiovascular disease, diabetes
mellitus, chronic renal impairment, familial hypercholesterolaemia
or an absolute risk of cardiovascular disease of more than 20% in
the ensuing 10 years are arbitrarily regarded as having sufficient
risk to justify drug treatment. Age is such an overwhelming
determinant of absolute cardiovascular risk that some recent
recommendations consider ‘lifetime’ risk. This diminishes the
pressure to treat very elderly patients and supports earlier
intervention in non-elderly patients.
Public health organisations also recommend target levels for
patients receiving drug treatment. High-risk patients should aim
for HDL-C >1 mmol/L (38 mg/dL) and fasting TG <2 mmol/L
(approximately 180 mg/dL), while target levels for LDL-C have
been reduced to 1 .8 mmol/L (76 mg/dL) or less. In general, total
cholesterol should be <5 mmol/L (190 mg/dL) during treatment,
and <4 mmol/L (approximately 150 mg/dL) in high-risk patients
and in secondary prevention of cardiovascular disease. Recent
trials have demonstrated continuous benefit of LDL-C reduction
to a level of 1 .4 mmol/L (54 mg/dL), so further reduction in
treatment targets may be anticipated.
Non-pharmacological management
Patients with lipid abnormalities should receive medical advice
and, if necessary, dietary counselling to:
• reduce intake of saturated and trans- unsaturated fat to
less than 7-1 0% of total energy
• reduce intake of cholesterol to <250 mg/day
• replace sources of saturated fat and cholesterol with
alternative foods, such as lean meat, low-fat dairy
376 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
products, polyunsaturated spreads and low-glycaemic-
index carbohydrates
• reduce energy-dense foods such as fats and soft drinks,
while increasing activity and exercise to maintain or lose
weight
• increase consumption of cardioprotective and nutrient-
dense foods, such as vegetables, unrefined
carbohydrates, fish, pulses, nuts, legumes, and fruit
• adjust alcohol consumption, reducing intake if excessive or
if associated with hypertension, hypertriglyceridaemia or
central obesity
• achieve additional benefits with preferential intake of foods
containing lipid-lowering nutrients such as n-3 fatty acids,
dietary fibre and plant sterols.
The response to diet is usually apparent within 3-4 weeks but
dietary adjustment may need to be introduced gradually. Although
hyperlipidaemia in general, and hypertriglyceridaemia in particular,
can be very responsive to these measures, LDL-C reductions
are often only modest in routine clinical practice. Explanation,
encouragement and persistence are often required to assist patient
adherence. Even minor weight loss can substantially reduce
cardiovascular risk, especially in centrally obese patients (p. 700).
All other modifiable cardiovascular risk factors should be
assessed and treated. If possible, intercurrent drug treatments
that adversely affect the lipid profile should be replaced.
Pharmacological management
The main diagnostic categories provide a useful framework
for management and the selection of first-line pharmacological
treatment (Fig. 14.14).
Hypercholesterolaemia
Hypercholesterolaemia can be treated with one or more of the
cholesterol-lowering drugs as described below.
Statins
These reduce cholesterol synthesis by inhibiting the HMGCoA
reductase enzyme. The reduction in cholesterol synthesis
up-regulates production of the LDLR, which increases clearance
of LDL and its precursor, IDL, resulting in a secondary reduction
in LDL synthesis. Statins reduce LDL-C by up to 60%, reduce
TG by up to 40% and increase HDL-C by up to 10%. They also
reduce the concentration of intermediate metabolites such as
isoprenes, which may lead to other effects such as suppression of
the inflammatory response. There is clear evidence of protection
against total and coronary mortality, stroke and cardiovascular
events across the spectrum of cardiovascular disease risk.
Statins are generally well tolerated and serious side-effects
are rare (well below 2%). Liver function test abnormalities and
muscle problems, such as myalgia, asymptomatic increase in
creatine kinase (CK), myositis and, infrequently, rhabdomyolysis,
are the most common. Side-effects are more likely in patients
who are elderly, debilitated or receiving other drugs that interfere
with statin degradation, which usually involves cytochrome P450
3A4 or glucuronidation.
Ezetimibe
Ezetimibe inhibits activity of the intestinal mucosal transporter
NPC1L1, which is responsible for absorption of dietary and
biliary cholesterol. The resulting depletion of hepatic cholesterol
up-regulates hepatic LDLR production. This mechanism of
action is synergistic with the effect of statins. Monotherapy in
a 10 mg/day dose reduces LDL-C by 15-20%. Slightly greater
(17-25%) incremental LDL-C reduction occurs when ezetimibe
is added to statins. Ezetimibe is well tolerated, and evidence of
a beneficial effect on cardiovascular disease endpoints is now
available. Plant sterol-supplemented foods, which also reduce
cholesterol absorption, lower LDL-C by 7-15%.
Bile acid-sequestering resins
Drugs in this class include colestyramine, colestipol and
colesevelam. These prevent the reabsorption of bile acids,
thereby increasing de novo bile acid synthesis from hepatic
cholesterol. As with ezetimibe, the resultant depletion of hepatic
cholesterol up-regulates LDL receptor activity and reduces LDL-C
in a manner that is synergistic with the action of statins. Resins
reduce LDL-C and modestly increase HDL-C, but may increase
TG. They are safe but may interfere with bioavailability of other
drugs. Colesevelam has fewer gastrointestinal effects than older
Fig. 14.14 Flow chart for the drug treatment of hyperlipidaemia. Interrupt treatment if creatine kinase is more than 5-10 times the upper limit of
normal, or if elevated with muscle symptoms, or if alanine aminotransferase is more than 2-3 times the upper limit. To convert triglyceride (TG) in mmol/L
to mg/dL, multiply by 88. To convert low-density lipoprotein (LDL)-C in mmol/L to mg/dL, multiply by 38.
Lipids and lipoprotein metabolism • 377
preparations that are less well tolerated. The depletion of bile
acids is sensed via the farnesyl X receptor and the response
may also improve glucose metabolism.
PCSK9 inhibitors
Monoclonal antibodies have been developed that neutralise
PCSK9, an enzyme that degrades the LDLR. This causes
levels of LDLR to increase, which markedly reduces LDL-C.
The PCSK9 inhibitors currently available are evolocumab and
alirocumab, which are administered by subcutaneous injection
every 2-4 weeks. These drugs are well tolerated and highly
effective. Reductions in LDL-C of about 50-60% have been
observed in patients who have not responded adequately to
standard lipid-lowering therapy and this has been accompanied
by a reduction in the risk of cardiovascular events of about 15%.
The PCSK9 inhibitors do not deplete intracellular concentrations
and, because of that, do not trigger compensatory mechanisms
that blunt the effect of other cholesterol-lowering medications.
Nicotinic acid
Pharmacological doses reduce peripheral fatty acid release, with
the result that VLDL and LDL decline while HDL-C increases.
Recent randomised clinical trials have been disappointing
regarding effects on atherosclerosis and cardiovascular events.
The same may be said of novel agents that inhibit cholesterol
ester transfer protein. Neither of these HDL-C-raising drugs is
indicated in current lipid management.
Combination therapy
In many patients, treatment of predominant hypercholesterolaemia
can be achieved by diet plus the use of a statin in sufficient
doses to achieve target LDL-C levels. Patients who do not
reach LDL targets on the highest tolerated statin dose, or who
are intolerant of statins, may receive ezetimibe, plant sterols, or
resins. Ezetimibe and resins are safe and effective in combination
with a statin because the mechanisms of action of individual
therapies complement each other while blunting each other’s
compensatory mechanisms.
Hypertriglyceridaemia
Predominant hypertriglyceridaemia can be treated with one of
the TG-lowering drugs described below (see Fig. 14.14).
Fibrates
These stimulate peroxisome prol iterator-activated receptor (PPAR)
alpha, which controls the expression of gene products that
mediate the metabolism of TG and HDL. As a result, synthesis
of fatty acids, TG and VLDL is reduced, while that of lipoprotein
lipase, which catabolises TG, is enhanced. In addition, production
of Apo A1 and ABC A1 is up-regulated, leading to increased
reverse cholesterol transport via HDL. Consequently, fibrates
reduce TG by up to 50% and increase HDL-C by up to 20%,
but LDL-C changes are variable.
Fewer large-scale trials have been conducted with fibrates
than with statins. The results are less conclusive, but reduced
rates of cardiovascular disease have been reported with fibrate
therapy in the subgroup of patients with low HDL-C levels and
elevated TG (TG >2.3 mmol/L (200 mg/dL)). Fibrates are usually
well tolerated but share a similar side-effect profile to statins. In
addition, they may increase the risk of cholelithiasis and prolong
the action of anticoagulants. Accumulating evidence suggests
that they may also have a protective effect against diabetic
microvascular complications.
Highly polyunsaturated long-chain n-3 fatty acids
These include eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA), which comprise approximately 30% of the fatty
acids in fish oil. EPA and DHA are potent inhibitors of VLDL TG
formation. Intakes of more than 2 g n-3 fatty acid (equivalent to 6 g
of most forms of fish oil) per day lower TG in a dose-dependent
fashion. Up to 50% reduction in TG may be achieved with 15 g
fish oil per day. Changes in HDL-C are variable but fish oils do not
routinely reduce LDL-C. Fish oil fatty acids have also been shown
to inhibit platelet aggregation and improve cardiac arrhythmia
in animal models. Dietary and pharmacological trials suggested
that n-3 fatty acids may reduce mortality from coronary heart
disease, but the benefit of fish oil supplements has been less
conclusive in recent trials. Fish oils appear to be safe and well
tolerated but dietary fish consumption is the preferred source.
Patients with predominant hypertriglyceridaemia who do not
respond to lifestyle intervention can be treated with fibrates
or fish oil, depending on individual response and tolerance. If
target levels are not achieved, the fibrates, fish oil and possibly
nicotinic acid can be combined. Massive hypertriglyceridaemia
may require more aggressive limitation of dietary fat intake
(<10-20% energy as fat). Any degree of insulin deficiency should
be corrected because insulin is required for optimal activity of
lipoprotein lipase. The initial target for patients with massive
hypertriglyceridaemia is TG <10 mmol/L (880 mg/dL), to reduce
the risk of acute pancreatitis.
Mixed hyperlipidaemia
Mixed hyperlipidaemia can be difficult to treat. First-line therapy
with statins alone is unlikely to achieve target levels once fasting
TGs exceed approximately 4 mmol/L (350 mg/dL). Fibrates
• Prevalence of atherosclerotic cardiovascular disease: greatest
in old age.
• Associated cardiovascular risk: lipid levels become less
predictive, as do other risk factors apart from age itself.
• Benefit of statin therapy: maintained up to the age of 80 years
but evidence is lacking beyond this.
• Life expectancy and statin therapy: lives saved by intervention
are associated with shorter life expectancy than in younger patients,
and so the impact of statins on quality-adjusted life years is smaller
in old age.
14.30 Dyslipidaemia in pregnancy
• Lipid metabolism: lipid and lipoprotein levels increase during
pregnancy. This includes an increase in low-density lipoprotein
cholesterol, which resolves post-partum. Remnant dyslipidaemia
and hypertriglyceridaemia may be exacerbated during pregnancy.
• Treatment: dyslipidaemia is rarely thought to warrant urgent
treatment so pharmacological therapy is usually contraindicated
when conception or pregnancy is anticipated. Teratogenicity has
been reported with systemically absorbed agents, and non-absorbed
agents may interfere with nutrient bioavailability.
• Monitoring: while still uncommon among women of child-bearing
age, cardiovascular disease is increasing in prevalence. Pre¬
conception cardiovascular review should be considered for women
at high risk to optimise medications for pregnancy and to ensure
that the patient will be able to withstand the demands of pregnancy
and labour.
14.29 Management of hyperlipidaemia in old age
378 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
are first-line therapy for dysbetalipoproteinaemia, but they may
not control the cholesterol component in other forms of mixed
hyperlipidaemia. Combination therapy is often required. Effective
combinations include:
• statin plus fenofibrate (recognising that the risk of
myopathy is increased with gemfibrozil, but fenofibrate is
relatively safe in this regard)
• statin plus fish oil when TG is not too high
• fibrate plus ezetimibe when cholesterol is not too high.
Monitoring of therapy
The effects of lipid-lowering therapy should be assessed after
6 weeks (12 weeks for fibrates). At this point, it is prudent to
review side-effects, lipid response (see target levels above), CK
and liver function tests. During longer-term follow-up, adherence to
treatment, diet and exercise should be assessed, with monitoring
of weight, blood pressure and lipid levels. The presence of
cardiovascular symptoms or signs should be noted and absolute
cardiovascular risk assessed periodically. Effective statin therapy
may be associated with a paradoxical and as yet unexplained
increase in coronary calcium score.
It is not necessary to perform routine checks of CK and
liver function unless symptoms occur, or if statins are used in
combination with fibrates, or other drugs that may interfere with
their clearance. If myalgia or weakness occurs in association
with CK elevation over 5-10 times the upper limit of normal, or
if sustained alanine aminotransferase (ALT) elevation more than
2-3 times the upper limit of normal occurs that is not accounted
for by fatty liver (p. 882), treatment should be discontinued and
alternative therapy sought.
The principles of the management of dyslipidaemia can be
applied broadly, but the objectives of treatment in the elderly (Box
14.29) and the safety of pharmacological therapy in pregnancy
(Box 14.30) warrant special consideration.
The porphyrias
This group of disorders is caused by inherited abnormalities in the
haem biosynthetic pathway (Fig. 14.15). Most of the described
forms are due to partial enzyme deficiencies with a dominant
mode of inheritance. They are commonly classified as hepatic
or erythropoietic, depending on whether the major site of excess
porphyrin production is in the liver or red cell.
The porphyrias have a penetrance in the order of 25%,
emphasising the importance of environmental factors in disease
expression. In porphyria cutanea tarda (PCT), which is the most
Metabolites
Pathway
Glycine + succinyl CoA
8-aminolaevulinic acid (ALA)
Porphobilinogen (PBG)
Hydroxymethylbilane
Coproporphyrin I (Copro I)
Uroporphyrin I (Uro I)
Uroporphyrinogen I
Isocoproporphyrin
Uroporphyrinogen
Porphyria
(Isocopro)
decarboxylase
cutanea tarda
♦■■■■■■■■■■■■
▼
Coproporphyrinogen III
Coproporphyrin III
Coproporphyrinogen
Hereditary
(Copro III)
1
oxidase
coproporphyria
Protoporphyrinogen IX
Protoporphyrin IX (proto IX)
+Fe2+
▼
Haem
Enzyme
Deficiency Symptom-
disease atology
ALA dehydratase Plumboporphyria B ©
PBG deaminase
4
Acute intermittent
porphyria
»•
Uroporphyrinogen Congenital ^ p
erythropoietic porphyria
synthetase
Protoporphyrinogen
oxidase
Ferrochelatase
i
N + P
Variegate porphyria N + P
-
Erythropoietic p
protoporphyria
Fig. 14.15 Haem biosynthetic pathway and enzyme defects responsible for the porphyrias. (ALA = 5-aminolaevulinic acid; CoA = co-enzyme A;
N = neurovisceral; P = photosensitive; PBG = porphobilinogen)
The porphyrias • 379
1 14.31 Diagnostic biochemical findings in the porphyrias
Elevated porphyrins and precursors
Condition
Blood
Urine
Faeces
ALA dehydratase deficiency (plumboporphyria)
Proto IX2
ALA, Copra III2
Acute intermittent porphyria (AIP)
ALA, PBG
Congenital erythropoietic porphyria (CEP)
Uro 1
Urol
Copro 1
Porphyria cutanea tarda (PCT)
Urol
Isocopro
Hereditary coproporphyria (HCP)
ALA, PBG, Copro III
Copro III
Variegate porphyria (VP)
ALA, PBG, Copro III
Proto IX
Erythropoietic protoporphyria (EPP)
Proto IX
Proto IX
1 Refer to Figure 14.15 for metabolic pathways. The paradoxical rise in coproporphyrin III (Copra III) and protoporphyrin (Proto) in this very rare condition is poorly understood.
(ALA = 5-aminolaevulinic acid; Isocopro = isocoproporphyrin; PBG = porphobilinogen; Uro = uroporphyrin)
common cause of porphyria, environmental triggers include
alcohol, iron accumulation, exogenous oestrogens and exposure
to various chemicals. Many cases are associated with hepatitis C
infection and this should always be screened for on presentation.
Clinical features
The clinical features of porphyria fall into two broad categories:
photosensitivity and acute neurovisceral syndrome. The enzyme
defects responsible for the diseases are shown in Figure 14.15.
Photosensitive skin manifestations, attributable to excess
production and accumulation of porphyrins in the skin, cause pain,
erythema, bullae, skin erosions, hirsutism and hyperpigmentation,
and occur predominantly on areas of the skin that are exposed to
sunlight (p. 1 220). The skin also becomes sensitised to damage
from minimal trauma.
The other pattern of presentation is with an acute neurological
syndrome. This almost always presents with acute abdominal
pain together with features of autonomic dysfunction, such as
tachycardia, hypertension and constipation. Neuropsychiatric
manifestations, hyponatraemia due to inappropriate ADH release
(p. 357), and an acute neuropathy may also occur (p. 1138). The
neuropathy is predominantly motor and may, in severe cases,
progress to respiratory failure.
There is no proven explanation for the episodic nature of the
attacks in porphyria, which can relapse and remit or follow a
prolonged and unremitting course. Sometimes, specific triggers
can be identified, such as alcohol, fasting, or drugs such as
anticonvulsants, sulphonamides, oestrogen and progesterone.
The oral contraceptive pill is a common precipitating factor. In a
significant number, no precipitant can be identified.
Investigations
The diagnosis of porphyria and classification into the various
forms have traditionally relied on measurements of porphyrins
and porphyrin precursors found in blood, urine and faeces (Box
14.31). The diagnosis is straightforward when the metabolites
are significantly elevated, but this is not always the case in
asymptomatic individuals who may have normal porphyrin studies.
More recently, measurement of the enzymes that are deficient in
the various porphyrias has provided further diagnostic information.
An example is measurement of porphobilinogen deaminase
activity in red blood cells to diagnose acute intermittent porphyria.
There is often considerable overlap between enzyme activities
in affected and normal subjects, however. Furthermore, some
of the enzymes occur in the mitochondria, for which it is more
difficult to obtain suitable specimens for analysis. All the genes
of the haem biosynthetic pathway have now been characterised.
This has made it possible to identify affected individuals in
families by genetic testing, a significant advance considering
that penetrance of porphyria is low.
Metabolite excretory patterns are always grossly abnormal
during an acute attack or with cutaneous manifestations of
porphyria, and are diagnostic of the particular porphyria. A normal
metabolite profile under these circumstances effectively excludes
porphyria. Metabolites usually remain abnormal for long periods
after an acute attack, and in some individuals never return to
normal. The diagnosis is not so straightforward in patients who are
in remission, or in asymptomatic individuals with a positive family
history. Neurological porphyria rarely manifests before puberty,
nor can it be readily diagnosed after the menopause as porphyrin
excretion may be normal. Genetic testing for disease-specific
mutations can clarify the situation.
Management
For patients predisposed to neurovisceral attacks, general
management includes avoidance of any agents known to
precipitate acute porphyria. Specific management includes
intravenous glucose, as provision of 5000 kilojoules per day can,
in some cases, terminate acute attacks through a reduction in
5-aminolaevulinic acid (ALA) synthetase activity, leading to reduced
ALA and porphyrin synthesis. More recently, administration of
haem (in various forms such as haematin or haem arginate)
has been shown to reduce metabolite excretory rates, relieve
pain and accelerate recovery. Cyclical acute attacks in women
sometimes respond to suppression of the menstrual cycle using
gonadotrophin-releasing hormone analogues. In rare cases with
frequent prolonged attacks or attacks intractable to treatment,
liver transplantation has been effective.
There are few specific or effective measures to treat the
photosensitive manifestations. The primary goal is to avoid sun
exposure and skin trauma. Barrier sun creams containing zinc or
titanium oxide are the most effective products. New colourless
creams containing nanoparticle formulations have improved
patient acceptance. Beta-carotene is used in some patients with
erythropoietic porphyria with some efficacy. Afamelanotide, a
synthetic analogue of alpha-melanocyte stimulating hormone (a-
MSH), has also been shown to provide protection in erythropoietic
protoporphyria, and is now undergoing approval in many countries.
In porphyria cutanea tarda, a course of venesections to remove
iron can result in long-lasting clinical and biochemical remission,
380 • CLINICAL BIOCHEMISTRY AND METABOLIC MEDICINE
especially if exposure to identified precipitants, such as alcohol
or oestrogens, is reduced. Alternatively, a prolonged course of
low-dose chloroquine therapy is effective.
Further information
Journal articles
Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on
diagnosis and treatment of hyponatraemia. Eur J Endocrinol 2014;
1 70:G1-G47.
Walsh S, Unwin R. Renal tubular disorders. Clin Med 2012;
1 2(5):476-479.
Websites
emedicine.medscape.com The Nephrology link on this site contains a
useful compendium of articles.
lipidsonline.org Summarises management strategies for
dyslipidaemia.
ncbi.nlm.nih.gov The link to OMIM (Online Mendelian Inheritance in
Man) provides updated information on the genetic basis of
metabolic disorders.
porphyria-europe.com and drugs-porphyria.org Excellent resources on
drug safety in porphyria.
B Conway
PJ Phelan
GD Stewart
Nephrology and urology
Clinical examination of the kidney and urinary tract 382
Renal involvement in systemic conditions 409
Functional anatomy and physiology 384
Acute kidney injury 41 1
Investigation of renal and urinary tract disease 386
Chronic kidney disease 415
Glomerular filtration rate 386
Renal replacement therapy 420
Urine investigations 387
Conservative treatment 421
Blood tests 388
Haemodialysis 421
Imaging 389
Haemofiltration 423
Renal biopsy 391
Haemodiafiltration 423
Presenting problems in renal and urinary tract disease 391
Peritoneal dialysis 424
Oliguria/anuria 391
Renal transplantation 424
Haematuria 391
Proteinuria 392
Oedema 395
Renal disease in pregnancy 426
Renal disease in adolescence 426
Hypertension 396
Drugs and the kidney 426
Loin pain 396
Drug-induced renal disease 426
Dysuria 396
Prescribing in renal disease 426
Frequency 396
Infections of the urinary tract 426
Polyuria 396
Nocturia 397
Urolithiasis 431
Urinary incontinence 397
Diseases of the collecting system and ureters 433
Congenital abnormalities 433
Glomerular diseases 397
Glomerulonephritis 397
Tubulo-interstitial diseases 401
Genetic renal diseases 403
Retroperitoneal fibrosis 434
Tumours of the kidney and urinary tract 434
Urinary incontinence 436
Inherited glomerular diseases 403
Prostate disease 437
Inherited tubulo-interstitial diseases 404
Testicular tumours 439
Isolated defects of tubular function 405
Cystic diseases of the kidney 405
Renal vascular diseases 406
Renal artery stenosis 406
Acute renal infarction 408
Diseases of small intrarenal vessels 408
Erectile dysfunction 440
382 • NEPHROLOGY AND UROLOGY
Clinical examination of the kidney and urinary tract
Many diseases of the kidney and urinary
tract are clinically silent, at least in the early
stages. Accordingly, it is common for these
conditions to be detected first by routine
blood tests or on dipstick testing of the
urine. Several important abnormalities can
also be picked up on physical examination,
however, and these are summarised
below.
5 Fundoscopy
A Hypertensive changes
4 Jugular venous pressure
Elevated in fluid overload
3 Blood pressure
Often elevated
2 Skin
Yellow complexion*
Bruising*
Excoriation of pruritus*
Reduced skin turgor in
fluid depletion
1 Hands
A Splinter haemorrhages
A ‘Brown line’ pigmentation
of nails
6 Lungs
Crepitations in fluid overload
Observation
• Tiredness
• Respiratory rate and depth
increased in metabolic acidosis
• Pallor*
*Features of advanced chronic kidney
disease (see also Fig. 15.22)
7 Heart
Extra heart sounds in fluid
overload
Pericardial friction rub*
8 Abdomen
Renal mass
Local tenderness
Renal or other arterial bruits
in renal vascular disease
Rectal examination — prostate
9 Genitalia
Scrotal swellings
A Phimosis
10 Sacral oedema
Ankle oedema
12 Peripheral neuropathy*
13 Urinalysis for blood and
protein
14 Urine microscopy
See Fig. 15.3
Clinical examination of the kidney and urinary tract
383
Blood pressure
measurements
Blood tests for abnormal Urinalysis for protein, blood,
creatinine and electrolytes nitrites and leucocytes
Digital rectal examination for Checking sacrum and ankles for pitting oedema
prostate enlargement
Clinical examination techniques to evaluate urological and renal abnormalities. Inset (Dipstick): From Pitkin J, Peattie AB, Magowan BA. Obstetrics
and gynaecology: An lilustrated colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2003.
Bladder
Pubic bones
Corpus spongiosum
Corpus cavernosum
Urethra
Gians penis
Prepuce
Ureter
Seminal vesicle
Rectum
Ejaculatory duct
Prostate gland
Anus
Vas deferens
Epididymis
Testis
Scrotum
Male lower urinary tract demonstrating the relationship of the bladder, urethra, vas deferens and testes.
384 • NEPHROLOGY AND UROLOGY
This chapter describes the disorders of the kidneys and urinary
tract that are commonly encountered in routine practice, as
well as giving an overview of the highly specialised field of renal
replacement therapy. Disorders of renal tubular function, which
may cause alterations in electrolyte and acid-base balance, are
described in Chapter 14.
Functional anatomy and physiology
The kidneys
The kidneys play a central role in excretion of many metabolic
breakdown products, including ammonia and urea from protein,
creatinine from muscle, uric acid from nucleic acids, drugs and
toxins. They achieve this by making large volumes of an ultrafiltrate
of plasma (120 mL/min, 170 L724 hrs) at the glomerulus, and
selectively reabsorbing components of this ultrafiltrate at points
along the nephron. The rates of filtration and reabsorption are
controlled by many hormonal and haemodynamic signals to
regulate fluid and electrolyte balance (p. 349), blood pressure
(p. 447), and acid-base (p. 363) and calcium-phosphate
homeostasis (pp. 367 and 368). In addition, the kidneys activate
vitamin D and control the synthesis of red blood cells by producing
erythropoietin. Strategies to replace each of these important
functions are required when managing patients with kidney failure.
Each kidney is approximately 11-14 cm in length in healthy
adults; they are located retroperitoneally on either side of
the aorta and inferior vena cava between the 12th thoracic
and 3rd lumbar vertebrae (Fig. 15.1 A). The right kidney is
usually a few centimetres lower because the liver lies above
it. Both kidneys rise and descend several centimetres with
respiration.
The kidneys have a rich blood supply and receive approximately
20-25% of cardiac output through the renal arteries, which arise
from the abdominal aorta. The renal arteries undergo various
subdivisions within the kidney, eventually forming interlobular
arteries that run through the renal cortex. These eventually give
rise to afferent glomerular arterioles that supply the glomeruli. The
efferent arteriole, leading from the glomerulus, supplies the distal
nephron and medulla in a ‘portal’ circulation (Fig. 15.1 B). This
highly unusual arrangement of two serial capillary beds reflects
the role of the afferent and efferent arterioles in autoregulation
of glomerular filtration.
The nephron
Each kidney contains approximately 1 million individual functional
units, called nephrons. Each nephron consists of a glomerulus,
which is responsible for ultrafiltration of blood, a proximal renal
tubule, a loop of Henle, a distal renal tubule and a collecting duct,
which together are responsible for selective reabsorption of water
and electrolytes that have been filtered at the glomerulus (see
Fig. 14.2, p. 350, and Fig. 15.1 B). Under normal circumstances,
more than 99% of the 1 70 L of glomerular filtrate that is produced
each day is reabsorbed in the tubules. The remainder passes
through the collecting ducts of multiple nephrons and drains
into the renal pelvis and ureters.
The glomerulus
The glomerulus comprises a tightly packed loop of capillaries
supplied by an afferent arteriole and drained by an efferent
arteriole. It is surrounded by a cup-shaped extension of the
proximal tubule termed Bowman’s capsule, which is composed
of epithelial cells. The glomerular capillary endothelial cells contain
pores (fenestrae), through which circulating molecules can pass
to reach the underlying glomerular basement membrane (GBM),
which is formed by fusion of the basement membranes of
tubular epithelial and vascular endothelial cells (Fig. 15.1C and
D). Glomerular epithelial cells (podocytes) have multiple long
foot processes that interdigitate with those of the adjacent
epithelial cells, thereby maintaining a selective barrier to filtration
(Fig. 15.1 E). Mesangial cells lie in the central region of the
glomerulus. They have contractile properties similar to those
of vascular smooth muscle cells and play a role in regulating
glomerular filtration rate.
Under normal circumstances, the glomerulus is impermeable
to proteins the size of albumin (67 kDa) or larger, while
proteins of 20 kDa or smaller are filtered freely. The ability of
molecules between 20 and 67 kDa to pass through the GBM
is variable and depends on the size (smaller molecules are
filtered more easily) and charge (positively charged molecules
are filtered more easily). Very little lipid is filtered by the
glomerulus.
Filtration pressure at the glomerulus is normally maintained
at a constant level, in the face of wide variations in systemic
blood pressure and cardiac output, by alterations in muscle
tone within the afferent and efferent arterioles and mesangial
cells. This is known as autoregulation. Reduced renal perfusion
pressure increases local production of prostaglandins that mediate
vasodilatation of the afferent arteriole, thereby increasing the
intraglomerular pressure (Fig. 15.1 D). In addition, renin is released
by specialised smooth muscle cells in the juxtaglomerular
apparatus in response to reduced perfusion pressure, stimulation
of sympathetic nerves or low sodium concentration of fluid in
the distal convoluted tubule at the macula densa. Renin cleaves
angiotensinogen to release angiotensin I, which is further cleaved
by angiotensin-converting enzyme (ACE) to produce angiotensin
II. This restores glomerular perfusion pressure in the short term
by causing vasoconstriction of the efferent arterioles within the
kidney to raise intraglomerular pressure selectively (Fig. 15.1 D),
and by inducing systemic vasoconstriction to increase blood
pressure and thus renal perfusion pressure. In the longer term,
angiotensin II increases plasma volume by stimulating aldosterone
release, which enhances sodium reabsorption by the renal
tubules (see Fig. 18.18, p. 666). Consumption of non-steroidal
anti-inflammatory preparations and renin-angiotensin system
inhibitors in the context of volume depletion may impair the ability
of the kidney to maintain glomerular filtration and exacerbate
pre-renal failure (see Fig. 15.19, p. 413).
Renal tubules, loop of Henle and collecting ducts
The proximal renal tubule, loop of Henle, distal renal tubule
and collecting ducts are responsible for reabsorption of water,
electrolytes and other solutes, as well as regulating acid-base
balance, as described in detail on page 350 and in Figure 14.3.
They also play a key role in regulating calcium homeostasis
by converting 25-hydroxyvitamin D to the active metabolite
1 ,25-dihydroxyvitamin D (p. 1049). Failure of this process
contributes to the pathogenesis of hypocalcaemia and bone
disease that occurs in chronic kidney disease (CKD, p. 415).
Fibroblast-like cells that lie in the interstitium of the renal cortex
are responsible for production of erythropoietin, which in turn is
required for production of red blood cells. Erythropoietin synthesis
is regulated by oxygen tension; anaemia and hypoxia increase
production, whereas polycythaemia and hyperoxia inhibit it.
Functional anatomy and physiology • 385
Mesangial
cell "
Mesangial
matrix ’
Prostaglandins
vasodilate
Afferent
arteriole
Macula densa
Foot process Epithelial cell
(podocyte)
Fig. 15.1 Functional anatomy of the kidney. [A] Anatomical relationships of the kidney. [§] A single nephron. For the functions of different segments,
see Figures 14.2 and 14.3 (pp. 350 and 351). [C] Histology of a normal glomerulus. [D] Schematic cross-section of a glomerulus, showing five capillary
loops, to illustrate structure and show cell types. [T] Electron micrograph of the filtration barrier. (GBM = glomerular basement membrane) (C) Courtesy of
Dr J.G. Simpson, Aberdeen Royal Infirmary.
386 • NEPHROLOGY AND UROLOGY
Failure of erythropoietin production plays an important role in
the pathogenesis of anaemia in CKD.
| The ureters and bladder
The ureters drain urine from the renal pelvis (Fig. 15.1 A) and
deliver it to the bladder, a muscular organ that lies anteriorly
in the lower part of the pelvis, just behind the pubic bone.
The function of the bladder is to store and then release urine
during micturition. The bladder is richly innervated. Sympathetic
nerves arising from T10-L2 relay in the pelvic ganglia to cause
relaxation of the detrusor muscle and contraction of the bladder
neck (both via a-adrenoceptors), thereby preventing release
of urine from the bladder. The distal sphincter mechanism
is innervated by somatic motor fibres from sacral segments
S2-4, which reach the sphincter either by the pelvic plexus
or via the pudendal nerves. Afferent sensory impulses pass
to the cerebral cortex, from where reflex-increased sphincter
tone and suppression of detrusor contraction inhibit micturition
until it is appropriate. Conversely, parasympathetic nerves
arising from S2-4 stimulate detrusor contraction, promoting
micturition.
The micturition cycle has a storage (filling) phase and a voiding
(micturition) phase. During the filling phase, the high compliance
of the detrusor muscle allows the bladder to fill steadily without
a rise in intravesical pressure. As bladder volume increases,
stretch receptors in its wall cause reflex bladder relaxation and
increased sphincter tone. The act of micturition is initiated first by
voluntary and then by reflex relaxation of the pelvic floor and distal
sphincter mechanism, followed by reflex detrusor contraction.
These actions are coordinated by the pontine micturition centre.
Intravesical pressure remains greater than urethral pressure until
the bladder is empty.
The prostate gland
The prostate gland is situated at the base of the bladder,
surrounding the proximal urethra (p. 383). Exocrine glands
within the prostate produce fluid, which comprises about 20%
of the volume of ejaculated seminal fluid and is rich in zinc and
proteolytic enzymes. The remainder of the ejaculate is formed in
the seminal vesicles and bulbo-urethral glands, with spermatozoa
arising from the testes.
Smooth muscle fibres within the prostate, which are under
sympathetic control, play a role in controlling urine flow
through the bulbar urethra, and also contract at orgasm to
move seminal fluid through ejaculatory ducts into the bulbar
urethra (emission). Contraction of the bulbocavernosus muscle
(via a spinal muscle reflex) then ejaculates the semen out of
the urethra.
The penis
Blood flow into the corpus cavernosum of the penis is controlled
by sympathetic nerves from the thoracolumbar plexus, which
maintain smooth muscle contraction (p. 383). In response to
afferent input from the glans penis and from higher centres,
pelvic splanchnic parasympathetic nerves actively relax the
cavernosal smooth muscle via neurotransmitters such as nitric
oxide, acetylcholine, vasoactive intestinal polypeptide (VIP) and
prostacyclin, with consequent dilatation of the lacunar space. At
the same time, draining venules are compressed, trapping blood
in the lacunar space with consequent elevation of pressure and
erection (tumescence) of the penis.
Investigation of renal and urinary
tract disease
Glomerular filtration rate
The glomerular filtration rate (GFR) is the sum of the ultrafiltration
rates from plasma into the Bowman’s space in each nephron
and is a measure of renal excretory function. It is proportionate
to body size and the reference value is usually expressed after
correction for body surface area as 120+25 ml_/min/1.73 m2.
The GFR may be measured directly by injecting and measuring
the clearance of compounds such as inulin or radiolabelled
ethylenediamine-tetra-acetic acid (EDTA), which are completely
filtered at the glomerulus and are not secreted or reabsorbed
by the renal tubules (Box 15.1). This is not performed routinely,
however, and is usually reserved for special circumstances,
such as the assessment of renal function in potential live kidney
donors. Instead, GFR is usually assessed indirectly in clinical
15.1 How to estimate glomerular filtration rate (GFR)
Measuring GFR
• Direct measurement using labelled ethylenediamine-tetra-acetic
acid (EDTA) or inulin
• Creatinine clearance (CrCI):
Minor tubular secretion of creatinine causes CrCI to exaggerate
GFR when renal function is poor; can be affected by drugs (e.g.
trimethoprim, cimetidine)
Needs 24-hr urine collection (inconvenient and often unreliable)
nni/ . , . . urine creatinine concentration (iimol/L) x volume (ml_)
CrCI (mL/min) = - — - - - - — -
plasma creatinine concentration (jimol/L) x time (min)
Estimating GFR with equations
• The Modification of Diet in Renal Disease (MDRD) study equation
(see www.renal.org/eGFR):
Requires knowledge of age and sex only; it can therefore be
reported automatically by laboratories
For limitations, see Box 15.2
eGFR = 1 75* x (creatinine in jLimol/L/88.4)_1 154 x(age in yrs)-0-203
x (0.742 if female) x (1.21 if black)
• The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
equation:
More accurately estimates the actual GFR than the MDRD eGFR
in those with relatively preserved renal function
eGFR = 141 x min (SCr/K, 1)a x max (SCr/K, 1)-t209x0.993Age
x 1 .01 8 (if female) xl .1 59 (if black)
Where SCr = serum creatinine in |imol/L
k=61 .9 if female and 79.6 if male
a=-0.329 if female and -0.411 if male
min = whichever is the minimum of serum creatinine/K or 1
max = whichever is the maximum of serum creatinine/K or 1
• No equations perform well in unusual circumstances, such as
extremes of body (and muscle) mass or in acutely unwell patients
(see Box 15.2)
*A correction factor of 175 is used for isotope dilution mass spectrometry
traceable creatinine measurements. To convert creatinine in mg/dL to jimol/L,
multiply by 88.4.
Investigation of renal and urinary tract disease • 387
Fig. 15.2 Serum creatinine and the glomerular filtration rate (GFR).
[A~| The relationship between serum creatinine and estimated GFR
(eGFR) is non-linear; small increases above the normal range (e.g.
80-100 jxmol/L; green lines) can therefore indicate a substantial decline in
renal function (e.g. 105-80 mL/min/1 .73 m2; conversely, in the high
range, large changes in creatinine (e.g. 400-600 pmol/L; blue lines) can
occur with only small declines in renal function (e.g. 20-15 mL7
min/1 ,73m2). [§] Creatinine is dependent on muscle mass; the same
creatinine value may therefore reflect very different levels of renal function
depending on the age and sex of the individual. To convert creatinine in
mg/dL to jimol/L, multiply by 88.4.
practice by measuring serum levels of endogenously produced
compounds that are excreted by the kidney. The most widely used
is serum creatinine, which is produced by muscle at a constant
rate, is almost completely filtered at the glomerulus, and is not
reabsorbed. Although creatinine is secreted to a small degree
by the proximal tubule, this is only usually significant in terms of
GFR estimation in severe renal impairment, where it accounts
for a larger proportion of the creatinine excreted. Accordingly,
provided muscle mass remains constant, changes in serum
creatinine concentrations closely reflect changes in GFR. The
relationship between serum creatinine and GFR is not linear,
however, and a modest elevation in serum creatinine above
the normal range may therefore reflect a substantial decline in
GFR (Fig. 15.2). For this reason, several methods have been
developed to estimate GFR from serum creatinine measurements
(see Box 15.1) but the most widely used is the Modification of
Diet in Renal Disease (MDRD) equation. Routine reporting by
laboratories of estimated GFR (eGFR) has increased recognition
of moderate kidney damage and encouraged early deployment
15.2 Limitations of estimated glomerular filtration
rate (eGFR)
• It is only an estimate, with wide confidence intervals (90% of
patients will have eGFR within 30% of their measured GFR, and
98% within 50%)
• It is based on serum creatinine, and so may over-estimate actual
GFR in patients with low muscle mass (e.g. those with cachexia,
amputees) and under-estimate actual GFR in individuals taking
creatine supplements (creatinine is a metabolite of creatine) or
trimethoprim (inhibits secretion of creatinine)
• Creatinine level must be stable over days; eGFR is not valid in
assessing acute kidney injury
• It tends to under-estimate normal or near-normal function, so
slightly low values should not be over- interpreted
• In the elderly, who constitute the majority of those with low eGFR,
there is controversy about categorising people as having chronic
kidney disease (Box 15.3) on the basis of eGFR alone, particularly
at stage 3A, since there is little evidence of adverse outcomes when
eGFR is >45 mL/min/1 .73 m2 unless there is also proteinuria
• eGFR is not valid in under-1 8s or during pregnancy
• Ethnicity is not taken into account in routine laboratory reporting;
the laboratory eGFR value should therefore be multiplied by 1 .21 for
black people
• Few patients will understand eGFR in terms of mL/min/1 .73 m2;
it may therefore be helpful to assume that a GFR of 100 mU
min/1 .73 m2 is approximately normal and to discuss eGFR values in
terms of a percentage of normal, e.g. 25 mL/min/1 .73 m2=25% of
normal kidney function
of protective therapies; however, some limitations remain (Boxes
15.2 and 15.3). In particular, the MDRD formula is based on the
serum creatinine value and so is heavily influenced by muscle
mass; eGFR may therefore be misleading in individuals whose
muscle bulk is outside the normal range for their sex and age.
Measurement of other endogenous metabolites, such as cystatin
C, may provide a more accurate estimate of GFR in this setting;
this test, however, is not yet widely available in routine clinical
practice.
Direct measurement of creatinine clearance by collecting a
24-hour urine sample and relating serum creatinine levels to
urinary creatinine excretion (see Box 15.1) is now less commonly
performed due to the difficulty in obtaining accurate 24-hour urine
collections. It may still have a role in assessing renal function in
patients at extremes of muscle mass, where the creatinine-based
equations perform poorly.
Urine investigations
Screening for the presence of blood (p. 391), protein (p. 392),
glucose, ketones, nitrates and leucocytes, and assessment of
urinary pH and osmolality can be achieved by dipstick testing.
The presence of leucocytes and nitrites in urine is indicative of
renal tract infection. Urine pH can provide diagnostic information
in the assessment of renal tubular acidosis (p. 365).
Urine microscopy (Fig. 15.3) may detect dysmorphic
erythrocytes, which suggest the presence of nephritis or red
cell casts, indicative of glomerular disease. White cell casts
are strongly suggestive of pyelonephritis. Microscopy may also
detect the presence of bacteria in those with urinary infection
and crystals in patients with renal stone disease. It should be
noted that calcium oxalate and urate crystals can sometimes
be found in normal urine that has been left to stand, due to
crystal formation ex vivo.
388 • NEPHROLOGY AND UROLOGY
il
15.3 Stages of chronic kidney disease (CKD)
Stage
Definition2
Description
Prevalence4
Clinical presentation5
1
Kidney damage3 with normal or
high GFR (>90)
Normal function
3.5%
Asymptomatic
2
Kidney damage and GFR
60-89
Mild CKD
3.9%
Asymptomatic
3A
3B
GFR 45-59
GFR 30-44
Mild to moderate CKD
Moderate to severe CKD
7.6% (3A
and 3B
combined)
Usually asymptomatic
Anaemia in some patients at 3B
Most are non-progressive or progress very slowly
4
GFR 15-29
Severe CKD
0.4%
First symptoms often at GFR <20
Electrolyte problems likely as GFR falls
5
GFR <15 or on dialysis
Kidney failure
0.1%
Significant symptoms and complications usually present
Dialysis initiation varies but usually at GFR <10
Stages of CKD 1-5 were originally defined by the US National Kidney Foundation Kidney Disease Quality Outcomes Initiative 2002. In the 2013 Kidney Disease Outcomes
Quality Initiative (K/D0QI) CKD guideline update, the suffices A1, A2 and A3 are recommended, indicating the presence of albuminuria of <30, 30-300 and >300 mg/
24 hrs respectively, in view of the prognostic importance of albuminuria. 2Two GFR values 3 months apart are required to assign a stage. All GFR values are in ml_/
min/1 .73 m2. 3Kidney damage means pathological abnormalities or markers of damage, including abnormalities in urine tests or imaging studies. Tram Hill NR, Fatoba ST,
Oke JL et al. Global prevalence of chronic kidney disease - a systematic review and meta-analysis. PLoS One 2016; 1 1 :e01 58765. Tor further information, see page 415.
|Ak ^
Fig. 15.3 Urine microscopy. [j| Erythrocytes due to bleeding from lower
in the urinary tract (x400). \S\ Dysmorphic erythrocytes due to glomerular
inflammation (x400). [C] Hyaline casts in normal urine. [D] Erythrocytes
and a red cell cast in glomerulonephritis (xlOO). Panels A-C are phase
contrast images; D is a bright field image. (A, B) Courtesy of Dr G.M.
ladorola and Dr F. Quarello, B. Bosco Hospital, Turin (from www.sin-italia
. org/imago/sediment/sed. htm).
Urine collection over a 24-hour period may be performed to
measure excretion of solutes, such as calcium, oxalate and urate,
in patients with recurrent renal stone disease (p. 431). Proteinuria
can also be measured on 24-hour collections but is usually now
quantified by protein/creatinine ratio on spot urine samples.
Other dynamic tests of tubular function, including concentrating
ability (p. 688), ability to excrete a water load (p. 357) and
ability to excrete acid (p. 415), and calculation of fractional
calcium, phosphate or sodium excretion, are valuable in some
circumstances but are usually performed in very specific contexts.
The fractional excretion of these ions can be calculated by the
general formula: 1 00 x (urine concentration of analyte x serum
creatinine) / (serum concentration of analyte x urinary creatinine).
Calculation of fractional excretion of sodium (FENa) can help in
the setting of acute kidney injury (AKI) to differentiate volume
depletion, when the tubules are avidly conserving sodium (FENa
typically <1.0%), from acute tubular necrosis, when the tubules
are damaged and are less able to conserve sodium (FENa typically
>1.0%). In clinical practice this is seldom required.
Blood tests
Haematology
A normochromic normocytic anaemia is common in CKD and
is due in part to deficiency of erythropoietin and bone marrow
suppression secondary to toxins retained in CKD. Other causes
of anaemia include iron deficiency from urinary tract bleeding, and
haemolytic anaemia secondary to disorders such as haemolytic
uraemic syndrome (HUS) and thrombotic thrombocytopenic
purpura (TTP). Other abnormalities may be observed that reflect
underlying disease processes, such as neutrophilia and raised
erythrocyte sedimentation rate (ESR) in vasculitis or sepsis, and
lymphopenia and raised ESR in systemic lupus erythematosus
(SLE). Fragmented red cells on blood film and low platelets may
be observed in thrombotic microangiopathies such as HUS/TTP
and malignant hypertension. Pancytopenia may occur in SLE or
bone marrow suppression due to myeloma.
Biochemistry
Abnormalities of routine biochemistry are common in renal disease.
Serum levels of creatinine may be raised, reflecting reduced GFR
(see above), as may serum potassium. Serum levels of urea are
often increased in kidney disease but this analyte has limited
value as a measure of GFR since levels increase with protein
intake, following gastrointestinal haemorrhage and in catabolic
states. Conversely, urea levels may be reduced in patients with
chronic liver disease or anorexia and in malnourished patients,
independently of changes in renal function. In the absence of
the other causes mentioned above, an elevated urea:creatinine
Investigation of renal and urinary tract disease • 389
ratio is indicative of volume depletion and pre-renal failure. Serum
calcium tends to be reduced and phosphate increased in CKD, in
association with high parathyroid hormone (PTH) levels caused by
reduced production of 1 ,25-dihydroxyvitamin D (1 ,25(OH)2D) by
the kidney (secondary hyperparathyroidism). In some patients, this
may be accompanied by raised serum alkaline phosphatase levels,
which are indicative of renal osteodystrophy. Serum bicarbonate
may be low in renal failure and in renal tubular acidosis. Serum
albumin may be low in liver disease, as a negative acute phase
response or due to malnutrition/malabsorption, but if it is a new
finding it should prompt urinalysis to exclude nephrotic syndrome.
Other biochemical abnormalities may be observed that reflect
underlying disease processes, such as raised glucose and HbA1c
levels in diabetes mellitus (p. 726) and raised levels of C-reactive
protein (CRP) in sepsis and vasculitis.
| Immunology
Antinuclear antibodies, antibodies to extractable nuclear antigens
and anti-double-stranded DNA antibodies may be detected
in patients with renal disease secondary to SLE (p. 1034).
Antineutrophil cytoplasmic antibodies (ANCAs) may be detected
in patients with glomerulonephritis secondary to systemic
vasculitis (p. 1040), as may antibodies to GBM in patients with
Goodpasture’s syndrome (p. 401), and low levels of complement
may be observed in a number of kidney diseases (see Box
15.17, p. 401).
Imaging
Ultrasound
Renal ultrasound is a valuable non-invasive technique that may
be performed to assess renal size and to investigate patients
who are suspected of having obstruction of the urinary tract
(Fig. 15.4), renal tumours, cysts or stones. Ultrasound can also
be used to provide images of the prostate gland and bladder,
and to estimate the completeness of emptying in patients
with suspected bladder outflow obstruction. In addition, it can
reveal other abdominal, pelvic and retroperitoneal pathology.
Ultrasonography may show increased signal in the renal cortex
with loss of distinction between cortex and medulla, which is
characteristic of CKD. Doppler imaging can be used to study
blood flow in extrarenal and larger intrarenal vessels, and to
assess the resistivity index (peak systolic velocity - end -diastolic
velocity/peak systolic velocity in the intrarenal arteries), which
may be elevated (>0.7) in various diseases, including acute
tubular necrosis and rejection of a renal transplant. However,
renal ultrasound is operator-dependent and the results are often
less clear in obese patients.
Computed tomography
Computed tomography urography (CTU) is used to evaluate
cysts and mass lesions in the kidney or filling defects within the
collecting systems. It usually entails an initial scan without contrast
medium, and subsequent scans following injection of contrast
to obtain a nephrogram image and images during the excretory
phases. CTU has largely replaced the previous gold-standard
investigation of intravenous urography (IVU) for investigation of the
upper urinary tract, having the advantage of providing complete
staging information and details of surrounding organs. Contrast
enhancement is particularly useful for characterising mass lesions
within the kidney and differentiating benign from malignant
lesions (see Fig. 15.32A, p. 435). CT without contrast gives
clear definition of retroperitoneal anatomy regardless of obesity
and is superior to ultrasound in this respect. Non-contrast CT of
kidneys, ureters and bladder (CTKUB) is the method of choice
for demonstrating stones within the kidney or ureter (see Fig.
15.29, p. 432). For investigation of patients with renal trauma,
a triple-phase CT scan with a delayed phase, to assess the
integrity of the collecting system, is performed. Drawbacks of
contrast-enhanced CT scans include the fact that relatively large
doses of contrast medium are required, which can cause renal
dysfunction, and that the radiation dose is significant (Box 15.4).
| Magnetic resonance imaging
Magnetic resonance imaging (MRI) offers excellent resolution
and gives good distinction between different tissue types (see
Fig. 15.15, p. 406). It is very useful for local staging of prostate,
bladder and penile cancers. Magnetic resonance angiography
(MRA) provides an alternative to CT for imaging renal vessels
but involves administration of gadolinium-based contrast media,
which may carry risks for patients with impaired renal function
(Box 15.4). Whilst MRA gives good images of the main renal
vessels, stenosis of small branch arteries may be missed.
Renal arteriography
Renal arteriography involves taking X-rays following an injection of
contrast medium directly into the renal artery. The main indication
is to investigate renal artery stenosis (p. 406) or haemorrhage
following renal trauma. Renal angiography can often be combined
with therapeutic balloon dilatation or stenting of the renal artery. It
can be used to occlude bleeding vessels and arteriovenous fistulae
by the insertion of thin platinum wires (coils). These curl up within
the vessel and promote thrombosis, thereby securing haemostasis.
[a] Normal kidney [b] Simple renal cyst [c] Hydronephrosis [d] Renal stone [e] Renal tumour T 1 b
Fig. 15.4 Renal ultrasound. [A] Normal kidney. The normal cortex is less echo-dense (blacker) than the adjacent liver. (RC = renal cortex; RS = renal
sinus - calyx, renal pelvis, blood vessels, sinus fat) [§] Typical simple renal cyst: round, echo-free content, no septa, posterior acoustic enhancement. (C =
calyx; P = thinned parenchyma; RP = renal pelvis; U = ureter) [C] The renal pelvis and calyces are dilated due to obstruction. The thinness of the
parenchyma indicates chronic obstruction. [6] A typical renal stone with posterior shadowing. (AS = posterior acoustic shadow) [|] A Tib renal tumour. (K
= kidney; L = liver; T = tumour) (A-E) Courtesy of Dr Tobias Klatte, Addenbrooke’s Hospital, Cambridge.
390 • NEPHROLOGY AND UROLOGY
15.4 Renal complications of radiological
investigations
Contrast nephrotoxicity
• Acute deterioration in renal function commencing <48 hrs after
administration of IV radiographic contrast media
Risk factors
• Pre-existing renal impairment
• Use of high-osmolality, ionic contrast media and repetitive dosing in
short time periods
• Diabetes mellitus
• Myeloma
Prevention
• Provide hydration with free oral fluids plus IV isotonic saline
500 mL, then 250 mlThr during procedure
• Avoid nephrotoxic drugs; withhold non-steroidal anti-inflammatory
drugs (NSAIDs). Omit metformin for 48 hrs after the procedure, in
case renal impairment occurs
• A/-acetylcysteine may provide some protection but data are
conflicting
• If the risks are high, consider alternative methods of imaging
Cholesterol atheroembolism
• Typically follows days to weeks after intra-arterial investigations or
interventions (p. 409)
Nephrogenic sclerosing fibrosis after MRI contrast agents
• Chronic progressive sclerosis of skin, deeper tissues and other
organs, associated with gadolinium-based contrast agents
• Only reported in patients with renal impairment, typically on dialysis
or with GFR <15 mLymin/1.73 m2, but caution is advised in
patients with GFR <30 mL7min/1 .73 m2
Pyelography
Pyelography involves direct injection of contrast medium into the
collecting system from above (antegrade) or below (retrograde).
It offers the best views of the collecting system and upper tract,
and is often used to identify the cause of urinary tract obstruction
(p. 391). Antegrade pyelography requires the insertion of a
fine needle into the pelvicalyceal system under ultrasound
or radiographic control. In addition to visualising the cause
of obstruction, percutaneous nephrostomy drainage can be
established and often stents can be passed through any
obstruction. Retrograde pyelography can be performed by
inserting a ureteric catheter into the ureteric orifice at cystoscopy
(Fig. 15.5) and again a stent can be inserted to bypass any
obstruction.
Radionuclide studies
These are functional studies requiring the injection of gamma
ray-emitting radiopharmaceuticals that are taken up and excreted
by the kidney, a process that can be monitored by an external
gamma camera.
Dynamic radionuclide studies are performed with
mercaptoacetyltriglycine labelled with technetium (99mTc-MAG3),
which is filtered by the glomerulus and excreted into the urine.
Imaging following 99mTc-MAG3 injection can provide valuable
information about the perfusion of each kidney but is not a
reliable method for identifying renal artery stenosis. In patients
with significant obstruction of the outflow tract, 99mTc-MAG3
persists in the renal pelvis and a loop diuretic fails to accelerate
its disappearance. This can be useful in determining the functional
significance of an equivocally obstructed collecting system
without undertaking pyelography.
Fig. 15.5 Retrograde pyelography. The best views of the normal
collecting system are shown by pyelography. A catheter has been passed
into the left renal pelvis at cystoscopy. The anemone-like calyces are
sharp-edged and normal. Courtesy of Dr A. P. Bayliss and Dr P. Thorpe,
Aberdeen Royal Infirmary.
Formal measurements of GFR can be made by radionuclide
studies following the injection of diethylenetriamine penta-acetic
acid (99mTc-DPTA).
Static radionuclide studies are performed with
dimercaptosuccinic acid labelled with technetium (99mTc-DMSA),
which is taken up by proximal tubular cells. Following intravenous
injection, images of the renal cortex are obtained that show the
shape, size and relative function of each kidney (Fig. 15.6). This
is a sensitive method for demonstrating cortical scarring in reflux
nephropathy and a way of assessing the individual function of
each kidney.
Radionuclide bone scanning following the injection of methylene
diphosphonate (99mTc-MDP) is indicated to assess the presence
and extent of bone metastases in men with advanced prostate
cancer (p. 438).
LEFT = 61% RIGHT = 39%
POSTERIOR
Fig. 15.6 DMSA radionuclide scan. A posterior view is shown of a
normal left kidney and a small right kidney (with evidence of cortical scarring
at upper and lower poles) that contributes only 39% of total renal function.
Presenting problems in renal and urinary tract disease • 391
15.5 Renal biopsy
Indications
• Acute kidney injury and chronic kidney disease of uncertain
aetiology
• Nephrotic syndrome or glomerular proteinuria (proteimcreatinine
ratio >100 mg/mol) in adults
• Nephrotic syndrome in children that has atypical features or is not
responding to treatment
• Nephritic syndrome
• Renal transplant dysfunction
• Rarely performed for isolated haematuria or isolated low-grade
proteinuria in the absence of impaired renal function or evidence of
a multisystem disorder
Contraindications
• Disordered coagulation or thrombocytopenia. Aspirin and other
antiplatelet agents increase bleeding risk
• Uncontrolled hypertension
• Kidneys <60% predicted size
• Solitary kidney* (except transplants)
Complications
• Pain, usually mild
• Bleeding into urine, usually minor but may produce clot colic and
obstruction
• Bleeding around the kidney, occasionally massive and requiring
angiography with intervention, or surgery
• Arteriovenous fistula, rarely significant clinically
*Relative contraindication.
Renal biopsy
Renal biopsy is used to establish the diagnosis and severity
of renal disease in order to judge the prognosis and need for
treatment (Box 15.5). The procedure is performed transcutaneously
under local anaesthetic with ultrasound or contrast radiography
guidance to ensure accurate needle placement into a renal pole.
Light microscopy, electron microscopy and immunohistological
assessment of the specimen may all be required.
Presenting problems in renal and
urinary tract disease
Oliguria/anuria
Oliguria is defined as being present when less than 400 mL of
urine is passed per day, whereas anuria is deemed to exist when
less than 1 00 mL of urine is passed per day.
The volume of urine produced represents a balance between
the amount of fluid that is filtered at the glomerulus and that
reabsorbed by the renal tubules. When GFR is low, urine volumes
may still be normal if tubular reabsorption is also reduced; hence
urine volume alone is a poor indicator of the severity of kidney
disease. Oliguria and anuria may be caused by a reduction in
urine production, as in pre-renal AKI, when GFR is reduced
and tubular homeostatic mechanisms increase reabsorption to
conserve salt and water. A high solute load or associated tubular
dysfunction may, however, produce normal or high urine volumes
in such cases until the pre-renal insult becomes severe and GFR
is markedly reduced, such as occurs in diabetic ketoacidosis
1 5.6 Causes of anuria (< 1 00 mL urine output per day)
Condition
Examples
Urinary obstruction
(complete)
Urinary retention due to prostatic
enlargement, urethral stenosis, bladder
tumour
Bilateral ureteric obstruction due to
retroperitoneal fibrosis, cancer,
radiation injury
Bilateral renal stones (usually staghorn
calculi)
Massive crystalluria obstruction of
tubules (rare)
Lack of renal perfusion
(bilateral)
Aortic dissection involving renal arteries
Severe acute tubular necrosis
Severe functional hypoperfusion
(cardiorenal, hepatorenal)
Rapidly progressive
glomerulonephritis
Anti-glomerular basement membrane
disease, severe antineutrophil
cytoplasmic antibody (ANCA) vasculitis
(100% glomerular crescents on biopsy)
with marked glycosuria. Urine volumes are variable in AKI due
to intrinsic renal disease, but a rapid decline in urine volume
may be observed. Anuria should prompt a differential including
complete urinary obstruction, severe vascular compromise or
rapidly progressive glomerulonephritis (Box 15.6).
Obstruction of the renal tract can produce oliguria and anuria,
but to do so, obstruction must be complete and occur distal to
the bladder neck, be bilateral, or be unilateral on the side of a
single functioning kidney. Unilateral ureteric obstruction may not
lead to any noticeable reduction in urine output. The presence
of pain that is exacerbated by a fluid load suggests an acute
obstruction of the renal tract, and its characteristics may be of
value in reaching a diagnosis. Obstruction at the bladder neck
is associated with lower midline abdominal discomfort, whereas
ureteric obstruction typically presents as loin pain radiating to
the groin and at the level of the renal pelvis may present as
flank pain. Chronic obstruction rarely produces pain but may
give rise to a dull ache. Urethral strictures should be considered
as a possible cause, especially in patients with a history of
instrumentation of the renal tract.
The presence of bladder enlargement in a middle-aged or
elderly man suggests benign or malignant enlargement of the
prostate gland as a potential cause of oliguria or anuria (pp. 437
and 438). It is important to note that many cases of acute urinary
retention are observed after general anaesthesia, particularly in
patients with pre-existing prostatic enlargement. Partial obstruction
can be associated with a normal or even high urine volume due to
chronic tubular injury, which causes loss of tubular concentrating
ability. Management of oliguria and anuria should be directed at
the underlying cause and is outlined later in the chapter (p. 41 3).
Haematuria
Healthy individuals may have occasional red blood cells in
the urine (up to 12 500 cells/mL), but the presence of visible
(macroscopic) haematuria or non-visible haematuria (microscopic,
only detectable on dipstick testing) is indicative of significant
bleeding from somewhere in the urinary tract (Fig. 15.7). Once
infection, menstruation and causes of a positive urinary dipstick
in the absence of red cells (haemoglobinuria/myoglobinuria) have
392 • NEPHROLOGY AND UROLOGY
15.7 Interpretation of non-visible haematuria
Dipstick test
positive
Haematuria
Urine microscopy
White blood cells
Abnormal epithelial cells
Red cell casts i
Dysmorphic erythrocytes
(phase contrast
microscopy) J
Suggested cause
Infection
Tumour
Glomerular
bleeding*
Haemoglobinuria
No red cells
Intravascular
haemolysis
Myoglobinuria
(brown urine)
No red cells
Rhabdomyolysis
*Glomerular bleeding implies that the GBM is ruptured. It can occur
physiologically following very strenuous exertion but usually indicates intrinsic
renal disease and is an important feature of the nephritic syndrome.
Polyarteritis
nodosa
Vascular
malformation
Renal infarction
Coagulation
disorders
Renal tumour
Glomerulonephritis
Small-vessel
vasculitis
Systemic lupus
erythematosus
Other glomerular
diseases
Interstitial nephritis
ma
Pyelonephritis
Cystitis
Calculus
Ureteric tumour
- -Trauma
- Calculus
Bladder tumour
Benign prostatic
enlargement
Urethritis
Prostate cancer
Trauma
Fig. 15.7 Causes of haematuria.
been excluded (Box 15.7), both visible and persistent non-visible
haematuria require investigation, as they may be caused by
malignancy or indicate glomerulonephritis.
Visible haematuria is most likely to be caused by tumour,
which can affect any part of the urogenital tract (Fig. 15.7),
and patients with visible haematuria must therefore be referred
to urology for imaging (ultrasound or CT scan) and cystoscopy
(Fig. 15.8). Other common causes of visible haematuria are urine
infection and stones. Visible haematuria may also be encountered
in patients with IgA nephropathy, typically following an upper
respiratory tract infection.
Non-visible haematuria may also indicate an underlying tumour,
and all patients over 40 years old with persistent (detected on
at least 2 of 3 consecutive dipstick tests) non-visible haematuria
should therefore undergo imaging and cystoscopy. In younger
patients, an underlying tumour is much less likely, and if a
15.8 Investigation of nephritic syndrome
Cause Investigations
Rapidly progressive glomerulonephritis (RPGN)
Post- infectious
glomerulonephritis
Anti-GBM disease
Small-vessel vasculitis
Lupus nephritis
ASOT, C3, C4
Anti-GBM antibody
p-ANCA, c-ANCA
ANA, dsDNA, C3, C4
Mild glomerulonephritic presentation
IgA nephropathy Serum IgA (polyclonal rise in 50% of
patients)
Mesangioprol iterative C3, C4, hepatitis B,C + HIV serology,
glomerulonephritis ANA, dsDNA, immunoglobulins, PPE
Alport’s syndrome* Genetic screening, hearing test
*Not a glomerulonephritis but may present in a similar manner with haematuria,
variable proteinuria, hypertension and slowly declining renal function.
(ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; ASOT
= anti -streptolysin 0 titre; 03, 04 = complement proteins 3, 4; dsDNA =
double-stranded DNA; GBM = glomerular basement membrane; HIV = human
immunodeficiency virus; IgA = immunoglobulin A; PPE = plasma protein
electrophoresis)
glomerular cause is not suspected (see below), it may be
appropriate to manage them by periodic observation in primary
care, although occasionally these individuals develop significant
overt renal disease during follow-up.
Glomerular bleeding occurs when inflammatory, destructive
or degenerative processes disrupt the GBM, permitting passage
of red blood cells into the urine. A characteristic feature of
glomerular bleeding is an ‘active urinary sediment’ (the presence
of dysmorphic red blood cells or red cell casts on microscopy);
this is not always present, however. Patients with visible and
non-visible haematuria should also be assessed for hypertension,
proteinuria, reduced/declining renal function, family history of
renal disease or features of systemic disease (Fig. 15.8). The
presence of any of these features raises the possibility of intrinsic
renal pathology and warrants referral to nephrology for further
investigation, including consideration of renal biopsy.
|Nephritic syndrome
The nephritic syndrome is characterised by the presence of
haematuria in association with hypertension, oliguria, fluid
retention and reduced/declining renal function. Many patients with
glomerulonephritis, particularly those with milder disease, do not
exhibit all of these features; their combined presence, however,
is typical of a rapidly progressive glomerulonephritis and warrants
urgent investigation. In many cases, investigation will include
a renal biopsy to confirm diagnosis and guide management,
but less invasive investigations may also be useful (Box 15.8).
Patients with nephritic syndrome may also exhibit varying
degrees of proteinuria, including nephrotic-range proteinuria; the
prominence of haematuria on dipstick should, however, alert the
physician to the possibility of a glomerulonephritis. Indeed, it is
important to recognise that the characteristic features of nephritic
syndrome and nephrotic syndrome do not always present in
isolation, but should be considered to be the extreme phenotypes
at either end of a spectrum of presentations (Fig. 15.9).
Proteinuria
While very small amounts of high-molecular-weight proteins
and moderate amounts of low-molecular-weight proteins pass
Presenting problems in renal and urinary tract disease • 393
Visible haematuria
Persistent non-visible haematuria
Exclude menstruation/UTI
2 of 3 positive dipsticks
Check BP, eGFR
Exclude menstruation/UTI
Assess: BP, eGFR, ACR
r
Normal
Abnormal
I
i
\
OR
>40 years
<40 years
Family history of renal disease
Evidence of systemic disease
I
▼ _ ± _ _ ± _ _ V _ _ V
Refer to urology
Observation
Refer to nephrology
Ultrasound/CT renal tracts
*Symptomatic NVH
Annual: urinalysis, BP,
Consider renal biopsy
Cystoscopy
ACR, eGFR
Fig. 15.8 Investigation of haematuria. *Symptomatic: lower urinary tract voiding symptoms such as hesitancy, frequency, urgency and dysuria. (ACR =
albumin:creatinine ratio; BP = blood pressure; CT = computed tomography; eGFR = estimated glomerular filtration rate; NVH = non-visible haematuria;
UTI = urinary tract infection)
SLE
IgA nephropathy
Amyloid
Haematuria
Proteinuria
MCGN
Minimal change Diabetic
nephropathy nephropathy
FSGS
Membranous
nephropathy
Post-streptococcal Anti-GBM
glomerulonephritis disease
Small-
vessel
vasculitis
Nephrotic
Mechanism
• Injury to podocytes
• Changed architecture
Scarring
Deposition of matrix or other elements
Clinical features
• Overt proteinuria: usually > 3.5 g/24 hrs
(urine may be frothy)
• Hypoalbuminaemia (> 30 g/L)
• Oedema and generalised fluid retention
• Possible intravascular volume depletion with
hypotension, or intravascular expansion
with hypertension
Nephritic
Mechanism
• Inflammation
• Reactive cell proliferation
• Breaks in GBM
• Crescent formation
Clinical features
• Haematuria (red or brown urine)
• Oedema and generalised fluid retention
• Hypertension
• Oliguria
• Reduced renal function
Fig. 15.9 Nephritic and nephrotic syndrome. At one extreme, specific injury to podocytes causes proteinuria and nephrotic syndrome. The histology to
the left shows diabetic nephropathy. At the other end of the spectrum, inflammation leads to cell damage and proliferation, breaks form in the glomerular
basement membrane (GBM) and blood leaks into urine. In its extreme form, with acute sodium retention and hypertension, such disease is labelled
nephritic syndrome. The histology to the right shows a glomerulus with many extra nuclei from proliferating intrinsic cells, and influx of inflammatory cells
leading to crescent formation (arrows) in response to severe post-infectious glomerulonephritis. (FSGS = focal and segmental glomerulosclerosis; IgA =
immunoglobulin A; MCGN = mesangiocapillary glomerulonephritis; SLE = systemic lupus erythematosus)
through the healthy GBM, these proteins normally are completely
reabsorbed by receptors on tubular cells. Hence, in healthy
individuals, less than 150 mg of protein is excreted in the urine
each day, much of which is derived from tubular cells. This
includes Tamm-Horsfall protein (uromodulin), encoded by the
UMOD gene that has recently been linked to tubulo-interstitial
disease (see Box 1 5.20, p. 405). The presence of larger amounts
of protein is usually indicative of significant renal disease.
Proteinuria is usually asymptomatic and is often picked up
by urinalysis, although large amounts of protein may make
the urine frothy. Transient proteinuria can occur after vigorous
exercise, during fever, in heart failure and in people with urinary
394 • NEPHROLOGY AND UROLOGY
15.9 Quantifying proteinuria in random urine samples
ACR'
PCR2 Typical dipstick results3
Significance
<3.5 (female)
<2.5 (male)
<25
Normal
3.5-30
25-50
Moderately elevated albuminuria
30-70
50-1 00 + to ++
Dipstick positive
70-300
1 00—350 +- 1- to +- 1— i-
Glomerular disease more likely; equivalent to >1 g/24 hrs
>300
>350 +++to++++
Nephrotic range: almost always glomerular disease, equivalent to > 3.5 g/24 hrs
Trinary albumin (mg/L)/urine creatinine (mmol/L). 2Urine protein (mg/L)/urine creatinine (mmol/L). (If urine creatinine is measured in mg/dL, reference values for PCR and
ACR can be derived by dividing by 1 1 .31 .) 3Dipstick results are affected by urine concentration and are occasionally weakly positive on normal samples.
tract infection. Patients should be assessed for the presence of
these conditions and urine testing repeated once the potential
trigger has been treated or resolved.
Testing for proteinuria is best done on an early morning sample,
as some individuals exhibit orthostatic proteinuria. In these
patients, typically less than 1 g/24 hrs of protein is excreted only
in association with an upright posture, the first morning sample
being negative. Orthostatic proteinuria is regarded as a benign
disorder that does not require treatment.
I Moderately elevated albuminuria
(microalbuminuria)
In healthy individuals, there is virtually no urinary excretion of
large-molecular-weight serum proteins, such as albumin, in
contrast to modest urinary excretion of tubule-derived proteins.
The presence of even moderate amounts of albuminuria (previously
referred to as microalbuminuria) is therefore abnormal, and may
indicate early glomerular pathology, at a time when the standard
dipstick test remains negative (Box 15.9). Screening for moderately
elevated albuminuria should be performed regularly in patients
with diabetes, as persistently elevated levels warrant therapy
with inhibitors of the renin-angiotensin-aldosterone system, even
in normotensive individuals, to reduce the rate of loss of renal
function (see Box 20.39, p. 758). Persistent moderately increased
albuminuria has also been associated with cardiovascular mortality
in patients with and without diabetes, but an explanation for this
association has not yet been established.
Overt (dipstick-positive) proteinuria
Urinary dipstick testing is a valuable screening tool for the
detection of proteinuria; it is only semi-quantitative, however, as
it is highly dependent on the concentration of the urine. Typically,
standard dipsticks test positive for protein once the urinary
protein exceeds approximately 0.5 g/24 hrs; however, trace to
1 + on dipstick may be observed in very concentrated urine from
individuals with no evidence of renal pathology. Hence all patients
with persistent proteinuria on dipstick should have the amount of
protein quantified to guide further investigations (Fig. 1 5.1 0). When
more than 1 g of protein per day is being excreted, glomerular
disease is likely and this is an indication for renal biopsy. Since
quantification by 24-hour urine collection is often inaccurate,
the protein:creatinine ratio (PCR) in a spot sample of urine is
preferred. This makes an allowance for the variable degree of
urinary dilution and can be used to extrapolate to 24-hour values
(Box 15.9). Changes in PCR also give valuable information about
the progression of renal disease and response to therapy in CKD.
Fig. 15.10 Investigation of proteinuria. (ACR = albumin:creatinine ratio;
PCR = protein :creatinine ratio.)
It is possible to measure albumin:creatinine ratio (ACR), but this
requires a more expensive immunoassay and is usually reserved
for situations when high sensitivity is required, such as detection
of the early stages of diabetic nephropathy (p. 757).
It is sometimes helpful to identify the type of protein in the
urine. Large amounts of low-molecular-weight proteins, such as
p2-microglobulin (molecular weight 12 kDa), in the urine suggest
renal tubular damage and are referred to as tubular proteinuria.
This rarely exceeds 1 .5-2 g/24 hrs (maximum PCR 1 50-200 mg/
mmol; see Box 15.9 for conversion of mg/mmol to mg/dL).
Free immunoglobulin light chains (molecular weight 25 kDa)
are filtered freely at the glomerulus but are poorly identified by
Presenting problems in renal and urinary tract disease • 395
dipstick tests. Hence, electrophoresis of the urine and specific
immunodetection methods are required to detect immunoglobulin
light chains, known as ‘Bence Jones protein’. This may occur in
AL amyloidosis (p. 81) and in B-cell dyscrasias but is particularly
important as a marker for myeloma (p. 966).
Nephrotic syndrome
Nephrotic syndrome is characterised by very heavy proteinuria
(>3.5 g/24 hrs), hypoalbuminaemia and oedema (see below).
Blood volume may be normal, reduced or increased. Renal sodium
retention is an early and universal feature; the mechanisms of
this are shown in Figure 14.5 (p. 354). The diseases that cause
nephrotic syndrome all affect the glomerulus (see Fig. 15.9),
either directly, by damaging podocytes, or indirectly, by causing
i
Cause Typical age group Investigations
Fulminant presentation
Minimal change Children, young
disease adults, occasionally
seen in older patients
Primary focal Young adults
segmental
glomerulosclerosis
Subacute presentation
Membranous Middle-aged to older Hepatitis B, C + HIV
nephropathy patients serology, ANA, dsDNA
Amyloid Older patients Immunoglobulins, PPE,
Bence Jones protein,
serum free light chains
Gradual progression
Diabetic Any age, but rarely Glucose, glycosylated
nephropathy <10 years from haemoglobin
diagnosis of type 1
diabetes
(ANA = antinuclear antibody; dsDNA = double-stranded DNA; HIV = human
immunodeficiency virus; PPE = plasma protein electrophoresis)
scarring or deposition of exogenous material such as amyloid
into the glomerulus.
Investigation of nephrotic syndrome usually involves renal
biopsy, although non-invasive tests may also be helpful in
suggesting the underlying cause (Box 15.10). In children, minimal
change disease is by far the most common cause of nephrotic
syndrome and therefore renal biopsy is not usually required
unless the patient fails to respond to high-dose glucocorticoid
therapy. Similarly, most patients with diabetes presenting with
nephrotic syndrome will have diabetic nephropathy, and so
renal biopsy is usually not performed unless the course of the
disease is atypical (rapidly increasing proteinuria or rapid decline
in renal function; p. 757).
Management of nephrotic syndrome should be directed at the
underlying cause. In addition, nephrotic syndrome is associated
with a number of complications (Box 15.1 1), which may require
supportive management unless the nephrosis is expected to
resolve rapidly, such as in glucocorticoid-responsive minimal
change disease.
Oedema
Oedema is caused by an excessive accumulation of fluid within
the interstitial space. Clinically, this can be detected by persistence
of an indentation in tissue following pressure on the affected area
(pitting oedema). Pitting oedema tends to accumulate in the
ankles during the day and improves overnight as the interstitial
fluid is reabsorbed. Non-pitting oedema is typical of lymphatic
obstruction and may also occur as the result of excessive matrix
deposition in tissues: for example, in hypothyroidism (p. 639) or
systemic sclerosis (p. 1037).
Clinical assessment
Dependent areas, such as the ankles and lower legs, are typically
affected first but oedema can be restricted to the sacrum in
bed-bound patients. With increasing severity, oedema spreads
to affect the upper parts of the legs, the genitalia and abdomen.
Ascites is common and often an earlier feature in children or young
adults, and in liver disease. Pleural effusions are common but frank
pulmonary oedema is rare. Facial oedema on waking is common.
Features of intravascular volume depletion (tachycardia, postural
hypotension) may occur when oedema is due to decreased
15.10 Investigation of nephrotic syndrome
None specific
None specific
1 15.11 Consequences of the nephrotic syndrome and their management
Feature
Mechanism
Consequence
Management
Hypoalbuminaemia
Urinary protein losses exceed synthetic capacity of
liver
Reduced oncotic pressure
Oedema
Treatment of underlying cause
Avid sodium retention
Secondary hyperaldosteronism
Additional poorly characterised intrarenal mechanisms
Oedema
Diuretics and a low-sodium diet*
Hypercholesterolaemia
Non-specific increase in lipoprotein synthesis by liver
in response to low oncotic pressure
High rate of atherosclerosis
Statins, ezetimibe
Hypercoagulability
Relative loss of inhibitors of coagulation (antithrombin
III, protein C and S) and increase in liver synthesis of
procoagulant factors
Venous thromboembolism
Consideration of prophylaxis in
chronic or severe nephrotic
syndrome
Infection
Hypogammaglobulinaemia due to urinary loss of
immunoglobulins
Pneumococcal and
meningococcal infection
Consideration of vaccination
*Severe nephrotic syndrome may need very large doses of combinations of diuretics acting on different parts of the nephron (e.g. loop diuretic plus thiazide plus amiloride).
In occasional patients with hypovolaemia, intravenous salt-poor albumin infusions may help to establish a diuresis, although efficacy is controversial. Over-diuresis risks
secondary impairment of renal function through hypovolaemia.
396 • NEPHROLOGY AND UROLOGY
i
oncotic pressure or increased capillary permeability. If oedema
is localised - for example, to one ankle but not the other - then
venous thrombosis, inflammation or lymphatic disease should
be suspected.
Investigations
Oedema may be due to a number of causes (Box 1 5.1 2), which
are usually apparent from the history and examination of the
cardiovascular system and abdomen. Blood should be taken for
measurement of urea and electrolytes, liver function and serum
albumin, and the urine tested for protein. Further imaging of the
liver, heart or kidneys may be indicated, based on history and
clinical examination. Where ascites or pleural effusions occur
in isolation, aspiration of fluid with measurement of protein and
glucose, and microscopy for cells, will usually help to clarify
the diagnosis in differentiating a transudate (typical of oedema)
from an exudate (more suggestive of local pathology, p. 564).
Management
Mild oedema usually responds to elevation of the legs, compression
stockings, or a thiazide or a low dose of a loop diuretic, such
as furosemide or bumetanide. In nephrotic syndrome, renal
failure and severe cardiac failure, very large doses of diuretics,
sometimes in combination, may be required to achieve a negative
sodium and fluid balance. Restriction of sodium intake and fluid
intake may be required. Diuretics are not helpful in the treatment
of oedema caused by venous or lymphatic obstruction or by
increased capillary permeability. Specific causes of oedema,
such as venous thrombosis, should be treated.
Hypertension
Hypertension is a very common feature of renal disease.
Additionally, the presence of hypertension identifies a population
at risk of developing CKD and current recommendations are
that hypertensive patients should have renal function checked
annually. Control of hypertension is very important in patients with
renal impairment because of its close relationship with further
decline of renal function (p. 420) and because of the exaggerated
cardiovascular risk associated with CKD. Pathophysiology and
management are discussed on pages 509 and 510.
Loin pain
Loin pain is often caused by musculoskeletal disease but can
be a manifestation of renal tract disease; in the latter case, it
may arise from renal stones, ureteric stones, renal tumours,
acute pyelonephritis and urinary tract obstruction. Acute loin
pain radiating anteriorly and often to the groin is termed renal
colic. When combined with haematuria, this is typical of ureteric
obstruction due to calculi (p. 431). Precipitation of loin pain
by a large fluid intake (Dietl’s crisis) suggests upper urinary
tract obstruction caused by a congenital abnormality of the
pelvi-ureteric junction (p. 433).
Dysuria
Dysuria refers to painful urination, often described as burning,
scalding or stinging, and commonly accompanied by suprapubic
pain. It is often associated with frequency of micturition and
a feeling of incomplete emptying of the bladder. By far the
most common cause is urinary tract infection, as described on
page 426. Other diagnoses that need to be considered in
patients with dysuria include sexually transmitted infections
(p. 329) and bladder stones (p. 431).
Frequency
Frequency describes daytime micturition more often than a
patient would expect. It may be a consequence of polyuria, when
urine volume is normal or high, but is also found in patients with
dysuria and prostatic diseases, when the urine volume is normal.
Polyuria
Polyuria is defined as a urine volume in excess of 3 L724 hrs.
Various underlying conditions, both renal and extrarenal, may
be responsible, as outlined in Box 15.13.
Investigation of polyuria includes measurement of urea,
creatinine and electrolytes, glucose, calcium and albumin. A
24-hour urine collection may be helpful to confirm the severity
of polyuria. The presence of nocturnal polyuria suggests a
i
• Excess fluid intake
• Osmotic diuresis: hyperglycaemia, hypercalcaemia
• Cranial diabetes insipidus
• Nephrogenic diabetes insipidus:
Rare inherited mutations in vasopressin receptor or aquaporin 2
genes
Lithium
Diuretics
Interstitial nephritis
Hypokalaemia
Hypercalcaemia
15.12 Causes of oedema
Increased total extracellular fluid
• Congestive heart failure
• Renal failure
• Liver disease
High local venous pressure
• Deep venous thrombosis or venous insufficiency
• Pregnancy
• Pelvic tumour
Low plasma oncotic pressure/serum albumin
• Nephrotic syndrome
• Liver failure
• Malnutrition/malabsorption
Increased capillary permeability
• Leakage of proteins into the interstitium, reducing the osmotic
pressure gradient that draws fluid into the lymphatics and blood
• Infection/inflammation
• Severe sepsis
• Calcium channel blockers
Lymphatic obstruction
• Infection: filariasis, lymphogranuloma venereum (pp. 290 and 341)
• Malignancy
• Radiation injury
• Congenital abnormality
15.13 Causes of polyuria
Glomerular diseases • 397
pathological cause. Investigation and management of suspected
diabetes insipidus are described on page 688.
Nocturia
Nocturia is defined as waking up at night to void urine. It may be
a consequence of polyuria but may also result from increased
fluid intake or diuretic use in the late evening (including caffeine).
Nocturia also occurs in CKD, and in prostatic enlargement
when it is associated with poor stream, hesitancy, incomplete
bladder emptying, terminal dribbling and urinary frequency due
to partial urethral obstruction (p. 437). Nocturia may also occur
due to sleep disturbance without any functional abnormalities
of the urinary tract.
Urinary incontinence
Urinary incontinence is defined as any involuntary leakage of
urine. It may occur in patients with a normal urinary tract, as
the result of dementia or poor mobility, or transiently during an
acute illness or hospitalisation, especially in older people (see
Box 15.54, p. 436). The pathophysiology, investigation and
management of urinary incontinence are discussed in detail
later in the chapter (p. 436).
Glomerular diseases
Glomerular diseases account for a significant proportion of acute
and chronic kidney disease. Most patients with glomerular disease
do not present acutely and are asymptomatic until abnormalities
are detected on routine screening of blood or urine samples.
There are many causes of glomerular damage, including
immunological injury, inherited diseases such as Alport’s
syndrome (p. 403), metabolic diseases such as diabetes mellitus
(p. 757), and deposition of abnormal proteins such as amyloid
in the glomeruli (p. 81). The glomerular cell types that may be
the target of injury are shown in Figure 15.11. Proteinuria is
the hallmark of glomerular disease; however, the response of the
glomerulus to injury and hence the predominant clinical features
vary according to the nature of the insult, ranging from fulminant
nephrotic syndrome to rapidly progressive glomerulonephritis
(see Fig. 15.9). Several prognostic indicators are common to all
causes of glomerulonephritis (Box 15.14) and may be helpful in
assessing the need for immunosuppressive therapy.
Glomerulonephritis
While glomerulonephritis literally means ‘inflammation of glomeruli’,
the term is often used more broadly to describe all types of
glomerular disease, even though some of these (e.g. minimal
change nephropathy) are not associated with inflammation.
15.14 Poor prognostic indicators in
glomerular disease
• Male sex
• Hypertension
• Persistent and severe proteinuria
• Elevated creatinine at time of presentation
• Rapid rate of decline in renal function
• Tubulo-interstitial fibrosis observed on renal biopsy
Most types of glomerulonephritis are immunologically mediated
and several respond to immunosuppressive drugs. Deposition
of antibody occurs in many types of glomerulonephritis and
testing for circulating or glomerular deposition of antibodies
may aid diagnosis (see Fig. 15.11 and Boxes 15.8 and 15.10).
In small-vessel vasculitis, no glomerular antibody deposition is
observed (pauci-immune), but the antibodies may be indirectly
pathogenic by activating neutrophils to promote endothelial
injury (Fig. 15.1 1).
Glomerulonephritis is generally classified in terms of the
histopathological appearances, as summarised in Box 15.15
and Figure 15.12. Many non-specialists find the terminology
used in describing glomerulonephritis to be confusing; some
definitions are provided in Box 15.16. It is important to stress
that the histological appearance rarely confirms a specific renal
disease but rather suggests a limited range of diagnoses, which
may be confirmed by further investigation. Conversely, some
diseases, such as lupus, are associated with more than one
histological pattern of injury. The most common histological
subtypes may be categorised according to their typical clinical
presentation, as discussed below. Genetic disorders associated
with glomerular disease are described later (p. 403).
Circulating immune complexes
Cryoglobulinaemia (Cryoglobulins in serum)
Serum sickness
Endocarditis
Endothelium (indirectly)
Small-vessel vasculitis
ANCA (serum)
GBM
Goodpasture's disease
Anti-GBM antibody (serum + IF on biopsy;
see Fig.15.12H)
Mesangium
IgA nephropathy (polyclonal rise in serum
IgA in 50% patients; IF on biopsy;
see Fig. 15. 12G)
Podocyte
Membranous nephropathy
Anti-phosphilipase A2 receptor 1
(serum + IF on biopsy; experimental
at present; see Fig. 15. 12F)
Planted
antigens
SLE - ANA,
anti-dsDNA (serum)
Post-infectious
glomerulonephritis
Fig. 15.11 Glomerulonephritis associated with antibody production.
Antibodies and antigen-antibody (immune) complexes may target or be
deposited in specific components of the glomerulus, resulting in different
patterns of histological injury and clinical presentation. Testing for antibody
deposition in the glomerulus by immunofluorescence (IF) on renal biopsy
tissue or for antibodies in the serum may aid diagnosis. Diagnostic tests
are shown in italics. (ANA = antinuclear antibody; ANCA = antineutrophil
cytoplasmic antibody; dsDNA = double-stranded DNA; GBM = glomerular
basement membrane; IgA = immunoglobulin A; SLE = systemic lupus
erythematosus)
398 • NEPHROLOGY AND UROLOGY
I Diseases typically presenting with
nephrotic syndrome
In these diseases, the injury is focused on the podocyte
and there is little histological evidence of inflammation or cell
proliferation in the glomerulus (non-proliferative, Fig. 15.12).
Minimal change and primary focal segmental glomerulosclerosis
(FSGS) typically present with fulminant nephrotic syndrome,
whereas in membranous nephropathy and secondary FSGS,
the nephrosis tends to be more indolent in nature. Other
causes of nephrotic syndrome due to systemic disease are
discussed elsewhere, including diabetic nephropathy (p. 757) and
amyloid (p. 81).
Minimal change nephropathy
Minimal change disease occurs at all ages but accounts for
most cases of nephrotic syndrome (see Box 15.15) in children
and about one-quarter of adult cases. It is caused by reversible
dysfunction of podocytes. On light microscopy, the glomeruli
appear normal (Fig. 15.12A), but fusion of podocyte foot
processes is observed on electron microscopy. The presentation
is with nephrotic syndrome, which typically is severe; it remits
15.15 Glomerulonephritis categorised by clinical presentation and histological classification
Histology
Immune deposits
Pathogenesis
Associations
Comments
Nephrotic presentation
Minimal change
Normal, except on
None
Unknown; probable
Atopy
Acute and often severe nephrotic
electron microscopy,
circulating factor
Drugs, most commonly
syndrome
where fusion of podocyte
promoting podocyte injury
NSAIDs
Good response to glucocorticoids
foot processes is observed
Some cases are genetic
Haematological
Dominant cause of idiopathic
(non-specific finding)
(p. 403)
malignancies
nephrotic syndrome in childhood
Focal segmental glomerulosclerosis (FSGS)
Segmental scars in
Non-specific
Unknown; circulating
APOL1 variant in people of
Primary FSGS presents as
some glomeruli
trapping in focal
factors may increase
West African descent
idiopathic nephrotic syndrome
No acute inflammation
scars
glomerular permeability
Causes of secondary FSGS
but is less responsive to
Podocyte foot process
Injury to podocytes may
include:
treatment than minimal change;
fusion seen in primary
be common feature
Healing of previous local
may progress to renal
FSGS
Some cases are genetic
glomerular injury
impairment, and can recur after
(p. 403)
HIV infection
transplantation
Heroin misuse
Secondary FSGS presents with
Morbid obesity
Chronic hypertension
variable proteinuria and outcome
Membranous nephropathy
Thickening of GBM
Granular
Antibodies to a podocyte
HLA-DQA1 (for idiopathic)
Common cause of adult
Progressing to increased
subepithelial IgG
surface antigen (commonly
Drugs:
idiopathic nephrotic syndrome
matrix deposition and
phospholipase A2 receptor
Penicillamine, NSAIDs,
One-third progress, one-third
glomerulosclerosis
1), with complement-
heavy metals
spontaneously remit and
dependent podocyte injury
Hepatitis B virus
one-third remain stable; may
Malignancy
respond to glucocorticoids and
Lupus1
immunosuppressants
Mild glomerulonephritic presentation
IgA nephropathy
Increased mesangial
Mesangial IgA
Unknown
Usually idiopathic, flares
Common disease with range of
matrix and cells
(and C3)
Mucosal infections (e.g.
triggered by upper
presentations, usually including
Focal segmental nephritis
helminths) may be involved
respiratory infection
haematuria and hypertension
in acute disease
Liver disease
Henoch-Schonlein purpura is an
Coeliac disease
acute IgA variant common in
children
Mesangiocapillary glomerulonephritis
Immunoglobulin type
Immunoglobulins
Deposition of circulating
Infections, autoimmunity or
Most common pattern found in
immune complexes or
monoclonal gammopathies
association with subacute
‘planted’ antigens
bacterial infection, but also with
cryoglobulinaemia ± hepatitis C
virus, and others
Complement type
Complement
Complement abnormalities,
Complement gene
In dense deposit disease,
components
inherited or acquired
mutations
intramembranous deposits
Dense deposit disease is
C3 nephritic factor and
No proven treatments
associated with abnormal
activation of alternative
complement pathway
partial lipodystrophy
Continued
Glomerular diseases • 399
15.15 Glomerulonephritis categorised by clinical presentation and histological classification - continued
Histology Immune deposits Pathogenesis Associations
Rapidly progressive glomerulonephritis presentation
Focal necrotising glomerulonephritis
Segmental inflammation
and/or necrosis in some
glomeruli ± crescent
formation
Variable according
to cause but
typically negative
(or ‘pauci-
immune’)
Small-vessel vasculitis,
often ANCA- mediated
Diffuse proliferative glomerulonephritis
Infection -related diffuse proliferative glomerulonephritis
Diffuse proliferation Subendothelial and
of endothelial and subepithelial
mesangial cells
Infiltration by neutrophils
and macrophages ±
crescent formation
3
Immune complex-mediated
(e.g. to streptococcal
infection with presumed
cross- reactive epitopes)
Primary or secondary
small-vessel vasculitis
Post-streptococcal
Concurrent infection with
staphylococci, endocarditis
Comments
Often occurs in systemic disease
Responds to treatment with
glucocorticoids and
immunosuppressants
Presents with severe sodium and
fluid retention, hypertension,
haematuria, oliguria
Usually resolves spontaneously
Anti-glomerular basement membrane disease
Usually crescentic Linear IgG along Autoantibodies to a3
nephritis GBM chain of type IV collagen in
GBM
H LA- DR 15 (previously
known as DR2)
Associated with lung
haemorrhage but renal or lung
disease may occur alone
Treat with glucocorticoids,
cyclophosphamide and plasma
exchange
Systemic lupus erythematosus can cause almost any histological injury pattern, most commonly membranous nephropathy or diffuse proliferative glomerulonephritis.
2ln addition to the association with infection and anti-GBM disease, a diffuse proliferative glomerulonephritis picture may also be seen with lupus and occasionally IgA
nephropathy, infection may also present with mesangioproliferative glomerulonephritis and membranous nephropathy (HI V).
(ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; APOL1 = apolipoprotein LI; GBM = glomerular basement membrane; HLA = human leucocyte
antigen; IgA = immunoglobulin A; NSAIDs = non-steroidal anti-inflammatory drugs)
[eI Crescentic GN
|~f] Membranous GN
] IgA nephropathy
[h] Anti-GBM disease
Fig. 15.12 Histopathology of glomerular disease. /SHI] Light microscopy) [A~| A normal glomerulus. Note the open capillary loops and thinness of
their walls. [B] Focal segmental glomerulosclerosis (GS). The portion of the glomerulus arrowed shows loss of capillary loops and cells, which are replaced
by matrix. [C] Focal necrotising glomerulonephritis (GN). A portion of the glomerulus (N = focal necrotising lesion) is replaced by bright pink material with
some ‘nuclear dust’. Neutrophils may be seen elsewhere in the glomerulus. There is surrounding interstitial inflammation (I). This is most commonly
associated with small-vessel vasculitis and may progress to crescentic nephritis (seeFfejP] Membranous glomerulonephritis. The capillary loops (C) are
thickened (compare with the normal glomerulus) and there is expansion of the mesangial regions by matrix deposition (M). Flowever, there is no gross
cellular proliferation or excess of inflammatory cells. |T] Crescentic glomerulonephritis. The lower part of Bowman’s space is occupied by a semicircular
formation (‘crescent’, Cr) of large pale cells, compressing the glomerular tuft. This is seen in aggressive inflammatory glomerulonephritis. Antibody
deposition in the glomerulus. /[FHB] Direct immunofluorescence) [F] Granular deposits of IgG along the basement membrane in a subepithelial pattern,
typical of membranous GN. [G] Immunoglobulin A (IgA) deposits in the mesangium, as seen in IgA nephropathy. \W\ Ribbon-like linear deposits of anti-GBM
antibodies along the glomerular basement membrane in Goodpasture’s disease. The glomerular structure is well preserved in all of these examples. (A, C,
D, E) Courtesy of Dr J.G. Simpson, Aberdeen Royal Infirmary. (F, G, H) Courtesy of Dr R. Herriot.
HI Normal glomerulus
IP] Focal segmental GS
[c] Focal necrotising GN [d] Membranous GN
400 • NEPHROLOGY AND UROLOGY
i
Light microscopy
• Focal: affecting some but not all glomeruli
• Diffuse : affecting >50% of glomeruli
• Segmental: affecting a portion of a glomerulus
• Global: affecting all of the glomerulus
• Necrotising: severe injury leading to an area of necrosis, usually
associated with vasculitis
• Crescentic: a crescent-shaped area of inflammatory cells
responding to severe glomerular injury
Electron microscopy
• Subendothelial immune deposits: found between the endothelial cell
and the GBM - often found in nephritic presentations
• Intramembranous immune deposits: found within the GBM - found
in the dense deposit variant of mesangiocapillary glomerulonephritis
• Subepithelial immune deposits: found between the epithelial cell
and the GBM - often found in nephrotic presentations, including
membranous presentation of lupus
(GBM = glomerular basement membrane)
with high-dose glucocorticoid therapy (1 mg/kg prednisolone for
6 weeks), though the response to therapy is often less satisfactory
in older patients. Some patients who respond incompletely
(glucocorticoid-resistant) or relapse frequently need maintenance
glucocorticoids (glucocorticoid dependence), cytotoxic therapy
or other agents. Glucocorticoid resistance in children warrants a
biopsy to exclude an alternative diagnosis, but if minimal change
is confirmed, a genetic cause should be considered (p. 403).
Minimal change disease typically does not progress to CKD but
can present with problems related to the nephrotic syndrome
(see Box 15.1 1) and complications of treatment.
Focal segmental glomerulosclerosis
Primary focal segmental glomerulosclerosis (FSGS) (Fig. 15.12B)
can occur in all age groups but is particularly common in people
of West African descent, who, compared with other ethnicities,
have a much higher carriage rate of an apolipoprotein LI i/\ POL1)
gene variant that is associated with increased risk of FSGS.
Histological analysis shows sclerosis initially limited to segments of
the glomeruli, which may also show positive staining for deposits
of C3 and IgM on immunofluorescence. Since FSGS is a focal
process, abnormal glomeruli may not be seen on renal biopsy if
only a few are sampled, leading to an initial diagnosis of minimal
change nephropathy. In most cases the underlying cause is
unknown (primary FSGS) and these patients typically present
with abrupt onset of severe nephrotic syndrome. Primary FSGS
may respond to high-dose glucocorticoid therapy (0. 5-2.0 mg/
kg/day) but the response is rarely as rapid or complete as for
minimal change disease. Immunosuppressive drugs, such as
ciclosporin, cyclophosphamide and mycophenolate mofetil, have
also been used but their efficacy is uncertain. Progression to CKD
is common in patients who do not respond to glucocorticoids
and the disease frequently recurs after renal transplantation.
FSGS may also be secondary to other diseases such as
human immunodeficiency virus (HI V) renal disease (particularly
in African Americans), morbid obesity or chronic hypertension.
In addition, it may reflect scarring from previous focal glomerular
injury resulting from HUS, cholesterol embolism or vasculitis.
Patients with secondary FSGS typically present with more
modest proteinuria than those with primary disease and
rarely exhibit full-blown nephrotic syndrome. Management of
secondary FSGS is focused on treating the underlying cause
and reducing proteinuria by inhibiting the renin-angiotensin
system (p. 417).
Membranous nephropathy
Membranous nephropathy is the most common cause of nephrotic
syndrome in Caucasian adults. It is caused by antibodies (usually
autoantibodies) directed at antigen(s) expressed on the surface
of podocytes, including the M-type phospholipase A2 receptor 1 .
While most cases are idiopathic, a proportion are associated with
other causes, such as heavy metal poisoning, drugs, infections,
lupus and tumours (see Box 15.15 and Fig. 15.1 2D and F).
Approximately one-third of patients with idiopathic membranous
nephropathy undergo spontaneous remission, one-third remain in
a nephrotic state, and one-third develop progressive CKD. High
doses of glucocorticoids and cyclophosphamide may improve
both the nephrotic syndrome and the long-term prognosis.
However, because of the toxicity of these regimens, many
nephrologists reserve such treatment for those with severe
nephrotic syndrome or deteriorating renal function. Treatment of
secondary membranous nephropathy is directed at the underlying
cause.
I Diseases typically presenting with mild
nephritic syndrome
Patients with mild glomerulonephritis typically present with non-
visible haematuria and modest proteinuria, and their renal disease
tends to follow a slowly progressive course. IgA nephropathy
and mesangiocapillary glomerulonephritis (MCGN) typically fall
in this category. Their presentation is highly variable, however;
IgA nephropathy occasionally presents with rapidly progressive
glomerulonephritis while MCGN may present with nephrotic
syndrome. Other diseases that present with haematuria, modest
proteinuria and slow progression include Alport’s syndrome (p. 403).
IgA nephropathy
This is one of the most common types of glomerulonephritis and
can present in many ways. Haematuria is the earliest sign and
non-visible haematuria is almost universal, while hypertension
is also very common. These are often detected during routine
screening: for example, at occupational medical examinations.
Proteinuria can also occur but is usually a later feature. In many
cases, there is slowly progressive loss of renal function leading
to end-stage renal disease (ESRD). A particular hallmark of IgA
nephropathy in young adults is the occurrence of acute self-limiting
exacerbations, often with visible haematuria, in association with
minor respiratory infections. This may be so acute as to resemble
acute post-infectious glomerulonephritis, with fluid retention,
hypertension and oliguria with dark or red urine. Characteristically,
the latency from clinical infection to nephritis is short: a few days
or less. Asymptomatic presentations dominate in older adults,
with non-visible haematuria, hypertension and reduction in GFR.
Occasionally, IgA nephropathy progresses rapidly in association
with crescent formation on biopsy. Management is largely directed
towards the control of blood pressure, with renin-angiotensin
system inhibitors preferable in those with proteinuria. There
is some evidence for additional benefit from several months
of high-dose glucocorticoid treatment in those at high-risk of
progressive disease (see Box 15.14), but no strong evidence
for other immunosuppressive agents. A role for other therapies,
such as fish oil, remains uncertain.
15.16 Terminology used in glomerulonephritis
Tubulo-interstitial diseases • 401
Henoch-Schonlein purpura
This condition most commonly occurs in children but can also
be observed in adults. It is a systemic vasculitis that often
arises in response to an infectious trigger. It presents with a
tetrad of features:
• a characteristic petechial rash typically affecting buttocks
and lower legs
• abdominal pain due to vasculitis involving the
gastrointestinal tract
• arthralgia
• renal disease characterised by visible or non-visible
haematuria, with or without proteinuria.
Renal biopsy shows mesangial IgA deposition and appearances
that are indistinguishable from acute IgA nephropathy (Fig.
15.12G). Treatment is supportive in nature; in most patients,
the prognosis is good, with spontaneous resolution, though
relapses are common. Some patients, particularly adults
and those with severe or persistent proteinuria, progress to
develop ESRD.
Mesangiocapillary glomerulonephritis
Mesangiocapillary glomerulonephritis (MCGN), also known as
membranoproliferative glomerulonephritis, is a pattern of injury
seen on renal biopsy that is characterised by an increase in
mesangial cellularity with thickening of glomerular capillary walls.
The typical presentation is with proteinuria and haematuria.
Several underlying causes have been identified, as summarised
in Box 15.15. It can be classified into two main subtypes. The
first is characterised by deposition of immunoglobulins within
the glomeruli. This subtype is associated with chronic infections,
autoimmune diseases and monoclonal gammopathy. The second
is characterised by deposition of complement in the glomeruli
and is associated with inherited or acquired abnormalities in the
complement pathway. This category comprises ‘dense deposit
disease’, which is typified by electron-dense deposits within the
GBM, and C3 glomerulonephritis that shows deposits similar to
immunoglobulin-type MCGN.
Treatment of MCGN associated with immunoglobulin deposits
consists of the identification and treatment of the underlying
disease, if possible, and the use of immunosuppressive drugs
such as mycophenolate mofetil or cyclophosphamide. There are
few specific treatments for MCGN associated with complement
dysregulation, although eculizumab, the anti-C5 inhibitor that
prevents formation of the membrane attack complex, has shown
promise.
I Diseases typically presenting with rapidly
progressive glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN) is characterised
by rapid loss of renal function over days to weeks, usually in
association with hypertension and oedema. Non-visible haematuria
is almost always present with variable amounts of proteinuria,
while characteristic red cell casts and dysmorphic red cells
may be observed on urine microscopy (see Fig. 15.3). Renal
biopsy typically shows crescentic lesions (see Fig. 15.12E),
often associated with necrotising lesions within the glomerulus
(Fig. 15.12C), particularly in small-vessel vasculitides.
This pattern of presentation is typical of post-infectious
glomerulonephritis, anti-GBM disease and small-vessel
vasculitides (p. 1040). It can also be observed in SLE (p. 1034)
and occasionally in IgA and other nephropathies (see Fig. 15.9).
15.17 Causes of glomerulonephritis associated with
low serum complement
• Post-infectious glomerulonephritis
• Subacute bacterial infection, especially endocarditis
• Systemic lupus erythematosus
• Cryoglobulinaemia
• Mesangiocapillary glomerulonephritis, usually complement type
Anti-glomerular basement membrane disease
Anti-GBM disease is a rare autoimmune disease in which antibodies
develop against the a3 chain of type 4 collagen GBM. Expression
of the a3 chain is largely restricted to the basement membranes
of glomeruli and lungs, and hence the disease may present with
rapidly progressive glomerulonephritis, lung haemorrhage, or
disease of both organs, when it is known as Goodpasture’s disease.
Goodpasture’s disease is more common in younger patients, while
elderly patients often present with renal-limited disease. Patients
with anti-GBM disease should be treated with plasma exchange
combined with glucocorticoids and immunosuppressants, but
early diagnosis is essential, as renal function is rarely recoverable
in those requiring dialysis at presentation.
The combination of glomerulonephritis and pulmonary
haemorrhage (Goodpasture’s syndrome) may also be observed
with small-vessel vasculitis (particularly granulomatosis with
polyangiitis, previously known as Wegener’s granulomatosis)
and lupus.
Infection-related glomerulonephritis
RPGN may occur either during or following an infection. In both
cases, circulating immune complexes are present and activation
of the complement system promotes consumption of complement
factors, resulting in low serum C3 and C4 concentration, as
observed in many causes of glomerulonephritis (Box 15.17).
Post-infectious glomerulonephritis is observed most commonly
in children and young adults, and typically presents 10 days after
a streptococcal throat infection or longer after a skin infection.
The clinical presentation ranges from mild abnormalities on
urinalysis to RPGN with severe AKI. The anti-streptolysin (ASO)
test is positive in up to 95% of patients with streptococcal throat
infections. Treatment is supportive, with control of blood pressure
and fluid overload with salt restriction, diuretics and dialysis if
required. Antibiotic therapy is rarely needed, as the renal disease
occurs after the infection has subsided. The medium-term
prognosis for children and most adults is good, with recovery
of renal function typical even in those requiring dialysis therapy.
Some patients may develop CKD 20-30 years after the original
presentation, however.
An immune complex-mediated disease may also be observed
during an infection, typically a staphylococcal infection such as
endocarditis, skin infection or pneumonia, but also with subacute
endocarditis due to Streptococcus viridans. This occurs more
commonly in older adults and the presentation tends not to be
as fulminant as with post-streptococcal disease. In addition to
supportive measures, antibiotic therapy is required, as infection
is usually concurrent with renal disease.
Tubulo-interstitial diseases
These diseases primarily affect the renal tubules and interstitial
components of the renal parenchyma. They are characterised
402 • NEPHROLOGY AND UROLOGY
by tubular dysfunction with electrolyte abnormalities, moderate
levels of proteinuria and varying degrees of renal impairment.
Often the urinary output may be relatively preserved for any given
GFR, and indeed there may be polyuria and nocturia.
Acute interstitial nephritis
Acute interstitial nephritis (AIN) is an immune-mediated disorder,
characterised by acute inflammation affecting the tubulo-
interstitium of the kidney. It is commonly drug-induced, with
proton pump inhibitors (PPIs) fast becoming the most common
cause, but can be caused by other toxins, and can complicate
a variety of systemic diseases and infections (Box 15.18).
Clinical features
The clinical presentation is typically with renal impairment
but, in some patients with drug-induced AIN, there may be
15.18 Causes of acute interstitial nephritis
Allergic
Many drugs but particularly:
• Penicillins • Proton pump inhibitors
• Non-steroidal anti- • Mesalazine (delayed)
inflammatory drugs (NSAIDs)
Immune
• Autoimmune nephritis ± uveitis
• Transplant rejection
Infections
• Acute bacterial pyelonephritis
• Tuberculosis
• Leptospirosis
• Hantavirus
Toxic
• Myeloma light chains
• Mushrooms ( Cortinarius )
signs of a generalised drug hypersensitivity reaction with
fever, rash and eosinophilia. Proteinuria is generally modest
(PCR <100 mg/mmol) and tubular in type (see Box 15.25,
p. 412). The urine may contain white blood cells and white cell
casts but is sterile on culture. Eosinophils are present in up to
70% of patients but this is a non-specific finding. AIN should
always be considered in patients with non-oliguric AKI. There
may be a rapid deterioration of renal function in some cases
of drug-induced AIN, causing the condition to be mistaken
for RPGN.
Investigations
Renal biopsy is usually required to confirm the diagnosis (Fig.
15.1 3D). This typically shows evidence of intense inflammation,
with infiltration of the tubules and interstitium by polymorphonuclear
leucocytes and lymphocytes. Eosinophils may also be observed,
especially in drug-induced AIN. Often granulomas may be evident,
especially in drug-induced AIN or sarcoidosis (p. 608). The
degree of chronic inflammation in a biopsy is a useful predictor
of long-term renal function. Eosinophiluria may be present but
is not a good discriminator for AIN.
Management
Some patients with drug-induced AIN recover following withdrawal
of the drug alone, but high-dose glucocorticoids (prednisolone
1 mg/kg/day) may accelerate recovery and prevent long-term
scarring. Other specific causes (see Box 15.18) should be
treated, if possible.
Chronic interstitial nephritis
Chronic interstitial nephritis (CIN) is characterised by renal
dysfunction with fibrosis and infiltration of the renal parenchyma
by lymphocytes, plasma cells and macrophages, in association
with tubular damage.
[a\ Normal tubular histology
[c] Acute pyelonephritis
[p] Acute interstitial nephritis
Fig. 15.13 Tubular histopathology. [A] Normal
tubular histology. The tubules are back to back.
Brush borders can be seen on the luminal borders of
cells in the proximal tubule. B] Acute tubular
necrosis. There are scattered breaks (B) in tubular
basement membranes, swelling and vacuolation of
tubular cells, and, in places, apoptosis and necrosis
of tubular cells with shedding of cells into the lumen.
During the regenerative phase, there is increased
tubular mitotic activity. The interstitium (I) is
oedematous and infiltrated by inflammatory cells. The
glomeruli (not shown) are relatively normal, although
there may be endothelial cell swelling and fibrin
deposition. [C] Acute bacterial pyelonephritis. A
widespread inflammatory infiltrate that includes many
neutrophils is seen. Granulocyte casts (G) are forming
within some dilated tubules (T). Other tubules are
scarcely visible because of the extent of the
inflammation and damage. [D] Acute (allergic)
interstitial nephritis. In this patient who received a
non-steroidal anti-inflammatory drug (NSAID), an
extensive mononuclear cell infiltrate (no neutrophils)
involving tubules (T) is seen. This inflammation does
not involve the glomeruli (not shown). Sometimes
eosinophils are prominent. Transplant rejection looks
similar to this.
Genetic renal diseases • 403
Pathophysiology
This disease may follow on from AIN that does not resolve, or
may be associated with ingestion of various toxins and drugs, or
with metabolic and chronic inflammatory diseases, as summarised
in Box 15.19. In many patients, CIN presents at a late stage
and no underlying cause can be identified. Genetic causes may
underlie many of these cases (p. 404). Toxins that have been
associated with CIN include those contained within the plant
Aristolochia clematitis (birthwort). These are probably responsible
for the severe nephrotoxicity that can be associated with treatment
with herbal medicines in Asia and for Balkan nephropathy, which
affects isolated rural communities in Bosnia, Bulgaria, Croatia,
Romania and Serbia, possibly through contaminated flour. The
nephropathy is commonly linked with tumours of the collecting
system and is probably due to the mutagenic effects of the plant
toxin on the urothelial epithelium. Ingestion of mushrooms within
the Cortinarius genus can cause a devastating and irreversible
renal tubular toxicity. It is encountered occasionally in Scandinavia
and Scotland.
■
I
Clinical features
Most patients with CIN present in adult life with CKD, hypertension
and small kidneys. Urinalysis abnormalities are non-specific. A
minority present with salt-losing nephropathy, characterised by
hypotension, polyuria and features of sodium and water depletion .
People with CIN have an impairment of urine-concentrating ability
and sodium conservation, which puts them at risk of AKI due to salt
and water depletion during an acute illness. Renal tubular acidosis
(p. 365) may complicate CIN but is seen most often in myeloma,
sarcoidosis, cystinosis, amyloidosis and Sjogren’s syndrome.
Management
Management is supportive in nature, with correction of acidosis
and hyperkalaemia; replacement of fluid and electrolytes, as
required; and renal replacement therapy if irreversible renal
damage has occurred.
Papillary necrosis
The renal papillae lie within a hypertonic environment in the renal
medulla, at the end of the vasa recta. They are susceptible to
ischaemic damage because of this and can undergo necrosis
when their vascular supply is impaired as the result of diabetes
mellitus, sickle-cell disease or long-term ingestion of NSAIDs.
The condition may occasionally occur in other diseases. There is
an association with pyelonephritis but it is difficult to determine
whether this is a cause of papillary necrosis or a complication. The
clinical presentation is variable. Some patients are asymptomatic
and clinically silent, whereas others present with renal colic and
renal impairment as necrosed papillae slough off and cause
ureteric obstruction. Urinalysis may be normal but more frequently
haematuria and sterile pyuria are present. Significant proteinuria
is unusual, unless there is renal failure. The imaging method of
choice to make the diagnosis is CTU or intravenous pyelography.
Management is based on relieving obstruction, where present,
and withdrawal of the offending drugs.
Genetic renal diseases
The advent of modern genetic techniques such as next-generation
sequencing has allowed us to understand the breadth of inherited
renal diseases on a much deeper level than before.
Inherited glomerular diseases
Alport’s syndrome
A number of uncommon diseases may involve the glomerulus in
childhood but the most important one affecting adults is Alport’s
syndrome. Most cases arise from a mutation or deletion of the
COL4A5 gene on the X chromosome, which encodes type IV
collagen, resulting in inheritance as an X-linked recessive disorder
(p. 48). Mutations in COL4A3 or COL4A4 genes are less common
and cause autosomal recessive disease. The accumulation of
abnormal collagen results in a progressive degeneration of the
GBM (Fig. 15.14). Affected patients progress from haematuria to
ESRD in their late teens or twenties. Female carriers of COL4A5
mutations usually have haematuria but less commonly develop
significant renal disease. Some other basement membranes
containing the same collagen isoforms are similarly involved,
notably in the cochlea, so that Alport’s syndrome is associated
with sensorineural deafness and ocular abnormalities.
Acute interstitial nephritis
• Any of the causes of acute interstitial nephritis, if persistent (see
Box 15.18)
Glomerulonephritis
• Varying degrees of interstitial inflammation occur in association with
most types of inflammatory glomerulonephritis
Immune/inflammatory
• Sarcoidosis
• Sjogren’s syndrome
• Chronic transplant rejection
• Systemic lupus erythematosus, primary autoimmune
Toxic
• Aristolochia in herbal medicines
• Lead
• Balkan nephropathy
• Mushrooms ( Cortinarius )
Drugs
• All drugs causing acute interstitial nephritis
• Tenofovir
• Lithium toxicity
• Analgesic nephropathy
• Ciclosporin, tacrolimus
Infection
• Consequence of severe pyelonephritis
Congenital/developmental
• Vesico-ureteric reflux: associated but causation not clear
• Renal dysplasias: often associated with reflux
• Inherited: now well recognised but mechanisms unclear
• Other: Wilson’s disease, sickle-cell nephropathy, medullary sponge
kidney (nephrocalcinosis)
Metabolic and systemic diseases
• Calcium phosphate crystallisation after excessive phosphate
administration (e.g. phosphate enemas in patients with chronic
kidney disease)
• Hypokalaemia
• Hyperoxaluria
15.19 Causes of chronic interstitial nephritis
404 • NEPHROLOGY AND UROLOGY
0.
Urinary space
c- Foot process
ikv\ of podocyte
Endothelial
cell
Glomerular
capillary
Fig. 15.14 Alport’s syndrome. [A] Diagrammatic structure of the normal glomerular basement membrane (GBM). [¥] The normal GBM (electron
micrograph) contains mostly the tissue-specific (a3, a4 and oc5) chains of type IV collagen. [C] In Alport’s syndrome, this network is disrupted and
replaced by al and a2 chains. Although the GBM appears structurally normal in early life, in time thinning appears, progressing to thickening, splitting
and degeneration. (B, C) Courtesy of Dr J. Collar, St Mary’s Hospital, London.
Angiotensin-converting enzyme (ACE) inhibitors may slow
but not prevent loss of kidney function. Patients with Alport’s
syndrome are good candidates for renal replacement therapy
(RRT), as they are young and usually otherwise healthy. They
can develop an immune response to the normal collagen
antigens present in the GBM of the donor kidney and, in a
small minority, anti-GBM disease develops and destroys the
allograft.
Thin glomerular basement membrane disease
In thin glomerular basement membrane disease there is glomerular
bleeding, which is usually non-visible, without associated
hypertension, proteinuria or a reduction in GFR. The glomeruli
appear normal by light microscopy but, on electron microscopy,
the GBM is abnormally thin. The condition may be familial and
some patients are carriers of Alport mutations. This does not
appear to account for all cases, and in many patients the cause
is unclear. Monitoring of these patients is advisable, as proteinuria
may develop in some and there appears to be an increased
rate of progressive CKD in the long term.
Hereditary nephrotic syndrome
Many genes have been discovered that cause early-onset
nephrotic syndrome, often with an FSGS pattern of injury.
Inheritance may be autosomal dominant or recessive, the former
conditions having a less severe and later-onset phenotype and
often exhibiting incomplete penetrance. The involved genes almost
all code for podocyte proteins, including nephrin (‘Finnish-type’
nephropathy) and podocin, which both cause early congenital
nephrotic syndrome. Autosomal dominant mutations in various
genes may cause FSGS as part of systemic syndromes; the
genes include INF2 (Charcot-Marie-Tooth disease), LMX1B
(nail-patella syndrome) and 1/1/7“ 7 (abnormal genitalia, Wilms’
tumour, mental retardation).
Inheriting variants in the APOL1 gene, which is observed
predominantly in people of West African ancestry, leads to a
greatly increased risk of kidney disease including FSGS (p. 400).
Inherited tubulo-interstitial diseases
It has become evident in recent years that a significant number
of cases of CKD with low or absent proteinuria have genetic
causes, which may be inherited in an autosomal dominant
or recessive pattern (Box 15.20). The histological pattern
of injury is identical to other forms of CIN (p. 402). This is a
heterogeneous group of inherited disorders. Small cysts are
sometimes evident, explaining the previous name of medullary
cystic kidney disease, but tubulo-interstitial nephritis is the
predominant pattern of injury. Many of these conditions, especially
those formerly known as nephronophthisis, are associated with
retinal dystrophies and brain or other abnormalities, and some may
be associated with hyperuricaemia or gout (UMOD or HNFI-beta
mutations). Modern genetics have brought clarity to a disease
spectrum comprising many different conditions with inexact
previous names.
1 15.20 Hereditary tubulo-interstitial kidney diseases
Inheritance
Gene(s)
Other name(s)
Clinical features
Autosomal
dominant
UMOD
MUC1
HNFI-beta
REN (codes for renin)
MCKD type 2
Juvenile hyperuricaemic nephropathy
MCKD type 1
Juvenile hyperuricaemic nephropathy
Juvenile hyperuricaemic nephropathy
Gout
Progressive CKD without other manifestations
Cystic kidneys, solitary kidney; gout;
M0DY; abnormal LFTs; pancreatic atrophy; hypomagnesaemia
Gout; hyperkalaemia; salt-losing nephropathy
Autosomal
recessive
NPHP genes
(17 discovered so far)
Nephronophthisis
Part of many syndromes (Bardet— Biedl)
Common cause of paediatric ESRD
Occurs earlier than AD interstitial nephritis
Extrarenal manifestation common (learning difficulty, eye/limb
problems)
(AD = autosomal dominant; CKD = chronic kidney disease; ESRD = end-stage renal disease; LFTs =
maturity-onset diabetes of the young)
liver function tests; MCKD = medullary cystic kidney disease; M0DY =
Genetic renal diseases • 405
Isolated defects of tubular function
An increasing number of disorders have been identified that are
caused by specific defects in transporter molecules expressed
in renal tubular cells. Only the most common are mentioned
here. Renal glycosuria is a benign autosomal recessive defect
of tubular reabsorption of glucose, caused by mutations of the
sodium/glucose co-transporter SGLT2. Glucose appears in the
urine in the presence of a normal blood glucose concentration.
It is notable that SGLT2 inhibitors have been developed as a
treatment for diabetes mellitus and evidence suggests they may
improve renal and cardiovascular outcomes.
Cystinuria is a rare condition, in which reabsorption of filtered
cystine, ornithine, arginine and lysine is defective. It is caused
by mutations in the SLC3A1 amino acid transporter gene. The
high concentration of cystine in urine leads to cystine stone
formation (p. 431).
Other uncommon tubular disorders include hereditary
hypophosphataemic rickets (p. 1052), in which reabsorption of
filtered phosphate is reduced; nephrogenic diabetes insipidus
(p. 687), in which the tubules are resistant to the effects of
vasopressin (antidiuretic hormone, ADH); and Bartter’s and
Gitelman’s syndromes, in which there is sodium- wasting and
hypokalaemia (p. 361).
The term ‘Fanconi’s syndrome’ is used to describe generalised
proximal tubular dysfunction. The condition typically presents with
low blood phosphate and uric acid concentrations, glycosuria,
aminoaciduria and proximal renal tubular acidosis. In addition
to the causes of interstitial nephritis described above, some
congenital metabolic disorders are associated with Fanconi’s
syndrome, notably Wilson’s disease, cystinosis and hereditary
fructose intolerance.
Renal tubular acidosis describes the common end-point
of a variety of diseases affecting distal (classical or type 1) or
proximal (type 2) renal tubular function. These syndromes are
described on page 365.
Cystic diseases of the kidney
It is common to encounter patients with a single renal cyst or
even multiple cysts as an incidental finding, especially in those
aged 50 years and over. Usually, these cysts are of no clinical
consequence and are asymptomatic, but occasionally they can
cause pain or haematuria. In addition, several specific diseases
are recognised as being caused by the formation of multiple renal
cysts. These are discussed in more detail below.
Adult polycystic kidney disease
Adult polycystic kidney disease (PKD) is a common condition,
with a prevalence of approximately 1:1000, and is inherited
as an autosomal dominant trait. Small cysts lined by tubular
epithelium develop from infancy or childhood and enlarge
slowly and irregularly. The surrounding normal kidney tissue is
compressed and progressively damaged. Mutations in the PKD1
gene account for 85% of cases and those in PKD2 for about
15% (coding for polycystin 1 and 2, respectively). ESRD occurs
in approximately 50% of patients with PKD1 mutations, with a
mean age of onset of 52 years, but in a minority of patients
with PKD2 mutations, with a mean age of onset of 69 years.
It has been estimated that between 5% and 10% of patients
on RRT have PKD.
15.21 Adult polycystic kidney disease: common
clinical features
• Vague discomfort in loin or abdomen due to increasing mass of
renal tissue
• Acute loin pain or renal colic due to haemorrhage into a cyst
• Hypertension
• Haematuria (with little or no proteinuria)
• Urinary tract or cyst infections
• Renal failure
Clinical features
Common clinical features are shown in Box 15.21. Affected
people are usually asymptomatic until later life but hypertension
usually occurs from the age of 20 onwards. One or both kidneys
may be palpable and the surface may feel nodular. About 30%
of patients with PKD also have hepatic cysts (see Fig. 22.39,
p. 893) but disturbance of liver function is rare. Sometimes
(almost always in women) this causes massive and symptomatic
hepatomegaly, usually concurrent with renal enlargement but
occasionally with only minor renal involvement. Berry aneurysms
of cerebral vessels are an associated feature in about 5% of
patients with PKD. This feature appears to be largely restricted
to certain families (and presumably specific mutations). Mitral
and aortic regurgitation is frequent but rarely severe, and colonic
diverticula and abdominal wall hernias may occur.
Investigations
The diagnosis is usually based on family history, clinical findings
and ultrasound examination. Ultrasound demonstrates cysts
in approximately 95% of affected patients over the age of 20
and is the screening method of choice, but may not detect
small developing cysts in younger subjects. Cysts may also be
identified by other imaging modalities, such as MRI (Fig. 15.15).
Simple renal cysts may occur in normal individuals but are
uncommon below the age of 30. The following criteria exist for
an ultrasound diagnosis of PKD in patients with a family history
but unknown genotype:
• 15-39 years of age: at least three unilateral or bilateral
kidney cysts
• 40-59 years of age: at least two cysts in each kidney
• 60 years or older: at least four cysts in each kidney.
It is now possible to make a molecular diagnosis by mutation
screening of PDK1 or PDK2 but this is seldom used in routine
clinical practice because the PKD1 gene is so large and has
many possible mutations. Next-generation sequencing allows
faster and simpler genetic screening for PKD1 and PKD2. This
is likely to be used in cases with an uncertain diagnosis (young
patients, few cysts, lack of family history), for workup of living
kidney donors, or for screening for mutations associated with a
worse prognosis (see below). Screening for intracranial aneurysms
is not generally indicated but can be done by MR angiography
in families with a history of subarachnoid haemorrhage. The
yield of screening is low, however, and the risk: benefit ratio of
intervention in asymptomatic aneurysms in this disease is not clear.
Management
Blood pressure control is important because cardiovascular
morbidity and mortality are so common in renal disease, but
evidence is lacking that controlling blood pressure to generally
recommended CKD targets (e.g. <1 30/80 mmHg) influences renal
outcomes. There are data suggesting that targeting a very low blood
pressure (<110/75 mmHg) with ACE inhibitors or angiotensin II
406 • NEPHROLOGY AND UROLOGY
0
causes cysts but also may cause a tubulo-interstitial pattern of
injury or congenital absence of a kidney. It also causes a form
of MODY (p. 733).
Autosomal recessive PKD is caused by mutations in the
PKHD1 gene, encoding fibrocystin. It is less common than
autosomal dominant PKD (about 1:20000 live births). Patients
often present in infancy or young childhood with renal cysts and
congenital hepatic fibrosis.
Some uncommon autosomal dominantly inherited conditions
are associated with multiple renal cysts and tumours in adult life.
In tuberous sclerosis (p. 1264), replacement of renal tissue by
multiple angiomyolipomas may occasionally cause renal failure
in adults. Patients may also develop renal cysts and have a
higher risk of renal cell carcinoma. Other organs affected include
the skin (adenoma sebaceum on the face) and brain (causing
seizures and mental retardation). The von Hippel-Lindau syndrome
(p. 1132) is associated with multiple renal cysts, renal adenomas
and renal adenocarcinoma. Other involved organs include the
central nervous system (haemangioblastomas), pancreas (serous
cystadenomas) and adrenals (phaeochromocytoma).
A number of other rarer inherited cystic diseases are recognised
that have some similarities to PKD but distinct genetic causes.
Multicystic dysplastic kidneys are often unilateral and are a
developmental abnormality found in children. Most of these seem
to involute during growth, leaving a solitary kidney in adults.
Acquired cystic kidney disease can develop in patients with
a very long history of renal failure, so it is not an inherited cystic
disease. It is associated with increased erythropoietin production
and sometimes with the development of renal cell carcinoma.
Renal vascular diseases
Fig. 15.15 MRI images of the kidneys. [A] Normal kidneys.
[§] Polycystic kidneys; although the kidney enlargement is extreme,
this patient had only slightly reduced GFR.
receptor blocker (ARBs) leads to slower increases in kidney volume,
but no improvements in eGFR decline were observed and these
targets are often not tolerated. This tight blood pressure target
did lead to a greater decline in left ventricular mass index, which
may have implications for improved cardiovascular risk later in life.
The vasopressin V2 receptor antagonist tolvaptan may retard
kidney volume increase and slow the rate of GFR decline. It has
now been licensed in many countries for patients at high risk of
progression. Risk factors for progression include large kidneys
(more specifically height-adjusted kidney volume), truncating
PKD1 mutations, and family history of early progression, as well
as male sex, hypertension, proteinuria and development of early
symptomatic cysts.
Patients with PKD are usually good candidates for dialysis
and transplantation. Sometimes kidneys are so large that one or
both have to be removed to make space for a renal transplant.
Otherwise, they are usually left in situ unless they are a source
of pain or infection.
Other cystic diseases
Renal cysts and diabetes syndrome is caused by HNFI-beta
mutations (see above); it has a varying renal phenotype that often
Diseases that affect renal blood vessels may cause renal
ischaemia, leading to acute or chronic kidney disease or
secondary hypertension. The rising prevalence of atherosclerosis
and diabetes mellitus in ageing populations has made renovascular
disease an important cause of ESRD.
Renal artery stenosis
A stenosis of more than 50% may be observed on imaging of
the renal arteries in up to 20% of older patients with advanced
kidney disease; however, a haemodynamically significant effect
will be present in only a relatively small proportion. Renal artery
stenosis is the most common cause of secondary hypertension,
with an estimated prevalence of about 2% in unselected patients,
but this may increase to 4% in older patients who have evidence
of atherosclerotic disease elsewhere. Most cases of renal artery
stenosis are caused by atherosclerosis but fibromuscular dysplasia
involving the vessel wall may be responsible in younger patients.
Rare causes include vasculitis, thromboembolism and aneurysms
of the renal artery.
Pathophysiology
Renal artery stenosis results in a reduction in renal perfusion
pressure, which activates the renin-angiotensin system, leading
to increased circulating levels of angiotensin II. This results in
hypertension by provoking vasoconstriction and increasing
aldosterone production by the adrenal, causing sodium retention
by the renal tubules (p. 351). Significant reduction of renal blood
flow occurs when there is more than 70% narrowing of the
artery, and this is commonly associated with distal, post-stenotic
Renal vascular diseases • 407
dilatation. Atherosclerotic lesions are typically ostial and are
associated with more widespread atherosclerosis within the
aorta and other vessels, particularly the iliac vessels. There is
often concurrent small-vessel disease in affected kidneys, due
to subclinical atheroemboli. As the stenosis becomes more
severe, global renal ischaemia leads to shrinkage of the affected
kidney and may cause renal failure if bilateral, or if unilateral in
the presence of a single kidney (ischaemic nephropathy).
In younger patients, fibromuscular dysplasia is a more likely
cause of renal artery stenosis. This is an uncommon disorder of
unknown cause. It is characterised by hypertrophy of the media
(medial fibroplasia), which narrows the artery but rarely leads
to total occlusion. It may be associated with disease in other
arteries; for example, those who have carotid artery dissections
are more likely to have renal arteries with this appearance. It
most commonly presents with hypertension in patients aged
15-30 years, and women are affected more frequently than
men. Irregular narrowing (beading) may occur in the distal renal
artery and this sometimes extends into the intrarenal branches
of the vessel. Rarely, renal artery stenosis may occur as a
complication of large-vessel vasculitis, such as Takayasu’s arteritis
and polyarteritis nodosa (pp. 1041 and 1042).
Untreated, atheromatous renal artery stenosis is thought to
progress to complete arterial occlusion in about 15% of cases.
This figure increases with more severe degrees of stenosis. If
the progression is gradual, collateral vessels may develop and
some function may be preserved, preventing infarction and
loss of kidney structure. Conversely, at least 85% of patients
with renal artery stenosis will not develop progressive renal
impairment, and many patients die from coronary, cerebral or
other vascular disease rather than renal failure. Unfortunately,
methods of predicting which patients are at risk of progression
or who will respond to treatment are still imperfect.
Clinical features
Renal artery stenosis can present in various ways including
hypertension, acute pulmonary oedema, progressive renal
failure (with bilateral disease) or a deterioration in renal function
when ACE inhibitors or ARBs are administered. Although many
patients experience a slight drop in GFR when commencing
these drugs, an increase in serum creatinine of 30% or more
raises the possibility of renal artery stenosis. Acute pulmonary
oedema is particularly characteristic of bilateral renovascular
disease. It typically occurs at night and is associated with severe
hypertension, often in the context of normal or only mildly impaired
renal and cardiac function. Clinical evidence of generalised
vascular disease may be observed, particularly in the legs and
in older patients with atherosclerotic renal artery stenosis. Clinical
features associated with an increased risk of renal artery stenosis
in hypertensive patients are summarised in Box 15.22. However,
given the risk of imaging and angiography in patients with renal
disease (see Box 15.4, p. 390), further investigation should only
be performed if intervention is being contemplated (see below).
Investigations
When appropriate, imaging of the renal vasculature with either CT
angiography or MR angiography should be performed to confirm
the diagnosis (Fig. 15.16). Both give good views of the main
renal arteries, the vessels predominantly involved and the most
amenable to intervention. Biochemical testing may reveal impaired
renal function and an elevated plasma renin activity, sometimes
with hypokalaemia due to hyperaldosteronism. Ultrasound may
also reveal a discrepancy in size between the two kidneys,
although this is insufficiently sensitive or specific to be of value
in diagnosis of renovascular disease in hypertensive patients.
Management
The first-line management in patients with renal artery stenosis
is medical therapy with anti hypertensive drugs, supplemented,
where appropriate, by statins and low-dose aspirin in those
with atherosclerotic disease. Interventions to correct the vessel
narrowing should be considered in:
• young patients (age below 40) suspected of having renal
artery stenosis
• those whose blood pressure cannot easily be controlled
with anti hypertensive agents
• those who have a history of ‘flash’ pulmonary oedema
• those with accelerated phase (malignant) hypertension
• those whose renal function is deteriorating.
The most commonly used technique is angioplasty. The best
results are obtained in non -atheromatous fibromuscular dysplasia,
where correction of the stenosis has a high chance of success in
improving blood pressure and protecting renal function. Beyond
the indications above, angioplasty and stenting is now rarely
15.22 Presentation and clinical features of
renal artery stenosis
Renal artery stenosis is more likely if:
• hypertension is severe, of recent onset or difficult to control
• kidneys are asymmetrical in size
• flash pulmonary oedema occurs repeatedly*
• there is peripheral vascular disease of the lower limbs
• there is renal impairment*
• renal function has deteriorated on angiotensin-converting enzyme
inhibitors or angiotensin II receptor blockers
Particularly with bilateral disease.
Fig. 15.16 Renal artery stenosis. A magnetic resonance angiogram
following injection of contrast. The abdominal aorta is severely irregular
and atheromatous. The left renal artery is stenosed (arrow).
408 • NEPHROLOGY AND UROLOGY
performed in atherosclerotic disease, as randomised trials such
as ASTRAL and CORAL have produced no convincing evidence
for overall benefit in terms of renal function, blood pressure
control or cardiovascular outcomes. The risks of angioplasty
and stenting include renal artery occlusion, renal infarction and
atheroemboli (p. 409) from manipulations in a severely diseased
aorta. Small-vessel disease distal to the stenosis may preclude
substantial functional recovery.
Acute renal infarction
This is an uncommon condition that occurs as the result of
sudden occlusion of the renal arteries. The presentation is
typically with loin pain of acute onset, usually in association with
non-visible haematuria, but pain may be absent in some cases.
Severe hypertension is common but not universal. Blood levels
of lactate dehydrogenase (LDH) and CRP are commonly raised.
The condition may be caused by thrombosis of a renal artery or
by thromboemboli from a distant source, when occlusion may
occur in branch arteries distal to the main renal artery. This
can cause multiple infarcts within the renal parenchyma of both
kidneys, which may be visualised by CT scanning. If occlusion
of the main renal arteries is bilateral or if there is occlusion in a
single functioning kidney, the presentation is with AKI and the
patient is typically anuric. Patients with bilateral occlusion usually
have evidence of widespread vascular disease and may show
evidence of aortic occlusion, with absent femoral pulses and
reduced lower limb perfusion. Management is largely supportive,
and includes anticoagulation if a source of thromboembolism
is identified. It is sometimes possible to perform stenting of an
acutely blocked main renal artery to try to restore renal blood
flow; in most cases, however, presentation is too late to salvage
renal function.
Diseases of small intrarenal vessels
Thrombotic microangiopathies
A number of conditions are associated with acute damage and
occlusion of small blood vessels (arterioles and capillaries) in
the kidney (Box 15.23) and other organs. A common feature
of these syndromes is microangiopathic haemolytic anaemia
(MAHA), in which haemolysis and red cell fragmentation arise
as consequences of damage incurred to red blood cells during
passage through the abnormal vessels. The red blood cell
fragments (schistocytes) may be observed on blood films,
together with laboratory features of intravascular haemolysis
(p. 947), including an elevated unconjugated bilirubin level, raised
serum LDH concentration and decreased circulating levels of
haptoglobin. A reticulocytosis is often seen. Endothelial injury
is pronounced, leading to increased platelet adherence and a
marked reduction in the platelet count. These abnormal blood
parameters should alert the physician to the possibility of a
thrombotic microangiopathy and may also be useful in monitoring
response to treatment. The key is to distinguish between the
various aetiologies, as the management differs according to the
primary cause (Box 15.23).
Haemolytic uraemic syndrome
Haemolytic uraemic syndrome (HUS) is characterised by
thrombotic microangiopathy that predominantly affects the renal
microcirculation, with involvement of other organs (including the
brain) observed in more severe cases.
The most common cause of HUS is infection with organisms
that produce enterotoxins called Shiga-like toxin or verotoxins. The
organisms most commonly implicated are enterohaemorrhagic
Escherichia coli (p. 263) and Shigella dysenteriae (p. 265). The
1 15.23 Thrombotic microangiopathies associated with acute renal damage
Condition
Typical features
Management
Primary thrombotic microangiopathies
Haemolytic uraemic syndrome:
Renal failure prominent in all causes
Shiga toxin +ve HUS
Bloody diarrhoea; check stool for Escherichia
coli 0157:H7
Supportive therapy
Complement-mediated
Positive family history; screen for complement
factor mutations
Plasma exchange, eculizumab
Drug-induced: quinine, calcineurin
and VEGF-A inhibitors
Drug exposure, fever with quinine
Cessation of offending drug
Thrombotic thrombocytopenic purpura
Neurological manifestations prominent; check
ADAMTS-13 activity
Plasma exchange (p. 979)
Thrombotic microangiopathy associated with systemic disorders
Disseminated intravascular
Clotting system involvement: elevated D-dimers,
Treatment of primary cause (p. 979)
coagulation (DIC)
low fibrinogen, prolonged PT and APTT
Malignancy
May occur with breast, prostate, lung, pancreas
and Gl tumours
Treatment of tumour where possible
Systemic sclerosis
Cutaneous features of systemic sclerosis
Blood pressure control with ACE inhibitors (p. 1037)
Pre-eclampsia and HELLP syndrome
Typically in third trimester; abnormal LFTs
Resolution with delivery (p. 1276)
Malignant hypertension
Blood pressure typically very high; evidence of
hypertensive retinopathy including papilloedema
Blood pressure control
(ACE = angiotensin-converting enzyme; ADAMTS-13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; APTT = activated partial
thromboplastin time; Gl = gastrointestinal; HELLP
= haemolysis, elevated liver enzymes and low platelets; HUS
= haemolytic uraemic syndrome; LFTs = liver function tests;
PT = prothrombin time; VEGF = vascular endothelial growth factor)
Renal involvement in systemic conditions • 409
E. coli 0157:H7 serotype is the best known but other serotypes
that produce verotoxins may also be responsible. Although these
bacteria live as commensals in the gut of cattle and other livestock,
they can cause haemorrhagic diarrhoea in humans when the
infection is contracted from contaminated food products, water
or other infected individuals. In a proportion of cases, verotoxin
produced by the organisms enters the circulation and binds to
specific glycolipid receptors that are expressed on the surface
of microvascular endothelial cells. Most cases are sporadic
but large outbreaks related to poor sanitation may occur. In
developed countries, Shiga-like toxin-associated HUS is now
the most common cause of AKI in children. Recovery is good
in most patients but sometimes RRT may be required for up
to 1 4 days. No other specific treatments have been shown to
accelerate renal recovery.
In the absence of bloody diarrhoea, other (atypical) causes
of HUS should be considered: in particular, abnormalities of
the complement system. Familial forms are due to mutations
in various genes that encode components or regulators of the
complement cascade, including factor H (CFH), factor B (CFB),
membrane co-factor protein (MCP) and complement component
3 (C3). The penetrance of familial HUS is incomplete, indicating
that environmental triggers are also involved: often infection,
including diarrhoea. Sporadic cases may be associated with the
development of autoantibodies to complement factor H. In addition
to supportive care, including RRT if necessary, management of
complement-mediated HUS includes plasma exchange to replace
complement component and remove pathogenic autoantibodies.
Recently, impressive results have been reported with the anti-C5
monoclonal antibody, eculizumab, which binds to C5, thereby
preventing activation of the terminal complement cascade.
Thrombotic thrombocytopenic purpura
Like HUS, thrombotic thrombocytopenic purpura (TTP) is
characterised by microangiopathic haemolytic anaemia and
thrombocytopenia; in contrast, however, the brain is more
commonly affected in TTP and involvement of the kidney is
usually less prominent. TTP is an autoimmune disorder caused
by antibodies against ADAMTS-13, which is involved in regulating
platelet aggregation, and a low (< 1 0%) serum ADAMTS-13
activity level may be useful in distinguishing TTP from HUS. This
distinction is important, as early therapy with plasma exchange
is crucial in TTP. More details are provided on page 979.
Cholesterol emboli
These present with renal impairment, haematuria, proteinuria and
sometimes eosinophilia with inflammatory features that can mimic
a small-vessel vasculitis. The symptoms are provoked by showers
of cholesterol-containing microemboli, arising in atheromatous
plaques in major arteries. The diagnosis should be suspected
when these clinical features occur in patients with widespread
atheromatous disease, who have undergone interventions such
as surgery or arteriography. They may also be precipitated by
anticoagulants and thrombolytic agents. On clinical examination,
signs of large-vessel disease and microvascular occlusion in
the lower limbs (ischaemic toes, livedo reticularis) are common
but not invariable (Fig. 15.17). There is no specific treatment.
Small-vessel vasculitis
Renal disease caused by small-vessel vasculitis usually presents
with a clinical picture typical of a glomerulonephritis (see Figs
15.9 and 15.12C, pp. 393 and 399). More information is given
on page 410.
Fig. 15.17 The foot of a patient who suffered extensive
atheroembolism following coronary artery stenting.
Renal involvement in
systemic conditions
The kidneys may be directly involved in a number of multisystem
diseases or secondarily affected by diseases of other organs.
Involvement may be at a pre-renal, renal (glomerular or interstitial)
or post-renal level. Many of the diseases are described in other
sections of this chapter or in other chapters of the book.
| Diabetes mellitus
Diabetic nephropathy is the most common cause of CKD in
developed countries. In patients with diabetes, there is a steady
advance from moderately elevated albuminuria (microalbuminuria)
to dipstick-positive proteinuria, in association with evolving
hypertensive and progressive renal failure, as described on
page 757. Few patients require renal biopsy to establish the
diagnosis, but atypical features such as very rapid progression
of proteinuria/decline in renal function or the absence of other
microvascular damage, including retinopathy, should lead to
suspicion that an alternative condition could be present.
Management with ACE inhibitors and ARBs to slow progression
is described on page 757. In some patients, proteinuria may
be eradicated and progression completely halted, even if renal
function is abnormal, although most still have progressive disease,
albeit at a slower rate. Emerging evidence suggests that SGLT2
inhibitors, such as empagliflozin, a new agent for diabetes that
causes glycosuria (p. 748), may lead to improved cardiovascular
and renal outcomes, at the expense of increased genital infections.
|Multiple myeloma
In myeloma, a malignant clone of plasma cells produces a
paraprotein, often a monoclonal light chain (p. 966). Renal
manifestations are dominated by these toxic light chains, which
may cause a variety of insults (Box 15.24). Hypercalcaemia may
also occur due to bony metastases.
Hepatic-renal disease
Severe hepatic dysfunction may cause a haemodynamically
mediated type of renal failure, hepatorenal syndrome (HRS),
described on page 864. Patients with chronic liver disease are
also predisposed to develop AKI (acute tubular necrosis) in
response to relatively minor insults, including bleeding, diuretic
therapy and infection. Differentiating true HRS from AKI can
be difficult. Patients with true HRS are often difficult to treat
410 • NEPHROLOGY AND UROLOGY
15.24 Renal manifestations of multiple myeloma
Condition
Presentation
Pathogenesis
Cast
nephropathy
(‘myeloma
kidney’)
AKI
Little/no proteinuria
Light chains combine
with Tamm-Horsfall
protein precipitating in
tubules
Fanconi’s
syndrome
Aminoaciduria,
phosphaturia,
glycosuria
Proximal (type II) RTA
Proximal tubular injury
due to light chain
deposition in tubular
epithelium
AL (primary)
amyloidosis
Proteinuria/nephrotic
syndrome
Renal impairment
Misfolded lights chains
(usually lambda) form
amyloid, which is
deposited in glomeruli
Monoclonal
immunoglobulin
deposition
disease*
Proteinuria (may be
in nephrotic range)
Renal impairment
Usually light chains
(frequently kappa) are
deposited in glomeruli,
causing a nodular
glomerulosclerosis
Hypercalcaemia
Thirst, polyuria, bony
and abdominal pain,
headache
Bony destruction from
metastases
*These may also occur as primary conditions without myeloma being present.
(AKI = acute kidney injury; RTA = renal tubular acidosis)
by dialysis and have a poor prognosis. Where treatment is
justified - for example, if there is a good chance of recovery or
of a liver transplant - slow or continuous treatments are less
likely to precipitate or exacerbate hepatic encephalopathy. IgA
nephropathy (p. 400) is more common in patients with chronic
liver disease.
Sarcoidosis
The most common renal manifestation of sarcoidosis is
hypercalcaemia from 1 -a-vitamin D formation in granulomas.
Less commonly, it may lead to a granulomatous interstitial
nephritis, sometimes presenting acutely, where renal function may
improve with glucocorticoid therapy. Postmortem examinations
reveal a chronic interstitial nephritis in 15-30% of patients with
sarcoidosis but clinically relevant disease appears to be much
less common.
Systemic vasculitis
Small-vessel vasculitis (p. 1040) commonly affects the kidneys,
with rapid and profound impairment of glomerular function.
Histologically, there is a focal inflammatory glomerulonephritis,
usually with focal necrosis (see Box 15.15, p. 398, and Fig.
15.12C, p. 399) and often with crescentic changes (see Fig.
15.12C). Typically, the patient is systemically unwell with an acute
phase response, weight loss and arthralgia. In some patients, it
presents as a kidney-limited disorder, with rapidly deteriorating
renal function and crescentic nephritis (a rapidly progressive
glomerulonephritis). In others, pulmonary haemorrhage may
occur, which can be life-threatening.
The most important cause is ANCA vasculitis (p. 1041).
Two subtypes are recognised, microscopic polyangiitis (MPA)
and granulomatosis with polyangiitis. Both may present with
glomerulonephritis and pulmonary haemorrhage, along with
constitutional symptoms. Gastrointestinal involvement and
neuropathy may also occur. Serological testing for antibodies
to myeloperoxidase (MPO) and proteinase 3 (PR3) is usually
positive but these are not specific and a biopsy of affected
tissue should be obtained, if possible, to confirm the diagnosis.
The standard treatment of glomerulonephritis associated with
systemic vasculitis is high-dose glucocorticoids combined with
cyclophosphamide, or mycophenolate mofetil (p. 1041). Recent
studies indicate that rituximab (p. 1 006), when combined with high-
dose glucocorticoids, is as effective as oral cyclophosphamide and
high-dose glucocorticoids in the treatment of ANCA-associated
vasculitis. Plasma exchange can offer additional benefit in patients
with progressive renal damage who are not responding adequately
to immunosuppressive therapy.
Glomerulonephritis secondary to vasculitis may rarely be seen
in rheumatoid arthritis, SLE and cryoglobulinaemia, although
SLE usually involves the kidney in different ways (see below).
Medium- to large-vessel vasculitis, such as polyarteritis nodosa
(p. 1042), does not cause glomerulonephritis but can cause
hypertension, renal aneurysms and infarction if the renal vessels
are involved.
Systemic sclerosis
Renal involvement is a serious complication of systemic sclerosis,
which is more likely to occur in diffuse cutaneous systemic
sclerosis (DCSS) than in limited cutaneous systemic sclerosis
(LCSS) (p. 1037). The renal lesion is caused by intimal cell
proliferation and luminal narrowing of intrarenal arteries and
arterioles. There is intense intrarenal vasospasm and plasma
renin activity is markedly elevated. Renal involvement usually
presents clinically with severe hypertension, microangiopathic
features and progressive oliguric renal failure (‘scleroderma
renal crisis’). Use of ACE inhibitors to control the hypertension
has improved the 1 -year survival from 20% to 75% but about
50% of patients continue to require RRT. Onset or acceleration
of the syndrome after glucocorticoid use or cessation of ACE
inhibitors is well described.
Systemic lupus erythematosus
Subclinical renal involvement, with non-visible haematuria and
proteinuria but minimally impaired or normal renal function, is
common in systemic lupus erythematosus (SLE). Usually, this is
due to glomerular disease, although interstitial nephritis may also
occur, particularly in patients with overlap syndromes such as
mixed connective tissue disease and Sjogren’s syndrome (p. 1 038).
Almost any histological pattern of glomerular disease can be
observed in SLE and the clinical presentation ranges from florid,
rapidly progressive glomerulonephritis to nephrotic syndrome.
The most common presentation is with subacute disease and
inflammatory features (haematuria, hypertension, variable renal
impairment), accompanied by heavy proteinuria that often reaches
nephrotic levels. In severely affected patients, the most common
histological pattern is a proliferative glomerulonephritis with
substantial deposits of immunoglobulins on immunofluorescence.
Randomised controlled trials have shown that the risk of ESRD in
lupus nephritis is significantly reduced by high-dose glucocorticoids
administered in combination with cyclophosphamide, usually given
as regular intravenous pulses. Subsequently, it has been shown
that the combination of glucocorticoids and mycophenolate
mofetil is equally as effective, for both induction and maintenance
treatment.
Many patients with SLE who develop ESRD go into remission,
possibly because of immunosuppression related to the ESRD.
Acute kidney injury • 411
Patients with ESRD caused by SLE are usually good candidates
for dialysis and transplantation. Although it may recur in renal
allografts, the immunosuppression required to prevent allograft
rejection usually controls SLE.
| Sickle-cell nephropathy
Improved survival of patients with sickle-cell disease (p. 951)
means that a high proportion now live to develop chronic
complications of microvascular occlusion. In the kidney, these
changes are most pronounced in the medulla, where the vasa
recta are the site of sickling because of hypoxia and hypertonicity.
Loss of urinary concentrating ability and polyuria are the earliest
changes; distal renal tubular acidosis and impaired potassium
excretion are typical. Papillary necrosis may also occur (p. 403). A
minority of patients develop ESRD. This is managed according to
the usual principles, but response to recombinant erythropoietin
is poor because of the haemoglobinopathy. Patients with sickle
trait have an increased incidence of unexplained non-visible
haematuria.
Acute kidney injury
Acute kidney injury (AKI), previously referred to as acute renal
failure, is not a diagnosis; rather it describes the situation where
there is a sudden and often reversible loss of renal function,
which develops over days or weeks and is often accompanied
by a reduction in urine volume. Approximately 7% of all
hospitalised patients and 20% of acutely ill patients develop
AKI. In uncomplicated AKI mortality is low, even when RRT is
required. In AKI associated with sepsis and multiple organ failure,
mortality is 50-70% and the outcome is usually determined by
the severity of the underlying disorder and other complications,
rather than by kidney injury itself. Elderly patients are at higher
risk of developing AKI and have a worse outcome (Box 15.25).
Pathophysiology
There are many causes of AKI and it is frequently multifactorial.
It is helpful to classify it into three subtypes:
• ‘pre-renal’, when perfusion to the kidney is reduced
• ‘renal’, when the primary insult affects the kidney itself
• ‘post-renal’, when there is obstruction to urine flow at any
point from the tubule to the urethra (Fig. 15.18).
In pre-renal AKI, a reduction in perfusion reduces GFR. If the
insult is not corrected, this may lead to ‘renal’ injury: namely,
acute tubular necrosis (ATN). Histologically, the kidney shows
inflammatory changes, focal breaks in the tubular basement
membrane and interstitial oedema (see Fig. 15.13B, p. 402).
Dead tubular cells may also be shed into the tubular lumen,
leading to tubular obstruction. Although tubular cell damage
is the dominant feature under the microscope, there may also
be profound alterations in the renal microcirculation. Renal AKI
may be caused by nephrotoxic drugs (p. 426), which can cause
ATN or allergic interstitial nephritis. The other common ‘renal’
cause is glomerulonephritis, in which there is direct inflammatory
damage to the glomeruli (p. 416).
Post-renal AKI occurs as the result of obstruction to the renal
tract. This leads to elevation of intraluminal ureteral pressure
transmitted to the nephrons after prolonged obstruction, with
a subsequent fall in GFR. If the obstruction is not relieved,
the low GFR is maintained by a drop in renal blood flow rate
via thromboxane A2 and angiotensin II. This leads to chronic
POST-RENAL
Urinary calculi (bilateral)
Retroperitoneal fibrosis
Benign prostatic
enlargement
Bladder cancer
Prostate cancer
Cervical cancer
Urethral stricture/valves
Meatal stenosis/phimosis
Fig. 15.18 Causes of acute kidney injury.
PRE-RENAL
Impaired perfusion:
• Cardiac failure
• Sepsis
• Blood loss
• Dehydration
• Vascular occlusion
RENAL
Glomerulonephritis
Small-vessel vasculitis
Acute tubular necrosis
• Drugs
• Toxins
• Prolonged hypotension
Interstitial nephritis
• Drugs
• Toxins
• Inflammatory disease
• Infection
renal injury over time (several weeks). Recovery of renal
function depends on the duration of obstruction and also the
pre-morbid GFR.
Clinical features
Early recognition and intervention is important in AKI; all
emergency admissions to hospital should have renal function,
blood pressure, temperature and pulse checked on arrival
and should undergo a risk assessment for the likelihood of
developing AKI. This includes looking at coexisting diseases
such as diabetes and vascular and liver disease, which make AKI
more likely, as well as gathering information on drug treatments
such as ACE inhibitors and NSAIDs, which may be associated
with renal dysfunction. If a patient is found to have a high serum
creatinine, it is important to establish whether this is an acute
or acute-on-chronic phenomenon, or a sign of CKD (see Fig.
15.22, p. 416). Previous measurements of renal function can
be of great value in differentiating these possibilities. Patients
with AKI need to be assessed quickly to determine the likely
underlying cause. Clinical features and pertinent investigations
for the different causes of AKI are shown in Box 15.25. Various
criteria have been proposed to classify AKI and to help identify
high-risk patients, guide treatment and provide information
regarding prognosis but are mostly used in a research setting
to standardise diagnosis. The most commonly used are the
KDIGO, AKIN and RIFLE criteria.
Pre-renal AKI
Patients with pre-renal AKI are typically hypotensive and
tachycardic with signs of poor peripheral perfusion, such as
delayed capillary return. Tachycardia and postural hypotension (a
fall in blood pressure of >20/10 mmHg from lying to standing) are
valuable signs of early hypovolaemia. Many patients with sepsis
412 • NEPHROLOGY AND UROLOGY
15.25 Categorising acute kidney injury based on history, examination and investigations
Type of AKI
History
Examination
Investigations
Pre-renal
Volume depletion (vomiting, diarrhoea,
Low BP (including postural drop)
Urine Na <20 mmol/L
burns, haemorrhage)
Tachycardia
Fractional excretion Na < 1 %
Drugs (diuretics, ACE inhibitors, ARBs,
Weight decrease
High urea:creatinine ratio
NSAIDs, calcineurin inhibitors, iodinated
Dry mucous membranes and
Urinalysis bland
contrast)
increased skin turgor
Liver disease
Cardiac failure
JVP not visible even when lying down
Renal
ATN
Prolonged pre-renal state
Vital signs
Urine Na >40 mmol/L
Sepsis
Fluid assessment
Fractional excretion Na > 1 %
Toxic ATN: drugs (aminoglycosides,
Limbs for compartment syndrome
Dense granular (‘muddy brown’)
cisplatin, tenofovir, methotrexate,
casts
iodinated contrast)
Other (rhabdomyolysis, snake bite,
Amanita mushrooms)
Creatine kinase
Glomerular
Rash, weight loss, arthralgia
Hypertension
Proteinuria, haematuria
Chest symptoms (pulmonary renal
Oedema
Red cell casts, dysmorphic red cells
syndromes)
Purpuric rash, uveitis, arthritis
ANCA, anti-GBM, ANA, C3 and C4
IV drug use
Viral hepatitis screen, HIV
Renal biopsy
Tubulo-interstitial
Interstitial nephritis: drugs (PPIs,
Fever
Leucocyturia
penicillins, NSAIDs)
Rash
Eosinophiluria (and a peripheral
Sarcoidosis
eosinophilia)
White cell casts
Minimal proteinuria
Tubular obstruction:
Paraprotein
1 . Myeloma (cast nephropathy)
Calcium (myeloma, sarcoidosis)
2. Tubular crystal nephropathy:
Urine microscopy for crystals
Drugs (aciclovir, indinavir,
Serum urate
triamterene, methotrexate)
Oxalate (fat malabsorption, ethylene
glycol)
Urate (tumour lysis)
Urine collection for oxalate
Vascular
Flank pain, trauma
BP (malignant hypertension)
Normal urinalysis or some haematuria
(including renal
Anticoagulation
Fundoscopy
C3 and C4 (cholesterol emboli, TMA)
infarction, renal vein
Recent angiography (cholesterol emboli)
Livedo reticularis (cholesterol emboli)
Doppler renal ultrasound
thrombosis, cholesterol
Nephrotic syndrome (renal vein
Sclerodactyly
CT angiography
emboli, malignant
thrombosis)
Platelets, haemolytic screen, LDH
hypertension)
Systemic sclerosis (renal crisis)
Consider ADAMTS1 3 and
Diarrhoea (HUS)
complement genetics (if TMA)
Post-renal
Prostate cancer history
Rectal examination (prostate and
Urinalysis frequently normal (may
Neurogenic bladder
anal tone)
reveal haematuria depending on
Cervical carcinoma
Distended bladder
cause)
Retroperitoneal fibrosis
Pelvic mass
Renal ultrasound (hydronephrosis)
Bladder outlet symptoms
Isotope renogram (delayed excretion)
if ultrasound inconclusive
(ACE = angiotensin-converting enzyme; ANA = antinuclear antibody; ANCA = ;
antineutrophil cytoplasmic antibody; ARBs = angiotensin receptor blockers; BP = blood pressure;
GBM = glomerular basement membrane; HIV = human immunodeficiency virus; HUS = haemolytic uraemic syndrome; JVP = jugular venous pulse; LDH = lactate
dehydrogenase; Na = sodium; NSAIDs = non-steroidal anti-inflammatory drugs; PPIs = proton pump inhibitors; TMA = thrombotic microangiopathy)
initially present with poor peripheral perfusion, as mentioned
above, but then show evidence of peripheral vasodilatation
once they have undergone initial resuscitation with intravenous
fluids. However, this is accompanied by relative underfilling of
the arterial tree and the kidney responds as it would to absolute
hypovolaemia, with renal vasoconstriction. It is important to note
that pre-renal AKI may also occur without systemic hypotension,
particularly in patients taking NSAIDs or ACE inhibitors (Fig. 15.19).
The cause of hypotension is often obvious, but concealed blood
loss can occur into the gastrointestinal tract, retroperitoneum,
following trauma (particularly with pelvic and femoral fractures),
and into the pregnant uterus. Large volumes of intravascular
fluid may also be lost into tissues after crush injuries or burns,
and in severe inflammatory skin diseases or sepsis. Uncorrected
renal hypoperfusion causing pre-renal azotaemia may progress
to ATN.
Renal AKI
Factors that can help differentiate the various causes of
intrinsic renal AKI are summarised in Box 15.25. Patients with
Acute kidney injury • 413
Afferent arteriole Efferent arteriole
Fig. 15.19 Renal haemodynamics and autoregulation of glomerular
filtration rate (GFR). It is evident from this figure how angiotensin¬
converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs)
may be associated with profound drops in GFR in the context of bilateral
renal artery stenosis or intravascular volume depletion (which decrease
perfusion to afferent arterioles). (NSAIDs = non-steroidal anti-inflammatory
drugs)
glomerulonephritis demonstrate haematuria and proteinuria,
and may have clinical manifestations of an underlying disease,
such as SLE or systemic vasculitis. Although blood tests,
including an immunological screen, should be performed to
clarify the diagnosis in glomerulonephritis, a renal biopsy is
usually required. Drug-induced acute interstitial nephritis is
harder to spot but should be suspected in a previously well
patient if there is an acute deterioration of renal function
coinciding with introduction of a new drug treatment. Drugs
that are commonly implicated include PPIs, NSAIDs and many
antibiotics.
Post-renal AKI
Patients should be examined clinically to look for evidence of
a distended bladder and should also undergo imaging with
ultrasound to detect evidence of obstruction above the level of the
bladder. Post-renal AKI is usually accompanied by hydronephrosis.
Management
Management options common to all forms of AKI are discussed
in more detail below and summarised in Box 15.26.
Haemodynamic status
If hypovolaemia is present, it should be corrected by replacement
of intravenous fluid or blood; excessive administration of fluid
should be avoided, since this can provoke pulmonary oedema and
worsen outcome in AKI. Monitoring of central venous pressure
may be of value in determining the rate of administration of
fluid in these circumstances. Balanced crystalloid solutions,
such as Plasma-Lyte, Hartmann’s or Ringer’s lactate, may be
preferable to isotonic saline (0.9% NaCI) when large volumes of
fluid resuscitation are required, in order to avoid hyperchloraemic
acidosis, but whether this substantially influences outcome
remains unclear. Administration of hydroxyethyl starch solutions
should be avoided, since they have been associated with higher
rates of established AKI. Critically ill patients may require inotropic
drugs to restore an effective blood pressure but clinical trials do
not support a specific role for low-dose dopamine.
Hyperkalaemia and acidosis
Hyperkalaemia is common, particularly in patients with
rhabdomyolysis, burns, haemolysis or metabolic acidosis
(p. 362). If serum K+ concentration is >6.5 mmol/L, this should
be treated immediately, as described in Box 14.17 (p. 363), to
prevent life-threatening cardiac arrhythmias. Metabolic acidosis
develops unless prevented by loss of hydrogen ions through
vomiting. Severe acidosis can be ameliorated with sodium
bicarbonate if volume status allows. Restoration of blood volume
will correct acidosis by restoring kidney function. Infusions of
isotonic sodium bicarbonate may also be used, if acidosis is
severe, to reduce life-threatening hyperkalaemia (Box 15.26).
Cardiopulmonary complications
Pulmonary oedema (Fig. 15.20) may be caused by the
administration of excessive amounts of fluids relative to urine
i
• Assess fluid status as this will determine fluid prescription:
If hypovolaemic: optimise systemic haemodynamic status with
fluid challenge and inotropic drugs if necessary
Once euvolaemic, match fluid intake to urine output plus an
additional 500 mL to cover insensible losses
If fluid-overloaded, prescribe diuretics (loop diuretics at high dose
will often be required); if the response is unsatisfactory, dialysis
may be required
• Administer calcium resonium to stabilise myocardium and glucose
and insulin to correct hyperkalaemia if K+ >6.5 mmol/L (see Box
14.17, p. 363) as a holding measure until a definitive method of
removing potassium is achieved (dialysis or restoration of renal
function)
• Consider administering sodium bicarbonate (100 mmol) to correct
acidosis if H+ is >100 nmol/L (pH <7.0)
• Discontinue potentially nephrotoxic drugs and reduce doses of
therapeutic drugs according to level of renal function
• Ensure adequate nutritional support
• Consider proton pump inhibitors to reduce the risk of upper
gastrointestinal bleeding
• Screen for intercurrent infections and treat promptly if present
• In case of urinary tract obstruction, drain lower or upper urinary
tract as necessary
Fig. 15.20 Pulmonary oedema in acute kidney injury. The
appearances are indistinguishable from left ventricular failure but the heart
size is usually normal. Blood pressure is often high.
15.26 Management of acute kidney injury
414 • NEPHROLOGY AND UROLOGY
output and by increased pulmonary capillary permeability. If
pulmonary oedema is present and urine output cannot be rapidly
restored, treatment with dialysis may be required to remove excess
fluid. Temporary respiratory support may also be necessary
using non-invasive ventilation. Once initial resuscitation has been
performed, fluid intake should be matched to urine output plus
500 mL per day to cover insensible losses, unless diarrhoea is
present, in which case additional fluids may be required.
Electrolyte disturbances
Electrolyte disturbances, such as dilutional hyponatraemia,
may occur if the patient has continued to drink freely despite
oliguria or has received inappropriate amounts of intravenous
dextrose. They can be avoided by paying careful attention to
fluid balance and by giving intravenous fluids slowly. Modest
hypocalcaemia is common but rarely requires treatment. Serum
phosphate levels are usually high but may fall in patients on daily
or continuous renal replacement therapy (CRRT), necessitating
phosphate replacement.
Dietary measures
Adequate nutritional support should be ensured and it is
important to give sufficient amounts of energy and adequate
amounts of protein; high protein intake should be avoided.
This is particularly important in patients with sepsis and burns
who are hypercatabolic. Enteral or parenteral nutrition may be
required (p. 707).
Infection
Patients with AKI are at substantial risk of intercurrent infection
because humoral and cellular immune mechanisms are depressed.
Regular clinical examination, supplemented by microbiological
investigation where appropriate, is required to diagnose infection.
If infection is discovered, it should be treated promptly according
to standard principles (Ch. 6).
Medications
Patients with drug-induced kidney injury (p. 402) should have the
offending drug withdrawn. Additionally, vasoactive medications,
such as NSAIDs and ACE inhibitors, should be discontinued, as
they may prolong AKI (see Fig 15.19). H2-receptor antagonists or
PPIs should be given to prevent gastrointestinal bleeding. Other
drug treatments should be reviewed and the doses adjusted if
necessary, to take account of renal function. Non-essential drug
treatments should be stopped.
Renal tract obstruction
In post-renal AKI, the obstruction should be relieved as soon
as possible. This may involve urinary catheterisation for bladder
outflow obstruction, or correction of ureteric obstruction with a
ureteric stent or percutaneous nephrostomy.
Renal replacement therapy
Conservative management can be successful in AKI with
meticulous attention to fluid balance, electrolytes and nutrition,
but RRT may be required in patients who are not showing signs
of recovery with these measures (Box 1 5.26). No specific cut-off
values for serum urea or creatinine have been identified at which
RRT should be commenced, and clinical trials of earlier versus later
RRT in unselected patients with AKI have not shown differences
in outcome. Furthermore, RRT can be a risky intervention, since
it requires the placement of central venous catheters that may
become infected and it may represent a major haemodynamic
AKI
Fig. 15.21 Recovery from acute kidney injury (AKI). Many patients
make a full recovery of renal function (1). If the insult is prolonged or prior
renal function not normal, however, patients may develop progressive
chronic kidney disease (2) or, rarely, irreversible, complete loss of renal
function (3). (ESRD = end-stage renal disease)
challenge in unstable patients. Accordingly, the decision to institute
RRT should be made on an individual basis, taking account of
the potential risks and benefits, comorbidity and an assessment
of whether early or delayed recovery is likely. Severe uraemia
with pericarditis and neurological signs (uraemic encephalopathy)
is uncommon in AKI but, when present, is a strong indication
for RRT; other indications are given in Box 15.35 (p. 422). The
two main options for RRT in AKI are intermittent haemodialysis
and CRRT (see Box 15.38, p. 424). Peritoneal dialysis is also
an option if haemodialysis is not available (p. 424).
Recovery from AKI
Most cases of AKI will recover after the insult resolves but recovery
may be impaired in pre-existing CKD or a prolonged severe insult
(Fig. 15.21). Recovery is heralded by a gradual return of urine
output and a steady improvement in plasma biochemistry. Initially,
there is often a diuretic phase in which urine output increases
rapidly and remains excessive for several days before returning
to normal. This may be due in part to tubular damage and to
temporary loss of the medullary concentration gradient. After
a few days, urine volume falls to normal as the concentrating
(fx
• Physiological change: nephrons decline in number with age and
average GFR falls progressively, so many elderly patients will have
established CKD and less functional reserve. Small acute declines in
renal function may therefore have a significant impact.
• Creatinine: as muscle mass falls with age, less creatinine is
produced each day. Serum creatinine can be misleading as a guide
to renal function.
• Renal tubular function: declines with age, leading to loss of
urinary concentrating ability.
• Drugs: increased drug prescription in older people (diuretics, ACE
inhibitors and NSAIDs) may contribute to the risk of AKI.
• Causes: infection, renal vascular disease, prostatic obstruction,
hypovolaemia and severe cardiac dysfunction are common.
• Mortality: rises with age, primarily because of comorbid conditions.
15.27 Acute kidney injury in old age
Chronic kidney disease • 415
mechanism and tubular reabsorption are restored. During the
recovery phase of AKI, it may be necessary to provide temporary
supplementation of bicarbonate, potassium and sometimes
calcium, phosphate and magnesium.
AKI in old age is described in Box 15.27.
Chronic kidney disease
Chronic kidney disease (CKD) refers to an irreversible deterioration
in renal function that usually develops over a period of years (see
Box 15.3, p. 388). Initially, it manifests only as a biochemical
abnormality but, eventually, loss of the excretory, metabolic and
endocrine functions of the kidney leads to the clinical symptoms
and signs of renal failure, collectively referred to as uraemia. When
death is likely without RRT (CKD stage 5), it is called end-stage
renal disease (ESRD).
Epidemiology
The social and economic consequences of CKD are considerable.
In many countries, estimates of the prevalence of CKD stages
3-5 (eGFR <60 mL/min/1.73 m2) are around 5-7%, mostly
affecting people aged 65 years and above (see Box 15.3). The
prevalence of CKD in patients with hypertension, diabetes and
vascular disease is substantially higher, and targeted screening for
CKD should be considered in these and other high-risk groups.
More than 25% of the population aged over 75 years have an
eGFR of <60 mLymin/1 .73 m2, mostly stage 3A CKD, which in
this context typically reflects an increased cardiovascular risk
burden. In these patients, investigation and management should
be focused on cardiovascular risk prevention, as very few will
ever develop ESRD. Many primary renal diseases, however, are
more common in the elderly, so investigation is warranted for
those with declining renal function or with haematuria/proteinuria
on dipstick.
Pathophysiology
Common causes of CKD are shown in Box 1 5.28. In many cases,
the underlying diagnosis is unclear, especially among the large
number of elderly patients with stage 3 CKD (see Box 15.3).
1 15.28 Common causes of chronic kidney disease
Disease
Proportion
Comments
Diabetes mellitus
20-40%
Large racial and
geographical differences
Interstitial diseases
20-30%
Often drug-induced
Glomerular diseases
10-20%
IgA nephropathy is most
common
Hypertension
5-20%
Causality controversial,
much may be secondary
to another primary renal
disease
Systemic inflammatory
diseases
5-10%
Systemic lupus
erythematosus, vasculitis
Renovascular disease
5%
Mostly atheromatous,
may be more common
Congenital and
inherited
5%
Polycystic kidney disease,
Alport’s syndrome
Unknown
5-20%
Many patients diagnosed at a late stage have bilateral small
kidneys; renal biopsy is rarely undertaken in this group since it is
more risky, less likely to provide a histological diagnosis because
of the severity of damage, and unlikely to alter management.
Clinical features
The typical presentation is for a raised urea and creatinine to
be found incidentally during routine blood tests, often during
screening of high-risk patients, such as those with diabetes or
hypertension. Most patients with slowly progressive disease are
asymptomatic until GFR falls below 30 mLymin/1 .73 m2 and some
can remain asymptomatic with much lower GFR values than this.
An early symptom is nocturia, due to the loss of concentrating
ability and increased osmotic load per nephron, but this is
non-specific. When GFR falls below 15-20 mLymin/1 .73 m2,
symptoms and signs are common and can affect almost all
body systems (Fig. 15.22). They typically include tiredness or
breathlessness, which may, in part, be related to renal anaemia
or fluid overload. With further deterioration in renal function,
patients may suffer pruritus, anorexia, weight loss, nausea,
vomiting and hiccups. In very advanced renal failure, respiration
may be particularly deep (Kussmaul breathing) due to profound
metabolic acidosis, and patients may develop muscular twitching,
fits, drowsiness and coma.
Investigations
The recommended investigations in patients with CKD are shown
in Box 15.29. Their main aims are:
• to exclude AKI requiring rapid investigation; in patients
with unexpectedly high urea and creatinine (when there is
an increase from previous results or no prior results are
available), renal function should be retested within 2 weeks
to avoid missing AKI
• to identify the underlying cause where possible, since this
may influence the treatment
• to identify reversible factors that may worsen renal
function, such as hypertension or urinary tract obstruction
• to screen for complications of CKD, such as anaemia and
renal osteodystrophy
• to screen for cardiovascular risk factors.
Referral to a nephrologist is appropriate for patients with
potentially treatable underlying disease and those who are
likely to progress to ESRD. Suggested referral criteria are listed
in Box 15.30.
Management
The aims of management in CKD are to:
• monitor renal function
• prevent or slow further renal damage
• limit complications of renal failure
• treat risk factors for cardiovascular disease
• prepare for RRT, if appropriate (p. 420).
Monitoring of renal function
The rate of change in renal function varies between patients
and may vary over time in each individual. Renal function should
therefore be monitored every 6 months in patients with stage
3 CKD, but more frequently in patients who are deteriorating
rapidly or have stage 4 or 5 CKD. A plot of GFR against time (Fig.
15.23) can demonstrate whether therapy has been successful
in slowing progression, detect any unexpected increase in the
rate of decline that may warrant further investigation, and help
416 • NEPHROLOGY AND UROLOGY
1 15.29 Suggested investigations in chronic kidney disease
Initial tests
Interpretation
Urea and creatinine
To assess stability/progression: compare to previous results
Urinalysis and quantification of proteinuria
Haematuria and proteinuria may indicate glomerular disease and need for biopsy (p. 391).
Proteinuria indicates risk of progressive CKD requiring preventive ACE inhibitor or ARB therapy
Electrolytes
To identify hyperkalaemia and acidosis
Calcium, phosphate, parathyroid hormone and
25(0H)D
Assessment of renal osteodystrophy
Albumin
Low albumin: consider malnutrition, inflammation, nephrotic syndrome
Full blood count (±Fe, ferritin, folate, B12)
If anaemic, exclude common non-renal explanations, then manage as renal anaemia
Lipids, glucose ±HbA1c
Cardiovascular risk high in CKD: treat risk factors aggressively
Renal ultrasound
Only if there are obstructive urinary symptoms, persistent haematuria, family history of polycystic
kidney disease or progressive CKD. Small kidneys suggest chronicity. Asymmetric renal size
suggests renovascular or developmental disease
Hepatitis and HIV serology
If dialysis or transplant is planned. Hepatitis B vaccination recommended if seronegative
Other tests
Consider relevant tests from Box 15.25, especially if the cause of CKD is unknown
(ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; 25(0H)D = 25-hydroxyvitamin D)
predict when ESRF will be reached to facilitate timely planning
for RRT.
Reduction of rate of progression
Slowing the rate of progression of CKD may reduce complications
and delay symptom onset and the need for RRT (Fig. 15.23).
Therapies directed towards the primary cause of CKD should
be employed where possible; tight blood pressure control is
applicable to CKD regardless of cause, however, and reducing
proteinuria is a key target in those with glomerular disease.
Antihypertensive therapy Lowering of blood pressure slows the
rate at which renal function declines in CKD, independently of
the agent used (apart from those with proteinuria; see below) and
Chronic kidney disease • 417
Fig. 15.23 Plot of estimated glomerular filtration rate (eGFR) against time in a patient with type 1 diabetes mellitus. After approximately 6 years
of monitoring (blue arrow), this patient entered an aggressive treatment programme aimed at optimising blood pressure (BP) and glycaemic control. The
reduction in BP was accompanied by a fall in proteinuria (proteimcreatinine ratio, PCR; shown in mg/mmol). At the previous rate of decline in renal function
(dashed line), he was likely to reach the level of renal function at which dialysis therapy is typically required (eGFR=10 mL/min/1.73 m2) within 18 months;
however, the relative stabilisation in his renal function (dotted line) means that this has been deferred, potentially for several years.
15.30 Criteria for referral of chronic kidney disease
patients to a nephrologist
• eGFR <30 mL/min/1.73 m2
• Rapid deterioration in renal function (>25% from previous or
>15 mL/min/1.73 m2/year)
• Significant proteinuria (PCR >100 mg/mmol or ACR >70 mg/
mmol), unless known to be due to diabetes and patient is already
on appropriate medications
• ACR >30 mg/mmol with non-visible haematuria
• Flypertension that remains poorly controlled despite at least four
antihypertensive medications
• Suspicion of renal involvement in multisystem disease
has additional benefits in lowering the risk of hypertensive heart
failure, stroke and peripheral vascular disease. No threshold for
beneficial effects has been identified and any reduction of blood
pressure appears to be beneficial. Various targets have been
suggested, such as 140/90 mmHg for patients with CKD and no
albuminuria (ACR <3 mg/mmol). A lower target of 130/80 mmHg
should be considered for those who have moderately elevated
albuminuria (ACR 3-3 mg/mmol), and is recommended for those
with an ACR of more than 30 mg/mmol. Even lower targets,
such as 125/75 mmHg, may be prudent in patients with CKD
and heavy proteinuria (PCR >100 mg/mmol or ACR >70 mg/
mmol). Achieving these blood pressure targets often requires
multiple drugs, and therapeutic success may be limited by
adverse effects and poor adherence.
Reduction of proteinuria Patients with proteinuria are at higher
risk of progression of renal disease, and there is strong evidence
that reducing proteinuria reduces the risk of progression. ACE
inhibitors and ARBs reduce proteinuria and retard the progression
of CKD. These effects are partly due to the reduction in blood
pressure but there is evidence for a specific beneficial effect in
patients with proteinuria (PCR >50 mg/mmol or ACR >30 mg/
mmol) through a reduction in glomerular perfusion pressure.
In addition, ACE inhibitors have been shown to reduce the
risk of cardiovascular events and all-cause mortality in CKD.
Accordingly, ACE inhibitors and/or ARBs should be prescribed
to all patients with diabetic nephropathy and patients with CKD
and proteinuria, irrespective of whether or not hypertension
is present.
While ACE inhibitors and ARBs are excellent drugs for patients
with diabetes or CKD and proteinuria, they need to be prescribed
with care in certain circumstances. Initiation of treatment with
ACE inhibitors and ARBs may be accompanied by an immediate
reduction in GFR; patients should therefore have their renal
function checked within 7-1 0 days of initiating or increasing the
dose of an ACE inhibitor or ARB. Treatment can be continued
so long as the reduction in GFR is not greater than 25% and
is not progressive. Angiotensin II is critical for autoregulation
of GFR in the context of low renal perfusion (see Fig. 15.1 D,
p. 385), and so ACE inhibitors or ARBs may exacerbate pre-renal
failure (see Fig. 15.19). Patients on ACE inhibitors/ARBs should
therefore be warned to stop taking the medication if they become
unwell, such as with fever, vomiting or diarrhoea, restarting once
they are better. This also applies to other common medications
used in patients with CKD, such as diuretics, metformin and
NSAIDs, and this advice may be reinforced by providing written
information such as ‘sick-day rule’ cards (Box 15.31). ACE
inhibitors and ARBs increase serum potassium and should not
be commenced in patients with baseline potassium >5.5 mmol/L.
In patients with serum potassium >6.0 mmol/L, the dose of
ACE inhibitors or ARBs should be reduced or discontinued
entirely, but only after all other measures to reduce potassium
have been considered (see below). Combination therapy with
ACE inhibitors and ARBs or direct renin inhibitors has not been
shown to reduce progression of kidney disease but is associated
with higher rates of hyperkalaemia and AKI, and is therefore to
be avoided.
418 • NEPHROLOGY AND UROLOGY
i
Treatment of complications
The kidneys have many functions in addition to excretion of waste
(p. 384). Treatments that substitute for all of the normal roles
of the kidneys must therefore be instigated to maintain normal
body homeostasis and prevent complications.
Maintenance of fluid and electrolyte balance The kidneys excrete
waste and regulate many electrolytes, and so patients with
CKD may accumulate waste products and develop electrolyte
abnormalities.
Urea is a key product of protein degradation and accumulates
with progressive CKD. All patients with stages 4 and 5 CKD
should be given dietetic advice aimed at preventing excessive
consumption of protein. Severe protein restriction is not
recommended, however; there is no evidence that this reduces
the rate of decline in renal function but may lead to malnutrition.
Potassium often accumulates in patients with advanced CKD,
who should be provided with dietary advice to reduce daily
potassium intake to below 70 mmol (Box 15.32). Potassium¬
binding compounds limit absorption of potassium from the gut
and may be a useful adjunctive therapy. Calcium resonium is
not recommended other than as a very short-term measure,
as it can be associated with bowel necrosis; however, newer
agents, such as zirconium cyclosilicate and patiromer, appear
promising for chronic use. Other measures that may help regulate
potassium include diuretic therapy and control of acidosis with
sodium bicarbonate (see below). Consideration should be
given to stopping or reducing drugs that elevate potassium,
such as potassium-sparing diuretics and ACE inhibitors/ARBs;
however, this has to be balanced against the potential benefit
that such drugs may have on retarding progression of renal
and cardiovascular disease, and hence withdrawal should be
reserved for when other measures have failed.
The inability of the failing kidney to excrete sodium and water
loads commonly leads to their accumulation, which may manifest
as oedema and may drive hypertension. Patients with evidence of
volume expansion should be instructed to consume a low-sodium
diet (<100 mmol/24 hrs), and in severe cases fluid intake should
also be restricted. Diuretics are commonly required, and as renal
function deteriorates, increasing doses of potent loop diuretics or
synergistic combinations of loop, thiazide and potassium-sparing
diuretics may be necessary.
Occasionally, some patients with tubulo-interstitial disease can
develop ‘salt-wasting’ disease and may require a high sodium
and water intake, including supplements of sodium salts, to
prevent fluid depletion and worsening of renal function.
Acid-base balance Reduced ability to excrete organic acids in
patients with CKD may lead to an anion-gap metabolic acidosis.
In addition, in patients with tubulo-interstitial disease or diabetic
nephropathy, there may be specific defects in acid-base regulation
within the kidney, causing a non-anion-gap renal tubular acidosis
(p. 365). Although acidosis is usually asymptomatic, it may be
associated with increased tissue catabolism and decreased
protein synthesis, and may exacerbate bone disease and the
rate of decline in renal function. Hence, plasma bicarbonate
concentrations should be maintained above 22 mmol/L by
prescribing sodium bicarbonate supplements (starting dose of
1 g 8-hourly, increasing as required). There is some evidence
that correcting acidosis may reduce the rate of decline in renal
function.
Renal bone disease Disturbances of calcium and phosphate
metabolism are almost universal in advanced CKD (Fig. 15.24).
The sequence of events that leads to renal bone disease is
complex, but two primary factors are impaired excretion of
phosphate and failure of the renal tubular cells to convert
25-hydroxyvitamin D to its active metabolite, 1 ,25-dihydroxyvitamin
D. A rise in serum phosphate levels promotes production of the
hormone fibroblast growth factor 23 (FGF23) from osteocytes
(Fig. 24.3, p. 986) and stimulates parathyroid hormone (PTH)
release and hyperplasia of the parathyroid glands. The FGF23
and PTH promote tubular phosphate excretion, thereby partly
compensating for the reduced glomerular filtration of phosphate.
The reduced 1 ,25-dihydroxyvitamin D levels impair intestinal
absorption of calcium. In addition, raised levels of serum
phosphate complex with calcium in the extracellular space, leading
to calcium phosphate deposition. Both the reduced absorption
and increased deposition of calcium cause hypocalcaemia,
which also stimulates PTH production by the parathyroid glands.
Hence in many patients with CKD, compensatory responses
initially maintain phosphate and calcium levels at the upper and
lower ends of their respective normal ranges, at the expense
of an elevated PTH level (secondary hyperparathyroidism). This
is associated with a gradual transfer of calcium and phosphate
from the bone to other tissues, leading to bone resorption
(osteitis fibrosa cystica), and in severe cases this may result in
bony pain and increased risk of fractures. Conversely there is
increased deposition of calcium phosphate in many tissues, most
notably blood vessels and heart valves, which may contribute
to the increased risk of cardiovascular disease in patients with
CKD (p. 420). In some cases, tertiary hyperparathyroidism
supervenes, due to autonomous production of PTH by the
enlarged parathyroid glands; this presents with hypercalcaemia.
Additional problems in bone metabolism include low bone turnover
(adynamic bone disease) in patients who have been over-treated
with vitamin D metabolites, osteomalacia with over-treatment of
15.31 Exemplar medicine sick-day card
When you are unwell with vomiting, diarrhoea or fever, stop taking the
following medications:
• ACE inhibitors: medicines ending in ‘-pril’, e.g. lisinopril, ramipril
• Angiotensin receptor blockers: medicines ending in ‘-sartan’, e.g.
irbesartan, losartan, candesartan
• Non-steroidal anti-inflammatory painkillers: e.g. ibuprofen (Brufen),
diclofenac (Voltarol)
• Diuretics: e.g. furosemide, bendroflumethiazide, indapamide,
spironolactone
• Metformin: a medicine for diabetes.
Restart when you are well again (after 24-48 hours of eating and
drinking normally).
15.32 Foods high in potassium
• Fruit: bananas, avocados, figs, rhubarb
• Vegetables: tomatoes, spinach, parsnips, courgettes, sprouts,
potatoes (including baked, fries, wedges; boiling vegetables reduces
potassium content)
• Sweets/snacks: crisps, chocolate, toffee, nuts (including peanut
butter)
• Drinks: beer, cider, wine (spirits contain less potassium), hot
chocolate, fruit juice, milk, yoghurt
• Salt substitutes, such as Lo-Salt: sodium chloride is substituted with
potassium chloride
Chronic kidney disease
419
Impaired renal function
iCa2+
absorption
Fig. 15.24 Pathogenesis of renal osteodystrophy. Low 1 ,25-dihydroxyvitamin D (1,25(0H)2D) levels cause calcium malabsorption and this, combined
with high phosphate levels, causes hypocalcaemia, which increases parathyroid hormone (PTH) production by the parathyroid glands. The raised level of
PTH increases osteoclastic bone resorption. Although production of fibroblast growth factor 23 (FGF23) from osteocytes also increases, promoting
phosphate excretion, this is insufficient to prevent hyperphosphataemia in advanced chronic kidney disease.
hyperphosphataemia (p. 369), and osteoporosis in patients with
poor nutritional intake.
The key focus in the management of renal bone disease should be
directed towards the two main driving factors, hyperphosphataemia
and inadequate activation of vitamin D. Hyperphosphataemia should
be treated by dietary restriction of foods with high phosphate
content (milk, cheese, eggs and protein-rich foods) and by the
use of phosphate-binding drugs. Various drugs are available,
including calcium carbonate, aluminium hydroxide, lanthanum
carbonate and polymer-based phosphate binders such as
sevelamer. The aim is to maintain serum phosphate values at
or below 1 .5 mmol/L (4.6 mg/dl_) if possible, but many of these
drugs are difficult to take and adherence can be a problem.
Active vitamin D metabolites (either 1 -a- hydroxy vitamin D or
1 ,25-dihydroxyvitamin D) should be administered in patients who
are hypocalcaemic or have serum PTH levels more than twice the
upper limit of normal. The dose should be adjusted to try to reduce
PTH levels to between 2 and 4 times the upper limit of normal to
limit hyperparathyroidism while avoiding over-suppression of bone
turnover and adynamic bone disease, but care must be exercised
in order to avoid hypercalcaemia. In patients with persistent
hypercalcaemia (tertiary hyperparathyroidism), parathyroidectomy
may be required. If parathyroidectomy is unsuccessful or not
possible, calcimimetic agents, such as cinacalcet, may be used.
These bind to the calcium-sensing receptor in the parathyroid
glands and reduce PTH secretion.
Anaemia Anaemia is common in patients with CKD and contributes
to many of the non-specific symptoms, including fatigue and
i
• Deficiency of erythropoietin
• Toxic effects of uraemia on marrow precursor cells
• Reduced red cell survival
• Blood loss due to capillary fragility and poor platelet function
• Reduced intake, absorption and utilisation of dietary iron
shortness of breath. Haemoglobin can be as low as 50-70 g/L
in CKD stage 5, although it is often less severe or absent in
patients with polycystic kidney disease. Several mechanisms
are implicated, as summarised in Box 15.33. Iron deficiency
is common in patients with CKD, and even more prevalent in
those on haemodialysis as a result of haemolysis in the dialysis
circuit. Hence many patients require iron supplements, which
may be given intravenously for those with iron intolerance or in
situations where adherence may be difficult. Once iron deficiency
and other causes of anaemia have been excluded or corrected,
recombinant human erythropoietin is very effective in correcting
the anaemia of CKD and improving symptoms. Erythropoietin
treatment does not influence mortality, however, and correcting
haemoglobin to normal levels may carry some extra risk, including
hypertension and thrombosis. The target haemoglobin is usually
between 100 and 120 g/L. Erythropoietin is less effective in the
presence of iron deficiency, active inflammation or malignancy,
in particular myeloma.
15.33 Causes of anaemia in chronic kidney disease
420 • NEPHROLOGY AND UROLOGY
Treatment of risk factors for cardiovascular disease
The risk of cardiovascular disease is substantially increased in
patients with a GFR below 60 mLymin/1 .73 m2 and in those with
proteinuria, the combination of reduced eGFR and proteinuria
being particularly unfavourable. Patients with CKD have a higher
prevalence of traditional risk factors for atherosclerosis, such as
hypertension, hyperlipidaemia and diabetes; however, additional
mechanisms of cardiovascular disease may also be implicated.
Left ventricular hypertrophy is commonly found in patients with
CKD, secondary to hypertension or anaemia. Calcification of
the media of blood vessels, heart valves, myocardium and the
conduction system of the heart is also common and may be
due, in part, to the high serum phosphate levels. Reflecting this
fact, serum FGF23 levels, which increase in response to serum
phosphate, are an independent predictor of mortality in CKD.
Both left ventricular hypertrophy and cardiac calcification may
increase the risk of arrhythmias and sudden cardiac death, which
is a much more common mode of death in patients with CKD
than in the general population, particularly in those with more
advanced disease and those on dialysis.
To reduce vascular risk, patients with CKD should be
encouraged to adopt a healthy lifestyle, including regular exercise,
and weight loss and smoking cessation where appropriate.
Lipid-lowering drugs reduce cardiovascular events in patients
with CKD, although their efficacy may be less once patients
require dialysis.
Preparing for renal replacement therapy
It is crucial for patients who are known to have progressive CKD
to be prepared well in advance for the institution of RRT. This
involves ensuring that they are referred to a nephrologist in a
timely manner, as those who are referred late, when they are
either at the stage of or very close to requiring dialysis, tend to
have poorer outcomes.
Several decisions need to be taken in discussion with the
patient and family. The first is to decide whether RRT is an
appropriate choice or whether conservative treatment might
be preferable (p. 421). This is especially relevant in patients
with significant comorbidity. For those who decide to go ahead
with RRT, there are further choices between haemodialysis and
peritoneal dialysis (Box 15.34), between hospital and home
treatment, and on referral for renal transplantation.
Since there is no evidence that early initiation of RRT improves
outcome, the overall aim is to commence RRT when symptoms
of CKD begin to impact on quality of life but before serious
complications have occurred. While there is wide variation between
patients, this typically occurs when the eGFR approaches 10 mU
min/1 .73 m2. This may be a useful marker to predict the timing
of initiation of RRT by extrapolating from a plot of serial eGFR
measurements over time (see Fig. 15.23).
Preparations for starting RRT should begin at least 1 2 months
before the predicted start date. This involves providing the
patient with psychological and social support, assessing home
circumstances and discussing the various choices of treatment
(Fig. 15.25). Depression is common in patients who are on or
approaching RRT, and support from the renal multidisciplinary
team should be provided both for them and for their relatives,
to explain and help them adapt to the changes to lifestyle that
may be necessary once RRT starts; this may help to reduce their
anxieties about these changes. Physical preparations include
establishment of timely access for haemodialysis or peritoneal
dialysis and vaccination against hepatitis B.
KM 15.34 Comparison of haemodialysis and
peritoneal dialysis
Haemodialysis
Peritoneal dialysis
Efficient; 4 hrs three times
per week is usually adequate
Less efficient; four exchanges per
day are usually required, each taking
30-60 mins (continuous ambulatory
peritoneal dialysis) or 8-10 hrs each
night (automated peritoneal dialysis)
2-3 days between treatments
A few hours between treatments
Requires visits to hospital
(although home treatment is
possible for some patients)
Performed at home
Requires adequate venous
circulation for vascular access
Requires an intact peritoneal cavity
without major scarring from previous
surgery
Careful adherence to diet and
fluid restrictions required
between treatments
Diet and fluid less restricted
Fluid removal compressed
into treatment periods; may
cause symptoms and
haemodynamic instability
Slow continuous fluid removal,
usually asymptomatic
Infections related to vascular
access may occur
Peritonitis and catheter-related
infections may occur
Patients are usually
dependent on others
Patients can take full responsibility
for their treatment
Renal replacement therapy
Renal replacement therapy (RRT) may be required on a temporary
basis in patients with AKI or on a permanent basis for those
with advanced CKD. Since the advent of long-term RRT in the
1 960s, the numbers of patients with ESRD who are kept alive
by dialysis and transplantation have increased considerably.
By the end of 2014, almost 59 000 patients were on RRT in
the UK, with a median age of 65 years. After a long period of
expansion, the number of patients on dialysis in the UK and USA
has begun to stabilise; however, the total number of patients on
RRT continues to expand, due to an increasing proportion (53%)
of patients with a functional transplant. The remaining patients
were on haemodialysis (41 %) and peritoneal dialysis (6%).
There are variations in the numbers of patients receiving RRT
in different countries because of differences in the incidence of
predisposing disease, as well as differences in medical practice.
For example, the incidence rate for RRT in the USA was about
three times higher than in the UK (363 versus 115 patients per
million population), and the prevalence rate was more than
twice as high (2034 versus 913 per million population). Diabetic
kidney disease is the most common cause of ESRD in many
countries, accounting for 26% of all ESRD in the UK and almost
50% in the USA. The large increase in the prevalence of type
2 diabetes in developing countries is resulting in a predictable
rise in cases of ESRD, which is challenging already stretched
health-care resources.
Survival on dialysis is strongly influenced by age and presence
of complications such as diabetes (Fig. 15.26). For this reason,
conservative care rather than RRT may be a more appropriate
option for older patients or those with extensive comorbidities
Although many young patients without extrarenal disease lead
Renal replacement therapy • 421
|A Haemodialysis
[b] Haemofiltration
Blood to patient
Dialysate
Blood to patient
Ultrafiltrate
Replacement
fluid
jc]|Peritoneal dialysis
[p] Transplantation
-Peritoneal cavity
-Peritoneal membrane
-PD fluid
-Catheter
External iliac artery
External iliac vein
Transplanted
kidney
Donor artery
Donor vein
Donor ureter
Bladder
Fig. 15.25 Options for renal replacement therapy, [a] In haemodialysis, there is diffusion of solutes from blood to dialysate across a semipermeable
membrane down a concentration gradient. [§] In haemofiltration, both water and solutes are filtered across a porous semipermeable membrane by a
pressure gradient. Replacement fluid is added to the filtered blood before it is returned to the patient. [C] In peritoneal dialysis (PD), fluid is introduced into
the abdominal cavity using a catheter. Solutes diffuse from blood across the peritoneal membrane to PD fluid down a concentration gradient, and water
diffuses through osmosis (see text for details). [D] In transplantation, the blood supply of the transplanted kidney is generally anastomosed to the external
iliac vessels and the ureter to the bladder. The transplanted kidney replaces all functions of the failed kidney.
normal and active lives on RRT, those aged 30-34 have a
mortality rate 25 times higher than that of age-matched controls.
The aim of RRT is to replace the excretory functions of the
kidney and to maintain normal electrolyte concentrations and fluid
balance. Various options are available, including haemodialysis,
haemofiltration, haemodiafiltration, peritoneal dialysis and renal
transplantation, and each of these is discussed in more detail
below. Indications for starting RRT in both AKI and CKD may
be found in Box 15.35.
Conservative treatment
In older patients with multiple comorbidities, conservative
treatment of stage 5 CKD, aimed at limiting the adverse symptoms
of ESRD without commencing RRT, is increasingly viewed as
a positive choice (Box 15.36). Current evidence suggests that
survival of these patients without dialysis can be similar or only
slightly shorter than that of patients who undergo RRT, but they
avoid the hospitalisation and interventions associated with dialysis.
Patients are offered full medical, psychological and social support
to optimise and sustain their existing renal function and to treat
complications, such as anaemia, for as long as possible, with
appropriate palliative care in the terminal phase of their disease.
Many of these patients enjoy a good quality of life for several
years. When quality of life on dialysis is poor, it is appropriate to
consider discontinuing it, following discussion with the patient
and family, and to offer palliative care.
Haemodialysis
Haemodialysis is the most common form of RRT in ESRD and
is also used in AKI. Haemodialysis involves gaining access to
the circulation, either through a central venous catheter or an
arteriovenous fistula or graft. The patient’s blood is pumped
through a haemodialyser, which allows bidirectional diffusion of
422 • NEPHROLOGY AND UROLOGY
m ■
1 15.35 Indications for dialysis with examples for AKI and CKD
Indication*
Acute examples
Chronic examples
Fluid overload
Acute pulmonary oedema
Intractable dependent oedema resistant to diuretics
Pulmonary oedema
Severe hypertension
Hyperkalaemia
High potassium (generally >6.5 mmol/L)
with ECG changes (especially broad QRS)
Potassium resistant to dietary control and medical
intervention
Uraemia
Pericarditis
Encephalopathy
Uraemic syndrome including anorexia, nausea, lethargy etc.
(generally not until eGFR <10 mL/min/1.73 m2)
Metabolic acidosis
Severe acidosis (H+ >79 nmol/L; pH <7.1)
Chronic acidosis resistant to bicarbonate therapy
Other (often relative indications)
Bleeding diathesis considered due to
uraemia-induced platelet dysfunction
Intractable anaemia despite erythropoietin and iron
Hyperphosphataemia despite binders
*The presence of anuria in AKI will modify the above indications, as these complications will not resolve if the patient is persistently anuric. Most indications to commence
chronic dialysis are relative indications; a holistic approach is taken to making this decision.
(ECG = electrocardiogram; eGFR = estimated glomerular filtration rate)
— 1 8-44 years, no diabetes
18-44 years, with diabetes
— 44-64 years, no diabetes
— 44-64 years, with diabetes
— >65 years, no diabetes
— >65 years, with diabetes
Fig. 15.26 Percentage survival after commencing renal replacement
therapy according to age group and presence of diabetes.
solutes between blood and the dialysate across a semipermeable
membrane down a concentration gradient (Fig. 15.25A). The
composition of the dialysate can be varied to achieve the desired
gradient, and fluid can be removed by applying negative pressure
to the dialysate side.
Haemodialysis in AKI
Haemodialysis offers the best rate of small solute clearance in
AKI, compared with other techniques such as haemofiltration,
but should be started gradually because of the risk of delirium
and convulsions due to cerebral oedema (dialysis disequilibrium).
Typically, 1-2 hours of dialysis is prescribed initially but,
subsequently, patients with AKI who are haemodynamically
stable can be treated by 4-5 hours of haemodialysis on alternate
days, or 2-3 hours every day. During dialysis, it is standard
practice to anticoagulate patients with heparin but the dose
may be reduced if there is a bleeding risk. Epoprostenol can
be used as an alternative but carries a risk of hypotension. In
patients undergoing short treatments and in those with abnormal
clotting, it may be possible to avoid anticoagulation altogether.
£
• Quality of life: age itself is not a barrier to good quality of life
on RRT.
• Coexisting cardiovascular disease: older people are more
sensitive to fluid balance changes, predisposing to hypotension
during dialysis with rebound hypertension between dialysis sessions.
A failing heart cannot cope with fluid overload, and pulmonary
oedema develops easily.
• Provision of treatment: often only hospital-provided haemodialysis
is suitable and older patients require more medical and nursing
time.
• Survival on dialysis: difficult to predict for an individual patient,
but old age plus substantial comorbidity are associated with poor
median survival. Similar survival may be achieved through
conservative care, without the complications associated with
dialysis.
• Withdrawal from dialysis: may be appropriate whenever quality of
life deteriorates irreversibly, usually in the context of severe
comorbidity.
• Transplantation: relative risks of surgery and immunosuppression
exclude most older people from transplantation.
• Conservative therapy: without dialysis but with adequate support.
This is an appropriate option for patients at high risk of
complications from dialysis, who have a limited prognosis and little
hope of functional recovery.
In AKI, dialysis is performed through a large-bore, dual-lumen
catheter inserted into the femoral or internal jugular vein
(Fig. 15.27A). Subclavian lines are avoided where possible,
largely due to bleeding risk. Also, thromboses or stenoses
here will compromise the ability to form a functioning fistula in
the arm if the patient fails to recover renal function and needs
chronic dialysis.
Haemodialysis in CKD
In CKD, vascular access for haemodialysis is gained by formation
of an arteriovenous fistula (AVF), usually in the forearm, up to
a year before dialysis is contemplated (Fig. 15.27B). After
4-6 weeks, increased pressure transmitted from the artery to
the vein leading from the fistula causes distension and thickening
of the vessel wall (arterialisation). Large-bore needles can then be
15.36 Renal replacement therapy in old age
Renal replacement therapy • 423
0
[b] Vein, expanded due to Mixed arteriovenous
Fig. 15.27 Haemodialysis access. [A] A tunnelled cuffed dialysis
catheter. Bj An arteriovenous fistula. [C] An arteriovenous graft.
inserted into the vein to provide access for each haemodialysis
treatment.
Preservation of arm veins is thus very important in patients
with progressive renal disease who may require haemodialysis
in the future. If creation of an AVF is not possible, synthetic
polytetrafluoroethylene (PTFE) grafts may be fashioned between
an artery and a vein, or central venous catheters may be used
for short-term access (Fig. 15.27C). These are tunnelled under
the skin to reduce infection risk. All patients must be screened
in advance for hepatitis B, hepatitis C and HIV, and vaccinated
against hepatitis B if they are not immune. All dialysis units should
have segregation facilities for hepatitis B-positive patients, given
its easy transmissibility. Patients with hepatitis C and HIV are
less infectious and can be treated satisfactorily using machine
segregation and standard infection control measures.
Haemodialysis is usually carried out for 3-5 hours three
times weekly, either at home or in an outpatient dialysis unit.
The intensity and frequency of dialysis should be adjusted to
achieve a reduction in urea during dialysis (urea reduction ratio)
of over 65%; below this level there is an associated increase
in mortality. Most patients notice an improvement in symptoms
during the first 6 weeks of treatment. The intensity of dialysis
can be increased by:
• escalating the number of standard sessions to four or
more per week
• performing short, frequent dialysis sessions of 2-3 hours
5-7 times per week
• performing nocturnal haemodialysis, when low blood-
pump speeds and single-needle dialysis are used for
approximately 8 hours overnight 5-6 times per week.
More frequent dialysis and nocturnal dialysis can achieve better
fluid balance and phosphate control, improve left ventricular mass
and possibly improve mortality, although the latter has not yet
been robustly demonstrated. Box 15.37 summarises some of
the problems related to haemodialysis.
Haemofiltration
This technique is principally used in the treatment of AKI as CRRT
(Box 1 5.38). Large volumes of water are filtered from blood across
a porous semipermeable membrane under a pressure gradient.
Solutes are removed via ‘solvent drag’. Replacement fluid of a
suitable electrolyte composition is added to the blood after it exits
the haemofilter. If removal of fluid is required, then less fluid is
added back than is removed (see Fig. 15.25B). Haemofiltration
may be either intermittent or continuous, and typically 1-2 L of
filtrate is replaced per hour (equivalent to a GFR of 15-30 ml_/
min/1 .73 m2); higher rates of filtration may be of benefit in patients
with sepsis and multi-organ failure. In continuous arteriovenous
haemofiltration (CAVH), the extracorporeal blood circuit is driven
by the arteriovenous pressure difference, but poor filtration rates
and clotting of the filter are common and this treatment has fallen
out of favour. Continuous venovenous haemofiltration (CWH) is
pump-driven, providing a reliable extracorporeal circulation. Issues
concerning anticoagulation are similar to those for haemodialysis,
but may be more problematic because longer or continuous
anticoagulation is necessary.
Haemodiafiltration
This technique combines haemodialysis with approximately
20-30 L of ultrafiltration (with replacement of filtrate) over
a 3-5-hour treatment. It uses a large-pore membrane and
combines the improved clearance of medium-sized molecules
observed in haemofiltration with the higher small-solute clearance
of haemodialysis. It is sometimes used in the treatment of
AKI, often as continuous therapy (Box 15.38). It is increasingly
favoured in the treatment of CKD but is more expensive
than haemodialysis and the long-term benefits are not yet
established.
424 • NEPHROLOGY AND UROLOGY
1 15.37 Problems with haemodialysis
Problem
Clinical features
Cause
Treatment
During treatments
Hypotension
Sudden iBP; often leg cramps;
Fluid removal and hypovolaemia
Saline infusion; exclude cardiac ischaemia;
sometimes chest pain
quinine may help cramp
Cardiac arrhythmias
Hypotension; sometimes chest pain
Potassium and acid-base shifts
Check K+ and arterial blood gases; review
dialysis prescription; stop dialysis
Haemorrhage
Blood loss (overt or occult);
Anticoagulation
Stop dialysis; seek source; consider
hypotension
Venous needle disconnection
heparin-free treatment
Air embolism
Circulatory collapse; cardiac arrest
Disconnected or faulty lines and
equipment malfunction
Stop dialysis
Dialyser hypersensitivity
Acute circulatory collapse
Allergic reaction to dialysis
Stop dialysis; change to different artificial
membrane or sterilisant
kidney
Between treatments
Pulmonary oedema
Breathlessness
Fluid overload
Ultrafiltration ± dialysis
Systemic sepsis
Rigors; fever; iBP
Usually involves vascular access
devices (catheter or fistula)
Blood cultures; antibiotics
(BP = blood pressure)
15.38 Types of continuous renal replacement therapy
(CRRT) used in AKI management
• CVVH: continuous venovenous haemofiltration
• CVVHD: continuous venovenous haemodialysis
• CVVHDF: continuous venovenous haemodiafiltration
*Most CRRT machines may perform all of these treatments. Continuous
arteriovenous treatments (i.e. continuous arteriovenous haemofiltration) have
fallen out of favour.
Peritoneal dialysis
Peritoneal dialysis is principally used in the treatment of CKD,
though it may occasionally be employed in AKI. It requires the
insertion of a permanent Silastic catheter into the peritoneal cavity
(see Fig. 15.25C). Two types are in common use. In continuous
ambulatory peritoneal dialysis (CAPD), about 2 L of sterile, isotonic
dialysis fluid are introduced and left in place for approximately
4-6 hours. Metabolic waste products diffuse from peritoneal
capillaries into the dialysis fluid down a concentration gradient.
The fluid is then drained and fresh dialysis fluid introduced, in
a continuous four-times-daily cycle. The inflow fluid is rendered
hyperosmolar by the addition of glucose or glucose polymer;
this results in net removal of fluid from the patient during each
cycle, due to diffusion of water from the blood through the
peritoneal membrane down an osmotic gradient (ultrafiltration).
The patient is mobile and able to undertake normal daily activities.
Automated peritoneal dialysis (APD) is similar to CAPD but uses
a mechanical device to perform the fluid exchanges during the
night, leaving the patient free, or with only a single exchange to
perform, during the day.
CAPD is particularly useful in children, as a first treatment
in adults with residual renal function, and as a treatment for
elderly patients with cardiovascular instability. The long-term
use of peritoneal dialysis may be limited by episodes of bacterial
peritonitis and damage to the peritoneal membrane, including
encapsulating peritoneal sclerosis, but some patients have
been treated successfully for more than 10 years. Box 15.39
summarises some of the problems related to CAPD treatment.
Renal transplantation
Renal transplantation offers the best chance of long-term survival
in ESRD and is the most cost-effective treatment. All patients
with ESRD should be considered for transplantation but many are
not suitable due to a combination of comorbidity and advanced
age (although no absolute age limit applies). Active malignancy,
vasculitis, cardiovascular disease and a high risk of recurrence
of renal disease (generally glomerulonephritides) are common
contraindications to transplantation.
Kidney grafts may be taken from a deceased donor in the UK
after brain death (40%) or circulatory death (24%), or from a living
donor (36%). As described on page 88, matching of a donor
to a specific recipient is strongly influenced by immunological
factors, since graft rejection is the major cause of transplant
failure. Compatibility of ABO blood group between donor and
recipient is usually required and the degree of matching for
major histocompatibility (MHC) antigens, particularly human
leucocyte antigen DR (HLA-DR), influences the incidence of
rejection. Immediately prior to transplantation, cross-matching
should be performed for anti-HLA antibodies (traditionally mixing
of recipient serum with donor lymphocytes) (p. 88). Positive tests
predict early rejection and worse graft survival. Although some
ABO- and HLA-incompatible transplants are now possible, this
involves appropriate preparation with pre-transplant plasma
exchange and/or immunosuppression, so that recipient antibodies
to the donor’s tissue are reduced to acceptably low levels. This
option is generally only available for living donor transplants
because of the preparation required. Paired exchanges, in which
a donor-recipient pair who are incompatible, either in blood group
or HLA, are computer-matched with another pair to overcome
the mismatch, are also used to help increase the number of
successful transplants that can be performed.
During the transplant operation, the kidney is placed in
the pelvis; the donor vessels are usually anastomosed to the
recipient’s external iliac artery and vein, and the donor ureter to
the bladder (see Fig. 15.25D). The native kidneys are usually left
in place but may be removed pre-transplant if they are a source
of repeated sepsis or to make room for a transplant in patients
with very large kidneys due to adult polycystic kidney disease.
Renal replacement therapy • 425
15.39 Problems with continuous ambulatory peritoneal dialysis
Problem
Clinical features
Cause
Treatment
Peritonitis
Cloudy drainage fluid;
abdominal pain and systemic
sepsis are variable
Usually entry of skin contaminants
via catheter; bowel organisms less
common
Culture of peritoneal dialysis fluid
Intraperitoneal antibiotics, tobramycin, vancomycin
Catheter removal sometimes required
Catheter exit site
infection
Erythema and pus around
exit site
Usually skin organisms
Antibiotics; sometimes surgical drainage
Ultrafiltration failure
Fluid overload
Damage to peritoneal membrane,
leading to rapid transport of glucose
and loss of osmotic gradient
Replacement of glucose with synthetic, poorly
absorbed polymers for some exchanges
(icodextrin)
Peritoneal
membrane failure
Inadequate clearance of urea
etc.
Scarring/damage to peritoneal
membrane
Increase in exchange volumes; consideration of
automated peritoneal dialysis or switch to
haemodialysis
Sclerosing peritonitis
Intermittent bowel obstruction
Malnutrition
Unknown; typically occurs after
many years
Switch to haemodialysis (may still progress)
Surgery and tamoxifen may be used
15.40 Common causes of renal allograft dysfunction
Time post transplant
Cause
Risk factors
Hours to days
Renal artery/vein thrombosis
Ureteric leak
Delayed graft function (i.e. transplant does not start working
immediately)
Hyperacute rejection
Technically difficult surgery
Thrombophilia/SLE
Small bladder/anuria pre-transplant
Prolonged cold ischaemia time*
Donation after circulatory death
Older, hypertensive donor with stroke as cause
of death, high tacrolimus level
Pre-formed anti-HLA antibodies
HLA mismatch
Previous transplant
Weeks
Acute rejection (especially <3 months; can occur later with
non-adherence/insufficient immunosuppression)
Pre-formed anti-HLA antibodies
HLA mismatch
Previous transplant
Months
BK virus nephropathy
Renal artery stenosis
Intensive immunosuppression
Ureteric stent use
Donor disease
Injury at organ retrieval
Years
Chronic allograft injury (often antibody-mediated)
Previous acute rejections
Non-adherence/insufficient immunosuppression
Any time
Tacrolimus/ciclosporin toxicity
Sepsis (opportunistic and conventional)
Recurrence of disease:
Early (FSGS/MCGN)
Later (IgA nephropathy/membranous glomerulonephritis)
High doses/serum levels
Concurrent use of drugs that inhibit cytochrome
P450 system
Primary FSGS and MCGN
Previous transplant recurrence
*Time from organ retrieval in the donor, with cold perfusion occurring ex vivo, until implantation into the recipient. (FSGS = focal segmental glomerulosclerosis; HLA =
human leucocyte antigen; IgA = immunoglobulin A; MCGN = mesangiocapillary glomerulonephritis; SLE = systemic lupus erythematosus)
All transplant patients require regular life-long follow-up to
monitor renal function and complications of immunosuppression.
Allograft dysfunction is often asymptomatic and picked up
during routine surveillance blood tests. The common causes
at different time points post transplant are summarised in Box
15.40. Immunosuppressive therapy (see Box 4.26, p. 89) is
required to prevent rejection and is more intensive in the early
post-transplantation period, when rejection risk is highest. A
common regimen is triple therapy with prednisolone; ciclosporin or
tacrolimus; and azathioprine or mycophenolate mofetil. Sirolimus
is an alternative that can be introduced later but is generally not
used initially due to impaired wound healing. Antibodies to deplete
or modulate specific lymphocyte populations are increasingly used
for induction and for treatment of glucocorticoid-resistant acute
rejection. Basiliximab, an interleukin (IL)-2 receptor antagonist,
is frequently used at induction to lower rates of rejection. Acute
cellular rejection is usually treated, in the first instance, by short
courses of high-dose glucocorticoids, such as intravenous
methylprednisolone on three consecutive days. Anti-lymphocyte
preparations (e.g. anti -thymocyte globulin, ATG) are used for
glucocorticoid-resistant rejection. Antibody-mediated rejection
is more difficult to treat and usually requires plasma exchange
426 • NEPHROLOGY AND UROLOGY
and intravenous immunoglobulin (p. 89). Complications of
immunosuppression include infections and malignancy (p. 89).
Approximately 50% of white patients develop skin malignancy
by 15 years after transplantation.
The prognosis after kidney transplantation is good. Recent
UK statistics for transplants from cadaver donors indicate 96%
patient survival and 93% graft survival at 1 year, and 88%
patient survival and 84% graft survival at 5 years. Even better
figures are obtained with living donor transplantation (91 % graft
survival at 5 years).
Renal disease in pregnancy
Pregnancy has important physiological effects on the renal system.
Some diseases are more common in pregnancy (Box 15.41),
the manifestations of others are modified during pregnancy,
and a few diseases, such as pre-eclampsia (see Box 30.8,
p. 1276), are unique to pregnancy. These are discussed in
detail in Chapter 30.
15.41 Renal diseases in pregnancy
• Eclampsia: severe hypertension, encephalopathy and fits
• Disseminated intravascular coagulation
• Thrombotic microangiopathy: may also occur post-partum
(post-partum thrombotic thrombocytopenic purpura/haemolytic
uraemic syndrome)
• Acute fatty liver of pregnancy
• ‘HELLP’ syndrome: haemolysis, elevated liver enzymes, low
platelets (thrombotic microangiopathy with abnormal liver function)
Renal disease in adolescence
drugs and their metabolites. Some may reach high concentrations
in the renal cortex as a result of proximal tubular transport
mechanisms. Others are concentrated in the medulla by the
operation of the countercurrent system. The same applies to
certain toxins.
Toxic renal damage may occur by a variety of mechanisms
(Box 1 5.43). Very commonly, drugs contribute to the development
of acute tubular necrosis as one of multiple insults. Numerically,
reactions to NSAIDs and ACE inhibitors are the most important.
Haemodynamic renal impairment, acute tubular necrosis and
allergic reactions are usually reversible if recognised early enough.
Other types, however, especially those associated with extensive
fibrosis, are less likely to be reversible.
|jlon-steroidal anti-inflammatory drugs
Impairment of renal function may develop in patients on NSAIDs,
since prostaglandins play an important role in regulating renal
blood flow by vasodilating afferent arterioles (see Fig. 15.19,
p. 41 3). This is particularly likely in patients with other disorders,
such as volume depletion, heart failure, cirrhosis, sepsis and
pre-existing renal impairment. In addition, idiosyncratic immune
reactions may occur, causing minimal change nephrotic syndrome,
membranous nephropathy (p. 400) and acute interstitial nephritis
(p. 402). Analgesic nephropathy (p. 403) is now a rare complication
of long-term use.
ACE inhibitors
These abolish the compensatory angiotensin ll-mediated
vasoconstriction of the glomerular efferent arteriole that takes
place in order to maintain glomerular perfusion pressure distal
to a renal artery stenosis and in renal hypoperfusion (see Figs
15.1 and 15.19, pp. 385 and 413). Monitoring of renal function
before and after initiation of therapy is essential and an expected
rise in creatinine of about 20% is frequently observed.
Many causes of renal failure present during infancy or childhood,
such as congenital urological malformations and inherited
disorders like cystinosis and autosomal recessive polycystic
kidney disease. The consequences continue throughout the
patient’s life and the situation often arises whereby patients
transition from paediatric to adult nephrology services. Some
of the issues and challenges surrounding this transition are
summarised in Box 15.42.
15.42 Kidney disease in adolescence
• Adherence: young adults moving from parental supervision may
become disengaged. There may also be reduced adherence to
prophylactic and therapeutic treatment.
• Adverse events: there is an increased risk of transplant loss and
other adverse events in young adults on renal replacement therapy.
• Management: joint transition clinics should be established with the
paediatric team to facilitate transfer to adult specialist clinics.
The kidney is susceptible to damage by drugs because it is the
route of excretion of many water-soluble compounds, including
Prescribing in renal disease
Many drugs and drug metabolites are excreted by the kidney
and so the presence of renal impairment alters the required
dose and frequency (p. 31).
Infections of the urinary tract
In health, bacterial colonisation is confined to the lower end of
the urethra and the remainder of the urinary tract is sterile (see
Ch. 6). The urinary tract can become infected with various bacteria
but the most common is E. coli derived from the gastrointestinal
tract. The most common presenting problem is cystitis with
urethritis (generally referred to as urinary tract infection).
Urinary tract infection
Urinary tract infection (UTI) is the term used to describe acute
urethritis and cystitis caused by a microorganism. It is a common
disorder, accounting for 1-3% of consultations in general
medical practice. The prevalence of UTI in women is about 3%
at the age of 20, increasing by about 1 % in each subsequent
decade. In males, UTI is uncommon, except in the first year of
life and in men over 60, when it may complicate bladder outflow
obstruction.
Infections of the urinary tract • 427
1 15.43 Mechanisms and examples of drug-induced renal disease/dysfunction
Mechanism
Drug or toxin
Comments
Haemodynamic
NSAIDs
ACE inhibitors
Radiographic contrast media
Reduce renal blood flow due to inhibition of prostaglandin
synthesis causing afferent arteriolar vasoconstriction
Reduce efferent glomerular arteriolar tone, so especially
problematic in the presence of renal artery stenosis and other
causes of renal hypoperfusion (e.g. NSAIDs)
Multifactorial aetiology may include intense vasoconstriction
Acute tubular necrosis
Aminoglycosides, amphotericin
Paracetamol overdose
Radiographic contrast media
In most examples there is evidence of direct tubular toxicity but
haemodynamic and other factors probably contribute
May occur with or without serious hepatotoxicity
Directly toxic to proximal tubular cells
Loss of tubular/collecting
duct function
Lithium
Cisplatin
Aminoglycosides, amphotericin
Dose-related, partially reversible loss of concentrating ability
Occurs at lower exposures than cause acute tubular necrosis
Glomerulonephritis
(immune-mediated)
Penicillamine, gold
Penicillamine, propylthiouracil, hydralazine
NSAIDs
Membranous nephropathy
Crescentic or focal necrotising glomerulonephritis in association
with ANCA and systemic small-vessel vasculitis
Minimal change nephropathy, membranous nephropathy
Interstitial nephritis
(immune-mediated)
NSAIDs, penicillins, proton pump inhibitors,
many others
Acute interstitial nephritis
Interstitial nephritis
(toxicity)
Lithium
Ciclosporin, tacrolimus
As a consequence of acute toxicity
Chronic interstitial nephritis
Interstitial nephritis (with
papillary necrosis)
Various NSAIDs (p. 403)
Ischaemic damage secondary to NSAID effects on renal blood flow
Tubular obstruction
(crystal formation)
Aciclovir
Chemotherapy
Crystals of the drug form in tubules
Aciclovir is now more common than the original example of
sulphonamides
Uric acid crystals form as a consequence of tumour lysis (typically,
a first-dose effect in haematological malignancy)
Nephrocalcinosis
Oral sodium phosphate-containing bowel
cleansing agents
Precipitation of calcium phosphate occurring in 1-4% and
exacerbated by volume depletion
Usually mild but damage can be irreversible
Retroperitoneal fibrosis
Ergolinic dopamine agonists (cabergoline),
methysergide*, practolol*
Idiopathic retroperitoneal fibrosis is more common (p. 434)
*These drugs are no longer in use in the UK.
(ACE = angiotensin-converting enzyme; ANCA = antineutrophil cytoplasmic antibody; NSAIDs =
non-steroidal anti-inflammatory drugs)
Pathophysiology
Urine is an excellent culture medium for bacteria; in addition, the
urothelium of susceptible persons may have more receptors, to
which virulent strains of E. coli become adherent. In women,
the ascent of organisms into the bladder is easier than in men;
the urethra is shorter and the absence of bactericidal prostatic
secretions may be relevant. Sexual intercourse may cause minor
urethral trauma and transfer bacteria from the perineum into
the bladder. Instrumentation of the bladder may also introduce
organisms. Multiplication of organisms then depends on a number
of factors, including the size of the inoculum and virulence of
the bacteria. Conditions that predispose to UTI are shown in
Box 15.44.
Clinical features
Typical features of cystitis and urethritis include:
• abrupt onset of frequency of micturition and urgency
• burning pain in the urethra during micturition (dysuria)
• suprapubic pain during and after voiding
• intense desire to pass more urine after micturition, due to
spasm of the inflamed bladder wall (strangury)
• urine that may appear cloudy and have an unpleasant odour
• non-visible or visible haematuria.
Systemic symptoms are usually slight or absent. However,
infection in the lower urinary tract can spread to cause acute
pyelonephritis. This is suggested by prominent systemic symptoms
with fever, rigors, vomiting, hypotension and loin pain, guarding
or tenderness, and may be an indication for hospitalisation. Only
about 30% of patients with acute pyelonephritis have associated
symptoms of cystitis or urethritis. Prostatitis is suggested by
perineal or suprapubic pain, pain on ejaculation and prostatic
tenderness on rectal examination.
The differential diagnosis of lower urinary tract symptoms
includes urethritis due to sexually transmitted disease, notably
chlamydia (p. 340) and urethritis associated with reactive arthritis
(p. 1031). Some patients, usually female, have symptoms
suggestive of urethritis and cystitis but no bacteria are cultured
from the urine (the ‘urethral syndrome’). Possible explanations
include infection with organisms not readily cultured by ordinary
428 • NEPHROLOGY AND UROLOGY
1 5.44 Risk factors for urinary tract infection
Bladder outflow obstruction
• Benign prostatic enlargement
• Urethral stricture
• Prostate cancer
Anatomical abnormalities
• Vesico-ureteric reflux
• Bladder fistula
• Uterine prolapse
Neurological problems
• Multiple sclerosis
• Diabetic neuropathy
• Spina bifida
Foreign bodies
• Urethral suprapubic catheter
• Nephrostomy tube
• Ureteric stent
• Urolithiasis
Loss of host defences
• Atrophic urethritis and vaginitis
• Diabetes mellitus
in post-menopausal women
15.45 Investigation of patients with urinary
tract infection
All patients
• Dipstick* estimation of nitrite, leucocyte esterase and glucose
• Microscopy/cytometry of urine for white blood cells, organisms
• Urine culture
Infants, children, and anyone with fever or complicated infection
• Full blood count; urea, electrolytes, creatinine
• Blood cultures
Pyelonephritis: men; children; women with recurrent infections
• Renal tract ultrasound or CT
• Pelvic examination in women, rectal examination in men
Continuing haematuria or other suspicion of bladder lesion
• Cystoscopy
*May substitute for microscopy and culture in simple uncomplicated infection.
methods (such as Chlamydia and certain anaerobes), intermittent
or low-count bacteriuria, reaction to toiletries or disinfectants,
symptoms related to sexual intercourse, or post-menopausal
atrophic vaginitis.
The differential diagnosis of acute pyelonephritis includes
pyelonephrosis, acute appendicitis, diverticulitis, cholecystitis,
salpingitis, ruptured ovarian cyst or ectopic pregnancy. In
pyelonephrosis due to upper urinary tract obstruction, patients
may become extremely ill, with fever, leucocytosis and positive
blood cultures. With a perinephric abscess, there is marked pain
and tenderness, and often bulging of the loin on the affected
side. Urinary symptoms may be absent in this situation and urine
testing negative, containing neither pus cells nor organisms.
Investigations
An approach to investigation is shown in Box 15.45. In an
otherwise healthy woman with a single lower urinary tract infection,
urine culture prior to treatment is not mandatory. Investigation
is necessary, however, in patients with recurrent infection or
after failure of initial treatment, during pregnancy, or in patients
susceptible to serious infection, such as the immunocompromised,
those with diabetes or an indwelling catheter, and older people
(Box 15.46). The diagnosis can be made from the combination
if
• Prevalence of asymptomatic bacteriuria: rises with age. Among
the most frail in institutional care it rises to 40% in women and
30% in men.
• Decision to treat: treating asymptomatic bacteriuria does not
improve chronic incontinence or decrease mortality or morbidity from
symptomatic urinary infection. It risks adverse effects from the
antibiotic and promotion of the emergence of resistant organisms.
Bacteriuria should not be treated in the absence of urinary symptoms.
• Source of infection: the urinary tract is the most frequent source
of bacteraemia in older patients admitted to hospital.
• Incontinence: new or increased incontinence is a common
presentation of UTI in older women.
• Treatment: post-menopausal women with acute lower urinary tract
symptoms may require longer than 3 days’ therapy.
of typical clinical features and abnormalities on urinalysis. Most
urinary pathogens can reduce nitrate to nitrite, and neutrophils
and nitrites can usually be detected in symptomatic infections by
urine dipstick tests for leucocyte esterase and nitrite, respectively.
The absence of both nitrites and leucocyte esterase in the urine
makes UTI unlikely. Interpretation of bacterial counts in the
urine, and of what is a ‘significant’ culture result, is based on
probabilities. Urine taken by suprapubic aspiration should be
sterile, so the presence of any organisms is significant. If the
patient has symptoms and there are neutrophils in the urine,
a small number of organisms is significant. In asymptomatic
patients, more than 105 organisms/mL is usually regarded as
significant (asymptomatic bacteriuria; see below).
Typical organisms causing UTI in the community include
E. coli derived from the gastrointestinal tract (about 75% of
infections), Proteus spp., Pseudomonas spp., streptococci and
Staphylococcus epidermidis. In hospital, E coli still predominates
but Klebsiella and streptococci are becoming more common.
Certain strains of E. coli have a particular propensity to invade
the urinary tract.
Investigations to detect underlying predisposing factors for
UTI are used selectively, most commonly in children, men or
patients with recurrent infections (see Box 15.45).
Management
Antibiotics are recommended in all cases of proven UTI (Box
15.47). If urine culture has been performed, treatment may
be started while awaiting the result. For infection of the lower
urinary tract, treatment for 3 days is the norm and is less likely to
induce significant alterations in bowel flora than more prolonged
therapy. Trimethoprim or nitrofurantoin is the usual first choice
of drug for initial treatment; however, between 1 0% and 40% of
organisms causing UTI are resistant to trimethoprim, the lower
rates being seen in community-based practice. Trimethoprim
and nitrofurantoin are not recommended if eGFR is <30 ml_/
min/1 .73m2 due to reduced efficacy/increased risk of toxicity.
In addition, trimethoprim may increase serum potassium and
creatinine levels and lead to artefactual reductions in eGFR,
which resolve once the drug is discontinued. Quinolone antibiotics
such as ciprofloxacin and norfloxacin, and cefalexin are also
generally effective. Co-amoxiclav and amoxicillin are no longer
recommended as blind therapy, as up to 30% of organisms
are resistant. They may be used once cultures confirm that the
organism is sensitive. Penicillins and cephalosporins are safe to
use in pregnancy but trimethoprim, sulphonamides, quinolones
and tetracyclines should be avoided.
15.46 Urinary infection in old age
Infections of the urinary tract • 429
1 15.47 Antibiotic regimens for urinary tract infection in adults
Scenario
Drug
Regimen
Duration
Comment
Cystitis
First choices
Trimethoprim
200 mg twice daily
Second choices1
Nitrofurantoin
Cefalexin
50 mg 4 times daily
250 mg 4 times daily
► 3 days
7-1 0 days in men
Ciprofloxacin
250 mg twice daily
Pivmecillinam
400 mg 3 times daily
In pregnancy
Nitrofurantoin
50 mg 4 times daily
| 7 days
Avoid trimethoprim and quinolones during
Cefalexin
250 mg 4 times daily
pregnancy; avoid nitrofurantoin at term
Prophylactic therapy
First choice
Trimethoprim
100 mg at night
| Continuous
Second choice1
Nitrofurantoin
50 mg at night
Pyelonephritis
First choice
Cefalexin
Ciprofloxacin
1 g 4 times daily
500 mg twice daily
1 4 days i
7 days J
Admit to hospital if no response within 24 hrs
Second choice
Gentamicin2
Adjust dose according to renal function -
and serum levels
| 1 4 days
Switch to appropriate oral agent as soon as
possible
Cefuroxime
750-1500 mg 3 times daily
Epididymo-orchitis
First choice
Ciprofloxacin
500 mg twice daily
Young men
Doxycycline
100 mg twice daily
| 1 4 days
Refer young men to genito-urinary
Older men
Ciprofloxacin
500 mg twice daily
department to check for Neisseria
gonorrhoeae , which requires addition of a
single dose of ceftriaxone 500 mg IM
Acute prostatitis
First choice
Trimethoprim
200 mg twice daily ]
| 28 days
Second choice
Ciprofloxacin
500 mg twice daily j
all cases, the choice of drug should take locally determined antibiotic resistance patterns into account. 2See Hartford nomogram (Fig. 6.18, p. 1 22).
(IM = intramuscular)
In more severe infection, antibiotics should be continued for
7-1 4 days. Seriously ill patients may require intravenous therapy
with gentamicin for a few days (Box 15.47), later switching to
an oral agent.
A fluid intake of at least 2 L/day is usually recommended,
although this is not based on evidence and may make symptoms
of dysuria worse.
Persistent or recurrent UTI
If the causative organism persists on repeat culture despite
treatment, or if there is reinfection with any organism after an
interval, then an underlying cause is more likely to be present
(see Box 15.44) and more detailed investigation is justified (see
Box 15.45). In women, recurrent infections are common and
investigation is justified only if infections are frequent (three or
more per year) or unusually severe. Recurrent UTI, particularly in
the presence of an underlying cause, may result in permanent
renal damage, whereas uncomplicated infections rarely (if ever)
do so (see chronic reflux nephropathy, p. 430).
If an underlying cause cannot be treated, suppressive antibiotic
therapy (see Box 15.47) can be used to prevent recurrence
and reduce the risk of sepsis and renal damage. Urine should
be cultured at regular intervals; a regimen of two or three
antibiotics in sequence, rotating every 6 months, is often used
in an attempt to reduce the emergence of resistant organisms.
Other simple measures may help to prevent recurrence (Box
15.48). Trimethoprim or nitrofurantion is recommended for
prophylaxis. Alternative antibiotics include cefalexin, co-amoxiclav
15.48 Prophylactic measures to be adopted by
women with recurrent urinary infections
• Fluid intake of at least 2 LVday
• Regular complete emptying of bladder
• Good personal hygiene
• Emptying of bladder before and after sexual intercourse
• Cranberry juice/tablets may be effective
and ciprofloxacin, but these should be avoided if possible because
of adverse effects and the generation of resistance.
Asymptomatic bacteriuria
This is defined as more than 105 organisms/mL in the urine of
apparently healthy asymptomatic patients. Approximately 1 %
of children under the age of 1 year, 1 % of schoolgirls, 0.03%
of schoolboys and men, 3% of non-pregnant adult women
and 5% of pregnant women have asymptomatic bacteriuria.
It is increasingly common in those aged over 65. There is no
evidence that this condition causes renal scarring in adults who
are not pregnant and have a normal urinary tract, and, in general,
treatment is not indicated. Up to 30% will develop symptomatic
infection within 1 year, however. Treatment is required in infants,
pregnant women and those with urinary tract abnormalities.
Catheter-related bacteriuria
In patients with a urinary catheter, bacteriuria increases the risk
of Gram-negative bacteraemia five-fold. Bacteriuria is common,
430 • NEPHROLOGY AND UROLOGY
however, and almost universal during long-term catheterisation.
Treatment is usually avoided in asymptomatic patients, as this may
promote antibiotic resistance. Careful sterile insertion technique
is important and the catheter should be removed as soon as
it is not required.
Acute pyelonephritis
The kidneys are infected in a minority of patients with UTI. Acute
renal infection (pyelonephritis) presents as a classic triad of loin
pain, fever and tenderness over the kidneys. The renal pelvis
is inflamed and small abscesses are often evident in the renal
parenchyma (see Fig. 15.13C, p. 402).
Renal infection is almost always caused by organisms ascending
from the bladder, and the bacterial profile is the same as for
lower urinary tract infection (p. 428). Rarely, bacteraemia may
give rise to renal or perinephric abscesses, most commonly due
to staphylococci. Predisposing factors, such as cysts or renal
scarring, facilitate infection.
Rarely, acute pyelonephritis is associated with papillary
necrosis. Fragments of renal papillary tissue are passed per
urethra and can be identified histologically. They may cause
ureteric obstruction and, if this occurs bilaterally or in a single
kidney, it may lead to AKI. Predisposing factors include diabetes
mellitus, chronic urinary obstruction, analgesic nephropathy and
sickle-cell disease. A necrotising form of pyelonephritis with
gas formation, ‘emphysematous pyelonephritis’, is occasionally
seen in patients with diabetes mellitus. Xanthogranulomatous
pyelonephritis is a chronic infection that can resemble renal cell
cancer. It is usually associated with obstruction, is characterised
by accumulation of foamy macrophages and generally requires
nephrectomy. Infection of cysts in polycystic kidney disease
(p. 405) calls for prolonged antibiotic treatment.
Appropriate investigations are shown in Box 15.45 and
management is described above and in Box 15.47. Intravenous
rehydration may be needed in severe cases. If complicated
infection is suspected or response to treatment is not prompt,
urine should be re-cultured and renal tract ultrasound performed
to exclude urinary tract obstruction or a perinephric collection. If
obstruction is present, drainage by a percutaneous nephrostomy
or ureteric stent should be considered.
| Tuberculosis
Tuberculosis of the kidney and renal tract is secondary to
tuberculosis elsewhere (p. 588) and is the result of blood-borne
infection. Initially, lesions develop in the renal cortex; these may
ulcerate into the renal pelvis and involve the ureters, bladder,
epididymis, seminal vesicles and prostate. Calcification in the
kidney and stricture formation in the ureter are typical.
Clinical features may include symptoms of bladder involvement
(frequency, dysuria); haematuria (sometimes macroscopic);
malaise, fever, night sweats, lassitude and weight loss; loin
pain; associated genital disease; and chronic renal failure
as a result of urinary tract obstruction or destruction of
kidney tissue.
Neutrophils are present in the urine but routine urine culture may
be negative (‘sterile pyuria’). Special techniques of microscopy and
culture may be required to identify tubercle bacilli and are most
usefully performed on early morning urine specimens. Bladder
involvement should be assessed by cystoscopy. Radiology of
the urinary tract and a chest X-ray to look for pulmonary
tuberculosis are mandatory. Anti-tuberculous chemotherapy
follows standard regimens (p. 592). Surgery to relieve urinary
tract obstruction or to remove a very severely infected kidney
may be required.
| Reflux nephropathy
This condition, which was previously known as chronic
pyelonephritis, is a specific type of chronic interstitial nephritis
associated with vesico-ureteric reflux (VUR) in early life and with
the appearance of scars in the kidney, as demonstrated by
various imaging techniques. About 12% of patients in Europe
requiring treatment for ESRD may have this disorder but diagnostic
criteria are imprecise.
Pathophysiology
Reflux nephropathy is thought to be due to chronic reflux of urine
from the bladder into the ureters, in association with recurrent UTI
in childhood. It was previously assumed that ascending infection
was necessary for progressive renal damage in patients with
VUR but there is evidence to suggest that renal scars can occur,
even in the absence of infection. Furthermore, epidemiological
surveys and controlled trials have found that efforts to correct
VUR by using surgical or other means are ineffective in halting
progression of the disease.
Susceptibility to VUR has a genetic component and may be
associated with renal dysplasia and other congenital abnormalities
of the urinary tract. It can be connected with outflow obstruction,
usually caused by urethral valves, but usually occurs with an
apparently normal bladder.
Clinical features
Usually, the renal scarring and dilatation are asymptomatic and
the patient may present at any age with hypertension (sometimes
severe), proteinuria or features of CKD. There may be no history
of overt UTI. However, symptoms arising from the urinary tract
may be present and include frequency of micturition, dysuria and
aching lumbar pain. VUR may occur in children but diminishes
as the child grows, and usually has disappeared by adulthood.
Urinalysis often shows the presence of leucocytes and moderate
proteinuria (usually <1 g/24 hrs) but these are not invariable. The
risk of renal stone formation is increased. A number of women
first present with hypertension and/or proteinuria in pregnancy.
Children and adults with small or unilateral renal scars have a
good prognosis, provided renal growth is normal. With significant
unilateral scars there is usually compensatory hypertrophy of
the contralateral kidney. In patients with more severe bilateral
disease, prognosis is related to the severity of renal dysfunction,
hypertension and proteinuria. If the serum creatinine is normal
and hypertension and proteinuria are absent, then the long-term
prognosis is usually good.
Investigations
Renal scarring can be detected by ultrasound but it has poor
sensitivity and is only capable of detecting major defects and
excluding significant obstruction. Radionuclide DIVISA scans are
more sensitive (see Fig. 15.6, p. 390), and serial imaging by MRI
or CT may be useful in assessing progression. Abnormalities
may be unilateral or bilateral and of any grade of severity. Gross
scarring of the kidneys, commonly at the poles, is seen, with
reduced kidney size and narrowing of the cortex and medulla.
Renal scars may be juxtaposed to dilated calyces. In patients
who develop heavy proteinuria and hypertension, renal biopsies
show glomerulomegaly and focal glomerulosclerosis, probably as
a secondary response to reduced nephron numbers. Radionuclide
Urolithiasis • 431
Fig. 15.28 Vesico-ureteric reflux (grade IV) shown by micturating
cystogram. The bladder has been filled with contrast medium through a
urinary catheter. After micturition, there was gross vesico-ureteric reflux
into widely distended ureters and pelvicalyceal systems. Courtesy of Dr
A.P. Bayliss and Dr P. Thorpe, Aberdeen Royal Infirmary.
techniques can also be used to demonstrate VUR as a non-
invasive alternative to micturating cystourethrography (MCUG; the
bladder is filled with contrast media through a urinary catheter
and images are taken during and after micturition; Fig. 15.28).
As surgical intervention for VUR has declined in popularity (see
below), however, this type of imaging is used less often.
Management
Infection, if present, should be treated; if recurrent, it should
be prevented with prophylactic therapy, as described for UTI
(p. 429). If recurrent pyelonephritis occurs in an abnormal
kidney with minimal function, nephrectomy may be indicated.
Occasionally, hypertension is cured by the removal of a diseased
kidney when the disease is predominantly or entirely unilateral.
As most childhood reflux tends to disappear spontaneously and
trials have shown small or no benefits from anti-reflux surgery,
such intervention is now less common. Severe reflux may be
managed by ureteric reimplantation or subtrigonal injection of
Teflon or polysaccharide (STING) beneath the ureteric orifice.
Urolithiasis
Renal stone disease is common, affecting people of all countries
and ethnic groups. In the UK, the prevalence is about 1 .2%,
with a lifetime risk of developing a renal stone by age 60-70 of
approximately 7% in men. In some regions, the risk is higher,
most notably in countries such as Saudi Arabia, where the
lifetime risk of developing a renal stone in men aged 60-70 is
just over 20%.
Pathophysiology
Urinary calculi consist of aggregates of crystals, usually containing
calcium or phosphate in combination with small amounts of
15.49 Composition of renal stones
Composition
Percentage
Calcium oxalate1
60%
Calcium phosphate
15%
Uric acid
10%
Magnesium ammonium phosphate (struvite)2
15%
Cystine and others
1%
Atones often contain small amounts of calcium phosphate.
Associated with
urine infection.
i
Environmental and dietary causes
• Low urine volumes: high ambient temperatures, low fluid intake
• Diet: high protein, high sodium, low calcium
• High sodium excretion
• High oxalate excretion
• High urate excretion
• Low citrate excretion
Acquired causes
• Hypercalcaemia of any cause (p. 661)
• Ileal disease or resection (increases oxalate absorption and urinary
excretion)
• Renal tubular acidosis type I (distal, p. 365)
Congenital and inherited causes
• Familial hypercalciuria
• Medullary sponge kidney
• Cystinuria
• Renal tubular acidosis type I (distal)
• Primary hyperoxaluria
proteins and glycoproteins. The most common types are
summarised in Box 15.49. A number of risk factors have been
identified for renal stone formation (Box 15.50). In developed
countries, however, most calculi occur in healthy young men, in
whom investigations reveal no clear predisposing cause. Renal
stones vary greatly in size, from sand-like particles anywhere
in the urinary tract to large, round stones in the bladder. In
developing countries, bladder stones are common, particularly
in children. In developed countries, the incidence of childhood
bladder stones is low; renal stones in adults are more common.
Staghorn calculi fill the whole renal pelvis and branch into the
calyces (Fig. 15.29); they are usually associated with infection
and composed largely of struvite. Deposits of calcium may be
present throughout the renal parenchyma, giving rise to fine
calcification within it (nephrocalcinosis), especially in patients with
renal tubular acidosis, hyperparathyroidism, vitamin D intoxication
and healed renal tuberculosis. Cortical nephrocalcinosis may
occur in areas of cortical necrosis, typically after AKI in pregnancy
or other severe AKI.
Clinical features
The clinical presentation is highly variable. Many patients with
renal stone disease are asymptomatic, whereas others present
with pain, haematuria, UTI or urinary tract obstruction. A common
presentation is with acute loin pain radiating to the anterior
15.50 Predisposing factors for kidney stones
432 • NEPHROLOGY AND UROLOGY
Fig. 15.29 Computed tomogram of the kidneys, ureters and bladder
(CTKUB): coronal view showing a staghorn calculus in the left kidney.
Courtesy of Dr I . Mendichovszky, University of Cambridge.
abdominal wall, together with haematuria: a symptom complex
termed renal or ureteric colic. This is most commonly caused
by ureteric obstruction by a calculus but the same symptoms
can occur in association with a sloughed renal papilla, tumour
or blood clot. The patient is suddenly aware of pain in the loin,
which radiates round the flank to the groin and often into the
testis or labium, in the sensory distribution of the first lumbar
nerve. The pain steadily increases in intensity to reach a peak
in a few minutes. The patient is restless and generally tries
unsuccessfully to obtain relief by changing position or pacing the
room. There is pallor, sweating and often vomiting. Frequency,
dysuria and haematuria may occur. The intense pain usually
subsides within 2 hours but may continue unabated for hours
or days. It is usually constant during attacks, although slight
fluctuations in severity may be seen. Subsequent to an attack of
renal colic, intermittent dull pain in the loin or back may persist
for several hours.
Investigations
Patients with symptoms of renal colic should be investigated
to determine whether or not a stone is present, to identify its
location and to assess whether it is causing obstruction. About
90% of stones contain calcium and these can be visualised on
plain abdominal X-ray (radio-opaque stones) but non-contrast
CTKUB (Fig. 15.29) is the gold standard for diagnosing a stone
within the kidney or ureter, as 99% are visible using this method.
Ultrasound can show stones within the kidney and dilatation
of the renal pelvis and ureter if the stone is obstructing urine
flow; it is useful in unstable patients or young women, in whom
exposure to ionising radiation is undesirable.
A minimum set of investigations (Box 15.51) should be
performed in patients with a first renal stone. The yield of more
detailed investigation is low, and hence usually reserved for young
15.51
Investigations for renal stones
First
Recurrent
Sample
Test
stone
stone
Stone
Chemical composition1
y
Blood
Calcium
/
y
Phosphate
y
y
Uric acid
y
y
Urea and electrolytes
y
y
Bicarbonate
y
y
Parathyroid hormone2
(✓)
Urine
Dipstick test for protein,
y
y
blood, glucose
Amino acids
y
24-hr urine
Urea
y
Creatinine clearance
y
Sodium
y
Calcium
y
Oxalate
y
Uric acid
y
The most valuable test if a stone can be obtained.
20nly if serum calcium or
urinary calcium excretion is high.
patients, those with recurrent or multiple stones, or those with
complicated or unexpected presentations. Chemical analysis of
stones is often helpful in defining the underlying cause. Since
most stones pass spontaneously through the urinary tract, ideally
the urine should be sieved for a few days after an episode of
colic in order to collect the calculus for analysis.
Management
The immediate treatment of renal colic is with analgesia and
antiemetics. Renal colic is often unbearably painful and demands
powerful analgesia; diclofenac orally or as a suppository (100 mg)
is often very effective, followed by morphine (10-20 mg) or
pethidine (100 mg) intramuscularly. Around 90% of stones of
less than 4 mm diameter pass spontaneously, but this applies
to only 1 0% of stones bigger than 6 mm, and these may require
intervention (see below). Patients with renal or ureteric stones are
at high risk of infection; if surgery is contemplated, the patient
should be covered with appropriate antibiotics. Immediate action
is required if infection occurs in the stagnant urine proximal to
the stone (pyonephrosis), and in patients with a solitary kidney
who develop anuria in association with a stone in the ureter.
Stones that do not pass spontaneously through the urinary
tract may need to be removed surgically, using ureteroscopy
and stone fragmentation usually with a laser, or percutaneous
nephrolithotomy (PCNL) and fragmentation with an ultrasonic
disaggregator. Alternatively, stones can be fragmented by
extracorporeal shock wave lithotripsy (ESWL), in which shock
waves generated outside the body are focused on the stone,
breaking it into small pieces that can pass easily down the ureter.
The indications for intervention to manage or remove stones
from the renal tract are summarised in Box 15.52. Procedures
vary, depending on the site (Fig. 15.30).
Measures to prevent further stone formation are guided by the
investigations in Box 15.51. Some general principles apply to
almost every patient with calcium-containing stones (Box 1 5.53).
More specific measures apply to some types. Urate stones can
be prevented by allopurinol but its role in patients with calcium
Diseases of the collecting system and ureters • 433
KM 15.52 Indications for intervention to manage and
remove stones from the urinary tract
Clinical presentation
Procedure
Obstruction and/or anuria
Emergency nephrostomy or stent
Pyonephrosis associated with
stone
Emergency nephrostomy or stent
Stone in a patient with solitary
kidney
Urgent PCNL, stent, ESWL or
ureteroscopy*
Severe pain and persistence of
stone in renal tract
Urgent PCNL, stent, ESWL or
ureteroscopy*
Pain and persistence of stone in
renal tract
Elective PCNL, ESWL or
ureteroscopy*
Procedure depends on site of stone; see Fig. 15.30.
(ESWL = extracorporeal shock wave lithotripsy; PCNL = percutaneous
nephrolithotomy)
Fig. 15.30 Options for removal of urinary stones. X A patient
undergoing extracorporeal shock wave lithotripsy (ESWL). [B] The
procedures that are used for removal of stones in the urinary tract, shown
in relation to the site of the stone. (PCNL = percutaneous nephrolithotomy)
15.53 Measures to prevent calcium stone formation
Diet
Fluid
• At least 2 L output per day (intake 3-4 L): check with 24-hr urine
collections
• Intake distributed throughout the day (especially before bed)
Sodium
• Restrict intake
Protein
• Moderate, not high
Calcium
• Maintain good calcium intake (calcium forms an insoluble salt with
dietary oxalate, lowering oxalate absorption and excretion)
• Avoid calcium supplements separate from meals (increase calcium
excretion without reducing oxalate excretion)
Oxalate
• Avoid foods that are rich in oxalate (spinach, rhubarb)
Drugs
Thiazide diuretics
• Reduce calcium excretion
• Valuable in recurrent stone-formers and hypercalciuria
Allopurinol
• If urate excretion high (unproven except for urate stones)
Avoid
• Vitamin D supplements (increase calcium absorption and excretion)
• Vitamin C supplementation (increases oxalate excretion)
stones and high urate excretion is uncertain. Stones formed in
cystinuria can be reduced by penicillamine therapy. It may also
be helpful to attempt to alkalinise the urine with sodium
bicarbonate, as a high pH discourages urate and cystine stone
formation.
Diseases of the collecting system
and ureters
Congenital abnormalities
Various congenital anomalies of the urinary tract can occur (Fig.
15.31); they affect more than 10% of infants. If not immediately
lethal, they can lead to complications in later life, including
obstructive nephropathy and CKD.
| Single kidneys
About 1 in 500 infants is born with only one kidney. Although
this is usually compatible with normal life, it may be associated
with other abnormalities.
Ij/ledullary sponge kidney disease
Medullary sponge kidney is a congenital disorder characterised by
malformation of the papillary collecting ducts in the pericalyceal
region of the renal pyramids. This leads to the formation of
microscopic and large medullary cysts. Patients often present as
adults with renal stones but the prognosis is generally good. The
diagnosis is made by ultrasound, CT or intravenous urography,
where contrast medium is seen to fill dilated or cystic tubules,
which are sometimes calcified.
434 • NEPHROLOGY AND UROLOGY
Renal agenesis/
dysplasia
Ectopic kidney
Single kidney
PUJ obstruction
Horseshoe
kidney
Duplex ureter
Ectopic ureter
Megaureter
Ureterocele
Vesico-ureteric
reflux
Urethral valves
Fig. 15.31 Congenital abnormalities of the urinary tract. (PUJ =
pelvi-ureteric junction)
Ureterocele
A ureterocele occurs behind a pin-hole ureteric orifice when the
intramural part of the ureter dilates and bulges into the bladder. It
can become very large and cause lower urinary tract obstruction.
Incision of the pin-hole opening relieves the obstruction.
Ectopic ureters and duplex kidneys
Ectopic ureters occur with congenital duplication of one or both
kidneys (duplex kidneys). Developmentally, the ureter has two
main branches and, if this arrangement persists, the two ureters
of the duplex kidneys may drain separately into the bladder. The
lower pole moiety enters the bladder superiorly and laterally,
while the upper pole moiety enters the bladder inferomedially to
the lower pole moiety ureter or, more rarely, enters the vagina
or seminal vesicle. The lower pole moiety has an ineffective
valve mechanism, so that urine passes up the ureter on voiding
(vesico-ureteric reflux, p. 430), whereas the upper pole moiety
is often associated with a ureterocele.
| Megaureter
A megaureter is a ureter dilated to more than 5 mm in diameter.
It may be obstructed or non-obstructed and refluxing or non¬
refluxing. Some 50% of cases are asymptomatic but patients
may present with pain, haematuria or infection. Radiographic
and pressure/flow studies may be needed to determine whether
there is obstruction to urine flow. Patients with symptoms or
reduced renal function are treated. Ideally, treatment is expectant
with antibiotic prophylaxis. Surgery (narrowing of the ureter
and/or reimplantation) may, however, be needed for recurrent
symptoms, reduction of more than 10% in renal function or
complications (i.e. stones).
|Pelvi-ureteric junction obstruction
Pelvi-ureteric junction obstruction (PUJO) causes idiopathic
hydronephrosis and results from a functional obstruction at the
junction of the ureter and renal pelvis. The abnormality is likely
to be congenital and is often bilateral. It can be seen in very
young children but gross hydronephrosis may present at any
age. The common presentation is ill-defined renal pain or ache,
exacerbated by drinking large volumes of liquid (Dietl’s crisis).
Rarely, it is asymptomatic. The diagnosis is often suspected
after ultrasound or CT scan, and can be confirmed with a
99mTc-MAG3 renogram followed by diuretic. In a PUJO, the
MAG3 renogram shows a pathognomonic ‘rising curve’ as the
radioisotope accumulates in the renal pelvis and still does not
drain following the diuretic injection. Treatment is surgical excision
of the pelvi-ureteric junction and reanastomosis (pyeloplasty),
which can now be performed laparoscopically. Less invasive
alternatives are also possible, including balloon dilatation and
endoscopic pyelotomy, but are generally less effective.
Retroperitoneal fibrosis
Fibrosis of the retroperitoneal connective tissues may encircle and
compress the ureter(s), causing obstruction. The fibrosis is most
commonly idiopathic but can represent a reaction to infection,
radiation or aortic aneurysm, or be caused by metastatic cancer.
It is recognised as part of the spectrum of disorders associated
with elevated lgG4 levels (p. 890). Rarely, it can be associated
with inflammatory bowel disease. Patients usually present with
ill-defined symptoms of ureteric obstruction. Typically, there is
an acute phase response (high CRP and ESR, and polyclonal
hypergammaglobulinaemia). Imaging with CT or IVU shows
ureteric obstruction with medial deviation of the ureters. Idiopathic
retroperitoneal fibrosis may respond well to glucocorticoids (with
a reduction in inflammatory marker levels) but ureteric stenting is
often necessary to relieve obstruction and preserve renal function.
Failure to improve indicates the need for surgery (ureterolysis),
both to relieve obstruction and to exclude malignancy.
Tumours of the kidney and
urinary tract
Several malignant tumours can affect the kidney and urinary
tract, including renal cell cancer, upper urinary tract urothelial
cancers, bladder carcinoma, prostate carcinoma, and cancers
of the testis and penis. The urogenital tract can also be affected
by benign tumours and secondary tumour deposits, which can
cause obstructive uropathy. Renal cell cancer and bladder
carcinoma are described here, while prostate cancer (p. 438)
and testicular tumours (p. 439) are covered later in this chapter.
|Renal cell cancer
Renal cell cancer (RCC) is by far the most common malignant
tumour of the kidney in adults, making up 2.5% of all adult
cancers, with a prevalence of 1 6 cases per 1 00000 population. It
is twice as common in males. The peak incidence is between 65
and 75 years of age and it is uncommon before 40. The tumour
arises from renal tubular cells. Haemorrhage and necrosis give
the cut surface a characteristic mixed golden-yellow and red
appearance (Fig. 15.32B). Microscopically, clear cell RCCs are
the most common histological subtype (85%), with papillary,
Tumours of the kidney and urinary tract • 435
Fig. 15.32 Renal cell cancer. [A] In this CT, the right kidney is expanded by a low-density tumour, which fails to take up contrast material. Tumour is
shown extending into the renal vein and inferior vena cava (arrow). [6] Pathology specimen showing typical necrosis of a renal cell cancer. (A, B) Courtesy
of Dr A. P. Bayliss and Dr P. Thorpe, Aberdeen Royal Infirmary.
chromophobe and collecting duct tumours comprising the
remainder. In RCC, there is potentially spread along the renal
vein and the inferior vena cava. Direct invasion of perinephric
tissues is common. Lymphatic spread occurs to para-aortic
nodes, while blood-borne metastases (which may be solitary)
most commonly develop in the lungs, bone and brain.
Clinical features
In 50% of patients, asymptomatic renal tumours are identified as
an incidental finding during imaging investigations carried out for
other reasons. Among symptomatic patients, about 60% present
with haematuria, 40% with loin pain and 25% with a palpable
mass. About 10% present with a triad of pain, haematuria and
a mass; this usually represents advanced disease. A remarkable
range of systemic effects may be present, including fever, raised
ESR, polycythaemia, disorders of coagulation, hypercalcaemia,
and abnormalities of plasma proteins and liver function tests.
The patient may present with pyrexia of unknown origin (PUO)
or, rarely, with neuropathy. Some of these systemic effects are
caused by secretion of products by the tumour, such as renin,
erythropoietin, parathyroid hormone-related protein (PTHrP)
and gonadotrophins. The effects disappear when the tumour is
removed but may reappear when metastases develop.
Investigations
Ultrasound is often the initial investigation and allows differentiation
between solid tumour and simple renal cysts. If the results are
suggestive of a tumour, contrast-enhanced CT of the abdomen
and chest should be performed for staging (Fig. 15.32A). For
tumours with no evidence of metastatic spread and when the
nature of the lesion is uncertain, ultrasound or CT-guided biopsy
may be used to avoid nephrectomy for benign disease.
Management
Radical nephrectomy that includes the perirenal fascial envelope
is the treatment of choice. Nephrectomy is commonly performed
laparoscopically, with equivalent outcomes to open surgery.
Partial nephrectomy, which may be carried out by open or
minimally invasive surgery, is recommended for tumours of 4 cm
or less, as there is a lower incidence of long-term cardiac- and
renal-related morbidity. Patients at high operative risk who
have small tumours may also be treated percutaneously by
cryotherapy or radiofrequency ablation. There is an evolving
role for active surveillance with serial imaging in selected
patients with small renal masses of less than 4 cm. Surgery
may also play a role in the treatment of solitary metastases,
since these can remain single for long periods and excision may
be curative.
RCC is resistant to most chemotherapeutic agents. For many
years, cytokine therapy with interferon and interleukin-2 was
used in metastatic renal cancer but, in recent years, two new
classes of targeted drugs have been introduced and are now
the mainstay of therapy. These are the tyrosine kinase inhibitors
sunitinib and pazopanib, and the mammalian target of rapamycin
(mTOR) inhibitors temsirolimus and everolimus.
In previous years, patients who presented with distant
metastases were treated with cytoreductive nephrectomy,
in which nephrectomy was coupled with systemic cytokine
treatment, since this was shown to improve survival as compared
with either treatment in isolation. It is, at present, unclear
whether this survival benefit still prevails with the newer agents
mentioned above.
Studies that antedate the introduction of these new agents
show that, if the tumour is confined to the kidney, 5-year survival
is 75%, but this falls to 5% when there are distant metastases.
Urothelial tumours
Tumours arising from the transitional epithelium of the renal tract
can affect the renal pelvis, ureter, bladder or urethra. They are
rare under the age of 40, affect men 3-4 times more often than
women, and account for about 3% of all malignant tumours.
The bladder is by far the most frequently affected site. Although
almost all tumours are transitional cell carcinomas (otherwise
known as urothelial cancers), squamous carcinoma may occur
in urothelium that has undergone metaplasia, usually following
chronic inflammation due to stones or schistosomiasis. The
appearance of a transitional cell tumour ranges from a delicate
papillary structure with a relatively good prognosis to a solid
ulcerating mass in more aggressive disease.
436 • NEPHROLOGY AND UROLOGY
Pathophysiology
Risk factors include cigarette smoking and exposure to industrial
carcinogens such as aromatic amines, aniline dyes and aldehydes.
Clinical features
More than 80% of patients present with painless, visible
haematuria. It should be assumed that such bleeding is from a
tumour until proven otherwise (p. 391). Tumours of the ureter or
bladder may also cause symptoms of obstruction, depending on
the site of involvement, and tumours of the bladder present with
dysuria or storage symptoms. Physical examination is usually
unremarkable, except in patients with very advanced disease,
when bimanual examination may reveal a palpable mass.
Investigations
Cystoscopy (usually flexible cystoscopy under a local anaesthetic)
is mandatory to evaluate the bladder in cases of haematuria or
suspected bladder cancer. Imaging of the upper urinary tract
(CT urogram is the gold standard but IVU combined with renal
ultrasound is also acceptable) is also important to rule out
abnormalities of the kidney, ureters and renal pelvis in patients
with haematuria. If a suspicious defect is seen on CT urography
or IVU in the ureter or renal pelvis, a retrograde ureteropyelogram,
ureteroscopy and biopsy are required. If evidence of a solid
invasive urothelial tumour is found, CT of the abdomen, pelvis
and chest should be performed to define tumour stage.
Management
Most bladder tumours are low-grade superficial lesions that can
be successfully treated endoscopically by transurethral resection
of the tumour. Intravesical chemotherapy with mitomycin C is
usually administered as a one-off treatment post resection to
prevent tumour recurrence, or may be given as a prolonged
course to treat multiple low-grade bladder tumours. Patients
with carcinoma in situ have a high risk of progression to invasive
cancer. These patients often respond well to intravesical bacille
Calmette-Guerin (BCG) treatment but more radical treatment may
also be needed if this is unsuccessful. Following initial treatment
and endoscopic clearance of bladder tumours, regular check
cystoscopies are required to look for evidence of recurrence.
Patients with recurrences of superficial disease can usually
be treated by further resection and diathermy, but if this is
unsuccessful, a cystectomy may be needed.
The management of invasive bladder tumours involves radical
cystectomy with urinary diversion into an incontinent ileal conduit
or a continent catheterisable bowel pouch; the latter is usually
reserved for patients under the age of 70 years.
The prognosis of bladder tumours depends on tumour stage
and grade. About 5% of patients with low-grade superficial
bladder cancer progress to develop invasion of the bladder
muscle, compared with about 50% of those with high-grade
superficial bladder cancers. Overall, the 5-year survival for patients
with muscle-invasive bladder cancer of either grade is 50-70%.
Urothelial cell carcinoma of the renal pelvis and ureter is usually
treated by open or laparoscopic nephro-ureterectomy, but if the
tumour is solitary and low-grade, it can be treated endoscopically.
I Inherited tumour syndromes affecting
the renal tract
Some uncommon autosomal dominantly inherited conditions
are associated with multiple renal tumours in adult life. In
tuberous sclerosis (p. 1264), replacement of renal tissue by
multiple angiomyolipomas (tubers) may occasionally cause renal
failure in adults; they may also bleed, requiring embolisation.
The von Hippel-Lindau syndrome (p. 1132) is associated with
multiple renal cysts, renal adenomas and clear cell renal cell
cancers. Other organs affected include the central nervous
system (haemangioblastomas), pancreas and adrenals
(phaeochromocytoma).
Urinary incontinence
Urinary incontinence is defined as any involuntary leakage of
urine. It may occur in patients with a normal urinary tract, as
the result of dementia or poor mobility, or transiently during an
acute illness or hospitalisation, especially in older people (Box
1 5.54). The prevalence of any form of incontinence in all females
is 25-45%, with a concomitant socioeconomic burden. Childbirth,
hysterectomy, obesity, recurrent UTI, smoking, caffeine and
constipation are risk factors for incontinence.
Pathophysiology
As urine accumulates in the bladder during the storage phase,
the sphincter tone gradually increases, but there are no significant
changes in vesical pressure, detrusor pressure or intra-abdominal
pressure. During voiding, intravesical pressure increases as a result
of detrusor contraction and the sphincter relaxes, allowing urine to
flow from the bladder until it is empty. Clinical disorders associated
with incontinence are connected with various abnormalities in
this cycle and these are discussed in more detail below.
Stress incontinence
This occurs because passive bladder pressure exceeds the
urethral pressure, due either to poor pelvic floor support or a
weak urethral sphincter. Usually there is an element of both
these factors. Stress incontinence is very common in women
and seen most frequently following childbirth. It is rare in men
and usually follows surgery to the prostate. The presentation
is with incontinence during coughing, sneezing or exertion. In
women, perineal inspection may reveal leakage of urine when
the patient coughs.
Urge incontinence
This usually occurs because of detrusor over-activity, which
produces an increased bladder pressure that overcomes the
urethral sphincter. Urgency with or without incontinence may
also be driven by a hypersensitive bladder resulting from UTI
or a bladder stone. Detrusor over-activity is usually idiopathic,
• Prevalence: urinary incontinence affects 15% of women and 10%
of men aged over 65 years.
• Cause: incontinence may be transient and due to delirium, urinary
infection, medication (such as diuretics), faecal impaction or
restricted mobility, and these should be treated before embarking
on further specific investigation.
• Detrusor over-activity: established incontinence in old age is most
commonly due to detrusor over-activity, which may be caused by
damage to central inhibitory centres or local detrusor muscle
abnormalities.
• Catheterisation: poor manual dexterity or cognitive impairment may
necessitate the help of a carer to assist with intermittent
catheterisation.
15.54 Incontinence in old age
Prostate disease • 437
other than in patients with neurological conditions such as
spina bifida or multiple sclerosis, in whom it is neurogenic
(p. 1093). The incidence of urge incontinence increases with age,
occurring in 1 0-1 5% of the population aged over 65 years and
in approximately 50% of patients requiring nursing home care.
It is also seen in men with lower urinary tract obstruction and
most often remits after the obstruction is relieved.
Continual incontinence
This is suggestive of a fistula, usually between the bladder and
vagina (vesicovaginal), or the ureter and vagina (ureterovaginal).
It is most common following gynaecological surgery but is
also seen in patients with gynaecological malignancy or post
radiotherapy. In parts of the world where obstetric services are
scarce, prolonged obstructed labour can be a common cause of
vesicovaginal fistulae. Continual incontinence may also be seen
in infants with congenital ectopic ureters. Occasionally, stress
incontinence is so severe that the patient leaks continuously.
Overflow incontinence
This occurs when the bladder becomes chronically over-distended
and may lead to AKI (high-pressure chronic urinary retention). It is
most commonly seen in men with benign prostatic enlargement
or bladder neck obstruction (see below) but may arise in either
sex as a result of failure of the detrusor muscle (atonic bladder).
The latter may be idiopathic but more commonly is the result
of damage to the pelvic nerves, either from surgery (commonly,
hysterectomy or rectal excision), trauma or infection, or from
compression of the cauda equina by disc prolapse, trauma
or tumour. Incontinence due to prostatic enlargement can be
regarded as a type of overflow incontinence.
Post-micturition dribble
This is very common in men, even in the relatively young. It is
due to a small amount of urine becoming trapped in the U-bend
of the bulbar urethra, which leaks out when the patient moves.
Post-micturition dribble is more pronounced if associated with a
urethral diverticulum or urethral stricture. It may occur in women
with a urethral diverticulum and may mimic stress incontinence.
Clinical features
Patients should be encouraged to keep a voiding diary, including
the measured volume voided, frequency of voiding, a note of
incontinence pad usage, precipitating factors and associated
features, such as urgency, since this can be of diagnostic
value. Structured questionnaires may help objectively quantify
symptoms. The patient should be assessed for evidence of
cognitive impairment and impaired mobility. A neurological
assessment should be performed to detect disorders such
as multiple sclerosis that may affect the nervous supply of the
bladder, and the lumbar spine should be inspected for features
of spina bifida occulta. Perineal sensation and anal sphincter tone
should be assessed. Rectal examination is needed to assess
the prostate in men and to exclude faecal impaction as a cause
of incontinence. Genital examination should be done to identify
phimosis or paraphimosis in men, and vaginal mucosal atrophy,
cystoceles or rectoceles in women.
Investigations
Urinalysis and culture should be performed in all patients.
Ultrasound examination can be helpful in identifying patients with
overflow incontinence who have incomplete bladder emptying,
as they may reveal a significant amount of fluid in the bladder
(>100 ml_) post micturition. Urine flow rates and full urodynamic
assessment by cystometrography may be required to diagnose
the type of incontinence and are indicated in selected cases
when the diagnosis is unclear on clinical grounds. A CT scan
and cystoscopy should be performed in patients with continual
incontinence who are suspected of having a fistula. Imaging
with MRI is indicated when a urethral diverticulum is suspected.
Management
Weight reduction in obese patients will aid resolution of
incontinence. Women with stress incontinence respond well to
physiotherapy. The mainstay of treatment for urge incontinence
is bladder retraining, which involves teaching patients to hold
more urine voluntarily in their bladder, assisted by anticholinergic
medication. Surgery may be required in patients who have
severe daytime incontinence despite conservative treatment. The
treatment of incontinence secondary to fistula formation is surgical.
Patients with overflow incontinence due to bladder obstruction
should be treated surgically or with long-term catheterisation
(intermittent or continuous). Incontinence secondary to neurological
diseases can be managed by intermittent self-catheterisation.
This results from inflammation of the prostate gland. Acute or
chronic bacterial prostatitis can be caused by infection with the
same bacteria that are associated with UTI (p. 426) but prostatitis
can also be ‘non-bacterial’, in which case no organism can be
cultured from the urine. This is also known as chronic pelvic
pain syndrome. Clinical features of prostatitis include frequency,
dysuria, painful ejaculation, perineal or groin pain, difficulty
passing urine and, in acute disease, considerable systemic
disturbance. The prostate is enlarged and tender. Bacterial
prostatitis is confirmed by a positive culture from urine or from
urethral discharge obtained after prostatic massage, and the
treatment of choice is a quinolone antibiotic. A 4-6-week course
of antibiotics is required (see Box 15.47, p. 429). Treatment of
chronic pelvic pain syndrome is challenging but some patients
respond to a combination of a-blockers, NSAIDs and amitriptyline.
Benign prostatic enlargement
Benign prostatic enlargement (BPE) is extremely common. It has
been estimated that about half of all men aged 80 years and over
will have lower urinary tract symptoms associated with bladder
outlet obstruction (BOO) due to BPE. Benign prostatic hyperplasia
(BPH) is the histological abnormality that underlies BPE.
Pathophysiology
The prostate gland increases in volume by 2.4 cm3 per year
on average from 40 years of age. The process begins in the
periurethral (transitional) zone and involves both glandular and
stromal tissue to a variable degree. The cause is unknown,
although BPE does not occur in patients with hypogonadism,
suggesting that hormonal factors may be important.
Clinical features
The primary symptoms of BPE arise because of difficulty in
voiding urine due to obstruction of the urethra by the prostate;
these voiding symptoms consist of hesitancy, poor urinary
flow and a sensation of incomplete emptying. Other storage
438 • NEPHROLOGY AND UROLOGY
15.55 The International Prostate Symptom
Score (IPSS)
Symptom
Question
Example
score
Straining
How often have you had to push or
strain to begin urination?
1
Urgency
How often have you found it difficult to
postpone urination?
2
Hesitancy
How often have you found that you
stopped and started again several
times when you urinated?
1
Incomplete
emptying
How often have you had a sensation of
not emptying your bladder completely
after you finished urinating?
3
Frequency
How often have you had to urinate
again less than 2 hours after you
finished urinating?
1
Weak
stream
How often have you had a weak
urinary stream?
2
Nocturia
How many times did you most typically
get up to urinate from the time you
went to bed at night until the time you
got up in the morning?
1
Total score
11
0 = not at all; 1 = less than one-fifth of the time; 2 = less than half
the time; 3 = about half of the time; 4 = more than half of the time;
5 = almost always.
A score of 0-7 indicates mild symptoms, 8-19 moderate symptoms
and 20-35 severe symptoms. In the example shown, the patient
had moderate symptoms.
symptoms include urinary frequency, urgency of micturition and
urge incontinence, although these are not specific to BPE. Some
patients present suddenly with acute urinary retention, when
they are unable to micturate and develop a painful, distended
bladder. This is often precipitated by excessive alcohol intake,
constipation or prostatic infection. Severity of symptoms can be
ascertained by using the International Prostate Symptom Score
(IPSS) questionnaire (Box 15.55), which serves as a valuable
starting point for assessment of the patient. Once a baseline
value is established, any improvement or deterioration may be
monitored on subsequent visits. The IPSS may be combined with
a quality-of-life score, in which patients are asked the following
question: ‘If you were to spend the rest of your life with your
urinary condition the way it is now, how would you feel about
that?’ Responses range from 0 (delighted) to 6 (terrible).
Patients may also present with chronic urinary retention. Here,
the bladder slowly distends due to inadequate emptying over
a long period of time. Patients with chronic retention can also
develop acute retention: so-called acute-on-chronic retention.
This condition is characterised by pain-free bladder distension,
which may result in hydroureter, hydronephrosis and renal failure
(high-pressure chronic retention, of which nocturnal incontinence is
a pathognomonic symptom). On digital rectal examination (DRE),
patients with BPE have evidence of prostatic enlargement with a
smooth prostate gland. Abdominal examination may also reveal
evidence of bladder enlargement in patients with urinary retention.
Investigations
The diagnosis of BOO secondary to BPE is a clinical one but
flow rates can be accurately measured with a flow meter,
15.56 Treatment for benign prostatic enlargement
Medical
• Prostate <30 g: a-adrenoceptor blockers
• Prostate >30 g: 5a-reductase inhibitors ± a-adrenoceptor blockers
Surgical
• Transurethral resection of the prostate (TURP)
• Laser enucleation
• Laser vaporisation
• Open prostatectomy
post-void residual volume of urine assessed with ultrasound,
and prostate volume by transrectal ultrasound scan (TRUS).
Objective assessment of obstruction is possible by urodynamics
but this is seldom required. If symptoms or signs, such as a
palpable bladder, nocturnal enuresis, recurrent UTI or a history
of renal stones, are present, renal function should be assessed;
if it is abnormal, screening should be conducted for evidence of
obstructive uropathy by ultrasound examination.
Management
Patients who present with acute retention require urgent treatment
and should undergo immediate catheterisation to relieve the
obstruction. Those with mild to moderate symptoms can be
treated by medication (Box 15.56). The first-line treatments are
a! A-adrenoceptor blockers such as tamsulosin, which reduce the
tone of smooth muscle cells in the prostate and bladder neck,
thereby reducing the obstruction. The 5a-reductase inhibitors
finasteride and dutasteride inhibit conversion of testosterone to
the nine times more potent di hydrotestosterone in the prostate
and so cause the prostate to reduce in size. This class of drugs
is indicated in patients with an estimated prostate size of more
than 30 g or a prostate-specific antigen (PSA) level of more than
1 .4 ng/mL. Patients who fail to respond to a single drug may
be treated with a combination of a-blockers and 5a-reductase
inhibitors, since this is more efficacious than either agent alone.
Symptoms that are resistant to medical therapy require surgical
treatment to remove some of the prostate tissue that is causing
urethral obstruction. This is usually achieved by transurethral
resection of the prostate (TURP) but enucleation of the prostate
by holmium laser or vaporisation by potassium-titanyl-phosphate
(KTP) laser (Greenlight laser) is equally effective and has potentially
fewer complications. Open surgery is rarely needed, unless the
gland is very large.
| Prostate cancer
Prostate cancer is the most common malignancy in men in the
UK, with a prevalence of 105 per 100000 population. It is also
common in northern Europe and the USA (particularly in the
African American population) but is rare in China and Japan. It
is uncommon in India but the incidence is increasing. Prostate
cancer rarely occurs before the age of 50 and has a mean age
at presentation of 70 years.
Pathophysiology
Prostate cancers tend to arise within the peripheral zone of
the prostate and almost all are adenocarcinomas. Metastatic
spread to pelvic lymph nodes occurs early and metastases to
bone, mainly the lumbar spine and pelvis, are common. Genetic
factors are known to play an important role in pathogenesis,
Testicular tumours • 439
and multiple genetic loci have been found to predispose to the
disease in genome-wide association studies. A family history of
prostate cancer greatly increases a man’s chances of developing
the disease.
Clinical features
Most patients either are asymptomatic or present with lower
urinary tract symptoms indistinguishable from BPE. On DRE
the prostate may feel nodular and stony-hard, and the median
sulcus may be lost, but up to 45% of tumours are impalpable.
Symptoms and signs due to metastases are much less common
at the initial presentation but may include back pain, weight loss,
anaemia and obstruction of the ureters.
Investigations
Measurement of PSA levels in a peripheral blood sample,
together with DRE, is the cornerstone of diagnosis. Prior to
a PSA test, men should be given careful counselling about
the limitations of the test: namely, a normal level does not
exclude prostate cancer, while a high value does not confirm the
diagnosis but will open a discussion about biopsy and possible
future treatments with potential side-effects (Box 15.57). The
need for radical treatment of localised prostate cancer is still
not established; radical treatments have significant potential
morbidity and mortality, yet early identification and treatment
of prostate cancer may save lives. Current evidence suggests
that population-based screening for prostate cancer with PSA
is of limited value, due in part to the fact that over 700 patients
would need to be screened to cure 1 man of prostate cancer.
Individuals suspected of having prostate cancer, based on an
elevated PSA and/or abnormal DRE, should undergo transrectal
ultrasound-guided prostate biopsies. About 40% of patients
with a serum PSA of 4.0-10 ng/mL or more will have prostate
cancer on biopsy, although 25% of patients with a PSA of less
than 4 ng/mL may also have prostate cancer. Occasionally, a
small focus of tumour is found incidentally in patients undergoing
TURP for benign hyperplasia. If the diagnosis of prostate cancer is
confirmed, staging should be performed by pelvic MRI to assess
15.57 Advantages and disadvantages of
prostate-specific antigen (PSA) testing in order to
identify men with prostate cancer
Advantages
• Identification of prostate cancer at a treatable stage, which
otherwise may not have been identified*
Disadvantages
• High false-positive rate: 50-60% of men with an elevated PSA will
not have prostate cancer
• High false- negative rate: 25% of men with a normal PSA have
prostate cancer
• Leads to further invasive tests (biopsy) with morbidity (e.g. sepsis or
bleeding)
• May lead to diagnosis of prostate cancer, which is often
over-treated by surgery or radiotherapy with associated side-effects
(e.g. impotence or incontinence)
• If PSA is elevated but biopsy is normal, there is a potential need for
further testing and associated anxiety
*The advantages of identifying prostate cancer earlier than would be the case if
the man developed symptomatic disease must be considered against the
limitations of PSA testing.
the presence and extent of local involvement. An isotope bone
scan should be carried out if distant metastases are suspected
(rare if the PSA is below 20 ng/mL); very high levels of serum PSA
(>100 ng/mL) almost always indicate distant bone metastases.
Following diagnosis, serial assessment of PSA levels is useful
for monitoring response to treatment and disease progression.
Management
Tumour confined to the prostate is potentially curable by
radical prostatectomy, radical radiotherapy or brachytherapy
(implantation of small radioactive particles into the prostate).
These options should be considered only in patients with more
than 1 0 years’ life expectancy. Patients who are found to have
small-volume, low-grade disease do not appear to require
specific treatment but should be followed up periodically with
PSA testing, DRE and a schedule of biopsies; this is known
as active surveillance. Prostatic cancer, like breast cancer,
is sensitive to steroid hormones; metastatic prostate cancer
is treated by androgen depletion, involving either surgery
(orchidectomy) or, more commonly, androgen-suppressing
drugs. Androgen receptor blockers, such as bicalutamide or
cyproterone acetate, may also prevent tumour cell growth.
Gonadotrophin-releasing hormone (GnRH) analogues, such as
goserelin, continuously occupy pituitary receptors, preventing
them from responding to the GnRH pulses that normally stimulate
luteinising hormone (LH) and follicle-stimulating hormone (FSH)
release. This initially causes an increase in testosterone before
producing a prolonged reduction, and for this reason the initial
dose must be covered with an androgen receptor blocker to
prevent a tumour flare.
A small proportion of patients fail to respond to endocrine
treatment. A larger number respond for a year or two but then
the disease progresses. Chemotherapy with docetaxel can then
be effective and provide a modest (around 3 months) survival
advantage. Radiotherapy is useful for localised bone pain but the
basis of treatment remains pain control by analgesia (p. 1331).
Provided that patients do not die of another cause, the 1 0-year
survival rate of patients with tumours localised to the prostate
is 95%, but if metastases are present, this falls to 10%. Life
expectancy is not reduced in patients with small foci of tumour.
Testicular tumours
Testicular tumours are uncommon, with a prevalence of 5 cases
per 100000 population. They occur mainly in young men aged
between 20 and 40 years. They often secrete a-fetoprotein
(AFP) and (3-human chorionic gonadotrophin ((3-hCG), which are
useful biochemical markers for both diagnosis and prognosis.
Seminoma and teratoma account for 85% of all tumours of the
testis. Leydig cell tumours are less common.
Seminomas arise from seminiferous tubules and represent a
relatively low-grade malignancy. Metastases can occur through
lymphatic spread, however, and typically involve the lungs.
Teratomas arise from primitive germinal cells and tend to
occur at a younger age than seminomas. They may contain
cartilage, bone, muscle, fat and a variety of other tissues, and
are classified according to the degree of differentiation. Well-
differentiated tumours are the least aggressive; at the other
extreme, trophoblastic teratoma is highly malignant. Occasionally,
teratoma and seminoma occur together.
Leydig cell tumours are usually small and benign but secrete
oestrogens, leading to presentation with gynaecomastia (p. 657).
440 • NEPHROLOGY AND UROLOGY
Clinical features and investigations
The common presentation is incidental discovery of a painless
testicular lump, although some patients complain of a
testicular ache.
All suspicious scrotal lumps should be imaged by ultrasound.
Serum levels of AFP and (3-hCG are elevated in extensive
disease. Oestradiol may be elevated, suppressing LH, FSH
and testosterone. Accurate staging is based on CT of the lungs,
liver and retroperitoneal area.
Management and prognosis
The primary treatment is surgical orchidectomy. Subsequent
treatment depends on the histological type and stage. Radiotherapy
is the treatment of choice for early-stage seminoma. Teratoma
confined to the testes may be managed conservatively, but more
advanced cancers are treated with chemotherapy, usually the
combination of bleomycin, etoposide and cisplatin. Follow-up
is by CT and assessment of AFP and (3-hCG. Retroperitoneal
lymph node dissection is now performed only for residual or
recurrent nodal masses.
The 5-year survival rate for patients with seminoma is 90-95%.
For teratomas, the 5-year survival varies between 60% and 95%,
depending on tumour type, stage and volume.
Erectile dysfunction
Causes of erectile failure are shown in Box 15.58. Vascular,
neuropathic and psychological causes are most common.
Exclusion of previously unrecognised cardiovascular disease is
important in men presenting with erectile dysfunction. With the
exception of diabetes mellitus, endocrine causes are relatively
uncommon and are characterised by loss of libido, as well as
erectile dysfunction. Erectile dysfunction and reduced libido occur
in over 50% of men with advanced CKD or those on dialysis,
and is a markedly under-diagnosed problem. It is important to
i
discuss matters frankly with the patient, and to establish whether
there are associated features of hypogonadism (p. 655) and if
erections occur at any other time. If the patient has erections
on wakening, vascular and neuropathic causes are much less
likely and a psychological cause should be suspected.
Investigations
Blood should be taken for glucose, lipids, thyroid function tests,
prolactin, testosterone, LH and FSH. A number of further tests
are available but are rarely employed because they do not usually
influence management. These include nocturnal tumescence
monitoring (using a plethysmograph placed around the shaft
of the penis overnight) to establish whether blood supply and
nerve function are sufficient to allow erections to occur during
sleep; intracavernosal injection of prostaglandin to test the
adequacy of blood supply; internal pudendal artery angiography;
and tests of autonomic and peripheral sensory nerve conduction.
Management
First-line therapy is usually with oral phosphodiesterase type
5 inhibitors, such as sildenafil, which elevate cyclic guanosine
monophosphate (cGMP) levels in vascular smooth muscle cells
of the corpus cavernosum, causing vasodilatation and penile
erection. Co-administration of these drugs with nitric oxide
donors, such as glycerol trinitrate, is contraindicated because of
the risk of severe hypotension. Other treatments for impotence
include self-administered intracavernosal injection or urethral
administration of prostaglandin El ; vacuum devices that achieve
an erection maintained by a tourniquet around the base of the
penis; and prosthetic implants, either of a fixed rod or an inflatable
reservoir. Psychotherapy involving the patient and sexual partner
may be helpful for psychological problems. Erectile dysfunction
associated with peripheral neuropathy and vascular disease
is difficult to treat. If hypogonadism is detected, it should be
managed as described on page 655.
Further information
Websites
edren.org Renal Unit, Royal Infirmary of Edinburgh; information about
individual diseases, protocols for immediate in-hospital management
and more.
edrep.org/resources Educational resources.
nephron.com The links under ‘Physicians’ include useful urology
pages, eGFR and other calculators, and other resources.
renal.org/ckd UK Renal Association; current UK guidelines on the
detection, referral and management of CKD.
renalfellow.blogspot.co.uk/ Educational blog written by renal trainees
for trainees.
uroweb.org/guidelines European Association of Urology guidelines;
current European guidelines on the management of all common
urological conditions.
With reduced libido
• Hypogonadism
• Depression
With intact libido
• Psychological problems, including anxiety
• Vascular insufficiency (atheroma)
• Neuropathic causes (diabetes mellitus, alcohol excess, multiple
sclerosis)
• Drugs ((3-blockers, thiazide diuretics)
15.58 Causes of erectile dysfunction
DE Newby
NR Grubb
Cardiology
Clinical examination of the cardiovascular system 442
Functional anatomy and physiology 444
Anatomy 444
Physiology 446
Investigation of cardiovascular disease 448
Electrocardiogram 448
Cardiac biomarkers 450
Chest X-ray 450
Echocardiography 451
Computed tomography 452
Magnetic resonance imaging 452
Cardiac catheterisation 453
Electrophysiology 454
Radionuclide imaging 454
Presenting problems in cardiovascular disease 454
Chest pain on exertion 454
Severe prolonged chest pain 455
Breathlessness 455
Syncope 455
Palpitation 455
Cardiac arrest 456
Abnormal heart sounds 457
Heart failure 461
Cardiac arrhythmias 468
Principles of management of cardiac arrhythmias 479
Anti-arrhythmic drugs 479
Non-pharmacological treatments 482
Coronary artery disease 484
Angina pectoris 487
Acute coronary syndrome 493
Non-cardiac surgery in patients with heart disease 501
Peripheral arterial disease 502
Diseases of the aorta 505
Aortic aneurysm 505
Aortic dissection 506
Aortitis 508
Marfan’s syndrome 508
Coarctation of the aorta 508
Hypertension 508
Diseases of the heart valves 514
Rheumatic heart disease 515
Mitral valve disease 517
Aortic valve disease 521
Tricuspid valve disease 525
Pulmonary valve disease 526
Prosthetic valves 526
Infective endocarditis 527
Congenital heart disease 531
Diseases of the myocardium 538
Myocarditis 538
Cardiomyopathy 538
Cardiac tumours 541
Diseases of the pericardium 542
442 • CARDIOLOGY
Clinical examination of the cardiovascular system
6 Face, mouth and eyes
Pallor
Central cyanosis
Dental caries
Fundi (retinopathy)
Stigmata of
hyperlipidaemia
and thyroid disease
5 Jugular venous pulse
(see opposite)
Height
Waveform
A Malar flush
A Poor oral hygiene in a
patient with infective
endocarditis
A Jugular venous pulse
4 Carotid pulses
Volume
Character
Bruits
(see opposite)
3 Blood pressure
2 Radial pulse
Rate
Rhythm
1 Hands
Clubbing
Splinter haemorrhages
and other stigmata of
infective endocarditis
A Splinter haemorrhage
A Cyanosis and clubbing in a
patient with complex cyanotic
congenital heart disease
Observation
Symptoms and well-being
• Breathlessness
• Distress etc.
Body habitus
• Body mass (obesity, cachexia)
• Marfan’s and other syndromes
Tissue perfusion
• Skin temperature
• Sweating
• Urine output
A Xanthelasma
7 Precordium
Inspect
Palpate
(see opposite)
8 Auscultation
(see opposite)
9 Back
Lung crepitations
Sacral oedema
10 Abdomen
Hepatomegaly
Ascites
Aortic aneurysm
Bruits
11 Tendon xanthomas
(hyperlipidaemia)
12 Femoral pulses
Radio-femoral delay
Bruits
13 Legs
Peripheral pulses
Oedema
r ■
> I
jft I
Jiv > M
j
¥
\
A Vasculitis in a
patient with
infective
endocarditis
A Peripheral
oedema in a
patient with
congestive
cardiac failure
Insets (Splinter haemorrhage, jugular venous pulse, malar flush, tendon xanthomas) From Newby D, Grubb N. Cardiology: an illustrated colour text.
Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005.
Clinical examination of the cardiovascular system • 443
4 Examination of the
arterial pulse
• The character of the pulse is determined
by stroke volume and arterial compliance,
and is best assessed by palpating a major
artery, such as the carotid or brachial
artery.
• Aortic regurgitation, anaemia, sepsis and
other causes of a large stroke volume
typically produce a bounding pulse with a
high amplitude and wide pulse pressure
(panel A).
• Aortic stenosis impedes ventricular
emptying. If severe, it causes a
slow-rising, weak and delayed pulse
(panel A).
• Sinus rhythm produces a pulse that is
regular in time and force. Arrhythmias
may cause irregularity. Atrial fibrillation
produces a pulse that is irregular in time
and volume (panel B).
m
5 Examination of the jugular
venous pulse
The internal jugular vein, superior vena cava
and right atrium are in continuity, so the
height of the jugular venous pulsation
reflects right atrial pressure. When the
patient is placed at 45°, with the head
supported and turned to the left, the jugular
venous pulse is visible along the line of the
sternocleidomastoid muscle (see opposite).
In health it is normally just visible above the
clavicle.
• The height of the jugular venous pulse is
determined by right atrial pressure and is
therefore elevated in right heart failure
and reduced in hypovolaemia.
• If the jugular venous pulse is not easily
seen, it may be exposed by applying firm
pressure over the abdomen.
• In sinus rhythm, the two venous peaks,
the a and v waves, approximate to atrial
and ventricular systole, respectively.
• The x descent reflects atrial relaxation
and apical displacement of the tricuspid
valve ring. The y descent reflects atrial
emptying early in diastole. These signs
are subtle.
• Tricuspid regurgitation produces giant v
waves that coincide with ventricular
systole.
8 Auscultation of the heart
• Use the diaphragm to examine at the
apex, lower left sternal edge (tricuspid
area) and upper left (pulmonary area) and
right (aortic area) sternal edges.
• Use the bell to examine low-pitched
noises, particularly at the apex for
the mid-diastolic murmur of mitral
stenosis.
• Time the sounds and murmurs by feeling
the carotid pulse; the first heart sound
(SI) just precedes the upstroke of the
pulse and the second heart sound (S2) is
out of step with it. If present, a third heart
sound (S3) immediately follows S2, and a
fourth heart sound (S4) just precedes SI .
Systolic murmurs are synchronous with
the pulse.
• Listen for radiation of systolic murmurs,
over the base of the neck (aortic
stenosis) and in the axilla (mitral
incompetence).
• Listen over the left sternal border with
the patient sitting forward (aortic
incompetence), then at the apex with the
patient rolled on to the left side (mitral
stenosis).
Distinguishing venous/arterial
pulsation in the neck
• The venous pulse has two peaks in each
cardiac cycle; the arterial pulse has one
peak.
• The height of the venous pulse varies
with respiration (falls on inspiration) and
position.
• Abdominal compression causes the
venous pulse to rise.
• The venous pulse is not easily palpable
and can be occluded with light pressure.
7 Palpation of the precordium
Technique
• Place fingertips over apex (1) to assess
for position and character. Place heel of
hand over left sternal edge (2) for a
parasternal heave or ‘lift’. Assess for
thrills in all areas, including the aortic and
pulmonary areas (3). Normal position is
the 5th or 6th intercostal space, at the
mid-clavicular line.
Common abnormalities of
the apex beat
• Volume overload, such as mitral or
aortic regurgitation: displaced,
thrusting
• Pressure overload, such as aortic
stenosis, hypertension: discrete,
heaving
• Dyskinetic, such as left ventricular
aneurysm: displaced, incoordinate
Other abnormalities
• Palpable SI (tapping apex beat: mitral
stenosis)
• Palpable P2 (severe pulmonary
hypertension)
• Left parasternal heave or ‘lift’ felt by
heel of hand (right ventricular
hypertrophy)
• Palpable thrill (aortic stenosis)
The haemodynamic effects of respiration are discussed on page 447, and the analysis and interpretation of heart sounds and
murmurs on page 457.
444 • CARDIOLOGY
Cardiovascular disease is the most frequent cause of adult death
in the Western world. In the UK, one-third of men and one-quarter
of women will die as a result of ischaemic heart disease. In many
developed countries, the incidence of ischaemic heart disease
has been falling for the last two or three decades, but it is rising
in Eastern Europe and Asia. Cardiovascular disease will soon
become the leading cause of death on all continents. Strategies
for the treatment and prevention of heart disease can be highly
effective and have been subjected to rigorous evaluation. The
evidence base for the treatment of cardiovascular disease is
stronger than for almost any other disease group.
Valvular heart disease is common but the aetiology varies
in different parts of the world. On the Indian subcontinent and
in Africa, it is predominantly due to rheumatic fever, whereas
calcific aortic valve disease is the most common problem in
developed countries.
Prompt recognition of the development of heart disease is
limited by two key factors. Firstly, it is often latent; coronary artery
disease can proceed to an advanced stage before the patient
notices any symptoms. Secondly, the diversity of symptoms
attributable to heart disease is limited, so different pathologies
may frequently present with the same symptoms.
Functional anatomy and physiology
Anatomy
The heart acts as two serial pumps that share several electrical
and mechanical components. The right heart circulates blood
to the lungs where it is oxygenated, and the left heart circulates
it to the rest of the body (Fig. 16.1). The atria are thin-walled
structures that act as priming pumps for the ventricles, which
provide most of the energy required to maintain the circulation.
The atria are situated posteriorly within the mediastinum where the
left atrium (LA) sits anterior to the oesophagus and descending
aorta. The right atrium (RA) receives blood from the superior and
inferior venae cavae and the coronary sinus. The LA receives
blood from four pulmonary veins, two from each of the left and
right lungs. The ventricles are thick-walled structures, adapted
to circulating blood through large vascular beds under pressure.
The atria and ventricles are separated by the annulus fibrosus,
which forms the skeleton for the atrioventricular (AV) valves
and electrically insulates the atria from the ventricles. The right
ventricle (RV) is about 2-3 mm thick and triangular in shape.
It extends from the annulus fibrosus to near the cardiac apex
and sits anterior and to the right of the left ventricle (LV). The
anterosuperior surface of the RV is rounded and convex, and its
posterior extent is bounded by the interventricular septum, which
bulges into the chamber. Its upper extent is conical, forming the
conus arteriosus or outflow tract, from which the pulmonary artery
arises. The LV is more conical in shape and in cross-section is
nearly circular. It extends from the LA to the apex of the heart.
The LV myocardium is normally around 10 mm thick because
it pumps blood at a higher pressure than the RV.
Normally, the heart occupies less than 50% of the transthoracic
diameter in the frontal plane, as seen on a chest X-ray. On
the patient’s left, the cardiac silhouette is formed by the aortic
arch, the pulmonary trunk, the left atrial appendage and the
LV. On the right, the silhouette is formed by the RA and the
superior and inferior venae cavae, and the lower right border
is formed by the RV (Fig. 16.2). In disease states or congenital
cardiac abnormalities, the silhouette may change as a result of
hypertrophy or dilatation.
Coronary circulation
The left main and right coronary arteries arise from the left and
right sinuses of the aortic root, distal to the aortic valve (Fig.
16.3). Within 2.5 cm of its origin, the left main coronary artery
divides into the left anterior descending artery (LAD), which runs
in the anterior interventricular groove, and the left circumflex
artery (CX), which runs posteriorly in the atrioventricular groove.
Superior vena cava
Pulmonary artery
Systolic 15-30
Diastolic 5-15
Mean 1 0-20
Right atrium
0-5
Right ventricle
Systolic 15-30
End-diastolic 0-5
Inferior vena cava
Aorta
Systolic 90-140
Diastolic 60-90
Mean 70-105
Left atrium
4-12
Left ventricle
Systolic 90-140
End-diastolic 4-12
Fig. 16.1 Direction of blood flow through the heart. The blue arrows show deoxygenated blood moving through the right heart to the lungs.
The red arrows show oxygenated blood moving from the lungs to the systemic circulation. The normal pressures are shown for each chamber in mmHg.
Functional anatomy and physiology • 445
Pulmonary artery
Fig. 16.2 Surface anatomy of the heart. The positions of the major
cardiac chambers and heart valves are shown. (LV = left ventricle;
RA = right atrium; RV = right ventricle)
Left coronary artery
Aorta
Superior
vena cava
Sinoatrial node
Right coronary
artery (RCA)
Circumflex
artery (CX)
Atrioventricular
node
Inferior
vena cava
Posterior
descending
Left main coronary artery
Pulmonary artery
and valve
Left anterior
descending
artery (LAD)
Septal
perforator
branches
Diagonal
branches
Obtuse
marginal
Apex
Fig. 16.3 The coronary arteries: anterior view.
The LAD gives branches to supply the anterior part of the
septum (septal perforators) and the anterior, lateral and apical
walls of the LV. The CX gives marginal branches that supply
the lateral, posterior and inferior segments of the LV. The right
coronary artery (RCA) runs in the right atrioventricular groove,
giving branches that supply the RA, RV and inferoposterior
aspects of the LV. The posterior descending artery runs in the
posterior interventricular groove and supplies the inferior part of
the interventricular septum. This vessel is a branch of the RCA
in approximately 90% of people (dominant right system) and
is supplied by the CX in the remainder (dominant left system).
The coronary anatomy varies greatly from person to person and
there are many normal variants.
The RCA supplies the sinoatrial (SA) node in about 60% of
individuals and the AV node in about 90%. Proximal occlusion
of the RCA therefore often results in sinus bradycardia and may
also cause AV nodal block. Abrupt occlusion of the RCA, due
Left bundle
branch
Bundle of His
Sinoatrial node
Left atrium
Right
ventricle
Left anterior
fascicle
Left posterior
fascicle
Left ventricle
Purkinje fibres
Atrioventricular
(AV) node
Right bundle
branch
Fig. 16.4 The cardiac conduction system. Depolarisation starts in the
sinoatrial node and spreads through the atria (blue arrows), and then
through the atrioventricular node (black arrows). Depolarisation then
spreads through the bundle of His and the bundle branches to reach the
ventricular muscle (red arrows). Repolarisation spreads from epicardium to
endocardium (green arrows).
to coronary thrombosis, results in infarction of the inferior part
of the LV and often the RV. Abrupt occlusion of the LAD or CX
causes infarction in the corresponding territory of the LV, and
occlusion of the left main coronary artery is usually fatal.
The venous system follows the coronary arteries but drains
into the coronary sinus in the atrioventricular groove, and then to
the RA. An extensive lymphatic system drains into vessels that
travel with the coronary vessels and then into the thoracic duct.
| Conduction system
The SA node is situated at the junction of the superior vena
cava and RA (Fig. 16.4). It comprises specialised atrial cells that
depolarise at a rate influenced by the autonomic nervous system
and by circulating catecholamines. During normal (sinus) rhythm,
this depolarisation wave propagates through both atria via sheets
of atrial myocytes. The annulus fibrosus forms a conduction barrier
between atria and ventricles, and the only pathway through it is
the AV node. This is a midline structure, extending from the right
side of the interatrial septum, penetrating the annulus fibrosus
anteriorly. The AV node conducts relatively slowly, producing a
necessary time delay between atrial and ventricular contraction.
The His-Purkinje system is composed of the bundle of His
extending from the AV node into the interventricular septum,
the right and left bundle branches passing along the ventricular
septum and into the respective ventricles, the anterior and
posterior fascicles of the left bundle branch, and the smaller
Purkinje fibres that ramify through the ventricular myocardium.
The tissues of the His-Purkinje system conduct very rapidly and
allow near-simultaneous depolarisation of the entire ventricular
myocardium.
Nerve supply of the heart
The heart is innervated by both sympathetic and parasympathetic
fibres. Adrenergic nerves from the cervical sympathetic chain
supply muscle fibres in the atria and ventricles, and the electrical
conducting system. Activation of p! -adrenoceptors in the heart
results in positive inotropic and chronotropic effects, whereas
activation of p2-adrenoceptors in vascular smooth muscle causes
vasodilatation. Parasympathetic pre-ganglionic fibres and sensory
fibres reach the heart through the vagus nerves. Cholinergic neves
supply the AV and SA nodes via muscarinic (M2) receptors.
446 • CARDIOLOGY
Under resting conditions, vagal inhibitory activity predominates
and the heart rate is slow. Adrenergic stimulation, associated
with exercise, emotional stress, fever and so on, causes the heart
rate to increase. In disease states, the nerve supply to the heart
may be affected. For example, in heart failure the sympathetic
system may be up-regulated, and in diabetes mellitus the nerves
themselves may be damaged by autonomic neuropathy (p. 758)
so that there is little variation in heart rate.
Physiology
Myocardial contraction
Myocardial cells (myocytes) are about 50-100 jim long; each cell
branches and interdigitates with adjacent cells. An intercalated disc
permits electrical conduction via gap junctions, and mechanical
conduction via the fascia adherens, to adjacent cells (Fig. 1 6.5A).
The basic unit of contraction is the sarcomere (2 jam long),
which is aligned to those of adjacent myofibrils, giving a striated
appearance due to the Z-lines (Fig. 1 6.5B and C). Actin filaments
are attached at right angles to the Z-lines and interdigitate with
thicker parallel myosin filaments. The cross-links between actin and
myosin molecules contain myofibrillar adenosine triphosphatase
(ATPase), which breaks down adenosine triphosphate (ATP) to
provide the energy for contraction (Fig. 16.5E). Two chains of
actin molecules form a helical structure, with a second molecule,
tropomyosin, in the grooves of the actin helix, and a further
molecule complex, troponin, attached to every seventh actin
molecule (Fig. 16.5D).
During the plateau phase of the action potential, calcium ions
enter the cell and are mobilised from the sarcoplasmic reticulum.
They bind to troponin and thereby precipitate contraction by
shortening of the sarcomere through the interdigitation of the actin
and myosin molecules. The force of cardiac muscle contraction, or
inotropic state, is regulated by the influx of calcium ions through
‘slow calcium channels’. The extent to which the sarcomere can
shorten determines stroke volume of the ventricle. It is maximally
shortened in response to powerful inotropic drugs or marked
exercise. However, the enlargement of the heart seen in heart
failure is due to slippage of the myofibrils and adjacent cells
rather than lengthening of the sarcomere.
Cardiac peptides
Cardiomyocytes secrete peptides that have humoral effects on
the vasculature and kidneys. Atrial natriuretic peptide (ANP) is a
Sarcoplasmic reticulum
Fig. 16.5 Schematic of myocytes and the contraction process within a muscle fibre. [A] Myocytes are joined together through intercalated discs.
[W1 Within the myocytes, myofibrils are composed of longitudinal and transverse tubules extending from the sarcoplasmic reticulum. [C] The expanded
section shows a schematic of an individual sarcomere with thick filaments composed of myosin and thin filaments composed primarily of actin. [jj] Actin
filaments are composed of troponin, tropomyosin and actin subunits. [E] The three stages of contraction, resulting in shortening of the sarcomere. (1) The
actin-binding site is blocked by tropomyosin. (2) ATP-dependent release of calcium ions, which bind to troponin, displacing tropomyosin. The binding site
is exposed. (3) Tilting of the angle of attachment of the myosin head, resulting in fibre shortening. (ADP = adenosine diphosphate; ATP = adenosine
triphosphate)
Functional anatomy and physiology • 447
28-amino acid peptide, which includes an amino acid ring that
acts as a vasodilator, thereby reducing blood pressure (BP),
and acts as a diuretic by promoting renal excretion of water and
sodium. It is released by atrial myocytes in response to stretch.
Brain natriuretic peptide (BNP), which was originally identified in
extracts of porcine brain, is a 32-amino acid polypeptide produced
by ventricular cardiomyocytes in response to stretch, as occurs
in heart failure. Like ANP, it has diuretic properties. Neprilysin
is an enzyme present in the circulation that is produced by the
kidney and other tissues. It breaks down ANP, BNP and other
proteins and, in so doing, acts as a vasoconstrictor. It forms a
therapeutic target in patients with heart failure (p. 466).
Circulation
The RA receives deoxygenated blood from the superior and
inferior venae cavae and discharges blood to the RV, which in
turn pumps it into the pulmonary artery. Blood passes through
the pulmonary arterial and alveolar capillary bed, where it is
oxygenated, then drains through the pulmonary veins into the
LA. Blood then passes into the LV, which pumps it into the
aorta (see Fig. 16.1). During ventricular contraction (systole),
the tricuspid valve in the right heart and the mitral valve in the
left heart close, and the pulmonary and aortic valves open. In
diastole, the pulmonary and aortic valves close, and the two
AV valves open. Collectively, these atrial and ventricular events
constitute the cardiac cycle of filling and ejection of blood from
one heart beat to the next. Blood passes from the heart through
the large central elastic arteries into muscular arteries before
encountering the resistance vessels, and ultimately the capillary
bed, where there is exchange of nutrients, oxygen and waste
products of metabolism. The central arteries, such as the aorta,
are predominantly composed of elastic tissue with little or no
vascular smooth muscle cells. When blood is ejected from
the heart, the compliant aorta expands to accommodate the
volume of blood before the elastic recoil sustains BP and flow
following cessation of cardiac contraction. This is called the
Windkessel effect and it prevents excessive rises in systolic
BP while sustaining diastolic BP, thereby reducing cardiac
afterload and maintaining coronary perfusion. These benefits
are lost with progressive arterial stiffening, which occurs with
ageing and advanced renal disease. Passing down the arterial
tree, vascular smooth muscle cells progressively play a greater
role until the resistance arterioles are encountered. Although all
vessels contribute, the resistance vessels (diameter 50-200 pm)
provide the greatest contribution to systemic vascular resistance,
with small changes in radius having a marked influence on blood
flow; resistance is inversely proportional to the fourth power
of the radius (Poiseuille’s Law). The tone of these resistance
vessels is tightly regulated by humoral, neuronal and mechanical
factors. Neurogenic constriction operates via a-adrenoceptors
on vascular smooth muscle, and dilatation via muscarinic and
p2-adrenoceptors. In addition, systemic and locally released
vasoactive substances influence tone; vasoconstrictors include
noradrenaline (norepinephrine), angiotensin II and endothelin-1 ,
whereas adenosine, bradykinin, prostaglandins and nitric oxide
are vasodilators. Resistance to blood flow rises with viscosity
and is mainly influenced by the haematocrit.
Coronary blood vessels receive sympathetic and parasym¬
pathetic innervation. While stimulation of a-adrenoceptors
causes vasoconstriction and stimulation of (32-adrenoceptors
causes vasodilatation, the predominant effect of sympathetic
stimulation in coronary arteries is vasodilatation. Parasympathetic
stimulation also causes modest dilatation of normal coronary
arteries. Because of these homeostatic mechanisms that regulate
vessel tone, narrowing or stenosis in a coronary artery does not
limit flow, even during exercise, until the cross-sectional area of
the vessel is reduced by at least 70%.
Endothelium
The endothelium plays a vital role in the control of vascular
homeostasis. It synthesises and releases many vasoactive
mediators that cause vasodilatation, including nitric oxide,
prostacyclin and endothelium-derived hyperpolarising factor,
and vasoconstriction, including endothelin-1 and angiotensin II.
A balance exists whereby the release of such factors contributes
to the maintenance and regulation of vascular tone and BP.
Damage to the endothelium may disrupt this balance and lead
to vascular dysfunction, tissue ischaemia and hypertension.
The endothelium has a major influence on key regulatory steps
in the recruitment of inflammatory cells and on the formation
and dissolution of thrombus. Once activated, the endothelium
expresses surface receptors such as E-selectin, intercellular
adhesion molecule type 1 (ICAM-1) and platelet-endothelial
cell adhesion molecule type 1 (PECAM-1), which mediate rolling,
adhesion and migration of inflammatory leucocytes into the
subintima. The endothelium also stores and releases the multimeric
glycoprotein von Willebrand factor, which promotes thrombus
formation by linking platelet adhesion to denuded surfaces,
especially in the arterial vasculature. In contrast, once intravascular
thrombus forms, tissue plasminogen activator is rapidly released
from a dynamic storage pool within the endothelium to induce
fibrinolysis and thrombus dissolution. These processes are critically
involved in the development and progression of atherosclerosis,
and endothelial function and injury are seen as central to the
pathogenesis of many cardiovascular disease states.
Respiration
Cardiac output, BP and pulse rate change with respiration as
the result of changes in blood flow to the right and left heart, as
summarised in Box 16.1 . During inspiration the fall in intrathoracic
pressure causes increased return of venous blood into the chest
and right side of the heart, which increases cardiac output from
the RV. A substantial amount of blood is sequestered in the lungs,
however, due to increased capacitance of the pulmonary vascular
bed, which causes a reduction in blood flow to the left side of
the heart. This causes a reduction in cardiac output from the LV
and a slight fall in BP. With expiration the opposite sequence of
events occurs; there is a fall in venous return to the right heart
with a reduction in RV output, and a rise in the venous return
to the left side of the heart with an increase in LV output. As
the result of these changes, BP normally falls during inspiration
i
16.1 Haemodynamic effects of respiration
Inspiration
Expiration
Jugular venous pressure
Falls
Rises
Blood pressure
Falls (up to 10 mmHg)
Rises
Heart rate
Accelerates
Slows
Second heart sound
Splits*
Fuses*
Inspiration prolongs right ventricular ejection, delaying P2, and shortens left
ventricular ejection, bringing forward A2; expiration produces the opposite effects.
448 • CARDIOLOGY
but rises during expiration. These changes are exaggerated in
patients with severe airways obstruction secondary to asthma
or chronic obstructive pulmonary disease (COPD) leading to
pulsus paradoxus, which describes an exaggerated fall in BP
during inspiration. As well as being found in airways obstruction,
pulsus paradoxus is also characteristic of cardiac tamponade
(p. 544). Here, cardiac filling is constrained by external pressure,
and on inspiration compression of the RV impedes the normal
increase in flow through it on inspiration. The interventricular
septum then moves to the left, impeding left ventricular filling and
cardiac output. This produces a marked fall in BP (> 1 0 mmHg
fall during inspiration).
Investigation of
cardiovascular disease
Several investigations may be required in the diagnosis of cardiac
disease and assessment of its severity. Basic tests, such as
electrocardiography, chest X-ray and echocardiography, can
be performed in an outpatient clinic or at the bedside, whereas
more complex procedures such as cardiac catheterisation,
radionuclide imaging, computed tomography (Cl) and magnetic
resonance imaging (MRI) require specialised facilities.
Electrocardiogram
The electrocardiogram (ECG) is used to assess cardiac rhythm
and conduction, and is the main test used in the diagnosis of
myocardial ischaemia and infarction.
The physiological basis of an ECG recording is the fact that
electrical depolarisation of myocardial tissue produces a small
dipole current, which can be detected by electrode pairs on
the body surface. These signals are amplified and either printed
or displayed on a monitor (Fig. 16.6). During sinus rhythm, the
SA node triggers atrial depolarisation, producing a P wave.
Depolarisation proceeds slowly through the AV node, which
is too small to produce a depolarisation wave detectable from
the body surface. The bundle of His, bundle branches and
Purkinje system are then activated, initiating ventricular myocardial
depolarisation, which produces the QRS complex. The muscle
mass of the ventricles is much larger than that of the atria, so
(0.12 sec) (0.10 sec)
PR interval QT interval
(0.20 sec) (0.42 sec at rate of 60/min)
Fig. 16.6 The electrocardiogram. The components correspond to
depolarisation and repolarisation, as depicted in Figure 16.4. The upper
limit of the normal range for each interval is given in brackets.
the QRS complex is larger than the P wave. The interval between
the onset of the P wave and the onset of the QRS complex is
termed the ‘PR interval’ and largely reflects the duration of AV
nodal conduction. Injury to the left or right bundle branch delays
ventricular depolarisation, widening the QRS complex. Selective
injury of one of the left fascicles (hemiblock, p. 479) affects the
electrical axis. Repolarisation is slower and spreads from the
epicardium to the endocardium. Atrial repolarisation does not
cause a detectable signal but ventricular repolarisation produces
the T wave. The QT interval represents the total duration of
ventricular depolarisation and repolarisation.
The 12-lead ECG
The 12-lead ECG (Box 16.2) is generated from 10 electrodes
that are attached to the skin. One electrode is attached to each
limb and six electrodes are attached to the chest. In addition,
the left arm, right arm and left leg electrodes are attached to a
central terminal acting as an additional virtual electrode in the
centre of the chest (the right leg electrode acts as an earthing
electrode). The 12 ‘leads’ of the ECG refer to recordings made
from pairs or sets of these electrodes. They comprise three
groups: three dipole limb leads, three augmented voltage limb
leads and six unipole chest leads.
Leads I, II and III are the dipole limb leads and refer to
recordings obtained from pairs of limb electrodes. Lead I records
16.2 How to read a 12-lead electrocardiogram:
examination sequence
Rhythm strip
(lead II)
To determine heart rate and rhythm
Cardiac axis
Normal if QRS complexes +ve in leads I/ll
P-wave shape
Tall P waves denote right atrial enlargement
(P pulmonale) and notched P waves denote left
atrial enlargement (P mitrale)
PR interval
Normal = 0.12-0.20 sec. Prolongation denotes
impaired atrioventricular nodal conduction. A
short PR interval occurs in Wolff— Parki nson—
White syndrome (p. 474)
QRS duration
If >0.12 sec, ventricular conduction is abnormal
(left or right bundle branch block)
QRS amplitude
Large QRS complexes occur in slim young
patients and in patients with left ventricular
hypertrophy
Q waves
May signify previous myocardial infarction
ST segment
ST elevation may signify myocardial infarction,
pericarditis or left ventricular aneurysm; ST
depression may signify ischaemia or infarction
T waves
T-wave inversion has many causes, including
myocardial ischaemia or infarction, and
electrolyte disturbances
QT interval
Normal <0.42 sec. QT prolongation may occur
with congenital long QT syndrome, low K+, Mg2+
or Ca2+, and some drugs (see Box 16.26, p. 476)
ECG conventions
Depolarisation towards electrode: +ve deflection
Depolarisation away from electrode: -ve
deflection
Sensitivity: 1 0 mm = 1 mV
Paper speed: 25 mm per sec
Each large (5 mm) square = 0.2 sec
Each small (1 mm) square = 0.04 sec
Heart rate = 1500/RR interval (mm) (i.e. 300 -*■
number of large squares between beats)
Investigation of cardiovascular disease • 449
the signal between the right (negative) and left (positive) arms.
Lead II records the signal between the right arm (negative) and
left leg (positive). Lead III records the signal between the left arm
(negative) and left leg (positive). These three leads thus record
electrical activity along three different axes in the frontal plane.
Leads aVR, aVL and aVF are the augmented voltage limb leads.
These record electrical activity between a limb electrode and a
modified central terminal. For example, lead aVL records the signal
between the left arm (positive) and a central (negative) terminal,
formed by connecting the right arm and left leg electrodes (Fig.
16.7). Similarly augmented signals are obtained from the right
arm (aVR) and left leg (aVF). These leads also record electrical
activity in the frontal plane, with each lead 1 20° apart. Lead aVF
thus examines activity along the axis +90°, and lead aVL along
the axis -30°, and so on.
When depolarisation moves towards a positive electrode,
it produces a positive deflection in the ECG; depolarisation
in the opposite direction produces a negative deflection. The
aVR (210°) aVL (-30°)
Fig. 16.7 The appearance of the ECG from different leads in the
frontal plane. [A] Normal. OB Left axis deviation, with negative deflection
in lead II and positive in lead I. [C] Right axis deviation, with negative
deflection in lead I and positive in lead II.
H Bundle of His Left [b]
Fig. 16.8 The sequence of activation of the ventricles. 0 Activation
of the septum occurs first (red arrows), followed by spreading of the
impulse through the left ventricle (LV, blue arrows) and then the right
ventricle (RV, green arrows). [B_ Normal electrocardiographic complexes
from leads \A and V6.
average vector of ventricular depolarisation is known as the
frontal cardiac axis. When the vector is at right angles to a lead,
the depolarisation in that lead is equally negative and positive
(isoelectric). In Figure 16.7A, the QRS complex is isoelectric
in aVL, negative in aVR and most strongly positive in lead II;
the main vector or axis of depolarisation is therefore 60°. The
normal cardiac axis lies between -30° and +90°. Examples of
left and right axis deviation are shown in Figures 16.7B and C.
There are six chest leads, V^Vg, derived from electrodes placed
on the anterior and lateral left side of the chest, over the heart.
Each lead records the signal between the corresponding chest
electrode (positive) and the central terminal (negative). Leads
V1 and V2 lie approximately over the RV, V3 and V4 over the
interventricular septum, and V5 and V6 over the LV (Fig. 16.8).
The LV has the greater muscle mass and contributes the major
component of the QRS complex.
The shape of the QRS complex varies across the chest leads.
Depolarisation of the interventricular septum occurs first and
moves from left to right; this generates a small initial negative
deflection in lead V6 (Q wave) and an initial positive deflection
in lead (R wave). The second phase of depolarisation is
activation of the body of the LV, which creates a large positive
deflection or R wave in V6 (with reciprocal changes in Vi). The
third and final phase involves the RV and produces a small
negative deflection or S wave in V6.
Exercise ECG
In exercise or stress electrocardiography a 12-lead ECG is
recorded during exercise on a treadmill or bicycle ergometer.
It is similar to a resting ECG, except that the limb electrodes
are placed on the shoulders and hips rather than the wrists
and ankles. The Bruce Protocol is the most commonly used.
During an exercise ECG, BP is recorded and symptoms are
assessed. Common indications for exercise testing are shown
in Box 16.3. The test is considered positive if angina occurs,
BP falls or fails to increase, or if there are ST segment shifts of
more than 1 mm (see Fig. 16.57, p. 490). Exercise testing is
useful in confirming the diagnosis of coronary artery disease in
patients with suspected angina, and under these circumstances
has good sensitivity and specificity (Box 16.3). False-negative
450 • CARDIOLOGY
i
results can, however, occur in patients with coronary artery
disease, and not all patients with a positive test have coronary
disease. This is especially true in low-risk individuals, such as
asymptomatic young or middle-aged women, in whom an
abnormal response is more likely to represent a false-positive
than a true-positive test. Stress testing is contraindicated in the
presence of acute coronary syndrome, decompensated heart
failure and severe hypertension.
| Ambulatory ECG
Ambulatory ECG recordings can be obtained using a portable
digital recorder. These devices usually provide limb lead ECG
recordings only, on a continuous basis for periods of between
1 and 7 days. The main indication for ambulatory ECG is in the
investigation of patients with suspected arrhythmia, such as those
with intermittent palpitation, dizziness or syncope. In this situation
a standard ECG provides only a snapshot of the cardiac rhythm
and is unlikely to detect an intermittent arrhythmia, so a longer
period of recording is required (see Fig. 1 6.32, p. 469). Ambulatory
ECG can also be used to assess rate control in patients with
atrial fibrillation, and to detect transient myocardial ischaemia
using ST segment analysis. If symptoms are infrequent, special
recorders can be issued that can be activated by the patient
when a symptom episode occurs and placed on the chest wall
to record the cardiac rhythm at that point in time. With some
devices, the recording can be transmitted to hospital electronically.
If the symptoms are very infrequent but potentially serious, such
as syncope, implantable ‘loop recorders’ resembling a leadless
pacemaker can be used and implanted subcutaneously to record
cardiac rhythm for prolonged periods of between 1 and 3 years.
Cardiac biomarkers
Several biomarkers are available that can be measured
in peripheral blood to assess myocardial dysfunction and
ischaemia.
Brain natriuretic peptide
Brain natriuretic peptide (BNP) is a peptide hormone of 32 amino
acids with diuretic properties. It is secreted by the LV as a 108-
amino acid prohormone, which is cleaved to produce active BNP,
and an inactive 76-amino acid N-terminal fragment (NT-proBNP).
Circulating levels are elevated in conditions associated with
LV systolic dysfunction. Generally, NT-proBNP is measured in
preference to BNP since it has a longer half-life. Measurements
of NT-proBNP are indicated for the diagnosis of LV dysfunction
and to assess prognosis and response to therapy in patients
with heart failure (p. 461).
Cardiac troponins
Troponin I and troponin T are structural cardiac muscle proteins
(see Fig. 16.5) that are released during myocyte damage and
necrosis, and represent the cornerstone of the diagnosis of
acute myocardial infarction (Ml, Box 16.47, p. 493). Modern
assays are extremely sensitive, however, and can detect minor
degrees of myocardial damage, so that elevated plasma troponin
concentrations may be observed in conditions other than acute
Ml, such as pulmonary embolus, septic shock and pulmonary
oedema.
Chest X-ray
This is useful for determining the size and shape of the heart,
and the state of the pulmonary blood vessels and lung fields.
Most information is given by a postero-anterior (PA) projection
taken in full inspiration. Anteroposterior (AP) projections can be
performed when patient movement is restricted but result in
magnification of the cardiac shadow.
An estimate of overall heart size can be made by comparing
the maximum width of the cardiac outline with the maximum
internal transverse diameter of the thoracic cavity. The term
cardiomegaly is used to describe an enlarged cardiac silhouette
when the ratio of cardiac width to the width of the lung fields
is greater than 0.5. Cardiomegaly can be caused by chamber
dilatation, especially left ventricular dilatation, or by a pericardial
effusion, but may also be due to a mediastinal mass or pectus
excavatum (p. 628). Cardiomegaly is not a sensitive indicator of
left ventricular systolic dysfunction since the cardiothoracic ratio
is normal in many patients with poor left ventricular function and
is not specific, since many patients with cardiomegaly on chest
X-ray have normal echocardiograms.
Dilatation of individual cardiac chambers can be recognised by
the characteristic alterations to the cardiac silhouette (Fig. 1 6.9):
• Left atrial dilatation results in prominence of the left atrial
appendage, creating the appearance of a straight left
heart border, a double cardiac shadow to the right of
the sternum, and widening of the angle of the carina
(bifurcation of the trachea) as the left main bronchus is
pushed upwards.
• Right atrial enlargement projects from the right heart
border towards the right lower lung field.
• Left ventricular dilatation causes prominence of the left
heart border and enlargement of the cardiac silhouette.
Left ventricular hypertrophy produces rounding of the left
heart border (Fig. 16.10).
• Right ventricular dilatation increases heart size, displaces
the apex upwards and straightens the left heart border.
Lateral or oblique projections may be useful for detecting
pericardial calcification in patients with constrictive pericarditis
(p. 543) or a calcified thoracic aortic aneurysm, as these
abnormalities may be obscured by the spine on the PA view.
The lung fields on the chest X-ray may show congestion and
oedema in patients with heart failure (see Fig. 16.27, p. 464),
and an increase in pulmonary blood flow (‘pulmonary plethora’)
in those with left-to-right shunt. Pleural effusions may also occur
in heart failure.
16.3 Exercise testing
Indications
• To confirm the diagnosis of angina
• To evaluate stable angina
• To assess prognosis following myocardial infarction
• To assess outcome after coronary revascularisation, e.g. coronary
angioplasty
• To diagnose and evaluate the treatment of exercise-induced
arrhythmias
High-risk findings
• Low threshold for ischaemia (within stage 1 or 2 of the Bruce
Protocol)
• Fall in blood pressure on exercise
• Widespread, marked or prolonged ischaemic ECG changes
• Exercise-induced arrhythmia
Investigation of cardiovascular disease • 451
Distended
pulmonary veins
Enlarged
pulmonary
trunk
Splaying
of carina
Enlarged
left atrium
‘Double shadow’ of left
atrial enlargement
Fig. 16.9 Chest X-ray of a patient with mitral stenosis and
regurgitation indicating enlargement of the LA and prominence of the
pulmonary artery trunk.
Dilated Normal-sized
ascending aorta aortic arch
Large left ventricle
Fig. 16.10 Chest X-ray of a patient with aortic regurgitation, left
ventricular enlargement and dilatation of the ascending aorta.
16.4 Common indications for echocardiography
• Assessment of left ventricular function
• Diagnosis and quantification of severity of valve disease
• Identification of vegetations in endocarditis
• Identification of structural heart disease in atrial fibrillation,
cardiomyopathies or congenital heart disease
• Detection of pericardial effusion
• Identification of structural heart disease or intracardiac thrombus in
systemic embolism
Fig. 16.11 Doppler echocardiography in aortic stenosis. [A] The
aortic valve is imaged and a Doppler beam passed directly through the left
ventricular outflow tract and the aorta into the turbulent flow beyond the
stenosed valve. |l] The velocity of the blood cells is recorded to determine
the maximum velocity and hence the pressure gradient across the valve. In
this example, the peak velocity is approximately 450 cm/sec (4.5 m/sec),
indicating severe aortic stenosis (peak gradient of 81 mmHg).
Echocardiography
Transthoracic echocardiography
Transthoracic echocardiography, commonly referred to as ‘echo’,
is obtained by placing an ultrasound transducer on the chest
wall to image the heart structures as a real-time two-dimensional
‘slice’. This can be used for rapid evaluation of various aspects
of cardiac structure and function. Common indications for
echocardiography are shown in Box 16.4.
| Doppler echocardiography
Doppler echocardiography provides information on blood flow
within the heart and the great vessels. It is based on the Doppler
principle that sound waves reflected from moving objects,
such as red blood cells, undergo a frequency shift. Doppler
echocardiography can therefore detect the speed and direction
of blood flow in the heart chambers and great vessels. The
greater the frequency shift, the faster the blood is moving. The
information can be presented either as a plot of blood velocity
against time for a particular point in the heart (Fig. 16.1 1) or as
452 • CARDIOLOGY
Tricuspid valve
Right ventricle
Left ventricle (dilated)
Mitral valve (regurgitant)
I
Right atrium Left atrium
Fig. 16.12 Echocardiographic illustration of the principal cardiac
structures in the ‘four-chamber’ view. Colour-flow Doppler has been
used to demonstrate mitral regurgitation: a flame-shaped (yellow/blue)
turbulent jet into the left atrium.
a colour overlay on a two-dimensional real-time echo picture
(colour-flow Doppler, Fig. 16.12). Doppler echocardiography
is useful in the detection of valvular regurgitation, where the
direction of blood flow is reversed and turbulence is seen, and is
also used to detect pressure gradients across stenosed valves.
For example, the normal resting systolic flow velocity across the
aortic valve is approximately 1 m/sec; in the presence of aortic
stenosis, this is increased as blood accelerates through the
narrow orifice. In severe aortic stenosis, the peak aortic velocity
may be increased to 5 m/sec (see Fig. 1 6.1 1). An estimate of the
pressure gradient across a valve or lesion is given by the modified
Bernoulli equation:
Pressure gradient (mmHg)
= 4 x (peak velocity in m/sec)2
Advanced techniques include three-dimensional echocardiogra¬
phy, intravascular ultrasound (defines vessel wall abnormalities and
guides coronary intervention), intracardiac ultrasound (provides
high-resolution images), tissue Doppler imaging (quantifies myo¬
cardial contractility and diastolic function) and speckle tracking
(assesses myocardial motion and strain).
iJYansoesophageal echocardiography
Transoesophageal echocardiography (TOE) involves passing
an endoscope-like ultrasound probe into the oesophagus and
upper stomach under light sedation and positioning it behind
the LA. It is particularly useful for imaging structures such as
the left atrial appendage, pulmonary veins, thoracic aorta and
interatrial septum, which may be poorly visualised by transthoracic
echocardiography, especially if the patient is overweight or has
obstructive airway disease. The high-resolution images that can
be obtained makes TOE particularly valuable for investigating
patients with prosthetic (especially mitral) valve dysfunction,
congenital abnormalities such as atrial septal defects, aortic
dissection, infective endocarditis (vegetations that are too small
to be detected by transthoracic echocardiography) and systemic
embolism (intracardiac thrombus or masses).
Fig. 16.13 Computed tomography coronary angiography,
demonstrating normal coronary arteries (arrows). U Three-
dimensional image. §] Two-dimensional image.
Stress echocardiography
Stress echocardiography is used to investigate patients with
suspected coronary artery disease who are unsuitable for exercise
stress testing, such as those with mobility problems or pre-existing
bundle branch block. A two-dimensional echo is performed
before and after infusion of a moderate to high dose of an
inotrope, such as dobutamine. Myocardial segments with poor
perfusion become ischaemic and contract poorly under stress,
manifesting as a wall motion abnormality on the scan. Stress
echocardiography is sometimes used to examine myocardial
viability in patients with impaired left ventricular function. Low-dose
dobutamine can induce contraction in ‘hibernating’ myocardium;
such patients may benefit from bypass surgery or percutaneous
coronary intervention.
Computed tomography
Computed tomography (CT) is useful for imaging the cardiac
chambers, great vessels, pericardium, and mediastinal structures
and masses. Multidetector scanners can acquire up to 320
slices per rotation, allowing very high-resolution imaging in a
single heart beat. CT is often performed using a timed injection
of X-ray contrast to produce clear images of blood vessels
and associated pathologies. Contrast scans are very useful for
imaging the aorta in suspected aortic dissection (see Fig. 16.74,
p. 507), and the pulmonary arteries and branches in suspected
pulmonary embolism (p. 619).
Some centres use cardiac CT scans for quantification of
coronary artery calcification, which may serve as an index of
cardiovascular risk. However, modern multidetector scanning
allows non-invasive coronary angiography (Fig. 16.13) with a
spatial resolution approaching that of conventional coronary
arteriography and at a lower radiation dose. CT coronary
angiography is particularly useful in the initial assessment of
patients with chest pain and a low or intermediate likelihood of
disease, since it has a high negative predictive value in excluding
coronary artery disease. Modern volume scanners are also able
to assess myocardial perfusion, often at the same sitting.
Magnetic resonance imaging
Magnetic resonance imaging (MRI) can be used to generate cross-
sectional images of the heart, lungs and mediastinal structures.
It provides better differentiation of soft tissue structures than CT
Investigation of cardiovascular disease • 453
but is poor at demonstrating calcification. MRI scans need to
be ‘gated’ to the ECG, allowing the scanner to produce moving
images of the heart and mediastinal structures throughout the
cardiac cycle. MRI is very useful for imaging the aorta, including
suspected dissection (see Fig. 16.73, p. 507), and can define
the anatomy of the heart and great vessels in patients with
congenital heart disease. It is also useful for detecting infiltrative
conditions affecting the heart and for evaluation of the RV that
is difficult to image by echocardiography.
Physiological data can be obtained from the signal returned
from moving blood, which allows quantification of blood flow
across regurgitant or stenotic valves. It is also possible to analyse
regional wall motion in patients with suspected coronary disease
or cardiomyopathy.
Myocardial perfusion and viability can also be readily assessed
by MRI. When enhanced by gadolinium-based contrast media,
areas of myocardial hypoperfusion can be identified with better
spatial resolution than nuclear medicine techniques. Later
redistribution of this contrast, so-called delayed enhancement,
can be used to identify myocardial scarring and fibrosis: this
is a particular strength of cardiac MRI (Fig. 16.14). This can
help in selecting patients for revascularisation procedures, or in
identifying those with myocardial infiltration, such as that seen
with sarcoid heart disease and arrhythmogenic right ventricular
cardiomyopathy.
Cardiac catheterisation
This involves passing a specialised catheter through a peripheral
vein or artery into the heart under X-ray guidance. Cardiac
catheterisation allows BP and oxygen saturation to be measured
in the cardiac chambers and great vessels, and is used to
perform angiograms by injecting contrast media into a chamber
or blood vessel.
Left heart catheterisation involves accessing the arterial
circulation, usually through the radial artery, to allow catheterisation
of the aorta, LV and coronary arteries. Coronary angiography
is the most widely performed procedure, in which the left
and right coronary arteries are selectively imaged, providing
information about the extent and severity of coronary stenoses,
thrombus and calcification (Fig. 16.15). Additional anatomical
Fig. 16.14 Cardiac magnetic resonance imaging. {K\ Recent inferior myocardial infarction with black area of microvascular obstruction (arrow). [§] Old
anterior myocardial infarction with large area of subendocardial delayed gadolinium enhancement (white area, arrows).
Diagnostic
catheter
Left main
stem artery
Stenosis
Left anterior
descending
artery
Circumflex
artery
Fig. 16.15 The left anterior descending and circumflex coronary arteries with a stenosis (arrow) in the left anterior descending vessel.
II\ Coronary artery angiogram. JS] Schematic of the vessels and branches.
454 • CARDIOLOGY
(intravascular ultrasound, optical coherence tomography) or
functional (pressure wire) assessments are sometimes used
to define plaque characteristics and severity more precisely.
This permits planning of percutaneous coronary intervention
and coronary artery bypass graft surgery. Left ventriculography
can be performed during the procedure to determine the size
and function of the LV and to demonstrate mitral regurgitation.
Aortography defines the size of the aortic root and thoracic
aorta, and can help quantify aortic regurgitation. Left heart
catheterisation is a day-case procedure and is relatively safe,
with serious complications occurring in only approximately 1
in 1 000 cases.
Right heart catheterisation is used to assess right heart and
pulmonary artery pressures, and to detect intracardiac shunts by
measuring oxygen saturations in different chambers. For example,
a step up in oxygen saturation from 65% in the RA to 80% in
the pulmonary artery is indicative of a large left-to-right shunt
that might be due to a ventricular septal defect. Cardiac output
can also be measured using thermodilution techniques. Left atrial
pressure can be measured directly by puncturing the interatrial
septum from the RA with a special catheter. For most purposes,
however, a satisfactory approximation to left atrial pressure can
be obtained by ‘wedging’ an end-hole or balloon catheter in a
branch of the pulmonary artery. Swan-Ganz balloon catheters
are often used to monitor pulmonary ‘wedge’ pressure as a
guide to left heart filling pressure in critically ill patients (p. 206).
Electrophysiology
Patients with known or suspected arrhythmia are investigated
by percutaneous placement of electrode catheters into the heart
via the femoral and neck veins. An electrophysiology study (EPS)
is most commonly performed to evaluate patients for catheter
ablation and is normally done at the same time as the ablation
procedure. EPS is occasionally used for risk stratification of
patients suspected of being at risk of ventricular arrhythmias.
Radionuclide imaging
Radionuclide imaging can be used to evaluate cardiac function
but is declining in popularity due to the availability of MRI, which
does not involve exposure to radiation and provides equivalent
or superior quality data to radionuclide imaging.
Blood pool imaging
The patient is given an intravenous injection of radioisotope-
labelled blood cells, and after 4-5 minutes the distribution of
isotope in the heart is evaluated by a gamma camera at different
phases of the cardiac cycle, thereby permitting the calculation
of ventricular ejection fractions. It also allows the assessment
of the size and ‘shape’ of the cardiac chambers.
| Myocardial perfusion scanning
The patient is given an intravenous injection of a radioactive
isotope, such as "technetium tetrofosmin, and scintiscans of
the myocardium are subsequently obtained by gamma camera
at rest and during stress (see Fig. 16.58, p. 490). Either exercise
stress or pharmacological stress (using the inotrope dobutamine
or the vasodilator dipyridamole) can be used. More sophisticated
quantitative information can be obtained with positron emission
tomography (PET), which can also be used to assess myocardial
metabolism, but this is available in only a few centres.
Presenting problems in
cardiovascular disease
Cardiovascular disease gives rise to a relatively limited range of
symptoms. Making the correct diagnosis depends on careful
analysis of the factors that provoke symptoms, the subtle
differences in how they are described by the patient, the clinical
findings and the results of investigations. A close relationship
between symptoms and exercise is the hallmark of heart disease.
The New York Heart Association (NYHA) functional classification
is used to grade disability (Box 16.5).
Chest pain on exertion
There are many other non-cardiac causes of chest pain, as
discussed in Chapter 10. This section will focus on exertional
chest pain, which is a typical presenting symptom of coronary
artery disease.
Clinical assessment
A careful history is crucial in determining whether chest pain is
cardiac or not. Chest pain on effort is the hallmark of angina
pectoris (Fig. 16.16). The reproducibility, predictability and
relationship to physical exertion (and occasionally emotion) of
the chest pain are the most important features. The duration of
symptoms should be noted because patients with recent-onset
angina are at greater risk than those with long-standing and
unchanged symptoms. Physical examination is often normal but
Fig. 16.16 Typical ischaemic cardiac pain. Characteristic hand
gestures used to describe cardiac pain. Typical radiation of pain is shown
in the schematic.
Presenting problems in cardiovascular disease • 455
may reveal evidence of risk factors for cardiovascular disease,
such as xanthoma or xanthelasma indicating hyperlipidaemia
(p. 373). Signs of anaemia (p. 923) or thyrotoxicosis (p. 635) may
be identified, both of which can exacerbate angina. Cardiovascular
examination may reveal evidence of left ventricular dysfunction
(p. 442) or cardiac murmurs in patients with aortic valve disease
and hypertrophic cardiomyopathy. Other manifestations of arterial
disease, such as bruits and loss of peripheral pulses, may also
be observed.
Investigations
A full blood count, fasting blood glucose, lipids, thyroid function
tests and a 12-lead ECG are the most important baseline
investigations. An exercise ECG is helpful in identifying high-risk
patients who require further investigation and treatment but
cannot reliably exclude the presence of coronary artery disease
(p. 449). In patients with chest pain where the exercise ECG is
normal but where there is a suspicion of coronary artery disease,
CT coronary angiography should be performed. If a murmur is
found, echocardiography should be performed to check for valve
disease or hypertrophic cardiomyopathy.
Severe prolonged chest pain
Severe prolonged cardiac chest pain may be due to acute
myocardial infarction or to unstable angina (p. 493). These are
known collectively as the acute coronary syndromes.
Clinical assessment
Acute coronary syndrome is suggested by a previous history of
stable angina but an episode of acute severe chest pain at rest
can be the first presentation of coronary artery disease. Making
the correct diagnosis depends on analysing the character of the
pain and its associated features. Physical examination may reveal
signs of risk factors for coronary artery disease as described for
exertional chest pain, and pallor or sweating, which is indicative of
autonomic disturbance and typical of acute coronary syndrome.
Other features, such as arrhythmia, hypotension and heart failure,
may occur. Patients presenting with symptoms consistent with
an acute coronary syndrome require admission to hospital and
urgent investigation because there is a high risk of avoidable
complications.
Investigations
A 1 2-lead ECG is mandatory and is the most useful method of
initial triage, along with measurement of serum troponin I or T.
The diagnosis of an acute coronary syndrome is supported by
ST segment elevation or depression on ECG and an elevated
level of troponin I or T, which demonstrates that there has been
myocardial damage.
If the diagnosis remains unclear after initial investigation,
repeat ECG recordings should be performed and are particularly
useful if they can be obtained during an episode of pain. If the
plasma troponin concentrations are normal at baseline, repeat
measurements should be made 6-1 2 hours after the onset of
symptoms or admission to hospital. New ECG changes or an
elevated plasma troponin concentration confirm the diagnosis
of an acute coronary syndrome. If the pain settles and does not
recur, there are no new ECG changes and troponin concentrations
remain normal, the patient can be discharged from hospital but
further investigations may be indicated to look for evidence of
coronary artery disease, as discussed on page 484.
Management
The differential diagnosis and management of acute coronary
syndrome are described in more detail on pages 494 and 498.
Breathlessness
Cardiac causes of breathlessness include cardiac arrhythmias,
acute and chronic heart failure, acute coronary syndrome, valvular
disease, cardiomyopathy and constrictive pericarditis, all discussed
later in this chapter. The differential diagnosis of breathlessness is
wide, however, and has many other non-cardiac causes. These
are discussed in more detail on pages 179 and 557.
Syncope
The term ‘syncope’ refers to loss of consciousness due to reduced
cerebral perfusion. The differential diagnosis, investigation and
management of syncope are discussed on page 1 81 .
Palpitation
Palpitation is a common and sometimes frightening symptom
that is usually due to a disorder of cardiac rhythm. Patients use
the term to describe many sensations, including an unusually
erratic, fast, slow or forceful heart beat, or even chest pain or
breathlessness.
Clinical assessment
Initial evaluation should concentrate on determining the likely
mechanism of palpitation and whether or not there is significant
underlying heart disease. A detailed description of the sensation
is essential and patients should be asked to describe their
symptoms clearly, or to demonstrate the sensation of rhythm
by tapping with their hand. A provisional diagnosis can usually
be made on the basis of a thorough history (Box 16.6 and
Fig. 16.17). Recurrent but short-lived bouts of an irregular
heart beat are usually due to atrial or ventricular extrasystoles
(ectopic beats). Some patients will describe the experience as
a ‘flip’ or a ‘jolt’ in the chest, while others report dropped or
missed beats. Extrasystoles are often more frequent during
periods of stress or debility; they can be triggered by alcohol or
nicotine.
Episodes of a pounding, forceful and relatively fast (90-120/
min) heart beat are a common manifestation of anxiety. These
may also reflect a hyperdynamic circulation, such as anaemia,
pregnancy and thyrotoxicosis, and can occur in some forms of
valve disease such as aortic regurgitation. Discrete bouts of a
16.6 How to evaluate palpitation
• Is the palpitation continuous or intermittent?
• Is the heart beat regular or irregular?
• What is the approximate heart rate?
• Do symptoms occur in discrete attacks?
Is the onset abrupt? How do attacks terminate?
• Are there any associated symptoms?
Chest pain, lightheadedness, polyuria (a feature of
supraventricular tachycardia, p. 473)
• Are there any precipitating factors, such as exercise or alcohol excess?
• Is there a history of structural heart disease, such as coronary
artery disease or valvular heart disease?
456 • CARDIOLOGY
Supraventricular
tachycardia
Ventricular
tachycardia
Sinus tachycardia
High stroke volume,
e.g. anaemia, anxiety,
valve disease
Fig. 16.17 A simple approach to the diagnosis of palpitation.
very rapid (over 120/min) heart beat are more likely to be due
to a paroxysmal supraventricular or ventricular tachycardia.
In contrast, episodes of atrial fibrillation typically present with
irregular and usually rapid palpitation.
Investigation
If initial assessment suggests that the palpitation is due to an
arrhythmia, the diagnosis should be confirmed by an ECG
recording during an episode using an ambulatory ECG monitor
or a patient-activated ECG recorder. Additional investigations
may be required depending on the nature of the arrhythmia, as
discussed on page 468.
Management
Palpitation is usually benign and even if the patient’s symptoms are
due to an arrhythmia, the outlook is good if there is no underlying
structural heart disease. Most cases are due to an awareness of
the normal heart beat, a sinus tachycardia or benign extrasystoles,
in which case an explanation and reassurance may be all that
is required. Palpitation associated with pre-syncope or syncope
(p. 181) may reflect more serious structural or electrical disease
and should be investigated without delay. Other arrhythmias may
require treatment, as discussed in more detail on page 479.
Cardiac arrest
Cardiac arrest describes the sudden and complete loss of cardiac
output due to asystole, ventricular tachycardia or fibrillation, or loss
of mechanical cardiac contraction (pulseless electrical activity).
The clinical diagnosis is based on the victim being unconscious
and pulseless; breathing may take some time to stop completely
after cardiac arrest. Death is virtually inevitable, unless effective
treatment is given promptly. Sudden cardiac death is usually
caused by a catastrophic arrhythmia and accounts for 25-30%
of deaths from cardiovascular disease, claiming an estimated
70 000 to 90 000 lives each year in the UK. Many of these deaths
are potentially preventable.
Pathogenesis
Coronary artery disease is the most common cause of cardiac
arrest. Ventricular fibrillation or ventricular tachycardia is common
Fig. 16.18 Ventricular fibrillation. A bizarre chaotic rhythm, initiated in
this case by two ventricular ectopic beats in rapid succession.
16.7 Causes of sudden arrhythmic death
Coronary artery disease (85%)
• Myocardial ischaemia
• Acute myocardial infarction
• Prior myocardial infarction with myocardial scarring
Structural heart disease (10%)
• Aortic stenosis (p. 521)
• Hypertrophic cardiomyopathy (p. 539)
• Dilated cardiomyopathy (p. 539)
• Arrhythmogenic right ventricular dysplasia (p. 540)
• Congenital heart disease (p. 531)
No structural heart disease (5%)
• Long QT syndrome (p. 476)
• Brugada syndrome (p. 477)
• Wolff— Parkinson— White syndrome (p. 474)
• Adverse drug reactions (torsades de pointes, p. 476)
• Severe electrolyte abnormalities
in the first few hours of Ml and many victims die before medical
help is sought. Up to one-third of people developing Ml die before
reaching hospital, emphasising the importance of educating the
public to recognise symptoms and to seek medical help quickly.
Acute myocardial ischaemia in the absence of infarction can also
cause these arrhythmias, but less commonly. Patients with a
history of previous Ml are at increased risk of sudden arrhythmic
death, especially if there is extensive left ventricular scarring
and impairment, or if there is ongoing myocardial ischaemia.
Cardiac arrest may be caused by ventricular fibrillation (Fig.
16.18), pulseless ventricular tachycardia (p. 457), asystole or
pulseless electrical activity. These can complicate many types of
heart disease, including cardiomyopathies, and sometimes can
occur in the absence of recognised structural abnormalities. The
causes are listed in Box 16.7. Sudden death less often occurs
because of an acute mechanical catastrophe such as cardiac
rupture or aortic dissection (pp. 496 and 506).
Clinical assessment and management
Basic life support
When a patient with suspected cardiac arrest is encountered,
the ABCDE approach to management should be followed; this
involves prompt assessment and restoration of the Airway,
maintenance of ventilation using rescue Breathing (‘mouth-to-
mouth’ breathing), and maintenance of the Circulation using
chest compressions; Disability, in resuscitated patients, refers
to assessment of neurological status, and Exposure entails
removal of clothes to enable defibrillation, auscultation of the
chest, and assessment for a rash caused by anaphylaxis, for
injuries and so on (Fig. 16.19). The term basic life support (BLS)
Presenting problems in cardiovascular disease • 457
In-hospital resuscitation
Collapsed /sick patient
Shout for HELP and assess patient
NO
K
Signs of life?
YES
w
Call resuscitation
team
CPR 30:2
with oxygen and
airway adjuncts
Apply pads/monitor
Attempt defibrillation
if appropriate
Assess ABCDE
Recognise and treat
Oxygen, monitoring,
IV access
Call resuscitation
team if
appropriate
- ■ -
Advanced
life support
when resuscitation
team arrives
Handover to
resuscitation
team
Fig. 16.19 Algorithm for adult basic life support. For further
information, see www.resus.org.uk. (CPR = cardiopulmonary resuscitation)
From Resuscitation Council (UK) guidelines: https://www.resus.org.uk/
resuscitation-guidelines/in-hospital-resuscitation/.
encompasses manoeuvres that aim to maintain a low level of
circulation until more definitive treatment with advanced life
support can be given. Chest compression-only (‘hands-only’)
cardiopulmonary resuscitation (CPR) is easier for members of
the public to learn and administer, and is now advocated in
public education campaigns.
Advanced life support
Advanced life support (ALS) (Fig. 16.20) aims to restore normal
cardiac rhythm by defibrillation when the cause of cardiac arrest
is a tachyarrhythmia, or to restore cardiac output by correcting
other reversible causes of cardiac arrest. The initial priority is to
assess the patient’s cardiac rhythm by attaching a defibrillator
or monitor. Once that this has been done, treatment should be
instituted based on the clinical findings.
Ventricular fibrillation or pulseless ventricular tachycardia
should be treated with immediate defibrillation. Defibrillation is
more likely to be effective if a biphasic shock defibrillator is used,
where the polarity of the shock is reversed midway through its
delivery. Defibrillation is usually administered using a 150-joule
biphasic shock, and CPR resumed immediately for 2 minutes
without attempting to confirm restoration of a pulse because
restoration of mechanical cardiac output rarely occurs immediately
after successful defibrillation. If, after 2 minutes, a pulse is not
restored, a further biphasic shock of 150-200 joules should be
given. Thereafter, additional biphasic shocks of 150-200 joules
are given every 2 minutes after each cycle of CPR. During
resuscitation, adrenaline (epinephrine, 1 mg IV) should be
given every 3-5 minutes and consideration given to the use
of intravenous amiodarone, especially if ventricular fibrillation or
ventricular tachycardia re-initiates after successful defibrillation.
Ventricular fibrillation of low amplitude, or ‘fine VF’, may
mimic asystole. If asystole cannot be confidently diagnosed,
the patient should be treated for VF and defibrillated. If an
electrical rhythm is observed that would be expected to produce
a cardiac output, ‘pulseless electrical activity’ is present. Pulseless
electrical activity should be treated by continuing CPR and
adrenaline (epinephrine) administration while seeking such causes.
Asystole should be treated similarly, with the additional support
of atropine and sometimes external or transvenous pacing in
an attempt to generate an electrical rhythm. There are many
potentially reversible causes of cardiac arrest; the main ones
can be easily remembered as a list of four Hs and four Ts
(Fig. 16.20).
The Chain of Survival
This term refers to the sequence of events that is necessary to
maximise the chances of a cardiac arrest victim surviving (Fig.
16.21). Survival is most likely if all links in the chain are strong:
that is, if the arrest is witnessed, help is called immediately, basic
life support is administered by a trained individual, the emergency
medical services respond promptly, and defibrillation is achieved
within a few minutes. Good training in both basic and advanced
life support is essential and should be maintained by regular
refresher courses. In recent years, public access defibrillation has
been introduced in places of high population density, particularly
where traffic congestion may impede the response of emergency
services, such as railway stations, airports and sports stadia.
Designated individuals can respond to a cardiac arrest using
BLS and an automated external defibrillator.
Survivors of cardiac arrest
Patients who survive a cardiac arrest caused by acute Ml need
no specific treatment beyond that given to those recovering from
an uncomplicated infarct, since their prognosis is similar (p. 498).
Those with reversible causes, such as exercise- induced ischaemia
or aortic stenosis, should have the underlying cause treated
if possible. Survivors of ventricular tachycardia or ventricular
fibrillation arrest in whom no reversible cause can be identified
may be at risk of another episode, and should be considered for
an implantable cardiac defibrillator (p. 483) and anti-arrhythmic
drug therapy. In these patients, the risk is reduced by treatment
of heart failure with p-adrenoceptor antagonists (P-blockers) and
angiotensin-converting enzyme (ACE) inhibitors, and by coronary
revascularisation.
Abnormal heart sounds
The first indication of heart disease may be the discovery of
an abnormal sound on auscultation (Box 16.8). This may be
incidental - for example, during a routine childhood examination
- or may be prompted by symptoms of heart disease.
Clinical assessment
The aims of clinical assessment are, firstly, to determine if
the abnormal sound is cardiac; secondly, to determine if it is
pathological; and thirdly, to try to determine its cause.
Is the sound cardiac?
Additional heart sounds and murmurs demonstrate a consistent
relationship to a specific part of the cardiac cycle, whereas
extracardiac sounds, such as a pleural rub or venous hum,
458 • CARDIOLOGY
Advanced life support
Fig. 16.20 Algorithm for adult advanced life support. For further information, see www.resus.org.uk. (CPR = cardiopulmonary resuscitation:
PEA = pulseless electrical activity; VF = ventricular fibrillation; VT = ventricular tachycardia) From Resuscitation Council (UK) guidelines:
https://www. resus. org. uk/resuscitation-guidelines/adult-advanced-life-support/.
Fig. 16.21 The Chain of Survival in cardiac arrest. (ALS = advanced life support; CPR = cardiopulmonary resuscitation)
Presenting problems in cardiovascular disease • 459
16.8 Normal and abnormal heart sounds
Sound
Timing
Characteristics
Mechanisms
Variable features
First heart
sound (SI)
Onset of systole
Usually single or
narrowly split
Closure of mitral and tricuspid
valves
Loud: hyperdynamic circulation (anaemia,
pregnancy, thyrotoxicosis); mitral stenosis
Soft: heart failure; mitral regurgitation
Second heart
sound (S2)
End of systole
Split on inspiration
Single on expiration
(p. 447)
Closure of aortic and pulmonary
valve
A2 first
P2 second
Fixed wide splitting with atrial septal defect
Wide but variable splitting with delayed right
heart emptying (right bundle branch block)
Reversed splitting due to delayed left heart
emptying (left bundle branch block)
Third heart
sound (S3)
Early in diastole,
just after S2
Low pitch, often
heard as ‘gallop’
From ventricular wall due to
abrupt cessation of rapid filling
Physiological: young people, pregnancy
Pathological: heart failure, mitral regurgitation
Fourth heart
sound (S4)
End of diastole,
just before SI
Low pitch
Ventricular origin (stiff ventricle
and augmented atrial contraction)
related to atrial filling
Absent in atrial fibrillation
A feature of severe left ventricular hypertrophy
Systolic clicks
Early or
mid-systole
Brief, high-intensity
sound
Valvular aortic stenosis
Valvular pulmonary stenosis
Floppy mitral valve
Prosthetic heart sounds from
opening and closing of normally
functioning mechanical valves
Click may be lost when stenotic valve becomes
thickened or calcified
Prosthetic clicks lost when valve obstructed by
thrombus or vegetations
Opening snap
(OS)
Early in diastole
High pitch, brief
duration
Opening of stenosed leaflets of
mitral valve
Prosthetic heart sounds
Moves closer to S2 as mitral stenosis becomes
more severe. May be absent in calcific mitral
stenosis
i
• Soft • No radiation
• Mid -systolic • No other cardiac abnormalities
• Heard at left sternal edge
do not. Pericardial friction produces a characteristic scratching
noise termed a pericardial rub, which may have two components
corresponding to atrial and ventricular systole, and may vary
with posture and respiration.
Is the sound pathological?
Pathological sounds and murmurs are the product of turbulent
blood flow or rapid ventricular filling due to abnormal loading
conditions. Some added sounds are physiological but may also
occur in pathological conditions; for example, a third sound
is common in young people and in pregnancy but is also a
feature of heart failure (Box 16.8). Similarly, a systolic murmur
due to turbulence across the right ventricular outflow tract may
occur in hyperdynamic states such as anaemia or pregnancy,
but may also be due to pulmonary stenosis or an intracardiac
shunt leading to volume overload of the RV, such as an atrial
septal defect. Benign murmurs do not occur in diastole (Box
16.9) , and systolic murmurs that radiate or are associated with
a thrill are almost always pathological.
What is the origin of the sound?
Timing, intensity, location, radiation and quality are all useful clues
to the origin and nature of an additional sound or murmur (Box
16.10) . Radiation of a murmur is determined by the direction
of turbulent blood flow and is detectable only when there is a
high-velocity jet, such as in mitral regurgitation (radiation from
apex to axilla) or aortic stenosis (radiation from base to neck).
Similarly, the pitch and quality of the sound can help to distinguish
16.10 How to assess a heart murmur
When does it occur?
• Time the murmur using heart sounds, carotid pulse and the apex
beat. Is it systolic or diastolic?
• Does the murmur extend throughout systole or diastole or is it
confined to a shorter part of the cardiac cycle?
How loud is it? (intensity)
• Grade 1 : very soft (audible only in ideal conditions)
• Grade 2: soft
• Grade 3: moderate
• Grade 4: loud with associated thrill
• Grade 5: very loud
• Grade 6: heard without stethoscope
Note: Diastolic murmurs are very rarely above grade 4
Where is it heard best? (location)
• Listen over the apex and base of the heart, including the aortic and
pulmonary areas
Where does it radiate?
• Listen at the neck, axilla or back
What does it sound like? (pitch and quality)
• Pitch is determined by flow (high pitch indicates high-velocity flow)
• Is the intensity constant or variable?
the murmur, such as the ‘blowing’ murmur of mitral regurgitation
or the ‘rasping’ murmur of aortic stenosis. The position of a
murmur in relation to the cardiac cycle is crucial and should be
assessed by timing it with the heart sounds, carotid pulse and
apex beat (Figs 16.22 and 16.23).
Systolic murmurs
Ejection systolic murmurs are associated with ventricular
outflow tract obstruction and occur in mid-systole with a
16.9 Features of a benign or innocent heart murmur
460 • CARDIOLOGY
1 6.1 1 Features of some common systolic murmurs
Condition
Timing and duration
Quality
Location and radiation
Associated features
Aortic stenosis
Mid-systolic
Loud, rasping
Base and left sternal edge,
radiating to suprasternal notch
and carotids
Single second heart sound
Ejection click (in young patients)
Slow rising pulse
Left ventricular hypertrophy (pressure overload)
Mitral regurgitation
Pansystolic
Blowing
Apex, radiating to axilla
Soft first heart sound
Third heart sound
Left ventricular hypertrophy (volume overload)
Ventricular septal
defect
Pansystolic
Harsh
Lower left sternal edge,
radiating to whole precordium
Thrill
Biventricular hypertrophy
Benign
Mid-systolic
Soft
Left sternal edge, no radiation
No other signs of heart disease
ECG
Fig. 16.22 The relationship of the cardiac cycle to the ECG, the left
ventricular pressure wave and the position of heart sounds.
crescendo-decrescendo pattern, reflecting the changing velocity of
blood flow (Box 1 6.1 1). Pansystolic murmurs maintain a constant
intensity and extend from the first heart sound throughout systole
to the second heart sound, sometimes obscuring it. They occur
when blood leaks from a ventricle into a low-pressure chamber
at an even or constant velocity. Mitral regurgitation, tricuspid
regurgitation and ventricular septal defect are the only causes of
a pansystolic murmur. Late systolic murmurs are unusual but may
Ejection systolic murmur
(aortic stenosis, pulmonary
stenosis, aortic or
pulmonary flow murmurs)
Pansystolic murmur
(mitral regurgitation,
tricuspid regurgitation,
ventricular septal defect)
Late systolic murmur
(mitral valve prolapse)
Early diastolic murmur
(aortic or pulmonary
regurgitation)
lx
Mid-diastolic murmur
(mitral stenosis, tricuspid
stenosis, mitral or
tricuspid flow murmurs)
J
Opening
Fig. 16.23 The timing and pattern of cardiac murmurs.
occur in mitral valve prolapse, if the mitral regurgitation is confined
to late systole, and hypertrophic obstructive cardiomyopathy, if
dynamic obstruction occurs late in systole.
Diastolic murmurs
These are due to accelerated or turbulent flow across the mitral or
tricuspid valves. They are low-pitched noises that are often difficult
to hear and should be evaluated with the bell of the stethoscope.
A mid-diastolic murmur may be due to mitral stenosis (located at
the apex and axilla), tricuspid stenosis (located at the left sternal
edge), increased flow across the mitral valve (for example, the
to-and-fro murmur of severe mitral regurgitation) or increased
flow across the tricuspid valve (for example, a left-to-right shunt
through a large atrial septal defect). Early diastolic murmurs have
a soft, blowing quality with a decrescendo pattern and should
be evaluated with the diaphragm of the stethoscope. They are
due to regurgitation across the aortic or pulmonary valves and
are best heard at the left sternal edge, with the patient sitting
forwards in held expiration.
Presenting problems in cardiovascular disease • 461
Continuous murmurs
These result from a combination of systolic and diastolic flow,
such as occurs with a persistent ductus arteriosus, and must be
distinguished from extracardiac noises such as bruits from arterial
shunts, venous hums (high rates of venous flow in children) and
pericardial friction rubs.
Investigations
If clinical evaluation suggests that the additional sound is cardiac
and likely to be pathological, then echocardiography is indicated
to determine the underlying cause.
Management
Management of patients with additional cardiac sounds depends
on the underlying cause. More details are provided in the sections
on specific valve defects and congenital anomalies later in this
chapter (pp. 514 and 531).
Heart failure
Heart failure describes the clinical syndrome that develops when
the heart cannot maintain adequate output, or can do so only
at the expense of elevated ventricular filling pressure. In mild to
moderate forms of heart failure, symptoms occur only when the
metabolic demand increases during exercise or some other form
of stress. In severe heart failure, symptoms may be present at
rest. In clinical practice, heart failure may be diagnosed when
a patient with significant heart disease develops the signs or
symptoms of a low cardiac output, pulmonary congestion or
systemic venous congestion at rest or on exercise. Three types
of heart failure are recognised.
Left heart failure
This is characterised by a reduction in left ventricular output and an
increase in left atrial and pulmonary venous pressure. If left heart
failure occurs suddenly - for example, as the result of an acute
Ml - the rapid increase in left atrial pressure causes pulmonary
oedema. If the rise in atrial pressure is more gradual, as occurs
with mitral stenosis, there is reflex pulmonary vasoconstriction,
which protects the patient from pulmonary oedema. However,
the resulting increase in pulmonary vascular resistance causes
pulmonary hypertension, which in turn impairs right ventricular
function.
Right heart failure
This is characterised by a reduction in right ventricular output and
an increase in right atrial and systemic venous pressure. The most
common causes are chronic lung disease, pulmonary embolism
and pulmonary valvular stenosis. The term ‘cor pulmonale’ is
used to describe right heart failure that is secondary to chronic
lung disease.
Biventricular heart failure
In biventricular failure, both sides of the heart are affected.
This may occur because the disease process, such as dilated
cardiomyopathy or ischaemic heart disease, affects both ventricles
or because disease of the left heart leads to chronic elevation
of the left atrial pressure, pulmonary hypertension and right
heart failure.
Epidemiology
Heart failure predominantly affects the elderly; the prevalence
rises from 1 % in those aged 50-59 years to over 1 0% in those
aged 80-89 years. In the UK, most patients admitted to hospital
with heart failure are more than 70 years old; they typically remain
hospitalised for a week or more and may be left with chronic
disability. Although the outlook depends, to some extent, on
the underlying cause of the problem, untreated heart failure
generally carries a poor prognosis; approximately 50% of patients
with severe heart failure due to left ventricular dysfunction will
die within 2 years because of either pump failure or malignant
ventricular arrhythmias. The most common causes are coronary
artery disease and myocardial infarction but almost all forms of
heart disease can lead to heart failure, as summarised in Box
16.12. An accurate diagnosis is important because treatment
of the underlying cause may reverse heart failure or prevent its
progression.
Pathogenesis
Heart failure occurs when cardiac output fails to meet the
demands of the circulation. Cardiac output is determined by
preload (the volume and pressure of blood in the ventricles at
the end of diastole), afterload (the volume and pressure of blood
in the ventricles during systole) and myocardial contractility,
forming the basis of Starling’s Law (Fig. 16.24). The causes of
heart failure are discussed below.
Fig. 16.24 Starling’s Law. Normal (A), mild (B), moderate (C) and severe
(D) heart failure. Ventricular performance is related to the degree of
myocardial stretching. An increase in preload (end-diastolic volume,
end-diastolic pressure, filling pressure or atrial pressure) will therefore
enhance function; however, overstretching causes marked deterioration. In
heart failure, the curve moves to the right and becomes flatter. An increase
in myocardial contractility or a reduction in afterload will shift the curve
upwards and to the left (green arrow).
Ventricular dysfunction
Ventricular dysfunction is the most common cause of heart
failure. This can occur because of impaired systolic contraction
due to myocardial disease, or diastolic dysfunction where there
is abnormal ventricular relaxation due to a stiff, non-compliant
ventricle. This is most commonly found in patients with left
ventricular hypertrophy. Systolic dysfunction and diastolic
dysfunction often coexist, particularly in patients with coronary
artery disease. Ventricular dysfunction reduces cardiac output,
which, in turn, activates the sympathetic nervous system (SNS)
and renin-angiotensin-aldosterone system (RAAS). Under normal
circumstances, activation of the SNS and RAAS supports cardiac
function but, in the setting of impaired ventricular function, the
consequences are negative and lead to an increase in both
afterload and preload (Fig. 16.25). A vicious circle may then be
462 • CARDIOLOGY
1 16.12 Mechanisms of heart failure
Cause
Examples
Features
Reduced ventricular
contractility
Myocardial infarction (segmental dysfunction)
Myocarditis/cardiomyopathy (global dysfunction)
In coronary artery disease, ‘akinetic’ or ‘dyskinetic’ segments
contract poorly and may impede the function of normal
segments by distorting their contraction and relaxation patterns
Progressive ventricular dilatation
Ventricular outflow
obstruction
(pressure overload)
Hypertension, aortic stenosis (left heart failure)
Pulmonary hypertension, pulmonary valve stenosis (right
heart failure)
Initially, concentric ventricular hypertrophy allows the ventricle
to maintain a normal output by generating a high systolic
pressure. Later, secondary changes in the myocardium and
increasing obstruction lead to failure with ventricular dilatation
and rapid clinical deterioration
Ventricular inflow
obstruction
Mitral stenosis, tricuspid stenosis
Small, vigorous ventricle; dilated, hypertrophied atrium. Atrial
fibrillation is common and often causes marked deterioration
because ventricular filling depends heavily on atrial contraction
Ventricular volume
overload
Left ventricular volume overload (mitral or aortic
regurgitation)
Ventricular septal defect
Right ventricular volume overload (atrial septal defect)
Increased metabolic demand (high output)
Dilatation and hypertrophy allow the ventricle to generate a
high stroke volume and help to maintain a normal cardiac
output. However, secondary changes in the myocardium lead
to impaired contractility and worsening heart failure
Arrhythmia
Atrial fibrillation
Tachycardia
Complete heart block
Tachycardia does not allow for adequate filling of the heart,
resulting in reduced cardiac output and back pressure
Prolonged tachycardia causes myocardial fatigue
Bradycardia limits cardiac output, even if stroke volume is
normal
Diastolic
dysfunction
Constrictive pericarditis
Restrictive cardiomyopathy
Left ventricular hypertrophy and fibrosis
Cardiac tamponade
Marked fluid retention and peripheral oedema, ascites, pleural
effusions and elevated jugular veins
Bi-atrial enlargement (restrictive filling pattern and high atrial
pressures). Atrial fibrillation may cause deterioration
Good systolic function but poor diastolic filling
Hypotension, elevated jugular veins, pulsus paradoxus, poor
urine output
Increased
blood
pressure and
cardiac work
Increased
afterload
Increased
blood
pressure and
cardiac work
▼ ▼
Myocyte loss
Myocardial
fibrosis
Heart failure
Reduced
cardiac output
Neurohumoral
activation
Sympathetic
nervous system
Renin -angiotensin
system
Vasopressin system
Endothelin system
Vasoconstriction
◄— 1
— ►
Sodium and
water retention
Increased
intravascular
volume
—
Fig. 16.25 Neurohumoral activation and compensatory mechanisms
in heart failure. There is a vicious circle in progressive heart failure.
established because any additional fall in cardiac output causes
further activation of the SNS and RAAS, and an additional
increase in peripheral vascular resistance.
Activation of the RAAS causes vasoconstriction and sodium
and water retention. This is primarily mediated by angiotensin II, a
potent constrictor of arterioles, in both the kidney and the systemic
circulation (Fig. 16.25). Activation of the SNS also occurs and
can initially sustain cardiac output through increased myocardial
contractility and heart rate. Prolonged sympathetic stimulation has
negative effects, however, causing cardiac myocyte apoptosis,
cardiac hypertrophy and focal myocardial necrosis. Sympathetic
stimulation also contributes to vasoconstriction and predisposes
to arrhythmias. Sodium and water retention is further enhanced by
the release of aldosterone, endothelin- 1 (a potent vasoconstrictor
peptide with marked effects on the renal vasculature) and, in
severe heart failure, vasopressin (antidiuretic hormone, ADH).
Natriuretic peptides are released from the atria in response to atrial
dilatation and compensate to an extent for the sodium-conserving
effect of aldosterone, but this mechanism is overwhelmed in
heart failure. Pulmonary and peripheral oedema occurs because
of high left and right atrial pressures, and is compounded by
sodium and water retention, caused by impairment of renal
perfusion and by secondary hyperaldosteronism. If the underlying
cause is a myocardial infarction, cardiac contractility is impaired
and SNS and RAAS activation causes hypertrophy of non-
infarcted segments, with thinning, dilatation and expansion
of the infarcted segment (see Fig. 16.64, p. 496). This leads
to further deterioration in ventricular function and worsening
heart failure.
Presenting problems in cardiovascular disease • 463
High-output failure
Sometimes cardiac failure can occur in patients without heart
disease due to a large arteriovenous shunt, or where there is an
excessively high cardiac output due to beri-beri (p. 714), severe
anaemia or thyrotoxicosis.
Valvular disease
Heart failure can also be caused by valvular disease in which
there is impaired filling of the ventricles due to mitral or tricuspid
stenosis; where there is obstruction to ventricular outflow,
as occurs in aortic and tricuspid stenosis and hypertrophic
cardiomyopathy; or as the result of ventricular overload secondary
to valvular regurgitation.
Clinical assessment
Heart failure may develop suddenly, as in Ml, or gradually, as
in valvular heart disease. When there is gradual impairment of
cardiac function, several compensatory changes take place. The
term compensated heart failure is sometimes used to describe
the condition of those with impaired cardiac function, in whom
adaptive changes have prevented the development of overt heart
failure. However, a minor event, such as an intercurrent infection
or development of atrial fibrillation, may precipitate acute heart
failure in these circumstances (Box 16.13). Similarly, acute heart
failure sometimes supervenes as the result of a decompensating
episode, on a background of chronic heart failure; this is called
acute-on-chronic heart failure.
Acute left heart failure
Acute left heart failure presents with a sudden onset of dyspnoea
at rest that rapidly progresses to acute respiratory distress,
orthopnoea and prostration. Often there is a clear precipitating
factor, such as an acute Ml, which may be apparent from the
history. The patient appears agitated, pale and clammy. The
peripheries are cool to the touch and the pulse is rapid, but in
some cases there may be an inappropriate bradycardia that
may contribute to the acute episode of heart failure. The BP is
usually high because of SNS activation, but may be normal or
low if the patient is in cardiogenic shock.
The jugular venous pressure (JVP) is usually elevated,
particularly with associated fluid overload or right heart failure.
In acute heart failure, there has been no time for ventricular
dilatation and the apex is not displaced. A ‘gallop’ rhythm, with
a third heart sound, is heard quite early in the development of
acute left-sided heart failure. A new systolic murmur may signify
acute mitral regurgitation or ventricular septal rupture. Chest
examination may reveal crepitations at the lung bases if there is
pulmonary oedema, or crepitations throughout the lungs if this
16.13 Factors that may precipitate or aggravate
heart failure in pre-existing heart disease
• Myocardial ischaemia or infarction
• Intercurrent illness
• Arrhythmia
• Inappropriate reduction of therapy
• Administration of a drug with negative inotropic ((3-blocker) or
fluid-retaining properties (non-steroidal anti-inflammatory drugs,
glucocorticoids)
• Pulmonary embolism
• Conditions associated with increased metabolic demand (pregnancy,
thyrotoxicosis, anaemia)
• Intravenous fluid overload
is severe. There may be an expiratory wheeze. Patients with
acute-on-chronic heart failure may have additional features of
chronic heart failure (see below). Potential precipitants, such as
an upper respiratory tract infection or inappropriate cessation
of diuretic medication, may be identified on clinical examination
or history-taking.
Chronic heart failure
Patients with chronic heart failure commonly follow a relapsing
and remitting course, with periods of stability and episodes of
decompensation, leading to worsening symptoms that may
necessitate hospitalisation. The clinical picture depends on the
nature of the underlying heart disease, the type of heart failure
that it has evoked, and the changes in the SNS and RAAS that
have developed (see Box 16.12 and Fig. 16.26).
Low cardiac output causes fatigue, listlessness and a poor
effort tolerance; the peripheries are cold and the BP is low.
To maintain perfusion of vital organs, blood flow is diverted
away from skeletal muscle and this may contribute to fatigue
and weakness. Poor renal perfusion leads to oliguria and
uraemia.
Pulmonary oedema due to left heart failure presents with
dyspnoea and inspiratory crepitations over the lung bases. In
contrast, right heart failure produces a high JVP with hepatic
congestion and dependent peripheral oedema. In ambulant
patients the oedema affects the ankles, whereas in bed-bound
patients it collects around the thighs and sacrum. Ascites or
pleural effusion may occur (Fig. 16.26). Heart failure is not the
only cause of oedema (Box 16.14).
Fig. 16.26 Clinical features of left and right heart failure.
(JVP = jugular venous pressure)
16.14 Differential diagnosis of peripheral oedema
• Cardiac failure: right or combined left and right heart failure,
pericardial constriction, cardiomyopathy
• Chronic venous insufficiency: varicose veins
• Hypoalbuminaemia: nephrotic syndrome, liver disease, protein¬
losing enteropathy; often widespread, can affect arms and face
• Drugs:
Sodium retention: fludrocortisone, non-steroidal anti¬
inflammatory drugs
Increasing capillary permeability: nifedipine, amlodipine
• Idiopathic: women > men
• Chronic lymphatic obstruction
464 • CARDIOLOGY
Chronic heart failure is sometimes associated with marked
weight loss (cardiac cachexia), caused by a combination
of anorexia and impaired absorption due to gastrointestinal
congestion, poor tissue perfusion due to a low cardiac output,
and skeletal muscle atrophy due to immobility.
Complications of heart failure
Several complications may occur in advanced heart failure, as
described below.
• Renal failure is caused by poor renal perfusion due to low
cardiac output and may be exacerbated by diuretic
therapy, ACE inhibitors and angiotensin receptor blockers
(ARBs).
• Hypokalaemia may be the result of treatment with
potassium-losing diuretics or hyperaldosteronism caused
by activation of the renin-angiotensin system and impaired
aldosterone metabolism due to hepatic congestion. Most
of the body’s potassium is intracellular and there may be
substantial depletion of potassium stores, even when the
plasma concentration is in the reference range.
• Hyperkalaemia may be due to the effects of drugs that
promote renal resorption of potassium, in particular the
combination of ACE inhibitors, ARBs and mineralocorticoid
receptor antagonists. These effects are amplified if
there is renal dysfunction due to low cardiac output or
atherosclerotic renal vascular disease.
• Hyponatraemia is a feature of severe heart failure and is a
poor prognostic sign. It may be caused by diuretic
therapy, inappropriate water retention due to high
vasopressin secretion, or failure of the cell membrane ion
pump.
• Impaired liver function is caused by hepatic venous
congestion and poor arterial perfusion, which frequently
cause mild jaundice and abnormal liver function tests;
reduced synthesis of clotting factors can make
anticoagulant control difficult.
• Thromboembolism. Deep vein thrombosis and pulmonary
embolism may occur due to the effects of a low cardiac
output and enforced immobility. Systemic emboli occur in
patients with atrial fibrillation or flutter, or with intracardiac
thrombus complicating conditions such as mitral stenosis,
Ml or left ventricular aneurysm.
• Atrial and ventricular arrhythmias are very common and
may be related to electrolyte changes such as
hypokalaemia and hypomagnesaemia, the underlying
cardiac disease, and the pro-arrhythmic effects of
sympathetic activation. Atrial fibrillation occurs in
approximately 20% of patients with heart failure and
causes further impairment of cardiac function. Ventricular
ectopic beats and runs of non-sustained ventricular
tachycardia are common findings in patients with heart
failure and are associated with an adverse prognosis.
• Sudden death occurs in up to 50% of patients with heart
failure and is most probably due to ventricular fibrillation.
Investigations
A chest X-ray should be performed in all cases. This may show
abnormal distension of the upper lobe pulmonary veins with the
patient in the erect position (Fig. 16.27). Vascularity of the lung
fields becomes more prominent and the right and left pulmonary
arteries dilate. Subsequently, interstitial oedema causes thickened
interlobular septa and dilated lymphatics. These are evident as
horizontal lines in the costophrenic angles (septal or ‘Kerley
Prominence
Reticular shadowing of upper lobe Enlarged hilar
of alveolar oedema blood vessels vessels
Septal or Enlarged cardiac
‘Kerley B’ lines silhouette; usually with
coexisting chronic
heart failure
Fig. 16.27 Radiological features of heart failure, jj] Chest X-ray of a
patient with pulmonary oedema. [§] Enlargement of lung base showing
septal or ‘Kerley B’ lines (arrow).
B’ lines). More advanced changes due to alveolar oedema
cause a hazy opacification spreading from the hilar regions, and
pleural effusions. Echocardiography is very useful and should be
considered in all patients with heart failure in order to:
• determine the aetiology
• detect hitherto unsuspected valvular heart disease, such
as occult mitral stenosis, and other conditions that may be
amenable to specific remedies
• identify patients who will benefit from long-term drug
therapy.
Serum urea, creatinine and electrolytes, haemoglobin and
thyroid function may help to establish the nature and severity of
the underlying heart disease and detect any complications. BNP
is elevated in heart failure and is a prognostic marker, as well
as being useful in differentiating heart failure from other causes
of breathlessness or peripheral oedema.
Management of acute heart failure
Acute heart failure with pulmonary oedema is a medical emergency
that should be treated urgently. The patient should initially be kept
rested, with continuous monitoring of cardiac rhythm, BP and
Presenting problems in cardiovascular disease • 465
16.15 Management of acute pulmonary oedema
Action
Effect
Sit the patient up
Reduces preload
Give high-flow oxygen
Corrects hypoxia
Ensure continuous positive airway pressure
(CPAP) of 5-1 0 mmHg by tight-fitting mask
Reduces preload and
pulmonary capillary
hydraulic gradient
Administer nitrates:*
IV glyceryl trinitrate (10-200 jig/min)
Buccal glyceryl trinitrate 2-5 mg
Reduces preload and
afterload
Administer a loop diuretic:
Furosemide (50-100 mg IV)
Combats fluid overload
*The dose of nitrate should be titrated upwards every 1 0 mins until there is an
improvement or systolic blood pressure is <110 mmHg.
pulse oximetry. Intravenous opiates can be of value in distressed
patients but must be used sparingly, as they may cause respiratory
depression and exacerbation of hypoxaemia and hypercapnia.
The key elements of management are summarised in Box 16.15.
If these measures prove ineffective, inotropic agents such as
dobutamine (2.5-10 jig/kg/min) may be required to augment
cardiac output, particularly in hypotensive patients. Insertion
of an intra-aortic balloon pump may be beneficial in patients
with acute cardiogenic pulmonary oedema and shock.
Following management of the acute episode, additional measures
must be instituted to control heart failure in the longer term, as
discussed below.
Management of chronic heart failure
The aims of treatment in chronic heart failure are to improve
cardiac function by increasing contractility, optimising preload
or decreasing afterload, and controlling cardiac rate and rhythm
(see Fig. 1 6.25). This can be achieved by a combination of drug
treatment or non-drug treatments, as discussed below.
Education
Education of patients and their relatives about the causes and
treatment of heart failure can improve adherence to a management
plan (Box 1 6.1 6). Some patients may need to weigh themselves
daily, as a measure of fluid load, and adjust their diuretic therapy
accordingly.
Drug treatment
A wide variety of drug treatments are now available for the
treatment of heart failure. Drugs that reduce preload are
appropriate in patients with high end-diastolic filling pressures
and evidence of pulmonary or systemic venous congestion,
whereas those that reduce afterload or increase myocardial
contractility are more useful in patients with signs and symptoms
of a low cardiac output.
Diuretics Diuretics promote urinary sodium and water excretion,
leading to a reduction in blood plasma volume (p. 354), which
in turn reduces preload and improves pulmonary and systemic
venous congestion. They may also reduce afterload and ventricular
volume, leading to a fall in ventricular wall tension and increased
cardiac efficiency. Although a fall in preload (ventricular filling
pressure) normally reduces cardiac output, patients with heart
failure are beyond the apex of the Starling curve, so there may
16.16 General measures for the management
of heart failure
Education
• Explanation of nature of disease, treatment and self-help strategies
Diet
• Good general nutrition and weight reduction for the obese
• Avoidance of high-salt foods and added salt, especially for patients
with severe congestive heart failure
Alcohol
• Moderation or elimination of alcohol consumption; alcohol-induced
cardiomyopathy requires abstinence
Smoking
• Cessation
Exercise
• Regular moderate aerobic exercise within limits of symptoms
Vaccination
• Consideration of influenza and pneumococcal vaccination
Forward
failure
Fatigue
Cardiac output
or ventricular
performance
Preload Backward failure
Dyspnoea/oedema
Fig. 16.28 The effect of treatment on ventricular performance
curves in heart failure. Diuretics and venodilators (A), angiotensin¬
converting enzyme (ACE) inhibitors and mixed vasodilators (B), and positive
inotropic agents (C).
be a substantial and beneficial fall in filling pressure with either no
change or an improvement in cardiac output (see Figs 1 6.24 and
16.28). Nevertheless, the dose of diuretics needs to be titrated
carefully so as to avoid excessive volume depletion, which can
cause a fall in cardiac output with hypotension, lethargy and
renal failure. This is especially likely in patients with a marked
diastolic component to their heart failure.
Oedema may persist, despite oral loop diuretic therapy, in
some patients with severe chronic heart failure, particularly
if there is renal impairment. Under these circumstances an
intravenous infusion of furosemide (5-10 mg/hr) may initiate a
diuresis. Combining a loop diuretic with a thiazide diuretic such
as bendroflumethiazide (5 mg daily) may also prove effective but
care must be taken to avoid an excessive diuresis.
Mineralocorticoid receptor antagonists, such as spironolactone
and eplerenone, are potassium-sparing diuretics that are of
particular benefit in patients with heart failure with severe left
ventricular systolic dysfunction. They have been shown to improve
long-term clinical outcome in individuals with severe heart failure
or heart failure following acute Ml but may cause hyperkalaemia,
particularly when used with an ACE inhibitor.
466 • CARDIOLOGY
Angiotensin-converting enzyme inhibitors ACE inhibitors play a
central role in the management of heart failure since they interrupt
the vicious circle of neurohumoral activation that is characteristic
of the disease by preventing the conversion of angiotensin I to
angiotensin II. This, in turn, reduces peripheral vasoconstriction,
activation of the sympathetic nervous system (Fig. 16.29), and
salt and water retention due to aldosterone release, as well as
preventing the activation of the renin-angiotensin system caused
by diuretic therapy.
In moderate and severe heart failure, ACE inhibitors can
produce a substantial improvement in effort tolerance and in
mortality. They can also improve outcome and prevent the onset
of overt heart failure in patients with poor residual left ventricular
function following Ml.
Adverse effects of ACE inhibitors include symptomatic
hypotension and impairment of renal function, especially in patients
with bilateral renal artery stenosis or those with pre-existing renal
disease. An increase in serum potassium concentration may also
occur, which can be beneficial in offsetting the hypokalaemia
associated with loop diuretic therapy. Short-acting ACE inhibitors
can cause marked falls in BP, particularly in the elderly or
when started in the presence of hypotension, hypovolaemia or
hyponatraemia. In stable patients without hypotension (systolic BP
over 100 mmHg), ACE inhibitors can usually be safely started in
• Incidence: rises with age and affects 5-10% of those in their
eighties.
• Common causes: coronary artery disease, hypertension and
calcific degenerative valvular disease.
• Diastolic dysfunction: often prominent, particularly in those with a
history of hypertension.
• ACE inhibitors: improve symptoms and mortality but are more
frequently associated with postural hypotension and renal
impairment than in younger patients.
• Loop diuretics: usually required but may be poorly tolerated in
those with urinary incontinence and men with prostate enlargement.
16.17 Congestive cardiac failure in old age
the community. In other patients, however, it is usually advisable
to withhold diuretics for 24 hours before starting treatment with a
small dose of a long-acting agent, preferably given at night (Box
16.18). Renal function and serum potassium must be monitored
and should be checked 1-2 weeks after starting therapy.
Angiotensin receptor blockers ARBs act by blocking the action
of angiotensin II on the heart, peripheral vasculature and kidney.
In heart failure, they produce beneficial haemodynamic changes
that are similar to the effects of ACE inhibitors (Fig. 16.29) but
are generally better tolerated. They have comparable effects on
mortality and are a useful alternative for patients who cannot
tolerate ACE inhibitors. Like ACE inhibitors they should be started
at a low dose and titrated upwards, depending on response
(Box 16.18). Unfortunately, they share all the more serious
adverse effects of ACE inhibitors, including renal dysfunction
and hyperkalaemia. ARBs are normally used as an alternative
to ACE inhibitors, but the two can be combined in patients with
resistant or recurrent heart failure.
Neprilysin inhibitors The only drug currently in this class is
sacubitril, a small-molecule inhibitor of neprilysin, which is
n i6.i8
Dosages of ACE inhibitors, B-blockers and
angiotensin receptor blockers in heart failure
Starting dose
Target dose
ACE inhibitors
Enalapril
2.5 mg twice daily
1 0 mg twice daily
Lisinopril
2.5 mg daily
20 mg daily
Ramipril
1.25 mg daily
10 mg daily
Angiotensin receptor blockers
Losartan
25 mg daily
100 mg daily
Candesartan
4 mg daily
32 mg daily
Valsartan
40 mg daily
160 mg daily
(3-blockers
Bisoprolol
1.25 mg daily
10 mg daily
Metoprolol
25 mg twice daily
1 00 mg twice daily
Carvedilol
3.125 mg twice daily
25 mg twice daily
Non-ACE
pathways
Angiotensinogen
f
Renin (kidney)
ACE inhibitors
Bradykinin
Anqiotensin
I-
Angiotensin I
Angiotensin- A x
converting
enzyme (ACE)
Inactive peptides
Angiotensin
receptor blockers
Aldosterone Vasoconstriction
I-
Salt and water
retention -
(3-blockers
Mineralocorticoid
receptor antagonists
Diuretics
\
Enhanced
sympathetic
activity
Vasodilatation
Fig. 16.29 Neurohumoral activation and sites of action of drugs used in the treatment of heart failure.
Presenting problems in cardiovascular disease • 467
responsible for the breakdown of the endogenous diuretics
ANP and BNP. Used in combination with the ARB valsartan
(sacubitril-valsartan), it has been shown to produce additional
symptomatic and mortality benefit over ACE inhibition and is
now recommended in the management of resistant heart failure.
Vasodilators These drugs are valuable in chronic heart failure,
when ACE inhibitors or ARBs are contraindicated. Venodilators,
such as nitrates, reduce preload, and arterial dilators, such as
hydralazine, reduce afterload (see Fig. 16.28). Their use is limited
by pharmacological tolerance and hypotension.
Beta-adrenoceptor blockers Beta-blockade helps to counteract
the deleterious effects of enhanced sympathetic stimulation and
reduces the risk of arrhythmias and sudden death. When initiated
in standard doses (3-blockers may precipitate acute-on-chronic
heart failure, but when given in small incremental doses they
can increase ejection fraction, improve symptoms, reduce the
frequency of hospitalisation and reduce mortality in patients with
chronic heart failure. A typical regimen is bisoprolol, starting
at a dose of 1 .25 mg daily and increased gradually over a
1 2-week period to a target maintenance dose of 1 0 mg daily.
Beta-blockers are more effective at reducing mortality than ACE
inhibitors, with a relative risk reduction of 33% versus 20%,
respectively.
Ivabradine Ivabradine acts on the lf inward current in the SA
node, resulting in reduction of heart rate. It reduces hospital
admission and mortality rates in patients with heart failure due to
moderate or severe left ventricular systolic impairment. In trials,
its effects were most marked in patients with a relatively high
heart rate (over 77/min), so ivabradine is best suited to patients
who cannot take (3-blockers or whose heart rate remains high
despite (3-blockade. It is ineffective in patients with atrial fibrillation.
Digoxin Digoxin (p. 482) can be used to provide rate control in
patients with heart failure and atrial fibrillation. In patients with
severe heart failure (NYHA class III— IV, see Box 16.5), digoxin
reduces the likelihood of hospitalisation for heart failure, although
it has no effect on long-term survival.
Amiodarone This is a potent anti-arrhythmic drug (p. 481)
that has little negative inotropic effect and may be valuable in
patients with poor left ventricular function. It is effective only in the
treatment of symptomatic arrhythmias and should not be used
as a preventative agent in asymptomatic patients. Amiodarone
is used for prevention of symptomatic atrial arrhythmias and
of ventricular arrhythmias when other pharmacological options
have been exhausted.
Non-pharmacological treatments
Implantable cardiac defibrillators These devices are indicated
in patients with symptomatic ventricular arrhythmias and heart
failure, since they improve prognosis and survival (p. 483).
Resynchronisation devices In patients with marked intraventricular
conduction delay, prolonged depolarisation may lead to
uncoordinated left ventricular contraction. When this is associated
with severe symptomatic heart failure, cardiac resynchronisation
devices may be helpful. Here, both the LV and RV are paced
simultaneously (Fig. 16.30) to generate a more coordinated
left ventricular contraction and improve cardiac output. This is
associated with improved symptoms and survival.
Coronary revascularisation Coronary artery bypass surgery or
percutaneous coronary intervention may improve function in
Fig. 16.30 Chest X-ray of a biventricular pacemaker and defibrillator
(cardiac resynchronisation therapy). The right ventricular lead (RV)
is in position in the ventricular apex and is used for both pacing and
defibrillation. The left ventricular lead (LV) is placed via the coronary sinus,
and the right atrial lead (RA) is placed in the right atrial appendage; both
are used for pacing only.
areas of the myocardium that are ‘hibernating’ because of
inadequate blood supply, and can be used to treat carefully
selected patients with heart failure and coronary artery disease.
If necessary, ‘hibernating’ myocardium can be identified by
stress echocardiography and specialised nuclear or magnetic
resonance imaging.
Cardiac transplantation Cardiac transplantation is an established
and successful treatment for patients with intractable heart failure.
Coronary artery disease and dilated cardiomyopathy are the
most common indications. The use of transplantation is limited
by the efficacy of modern drug and device therapies, as well
as the availability of donor hearts, so it is generally reserved for
young patients with severe symptoms despite optimal therapy.
Conventional heart transplantation is contraindicated in patients
with pulmonary vascular disease due to long-standing left heart
failure, complex congenital heart disease such as Eisenmenger’s
syndrome, or primary pulmonary hypertension because the RV of
the donor heart may fail in the face of high pulmonary vascular
resistance. However, heart-lung transplantation can be successful
in patients with Eisenmenger’s syndrome, and lung transplantation
has been used for primary pulmonary hypertension.
Although cardiac transplantation usually produces a dramatic
improvement in the recipient’s quality of life, serious complications
may occur:
• Rejection. In spite of routine therapy with ciclosporin A,
azathioprine and glucocorticoids, episodes of rejection are
common and may present with heart failure, arrhythmias
or subtle ECG changes. Cardiac biopsy is often used to
confirm the diagnosis before starting treatment with
high-dose glucocorticoids.
• Accelerated atherosclerosis. Recurrent heart failure is often
due to progressive atherosclerosis in the coronary arteries
of the donor heart. This is not confined to patients who
underwent transplantation for coronary artery disease and
is probably a manifestation of chronic rejection. Angina is
rare because the heart has been denervated.
468 • CARDIOLOGY
• Infection. Opportunistic infection with organisms such as
cytomegalovirus or Aspergillus remains a major cause of
death in transplant recipients.
Ventricular assist devices Because of the limited supply of donor
organs, ventricular assist devices (V AD) may be employed as a
bridge to cardiac transplantation and as short-term restoration
therapy following a potentially reversible insult such as viral
myocarditis. In some patients, VADs may be used as a long-term
therapy if no other options exist.
These devices assist cardiac output by using a roller, centrifugal
or pulsatile pump that, in some cases, is implantable and portable.
They withdraw blood through cannulae inserted in the atria or
ventricular apex and pump it into the pulmonary artery or aorta.
They are designed not only to unload the ventricles but also to
provide support to the pulmonary and systemic circulations.
Their more widespread application is limited by high complication
rates (haemorrhage, systemic embolism, infection, neurological
and renal sequelae), although some improvements in survival
and quality of life have been demonstrated in patients with
severe heart failure.
Cardiac arrhythmias
A cardiac arrhythmia is defined as a disturbance of the electrical
rhythm of the heart. Cardiac arrhythmias are often a manifestation
of structural heart disease but may also occur because of
abnormal conduction or depolarisation in an otherwise healthy
heart. There are many types of cardiac arrhythmia, as discussed
later in this section. By convention, however, a heart rate of
more than 1 00/min is called a tachycardia, and a heart rate of
less than 60/min is called a bradycardia.
Pathogenesis
Cardiac arrhythmias usually occur as the result of pathology
affecting the conduction system of the heart. The cardiac cycle
is normally initiated by an electrical discharge from the SA node.
The atria and ventricles then activate sequentially as electrical
depolarisation passes through specialised conducting tissues
(see Fig. 1 6.4, p. 445). The sinus node acts as a pacemaker and
its intrinsic rate is regulated by the autonomic nervous system;
vagal activity decreases the heart rate and sympathetic activity
increases heart rate through cardiac sympathetic nerves and
circulating catecholamines.
There are three main mechanisms of tachycardia:
• Increased automaticity. The tachycardia is produced by
spontaneous depolarisation of an ectopic focus in the
atria, atrioventricular junction or ventricles, often in
response to catecholamines. Single depolarisations lead to
atrial, junctional or ventricular premature (ectopic) beats.
Repeated depolarisation leads to atrial, junctional or
ventricular tachycardia.
• Re-entry. The tachycardia is initiated by an ectopic beat
and sustained by a re-entry circuit (Fig. 16.31). Most
tachyarrhythmias are caused by re-entry.
• Triggered activity. This can cause ventricular arrhythmias in
patients with coronary artery disease. It is a form of
secondary depolarisation arising from an incompletely
repolarised cell membrane. Arrhythmias may be
supraventricular (sinus, atrial or junctional) or ventricular in
origin.
Supraventricular rhythms usually produce narrow QRS
complexes because the ventricles are depolarised in their normal
sequence via the AV node, the bundle of His and associated
Purkinje fibres. In contrast, ventricular rhythms produce broad,
bizarre QRS complexes because the ventricles are activated in an
abnormal sequence. Occasionally, supraventricular tachycardia
can mimic ventricular tachycardia and present as a broad-complex
tachycardia due to coexisting bundle branch block or the presence
of an additional atrioventricular connection (accessory pathway,
see below).
Bradycardia may be due to reduced automaticity of the SA
node or abnormalities of conduction through the AV node. If the
sinus rate becomes unduly slow, another, more distal part of the
conducting system may assume the role of pacemaker. This is
known as an escape rhythm and may arise in the AV node or
His bundle (junctional rhythm) or in the ventricles (idioventricular
rhythm).
Clinical features
Many arrhythmias are asymptomatic but sustained tachycardias
typically present with rapid palpitation, dizziness, chest discomfort
or breathlessness. Extreme tachycardias can also cause syncope
because the heart is unable to contract or relax properly at
extreme rates. Bradycardias tend to cause symptoms that
reflect low cardiac output, including fatigue, lightheadedness and
syncope. Extreme bradycardias or tachycardias can precipitate
sudden death or cardiac arrest.
Investigations
The first-line investigation is a standard 12-lead ECG, which
can be diagnostic in many cases. If arrhythmias are intermittent
and the resting ECG is normal, an attempt should be made to
capture the abnormal rhythm using an ambulatory ECG or a
patient-activated ECG.
Fig. 16.31 The mechanism of re-entry. Re-entry can occur when there are two alternative pathways with different conducting properties, such as the
atrioventricular node and an accessory pathway, or an area of normal and an area of ischaemic tissue. Here, pathway A conducts slowly and recovers
quickly, while pathway B conducts rapidly and recovers slowly. (1) In sinus rhythm, each impulse passes down both pathways before entering a common
distal pathway. (2) As the pathways recover at different rates, a premature impulse may find pathway A open and B closed. (3) Pathway B may recover
while the premature impulse is travelling selectively down pathway A. The impulse can then travel retrogradely up pathway B, setting up a closed loop or
re-entry circuit. (4) This may initiate a tachycardia that continues until the circuit is interrupted by a change in conduction rates or electrical depolarisation.
Cardiac arrhythmias • 469
Management
Features of individual arrhythmias are discussed below.
Management depends on the nature of the arrhythmia and
the general principles of medical management are discussed
on page 479.
Sinus arrhythmia
This is defined as a cyclical alteration of the heart rate during
respiration, with an increase during inspiration and a decrease during
expiration. Sinus arrhythmia is a normal phenomenon and can be
quite pronounced in children. Absence of this normal variation in
heart rate with breathing or with changes in posture may be a
feature of diabetic neuropathy (p. 758), autonomic involvement in
patients with diseases of peripheral nerves (p. 1 1 38) or increased
sympathetic drive. Sinus arrhythmia does not require treatment.
I Sinus bradycardia
This may occur in healthy people at rest and is a common finding
in athletes. Some pathological causes are listed in Box 16.19. If
sinus bradycardia is asymptomatic, then no treatment is required.
Symptomatic sinus bradycardia may occur acutely during an
Ml and can be treated with intravenous atropine (0.6-1 .2 mg).
Patients with recurrent or persistent symptomatic sinus
bradycardia should be considered for pacemaker implantation.
| Sinus tachycardia
Sinus tachycardia is usually due to an increase in sympathetic
activity associated with exercise, emotion and pregnancy. Healthy
young adults can produce a rapid sinus rate, up to 200/min,
during intense exercise. Sinus tachycardia does not require
treatment but sometimes may reflect an underlying disease, as
summarised in Box 16.19.
Sick sinus syndrome
Sick sinus syndrome can occur at any age but is most common
in older people. It is caused by fibrosis, degenerative changes
or ischaemia of the SA node and is characterised by a variety
of arrhythmias (Box 16.20). The typical presentation is with
16.19 Some pathological causes of sinus
bradycardia and tachycardia
Sinus bradycardia
• Myocardial infarction
• Sinus node disease
(sick sinus syndrome)
• Hypothermia
• Hypothyroidism
Sinus tachycardia
• Anxiety
• Fever
• Anaemia
• Heart failure
Cholestatic jaundice
Raised intracranial pressure
Drugs ((3-blockers, digoxin,
verapamil)
Thyrotoxicosis
Phaeochromocytoma
Drugs ((3-agonists)
16.20 Common features of sinoatrial disease
• Sinus bradycardia • Paroxysmal atrial tachycardia
• Sinoatrial block (sinus arrest) • Atrioventricular block
• Paroxysmal atrial fibrillation
palpitation, dizzy spells or syncope, due to intermittent tachycardia,
bradycardia, or pauses with no atrial or ventricular activity (SA
block or sinus arrest) (Fig. 16.32).
A permanent pacemaker may benefit patients with troublesome
symptoms due to spontaneous bradycardias, or those with
symptomatic bradycardias induced by drugs required to prevent
tachyarrhythmias. Atrial pacing may prevent episodes of atrial
fibrillation. Pacing improves symptoms but not prognosis, and
is not indicated in patients who are asymptomatic.
Atrial ectopic beats
Atrial ectopic beats usually cause no symptoms but can give
the sensation of a missed beat or an abnormally strong beat.
The ECG (Fig. 16.33) shows a premature but otherwise normal
QRS complex; if visible, the preceding P wave has a different
morphology because the atria activate from an abnormal site. In
most cases these are of no consequence, although very frequent
atrial ectopic beats may herald the onset of atrial fibrillation.
Fig. 16.32 Sinoatrial disease (sick sinus syndrome). A continuous rhythm strip from a 24-hour ECG tape recording illustrating periods of sinus rhythm,
atrial ectopics, junctional beats, sinus bradycardia, sinus arrest and paroxysmal atrial fibrillation.
470 • CARDIOLOGY
Fig. 16.33 Atrial ectopic beats. The first, second and fifth complexes
are normal sinus beats. The third, fourth and sixth complexes are atrial
ectopic beats with identical QRS complexes and abnormal (sometimes
barely visible) P waves.
Treatment is rarely necessary but (3-blockers can be used if
symptoms are intrusive.
Atrial tachycardia
Atrial tachycardia may be a manifestation of increased atrial
automaticity, sinoatrial disease or digoxin toxicity. It produces a
narrow-complex tachycardia with abnormal P-wave morphology,
sometimes associated with AV block if the atrial rate is rapid.
It may respond to (3-blockers, which reduce automaticity, or
class I or III anti-arrhythmic drugs (see Box 16.30 below). The
ventricular response in rapid atrial tachycardias may be controlled
by AV node-blocking drugs. Catheter ablation (p. 484) can be
used to target the ectopic site and should be offered as an
alternative to anti-arrhythmic drugs in patients with recurrent atrial
tachycardia.
Atrial flutter
Atrial flutter is characterised by a large (macro) re-entry circuit,
usually within the right atrium encircling the tricuspid annulus.
The atrial rate is approximately 300/min, and is usually associated
with 2 : 1 , 3 : 1 or 4 : 1 AV block (with corresponding heart rates
of 150, 100 or 75/min). Rarely, in young patients, every flutter
wave is conducted, producing a rate of 300/min and, potentially,
haemodynamic compromise. The ECG shows saw-tooth flutter
waves (Fig. 1 6.34). When there is regular 2 : 1 AV block, it may be
difficult to identify flutter waves that are buried in QRS complexes
and T waves. Atrial flutter should always be suspected when
there is a narrow-complex tachycardia of 150/min. Carotid
sinus pressure or intravenous adenosine may help to establish
the diagnosis by temporarily increasing the degree of AV block
and revealing flutter waves (Fig. 16.35).
Management
Medical management with digoxin, (3-blockers or verapamil is
often successful in controlling the ventricular rate (p. 479). In
many cases, however, it may be preferable to try to restore
sinus rhythm by direct current (DC) cardioversion. Following
cardioversion, (3-blockers or amiodarone can be used to prevent
recurrent episodes of atrial flutter. Class Ic anti-arrhythmic drugs
such as flecainide are contraindicated because there is a risk of
slowing the flutter circuit, facilitating 1 : 1 AV nodal conduction and
producing a paradoxical extreme tachycardia and haemodynamic
compromise. Catheter ablation is a highly effective treatment,
offering a greater than 90% chance of complete cure, and is
the treatment of choice for patients with persistent symptoms.
Anticoagulant management in patients with atrial flutter, including
management around cardioversion, is identical to that of patients
with atrial fibrillation (p. 471).
_ _ - jly-l _ 1
^\T\Tn
III
Fig. 16.34 Atrial flutter. Simultaneous recording showing atrial flutter
with 4:1 atrioventricular block. Flutter waves are visible only in leads II
and III.
Carotid sinus pressure
i
• ill
ft ft A
II 11 11
|
mm
1 1 1 1 1 1 1
i iii iiiii mi
i ii ii mi iiiii in f mini in ii ii hi ii
Fig. 16.35 Carotid sinus pressure in atrial flutter: continuous trace.
The diagnosis of atrial flutter with 2 : 1 block was established when carotid
sinus pressure produced temporary atrioventricular block, revealing the
flutter waves.
Atrial fibrillation
Atrial fibrillation (AF) is the most common sustained cardiac
arrhythmia, with an overall prevalence of 0.5% in the adult
population of the UK. The prevalence rises with age, affecting
1 % of those aged 60-64 years, increasing to 9% of those aged
over 80 years. It is associated with significant morbidity and
a twofold increase in mortality. This is mainly because of its
association with underlying heart disease but also because of
its association with systemic embolism and stroke.
Pathogenesis
AF is a complex arrhythmia characterised by both abnormal
automatic firing and the presence of multiple interacting re-entry
circuits looping around the atria. Episodes of AF are initiated by
rapid bursts of ectopic beats arising from conducting tissue in
the pulmonary veins or from diseased atrial tissue. It becomes
sustained because of re-entrant conduction within the atria or
sometimes because of continuous ectopic firing (Fig. 16.36).
Re-entry is more likely to occur in atria that are enlarged or in
which conduction is slow, as is the case in many forms of heart
disease. During episodes of AF, the atria beat rapidly but in an
uncoordinated and ineffective manner. The ventricles are activated
irregularly at a rate determined by conduction through the AV
node. This produces the characteristic ‘irregularly irregular’ pulse.
The ECG (Fig. 1 6.37) shows normal but irregular QRS complexes;
there are no P waves but the baseline may show irregular
fibrillation waves. Commonly, AF is classified as paroxysmal
(intermittent episodes that self-term inate within 7 days), persistent
Cardiac arrhythmias • 471
Fig. 16.36 Mechanisms initiating atrial fibrillation. (1) Ectopic
beats, often arising from the pulmonary veins, trigger atrial fibrillation.
(2) Re-entry within the atria maintains atrial fibrillation, with multiple
interacting re-entry circuits operating simultaneously.
0
[B
1
-
— 1
Fig. 16.37 Two examples of atrial fibrillation. The QRS complexes are
irregular and there are no P waves. [A] There is usually a fast ventricular
rate, between 120 and 160/min, at the onset of atrial fibrillation.
Bl In chronic atrial fibrillation, the ventricular rate may be much slower,
due to the effects of medication and A V nodal fatigue.
(prolonged episodes that can be terminated by electrical or
pharmacological cardioversion) or permanent. It can be difficult
to identify what type of AF patients have at first presentation but
this usually becomes clearer as time progresses. Unfortunately
for many patients, paroxysmal AF becomes permanent as the
underlying disease process progresses. This is partly because of
electrophysiological changes that occur in the atria within a few
hours of the onset of AF and which tend to maintain fibrillation:
a process called electrical remodelling. When AF persists for a
period of months, structural remodelling also occurs, leading to
atrial fibrosis and dilatation that predispose to chronicity of the
AF. Early treatment of AF can sometimes prevent the arrhythmia
from becoming persistent.
Many forms of heart disease can present with AF (Box 1 6.21),
particularly those that are associated with enlargement or dilatation
of the atria. Alcohol excess, hyperthyroidism and chronic lung
disease are also common causes of AF, although multiple
predisposing factors may coexist, such as the combination of
alcohol, hypertension and coronary artery disease. About 50%
of all patients with paroxysmal AF and 20% of patients with
persistent or permanent AF have structurally normal hearts; this
is known as ‘lone atrial fibrillation’.
Clinical features
The typical presentation is with palpitation, breathlessness
and fatigue. In patients with poor ventricular function or valve
disease, AF may precipitate or aggravate cardiac failure because
16.21 Common causes of atrial fibrillation
• Coronary artery disease
• Alcohol
(including acute Ml)
• Cardiomyopathy
• Valvular heart disease,
• Congenital heart disease
especially rheumatic mitral
• Chest infection
valve disease
• Pulmonary embolism
• Hypertension
• Pericardial disease
• Sinoatrial disease
• Idiopathic (lone atrial
• Hyperthyroidism
fibrillation)
of loss of atrial function and heart rate control. A fall in BP
may cause lightheadedness, and chest pain may occur with
underlying coronary artery disease. In older patients, AF may
not be associated with a rapid ventricular rate and may be
asymptomatic, only to be discovered as a result of a routine
examination or an ECG. Asymptomatic AF may also present with
systemic embolism and is a major cause of stroke in the elderly.
Investigations
Assessment of patients with newly diagnosed AF should include a
full history, physical examination, a 12-lead ECG, echocardiogram
and thyroid function tests to exclude thyrotoxicosis. This is
an unusual but potentially treatable cause of AF. Additional
investigations may be needed to determine the nature and extent
of any underlying heart disease. In particular echocardiographic
assessment is useful to identify any structural heart disease,
particularly mitral valve disease.
Management
Management depends on whether the AF is transient or
persistent and whether there is a clear precipitating factor.
When AF complicates an acute illness such as a chest infection
or pulmonary embolism, treatment of the underlying disorder will
often restore sinus rhythm. Where AF does not resolve, the main
objectives are to control heart rate during periods of AF, restore
sinus rhythm, prevent recurrence of AF and reduce the risk of
thromboembolism. Management of paroxysmal and persistent
AF is discussed below.
Paroxysmal atrial fibrillation
Occasional attacks of AF that are well tolerated do not necessarily
require treatment. Beta-blockers are normally used as first-line
therapy if symptoms are troublesome, since they reduce the
ectopic firing that normally initiates the arrhythmia. They are
particularly useful for treating patients with AF associated with
coronary artery disease, hypertension and cardiac failure. Class
Ic drugs (see Box 1 6.30), such as propafenone or flecainide, are
also effective at preventing episodes but should not be given to
patients with coronary artery disease or left ventricular dysfunction.
Flecainide is seldom used alone, since it can precipitate atrial
flutter, and is usually prescribed with a rate-limiting |3-blocker.
Class III drugs can also be used; amiodarone is the most effective
agent for preventing AF but side-effects restrict its use to when
other measures fail. Dronedarone is an effective alternative but
is contraindicated in patients with heart failure or significant left
ventricular impairment. Digoxin and verapamil are not effective
for the prevention of AF but can help with rate control by slowing
conduction through the AV node. Catheter ablation can be
considered where anti-arrhythmic drug therapy is ineffective
or causes side-effects. Ablation can disconnect the pulmonary
veins from the LA electrically, preventing ectopic triggering
of AF. In addition, lines of conduction block can be created
472 • CARDIOLOGY
if
• Prevalence: rises with age, reaching 9% in those over 80 years.
• Symptoms: sometimes asymptomatic but often accompanied by
diastolic heart failure.
• Hyperthyroidism: atrial fibrillation may emerge as the dominant
feature of otherwise silent or occult hyperthyroidism.
• Cardioversion: followed by high rates (-70% at 1 year) of
recurrent atrial fibrillation.
• Stroke: atrial fibrillation is an important cause of cerebral embolism,
found in 15% of all stroke patients and 2-8% of those with
transient ischaemic attacks (TIAs).
• Anticoagulation: although the risk of thromboembolism rises, the
hazards of anticoagulation also become greater with age because of
increased comorbidity, particularly cognitive impairment and falls.
• Target INR: if anticoagulation is recommended in those over
75 years, care should be taken to maintain an INR below 3.0
because of the increased risk of intracranial haemorrhage.
• Directly acting oral anticoagulants: alternatives to warfarin. No
blood monitoring is required, there are fewer drug interactions, and
fixed dosing may aid adherence. Dabigatran dose is reduced from
150 mg twice daily to 110 mg twice daily in those over 80 or if
creatinine clearance is less than 30 mlVmin. Rivaroxaban dose is
reduced from 20 mg once daily to 15 mg once daily if creatinine
clearance is 30-49 mLymin, and is contraindicated below 30 mL/min.
16.22 Atrial fibrillation in old age
within the atria to prevent re-entry. Ablation prevents AF in
approximately 75% of patients with prior drug -resistant episodes,
although a repeat procedure is sometimes required before this is
achieved. Ablation for AF is an attractive treatment when drugs are
ineffective or poorly tolerated but may be complicated by cardiac
tamponade, stroke, phrenic nerve injury and, rarely, pulmonary
vein stenosis.
Persistent atrial fibrillation
There are two options for treating persistent AF. One is to
attempt to restore and maintain sinus rhythm and the second is
to accept the presence of AF and to try to control the ventricular
rate. With both options prophylaxis against thromboembolism is
required on either a short-term or long-term basis.
Rhythm control An attempt to restore sinus rhythm is particularly
appropriate if the arrhythmia causes troublesome symptoms and
if there is a modifiable or treatable underlying cause. Electrical
DC cardioversion (p. 482) or pharmacological cardioversion may
be used. Cardioversion is initially successful in most patients
but relapse is frequent (25-50% at 1 month and 70-90% at
1 year). Attempts to restore and maintain sinus rhythm are most
successful if AF has been present for less than 3 months, the
patient is young and there is no important structural heart disease.
Immediate cardioversion is appropriate if AF has been present
for less than 48 hours. In stable patients with no history of
structural heart disease, intravenous flecainide (2 mg/kg over
30 mins, maximum dose 1 50 mg) can be used for pharmacological
cardioversion and will restore sinus rhythm in 75% of patients
within 8 hours. In patients with structural or ischaemic heart
disease, intravenous amiodarone can be given through a central
venous catheter. Cardioversion is an alternative treatment and
is often effective when drugs fail. If AF has been present for
48 hours or longer, or if there is doubt about its duration, DC
cardioversion should be deferred until the patient has been
established on effective oral anticoagulation for a minimum of
4 weeks and any underlying problems, such as hypertension
or alcohol excess, have been corrected. Consideration should
be given to prophylactic treatment with amiodarone to reduce
the risk of recurrence. Catheter ablation is sometimes used to
restore and maintain sinus rhythm in resistant cases but is a
less effective treatment than for paroxysmal AF.
Rate control If sinus rhythm cannot be restored, treatment
should be directed at maintaining an appropriate heart rate.
Digoxin, (3-blockers and rate-limiting calcium antagonists, such
as verapamil or diltiazem (p. 479), reduce the ventricular rate
by slowing AV conduction. This alone may produce a striking
improvement in cardiac function, particularly in patients with mitral
stenosis. Beta-blockers and rate-limiting calcium antagonists are
more effective than digoxin at controlling the heart rate during
exercise and have additional benefits in patients with hypertension
or structural heart disease. Combination therapy with digoxin
and a (3-blocker can help with rate control but calcium channel
antagonists should not be used with (3-blockers because of the
risk of bradycardia.
In exceptional cases, poorly controlled and symptomatic AF
can be treated by implanting a permanent pacemaker and then
deliberately inducing complete AV nodal block with catheter
ablation. This is known as the ‘pace and ablate’ strategy.
Thromboprophylaxis Loss of atrial contraction and left atrial
dilatation cause stasis of blood in the LA and may lead to
thrombus formation in the left atrial appendage. This predisposes
patients to stroke and other forms of systemic embolism.
Patients undergoing cardioversion to restore sinus rhythm require
temporary anticoagulation to reduce the risk of systemic embolus.
This can be achieved with warfarin, aiming for an international
normalised ratio (INR) target of 2. 0-3.0. Increasingly, direct-acting
oral anticoagulant drugs (see below) are used as an alternative.
Anticoagulation should be started for at least 4 weeks before
cardioversion and should be maintained for at least 3 months
following successful cardioversion.
In patients with chronic AF, the annual risk of stroke is
influenced by many factors and a decision has to be made in
which the risk of stroke is balanced against the risk of bleeding
with anticoagulation. Patients with AF secondary to mitral valve
disease should always be anti coagulated because the risk is so
high. In other patients, clinical scoring systems can be used to
assess the risk of stroke and bleeding. The risk of stroke is usually
assessed by the CHA2DS2-VASc score (Box 16.23), whereas
the HAS-BLED score can be used to estimate the bleeding
risk (Box 16.24). Patients with a LIAS-BLED score of 3 or more
points may require more careful monitoring if anticoagulated.
In patients with intermittent AF, stroke risk is similar to that in
patients with persistent AF when adjusted for CHA2DS2-VASc
score. The risk of embolism is only weakly related to the frequency
and duration of AF episodes, so stroke prevention guidelines
do not distinguish between those with paroxysmal, persistent
and permanent AF.
Several agents can be used to reduce stroke risk in AF.
Warfarin therapy adjusted to a target INR of 2. 0-3.0 reduces
the risk of stroke by about two-thirds at the cost of an annual
risk of bleeding of 1-1.5% and is indicated for patients with a
CHA2Ds-VASc score of 2 or more, unless there are coexisting
clinical risk factors that increase the risk of bleeding. These include
peptic ulcer, uncontrolled hypertension, alcohol misuse, frequent
falls, poor adherence and the use of other drugs that might
interact with warfarin. If bleeding does occur in warfarin -treated
patients, anticoagulation can be reversed by administering vitamin
K or clotting factors.
The factor Xa inhibitors rivaroxaban, apixaban and edoxaban,
and the direct thrombin inhibitor dabigatran (collectively referred
Cardiac arrhythmias • 473
16.23 CHA2DS2-VASc stroke risk scoring system for
non-valvular atrial fibrillation
Parameter
Score
c
Congestive heart failure
1 point
H
Hypertension history
1 point
A2
Age >75 years
2 points
D
Diabetes mellitus
1 point
s2
Previous stroke or transient ischemic attack (TIA)
2 points
V
Vascular disease
1 point
A
Age 65-74 years
1 point
Sc
Sex category female
1 point
Maximum total score
9 points
Annual stroke risk
0 points = 0% (no prophylaxis required)
1 point = 1 .3% (oral anticoagulant recommended in males only)
2+ points = > 2.2% (oral anticoagulant recommended)
From European Society of Cardiology Clinical practice guidelines: atrial
(management of) 2010 and focused update (2012). Fur Heart J 2012;
33:2719-2747.
fibrillation
i
16.24 HAS-BLED bleeding risk scoring system for
patients receiving oral anticoagulation
Parameter
Score
H
Hypertension; current systolic blood pressure
>160 mmHg
1 point
A
Abnormal liver function (cirrhosis OR bilirubin > twice
upper limit of reference range or transaminases
> three times upper limit of reference range
1 point
Abnormal renal function (creatinine >200 jimol/L
(2.26 mg/dL)
1 point
S
Stroke history
1 point
B
Bleeding: prior major event
1 point
L
Labile INR on warfarin
1 point
E
Elderly: age >65 years
1 point
D
Drugs:
Use of antiplatelet drugs
1 point
High alcohol consumption
1 point
Maximum total score
9 points
HAS-BLED score of >3 points requires close patient monitoring
to as directly acting oral anticoagulants, or DOACs), can be used
as an alternative. They are at least as effective as warfarin at
preventing thrombotic stroke and are associated with a lower
risk of intracranial haemorrhage. Other advantages include the
lack of requirement for monitoring and the fact that they have
fewer drug interactions. Agents that reverse the effects of DOACs
have been developed. These include idarucizumab, which binds
to dabigatran and allows acute bleeding complications to be
managed more effectively.
Aspirin should not be used since it has little or no effect on
embolic stroke and is associated with significant bleeding risk.
Supraventricular tachycardia
The term supraventricular tachycardia (SVT) describes the
occurrence of a group of regular tachycardias that have a
Fig. 16.38 Supraventricular tachycardia. The rate is 180/min and the
QRS complexes are normal.
similar appearance on ECG. These are usually narrow-complex
tachycardias and are characterised by a re-entry circuit or
automatic focus involving the atria. The three principal types
are atrioventricular nodal re-entrant tachycardia (AVNRT),
atrioventricular re-entrant tachycardia (AVRT) and atrial
tachycardia. The term SVT is technically incorrect as, in many
cases, the ventricles also form part of the re-entry circuit.
Atrioventricular nodal re-entrant tachycardia
AVNRT is a type of SVT caused by re-entry in a circuit involving the
AV node and its two right atrial input pathways: a superior ‘fast’
pathway and an inferior ‘slow’ pathway (see Fig. 16.39A below).
This produces a regular tachycardia with a rate of 120-240/
min. It tends to occur in the absence of structural heart disease
and episodes may last from a few seconds to many hours. The
patient is usually aware of a rapid, very forceful, regular heart
beat and may experience chest discomfort, lightheadedness
or breathlessness. Polyuria, mainly due to the release of ANP,
is sometimes a feature. The ECG (Fig. 16.38) usually shows a
tachycardia with normal QRS complexes but occasionally there
may be rate-dependent bundle branch block.
Management
Treatment is not always necessary. However, an acute episode
may be terminated by carotid sinus pressure or by the Valsalva
manoeuvre. Adenosine (3-1 2 mg rapidly IV in incremental doses
until tachycardia stops) or verapamil (5 mg IV over 1 min) will
restore sinus rhythm in most cases. Intravenous p-blocker or
flecainide can also be used. In rare cases, when there is severe
haemodynamic compromise, the tachycardia should be terminated
by DC cardioversion (p. 482).
In patients with recurrent SVT, catheter ablation (p. 484) is
the most effective therapy and will permanently prevent SVT
in more than 90% of cases. Alternatively, prophylaxis with oral
p-blocker, verapamil or flecainide may be used but commits
predominantly young patients to long-term drug therapy and can
create difficulty in female patients, as these drugs are normally
avoided during pregnancy.
Atrioventricular re-entrant tachycardia
In this condition there is an abnormal band of conducting tissue
that connects the atria and ventricles. This so-called accessory
pathway comprises rapidly conducting fibres that resemble
Purkinje tissue, in that they conduct very rapidly and are rich in
sodium channels. In about 50% of cases, this pathway conducts
only in the retrograde direction (from ventricles to atria) and thus
does not alter the appearance of the ECG in sinus rhythm. This
is known as a concealed accessory pathway. In the rest, the
pathway also conducts in an antegrade direction (from atria to
ventricles), so AV conduction in sinus rhythm is mediated via
both the AV node and the accessory pathway, distorting the
QRS complex. Premature ventricular activation via the pathway
shortens the PR interval and produces a ‘slurred’ initial deflection
474 • CARDIOLOGY
|~A~| AV nodal re-entrant
tachycardia
|~B~| Wolff-Parkinson-White
syndrome: sinus rhythm
[c] Wolff-Parkinson-White
syndrome: orthodromic
tachycardia
|~D~1 Wolff-Parkinson-White
syndrome: atrial
fibrillation
Fig. 16.39 Atrioventricular nodal re-entrant tachycardia (AVNRT) and Wolff-Parkinson-White (WPW) syndrome. [A] AV node re-entrant
tachycardia. The mechanism of AVNRT occurs via two right atrial AV nodal input pathways: the slow (S) and fast (F) pathways. Antegrade conduction
occurs via the slow pathway; the wavefront enters the AV node and passes into the ventricles, at the same time re-entering the atria via the fast pathway.
In WPW syndrome, there is a strip of accessory conducting tissue that allows electricity to bypass the AV node and spread from the atria to the ventricles
rapidly and without delay. When the ventricles are depolarised through the AV node the ECG is normal, but when the ventricles are depolarised through the
accessory conducting tissue the ECG shows a very short PR interval and a broad QRS complex. [§] Sinus rhythm. In sinus rhythm, the ventricles are
depolarised through (1) the AV node and (2) the accessory pathway, producing an ECG with a short PR interval and broadened QRS complexes; the
characteristic slurring of the upstroke of the QRS complex is known as a delta wave. The degree of pre-excitation (the proportion of activation passing
down the accessory pathway) and therefore the ECG appearances may vary a lot, and at times the ECG can look normal. [C] Orthodromic tachycardia. This
is the most common form of tachycardia in WPW. The re-entry circuit passes antegradely through the AV node and retrogradely through the accessory
pathway. The ventricles are therefore depolarised in the normal way, producing a narrow-complex tachycardia that is indistinguishable from other forms of
supraventricular tachycardia. [D] Atrial fibrillation. In this rhythm, the ventricles are largely depolarised through the accessory pathway, producing an
irregular broad-complex tachycardia that is often more rapid than the example shown.
of the QRS complex, called a delta wave (Fig. 16.39B). This
is known as a manifest accessory pathway. As the AV node
and accessory pathway have different conduction speeds
and refractory periods, a re-entry circuit can develop, causing
tachycardia (Fig. 16.39C); when associated with symptoms, the
condition is known as Wolff-Parkinson-White syndrome. The
ECG during this tachycardia is almost indistinguishable from
that of AVNRT (Fig. 16.39A).
Management
Carotid sinus pressure or intravenous adenosine can terminate
the tachycardia. If AF occurs, it may produce a dangerously
rapid ventricular rate because the accessory pathway lacks
the rate-limiting properties of the AV node (Fig. 16.39D). This is
known as pre-excited atrial fibrillation and may cause collapse,
syncope and even death. It should be treated as an emergency,
usually with DC cardioversion.
Catheter ablation is first-line treatment in symptomatic patients
and is nearly always curative. Alternatively, prophylactic anti-
arrhythmic drugs, such as flecainide or propafenone (p. 481),
can be used to slow conduction in, and prolong the refractory
period of, the accessory pathway. Long-term drug therapy is
not the preferred treatment for most patients and amiodarone
should not be used, as its side-effect profile cannot be justified
and ablation is safer and more effective. Digoxin and verapamil
shorten the refractory period of the accessory pathway and
should not be used.
Ventricular premature beats
Ventricular premature beats (VPBs) are frequently found in healthy
people and their prevalence increases with age. Ectopic beats in
patients with otherwise normal hearts are more prominent at rest
and disappear with exercise. Sometimes VPBs are a manifestation
of subclinical coronary artery disease or cardiomyopathy but also
may occur in patients with established heart disease following
an Ml. Most patients with VPBs are asymptomatic but some
present with an irregular heart beat, missed beats or abnormally
strong beats, due to increased cardiac output of the post-ectopic
sinus beat. On examination the pulse is irregular, with weak
or missed beats as a result of the fact that the stroke volume
is low because left ventricular contraction occurs before filling
is complete (Fig. 16.40). The ECG shows broad and bizarre
complexes because the ventricles are activated sequentially rather
than simultaneously. The complexes may be unifocal (identical
beats arising from a single ectopic focus) or multifocal (varying
morphology with multiple foci, Fig. 16.40). ‘Couplet’ and ‘triplet’
are the terms used to describe two or three successive ectopic
beats. A run of alternating sinus and ventricular ectopic beats is
known as ventricular ‘bigeminy’. The significance depends on
the presence or absence of underlying heart disease.
Management
Treatment may not be necessary, unless the patient is highly
symptomatic, in which case p-blockers or, in some situations,
Cardiac arrhythmias • 475
Fig. 16.40 Ventricular ectopic beats. [A] There are broad, bizarre QRS complexes (arrows) with no preceding P wave in between normal sinus beats.
Their configuration varies, so these are multifocal ectopicsjjj} A simultaneous arterial pressure trace is shown. The ectopic beats result in a weaker pulse
(arrows), which may be perceived as a ‘dropped beat’.
catheter ablation can be used. There is no evidence that anti-
arrhythmic therapy improves prognosis but the discovery of very
frequent VPBs in a patient not known to have heart disease
should prompt further investigations with echocardiography
and an exercise ECG to screen for structural heart disease and
ischaemic heart disease. It is common for VPBs to occur during
the course of an acute Ml. Persistent, frequent VPBs (over 10/
hr) in patients who have survived the acute phase of Ml indicate
a poorer long-term outcome. In this situation, anti-arrhythmic
drugs do not improve and may even worsen prognosis. The
exception is p-blockers, which should be prescribed for other
reasons (p. 500). Similarly, heart failure of any cause is associated
with VPBs. While they indicate an adverse prognosis, this is not
improved by anti-arrhythmic drugs. Effective treatment of the
heart failure may suppress the ectopic beats. VPBs are also a
feature of digoxin toxicity.
|Ventricular tachycardia
Ventricular tachycardia (VT) occurs most commonly in the settings
of acute Ml, chronic coronary artery disease and cardiomyopathy.
It is associated with extensive ventricular disease, impaired left
ventricular function and ventricular aneurysm. In these settings,
VT may cause haemodynamic compromise or degenerate
into ventricular fibrillation (p. 456). VT is caused by abnormal
automaticity or triggered activity in ischaemic tissue, or by
re-entry within scarred ventricular tissue. Patients may complain
of palpitation or symptoms of low cardiac output, including
dyspnoea, lightheadedness and syncope. The ECG shows
tachycardia and broad, abnormal QRS complexes with a rate of
more than 120/min (Fig. 16.41). It may be difficult to distinguish
VT from SVT with bundle branch block or pre-excitation (WPW
syndrome) on ECG but features in favour of VT are listed in Box
16.25. A 12-lead ECG (Fig. 16.42) or electrophysiology study
(p. 454) may help establish the diagnosis. When there is doubt,
it is safer to manage the problem as VT.
Patients recovering from Ml sometimes have periods of
idioventricular rhythm (‘slow’ VT) at a rate only slightly above
the preceding sinus rate and below 120/min. These episodes
often reflect reperfusion of the infarct territory and may be a
good sign. They are usually self-limiting and asymptomatic, and
do not require treatment. Other forms of sustained VT require
treatment, often as an emergency.
Fig. 16.41 Ventricular tachycardia: fusion beat (arrow). In ventricular
tachycardia, there is independent atrial and ventricular activity. Occasionally,
a P wave is conducted to the ventricles through the A V node, producing a
normal sinus beat in the middle of the tachycardia (a capture beat); more
commonly, however, the conducted impulse fuses with an impulse from the
tachycardia (a fusion beat). This can occur only when there is atrioventricular
dissociation and is therefore diagnostic of ventricular tachycardia.
16.25 Features more in keeping with
ventricular tachycardia
• History of myocardial infarction
• Atrioventricular dissociation (pathognomonic)
• Capture/fusion beats (pathognomonic; see Fig. 16.41)
• Extreme left axis deviation
• Very broad QRS complexes (> 1 40 msecs)
• No response to carotid sinus massage or intravenous adenosine
Occasionally, VT occurs in patients with otherwise healthy hearts
(‘normal heart VT’), usually because of abnormal automaticity in
the right ventricular outflow tract or one of the fascicles of the
left bundle branch.
Management
Prompt action to restore sinus rhythm is required and should
usually be followed by prophylactic therapy. Synchronised DC
cardioversion is the treatment of choice if systolic BP is less
than 90 mmHg. If the arrhythmia is well tolerated, intravenous
amiodarone may be given as a bolus, followed by a continuous
infusion (p. 481). Intravenous lidocaine can be used but may
depress left ventricular function, causing hypotension or acute
heart failure. Hypokalaemia, hypomagnesaemia, acidosis and
hypoxia should be corrected if present.
Beta-blockers are effective at preventing VT by reducing
ventricular automaticity. Amiodarone can be added if additional
476 • CARDIOLOGY
control is needed. Class Ic anti-arrhythmic drugs should not be
used for prevention of VT in patients with coronary artery disease
or heart failure because they depress myocardial function and
can increase the likelihood of a dangerous arrhythmia. In patients
with poor left ventricular function or where VT is associated
with haemodynamic compromise, the use of an implantable
cardiac defibrillator is recommended (p. 483). Rarely, surgery
with resection of a ventricular aneurysm or catheter ablation can
be used to interrupt the arrhythmia focus or circuit in patients
with VT associated with a myocardial infarct scar. The treatment
of choice for VT occurring in a normal heart is catheter ablation,
which often can be curative.
aVR V1 V4
Torsades de pointes
This form of polymorphic VT is a complication of prolonged
ventricular repolarisation (prolonged QT interval). The ECG shows
rapid irregular complexes that seem to twist around the baseline
as the mean QRS axis changes (Fig. 16.43). The arrhythmia
is usually non-sustained and repetitive, but may degenerate
into ventricular fibrillation. During periods of sinus rhythm, the
ECG will usually show a prolonged QT interval (>0.44 sec in
men, >0.46 sec in women when corrected to a heart rate
of 60/m in).
Some of the common causes are listed in Box 16.26. The
arrhythmia is more common in women and is often triggered by
a combination of factors, such as administration of QT-prolonging
medications and hypokalaemia. The congenital long QT syndromes
are a family of genetic disorders that are characterised by mutations
in genes that code for cardiac sodium or potassium channels.
Long QT syndrome subtypes have different triggers, which are
important when counselling patients. Adrenergic stimulation
through vigorous exercise is a common trigger in long QT
type 1 , and a sudden noise may trigger arrhythmias in long QT
type 2. Arrhythmias are more common during sleep in type 3.
NT NTNTN\
t t t t t t t
Rhythm strip
Fig. 16.42 Ventricular tachycardia: 12-lead ECG. There are typically
very broad QRS complexes and marked left axis deviation. There is also
atrioventricular dissociation; some P waves are visible and others are
buried in the QRS complexes (arrows).
Management
Intravenous magnesium (8 mmol over 15 mins, then 72 mmol
over 24 hrs) should be given in all cases. If this is ineffective,
16.26 Causes of long QT interval and torsades
de pointes
Bradycardia
• Bradycardia compounds other factors that cause torsades de
pointes
Electrolyte disturbance
• Hypokalaemia
• Hypomagnesaemia
• Hypocalcaemia
Drugs*
• Disopyramide, flecainide and other class la, Ic anti-arrhythmic
drugs (p. 479)
• Sotalol, amiodarone and other class III anti-arrhythmic drugs
• Amitriptyline and other tricyclic antidepressants
• Chlorpromazine and other phenothiazines
• Erythromycin and other macrolides
Congenital syndromes
• Long QT1: gene affected KCNQI : K+ channel, 30-35%
• Long QT2: gene affected HERG : K+ channel, 25-30%
• Long QT3: gene affected SCNSA : Na+ channel, 5-10%
• Long QT4-12: rare; various genes implicated
*Many other drugs that are not shown can be associated with prolongation of the
QT interval. See www.crediblemeds.org for a complete list.
Fig. 16.43 Torsades de pointes. A bradycardia with a long QT interval is followed by polymorphic ventricular tachycardia that is triggered by an R on T
ectopic.
Cardiac arrhythmias • 477
atrial pacing should be tried, since it can suppress the arrhythmia
through rate-dependent shortening of the QT interval. Intravenous
isoprenaline is a reasonable alternative to pacing but should
be avoided in patients with the congenital long QT syndromes.
Once initial control has been achieved, efforts should be made to
identify and treat the underlying cause or stop medications that
predispose to the arrhythmia. If the underlying cause cannot be
corrected or the arrhythmia is the result of an inherited syndrome,
then long-term pharmacological therapy may be necessary.
Beta-blockers are effective at preventing syncope in patients
with congenital long QT syndrome. Some patients, particularly
those with extreme QT interval prolongation (>500 msecs)
or certain high-risk genotypes, should be considered for an
implantable defibrillator. Left stellate ganglion block may be of
value in patients with resistant arrhythmias.
Brugada syndrome is a related genetic disorder that may
present with polymorphic VT or sudden death. It is characterised
by a defect in sodium channel function and an abnormal ECG
(right bundle branch block and ST elevation in Vi and V2 but not
usually prolongation of the QT interval). The only known effective
treatment is an implantable defibrillator.
Atrioventricular block
This usually occurs as the result of disease affecting the AV
node. AV block can be intermittent, however, and may become
evident only when the conducting tissue is stressed by a rapid
atrial rate. Reflecting this fact, atrial tachyarrhythmias are often
associated with AV block (see Fig. 1 6.37). Episodes of ventricular
asystole may also complicate complete heart block or Mobitz
type II second-degree AV block. Several types of AV block are
recognised.
First-degree atrioventricular block
In this condition, AV conduction is delayed and so the PR interval
is prolonged (>0.20 sec; Fig. 16.44). It rarely causes symptoms
and does not usually require treatment.
Second-degree atrioventricular block
Here dropped beats occur because some impulses from the atria
fail to conduct to the ventricles. Two subtypes are recognised.
In Mobitz type I second-degree AV block (Fig. 16.45), there is
progressive lengthening of successive PR intervals, culminating
in a dropped beat. The cycle then repeats itself. This is known
as the Wenckebach phenomenon and is usually due to impaired
conduction in the AV node itself. The phenomenon may be
physiological and is sometimes observed at rest or during sleep
in athletic young adults with high vagal tone.
In Mobitz type II second-degree AV block (Fig. 1 6.46), the PR
interval of the conducted impulses remains constant but some
P waves are not conducted. This is usually caused by disease
of the His-Purkinje system and carries a risk of asystole.
In 2 : 1 AV block (Fig. 1 6.47), alternate P waves are conducted,
so it is impossible to distinguish between Mobitz type I and
type II block.
Third-degree atrioventricular block
In third-degree AV block, conduction fails completely and the
atria and ventricles beat independently. This is known as AV
dissociation, as shown in Fig. 16.48. Ventricular activity is
maintained by an escape rhythm arising in the AV node or
bundle of His (narrow QRS complexes) or the distal Purkinje
tissues (broad QRS complexes). Distal escape rhythms tend
to be slower and less reliable. Complete AV block (Box 1 6.27)
produces a slow (25-50/min), regular pulse that does not vary
with exercise, except in the case of congenital complete AV
block. There is usually a compensatory increase in stroke volume,
producing a large-volume pulse. Cannon waves may be visible
in the neck and the intensity of the first heart sound varies due
to the loss of AV synchrony.
Clinical features
The typical presentation is with recurrent syncope or ‘Stokes-
Adams’ attacks. These episodes are characterised by sudden
Fig. 16.44 First-degree atrioventricular block. The PR interval is
prolonged and measures 0.26 sec.
Fig. 16.45 Second-degree atrioventricular block (Mobitz type I - the Wenckebach phenomenon). The PR interval progressively increases until a P
wave is not conducted. The cycle then repeats itself. In this example, conduction is at a ratio of 4:3, leading to groupings of three ventricular complexes in
a row.
Fig. 16.46 Second-degree atrioventricular block (Mobitz type II). The PR interval of conducted beats is normal but some P waves are not conducted.
The constant PR interval distinguishes this from the Wenckebach phenomenon.
478 • CARDIOLOGY
Fig. 16.47 Second-degree atrioventricular block with fixed 2:1
block. Alternate P waves are not conducted. This may be due to Mobitz
type I or II block.
Fig. 16.48 Complete (third-degree) atrioventricular block. There is
complete dissociation of atrial and ventricular complexes. The atrial rate is
80/min and the ventricular rate is 38/min.
i
16.27 Causes of complete atrioventricular block
Congenital
Acquired
• Idiopathic fibrosis
• Trauma
• Myocardial infarction/
• Drugs:
ischaemia
Digoxin
• Inflammation:
p-blockers
Infective endocarditis
Calcium antagonists
Sarcoidosis
Chagas’ disease
Patients with symptomatic bradyarrhythmias associated with
AV block should be treated with a permanent pacemaker.
Asymptomatic first-degree or Mobitz type I second-degree AV
block (Wenckebach phenomenon) does not require treatment but
may be an indication of underlying heart disease. A permanent
pacemaker is usually indicated in patients with asymptomatic
Mobitz type II second-degree AV block or third-degree AV heart
block because of the risk of asystole and sudden death. Pacing
improves prognosis.
Bundle branch block
Damage to the right or left bundle branch of the conducting system
can occur as a result of many pathologies, including ischaemic
heart disease, hypertensive heart disease and cardiomyopathy.
However, right bundle branch block (RBBB) can occur as a
normal variant in healthy individuals (Box 16.28). In left bundle
branch block (LBBB) and RBBB, depolarisation proceeds through
a slow myocardial route in the affected ventricle rather than
through the rapidly conducting Purkinje tissues that constitute
the bundle branches. This causes delayed conduction into the
LV or RV, broadens the QRS complex (>0.1 2 sec) and produces
characteristic alterations in QRS morphology (Figs 1 6.49 and
1 16.28 Common causes of bundle branch block
Right bundle branch block
• Normal variant
• Congenital heart disease, e.g.
• Right ventricular hypertrophy
atrial septal defect
or strain, e.g. pulmonary
embolism
• Coronary artery disease
Left bundle branch block
• Coronary artery disease
• Aortic valve disease
• Hypertension
• Cardiomyopathy
loss of consciousness that occurs without warning and results
in collapse. A brief anoxic seizure (due to cerebral ischaemia)
may occur if there is prolonged asystole. There is pallor and a
death-like appearance during the attack, but when the heart
starts beating again there is a characteristic flush. In distinction to
epilepsy, recovery is rapid. Sinoatrial disease and neurocardiogenic
syncope (p. 181) may cause similar symptoms.
Management
This depends on the clinical circumstances. Acute inferior Ml
is often complicated by transient AV block because the right
coronary artery (RCA) supplies the AV node. There is usually
a reliable escape rhythm and, if the patient remains well, no
treatment is required. Symptomatic second- or third-degree AV
block may respond to atropine (0.6 mg IV, repeated as necessary)
or, if this fails, a temporary pacemaker. In most cases, the AV
block will resolve within 7-10 days.
Second- or third-degree AV heart block complicating acute
anterior Ml indicates extensive ventricular damage involving
both bundle branches and carries a poor prognosis. Asystole
may ensue and a temporary pacemaker should be inserted
promptly. If the patient presents with asystole, intravenous
atropine (3 mg) or intravenous isoprenaline (2 mg in 500 ml_
5% dextrose, infused at 1 0-60 mL/hr) may help to maintain the
circulation until a temporary pacing electrode can be inserted.
Temporary pacing can provide effective rhythm support in the
short term.
Fig. 16.49 Right bundle branch block. Note the wide QRS complexes with
‘M’-shaped configuration in leads ^ and V2 and a wide S wave in lead I.
Principles of management of cardiac arrhythmias • 479
(3-blockers
Digoxin
Verapamil
Diltiazem
Fig. 16.51 Classification of anti-arrhythmic drugs by site of action.
Fig. 16.50 Left bundle branch block. Note the wide QRS complexes
with loss of the Q wave or septal vector in lead I and ‘M’-shaped QRS
complexes in V5 and V6.
1 6.50). Damage to the left bundle can also occur after it divides
into anterior and posterior fascicles, when it is called hemiblock.
In this case, the QRS complex is not broadened but the direction
of ventricular depolarisation is changed, causing left axis deviation
in left anterior hemiblock and right axis deviation in left posterior
hemiblock (see Fig. 16.7, p. 449). The combination of RBBB
and left anterior or posterior hemiblock is known as bifascicular
block. LBBB usually signifies important underlying heart disease
and also causes ventricular incoordination, which may aggravate
symptoms in patients with heart failure. This can be treated in
selected patients by cardiac resynchronisation therapy (p. 484).
Principles of management
of cardiac arrhythmias
16.29 Classification of anti-arrhythmic drugs by
effect on the intracellular action potential
Class I: membrane-stabilising agents (sodium channel blockers)
(a) Block Na+ channel and prolong action potential
• Quinidine, disopyramide
(b) Block Na+ channel and shorten action potential
• Lidocaine, mexiletine
(c) Block Na+ channel with no effect on action potential
• Flecainide, propafenone
Class II: (3-adrenoceptor antagonists (p-blockers)
• Atenolol, bisoprolol, metoprolol
Class III: drugs whose main effect is to prolong the action potential
• Amiodarone, dronedarone, sotalol
Class IV: slow calcium channel blockers
• Verapamil, diltiazem
*Some drugs such as digoxin, ivabradine and adenosine have no place in this
classification, while others such as amiodarone have properties in more than
one class.
Cardiac arrhythmias can be managed with either anti-arrhythmic
drug therapy or external devices that depolarise the heart by
passing an electric current through it. These strategies are
relevant across a range of indications and are discussed in
more detail here.
Anti-arrhythmic drugs
Traditionally, the Vaughan Williams system has been used to
categorise anti-arrhythmic drugs based on their effects on the
action potential. More recently, increased understanding of the
mechanisms of action has allowed further subclassification,
based on the cardiac ion channels and receptors on which
they act (Box 16.29 and Fig. 16.51). The individual agents,
dosages and most common side-effects are summarised in
Box 1 6.30 and the general principles of use are summarised in
Box 16.31.
| Class I drugs
Class I drugs act principally by suppressing excitability and
slowing conduction in atrial or ventricular muscle. They block
sodium channels, of which there are several types in cardiac
tissue. These drugs should generally be avoided in patients with
heart failure because they depress myocardial function, and
class la and Ic drugs are often pro-arrhythmic.
Class la drugs
These prolong cardiac action potential duration and increase
the tissue refractory period. They are used to prevent both atrial
and ventricular arrhythmias.
Disopyramide
This is an effective drug but causes anticholinergic side-effects,
such as urinary retention, and can precipitate glaucoma. It can
480 • CARDIOLOGY
16.30 Uses, dosages and side-effects of anti-arrhythmic drugs
Drug
Main uses
Route
Dose (adult)
Important side-effects
Class 1
Disopyramide
Prevention and treatment of atrial
IV
2 mg/kg at 30 mg/min, then 0.4 mg/kg/hr
Myocardial depression, hypotension,
and ventricular tachyarrhythmias
Oral
(max 800 mg/day)
300-800 mg daily in divided dosage
dry mouth, urinary retention
Lidocaine
Treatment and short-term
IV
Bolus 50-100 mg, 4 mg/min for 30 mins,
Myocardial depression, delirium,
prevention of VT and VF
then 2 mg/min for 2 hrs, then 1 mg/min for
24 hrs
convulsions
Mexiletine
Prevention and treatment of
IV
Loading dose: 100-250 mg at 25 mg/min,
Myocardial depression,
ventricular tachyarrhythmias
then 250 mg in 1 hr, then 250 mg in 2 hrs
gastrointestinal irritation, delirium,
Maintenance therapy: 0.5 mg/min
dizziness, tremor, nystagmus, ataxia
Oral
200-250 mg 3 times daily
Flecainide
Prevention and treatment of atrial
IV
2 mg/kg over 10 mins, then if required
Myocardial depression, dizziness
and ventricular tachyarrhythmias
Oral
1.5 mg/kg/hr for 1 hr, then 0.1 mg/kg/hr
50-100 mg twice daily
Propafenone
Prevention and treatment of atrial
Oral
150 mg 3 times daily for 1 week, then
Myocardial depression, dizziness
and ventricular tachyarrhythmias
300 mg twice daily
Class II
Atenolol
Treatment and prevention of SVT
IV
2.5 mg at 1 mg/min, repeated at 5-min
intervals (max 10 mg)
Myocardial depression, bradycardia,
and AF, prevention of VEs and
Oral
25-100 mg daily
bronchospasm, fatigue, depression,
Bisoprolol
exercise-induced VF
Oral
2.5-10 mg daily
nightmares, cold peripheries
Metoprolol -
IV
5 mg over 2 mins to a maximum of 1 5 mg
Class III
Amiodarone
Serious or resistant atrial and
IV
5 mg/kg over 20-120 mins, then up to
Photosensitivity skin discoloration,
ventricular tachyarrhythmias
1 5 mg/kg/24 hrs
corneal deposits, thyroid
Oral
Initially 600-1200 mg/day, then
dysfunction, alveolitis, nausea and
100-400 mg daily
vomiting, hepatotoxicity, peripheral
neuropathy, torsades de pointes;
potentiates digoxin and warfarin
Dronedarone
Paroxysmal atrial fibrillation
Oral
400 mg twice daily
Renal and hepatic dysfunction
requiring regular blood monitoring
Sotalol*
AF, rarely ventricular
IV
1 0-20 mg slowly
Can cause torsades de pointes
tachyarrhythmias
Oral
40-160 mg twice daily
Class IV
Verapamil
Teatment of SVT, control of AF
IV
5-1 0 mg over 30 secs
Myocardial depression, hypotension.
Oral
40-120 mg 3 times daily or 240 mg SR daily
bradycardia, constipation
Other
Atropine
Treatment of bradycardia and/or
IV
0.6-3 mg
Dry mouth, thirst, blurred vision,
hypotension due to vagal
overactivity
atrial and ventricular extrasystoles
Adenosine
Teatment of SVT, aid to diagnosis
IV
3 mg over 2 secs, followed if necessary by 6
Flushing, dyspnoea, chest pain
in unidentified tachycardia
mg, then 12 mg at intervals of 1-2 mins
Avoid in asthma
Digoxin
Treatment and prevention of SVT,
IV
Loading dose: 0.5-1 mg (total), 0.5 mg over
Gastrointestinal disturbance,
rate control of AF
30 mins, then 0.25-0.5 mg after 4-6 hrs
xanthopasia, arrhythmias
Oral
0.5 mg repeated after 6 hrs, then
0.0625-0.25 mg daily
See Box 16.33
*Sotalol also has class II activity as a (3-blocker.
(AF = atrial fibrillation; IV = intravenous; SR = sustained-release formulation; SVT = supraventricular tachycardia; VE = ventricular ectopic; VF = ventricular fibrillation;
VT = ventricular tachycardia)
depress myocardial function and should be avoided in cardiac
failure.
Quinidine
Now rarely used, quinidine increases mortality and causes
gastrointestinal upset.
Class lb drugs
These shorten the action potential and tissue refractory period.
They act on channels found predominantly in ventricular
myocardium and so are used to treat or prevent VT and VF.
Lidocaine
This must be given intravenously and has a very short plasma
half-life.
Mexiletine
This can be given intravenously or orally but has many side-effects.
Class Ic drugs
These affect the slope of the action potential without altering
its duration or refractory period. They are used mainly for
prophylaxis of AF but are effective in prophylaxis and treatment
Principles of management of cardiac arrhythmias • 481
i
of supraventricular or ventricular arrhythmias. They are useful for
WPW syndrome because they block conduction in accessory
pathways. They should not be used in patients with previous
Ml because they increase the risk of arrhythmia in this setting.
Flecainide
This is effective for prevention of AF, and an intravenous infusion
may be used for pharmacological cardioversion of AF of less
than 24 hours’ duration. Since flecainide can cause slow atrial
flutter with a paradoxically rapid ventricular rate, it should be
prescribed along with an AV node-blocking drug such as a
p-blocker to control the ventricular rate.
Propafenone
This also has some (3-blocker (class II) properties. Important
interactions with digoxin, warfarin and cimetidine have been
described.
|j!lass II drugs
This group comprises the |3-adrenoceptor antagonists ((3-blockers).
These agents reduce the rate of SA node depolarisation and cause
relative block in the AV node, making them useful for rate control
in atrial flutter and AF. They can be used to prevent VT and SVT.
They reduce myocardial excitability and the risk of arrhythmic
death in patients with coronary artery disease and heart failure.
Non-selective (3-blockers
These act on both (31 and (32 receptors. Beta2-blockade causes side-
effects, such as bronchospasm and peripheral vasoconstriction.
Propranolol is non-selective and is subject to extensive first-
pass metabolism in the liver. The effective oral dose is therefore
unpredictable and must be titrated after treatment is started with a
small dose. Other non-selective drugs include nadolol and carvedilol.
Cardioselective (3-blockers
These act mainly on myocardial receptors and are relatively
well tolerated. Bisoprolol and metoprolol are examples of
cardioselective (3-blockers.
Sotalol
This is a racemic mixture of two isomers with non-selective
(3-blocker (mainly l-sotalol) and class III (mainly d-sotalol) activity.
It may cause torsades de pointes.
Class III drugs
Class III drugs act by prolonging the plateau phase of the action
potential, thus lengthening the refractory period. These drugs are
very effective at preventing atrial and ventricular tachyarrhythmias.
They cause QT interval prolongation and can predispose to
torsades de pointes and VT, especially in patients with other
predisposing risk factors (see Box 16.26). Disopyramide and
sotalol have some class III activity but the main drug in this class
is amiodarone, as discussed below.
Amiodarone
While amiodarone is primarily considered a class III drug, it also
has class I, II and IV activity. It is probably the most effective
drug currently available for controlling paroxysmal AF. It is also
used to prevent episodes of recurrent VT, particularly in patients
with poor left ventricular function or those with implantable
defibrillators (to prevent unnecessary DC shocks). Amiodarone
has a very long tissue half-life (25-110 days). An intravenous
or oral loading regime is often used to achieve therapeutic
tissue concentrations rapidly. The drug’s effects may last for
weeks or months after treatment has been stopped. Side-
effects are common (up to one-third of patients), numerous
and potentially serious. Drug interactions are also common
(see Box 16.30).
Dronedarone
Dronedarone is related to amiodarone but has a short tissue
half-life and fewer side-effects. It has recently been shown to
be effective at preventing episodes of atrial flutter and AF. It
is contraindicated in patients with permanent AF, or if there is
heart failure or left ventricular impairment, because it increases
mortality. Regular liver function test monitoring is required.
| Class IV drugs
These block the ‘slow calcium channel’, which is important for
impulse generation and conduction in atrial and nodal tissue,
although it is also present in ventricular muscle. Their main
indications are prevention of SVT (by blocking the AV node) and
rate control in patients with AF.
Verapamil
This is the most widely used drug in this class. Intravenous
verapamil may cause profound bradycardia or hypotension, and
should not be used in conjunction with (3-blockers.
Diltiazem
This has similar properties to verapamil.
Other anti-arrhythmic drugs
Atropine sulphate
Atropine is a muscarinic receptor antagonist that increases
the sinus rate and SA and AV conduction. It is the treatment
of choice for severe bradycardia or hypotension due to vagal
over-activity. It is used for initial management of symptomatic
bradyarrhythmias complicating inferior Ml, and in cardiac arrest
due to asystole. The usual dose is 0.6 mg IV, repeated if necessary
16.31 Anti-arrhythmic drugs: principles of use
Anti-arrhythmic drugs are potentially toxic and should be used carefully
according to the following principles:
• Many arrhythmias are benign and do not require specific treatment
• Precipitating or causal factors should be corrected if possible:
Alcohol excess
Caffeine consumption
Myocardial ischaemia
Hyperthyroidism
Acidosis
Hypokalaemia
Hypomagnesaemia
• If drug therapy is required, it is best to use as few drugs as
possible
• In difficult cases, programmed electrical stimulation
(electrophysiological study) may help to identify the optimum therapy
• When managing life-threatening arrhythmias, it is essential to
ensure that prophylactic treatment is effective. Ambulatory
monitoring and exercise testing may be of value
• Patients on long-term anti-arrhythmic drugs should be reviewed
regularly and attempts made to withdraw therapy if the factors that
precipitated the arrhythmias are no longer operative
• For patients with recurrent supraventricular tachycardia, radiofrequency
ablation is often preferable to long-term drug therapy
482 • CARDIOLOGY
i
16.32 Response to intravenous adenosine
Arrhythmia
Response
Supraventricular tachycardia
Termination
Atrial fibrillation, atrial flutter,
atrial tachycardia
Transient atrioventricular block
Ventricular tachycardia
No effect
16.33 Digoxin toxicity
Extracardiac manifestations
• Anorexia, nausea, vomiting
• Altered colour vision
• Diarrhoea
(xanthopsia)
Cardiac manifestations
• Bradycardia
• Atrial tachycardia (with
• Multiple ventricular ectopics
variable block)
• Ventricular bigeminy (alternate
• Ventricular tachycardia
ventricular ectopics)
• Ventricular fibrillation
to a maximum of 3 mg. Repeat dosing may be necessary
because the drug disappears rapidly from the circulation after
parenteral administration. Side-effects are listed in Box 16.30.
Adenosine
This works by binding to A1 receptors in conducting tissue,
producing a transient AV block lasting a few seconds. It is used
to terminate SVTs when the AV node is part of the re-entry circuit,
or to help establish the diagnosis in difficult arrhythmias, such as
atrial flutter with 2 : 1 AV block (see Fig. 1 6.35) or broad-complex
tachycardia (Boxes 16.30 and 16.32). Adenosine is given as an
intravenous bolus, initially 3 mg over 2 secs (see Box 16.30). If
there is no response after 1-2 minutes, 6 mg should be given; if
necessary, after another 1-2 minutes the maximum dose of 12 mg
may be given. Patients should be warned to expect short-lived
and sometimes distressing flushing, breathlessness and chest
pain. Adenosine can cause bronchospasm and should be avoided
in patients with asthma; its effects are greatly potentiated by
dipyridamole and inhibited by theophylline and other xanthines.
Digoxin
Digoxin is a glycoside purified from the European foxglove,
Digitalis lanata, which slows conduction and prolongs the
refractory period in the AV node. This effect helps to control
the ventricular rate in AF and may interrupt SVTs involving the
AV node. Digoxin also shortens refractory periods and enhances
excitability and conduction in other parts of the heart, including
accessory conduction pathways. It may therefore increase atrial
and ventricular ectopic activity and can lead to more complex
atrial and ventricular tachyarrhythmias. Digoxin is largely excreted
by the kidneys, and the maintenance dose (see Box 16.30)
should be reduced in children, older people and those with
renal impairment. It is widely distributed and has a long tissue
half-life (36 hours), so that effects may persist for several days.
Measurement of plasma digoxin concentration helps identify
digoxin toxicity or under-treatment (Box 16.33).
Non-pharmacological treatments
A variety of non-pharmacological treatments are available for
the treatment of arrhythmias. These include the use of electrical
devices that work by passing an electric current through the heart,
and catheter- based strategies that disrupt abnormal conduction
tissues responsible for the generation of arrhythmias.
1) Electrical cardioversion
Electrical cardioversion, also known as direct current (DC)
cardioversion, is useful for terminating an organised rhythm, such
as AF or VT. The electric current interrupts the arrhythmia and
produces a brief period of asystole, which is usually followed by
the resumption of sinus rhythm. Cardioversion is usually carried
out as an elective procedure under general anaesthesia. The
electric shock is delivered immediately after the R wave because,
if it is applied during ventricular repolarisation (on the T wave), it
may provoke VF. High-energy shocks may cause chest wall pain
post-procedure, so, if there is no urgency, it is appropriate to
begin with a lower-amplitude shock of about 50 joules initially,
going on to larger shocks if necessary.
Defibrillation
Defibrillators deliver a DC, high-energy, short-duration shock
via two large electrodes or paddles coated with conducting jelly
or a gel pad, positioned over the upper right sternal edge and
the apex. Defibrillators are primarily used in the management of
cardiac arrest due to VF and deliver an unsynchronised shock,
since the precise timing of the discharge is not important in this
situation. Modern units deliver a biphasic shock, during which
the shock polarity is reversed mid-shock. This reduces the total
shock energy required to depolarise the heart. In VF and other
emergencies, the energy of the first and second shocks should
be 1 50 joules and thereafter up to 200 joules; there is no need
for an anaesthetic, as the patient is unconscious.
Temporary pacemakers
Temporary pacing involves delivery of an electrical impulse
into the heart to initiate tissue depolarisation and to trigger
cardiac contraction. This is achieved by inserting a bipolar pacing
electrode through the internal jugular, subclavian or femoral
vein and positioning it at the apex of the RV, using fluoroscopic
imaging. The electrode is connected to an external pacemaker
with an adjustable energy output and pacing rate. The ECG of
right ventricular pacing is characterised by regular broad QRS
complexes with a left bundle branch block pattern. Each complex
is immediately preceded by a ‘pacing spike’ (Fig. 16.52). Nearly
all pulse generators are used in the ‘demand’ mode, so that
the pacemaker will operate only if the heart rate falls below a
preset level. Occasionally, temporary atrial or dual-chamber
pacing (see below) is used.
Temporary pacing is indicated in the management of transient
AV block and other arrhythmias complicating acute Ml or cardiac
surgery, to maintain the rhythm in other situations of reversible
bradycardia (such as metabolic disturbance or drug overdose),
or as a bridge to permanent pacing. Complications include
pneumothorax, brachial plexus or subclavian artery injury, local
infection or sepsis (usually with Staphylococcus aureus), and
pericarditis. Failure of the system may be due to lead displacement
or a progressive increase in the threshold (exit block) caused
by tissue oedema. Complication rates increase with time and
so a temporary pacing system should ideally not be used for
more than 7 days.
Transcutaneous pacing is administered by delivering an
electrical stimulus through two large adhesive gel pad electrodes
Principles of management of cardiac arrhythmias • 483
Fig. 16.52 Dual-chamber pacing. The first three beats show atrial and
ventricular pacing with narrow pacing spikes in front of each P wave and
QRS complex. The last four beats show spontaneous P waves with a
different morphology and no pacing spike; the pacemaker senses or tracks
these P waves and maintains atrioventricular synchrony by pacing the
ventricle after an appropriate interval.
placed over the apex and upper right sternal edge, or over the
anterior and posterior chest. It is easy and quick to set up,
but causes discomfort because it induces forceful pectoral
and intercostal muscle contraction. Modern external cardiac
defibrillators often incorporate a transcutaneous pacing system
that can be used during an emergency until transvenous pacing
is established.
Permanent pacemakers
Permanent pacemakers are small, flat, metal devices that are
implanted under the skin, usually in the pectoral area. They contain
a battery, a pulse generator, and programmable electronics
that allow adjustment of pacing and memory functions. Pacing
electrodes (leads) can be placed via the subclavian or cephalic
veins into the RV (usually at the apex), the right atrial appendage
or, to maintain AV synchrony, both.
Permanent pacemakers are controlled using an external
programmer through a wireless telemetry system, allowing rate,
output, timing and other parameters to be adjusted. This allows
the device settings to be tailored to the patient’s needs. Aside
from their therapeutic role, pacemakers store useful diagnostic
data about the patient’s heart rate trends and the occurrence
of tachyarrhythmias, such as VT.
Single-chamber atrial pacing is indicated in patients with SA
disease without AV block and also in patients with continuous AF
and bradycardia. Here the pacemaker acts as an external sinus
node. Dual-chamber pacing is most often used in patients with
second- or third-degree AV block. Here, the atrial electrode is
used to detect spontaneous atrial activity and trigger ventricular
pacing (Fig. 1 6.52), thereby preserving AV synchrony and allowing
the ventricular rate to increase, together with the sinus node rate,
during exercise and other forms of stress. Dual-chamber pacing
has many advantages over ventricular pacing, including superior
haemodynamics and better effort tolerance; a lower prevalence
of atrial arrhythmias in patients with SA disease; and avoidance
of ‘pacemaker syndrome’, in which a fall in BP and dizziness
occur due to loss of AV synchrony.
A code is used to signify the pacing mode (Box 16.34). For
example, a system that paces the atrium, senses the atrium and
is inhibited if it senses spontaneous activity is designated AAI.
Most dual-chamber pacemakers are programmed to a mode
termed DDD; in this case, ventricular pacing is triggered by a
sensed sinus P wave and inhibited by a sensed spontaneous
QRS complex. A fourth letter, ‘R’, is added if the pacemaker
has a rate response function. For example, the letters AAIR
indicate an atrial demand pacemaker with a rate response
function. Rate-responsive pacemakers are used in patients with
chronotropic incompetence, who are unable to increase their heart
16.34 International generic pacemaker code
Chamber paced
Chamber sensed
Response to sensing
0 = none
0 = none
0 = none
A = atrium
A = atrium
T = triggered
V = ventricle
V = ventricle
1 = inhibited
D = both
D = both
D = both
rate during exercise. These devices have a sensor that triggers
an increase in heart rate in response to movement or increased
respiratory rate. The sensitivity of the sensor is programmable,
as is the maximum paced heart rate.
Early complications of permanent pacing include pneumothorax,
cardiac tamponade, infection and lead displacement. Late
complications include infection (which usually necessitates
removing the pacing system), erosion of the generator or lead,
chronic pain related to the implant site, and lead fracture due
to mechanical fatigue.
| Implantable cardiac defibrillators
In addition to the functions of a permanent pacemaker, implantable
cardiac defibrillators (ICDs) can also detect and terminate life-
threatening ventricular tachyarrhythmias. ICDs are larger than
pacemakers mainly because of the need for a large battery and
capacitor to enable cardioversion or defibrillation. ICD leads
are similar to pacing leads but have one or two shock coils
along the length of the lead, used for delivering defibrillation.
ICDs treat ventricular tachyarrhythmias using overdrive pacing,
cardioversion or defibrillation. They are implanted in a similar
manner to pacemakers and carry a similar risk of complications.
In addition, patients can be prone to psychological problems and
anxiety, particularly if they have experienced repeated shocks
from their device.
The evidence- based indications for ICD implantation are shown
in Box 1 6.35. These can be divided into secondary prevention
indications, when patients have already had a potentially life-
threatening ventricular arrhyth mia, and primary prevention
indications, when patients are considered to be at significant future
risk of arrhythmic death. A common primary prevention indication
is in patients with inherited conditions associated with a high risk
of sudden cardiac death, such as long QT syndrome (p. 476),
hypertrophic cardiomyopathy (p. 539) and arrhythmogenic right
ventricular dysplasia (p. 540). Treatment with ICDs is expensive
16.35 Key indications for implantable cardiac
defibrillator therapy
Primary prevention
• After myocardial infarction, if the left ventricular ejection fraction is
<30%
• Mild to moderate symptomatic heart failure on optimal drug therapy,
with left ventricular ejection fraction <35%
• Some patients with inherited cardiac conditions (long QT syndrome,
cardiomyopathy)
Secondary prevention
• Survivors of ventricular fibrillation or ventricular tachycardia cardiac
arrest not having a transient or reversible cause
• Ventricular tachycardia with haemodynamic compromise or
significant left ventricular impairment (left ventricular ejection
fraction <35%)
484 • CARDIOLOGY
and so the indications for which the devices are routinely implanted
depend on the health-care resources available.
Cardiac resynchronisation therapy
Cardiac resynchronisation therapy (CRT) is a useful treatment
for selected patients with heart failure, in whom cardiac function
is impaired by the presence of left bundle branch block. This
conduction defect is associated with poorly coordinated left
ventricular contraction that can aggravate heart failure in
susceptible patients. The systems used to deliver CRT comprise
a right atrial lead, a right ventricular lead, and a third lead that
is placed via the coronary sinus into one of the veins on the
epicardial surface of the LV (see Fig. 16.30, p. 467). Simultaneous
septal and left ventricular epicardial pacing resynchronises left
ventricular contraction.
CRT improves symptoms and quality of life, and reduces
mortality in patients with moderate to severe (NYHA class III— IV)
heart failure who are in sinus rhythm, with left bundle branch
block and left ventricular ejection fraction of 35% or less. CRT
also prevents heart failure progression in similar patients with
mild (NYHA class l-ll) heart failure symptoms. These devices
are more effective in patients in sinus rhythm than in those
with AF. Most devices are also defibrillators (CRT-D) because
many patients with heart failure are predisposed to ventricular
arrhythmias. CRT pacemakers (CRT-P) are used when the focus
is palliation of symptoms rather than prolonging life.
Catheter ablation therapy
Catheter ablation therapy is the treatment of choice for patients
with SVT or atrial flutter, and is a useful treatment for some patients
with AF or ventricular arrhythmias (Fig. 1 6.53). It involves inserting
a series of catheter electrodes into the heart through the venous
system. These are used to record the activation sequence of
the heart in sinus rhythm, during tachycardia and after pacing
manoeuvres. Once the arrhythmia focus or circuit, such as an
accessory pathway in WPW syndrome, has been identified, a
catheter is used to ablate the culprit tissue. This can be done
either by using heat, which is termed radiofrequency ablation,
or by freezing, which is termed cryoablation. The procedure
takes approximately 1-4 hours and does not require a general
anaesthetic, although the patient may experience some discomfort
Fig. 16.53 Radiofrequency ablation. Ablation of the accessory
conducting pathway in Wolff— Parkinson— White syndrome (see text for
details). (A V = atrioventricular node)
during the ablation procedure. Serious complications are rare
(<1%) but include complete heart block requiring pacemaker
implantation, and cardiac tamponade. For many arrhythmias,
radiofrequency ablation is very attractive because it offers the
prospect of a lifetime cure, thereby eliminating the need for
long-term drug therapy.
The technique has revolutionised the management of many
arrhythmias and is now the treatment of choice for AVNRT and
AV re-entrant (accessory pathway) tachycardias, when it is
curative in over 90% of cases. Focal atrial tachycardias and atrial
flutter can also be treated by radiofrequency ablation, although
some patients subsequently experience episodes of AF. The
applications of the technique are expanding and it can now be
used to treat some forms of VT. Catheter ablation techniques
are also employed to prevent AF. This involves ablation at two
sites: the ostia of the pulmonary veins, from which ectopic beats
may trigger paroxysms of arrhythmia, and in the LA itself, where
re-entry circuits maintain AF, once established. This is effective at
reducing episodes of AF in around 70-80% of younger patients
with structurally normal hearts, and tends to be reserved for
patients with drug-resistant AF because the procedure carries a
risk of cardiac tamponade, and rarely stroke or death.
In patients with permanent AF and poor rate control, in whom
drugs are ineffective or are not tolerated, rate control can be
achieved by implantation of a permanent pacemaker, followed
by ablation of the AV node to induce complete AV block and
bradycardia, thus allowing the pacemaker to assume control
of the heart rate.
Coronary artery disease
Coronary artery disease (CAD) is the most common cause of
angina and acute coronary syndrome and the most common
cause of death worldwide. The World Health Organisation (WHO)
has estimated that 3.8 million men and 3.4 million women die from
cardiovascular disease (CVD) each year, and since 1990, more
people have died from CVD than any other cause. It also has a
devastating effect on quality of life. Disability-adjusted life years, a
measure of healthy years of life lost, can be used to indicate the
burden of disease rather than the resulting deaths. It has been
estimated that CAD is responsible for 10% of disability-adjusted
life years in low-income countries and 18% in high-income ones.
In the UK, 1 in 3 men and 1 in 4 women die from CAD, an
estimated 1 88 000 people have a myocardial infarct each year,
and approximately 2.3 million people are living with CAD. The
death rates from CAD in the UK are among the highest in Western
Europe (more than 70000 people) but are falling, particularly in
younger age groups; over the last 50 years, CAD mortality has
more than halved. In Eastern Europe and much of Asia, however,
the rates of CAD are rapidly rising. Occult CAD is common in
those who present with other forms of atherosclerotic vascular
disease, such as intermittent claudication or stroke, and is an
important cause of morbidity and mortality in these patients.
Pathogenesis
In the vast majority of patients, CAD is caused by atherosclerosis
(Box 1 6.36) but rarely it can occur as the result of aortitis (p. 508),
vasculitis (p. 1040) and autoimmune connective tissue diseases
(p. 1034). Atherosclerosis is a progressive inflammatory disorder
of the arterial wall that is characterised by focal lipid-rich deposits
of atheroma that remain clinically silent until they become large
enough to impair tissue perfusion, or until ulceration and disruption
Coronary artery disease • 485
of the lesion result in thrombotic occlusion or distal embolisation
of the vessel. Atherosclerosis begins early in life with deposits of
lipids in the vessel wall, which tend to occur at sites of altered
arterial shear stress, such as bifurcations, and are associated with
abnormalities of endothelial function at that site. Abnormalities of
arterial function have been detected among high-risk children and
adolescents, such as cigarette smokers and those with familial
hyperlipidaemia or hypertension. Early lesions have been found in
the arteries of victims of accidental death in the second and third
decades of life but clinical manifestations often do not appear
16.36 Coronary artery disease: clinical
manifestations and pathology
Clinical problem
Pathology
Stable angina
Ischaemia due to fixed atheromatous stenosis of
one or more coronary arteries
Unstable angina
Ischaemia caused by dynamic obstruction of a
coronary artery due to plaque rupture or erosion
with superimposed thrombosis
Myocardial
infarction
Myocardial necrosis caused by acute occlusion
of a coronary artery due to plaque rupture or
erosion with superimposed thrombosis
Heart failure
Myocardial dysfunction due to infarction or
ischaemia
Arrhythmia
Altered conduction due to ischaemia or infarction
Sudden death
Ventricular arrhythmia, asystole or massive
myocardial infarction
until the sixth, seventh or eighth decade. During evolution of an
atherosclerotic plaque, monocytes and other inflammatory cells
bind to receptors expressed by endothelial cells. Subsequently,
they migrate into the intima, and take up oxidised low-density
lipoprotein (LDL) particles by phagocytosis to become lipid-laden
macrophages or foam cells. Extracellular lipid pools appear in the
intimal space when foam cells die and release their contents (Fig.
16.54). In response to cytokines and growth factors produced
by activated macrophages, smooth muscle cells migrate from
the media of the arterial wall into the intima, and change from
a contractile to a fibroblastic phenotype, which can stabilise
the atherosclerotic lesion. If this is successful, the lipid core will
be covered by smooth muscle cells and matrix, producing a
stable atherosclerotic plaque that will remain asymptomatic until
it becomes large enough to obstruct arterial flow.
In an established atherosclerotic plaque, macrophages
mediate inflammation and smooth muscle cells promote repair.
If inflammation predominates, the plaque becomes active or
unstable and may be complicated by ulceration and thrombosis.
Cytokines, such as interleukin-1 , tumour necrosis factor-alpha,
interferon-gamma, platelet-derived growth factors and matrix
metal loproteinases, are released by activated macrophages. They
cause the intimal smooth muscle cells overlying the plaque to
become senescent and the collagen cross-links within the plaque
to degrade. This results in thinning of the protective fibrous cap,
making the lesion vulnerable to mechanical stress that ultimately
causes erosion, fissuring or rupture of the plaque surface (Fig.
1 6.54). Any breach in the integrity of the plaque will expose
its contents to blood and will trigger platelet aggregation and
Nomenclature and
main histology
Type 1 (initial) lesion
Isolated macrophage
foam cells
o
Type II (fatty streak) lesion
Mainly intracellular m |
lipid accumulation ^ JJ
Type III (intermediate) lesion
Type II changes and small In ))
extracellular lipid pools wk JJ
Type IV (atheroma) lesion
Type II changes and core i
of extracellular lipid
o
Type V (fibroatheroma) lesior
Lipid core and fibrotic layer,
or multiple lipid cores and |
fibrotic layers, or mainly
calcific, or mainly fibrotic
©
Type VI (complicated) lesion
Surface defect, i
haematoma-haemorrhage,
thrombus
©
Sequences in
progression
Main
growth
mechanism
Earliest
onset
Clinical
correlation
From
first
decade
Growth mainly
by lipid
accumulation
Clinically
silent
From
third
decade
i — 0-
Accelerated
smooth muscle
and collagen
increase
Clinically
silent
or overt
From
fourth
decade
Thrombosis,
haematoma
Fig. 16.54 The six stages of atherosclerosis. American Heart Association classification. From Stary HC, Chandler B, Dinsmore RE etal. A definition of
advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation 1995; 92:1355-1374. © 1995 American Heart
Association.
486 • CARDIOLOGY
thrombosis that extend into the atheromatous plaque and the
arterial lumen. This may cause partial or complete obstruction
at the site of the lesion or distal embolisation, resulting in
infarction or ischaemia of the affected organ. This common
mechanism underlies acute coronary syndromes, as well as
other manifestations of atherosclerotic disease such as lower
limb ischaemia (p. 502) and stroke (Ch. 26).
The number and complexity of arterial plaques increase with
age and risk factors (see below) but the rate of progression of
individual plaques is variable. There is a complex and dynamic
interaction between mechanical wall stress and atherosclerotic
lesions. Vulnerable plaques are characterised by a lipid-rich core,
a thin fibrocellular cap, speckled calcification and an increase
in inflammatory cells that release specific enzymes to degrade
matrix proteins. In contrast, stable plaques are typified by a small
lipid pool, a thick fibrous cap, heavy calcification and plentiful
collagenous cross-links. Fissuring or rupture tends to occur at
sites of maximal mechanical stress, particularly the margins of an
eccentric plaque, and may be triggered by a surge in BP, such
as during exercise or emotional stress. Surprisingly, most plaque
events are subclinical and heal spontaneously, although this may
allow thrombus to be incorporated into the lesion, producing
plaque growth and further obstruction to flow.
Atherosclerosis may induce complex changes in the media
that lead to arterial remodelling. Some arterial segments may
slowly constrict (negative remodelling), while others may gradually
enlarge (positive remodelling). These changes are important
because they may amplify or minimise the degree to which
atheroma encroaches into the arterial lumen.
Many risk factors have been identified for atherosclerosis
but the causes are incompletely understood, since unknown
factors account for up to 40% of the variation in risk from one
person to the next.
Age and sex
Age is the most powerful independent risk factor for atherosclerosis
and gender also plays a role. Pre-menopausal women have
lower rates of disease than men, although the gender difference
disappears after the menopause. Hormone replacement therapy
(HRT) is not effective in the prevention of CAD, and HRT in
post-menopausal women is associated with an increased risk
of cardiovascular events.
Genetics
Atherosclerotic CAD often runs in families and a positive family
history is common in patients with early-onset disease (age
<50 in men and <55 in women). Twin studies have shown that
a monozygotic twin of an affected individual has an eightfold
increased risk and a dizygotic twin a fourfold increased risk of
dying from CAD, compared to the general population due to
a combination of shared genetic, environmental and lifestyle
factors. The most common risk factors, such as hypertension,
hyperlipidaemia and diabetes mellitus, are inherited in a polygenic
manner.
Smoking
There is a strong relationship between cigarette smoking and
CAD, especially in younger (< 70 years) individuals, and this is
probably the most important modifiable risk factor.
Hypertension
The incidence of atherosclerosis increases as BP rises, and this
is related to systolic and diastolic BP, as well as pulse pressure.
Anti hypertensive therapy reduces cardiovascular mortality, stroke
and heart failure.
Hypercholesterolaemia
The risk of atherosclerosis rises with serum cholesterol
concentrations and lowering serum total and LDL cholesterol
concentrations reduces the risk of cardiovascular events.
Diabetes mellitus
This is a potent risk factor for all forms of atherosclerosis,
especially type 2 diabetes mellitus. It is often associated with
diffuse disease that is difficult to treat. Insulin resistance (normal
glucose homeostasis with high levels of insulin) is associated
with obesity and physical inactivity, and is also a risk factor for
CAD (p. 730). Glucose intolerance makes a major contribution
to the high incidence of ischaemic heart disease in people from
the Indian subcontinent and some other ethnic groups.
Haemostatic factors
Platelet activation and high plasma fibrinogen concentrations
are associated with an increased risk of coronary thrombosis,
whereas antiphospholipid antibodies are associated with recurrent
arterial thromboses (p. 977).
Physical activity
Regular exercise (brisk walking, cycling or swimming for
20 minutes two or three times a week) has a protective effect,
whereas inactivity roughly doubles the risk of CAD and is a
major risk factor for stroke.
Obesity
Obesity, particularly if central or truncal, is an independent
risk factor, although it is often associated with other adverse
factors such as hypertension, diabetes mellitus and physical
inactivity.
Alcohol
Excess alcohol consumption is associated with hypertension
and cerebrovascular disease.
Diet
Diets deficient in fresh fruit, vegetables and polyunsaturated fatty
acids are associated with an increased risk of cardiovascular
disease. The introduction of a Mediterranean-style diet reduces
cardiovascular events. However, dietary supplements, such as
vitamins C and E, beta-carotene, folate and fish oils, do not
reduce cardiovascular events and, in some cases, have been
associated with harm.
Personality
While certain personality traits are associated with an increased
risk of coronary disease there is no evidence to support the
popular belief that stress is a major cause of CAD.
Social deprivation
Social deprivation is strongly related to cardiovascular disease.
This may be partly due to associations with lifestyle risk
factors, such as smoking and alcohol excess, which are more
common in socially deprived individuals. Social deprivation
does appear to be an independent risk factor for cardiovascular
disease, however. Current guidelines recommend that treat¬
ment thresholds should be lowered for patients from socially
deprived areas.
Coronary artery disease • 487
The effect of risk factors can be multiplicative rather than
additive. People with a combination of risk factors are at greatest
risk and so assessment should take account of all identifiable
risk factors. It is important to distinguish between relative risk
(the proportional increase in risk) and absolute risk (the actual
chance of an event). For example, a man of 35 years with a
plasma cholesterol of 7 mmol/L (approximately 1 70 mg/dL), who
smokes 40 cigarettes a day, is much more likely to die from
coronary disease within the next decade than a non-smoking
man of the same age with a normal cholesterol, but the absolute
likelihood of his dying during this time is still small (high relative
risk, low absolute risk).
Management
Two approaches can be employed. Primary prevention aims
to introduce lifestyle changes or therapeutic interventions to
prevent CAD and other forms of atherosclerosis in the whole
population or in healthy individuals with an elevated risk of disease.
Secondary prevention involves initiating treatment in patients
who already have had an event, with the aim of reducing the
risk of subsequent events.
Primary prevention
The population-based strategy aims to modify the risk factors
of the whole population through diet and lifestyle advice, on
the basis that even a small reduction in smoking or average
cholesterol, or modification of exercise and diet will produce
worthwhile benefits (Box 16.37). Some risk factors, such as
obesity and smoking, are also associated with a higher risk of
other diseases and should be actively discouraged through public
health measures. The effectiveness of this approach has been
demonstrated by introduction of legislation to restrict smoking
in public places, which has been associated with reductions
in rates of Ml.
The targeted strategy aims to identify and treat high-risk
individuals, who usually have a combination of risk factors that
can be quantified by composite scoring systems. It is important
to consider the absolute risk of atheromatous cardiovascular
disease that an individual is facing before initiating treatment,
since this will help to determine whether the potential benefits of
intervention are likely to outweigh the expense, inconvenience and
possible side-effects of treatment. For example, a 65-year-old
man with an average BP of 150/90 mmHg, who smokes and
has diabetes mellitus with a totahhigh-density lipoprotein (HDL)
cholesterol ratio of 8, has a 10-year risk of Ml or stroke of
56%. Conversely, a 55-year-old woman who has an identical
BP, is a non-smoker, does not have diabetes mellitus, and has
a total: HDL cholesterol ratio of 6 has a much better outlook,
with a 10-year coronary Ml or stroke risk of 5.7%. Lowering
cholesterol will reduce the risk in both of these individuals by
30% and lowering BP will produce a further 20% reduction.
In combination, both strategies would reduce the risk of an
event from 56% to 25% in the male patient and from 5.7%
to 2.5% in the female patient. Thresholds for treatment vary
16.37 Population-based strategies to prevent
coronary disease
• Do not smoke
• Take regular exercise (minimum of 20 mins, three times per week)
• Maintain an ‘ideal’ body weight
• Eat a mixed diet rich in fresh fruit and vegetables
• Aim to get no more than 10% of energy intake from saturated fat
in different countries. In the UK and North America, current
guidelines recommend initiation of cholesterol and BP-lowering
therapies in individuals with a 10-year cardiovascular risk
of 7.5-10%.
Secondary prevention
This involves targeting interventions at individuals who already
have evidence of cardiovascular disease. Patients who recover
from a clinical event such as an Ml are usually keen to help
themselves and are particularly receptive to lifestyle advice,
such as dietary modification and smoking cessation. Additional
interventions that should be introduced in patients with angina
pectoris or an acute coronary syndrome are discussed in more
detail below.
Angina pectoris
Angina pectoris is a symptom complex caused by transient
myocardial ischaemia, which occurs whenever there is an
imbalance between myocardial oxygen supply and demand
(Box 16.38).
Pathogenesis
Atherosclerosis is by far the most common cause of angina
pectoris. Angina may also occur in aortic valve disease and
hypertrophic cardiomyopathy, and when the coronary arteries
are involved with vasculitis or aortitis. The underlying mechanisms
and risk factors for atherosclerosis have already been discussed.
Approximately 10% of patients who report stable angina on
effort have normal coronary arteries on angiography. The main
causes are discussed in more detail below.
Coronary artery spasm
Angina may result from vasospasm of the coronary arteries. This
may coexist with atherosclerosis, especially in unstable angina
(see below), but may occur as an isolated phenomenon in less
than 1 % of cases, in patients with normal coronary arteries on
angiography. This is sometimes known as variant angina; when
it is accompanied by transient ST elevation on the ECG, it is
termed Prinzmetal’s angina.
Syndrome X
The constellation of typical angina on effort, objective evidence
of myocardial ischaemia on stress testing, and normal coronary
arteries on angiography is sometimes known as syndrome X.
Many of these patients are women and the mechanism of their
i
16.38 Factors influencing myocardial oxygen supply
and demand
Oxygen demand: cardiac work
• Heart rate
• Left ventricular hypertrophy
• Blood pressure
• Myocardial contractility
• Valve disease
Oxygen supply: coronary blood flow
• Duration of diastole • Coronary vasomotor tone
• Coronary perfusion pressure • Oxygenation:
(aortic diastolic minus Haemoglobin
coronary sinus or right atrial Oxygen saturation
diastolic pressure)
*Coronary blood flow occurs mainly in diastole.
488 • CARDIOLOGY
16.39 Activities precipitating angina
Common
• Physical exertion • Heavy meals
• Cold exposure • Intense emotion
Uncommon
• Vivid dreams (nocturnal • Lying flat (decubitus angina)
angina)
symptoms is often unclear. This disorder is poorly understood; it
carries a good prognosis but may respond to anti -anginal therapy.
Other causes
Angina can occur in association with aortic stenosis, hypertrophic
obstructive cardiomyopathy and aortitis, all of which are discussed
in more detail later in this chapter. It may also rarely be found
in association with vasculitis (p. 1040).
Clinical features
The history is the most important factor in making the diagnosis
(p. 454). Stable angina is characterised by central chest pain,
discomfort or breathlessness that is predictably precipitated by
exertion or other forms of stress (Box 16.39), and is promptly
relieved by rest (see Fig. 10.1, p. 178). Some patients find the
discomfort comes when they start walking and that later it does
not return despite greater effort (‘warm-up angina’). The Canadian
Cardiovascular Society (CCS) scoring system is commonly used
to grade the severity of angina (Box 16.40). This is of clinical
value, not only in documenting the severity of angina but also
in assessing prognosis (p. 493).
Physical examination is frequently unremarkable but should
include a careful search for evidence of valve disease (particularly
aortic), important risk factors (hypertension, diabetes mellitus),
left ventricular dysfunction (cardiomegaly, gallop rhythm), other
manifestations of arterial disease (carotid bruits, peripheral arterial
disease), and unrelated conditions that may exacerbate angina
(anaemia, thyrotoxicosis).
Investigations
Symptoms are a poor guide to the extent of CAD. Because of
this, stress testing and non-invasive imaging are advisable in
patients who are potential candidates for revascularisation. An
algorithm for the investigation and treatment of patients with stable
angina is shown in Figure 16.55. The first-line investigation is
an exercise ECG, which should be performed using a standard
treadmill or bicycle ergometer protocol (p. 449) while monitoring
16.41 Risk stratification in stable angina
High risk
Low risk
Post- infarct angina
Predictable exertional angina
Poor effort tolerance
Good effort tolerance
Ischaemia at low workload
Ischaemia only at high workload
Left main or three-vessel disease
Single-vessel or two-vessel
disease
Poor left ventricular function
Good left ventricular function
*Patients may fall between these two categories.
the patient’s pulse, BP and general condition. Planar or down-
sloping ST segment depression of 1 mm or more is indicative of
ischaemia (Fig. 16.56). Up-sloping ST depression is less specific;
it often occurs in normal individuals and false-positive results can
occur with digoxin therapy, left ventricular hypertrophy, bundle
branch block and WPW syndrome. The amount of exercise
that can be tolerated and the extent of ST segment change
(Fig. 16.57) that occurs can be of value in identifying high-risk
individuals with severe coronary disease in combination with
other clinical features (Box 16.41). However, exercise testing
may be normal in a significant proportion of patients with CAD or
may be inconclusive because an adequate heart rate cannot be
achieved due to reduced mobility or other non-cardiac problems.
Accordingly, if clinical suspicion is high and the exercise ECG is
normal or inconclusive, further imaging with myocardial perfusion
scanning or stress echocardiography is indicated. A perfusion
defect present during stress but not at rest provides evidence of
reversible myocardial ischaemia (Fig. 16.58), whereas a persistent
perfusion defect seen during both phases of the study is usually
indicative of previous Ml. Increasingly, CT coronary arteriography
is being used to document the presence or absence of CAD
in patients with suspected angina. It can clarify the diagnosis,
help to guide optimal treatment and avoid the need for cardiac
catheterisation in patients who do not have CAD or who have
mild disease only (see Fig. 16.55).
Coronary angiography provides detailed anatomical information
about the extent and nature of CAD (see Fig. 16.15, p. 453). It
is usually performed when coronary artery bypass graft surgery
or percutaneous coronary intervention is being considered
(p. 491).
Management
This should begin with a careful explanation of the problem and
a discussion of the lifestyle and medical interventions that can
be deployed to relieve symptoms and improve prognosis (Box
1 6.42). Anxiety and misconceptions often contribute to disability;
for example, some patients avoid all forms of exertion because
they believe that each attack of angina is a ‘mini-heart attack’
that results in permanent damage. Education and reassurance
can dispel these misconceptions and make a huge difference
to the patient’s quality of life.
The principles of management involve:
• a careful assessment of the extent and severity of arterial
disease
• identification and treatment of risk factors
• advice on smoking cessation
• introduction of drug treatment for symptom control
• identification of high-risk patients for treatment to improve
life expectancy.
Coronary artery disease • 489
Fig. 16.55 A scheme for the investigation and
treatment of stable angina on effort. This scheme
is best adopted for patients without prior known
coronary artery disease. For patients with known
coronary artery disease, further stress imaging
(echocardiography, radionuclide perfusion or magnetic
resonance perfusion) rather than computed
tomography coronary angiography is recommended.
Fig. 16.56 Forms of exercise-induced ST depression. [A] Planar
ST depression is usually indicative of myocardial ischaemia.
BE Down-sloping depression also usually indicates myocardial
ischaemia. [C] Up-sloping depression may be a normal finding.
16.42 Advice to patients with stable angina
• Do not smoke
• Aim for an ideal body weight
• Take regular exercise (exercise up to, but not beyond, the point of
chest discomfort is beneficial and may promote collateral vessels)
• Avoid severe unaccustomed exertion, and vigorous exercise after a
heavy meal or in very cold weather
• Take sublingual nitrate before undertaking exertion that may induce
angina
All patients with angina secondary to CAD should receive
antiplatelet therapy. Low-dose (75 mg) aspirin should be
prescribed for all patients and continued indefinitely since it
reduces the risk of Ml. Clopidogrel (75 mg daily) is an equally
effective alternative if aspirin causes dyspepsia or other side-
effects. Similarly, all patients should be prescribed a statin, even
if cholesterol is normal.
Anti-anginal drug therapy
The goal of anti-anginal therapy is to control symptoms using a
regimen that is as simple as possible and does not cause side-
effects. Five groups of drug can be used in the prevention and
treatment of angina but there is little evidence that one group is
more effective than another. It is conventional to start therapy with
sublingual glyceryl trinitrate (GTN) and a (3-blocker, and then add
a calcium channel antagonist or a long-acting nitrate if needed. If
the combination of two drugs fails to achieve an acceptable
symptomatic response, revascularisation should be considered
Nitrates
Nitrates act directly on vascular smooth muscle to produce
venous and arteriolar dilatation. Several preparations are available,
490 • CARDIOLOGY
Fig. 16.57 A positive exercise test (chest leads only). The resting
12-lead ECG shows some minor T-wave changes in the inferolateral leads
but is otherwise normal. After 3 minutes’ exercise on a treadmill, there is
marked planar ST depression in leads V4 and V5 (right-hand offset).
Subsequent coronary angiography revealed critical three-vessel coronary
artery disease.
Fig. 16.58 A myocardial perfusion scan showing reversible anterior
myocardial ischaemia. The images are cross-sectional tomograms
of the left ventricle. The resting scans (left) show even uptake of the
"technetium-labelled tetrofosmin and look like doughnuts. During stress
there is reduced uptake of technetium, particularly along the anterior wall
(arrows), and the scans look like crescents (right).
| 16.43 Duration of action of some nitrate preparations
Preparation
Peak action
Duration of action
Sublingual GTN
4-8 mins
10-30 mins
Buccal GTN
4-10 mins
30-300 mins
Transdermal GTN
1-3 hrs
Up to 24 hrs
Oral isosorbide dinitrate
45-120 mins
2-6 hrs
Oral isosorbide mononitrate
45-120 mins
6-10 hrs
(GTN = glyceryl trinitrate)
as shown in Box 16.43. They help angina by lowering preload
and afterload, which reduces myocardial oxygen demand,
and by increasing myocardial oxygen supply through coronary
vasodilatation. Sublingual GTN, administered from a metered-dose
aerosol (400 jig per spray) or as a tablet (300 or 500 pg), is
indicated for acute attacks and will usually relieve an attack in
2-3 minutes. Patients should also be encouraged to use the drug
prophylactically before taking exercise that is liable to provoke
symptoms. Sublingual GTN has a short duration of action and
side-effects include headache, symptomatic hypotension and,
rarely, syncope. A more prolonged therapeutic effect can be
achieved by giving GTN transcutaneously as a patch (5-1 0 mg
daily) or as a slow-release buccal tablet (1-5 mg 4 times daily).
Isosorbide dinitrate (10-20 mg 3 times daily) and isosorbide
mononitrate (20-60 mg once or twice daily) can be given by
mouth, unlike GTN, which undergoes extensive metabolism in
the liver. Headache is common with oral nitrates but tends to
diminish if the patient perseveres with the treatment. Continuous
nitrate therapy can cause pharmacological tolerance but this
can be avoided by a 6-8-hour nitrate-free period, best achieved
at night when the patient is inactive. If nocturnal angina is a
predominant symptom, long-acting nitrates can be given at
the end of the day.
Beta-blockers
These lower myocardial oxygen demand by reducing heart
rate, BP and myocardial contractility, but they may provoke
bronchospasm in patients with asthma. The properties and
side-effects of p-blockers are discussed on page 500. In theory,
non-selective p-blockers may aggravate coronary vasospasm by
blocking coronary artery p2-adrenoceptors, and so a once-daily
cardioselective preparation such as slow-release metoprolol
(50-200 mg daily) or bisoprolol (5-15 mg daily) is preferable.
Beta-blockers should not be withdrawn abruptly, as rebound
effects may precipitate dangerous arrhythmias, worsening
angina or Ml. This is known as the p-blocker withdrawal
syndrome.
Calcium channel antagonists
These drugs lower myocardial oxygen demand by reducing
BP and myocardial contractility. Since dihydropyridine calcium
antagonists, such as nifedipine and amlodipine, may cause a
reflex tachycardia, it is best to use them in combination with a
p-blocker. In contrast, verapamil and diltiazem can be used as
monotherapy because they slow SA node firing, inhibit conduction
through the AV node and tend to cause bradycardia. They are
particularly useful when p-blockers are contraindicated. Calcium
channel antagonists reduce myocardial contractility and must be
used with care in patients with poor LV function, since they can
Coronary artery disease • 491
KM 16.44 Calcium channel antagonists used for the
treatment of angina
Drug
Dose
Feature
Nifedipine
5-20 mg 3 times
daily*
May cause marked tachycardia
Nicardipine
20-40 mg
3 times daily
May cause less myocardial
depression than the other
calcium antagonists
Amlodipine
2.5-10 mg daily
Ultra-long-acting
Verapamil
40-80 mg
3 times daily*
Commonly causes constipation;
useful anti-arrhythmic
properties (p. 481)
Diltiazem
60-1 20 mg
3 times daily*
Similar anti-arrhythmic
properties to verapamil
*0nce- or twice-daily slow-release preparations are available.
Fig. 16.59 Percutaneous coronary intervention. A guidewire is
advanced from the radial (or femoral) artery to the coronary artery under
radiographic control (1). A fine balloon catheter is then advanced over the
guidewire to the stenotic coronary artery and the balloon is inflated to
dilate the stenosis (2). When this has been achieved, a stent is usually
placed at the site of the stenosis to maintain patency of the artery (3) (see
text for more details).
aggravate or precipitate heart failure. Other unwanted effects
include peripheral oedema, flushing, headache and dizziness
(Box 16.44).
Potassium channel activators
Nicorandil (10-30 mg twice daily orally) is the only drug in this
class that is currently available for clinical use. It acts as a
vasodilator with effects on the arterial and venous systems,
and has the advantage that it does not exhibit the tolerance
seen with nitrates.
If channel antagonist
Ivabradine is the first of this class of drug. It induces bradycardia
by modulating ion channels in the sinus node. It does not inhibit
myocardial contractility and appears to be safe in patients with
heart failure.
Ranolazine
This drug inhibits the late inward sodium current in coronary
artery smooth muscle cells, with a secondary effect on calcium
flux and vascular tone, reducing angina symptoms.
Non-pharmacological treatments
Percutaneous coronary intervention
Percutaneous coronary intervention (PCI) involves passing a fine
guidewire across a coronary stenosis under radiographic control
and using it to position a balloon, which is then inflated to dilate
the stenosis (Fig. 16.59). This can be combined with deployment
of a coronary stent, which is a piece of metallic ‘scaffolding’ that
can be impregnated with drugs with antiproliferative properties
and that helps to maximise and maintain dilatation of a stenosed
vessel. The routine use of stents in appropriate vessels reduces
both acute complications and the incidence of clinically important
restenosis (Fig. 16.60).
Treatment with PCI often provides excellent symptom control
but it does not improve survival in patients with chronic stable
angina. It is mainly used in single- or two-vessel disease. Stenoses
in bypass grafts can be dilated, as well as those in the native
coronary arteries. The technique is often used to provide palliative
therapy for patients with recurrent angina after coronary artery
bypass grafting.
The main acute complications of PCI are occlusion of the
target vessel or a side branch by thrombus or a loose flap of
intima (coronary artery dissection), and consequent myocardial
damage. This occurs in about 2-5% of procedures and can
often be corrected by deploying a stent, although emergency
coronary artery bypass grafting may occasionally be required if
stenting is unsuccessful. Minor myocardial damage, as indicated
by elevation of sensitive intracellular markers (p. 497), occurs
in up to 10% of cases. The main long-term complication of
PCI is restenosis, in up to one-third of cases. This is due to a
combination of elastic recoil and smooth muscle proliferation and
tends to occur within 3 months. Stenting substantially reduces
the risk of restenosis, probably because it allows the operator
to achieve more complete dilatation. Drug-eluting stents reduce
this risk further by allowing an antiproliferative drug, such as
sirolimus or paclitaxel, to elute slowly from the coating and
prevent neo-intimal hyperplasia and in-stent restenosis. These are
especially indicated in diabetic patients, or in patients with long or
calcific lesions, or small target-vessel diameter. Recurrent angina
(affecting up to 5-10% of patients receiving an intracoronary
stent at 6 months) may require further PCI or bypass grafting.
The risk of complications and the likely success of the
procedure are closely related to the morphology of the stenoses,
the experience of the operator and the presence of important
comorbidity, such as diabetes and peripheral arterial disease. A
good outcome is less likely if the target lesion is complex, long,
eccentric or calcified, lies on a bend or within a tortuous vessel,
involves a branch or contains thrombus.
Adjunctive therapy with a potent platelet inhibitor such as the
P2Y12 receptor antagonists (clopidogrel, prasugrel or ticagrelor)
in combination with aspirin and heparin improves the outcome
following PCI.
Coronary artery bypass grafting
The internal mammary arteries, radial arteries or reversed
segments of the patient’s own saphenous vein can be used
to bypass coronary artery stenoses (Fig. 16.61). This usually
involves major surgery under cardiopulmonary bypass but,
in some cases, grafts can be applied to the beating heart:
‘off-pump’ surgery. The operative mortality is approximately
1 .5% but risks are higher in elderly patients, those with poor left
ventricular function and those with significant comorbidity, such as
renal failure.
Approximately 90% of patients are free of angina 1 year
after coronary artery bypass grafting (CABG), but fewer than
60% of patients are asymptomatic after 5 or more years. Early
post-operative angina is usually due to graft failure arising from
technical problems during the operation, or poor ‘run-off’ due
492 • CARDIOLOGY
0
Fig. 16.60 Primary percutaneous coronary intervention. J] Acute
right coronary artery occlusion. [§] Initial angioplasty demonstrates a large
thrombus filling defect (arrows). [C] Complete restoration of normal flow
following intracoronary stenting.
to disease in the distal native coronary vessels. Late recurrence
of angina may be caused by progressive disease in the native
coronary arteries or graft degeneration. Fewer than 50% of vein
grafts are patent 1 0 years after surgery. Arterial grafts have a
much better long-term patency rate, however, with more than
80% of internal mammary artery grafts patent at 1 0 years. This
has led many surgeons to consider total arterial revascularisation
during CABG surgery. Aspirin (75-1 50 mg daily) and clopidogrel
(75 mg daily) both improve graft patency, and one or the other
Fig. 16.61 Coronary artery bypass graft surgery. [A] Narrowed or
stenosed arteries are bypassed using saphenous vein grafts connected to
the aorta or by utilising the internal mammary artery. [§] Three-
dimensional reconstruction of multidetector CT of the heart. The image
shows the patent saphenous vein grafts (SVG) to the right coronary artery
(RCA), obtuse marginal branch (OM) and diagonal branch (LADD), and left
internal mammary artery graft (LIMA) to the left anterior descending (LAD)
coronary artery.
should be prescribed indefinitely. Intensive lipid-lowering therapy
slows the progression of disease in the native coronary arteries
and bypass grafts, and reduces clinical cardiovascular events.
There is substantial excess cardiovascular morbidity and mortality
in patients who continue to smoke after bypass grafting. Persistent
smokers are twice as likely to die in the 10 years following
surgery than those who give up at surgery.
Survival is improved by CABG in symptomatic patients
with left main stem stenosis or three-vessel coronary disease
when the LAD, CX and right coronary arteries are involved,
or two-vessel disease involving the proximal LAD coronary
artery. Improvement in survival is most marked in those with
impaired left ventricular function or positive stress testing prior to
surgery and in those who have undergone left internal mammary
artery grafting.
Neurological complications are common, with a 1-5% risk of
perioperative stroke. Between 30% and 80% of patients develop
Coronary artery disease • 493
short-term cognitive impairment that typically resolves within
6 months. There are also reports of long-term cognitive decline
that may be evident in more than 30% of patients at 5 years.
PCI and CABG are compared in Box 16.45.
Prognosis
The prognosis of CAD is related to the number of diseased
vessels and the degree of left ventricular dysfunction. A patient
with single-vessel disease and good left ventricular function
has a 5-year survival of more than 90%. In contrast, a patient
with severe left ventricular dysfunction and extensive three-
vessel disease has a 5-year survival of less than 30% unless
revascularisation is performed. Symptoms are a poor guide to
prognosis, since spontaneous improvement in angina due to the
development of collateral vessels is common. Nevertheless, the
5-year mortality of patients with severe angina (CCS angina scale
III or IV, see Box 1 6.40) is nearly double that of patients with mild
symptoms.
1 16.45 Comparison of percutaneous coronary
intervention (PCI) and coronary artery bypass
grafting (CABG)
PCI
CABG
Death
<0.5%
<1.5%
Myocardial
infarction*
2%
10%
Hospital stay
12-36 hrs
5-8 days
Return to work
2-5 days
6-1 2 weeks
Recurrent angina
15-20% at
6 months
1 0% at 1 year
Repeat
revascularisation
1 0-20% at 2 years
2% at 2 years
Neurological
complications
Rare
Common (see text)
Other complications
Emergency CABG
Vascular damage
related to access site
Diffuse myocardial
damage
Infection (chest,
wound)
Wound pain
*Defined as CK-MB >2x normal (p. 497).
16.46 Angina in old age
• Incidence: coronary artery disease increases in old age and affects
women almost as often as men.
• Comorbid conditions: anaemia and thyroid disease are common
and may worsen angina.
• Calcific aortic stenosis: common and should be sought in all older
people with angina.
• Atypical presentations: when myocardial ischaemia occurs,
age-related changes in myocardial compliance and diastolic
relaxation can cause the presentation to be with symptoms of heart
failure, such as breathlessness, rather than with chest discomfort.
• Angioplasty and coronary artery bypass surgery: provide
symptomatic relief, although with increased procedure-related
morbidity and mortality. Outcome is determined by the number of
diseased vessels, severity of cardiac dysfunction and the number of
concomitant diseases, as much as by age itself.
Acute coronary syndrome
Acute coronary syndrome is a term that encompasses both
unstable angina and myocardial infarction. Unstable angina
is characterised by new-onset or rapidly worsening angina
(crescendo angina), angina on minimal exertion or angina at
rest in the absence of myocardial damage. Myocardial infarction
differs from unstable angina, since there is evidence of myocardial
necrosis. The term acute myocardial infarction (Ml) should be
used when there is evidence of myocardial necrosis in a clinical
setting consistent with acute myocardial ischaemia. Under these
conditions, any one of the criteria shown in Box 16.47 fulfils
the criteria for the diagnosis of an acute Ml. The diagnosis of a
previous Ml can be made when any one of the features shown
in Box 16.48 is present.
Acute coronary syndrome may present as a new phenomenon
in patients with no previous history of heart disease or against
a background of chronic stable angina. Approximately 12% of
patients with acute coronary syndrome die within 1 month and
20% within 6 months of the index event. The risk markers that are
indicative of an adverse prognosis include recurrent ischaemia,
extensive ECG changes at rest or during pain, raised troponin
I or T levels, arrhythmias and haemodynamic complications
16.47 Criteria for diagnosis of an acute myocardial
infarction (Ml)
• Detection of a rise and/or fall of cardiac biomarker values
(preferably cardiac troponin (cTn)), with at least one value above the
99th centile upper reference limit (URL) and with at least one of the
following:
1 . Symptoms of ischaemia
2. New or presumed new significant ST segment-T wave (ST— T)
changes or new left bundle branch block (LBBB)
3. Development of pathological Q waves in the ECG
4. Imaging evidence of new loss of viable myocardium or new
regional wall motion abnormality
5. Identification of an intracoronary thrombus by angiography or
postmortem
• Cardiac death with symptoms suggestive of myocardial ischaemia
and presumed new ischaemic ECG changes or new LBBB, but
death occurred before cardiac biomarkers were obtained, or before
cardiac biomarker values would be increased
• Percutaneous coronary intervention (PCI)-related Ml is arbitrarily
defined by elevation of cTn values (> 5 x 99th centile URL) in
patients with normal baseline values (< 99th centile URL) or a rise
of cTn values >20% if the baseline values are elevated and are
stable or falling. In addition, either (i) symptoms suggestive of
myocardial ischaemia, or (ii) new ischaemic ECG changes, or (iii)
angiographic findings consistent with a procedural complication, or
(iv) imaging demonstration of new loss of viable myocardium or new
regional wall motion abnormality are required
• Stent thrombosis associated with Ml when detected by coronary
angiography or postmortem in the setting of myocardial ischaemia
and with a rise and/or fall of cardiac biomarker values with at least
one value above the 99th centile URL
• Coronary artery bypass grafting (CABG) -related Ml is arbitrarily
defined by elevation of cardiac biomarker values (>10x99th centile
URL) in patients with normal baseline cTn values (< 99th centile
URL). In addition, either (i) new pathological Q waves or new LBBB,
or (ii) angiographic documented new graft or new native coronary
artery occlusion, or (iii) imaging evidence of new loss of viable
myocardium or new regional wall motion abnormality is required
Adapted from Thygesen K, Alpert JS, Jaffe AS et al. Third universal definition of
myocardial infarction. Eur Heart J 2012; 33:2551-2267.
494 • CARDIOLOGY
(hypotension, mitral regurgitation) during episodes of ischaemia.
Careful assessment and risk stratification are important because
these guide the use of more complex pharmacological and
interventional treatments (Figs 16.62 and 16.70), which can
improve outcome (p. 501).
Pathogenesis
Acute coronary syndrome almost always occurs in patients who
have atherosclerosis. The culprit lesion that precipitates the acute
16.48 Criteria for diagnosis of a prior
myocardial infarction
• Pathological Q waves with or without symptoms in the absence of
non-ischaemic causes
• Imaging evidence of a region of loss of viable myocardium that is
thinned and fails to contract, in the absence of a non-ischaemic
cause
• Pathological findings of a prior myocardial infarction
Adapted from Thygesen K, Alpert JS, Jaffe AS et at. Third universal definition of
myocardial infarction. Eur Heart J 2012; 33:2551-2267.
event is usually a complex ulcerated or fissured atheromatous
plaque with adherent platelet-rich thrombus and local coronary
artery spasm (see Fig. 16.54). These vascular changes during
an acute coronary syndrome are dynamic, such that the degree
of obstruction may either increase, leading to complete vessel
occlusion, or regress due to the effects of platelet disaggregation
and endogenous fibrinolysis. In acute Ml, occlusive thrombus
is almost always present at the site of rupture or erosion of an
atheromatous plaque. The thrombus may undergo spontaneous
lysis over the course of the next few days, although, by this time,
irreversible myocardial damage has occurred. Without treatment,
the artery responsible for the Ml remains permanently occluded
in 20-30% of patients. Since the process of infarction progresses
over several hours (Fig. 16.63), most patients present when it
is still possible to salvage myocardium and improve outcome.
Clinical features
The differential diagnosis of acute coronary syndrome is wide and
includes most causes of central chest pain or collapse (p. 176).
Chest pain at rest is the cardinal symptom but breathlessness,
vomiting and collapse are also common features (Box 16.49).
1. Find points for each predictive factor
Killip
class
Points
SBP
(mmHg)
Points
Heart rate
(beats/min)
Points
Age
(years)
Points
Serum
creatinine
level
(pimol/L)
Points
1
0
<80
58
<50
0
<30
0
0-34
1
II
20
80-99
53
50-69
3
30-39
8
35-70
4
III
39
100-119
43
70-89
9
40-49
25
71-105
7
IV
59
120-139
34
90-109
15
50-59
41
106-140
10
140-159
24
110-149
24
60-69
58
141-176
13
160-199
10
150-199
38
70-79
75
177-353
21
>200
0
>200
46
80-89
91
>353
28
>90
100
Other risk
factors
Points
Cardiac arrest at
39
admission
ST-segment deviation
28
Elevated cardiac
14
enzyme levels
2. Sum points for all predictive factors
Creatinine
level
Cardiac
ST-segment
deviation
Elevated
Killip
class
+
SBP
+
Heart
rate
+
Age
+
+
arrest at
admission
+
+
cardiac enzyme
levels
—
Total
points
3. Look up risk corresponding to total points
Total points
<60
70
80
90
100
110
120
130
140
150
160
170
180
190
200
210
220
230
240
>250
Probability of
in-hospital death (%)
<0.2
0.3
0.4
0.6
0.8
1.1
1.6
2.1
2.9
3.9
5.4
7.3
9.8
13
18
23
29
36
44
>52
Examples
A patient has Killip class II, SBP of 99 mmHg, heart rate of 100 beats/min, is 65 years of age, has a serum creatinine level of
76 jumol/L, did not have a cardiac arrest at admission but did have ST-segment deviation and elevated enzyme levels. His
score would be: 20 + 53 + 15 + 58 + 7 + 0 + 28 + 14 = 195. This gives about a 16% risk of having an in-hospital death.
Similarly, a patient with Killip class I, SBP of 80 mmHg, heart rate of 60 beats/min, who is 55 years of age, has a serum
creatinine level of 30 jimol/L, and no risk factors would have the following score: 0 + 58 + 3 + 41 + 1 = 103. This gives
about a 0.9% risk of having an in-hospital death.
Fig. 16.62 Risk stratification in the acute coronary syndrome: the GRACE score. Killip class refers to a categorisation of the severity of heart failure
based on easily obtained clinical signs. The main clinical features are as follows: class I = no heart failure; class II = crackles audible halfway up the chest;
class III = crackles heard in all the lung fields; class IV = cardiogenic shock. To convert creatinine in |imol/L to mg/dL, divide by 88.4. (SBP = systolic
blood pressure) From Scottish Intercollegiate Guidelines Network (SIGN) Guideline no. 93 -Acute coronary syndromes; February 2007.
Coronary artery disease • 495
<DO<9
1 hour 4 hours 8 hours
| Infarction Ischaemia
Fig. 16.63 The time course of myocardial infarction. The relative
proportion of ischaemic, infarcting and infarcted tissue slowly changes over
a period of 12 hours. In the early stages of myocardial infarction, a
significant proportion of the myocardium in jeopardy is potentially
salvageable.
Hm 16.49 Clinical features of acute coronary syndromes
Symptoms
• Prolonged cardiac pain: chest,
• Nausea and vomiting
throat, arms, epigastrium or
• Breathlessness
back
• Collapse/syncope
• Anxiety and fear of impending
death
Physical signs
Signs of sympathetic activation
• Pallor
• Tachycardia
• Sweating
Signs of vagal activation
• Vomiting
• Bradycardia
Signs of impaired myocardial function
• Hypotension, oliguria, cold
• Third heart sound
peripheries
• Quiet first heart sound
• Narrow pulse pressure
• Diffuse apical impulse
• Raised jugular venous pressure
• Lung crepitations
Low-grade fever
Complications
• Mitral regurgitation
• Pericarditis
The pain occurs in the same sites as angina but is usually more
severe and lasts longer; it is often described as a tightness,
heaviness or constriction in the chest. In acute Ml the pain can
be excruciating, and the patient’s expression and pallor may
vividly convey the seriousness of the situation. Most patients are
breathless and, in some, this is the only symptom. Painless or
‘silent’ Ml may also occur and is particularly common in older
patients or those with diabetes mellitus. If syncope occurs, it
is usually caused by an arrhythmia or profound hypotension.
Vomiting and sinus bradycardia are often due to vagal stimulation
and are particularly common in patients with inferior Ml. Nausea
and vomiting may also be caused or aggravated by opiates
given for pain relief. Sometimes infarction occurs in the absence
of physical signs. Sudden death, from ventricular fibrillation or
asystole, may occur immediately and often within the first hour.
If the patient survives this most critical stage, the liability to
dangerous arrhythmias remains, but diminishes as each hour
goes by. It is vital that patients know not to delay calling for
help if symptoms occur. Complications may occur in all forms
of acute coronary syndrome but have become less frequent in
the modern era of immediate or early coronary revascularisation.
Specific complications of acute coronary syndromes and their
management are discussed below.
^9 16.50 Common arrhythmias in acute
coronary syndrome
• Ventricular fibrillation
• Atrial tachycardia
• Ventricular tachycardia
• Sinus bradycardia (particularly
• Accelerated idioventricular
after inferior myocardial
rhythm
infarction)
• Ventricular ectopics
• Atrioventricular block
• Atrial fibrillation
Arrhythmias
Arrhythmias are common in patients with acute coronary syndrome
(Box 1 6.50) but are often transient and of no haemodynamic or
prognostic importance. The risk of arrhythmia can be minimised
by adequate pain relief, rest and the correction of hypokalaemia.
VF occurs in 5-1 0% of patients who reach hospital and is thought
to be the major cause of death in those who die before receiving
medical attention. Prompt defibrillation restores sinus rhythm and
is life-saving. The prognosis of patients with early VF (within the
first 48 hours) who are successfully and promptly resuscitated is
identical to that of patients who do not suffer VF. The presence
of ventricular arrhythmias during the convalescent phase of acute
coronary syndrome may be a marker of poor ventricular function
and may herald sudden death. Selected patients may benefit
from electrophysiological testing and specific anti-arrhythmic
therapy (including ICDs, p. 483). AF is a common but frequently
transient arrhythmia, and usually does not require emergency
treatment. However, if it causes a rapid ventricular rate with
hypotension or circulatory collapse, prompt cardioversion is
essential. In other situations, digoxin or a fFblocker is usually
the treatment of choice. AF may be a feature of impending or
overt left ventricular failure, and therapy may be ineffective if heart
failure is not recognised and treated appropriately. Anticoagulation
is required if AF persists. Bradycardia may occur but does not
require treatment unless there is hypotension or haemodynamic
deterioration, in which case atropine (0.6-1 .2 mg IV) may be given.
Inferior Ml may be complicated by AV block, which is usually
temporary and often resolves following reperfusion therapy. If
there is clinical deterioration due to second-degree or complete
AV block, a temporary pacemaker should be considered. AV
block complicating anterior infarction is more serious because
asystole may suddenly supervene. A prophylactic temporary
pacemaker should be inserted in these patients (p. 482).
Recurrent angina
Patients who develop recurrent angina at rest or on minimal
exertion following an acute coronary syndrome are at high risk
and should be considered for prompt coronary angiography
with a view to revascularisation. Patients with dynamic ECG
changes and ongoing pain should be treated with intravenous
glycoprotein llb/llla receptor antagonists. Patients with resistant
pain or marked haemodynamic changes should be considered
for intra-aortic balloon counterpulsation and emergency coronary
revascularisation. Post-infarct angina occurs in up to 50%
of patients treated with thrombolysis. Most patients have a
residual stenosis in the infarct- related vessel, despite successful
thrombolysis, and this may cause angina if there is still viable
myocardium downstream. For this reason, all patients who have
received successful thrombolysis should be considered for early
(within the first 6-24 hours) coronary angiography with a view
to coronary revascularisation.
496 • CARDIOLOGY
Acute heart failure
Acute heart failure usually reflects extensive myocardial
damage and is associated with a poor prognosis. All the other
complications of Ml are more likely to occur when acute heart
failure is present. The assessment and management of heart
failure is discussed in more detail on pages 463 and 465.
Pericarditis
This only occurs following infarction and is particularly common
on the second and third days. The patient may recognise that a
different pain has developed, even though it is at the same site,
and that it is positional and tends to be worse or sometimes
present only on inspiration. A pericardial rub may be audible.
Opiate-based analgesia should be used. Non-steroidal (NSAIDs)
and steroidal anti-inflammatory drugs may increase the risk of
aneurysm formation and myocardial rupture in the early recovery
period, and should be avoided.
Dressler’s syndrome
This syndrome is characterised by persistent fever, pericarditis
and pleurisy, and is probably due to autoimmunity. The symptoms
tend to occur a few weeks or even months after Ml and often
subside after a few days. If the symptoms are prolonged or severe,
treatment with high-dose aspirin, NSAIDs or even glucocorticoids
may be required.
Papillary muscle rupture
This typically presents with acute pulmonary oedema and shock
due to the sudden onset of severe mitral regurgitation. Examination
usually reveals a pansystolic murmur and third heart sound but
the murmur may be quiet or absent in patients with severe mitral
regurgitation. The diagnosis is confirmed by echocardiography,
and emergency valve replacement may be necessary. Lesser
degrees of mitral regurgitation due to papillary muscle dysfunction
are common and may be transient.
Ventricular septum rupture
This usually presents with sudden haemodynamic deterioration
accompanied by a new and loud pansystolic murmur radiating
to the right sternal border, which may be difficult to distinguish
from acute mitral regurgitation. Rupture of the intraventricular
septum causes left-to-right shunting through a ventricular septal
defect, which tends to cause acute right heart failure rather
than pulmonary oedema. Doppler echocardiography and right
heart catheterisation will confirm the diagnosis. Treatment is by
emergency surgical repair; without this, the condition is usually fatal.
Ventricular rupture
Rupture of the ventricle may lead to cardiac tamponade and
is usually fatal (p. 544), although it is occasionally possible to
support a patient with an incomplete rupture until emergency
surgery can be performed.
Embolism
Thrombus often forms on the endocardial surface of freshly
infarcted myocardium. This can lead to systemic embolism
and occasionally causes a stroke or ischaemic limb. Venous
thrombosis and pulmonary embolism may occur but have become
less common with the use of prophylactic anticoagulants and
early mobilisation.
Ventricular remodelling
This is a potential complication of an acute transmural Ml due
to thinning and stretching of the infarcted segment. This leads
Fig. 16.64 Infarct expansion and ventricular remodelling. Full
thickness myocardial infarction causes thinning and stretching of the
infarcted segment (infarct expansion), which leads to increased wall stress
with progressive dilatation and hypertrophy of the remaining ventricle
(ventricular remodelling).
to an increase in wall stress with progressive dilatation and
hypertrophy of the remaining ventricle (ventricular remodelling,
Fig. 16.64). As the ventricle dilates, it becomes less efficient
and heart failure may supervene. Infarct expansion occurs over
a few days and weeks but ventricular remodelling can take
years. ACE inhibitor and mineralocorticoid receptor antagonist
therapies reduce late ventricular remodelling and can prevent
the onset of heart failure (p. 465).
Ventricular aneurysm
Ventricular aneurysm develops in approximately 1 0% of patients
with Ml and is particularly common when there is persistent
occlusion of the infarct- related vessel. Heart failure, ventricular
arrhythmias, mural thrombus and systemic embolism are all
recognised complications of aneurysm formation. Other features
include a paradoxical impulse on the chest wall, persistent ST
elevation on the ECG, and sometimes an unusual bulge from
the cardiac silhouette on the chest X-ray. Echocardiography is
diagnostic. Surgical removal of a left ventricular aneurysm carries
a high morbidity and mortality but is sometimes necessary.
Investigations
Electrocardiogram
The standard 1 2-lead ECG is central to confirming the diagnosis
but may be difficult to interpret if there is bundle branch block
or previous Ml. The initial ECG may be normal or non-diagnostic
in one-third of cases. Repeated ECGs are important, especially
where the diagnosis is uncertain or the patient has recurrent
or persistent symptoms. The earliest ECG change is usually
ST-segment deviation. With proximal occlusion of a major coronary
artery, ST-segment elevation (or new bundle branch block) is
seen initially, with later diminution in the size of the R wave
and, in transmural (full-thickness) infarction, development of a
Q wave. Subsequently, the T wave becomes inverted because
of a change in ventricular repolarisation; this change persists
after the ST segment has returned to normal. These sequential
features (Fig. 16.65) are sufficiently reliable for the approximate
age of the infarct to be deduced.
In non-ST segment elevation acute coronary syndrome, there
is partial occlusion of a major vessel or complete occlusion of
Coronary artery disease • 497
0 ® \c\
Fig. 16.65 The serial evolution of ECG changes in transmural
myocardial infarction. [A] Normal ECG complex. |j| Acute ST elevation
(‘the current of injury’). [C] Progressive loss of the R wave, developing Q
wave, resolution of the ST elevation and terminal T-wave inversion.
[Pi Deep Q wave and T-wave inversion. [1 Old or established infarct
pattern; the Q wave tends to persist but the T-wave changes become less
marked. The rate of evolution is very variable but, in general, stage B
appears within minutes, stage C within hours, stage D within days and
stage E after several weeks or months. This should be compared with the
12-lead ECGs in Figures 16.66-16.68.
Fig. 16.66 Recent anterior non-ST elevation (subendocardial)
myocardial infarction. This ECG demonstrates deep symmetrical T-wave
inversion, together with a reduction in the height of the R wave in leads V1(
V2, V3 and V4.
a minor vessel, causing unstable angina or partial-thickness
(subendocardial) Ml. This is usually associated with ST-segment
depression and T-wave changes. In the presence of infarction,
this may be accompanied by some loss of R waves in the
absence of Q waves (Fig. 16.66).
The ECG changes are best seen in the leads that ‘face’ the
ischaemic or infarcted area. When there has been anteroseptal
infarction, abnormalities are found in one or more leads from
Fig. 16.67 Acute transmural anterior myocardial infarction. This ECG
was recorded from a patient who had developed severe chest pain 6 hours
earlier. There is ST elevation in leads I, aVL, V2, V3, V4, V5 and V6, and
there are Q waves in leads V3, V4 and V5. Anterior infarcts with prominent
changes in leads V2, V3 and V4 are sometimes called ‘anteroseptal’
infarcts, as opposed to ‘anterolateral’ infarcts, in which the ECG changes
are predominantly found in V4, V5 and V6.
V! to V4, while anterolateral infarction produces changes from
V4 to V6, in aVL and in lead I. Inferior infarction is best shown in
leads II, III and aVF, while, at the same time, leads I, aVL and
the anterior chest leads may show ‘reciprocal’ changes of ST
depression (Figs 16.67 and 16.68). Infarction of the posterior
wall of the LV does not cause ST elevation or Q waves in the
standard leads, but can be diagnosed by the presence of
reciprocal changes (ST depression and a tall R wave in leads
Vi-V4). Some infarctions (especially inferior) also involve the RV.
This may be identified by recording from additional leads placed
over the right precordium.
Cardiac biomarkers
Serial measurements of serum troponin should be taken. In
unstable angina, there is no detectable rise in troponin and the
diagnosis is made on the basis of the clinical history and ECG
changes. In contrast, Ml causes a rise in plasma troponin T and
I concentrations and other cardiac muscle enzymes (p. 450; Fig.
16.69 and see Box 16.47). Levels of troponins T and I increase
within 3-6 hours, peak at about 36 hours and remain elevated
for up to 2 weeks. A full blood count may reveal the presence
of a leucocytosis, which reaches a peak on the first day. The
erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
are also elevated. Lipids should be measured within 24 hours of
presentation because there is often a transient fall in cholesterol
in the 3 months following infarction.
Radiography
A chest X-ray should be performed since this may demonstrate
pulmonary oedema that is not evident on clinical examination
(see Fig. 16.27, p. 464). The heart size is often normal but
16
498 • CARDIOLOGY
Fig. 16.68 Acute transmural inferolateral myocardial infarction. This
ECG was recorded from a patient who had developed severe chest pain
4 hours earlier. There is ST elevation in inferior leads II, III and aVF and
lateral leads V4, V5 and V6. There is also ‘reciprocal’ ST depression in leads
aVL and V2.
Fig. 16.69 Changes in plasma cardiac biomarker concentrations
after myocardial infarction. Creatine kinase (CK) and troponins T (Tn-T)
and I (Tn-I) are the first to rise, followed by aspartate aminotransferase
(AST) and then lactate (hydroxybutyrate) dehydrogenase (LDH). In patients
treated with reperfusion therapy, a rapid rise in plasma creatine kinase
(curve CK(R)) occurs, due to a washout effect.
there may be cardiomegaly due to pre-existing myocardial
damage.
Echocardiography
Echocardiography is normally performed before discharge from
hospital and is useful for assessing ventricular function and for
detecting important complications, such as mural thrombus,
cardiac rupture, ventricular septal defect, mitral regurgitation
and pericardial effusion.
Coronary angiography
Coronary arteriography should be considered with a view to
revascularisation in all patients at moderate or high risk of a further
I
16.51 Late management of myocardial infarction
Risk stratification and further investigation (see text)
Lifestyle modification
• Diet (weight control, •
lipid-lowering, ‘Mediterranean •
diet’)
Secondary prevention drug therapy
• Antiplatelet therapy (aspirin •
and/or clopidogrel)
• p-blocker •
• ACE inhibitor/ARB
• Statin
Rehabilitation
Cessation of smoking
Regular exercise
Additional therapy for control
of diabetes and hypertension
Mineralocorticoid receptor
antagonist
Devices
• Implantable cardiac defibrillator (high-risk patients)
(ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker)
event, including those who fail to settle on medical therapy, those
with extensive ECG changes, those with an elevated plasma
troponin and those with severe pre-existing stable angina (Fig.
16.70). This often reveals disease that is amenable to PCI or
urgent CABG (see below).
Management
All patients with suspected acute coronary syndrome should be
admitted urgently to hospital because there is a significant risk of
death or recurrent myocardial ischaemia during the early unstable
phase. Appropriate medical therapy can reduce the incidence
of these complications by at least 60%. The key elements of
immediate in-hospital management are shown in Figure 16.70.
Patients should ideally be managed in a dedicated cardiac unit,
where the necessary expertise, monitoring and resuscitation
facilities are available. Clinical risk factor analysis using tools such
as the GRACE score (see Fig. 16.62) should be performed to
identify patients that should be selected for intensive therapy, and
specifically early inpatient coronary angiography (thresholds vary,
but a score of 140 points or more indicates early intervention).
If there are no complications and risk factor analysis shows
that angiography is not required, the patient can be mobilised
from the second day and discharged after 2-3 days. Low-risk
patients without spontaneous angina should undergo an exercise
tolerance test approximately 4 weeks after the acute coronary
syndrome. This will help to identify those individuals with residual
myocardial ischaemia who require further investigation, and may
help to boost the confidence of the remainder. Management of
the acute event is discussed below and the principles of long-term
management are summarised in Box 16.51.
Analgesia
Adequate analgesia is essential, not only to relieve distress but also
to lower adrenergic drive and thereby reduce vascular resistance,
BP, infarct size and susceptibility to ventricular arrhythmias.
Intravenous opiates (initially, morphine sulphate 5-10 mg or
diamorphine 2.5-5 mg) and antiemetics (initially, metoclopramide
10 mg) should be administered, and titrated by giving repeated
small aliquots until the patient is comfortable. Intramuscular
injections should be avoided because the clinical effect may
be delayed by poor skeletal muscle perfusion, and a painful
haematoma may form following thrombolytic or antithrombotic
therapy.
Coronary artery disease • 499
Fig. 16.70 Summary of treatment for acute coronary syndrome (ACS). *Not required following PCI. For details of the GRACE score, see Figure 16.62.
(ACE = angiotensin-converting enzyme; ECG = electrocardiogram; GP = glycoprotein; IV = intravenous; LMW = low-molecular-weight; PCI = percutaneous
coronary intervention; PO = by mouth; SC = subcutaneous) Adapted from SIGN 93, Feb 2007, and updated in SIGN 148, April 2016.
Reperfusion therapy
Immediate reperfusion therapy with PCI (see Fig. 16.60) is
indicated when the ECG shows new bundle branch block or
characteristic ST-segment elevation in two contiguous leads
of 1 mm or more in the limb leads or 2 mm or more in the
chest leads. This procedure has revolutionised the outcomes
for these patients and is the treatment of choice for those
presenting within 12 hours of symptom onset (Fig. 16.70). If
PCI cannot be performed within 120 minutes for any reason,
and thrombolysis is contraindicated, the procedure should be
performed as soon as practically possible. Patients should be
considered for PCI within the first 24 hours, even if they have
reperfused spontaneously or with thrombolytic therapy. Coronary
artery patency is restored in over 95% of patients undergoing PCI.
The procedure preserves left ventricular function with a marked
reduction in the progression to heart failure, more than halves
rates of recurrent Ml and dramatically improves mortality with
more than 95% 1 -year survival rates in clinical trials. Successful
therapy is also associated with rapid pain relief, resolution
of acute ST elevation and occasional transient arrhythmias.
500 • CARDIOLOGY
Selected medium- to high-risk patients do benefit from in-hospital
coronary angiography and coronary revascularisation but this
does not need to take place in the first 1 2 hours unless there
are high-risk features, such as ongoing chest pain or ECG
changes. Reperfusion therapy with PCI confers no immediate
mortality benefit in patients with non-ST segment elevation acute
coronary syndrome.
Thrombolytic therapy
If primary PCI cannot be achieved in a timely manner (see Fig.
16.70), thrombolytic therapy should be administered. Although
the survival advantage is not as good as primary PCI, mortality is
reduced and this is maintained for at least 1 0 years. The benefit
of thrombolytic therapy is greatest in those patients who receive
treatment within the first 1 2 hours and especially the first 2 hours.
Modern thrombolytic agents, such as tenecteplase (TNK) and
reteplase (rPA), are analogues of human tissue plasminogen
activator and can be given as an intravenous bolus, assisting
prompt treatment in the emergency department or in the pre¬
hospital setting. The major hazard of thrombolytic therapy is
bleeding. Cerebral haemorrhage causes 4 extra strokes per
1000 patients treated, and the incidence of other major bleeds
is between 0.5% and 1 %. Accordingly, the treatment should be
withheld if there is a significant risk of serious bleeding (Box 1 6.52).
For some patients, thrombolytic therapy is contraindicated or fails
to achieve coronary arterial reperfusion (Fig. 16.70). Emergency
PCI may then be considered, particularly where there is evidence
of cardiogenic shock. Even where thrombolysis successfully
achieves reperfusion, PCI should be considered within 24 hours
to prevent recurrent infarction and improve outcome.
Antithrombotic therapy
Oral administration of 75-325 mg aspirin daily improves survival,
with a 25% relative risk reduction in mortality. The first tablet
(300 mg) should be given orally within the first 12 hours and
therapy should be continued indefinitely if there are no side-effects.
A P2Y12 receptor antagonist should be given in combination
with aspirin for up to 12 months. The strongest evidence is for
ticagrelor (180 mg, followed by 90 mg twice daily) but prasugrel
(60 mg, followed by 10 mg daily) is an alternative. If the patient is
intolerant of aspirin, clopidogrel is a suitable alternative (300 mg,
followed by 75 mg daily). Glycoprotein llb/llla receptor antagonists,
such as tirofiban and abciximab, block the final common pathway
of platelet aggregation and are potent inhibitors of platelet-rich
thrombus formation. They are of particular benefit in high-risk
patients with acute coronary syndromes who undergo PCI,
especially those with a high thrombus burden at angiography or
who have received inadequate prior antiplatelet therapy. These
intravenous agents are administered in addition to oral aspirin
and a P2Y12 inhibitor such as clopidogrel. Anticoagulation
further reduces the risk of thromboembolic complications, and
prevents re-infarction in the absence of reperfusion therapy or after
successful thrombolysis. Anticoagulation can be achieved using
unfractionated heparin, fractioned (low-molecular-weight) heparin
or a pentasaccharide such as subcutaneous fondaparinux (2.5 mg
daily). Comparative clinical trials show that the pentasaccharides
have the best safety and efficacy profile but low-molecular-weight
heparin, such as subcutaneous enoxaparin (1 mg/kg twice
daily), is a reasonable alternative. Anticoagulation should be
continued for 8 days or until discharge from hospital or coronary
revascularisation has been completed. A period of treatment with
warfarin should be considered if there is persistent AF or evidence
of extensive anterior infarction with mural thrombus because these
patients are at increased risk of systemic thromboembolism.
Anti-anginal therapy
Sublingual glyceryl trinitrate (300-500 pig) is a valuable first-
aid measure in unstable angina or threatened infarction, and
intravenous nitrates (glyceryl trinitrate 0.6-1 .2 mg/hr or isosorbide
dinitrate 1-2 mg/hr) are useful for the treatment of left ventricular
failure and the relief of recurrent or persistent ischaemic pain.
Intravenous (3-blockers (atenolol 5-10 mg or metoprolol 5-15 mg
given over 5 mins) relieve pain, reduce arrhythmias and improve
short-term mortality in patients who present within 1 2 hours of the
onset of symptoms (Fig. 16.70). However, they should be avoided
if there is heart failure (pulmonary oedema), hypotension (systolic
BP <105 mmHg) or bradycardia (heart rate <65/min). Nifedipine
or amlodipine can be added to the (3-blocker if there is persistent
chest discomfort but these drugs may cause tachycardia if used
alone. Verapamil and diltiazem should be used if a (3-blocker
is contraindicated. In the longer term, treatment with an oral
(3-blocker reduces long-term mortality by approximately 25%
among the survivors of an acute Ml. Patients with heart failure,
irreversible COPD or peripheral arterial disease derive similar,
if not greater, secondary preventative benefits from (3-blocker
therapy and should receive maintenance therapy unless it is poorly
tolerated. Unfortunately, a minority of patients do not tolerate
(3-blockers because of bradycardia, AV block, hypotension or
asthma.
Renin-angiotensin blockade
Long-term treatment with ACE inhibitors such as enalapril (1 0 mg
twice daily) or ramipril (2.5-5 mg twice daily) can counteract
ventricular remodelling, prevent the onset of heart failure, improve
survival, reduce recurrent Ml and avoid rehospitalisation. The
6
• Atypical presentation: often with anorexia, fatigue, weakness,
delirium or falls rather than chest pain.
• Case fatality: rises steeply. Hospital mortality exceeds 25% in
those over 75 years old, which is five times greater than that seen
in those aged less than 55 years.
• Survival benefit of treatments: not influenced by age. The
absolute benefit of evidence-based treatments may therefore be
greatest in older people.
• Hazards of treatments: rise with age (for example, increased risk
of intracerebral bleeding after thrombolysis) and are due partly to
increased comorbidity.
• Quality of evidence: older patients, particularly those with significant
comorbidity, were under-represented in many of the randomised
controlled clinical trials that helped to establish the treatment of
myocardial infarction. The balance of risk and benefit for many
treatments, such as thrombolysis and primary percutaneous
transluminal coronary angiography, in frail older people is uncertain.
16.53 Myocardial infarction in old age
16.52 Relative contraindications to thrombolytic
therapy
• Active internal bleeding
• Previous subarachnoid or intracerebral haemorrhage
• Uncontrolled hypertension
• Recent surgery (within 1 month)
• Recent trauma (including traumatic resuscitation)
• High probability of active peptic ulcer
• Pregnancy
Coronary artery disease • 501
benefits are greatest in those with overt heart failure (clinical
or radiological) but extend to patients with asymptomatic left
ventricular dysfunction and those with preserved left ventricular
function. They should therefore be considered in all patients
with acute coronary syndrome. Caution must be exercised in
hypovolaemic or hypotensive patients because ACE inhibition
may exacerbate hypotension and impair coronary perfusion. In
patients intolerant of ACE inhibitors, ARBs such as valsartan
(40-160 mg twice daily) or candesartan (4-16 mg daily) are
alternatives and are better tolerated.
Mineralocorticoid receptor antagonists
Patients with acute Ml and left ventricular dysfunction (ejection
fraction <35%) and either pulmonary oedema or diabetes
mellitus further benefit from additional mineralocorticoid receptor
antagonism (eplerenone 25-50 mg daily, or spironolactone
25-50 mg daily).
Lipid-lowering therapy
The benefits of lowering serum cholesterol following acute
coronary syndrome have been demonstrated in several large-scale
randomised trials. All patients should receive therapy with HMG
CoA reductase enzyme inhibitors (statins) after acute coronary
syndrome, irrespective of serum cholesterol concentrations.
Patients with serum LDL cholesterol concentrations above
3.2 mmol/L (approximately 1 20 mg/dL) benefit from more intensive
therapy, such as atorvastatin (80 mg daily). Other agents, such as
ezetimibe, fibrates, anion exchange resins and injectable PCSK9
inhibitors, may be used in cases where total cholesterol or LDL
cholesterol cannot be lowered adequately using statins alone.
Smoking cessation
The 5-year mortality of patients who continue to smoke cigarettes
is double that of those who quit smoking at the time of their
acute coronary syndrome. Giving up smoking is the single most
effective contribution a patient can make to his or her future. The
success of smoking cessation can be increased by supportive
advice and pharmacological therapy (p. 94).
Diet and exercise
Maintaining an ideal body weight, eating a Mediterranean-style
diet, taking regular exercise, and achieving good control of
hypertension and diabetes mellitus may all improve the long-term
outlook.
Rehabilitation
The necrotic muscle of an acute myocardial infarct takes
4-6 weeks to be replaced with fibrous tissue and it is conventional
to restrict physical activities during this period. When there are
no complications, the patient can mobilise on the second day,
return home in 2-3 days and gradually increase activity, with
the aim of returning to work in 4 weeks. The majority of patients
may resume driving after 1-4 weeks, although, in most countries,
drivers of heavy goods and public service vehicles require special
assessment before returning to work. Emotional problems, such
as denial, anxiety and depression, are common and must be
addressed. Some patients are severely and even permanently
incapacitated as a result of the psychological effects of acute
coronary syndrome rather than the physical ones, and all benefit
from thoughtful explanation, counselling and reassurance. Many
patients mistakenly believe that stress was the cause of their
heart attack and may restrict their activity inappropriately. The
patient’s spouse or partner will also require emotional support,
information and counselling. Formal rehabilitation programmes,
based on graded exercise protocols with individual and group
counselling, are often very successful and, in some cases, have
been shown to improve the long-term outcome.
Implantable defibrillators
ICDs are of benefit in preventing sudden cardiac death in patients
who have severe left ventricular impairment (ejection fraction
<30%) after Ml (p. 483).
Prognosis
The prognosis of patients who have survived an acute coronary
syndrome is related to the extent of residual myocardial ischaemia,
the degree of myocardial damage and the presence of ventricular
arrhythmias. In almost one-quarter of all cases of Ml, death occurs
within a few minutes without medical care. Half the deaths occur
within 24 hours of the onset of symptoms and about 40% of
all affected patients die within the first month. The prognosis
of those who survive to reach hospital is much better, with a
28-day survival of more than 85%. Patients with unstable angina
have a mortality of approximately half that of patients with Ml.
Early death is usually due to an arrhythmia and is independent
of the extent of Ml. However, late outcomes are determined by
the extent of myocardial damage, and unfavourable features
include poor left ventricular function, AV block and persistent
ventricular arrhythmias. The prognosis is worse for anterior
than for inferior infarcts. Bundle branch block and high cardiac
marker levels both indicate extensive myocardial damage. Old
age, depression and social isolation are also associated with a
higher mortality. Of those who survive an acute attack, more
than 80% live for a further year, about 75% for 5 years, 50%
for 1 0 years and 25% for 20 years.
Non-cardiac surgery in patients
with heart disease
Non-cardiac surgery, particularly major vascular, abdominal or
thoracic surgery, can precipitate serious perioperative cardiac
complications, such as Ml and death, in patients with CAD
and other forms of heart disease. Careful pre-operative cardiac
assessment may help to determine the balance of benefit versus
risk on an individual basis, and identify measures that minimise
the operative risk (Box 16.54).
A hypercoagulable state is part of the normal physiological
response to surgery, and may promote coronary thrombosis
leading to an acute coronary syndrome in the early post-operative
period. Patients with a history of recent PCI or acute coronary
syndrome are at greatest risk and, whenever possible, elective
non-cardiac surgery should be avoided for 3 months after such an
event. Where possible, antiplatelet agents, statins and (3-blocker
therapies should be continued throughout the perioperative period.
16.54 Major risk factors for cardiac complications
of non-cardiac surgery
• Recent (< 6 months) myocardial infarction or unstable angina
• Severe coronary artery disease: left main stem or three-vessel
disease
• Severe stable angina on effort
• Severe left ventricular dysfunction
• Severe valvular heart disease (especially aortic stenosis)
502 • CARDIOLOGY
Careful attention to fluid balance during and after surgery is
particularly important in patients with impaired left ventricular
function and valvular heart disease because vasopressin is
released as part of the normal physiological response to surgery
and, in these circumstances, the over-zealous administration of
intravenous fluids can easily precipitate heart failure. Patients
with severe valvular heart disease, particularly aortic stenosis
and mitral stenosis, are also at increased risk because they
may not be able to increase their cardiac output in response to
the stress of surgery.
AF may be triggered by hypoxia, myocardial ischaemia or
heart failure, and is a common post-operative complication in
patients with pre-existing heart disease. It usually terminates
spontaneously when the precipitating factors have been eliminated,
but digoxin or (3-blockers can be prescribed to control the
heart rate.
Peripheral arterial disease
Peripheral arterial disease (PAD) has been estimated to affect
about 20% of individuals aged 55-75 years in the UK. Only
25% of patients present with symptoms, the most common of
which is intermittent claudication (1C). About 1-2% of patients
with 1C per year progress to a point where amputation and/or
revascularisation are required. However, the annual mortality
rate of people with 1C is about 5%, which is 2-3 times higher
than the general population of the same age and gender. The
cause of death is typically an Ml or stroke, reflecting the fact
that 1C nearly always occurs in association with widespread
atherosclerosis.
Pathogenesis
In developed countries, almost all PAD is due to atherosclerosis
and the risk factors are the same as described in patients with
CAD. As with CAD, plaque rupture is responsible for the most
serious manifestations of PAD, and not infrequently occurs in
a plaque that hitherto has been asymptomatic. The clinical
manifestations depend on the anatomical site, the presence
or absence of a collateral supply, the speed of onset and the
mechanism of injury (Box 16.55). Approximately 5-10% of
patients with PAD have diabetes but this proportion increases
to 30-40% in those with severe limb ischaemia. The mechanism
of PAD in diabetes is atheroma affecting the medium-sized to
large arteries rather than obstructive microangiopathy and so
diabetes is not a contraindication to lower limb revascularisation.
Nevertheless, diabetic patients with PAD pose a number of
particular problems (Box 16.56).
Clinical features
Symptomatic PAD affects the legs about eight times more
commonly than the arms. Several locations may be affected,
including the aortoiliac vessels, the femoropopliteal vessels
and the infrapopliteal vessels. One or more of these segments
may be affected in a variable and asymmetric manner. In the
arm, the subclavian artery is the most common site of disease.
Peripheral artery disease can present clinically in a variety of
ways, as detailed below.
Intermittent claudication
This is the most common presentation of PAD affecting the
lower limbs. It is characterised by ischaemic pain affecting the
muscles of the leg. The pain is usually felt in the calf because
16.55 Factors influencing the clinical manifestations
of peripheral arterial disease (PAD)
Anatomical site
Cerebral circulation
• TIA, amaurosis fugax, vertebrobasilar insufficiency
Renal arteries
• Hypertension and renal failure
Mesenteric arteries
• Mesenteric angina, acute intestinal ischaemia
Limbs (legs » arms)
• Intermittent claudication, critical limb ischaemia, acute limb
ischaemia
Collateral supply
• In a patient with a complete circle of Willis, occlusion of one carotid
artery may be asymptomatic
• In a patient without cross-circulation, stroke is likely
Speed of onset
• Where PAD develops slowly, a collateral supply will develop
• Sudden occlusion of a previously normal artery is likely to cause
severe distal ischaemia
Mechanism of injury
Haemodynamic
• Plaque must reduce arterial diameter by 70% (‘critical stenosis’) to
reduce flow and pressure at rest. On exertion a moderate stenosis
may become ‘critical’. This mechanism tends to have a relatively
benign course due to collateralisation
Thrombotic
• Occlusion of a long-standing critical stenosis may be asymptomatic
due to collateralisation. However, acute rupture and thrombosis of a
non-haemodynamically significant plaque usually has severe
consequences
Atheroembolic
• Symptoms depend on embolic load and size
• Carotid (TIA, amaurosis fugax or stroke) and peripheral arterial (blue
toe/finger syndrome) plaque are common examples
Thromboembolic
• Usually secondary to atrial fibrillation
• The consequences are usually dramatic, as the thrombus load is
often large and occludes a major, previously healthy, non-
collateralised artery suddenly and completely
(TIA = transient ischaemic attack)
the disease most commonly affects the superficial femoral artery,
but it may be felt in the thigh or buttock if the iliac arteries are
involved. Typically, the pain comes on after walking, often once
a specific distance has been covered, and rapidly subsides
on resting. Resumption of walking leads to a return of the
pain. Most patients describe a cyclical pattern of exacerbation
and resolution due to the progression of disease and the
subsequent development of collaterals. When PAD affects
the upper limbs, arm claudication may occur, although this is
uncommon.
Critical limb ischaemia
Critical limb ischaemia (CLI) is defined as rest pain requiring
opiate analgesia, and/or ulceration or gangrene that has been
present for more than 2 weeks, in the presence of an ankle BP
of less than 50 mmHg. The typical progression of symptoms in
CLI is summarised in Figure 16.71. Rest pain only, with ankle
pressures above 50 mmHg, is known as subcritical limb ischaemia
(SCLI). The term severe limb ischaemia (SLI) is used to describe
Peripheral arterial disease • 503
1 16.56 Peripheral vascular disease in diabetes
Feature
Difficulty
Arterial calcification
Spuriously high ABPI due to incompressible
ankle vessels. Inability to clamp arteries for
the purposes of bypass surgery. Resistant to
angioplasty
Immunocompromise
Prone to rapidly spreading cellulitis,
gangrene and osteomyelitis
Multisystem arterial
disease
Coronary and cerebral arterial disease
increase the risks of intervention
Distal disease
Diabetic vascular disease has a predilection
for the calf vessels. Although vessels in the
foot are often spared, performing a
satisfactory bypass or angioplasty to these
small vessels is a technical challenge
Sensory neuropathy
Even severe ischaemia and/or tissue loss
may be completely painless. Diabetic patients
often present late with extensive destruction
of the foot. Loss of proprioception leads to
abnormal pressure loads and worsens joint
destruction (Charcot joints)
Motor neuropathy
Weakness of the long and short flexors and
extensors leads to abnormal foot
architecture, abnormal pressure loads, callus
formation and ulceration
Autonomic
neuropathy
Leads to a dry foot deficient in sweat that
normally lubricates the skin and is
antibacterial. Scaling and fissuring create a
portal of entry for bacteria. Abnormal blood
flow in the bones of the ankle and foot may
also contribute to osteopenia and bony
collapse
(ABPI = ankle-brachial pressure index)
the situation where either CLI and SCLI occurs. Whereas 1C
is usually due to single-segment plaque, SLI is always due to
multilevel disease. Many patients with SLI have not previously
sought medical advice, principally because they have other
comorbidity that prevents them from walking to a point where
1C develops. Patients with SLI are at high risk of losing their
limb, and sometimes their life, in a matter of weeks or months
without surgical bypass or endovascular revascularisation by
angioplasty or stenting. Treatment of these patients is difficult,
however, because most are elderly with extensive and severe
disease and significant multisystem comorbidities.
Acute limb ischaemia
This is most frequently caused by acute thrombotic occlusion of
a pre-existing stenotic arterial segment, thromboembolism, and
trauma that may be iatrogenic. The typical presentation is with
paralysis (inability to wiggle toes/fingers) and paraesthesia (loss
of light touch over the dorsum of the foot/hand), the so-called
‘Ps of acute ischaemia’ (Box 16.57). These features are non¬
specific, however, and inconsistently related to its severity.
Pain on squeezing the calf indicates muscle infarction and
impending irreversible ischaemia. All patients with suspected
acutely ischaemic limbs must be discussed immediately with a
vascular surgeon; a few hours can make the difference between
death/amputation and complete recovery of limb function.
If there are no contraindications (acute aortic dissection or
PH 16.57 Symptoms AND signs of acute limb ischaemia
Symptoms/signs
Comment
Pain
Pallor
Pulselessness
May be absent in complete acute ischaemia,
and can be present in chronic ischaemia
Perishing cold
Unreliable, as the ischaemic limb takes on
the ambient tempetature
Paraesthesia
Paralysis
Important features of impending irreversible
1 ischaemia
Fig. 16.71 Progressive night pain and the development of
tissue loss.
trauma, particularly head injury), an intravenous bolus of heparin
(3000-5000 U) should be administered to limit propagation of
thrombus and protect the collateral circulation. Distinguishing
thrombosis from embolism is frequently difficult but is important
because treatment and prognosis are different (Box 16.58).
Acute limb ischaemia due to thrombosis in situ can usually be
treated medically in the first instance with intravenous heparin
(target activated partial thromboplastin time (APTT) 2. 0-3.0),
antiplatelet agents, high-dose statins, intravenous fluids to avoid
dehydration, correction of anaemia, oxygen and sometimes
prostaglandins, such as iloprost. Embolism will normally result
in extensive tissue necrosis within 6 hours unless the limb is
revascularised. The indications for thrombolysis, if any, remain
controversial. Irreversible ischaemia mandates early amputation
or palliative care.
Atheroembolism
This may be a presenting feature of PAD affecting the subclavian
arteries. The presentation is with blue fingers, which are due to
504 • CARDIOLOGY
HB 16.58 Distinguishing features of embolism and
thrombosis in peripheral arteries
Clinical features
Embolism
Thrombosis
Severity
Complete (no
collaterals)
Incomplete
(collaterals)
Onset
Seconds or minutes
Hours or days
Limb
Leg 3 : 1 arm
Leg 1 0 : 1 arm
Multiple sites
Up to 15%
Rare
Embolic source
Present (usually
atrial fibrillation)
Absent
Previous claudication
Absent
Present
Palpation of artery
Soft, tender
Hard, calcified
Bruits
Absent
Present
Contralateral leg pulses
Present
Absent
Diagnosis
Clinical
Angiography
Treatment
Embolectomy,
warfarin
Medical, bypass,
thrombolysis
Prognosis
Loss of life > loss
of limb
Loss of limb >
loss of life
16.59 Clinical features of chronic lower
limb ischaemia
• Pulses: diminished or absent
• Bruits: denote turbulent flow but bear no relationship to the severity
of the underlying disease
• Reduced skin temperature
• Pallor on elevation and rubor on dependency (Buerger’s sign)
• Superficial veins that fill sluggishly and empty (‘gutter’) on minimal
elevation
• Muscle- wasting
• Skin and nails: dry, thin and brittle
• Loss of hair
small emboli lodging in digital arteries. This may be confused
with Raynaud’s phenomenon (p. 1035) but the symptoms of
atheroembolism are typically unilateral rather than bilateral as
in Raynaud’s.
Subclavian steal
This can be a feature of PAD affecting the upper limbs. The
presentation is with dizziness, cortical blindness and/or collapse,
which occurs when the arm is used and is thought to be caused
by diversion (or steal) of blood from the brain to the limbs via
the vertebral artery.
Investigations
The presence and severity of ischaemia can usually be determined
by clinical examination (Box 1 6.59) and measurement of the
ankle-brachial pressure index (ABPI), which is the ratio between
the highest systolic ankle and brachial blood pressures. In health,
the ABPI is over 1 .0, in 1C typically 0.5-0.9 and in CLI usually less
than 0.5. Further investigation with duplex ultrasonography, MRI
or CT with intravenous injection of contrast agents may be used
to characterise the sites of involvement further. Intra-arterial digital
subtraction angiography (IA-DSA) is usually reserved for those
undergoing endovascular revascularisation. Other investigations
should include a full blood count to look for evidence of treatable
secondary causes, such as thrombocythaemia; measurement of
16.60 Medical therapy for peripheral arterial disease
• Smoking cessation
• Regular exercise (30 mins of walking, three times per week)
• Antiplatelet agent (aspirin 75 mg or clopidogrel 75 mg daily)
• Reduction of cholesterol:
Statins
Diet
Weight loss
• Diagnosis and treatment of diabetes mellitus
• Diagnosis and treatment of associated conditions:
Hypertension
Anaemia
Heart failure
lipids to check for evidence of hyperlipidaemia; and measurement
of blood glucose to check for evidence of diabetes.
Management
Key elements of medical management are summarised in Box
16.60. This consists of smoking cessation (if applicable), taking
regular exercise, antiplatelet therapy with low-dose aspirin or
clopidogrel, therapy with a statin, and treatment of coexisting
disease such as diabetes, hypertension or polycythaemia.
Recently, the antiplatelet drug vorapaxar, a selective antagonist of
the protease-activated receptor 1 (PAR-1) that regulates platelet
activation, has been licensed in combination with either aspirin
or clopidogrel in patients with PAD. The peripheral vasodilator
cilostazol has been shown to improve walking distance and
should be considered in patients who do not respond adequately
to best medical therapy. Intervention with angioplasty, stenting,
endarterectomy or bypass is usually considered only after medical
therapy has been given at least 6 months to effect symptomatic
improvement, and then just in patients who are severely disabled
or whose livelihood is threatened by their disability. Subclavian
artery disease is usually treated by means of angioplasty
and stenting, as carotid-subclavian bypass surgery can be
technically difficult.
Buerger’s disease
Buerger’s disease or thromboangiitis obliterans is an inflammatory
disease of the arteries that is distinct from atherosclerosis and
usually presents in young (20-30 years) male smokers. It is
most common in those from the Mediterranean and North
Africa. It characteristically affects distal arteries, giving rise to
claudication in the feet or rest pain in the fingers or toes. Wrist
and ankle pulses are absent but brachial and popliteal pulses
are present. It may also affect the veins, giving rise to superficial
thrombophlebitis. It often remits if the patient stops smoking.
Symptomatic therapy with vasodilators such as prostacyclin and
calcium antagonists or sympathectomy may also be helpful. Major
limb amputation is the most frequent outcome if patients continue
to smoke.
|Raynaud’s syndrome
This common disorder affects 5-10% of young women aged
15-30 years in temperate climates. It does not progress to
ulceration or infarction, and significant pain is unusual. The
underlying cause is unclear and no investigation is necessary.
The patient should be reassured and advised to avoid exposure
to cold. Usually, no other treatment is required, although
Diseases of the aorta • 505
• Prevalence: related almost exponentially to age in developed
countries, although atherosclerosis is not considered part of the
normal ageing process.
• Statin therapy: no role in the primary prevention of atherosclerotic
disease in those over 75 years but reduces cardiovascular events in
those with established vascular disease, albeit with no reduction in
overall mortality.
• Presentation in the frail: frequently with advanced multisystem
arterial disease, along with a host of other comorbidities.
• Intervention in the frail: in those with extensive disease and
limited life expectancy, the risks of surgery may outweigh the
benefits, and symptomatic care is all that should be offered.
vasodilators such as nifedipine can may be helpful if symptoms are
troublesome. More severe Raynaud’s syndrome can also occur
in association with digital ulceration in patients with connective
tissue disease. This is discussed in more detail on page 1035.
Diseases of the aorta
Aortic aneurysm
Aortic aneurysm is defined to exist when there is an abnormal
dilatation of the aortic lumen. The most common site is the
infrarenal abdominal aorta. The suprarenal abdominal aorta
and a variable length of the descending thoracic aorta may be
affected in 10-20% of patients but the ascending aorta is usually
spared. Abdominal aortic aneurysms (AAAs) affect men three
times more commonly than women and are estimated to occur
in about 5% of men over the age of 60 years.
Pathogenesis
The most common cause of aortic aneurysm is atherosclerosis,
the risk factors for which have previously been described (p. 484).
Genetic factors that predispose to hypertension, hyperlipidaemia
and diabetes all play a role in the pathogenesis of aortic aneurysm
but there appears to be an additional and specific genetic
component since aortic aneurysm tends to run in families. This
may explain in part why only some patients with risk factors
for atheroma develop aneurysmal disease. Marfan’s syndrome
is an inherited disorder of connective tissue that is associated
with aortic aneurysm and aortic dissection (p. 508). The features
and management of this disorder are discussed on page 508.
Clinical features
The clinical presentation is dependent on the site of the aneurysm.
Thoracic aneurysms may typically present with acute severe chest
pain (p. 176) but other features, including aortic regurgitation,
compressive symptoms such as stridor (trachea, bronchus),
hoarseness (recurrent laryngeal nerve) and superior vena cava
syndrome, may occur (Fig. 16.72A). If the aneurysm erodes into
an adjacent structure, such as the oesophagus or bronchus,
the presentation may be with massive bleeding. AAAs affect the
infrarenal segment of the aorta. They can present in a number of
ways, as summarised in Box 1 6.62. The usual age at presentation
is 65-75 years for elective presentations and 75-85 years for
emergency presentations.
16.62 Abdominal aortic aneurysm (AAA):
common presentations
Incidental
• On physical examination, plain X-ray or, most commonly, abdominal
ultrasound
• Even large AAAs can be difficult to feel, so many remain undetected
until they rupture
• Studies are currently under way to determine whether screening will
reduce the number of deaths from rupture
Pain
• In the central abdomen, back, loin, iliac fossa or groin
Thromboembolic complications
• Thrombus within the aneurysm sac may be a source of emboli to
the lower limbs
• Less commonly, the aorta may undergo thrombotic occlusion
Compression
• Surrounding structures such as the duodenum (obstruction and
vomiting) and the inferior vena cava (oedema and deep vein
thrombosis)
Rupture
• Into the retroperitoneum, the peritoneal cavity or surrounding
structures (most commonly the inferior vena cava, leading to an
aortocaval fistula)
Investigations
Ultrasound is the best way of establishing the diagnosis of
an abdominal aneurysm and of following up patients with
asymptomatic aneurysms that are not yet large enough to warrant
surgical repair. In the UK, a national screening programme for
men over 65 years of age has been introduced using ultrasound
scanning. For every 10 000 men scanned, 65 ruptures are
prevented and 52 lives saved. CT provides more accurate
information about the size and extent of the aneurysm, the
surrounding structures and the presence of any other intra¬
abdominal pathology. It is the standard pre-operative investigation
but is not suitable for surveillance because of the high cost and
radiation dose.
Management
The risks of surgery generally outweigh the risks of rupture until
an asymptomatic AAA has reached a maximum of 5.5 cm in
diameter. All symptomatic AAAs should be considered for repair,
not only to rid the patient of symptoms but also because pain
often predates rupture. Distal embolisation is a strong indication
for repair, regardless of size, because otherwise limb loss is
common. Most patients with a ruptured AAA do not survive
to reach hospital, but if they do and surgery is thought to be
appropriate, there must be no delay in getting them to the
operating theatre to clamp the aorta.
Open AAA repair has been the treatment of choice in both
the elective and the emergency settings, and entails replacing
the aneurysmal segment with a prosthetic (usually Dacron)
graft. The 30-day mortality for this procedure is approximately
5-8% for elective asymptomatic AAA, 1 0-20% for emergency
symptomatic AAA and 50% for ruptured AAA. However,
patients who survive the operation to leave hospital have a
long-term survival approaching that of the normal population.
Increasingly, endovascular aneurysm repair (EVAR), using a
stent graft introduced via the femoral arteries in the groin, is
16.61 Atherosclerotic vascular disease in old age
506 • CARDIOLOGY
DILATED THORACIC SACCULAR THORACIC
Aortic dissection
JWL
Coronary M >
occlusionjpA.J
-( Type A )-
Aorti/
regurgitation
Neurological
deficit
Loss of
arm pulse
Renal or
mesenteric
occlusion
Loss of
leg pulse
Fig. 16.72 Types of aortic disease and their complications. [A] Types of aortic aneurysm, [j] Types of aortic dissection.
replacing open surgery. It is cost-effective and likely to become
the treatment of choice for infrarenal AAA. It is possible to treat
many suprarenal and thoraco-abdominal aneurysms by EVAR too.
If the aneurysm is secondary to Marfan’s syndrome, treatment
with (3-blockers reduces the rate of aortic dilatation and the risk
of rupture. Elective replacement of the ascending aorta may also
be considered in patients with evidence of progressive aortic
dilatation but carries a mortality of 5-10%.
Aortic dissection
Aortic dissection occurs when a breach in the integrity of the
aortic wall allows arterial blood to enter the media, which is
then split into two layers, creating a false lumen alongside the
existing or true lumen (Fig. 16.72B). The aortic valve may be
damaged and the branches of the aorta may be compromised.
Typically, the false lumen eventually re-enters the true lumen,
creating a double-barrelled aorta, but it may also rupture into
the left pleural space or pericardium with fatal consequences.
The peak incidence is in the sixth and seventh decades but
dissection can occur in younger patients, usually in association
with Marfan’s syndrome, pregnancy or trauma; men are affected
twice as frequently as women.
Pathogenesis
The primary event is often a spontaneous or iatrogenic tear in the
intima of the aorta; multiple tears or entry points are common.
Other dissections are triggered by primary haemorrhage in the
media of the aorta, which then ruptures through the intima into
the true lumen. This form of spontaneous bleeding from the
vasa vasorum is sometimes confined to the aortic wall, when it
may present as a painful intramural haematoma. Aortic disease
and hypertension are the most important aetiological factors but
other conditions may also be implicated (Box 16.63). Chronic
dissections may lead to aneurysmal dilatation of the aorta, and
thoracic aneurysms may be complicated by dissection. It can
therefore be difficult to identify the primary pathology.
Diseases of the aorta • 507
Aortic dissection is classified anatomically and for management
purposes into type A and type B (see Fig. 16.72B), involving or
sparing the ascending aorta, respectively. Type A dissections
account for two-thirds of cases and frequently also extend into
the descending aorta.
Clinical features
Involvement of the ascending aorta typically gives rise to anterior
chest pain, and involvement of the descending aorta to intrascapular
back pain. The pain is typically described as ‘tearing’ and very
abrupt in onset; collapse is common. Unless there is major
haemorrhage, the patient is invariably hypertensive. There may be
asymmetry of the brachial, carotid or femoral pulses and signs of
aortic regurgitation. Occlusion of aortic branches may cause Ml
(coronary), stroke (carotid), paraplegia (spinal), mesenteric infarction
with an acute abdomen (coeliac and superior mesenteric), renal
failure (renal) and acute limb (usually leg) ischaemia.
i
16.63 Risk factors for aortic dissection
• Hypertension (in 80%)
• Pregnancy (usually third
• Atherosclerosis
trimester)
• Coarctation
• Trauma
• Genetic:
• Iatrogenic:
Marfan’s syndrome
Ehlers— Danlos syndrome
• Fibromuscular dysplasia
• Previous cardiac surgery:
CABG
Aortic valve replacement
Cardiac catheterisation
Intra-aortic balloon pumping
(CABG
= coronary artery bypass grafting)
Investigations
The investigations of choice are CT or MR angiography (Figs 1 6.73
and 1 6.74), both of which are highly specific and sensitive. A chest
X-ray should be performed. It characteristically shows broadening
of the upper mediastinum and distortion of the aortic ‘knuckle’
but these findings are absent in 10% of cases. A left-sided
pleural effusion is common. The ECG may show left ventricular
hypertrophy in patients with hypertension or, rarely, changes
Fig. 16.73 Sagittal view of an MRI scan from a patient with
long-standing aortic dissection, illustrating a biluminal aorta. There is
sluggish flow in the false lumen (FL), accounting for its grey appearance.
(TL = true lumen)
Fig. 16.74 Images from a patient with an acute type B aortic dissection that had ruptured into the left pleural space and was repaired by
deploying an endoluminal stent graft. [A] CT scan illustrating an intimal flap (arrow) in the descending aorta and a large pleural effusion. [j| Aortogram
illustrating aneurysmal dilatation; a stent graft has been introduced from the right femoral artery and is about to be deployed. [C] CT scan after endoluminal
repair. The pleural effusion has been drained but there is a haematoma around the descending aorta. [D] Aortogram illustrating the stent graft. [E] Three-
dimensional reconstruction of an aortic stent graft. E, Courtesy of Dr T. Lawton.
508 • CARDIOLOGY
Fig. 16.75 Echocardiograms from a patient with a chronic aortic
dissection. Colour flow Doppler shows flow from the larger false lumen
(FL) into the true lumen (TL), characteristic of chronic disease.
of acute Ml (usually inferior). Doppler echocardiography may
show aortic regurgitation, a dilated aortic root and, occasionally,
the flap of the dissection. TOE is particularly helpful because
transthoracic echocardiography can provide images of the first
3-4 cm of the ascending aorta only (Fig. 16.75).
Management
The early mortality of acute dissection is approximately 1-5% per
hour and so treatment is urgently required. Initial management
comprises pain control and antihypertensive treatment. Type A
dissections require emergency surgery to replace the ascending
aorta. Type B aneurysms are treated medically unless there is
actual or impending external rupture, or vital organ (gut, kidneys)
or limb ischaemia, as the morbidity and mortality associated
with surgery are very high. The aim of medical management is
to maintain a mean arterial pressure (MAP) of 60-75 mmHg to
reduce the force of the ejection of blood from the LV. First-line
therapy is with (3-blockers; the additional a-blocking properties of
labetalol make it especially useful. Rate-limiting calcium channel
blockers, such as verapamil or diltiazem, are used if p-blockers
are contraindicated. Sodium nitroprusside may be considered
if these fail to control BP adequately.
Percutaneous or minimal access endoluminal repair is
sometimes possible and involves either ‘fenestrating’ (perforating)
the intimal flap so that blood can return from the false to the
true lumen (so decompressing the former), or implanting a stent
graft placed from the femoral artery (see Fig. 16.74).
Aortitis
Syphilis is a rare cause of aortitis that characteristically produces
saccular aneurysms of the ascending aorta containing calcification.
Other rare conditions associated with aortitis include Takayasu’s
disease (p. 1041), reactive arthritis (p. 1031), giant cell arteritis
(p. 1042) and ankylosing spondylitis (p. 1028).
Marfan’s syndrome
Marfan’s syndrome is an inherited disorder of connective
tissue that is associated with a high risk of aortic aneurysm
and dissection. It is inherited in an autosomal dominant manner
but some cases are due to new mutations. It is a rare disorder
that is estimated to affect about 0.02% of the population.
Marfan’s syndrome is caused by protein-coding mutations
affecting the FBN1 gene, which encodes fibrillin, an extracellular
matrix protein. The causal mutations disrupt the mechanical
integrity of connective tissue, giving rise to a wide range of
clinical features.
Clinical features
Aortic dissection and aneurysm are the most serious complications
of Marfan’s syndrome but many other clinical manifestations may
be observed. These include aortic and mitral valve regurgitation;
skin laxity and joint hypermobility; abnormalities of body habitus,
including long arms, legs and fingers (arachnodactyly), scoliosis,
pectus excavatum and a high-arched palate; ocular abnormalities,
such as lens dislocation and retinal detachment; and an increased
risk of pneumothorax.
Investigations
The diagnosis is usually suspected on the basis of the
characteristic clinical features and can be confirmed by genetic
testing. Imaging by chest X-ray may reveal evidence of aortic
dilatation but echocardiography is more sensitive and can also
demonstrate valvular disease, if present. Patients with Marfan’s
syndrome should undergo serial monitoring of the aortic root
by echocardiography; if evidence of dilatation is observed, then
elective surgery should be considered.
Management
Treatment with (3-blockers reduces the risk of aortic dilatation and
should be given in all patients with Marfan’s syndrome. Activities
that are associated with increases in cardiac output are best
avoided. Surgery to replace the aortic root can be performed
in patients with progressive aortic dilatation.
Coarctation of the aorta
Coarctation of the aorta is the term used to describe a narrowing
distal to the origin of the left subclavian artery. It is most commonly
due to congenital heart disease (p. 531), but narrowing of the
aorta leading to similar symptoms can occur in other conditions
such as Takayasu’s arteritis (p. 1041) and trauma. Diagnosis
and management of coarctation are discussed on page 534.
Hypertension
The risk of cardiovascular diseases such as stroke and CAD is
closely related to levels of BP. BP follows a normal distribution in
the general population and there is no specific cut-off above which
the risk of cardiovascular risk suddenly increases. The diagnosis of
hypertension is therefore made when systolic and diastolic values
rise above a specific threshold that corresponds to the level of
BP at which the risk of cardiovascular complications and benefits
of treatment outweigh the treatment costs and potential side-
effects of therapy. The British Hypertension Society classification,
provided in Box 16.64, defines mild hypertension as existing
when the BP is above 140/90 mmHg. Similar thresholds have
been published by the European Society of Hypertension and the
WHO-International Society of Hypertension. The cardiovascular
risks associated with high BP depend on the combination of risk
factors in an individual, such as age, gender, weight, physical
activity, smoking, family history, serum cholesterol, diabetes
mellitus and pre-existing vascular disease.
Diseases of the aorta • 509
i
16.64 Definition of hypertension
Category
Systolic blood
pressure (mmHg)
Diastolic blood
pressure (mmHg)
Blood pressure
Optimal
<120
<80
Normal
<130
85
High normal
130-139
85-89
Hypertension
Grade 1 (mild)
140-159
90-99
Grade 2 (moderate)
160-179
100-109
Grade 3 (severe)
>180
>110
Isolated systolic hypertension
Grade 1
140-159
<90
Grade 2
>160
<90
16.65 Causes of secondary hypertension
Alcohol
Obesity
Pregnancy
Renal disease
• Parenchymal renal disease,
particularly glomerulonephritis
Endocrine disease
• Phaeochromocytoma
• Cushing’s syndrome
• Primary hyperaldosteronism
(Conn’s syndrome)
• Glucocorticoid-suppressible
hyperaldosteronism
• Hyperparathyroidism
• Acromegaly
Drugs
Coarctation of the aorta
Renal vascular disease
Polycystic kidney disease
Primary hypothyroidism
Thyrotoxicosis
Congenital adrenal hyperplasia
due to 1 1 (3-hydroxylase or
17a- hydroxylase deficiency
Liddle’s syndrome (p. 361)
1 1 p-hydroxysteroid
dehydrogenase deficiency
Pathogenesis
Many factors may contribute to the regulation of BP and the
development of hypertension, including renal dysfunction,
peripheral resistance, vessel tone, endothelial dysfunction,
autonomic tone, insulin resistance and neurohumoral factors. In
more than 95% of cases, however, no specific underlying cause
of hypertension can be found. Such patients are said to have
essential hypertension. Hypertension is more common in some
ethnic groups, particularly African Americans and Japanese, and
approximately 40-60% is explained by genetic factors. Age is a
strong risk factor in all ethnic groups. Important environmental
factors include a high salt intake, heavy consumption of alcohol,
obesity and lack of exercise. Impaired intrauterine growth and low
birth weight are associated with an increased risk of hypertension
later in life. In about 5% of cases, hypertension is secondary to
a specific disease, as summarised in Box 16.65.
Hypertension has a number of adverse effects on the
cardiovascular system. In larger arteries (>1 mm in diameter),
the internal elastic lamina is thickened, smooth muscle is
hypertrophied and fibrous tissue is deposited. The vessels dilate
and become tortuous, and their walls become less compliant.
In smaller arteries (<1 mm), hyaline arteriosclerosis occurs in
the wall, the lumen narrows and aneurysms may develop.
Widespread atheroma develops and may lead to coronary
Fig. 16.76 Retinal changes in hypertension. [A] Grade 4 hypertensive
retinopathy showing swollen optic disc, retinal haemorrhages and multiple
cotton wool spots (infarcts). [S] Central retinal vein thrombosis showing
swollen optic disc and widespread fundal haemorrhage, commonly
associated with systemic hypertension. A and B, Courtesy of Dr B. Cullen.
and cerebrovascular disease, particularly if other risk factors
are present. These structural changes in the vasculature often
perpetuate and aggravate hypertension by increasing peripheral
vascular resistance and reducing renal blood flow, thereby
activating the renin-angiotensin-aldosterone axis (p. 461).
Clinical features
Hypertension is usually asymptomatic until the diagnosis is made
at a routine physical examination or when a complication arises.
Reflecting this fact, a BP check is advisable every 5 years in adults
over 40 years of age to pick up occult hypertension. Sometimes
clinical features may be observed that can give a clue to the
underlying cause of hypertension. These include radio-femoral
delay in patients with coarctation of the aorta (see Fig. 16.93,
p. 534), enlarged kidneys in patients with polycystic kidney
disease (p. 405), abdominal bruits that may suggest renal artery
stenosis (p. 406), and the characteristic facies and habitus of
Cushing’s syndrome (Box 16.65). Examination may also reveal
evidence of risk factors for hypertension, such as central obesity
and hyperlipidaemia. Other signs may be observed that are due
to the complications of hypertension. These include signs of left
ventricular hypertrophy, accentuation of the aortic component
of the second heart sound, and a fourth heart sound. AF is
common and may be due to diastolic dysfunction caused by
left ventricular hypertrophy or the effects of CAD.
Severe hypertension can cause left ventricular failure in the
absence of CAD, particularly when there is an impairment of
renal function. The optic fundi are often abnormal (see Fig. 16.76
below) and there may be evidence of generalised atheroma or
510 • CARDIOLOGY
16.66 Hypertensive retinopathy
Grade 1
• Arteriolar thickening, tortuosity and increased reflectiveness
(‘silver wiring’)
Grade 2
• Grade 1 plus constriction of veins at arterial crossings
(‘arteriovenous nipping’)
Grade 3
• Grade 2 plus evidence of retinal ischaemia (flame-shaped or blot
haemorrhages and ‘cotton wool’ exudates)
Grade 4
• Grade 3 plus papilloedema
16.67 How to measure blood pressure
• Use a machine that has been validated, well maintained and
properly calibrated
• Measure sitting BP routinely, with additional standing BP in elderly
and diabetic patients and those with possible postural hypotension;
rest the patient for 2 minutes
• Remove tight clothing from the arm
• Support the arm at the level of the heart
• Use a cuff of appropriate size (the bladder must encompass more
than two-thirds of the arm)
• Lower the pressure slowly (2 mmHg per second)
• Read the BP to the nearest 2 mmHg
• Use phase V (disappearance of sounds) to measure diastolic BP
• Take two measurements at each visit
specific complications, such as aortic aneurysm, PAD or stroke.
Examination of the optic fundi reveals a gradation of changes
linked to the severity of hypertension; fundoscopy can, therefore,
provide an indication of the arteriolar damage occurring elsewhere
(Box 16.66). ‘Cotton wool’ exudates are associated with retinal
ischaemia or infarction, and fade in a few weeks (Fig. 16.76A).
‘Hard’ exudates (small, white, dense deposits of lipid) and
microaneurysms (‘dot’ haemorrhages) are more characteristic
of diabetic retinopathy (see Fig. 27.8, p. 1176). Hypertension is
also associated with central retinal vein thrombosis (Fig. 16.76B).
Investigations
A decision to embark on antihypertensive therapy effectively
commits the patient to life-long treatment, so readings must be
as accurate as possible. The objectives are to:
• confirm the diagnosis by obtaining accurate, representative
BP measurements
• identify contributory factors and any underlying causes
• assess other risk factors and quantify cardiovascular risk
• detect any complications that are already present
• identify comorbidity that may influence the choice of
antihypertensive therapy.
Blood pressure measurements
BP measurements should be made to the nearest 2 mmHg,
in the sitting position with the arm supported, and repeated
after 5 minutes’ rest if the first recording is high (Box 16.67).
To avoid spuriously high readings in obese subjects, the cuff
should contain a bladder that encompasses at least two-thirds
of the arm circumference. Exercise, anxiety, discomfort and
unfamiliar surroundings can all lead to a transient rise in BP.
Sphygmomanometry, particularly when performed by a doctor,
can cause a transient elevation in BP, which has been termed
‘white coat’ hypertension. It has been estimated that up to 20%
of patients who are found to have raised BP at outpatient clinics
have a normal BP when it is recorded by automated devices used
at home. The risk of cardiovascular disease in these patients is
less than that in patients with sustained hypertension but greater
than that in normotensive subjects. If clinic BP measurements
show borderline levels of BP or if white coat hypertension is
suspected, then ambulatory measurement or home-based
measurements may be of value in confirming the diagnosis.
Ambulatory blood pressure measurements
A series of automated ambulatory BP measurements obtained
over 24 hours or longer provide a better profile than a limited
16.68 Investigation of hypertension
• Urinalysis for blood, protein and glucose
• Blood urea, electrolytes and creatinine
Hypokalaemic alkalosis may indicate primary hyperaldosteronism
but is usually due to diuretic therapy
• Blood glucose
• Serum total and HDL cholesterol
• Thyroid function tests
• 12-lead ECG (left ventricular hypertrophy, coronary artery disease)
(HDL = high-density lipoprotein)
number of clinic readings and correlate more closely with evidence
of target organ damage than casual BP measurements. Treatment
thresholds and targets (see Box 16.71 below) must be adjusted
downwards, however, because ambulatory BP readings are
systematically lower (approximately 12/7 mmHg) than clinic
measurements. The average ambulatory daytime (not 24-hour or
night-time) BP should be used to guide management decisions.
Home blood pressure measurements
Patients can measure their own BP at home using a range of
commercially available semi-automatic devices. The value of
such measurements is less well established and is dependent on
the environment and timing of the readings measured. Home or
ambulatory BP measurements are particularly helpful in patients
with unusually labile BP, those with refractory hypertension, those
who may have symptomatic hypotension, and those in whom
white coat hypertension is suspected.
Other investigations
All hypertensive patients should undergo a limited number
of investigations (Box 16.68) but additional investigations are
appropriate in patients younger than 40 years of age or those
with resistant hypertension (Box 16.69). Family history, lifestyle
(exercise, salt intake, smoking habit) and other risk factors should
also be recorded. A careful history will identify those patients
with drug- or alcohol-induced hypertension and may elicit the
symptoms of other causes of secondary hypertension, such as
phaeochromocytoma (paroxysmal headache, palpitation and
sweating, p. 675) or complications such as CAD.
Management
The objective of antihypertensive therapy is to reduce the
incidence of adverse cardiovascular events, particularly CAD,
stroke and heart failure. Randomised controlled trials have
Diseases of the aorta • 511
demonstrated that antihypertensive therapy can reduce the
incidence of stroke and, to a lesser extent, CAD. The relative
benefits (approximately 30% reduction in risk of stroke and 20%
reduction in risk of CAD) are similar in all patient groups, so the
absolute benefit of treatment (total number of events prevented)
16.69 Specialised investigation of hypertension
• Chest X-ray: to detect cardiomegaly, heart failure, coarctation of the
aorta
• Ambulatory BP recording: to assess borderline or ‘white coat’
hypertension
• Echocardiogram: to detect or quantify left ventricular hypertrophy
• Renal ultrasound: to detect possible renal disease
• Renal angiography: to detect or confirm the presence of renal artery
stenosis
• Urinary catecholamines: to detect possible phaeochromocytoma
(p. 675)
• Urinary cortisol and dexamethasone suppression test: to detect
possible Cushing’s syndrome (p. 666)
• Plasma renin activity and aldosterone: to detect possible primary
aldosteronism (p. 674)
Non-diabetic men
Non-smoker Smoker
Age under 50 years
180 r
i i i i i i i i i — i — i — i — i — i — i — i
345678910 345678910
TC:HDL TC:HDL
Age 50-59 years
180 r
I _ I _ I _ I _ I _ I _ I _ I I _ I _ I _ I _ I _ I _ I _ I
345678910 345678910
TC:HDL TC:HDL
Age 60 years and over
180 r
I _ I _ I _ I _ I _ I _ I _ I
345678910
TC:HDL
I _ I _ I _ I _ I _ I _ I _ I
345678910
TC:HDL
ft \
| | CVD risk < 10% over next 10 years
| | CVD risk 1 0-20% over next 1 0 years
| | CVD risk > 20% over next 1 0 years
SBP = systolic blood pressure (mmHg)
TC:HDL = serum total cholesterol to HDL cholesterol ratio
v.
CVD risk over
next 1 0 years
30%
10% 20%
is greatest in those at highest risk. For example, to extrapolate
from the Medical Research Council (MRC) Mild Hypertension
Trial (1985), 566 young patients would have to be treated with
bendroflumethiazide for 1 year to prevent 1 stroke, while in the
MRC trial of anti hypertensive treatment in the elderly (1992), 1
stroke was prevented for every 286 patients treated for 1 year.
A formal estimate of absolute cardiovascular risk, which takes
account of all the relevant risk factors, may help to determine
whether the likely benefits of therapy will outweigh its costs and
hazards. A variety of risk algorithms are available for this purpose,
such as the Joint British Societies risk calculator (Fig. 1 6.77 and see
‘Further information’). Most of the excess morbidity and mortality
associated with hypertension are attributable to CAD and many
treatment guidelines are therefore based on estimates of the
10-year CAD risk. Total cardiovascular risk can be estimated by
multiplying CAD risk by 4/3 (i.e. if CAD risk is 30%, cardiovascular
risk is 40%). The value of this approach can be illustrated by
comparing the two hypothetical cases on page 487.
Intervention thresholds
Systolic BP and diastolic BP are both powerful predictors of
cardiovascular risk. The British Hypertension Society management
Fig. 16.77 Example of cardiovascular risk prediction chart for
non-diabetic men. Cardiovascular risk is predicted from the patient’s age,
sex, smoking habit, BP and cholesterol ratio. The ratio of total to
high-density lipoprotein (HDL) cholesterol can be determined in a
non-fasting blood sample. Where HDL cholesterol concentration is
unknown, it should be assumed to be 1 mmol/L; the lipid scale should be
used as total serum cholesterol. Current guidelines suggest initiation of
primary prevention in individuals with a 10-year cardiovascular risk >20%.
Patients with diabetes mellitus should be assumed to have a 1 0-year
cardiovascular risk of >20% and receive secondary prevention therapy.
Modified charts exist for women. For further details, see www.who.int/
cardiovascular_diseases/guidelines/Pocket_GLJnformation.
• To estimate an individual’s absolute 10-year risk of developing
cardiovascular disease (CVD), choose the panel for the appropriate
gender, smoking status and age. Within this, define the level of risk from
the point where the coordinates for systolic blood pressure (SBP) and
ratio of the total to HDL-cholesterol cross.
• Highest-risk individuals (red areas) are those whose 10-year CVD risk
exceeds 20%, which is approximately equivalent to a 10-year coronary
artery disease risk of >15%. As a minimum, those with CVD risk >30%
(shown by the line within the red area) should be targeted and treated
now. When resources allow, others with a CVD risk >20% should be
targeted progressively.
• The chart also assists in identification of individuals with a moderately
high 10-year CVD risk, in the range of 10-20% (orange area) and those
in whom it is <10% (green area).
• Smoking status should reflect lifetime exposure to tobacco. For further
information, see www.bhf.org.uk.
From Joint British Societies Cardiovascular Risk Prediction Chart,
reproduced with permission from the University of Manchester.
512 • CARDIOLOGY
Clinic blood pressure
< 140/90 mmHg
Normotensive
Clinic blood pressure
> 140/90 mmHg
Clinic blood pressure
> 180/110 mmHg
If accelerated
hypertension1
or suspected
phaeochromocytoma2
Consider starting hypertensive
drug treatment immediately
T
Offer ABPM (or HBPM if ABPM is declined
or not tolerated)
Offer to assess cardiovascular risk
and target organ damage
r
ABPM/HBPM
ABPM/HBPM
Refer
same day
for
specialist
care
ABPM/HBPM
< 135/85 mmHg
Normotensive
If evidence
of target organ
damage
> 135/85 mmHg
Stage 1 hypertension
> 150/95 mmHg
Stage 2 hypertension
Consider alternative
causes for target
organ damage
If target organ damage
present or 1 0-yr
cardiovascular risk > 20% Offer
antihypertensive
drug treatment
If < 40 yrs Consider
specialist
referral
Offer to check blood pressure
at least every 5 yrs, more
often if blood pressure is close
to 140/90 mmHg
i
Offer lifestyle interventions
I
Offer patient education and interventions to support
adherence to treatment
Offer annual review of care to monitor blood pressure, provide
support and discuss lifestyle, symptoms and medication
Fig. 16.78 Management of hypertension: British Hypertension Society guidelines. 1Signs of papilloedema or retinal haemorrhage. 2Labile or postural
hypotension, headache, palpitations, pallor and diaphoresis. (ABPM = ambulatory blood pressure monitoring; HBPM = home blood pressure monitoring)
From NICE Clinical Guideline 127 - Hypertension in adults; August 201 1.
guidelines therefore utilise both readings, and treatment should
be initiated if they exceed the given threshold (Fig. 16.78).
Patients with diabetes or cardiovascular disease are at
particularly high risk and the threshold for initiating anti hypertensive
therapy is therefore lower (>140/90 mmHg) in these patient
groups. The thresholds for treatment in the elderly are the same
as for younger patients (Box 16.70).
Treatment targets
The optimum BP for reduction of major cardiovascular events
has been found to be 139/83 mmHg, and even lower in
patients with diabetes mellitus. Moreover, reducing BP below
this level causes no harm. The targets suggested by the British
Hypertension Society (Box 16.71) are ambitious. Primary care
strategies have been devised to improve screening and detection
of hypertension that, in the past, remained undetected in up to half
16.70 Hypertension in old age
• Prevalence: hypertension affects more than half of all people
over the age of 60 years (including isolated systolic
hypertension).
• Risks: hypertension is the most important risk factor for myocardial
infarction, heart failure and stroke in older people.
• Benefit of treatment: absolute benefit from therapy is greatest in
older people (at least up to age 80 years).
• Target blood pressure: targets be relaxed in older people
to 150/90 mmHg.
• Tolerance of treatment: antihypertensives are tolerated as well as
in younger patients.
• Drug of choice: low-dose thiazides but, in the presence of
coexistent disease such as gout or diabetes, other agents may be
more appropriate.
Diseases of the aorta • 513
i
16.71 Optimal target blood pressures
Age
Ambulatory or home
Clinic BP (mmHg) BP (mmHg)2
<80 years
<140/90 <135/85
>80 years
<150/90 <140/85
'Both systolic and diastolic values should be attained. Average BP during waking
hours.
of affected individuals. Application of new guidelines should help
establish patients on appropriate treatment, and allow step-up if
lifestyle modification and first-line drug therapy fail to control
hypertension.
Patients taking antihypertensive therapy require follow-up
at regular intervals to monitor BP, minimise side-effects and
reinforce lifestyle advice.
Non-drug therapy
Appropriate lifestyle measures may obviate the need for drug
therapy in patients with borderline hypertension, reduce the dose
and/or the number of drugs required in patients with established
hypertension, and directly reduce cardiovascular risk.
Correcting obesity, reducing alcohol intake, restricting
salt intake, taking regular physical exercise and increasing
consumption of fruit and vegetables can all lower BP. Moreover,
stopping smoking, eating oily fish and adopting a diet that is low
in saturated fat may produce further reductions in cardiovascular
risk that are independent of changes in BP.
Drug therapy
Thiazides The mechanism of action of these drugs is incompletely
understood and it may take up to a month for the maximum
effect to be observed. An appropriate daily dose is 2.5 mg
bendroflumethiazide or 0.5 mg cyclopenthiazide. More potent
loop diuretics, such as furosemide (40 mg daily) or bumetanide
(1 mg daily), have few advantages over thiazides in the treatment
of hypertension, unless there is substantial renal impairment or
they are used in conjunction with an ACE inhibitor.
ACE inhibitors ACE inhibitors (enalapril 20 mg daily, ramipril
5-10 mg daily or lisinopril 10-40 mg daily) are effective and
usually well tolerated. They should be used with care in patients
with impaired renal function or renal artery stenosis because
they can reduce glomerular filtration rate and precipitate renal
failure. Electrolytes and creatinine should be checked before
and 1-2 weeks after commencing therapy. Side-effects include
first-dose hypotension, cough, rash, hyperkalaemia and renal
dysfunction.
Angiotensin receptor blockers ARBs (irbesartan 150-300 mg
daily, valsartan 40-160 mg daily) have similar efficacy to ACE
inhibitors but they do not cause cough and are better tolerated.
Calcium channel antagonists Amlodipine (5-10 mg daily) and
nifedipine (30-90 mg daily) are effective and usually well-tolerated
antihypertensive drugs that are particularly useful in older people.
Side-effects include flushing, palpitations and fluid retention. The
rate-limiting calcium channel antagonists (diltiazem 200-300 mg
daily, verapamil 240 mg daily) can be useful when hypertension
coexists with angina but may cause bradycardia. The main
side-effect of verapamil is constipation.
Beta-blockers These are no longer used as first-line
anti hypertensive therapy, except in patients with another indication
for the drug such as angina. Metoprolol (100-200 mg daily),
atenolol (50-100 mg daily) and bisoprolol (5-10 mg daily), which
preferentially block cardiac pi -adrenoceptors, should be used
rather than non -selective agents that also block (32-adrenoceptors,
which mediate vasodilatation and bronchodilatation.
Combined p- and a-blockers Labetalol (200 mg-2.4 g daily
in divided doses) and carvedilol (6.25-25 mg twice daily) are
combined (3- and a-adrenoceptor antagonists that are sometimes
more effective than pure (3-blockers. Labetalol can be used as
an infusion in malignant phase hypertension (see below).
Other vasodilators A variety of other vasodilators may be
used. These include the a-i -adrenoceptor antagonists prazosin
(0.5-20 mg daily in divided doses), indoramin (25-100 mg twice
daily) and doxazosin (1-16 mg daily), and drugs that act directly
on vascular smooth muscle, such as hydralazine (25-1 00 mg
twice daily) and minoxidil (10-50 mg daily). Side-effects include
first-dose and postural hypotension, headache, tachycardia and
fluid retention. Minoxidil also causes increased facial hair and is
therefore unsuitable for female patients.
Aspirin Antiplatelet therapy is a powerful means of reducing
cardiovascular risk but may cause bleeding, particularly
intracerebral haemorrhage, in a small number of patients.
The benefits are thought to outweigh the risks in hypertensive
patients aged 50 years or over who have well-controlled BP
and either target organ damage or diabetes or a 10-year CAD
risk of at least 1 5% (or 1 0-year cardiovascular disease risk of at
least 20%).
Statins Treating hyperlipidaemia can produce a substantial
reduction in cardiovascular risk. These drugs are strongly
indicated in patients who have established vascular disease,
or hypertension with a high (at least 10% in 10 years) risk of
developing cardiovascular disease (p. 376).
Choice of antihypertensive drug
Trials that have compared thiazides, calcium antagonists, ACE
inhibitors and ARBs have not shown consistent differences in
outcome, efficacy, side-effects or quality of life. Beta-blockers,
which previously featured as first-line therapy in guidelines, have
a weaker evidence base. The choice of anti hypertensive therapy
is initially dictated by the patient’s age and ethnic background,
although cost and convenience will influence the exact drug and
preparation used. Response to initial therapy and side-effects
guide subsequent treatment. Comorbid conditions also have an
influence on initial drug selection (Box 16.72); for example, a
|3-blocker might be the most appropriate treatment for a patient
with angina. Thiazide diuretics and dihydropyridine calcium
channel antagonists are the most suitable drugs for treatment
in older people.
Combination therapy
Although some patients can be treated with a single
anti hypertensive drug, a combination of drugs is often required
to achieve optimal control (Fig. 16.79). Combination therapy
may be desirable for other reasons; for example, low-dose
therapy with two drugs may produce fewer unwanted effects
than treatment with the maximum dose of a single drug. Some
drug combinations have complementary or synergistic actions;
for example, thiazides increase activity of the renin-angiotensin
system, while ACE inhibitors block it.
514 • CARDIOLOGY
16.72 The influence of comorbidity on choice of antihypertensive drug therapy
Class of drug
Compelling indications
Possible indications
Caution
Compelling
contraindications
a-blockers
Benign prostatic hypertrophy
-
Postural hypotension,
heart failure1
Urinary incontinence
ACE inhibitors
Heart failure
Left ventricular dysfunction,
post-MI or established CAD
Type 1 diabetic nephropathy
Secondary stroke prevention4
Chronic renal disease2
Type 2 diabetic
nephropathy
Renal impairment2
PAD3
Pregnancy
Renovascular disease2
Angiotensin II receptor
blockers
ACE inhibitor intolerance
Type 2 diabetic nephropathy
Hypertension with left
ventricular hypertrophy
Heart failure in ACE-intolerant
patients, after Ml
Left ventricular
dysfunction after Ml
Intolerance of other
antihypertensive drugs
Proteinuric or chronic
renal disease2
Heart failure
Renal impairment2
PAD3
Pregnancy
(3-blockers
Ml, angina
Heart failure5
Heart failure5
PAD
Diabetes (except with CAD)
Asthma or chronic obstructive
pulmonary disease
Heart block
Calcium channel blockers
(dihydropyridine)
Older patients, isolated systolic
hypertension
Angina
-
-
Calcium channel blockers
(rate-limiting)
Angina
Older patients
Combination with
(3-blockade
Atrioventricular block, heart
failure
Thiazides or thiazide-like
diuretics
Older patients, isolated systolic
hypertension, heart failure,
secondary stroke prevention
Gout6
In heart failure when used as monotherapy. 2ACE inhibitors or ARBs may be beneficial in chronic renal failure and renovascular disease but should be used with caution,
close supervision and specialist advice when there is established and significant renal impairment. 3Caution with ACE inhibitors and ARBs in PAD because of association with
renovascular disease. 4ln combination with a thiazide or thiazide-like diuretic. 5(3-blockers are used increasingly to treat stable heart failure but may worsen acute heart
failure. 6Thiazides or thiazide-like diuretics may sometimes be necessary to control BP in people with a history of gout, ideally used in combination with allopurinol.
(ACE = angiotensin-converting enzyme; ARBs = angiotensin II receptor blockers; CAD = coronary artery disease; Ml= myocardial infarction; PAD = peripheral arterial disease)
Refractory hypertension
Refractory hypertension refers to the situation where multiple drug
treatments do not give adequate control of BP. Although this may
be due to genuine resistance to therapy in some cases, a more
common cause of treatment failure is non-adherence to drug
therapy. Resistant hypertension can also be caused by failure
to recognise an underlying cause, such as renal artery stenosis
or phaeochromocytoma. There is no easy solution to problems
with adherence but simple treatment regimens, attempts to
improve rapport with the patient and careful supervision can all
help. Spironolactone is a particularly useful addition in patients
with treatment-resistant hypertension.
Accelerated hypertension
Accelerated or malignant hypertension is a rare condition that can
complicate hypertension of any aetiology. It is characterised by
accelerated microvascular damage with necrosis in the walls of
small arteries and arterioles (fibrinoid necrosis) and by intravascular
thrombosis. The diagnosis is based on evidence of high BP and
rapidly progressive end-organ damage, such as retinopathy
(grade 3 or 4), renal dysfunction (especially proteinuria) and/or
hypertensive encephalopathy (see above). Left ventricular failure
may occur and, if this is untreated, death occurs within months.
Management
In accelerated phase hypertension, lowering BP too quickly may
compromise tissue perfusion due to altered autoregulation and
can cause cerebral damage, including occipital blindness, and
precipitate coronary or renal insufficiency. Even in the presence
of cardiac failure or hypertensive encephalopathy, a controlled
reduction to a level of about 150/90 mmHg over a period of
24-48 hours is ideal.
In most patients, it is possible to avoid parenteral therapy
and bring BP under control with bed rest and oral drug therapy.
Intravenous or intramuscular labetalol (2 mg/min to a maximum
of 200 mg), intravenous GTN (0.6-1 .2 mg/hr), intramuscular
hydralazine (5 or 10 mg aliquots repeated at half-hourly intervals)
and intravenous sodium nitroprusside (0.3-1 .0 jug/kg body weight/
min) are all effective but require careful supervision, preferably
in a high-dependency unit.
Diseases of the heart valves
The heart valves allow forward movement of blood through the
cardiac chambers when they are open and prevent backward flow
when they are closed. Diseased valve may become narrowed,
obstructing forward flow, or become leaky, causing backward
flow or regurgitation. Breathlessness is a common symptom
of valve disease, and acute severe breathlessness may be a
presenting symptom of valve failure. The causes of this are
shown in Box 16.73. Predisposition to valvular disease may
be genetically determined, can arise as the result of rheumatic
fever or infections, or can occur in association with dilatation of
Diseases of the heart valves • 515
Step 4 Resistant hypertension
A + C + D + consider
further diuretic4 or
a- or (3-blocker5
Consider seeking expert
advice
Fig. 16.79 Antihypertensive drug combinations. Black patients are
those of African or Caribbean descent and not mixed-race, Asian or
Chinese patients. ^ = Angiotensin-converting enzyme (ACE) inhibitor or
consider angiotensin II receptor blocker (ARB); choose a low-cost ARB.
2C = calcium channel blocker (CCB); a CCB is preferred but consider a
thiazide-like diuretic if a CCB is not tolerated or the person has oedema,
evidence of heart failure or a high risk of heart failure. 3D = thiazide-type
diuretic. Consider a low dose of spironolactone or higher doses of a
thiazide-like diuretic. At the time of publication by NICE (August 2011),
spironolactone did not have a UK marketing authorisation for this
indication. Informed consent should be obtained and documented.
Consider an a- or (3-blocker if further diuretic therapy is not tolerated,
or is contraindicated or ineffective. From NICE Clinical Guideline 127 -
Hypertension in adults; August 2011.
16.73 Causes of acute valve failure
Aortic regurgitation
• Aortic dissection
• Infective endocarditis
Mitral regurgitation
• Papillary muscle rupture due to acute myocardial infarction
• Infective endocarditis
• Rupture of chordae due to myxomatous degeneration
Prosthetic valve failure
• Mechanical valves: fracture, jamming, thrombosis, dehiscence
• Biological valves: degeneration with cusp tear
the cardiac chambers in heart failure. The principal causes of
valvular disease are summarised in Box 16.74.
Rheumatic heart disease
Acute rheumatic fever
Acute rheumatic fever usually affects children and young adults
between the ages of 5 and 1 5 years. It is now rare in high-income
countries in Western Europe and North America, where the
i
Valve regurgitation
• Congenital
• Acute rheumatic carditis
• Chronic rheumatic carditis
• Infective endocarditis
• Cardiac failure*
Valve stenosis
• Congenital
• Rheumatic carditis
• Senile degeneration
*Causes dilatation of the valve ring.
Syphilitic aortitis
Traumatic valve rupture
Senile degeneration
Damage to chordae and
papillary muscles
16.74 Principal causes of valve disease
incidence is about 0.5 cases per 1 00 000, but remains endemic in
the Indian subcontinent, Africa and South America. Recent studies
indicate that the current incidence of rheumatic heart disease in
India ranges between 1 3 and 1 50 cases per 1 00 000 population
per year and it is by far the most common cause of acquired heart
disease in childhood and adolescence in that country.
Pathogenesis
The condition is triggered by an immune-mediated delayed
response to infection with specific strains of group A streptococci,
which have antigens that cross-react with cardiac myosin and
sarcolemmal membrane proteins. Antibodies produced against the
streptococcal antigens cause inflammation in the endocardium,
myocardium and pericardium, as well as the joints and skin.
Histologically, fibrinoid degeneration is seen in the collagen of
connective tissues. Aschoff nodules are pathognomonic and occur
only in the heart. They are composed of multinucleated giant cells
surrounded by macrophages and T lymphocytes, and are not
seen until the subacute or chronic phases of rheumatic carditis.
Clinical features
Acute rheumatic fever is a multisystem disorder that usually
presents with fever, anorexia, lethargy and joint pain, 2-3 weeks
after an episode of streptococcal pharyngitis. There may be no
history of sore throat, however. Arthritis occurs in approximately
75% of patients. Other features include rashes, subcutaneous
nodules, carditis and neurological changes (Fig. 16.80). The
diagnosis, made using the revised Jones criteria (Box 16.75),
is based on two or more major manifestations, or one major
and two or more minor manifestations, along with evidence
of preceding streptococcal infection. A presumptive diagnosis
of acute rheumatic fever can be made without evidence of
preceding streptococcal infection in cases of isolated chorea
or pancarditis, if other causes of these have been excluded. In
cases of established rheumatic heart disease or prior rheumatic
fever, a diagnosis of acute rheumatic fever can be made based
only on the presence of multiple minor criteria and evidence of
preceding group A streptococcal pharyngitis.
Carditis
Rheumatic fever causes a pancarditis involving the endocardium,
myocardium and pericardium to varying degrees. Its incidence
declines with increasing age, ranging from 90% at 3 years to
around 30% in adolescence. It may manifest as breathlessness
(due to heart failure or pericardial effusion), palpitations or chest
pain (usually due to pericarditis or pancarditis). Other features
include tachycardia, cardiac enlargement and new or changed
516 • CARDIOLOGY
Oedema
(heart failure)
Erythema marginatum
Sydenham's chorea
St Vitus dance
Prior sore throat
Carditis
Dyspnoea (CCF)
Syncope
Pericarditis (pain, rub)
Carey Coombs murmur
Aortic or mitral
regurgitation
Heart block
Subcutaneous
nodules (over bones
or tendons)
Fever
Fig. 16.80 Clinical features of rheumatic fever. Bold labels indicate
Jones major criteria. (CCF = congestive cardiac failure) Inset (Erythema
marginatum) From Savin JA, Hunter JAA, Hepburn NC. Skin signs in
clinical medicine. London: Mosby-Wolfe, Elsevier; 1997.
asymmetric and migratory inflammation of the large joints typically
affects the knees, ankles, elbows and wrists. The joints are
involved in quick succession and are usually red, swollen and
tender for between a day and 4 weeks.
Skin lesions
Erythema marginatum occurs in less than 5% of patients. The
lesions start as red macules that fade in the centre but remain
red at the edges, and occur mainly on the trunk and proximal
extremities but not the face. The resulting red rings or ‘margins’
may coalesce or overlap (Fig. 16.80). Subcutaneous nodules
occur in 5-7% of patients. They are small (0. 5-2.0 cm), firm
and painless, and are best felt over extensor surfaces of bone
or tendons. They typically appear more than 3 weeks after the
onset of other manifestations and therefore help to confirm rather
than make the diagnosis.
Sydenham’s chorea
Sydenham’s chorea, also known as St Vitus dance, is a late
neurological manifestation that appears at least 3 months
after the episode of acute rheumatic fever, when all the other
signs may have disappeared. It occurs in up to one-third of
cases and is more common in females. Emotional lability may
be the first feature and is typically followed by purposeless,
involuntary, choreiform movements of the hands, feet or face.
Speech may be explosive and halting. Spontaneous recovery
usually occurs within a few months. Approximately one-quarter
of affected patients will go on to develop chronic rheumatic
valve disease.
16.75 Jones criteria for the diagnosis
of rheumatic fever
Major manifestations
• Carditis • Erythema marginatum
• Polyarthritis • Subcutaneous nodules
• Chorea
Minor manifestations
• Fever
• Arthralgia
• Raised erythrocyte
sedimentation rate or
C-reactive protein
Plus
• Supporting evidence of preceding streptococcal infection: recent
scarlet fever, raised antistreptolysin 0 or other streptococcal
antibody titre, positive throat culture*
*Evidence of recent streptococcal infection is particularly important if there is only
one major manifestation.
murmurs. A soft systolic murmur due to mitral regurgitation is
very common. A soft mid-diastolic murmur (the Carey Coombs
murmur) is typically due to valvulitis, with nodules forming on
the mitral valve leaflets. Aortic regurgitation occurs in 50% of
cases but the tricuspid and pulmonary valves are rarely involved.
Pericarditis may cause chest pain, a pericardial friction rub and
precordial tenderness. Cardiac failure may be due to myocardial
dysfunction or valvular regurgitation. ECG evidence commonly
includes ST and T wave changes. Conduction defects, including
AV block, sometimes occur and may cause syncope.
Arthritis
This is the most common major manifestation and occurs early
when streptococcal antibody titres are high. An acute painful,
Other features
Other systemic manifestations, such as pleurisy, pleural effusion
and pneumonia, may occur but are rare.
Investigations
Blood should be taken for measurement of ESR and CRP since
these are useful for monitoring progress of the disease (Box
16.76). Throat cultures should be taken but positive results are
obtained in only 10-25% of cases since the infection has often
resolved by the time of presentation. Serology for antistreptolysin
O antibodies (ASO) should be performed. Raised levels provide
supportive evidence for the diagnosis but are normal in one-fifth
of adult cases of rheumatic fever and most cases of chorea.
Echocardiography should be carried out and typically shows
mitral regurgitation with dilatation of the mitral annulus and
prolapse of the anterior mitral leaflet; it may also demonstrate
aortic regurgitation and pericardial effusion.
Management
The aims of management are to limit cardiac damage and
relieve symptoms.
Bed rest
Bed rest is important, as it lessens joint pain and reduces cardiac
workload. The duration should be guided by symptoms, along
with temperature, leucocyte count and ESR, and should be
continued until these have settled. Patients can then return to
normal physical activity but strenuous exercise should be avoided
in those who have had carditis.
Treatment of cardiac failure
Cardiac failure should be treated as necessary. Some patients,
particularly those in early adolescence, can develop a fulminant
form of the disease with severe mitral regurgitation and, sometimes,
concomitant aortic regurgitation. If heart failure in these cases
• Previous rheumatic fever
• Leucocytosis
• First-degree atrioventricular
block
Diseases of the heart valves • 517
i
does not respond to medical treatment, valve replacement may
be necessary and is often associated with a dramatic decline
in rheumatic activity. Occasionally, AV block may occur but is
seldom progressive and usually resolves spontaneously. Rarely,
pacemaker insertion may be required.
Antibiotics
A single dose of benzathine benzylpenicillin (1 .2 million U IM) or oral
phenoxymethyl penicillin (250 mg 4 times daily for 10 days) should
be given on diagnosis to eliminate any residual streptococcal
infection. If the patient is penicillin-allergic, erythromycin or a
cephalosporin can be used. Patients are susceptible to further
attacks of rheumatic fever if another streptococcal infection
occurs, and long-term prophylaxis with penicillin should be given
with oral phenoxymethylpenicillin (250 mg twice daily) or as
benzathine benzylpenicillin (1 .2 million U IM monthly), if adherence
is in doubt. Sulfadiazine or erythromycin may be used if the
patient is allergic to penicillin; sulphonamides prevent infection
but are not effective in the eradication of group A streptococci.
Further attacks of rheumatic fever are unusual after the age
of 21, when antibiotic treatment can usually be stopped. The
duration of prophylaxis should be extended if an attack has
occurred in the last 5 years, or if the patient lives in an area
of high prevalence and has an occupation (such as teaching)
with a high risk of exposure to streptococcal infection. In those
with residual heart disease, prophylaxis should continue until
1 0 years after the last episode or 40 years of age, whichever
is later. While long-term antibiotic prophylaxis prevents further
attacks of acute rheumatic fever, it does not protect against
infective endocarditis.
Aspirin
This usually relieves the symptoms of arthritis rapidly and
a response within 24 hours helps confirm the diagnosis. A
reasonable starting dose is 60 mg/kg body weight/day, divided
into six doses. In adults, 100 mg/kg per day may be needed
up to the limits of tolerance or a maximum of 8 g per day.
Mild toxicity includes nausea, tinnitus and deafness; vomiting,
tachypnoea and acidosis are more serious. Aspirin should be
continued until the ESR has fallen and then gradually tailed off.
Glucocorticoids
These produce more rapid symptomatic relief than aspirin and
are indicated in cases with carditis or severe arthritis. There is
no evidence that long-term steroids are beneficial. Prednisolone
(1 .0-2.0 mg/kg per day in divided doses) should be continued
until the ESR is normal and then tailed off.
Chronic rheumatic heart disease
Chronic valvular heart disease develops in at least half of those
affected by rheumatic fever with carditis. Two-thirds of cases
occur in women. Some episodes of rheumatic fever pass
unrecognised and it is possible to elicit a history of rheumatic
fever or chorea in only about half of all patients with chronic
rheumatic heart disease.
The mitral valve is affected in more than 90% of cases; the
aortic valve is the next most frequently involved, followed by the
tricuspid and then the pulmonary valve. Isolated mitral stenosis
accounts for about 25% of all cases, and an additional 40%
have mixed mitral stenosis and regurgitation.
Pathogenesis
The main pathological process in chronic rheumatic heart disease
is progressive fibrosis. The heart valves are predominantly
affected but involvement of the pericardium and myocardium
also occurs and may contribute to heart failure and conduction
disorders. Fusion of the mitral valve commissures and shortening
of the chordae tendineae may lead to mitral stenosis with
or without regurgitation. Similar changes in the aortic and
tricuspid valves produce distortion and rigidity of the cusps,
leading to stenosis and regurgitation. Once a valve has been
damaged, the altered haemodynamic stresses perpetuate
and extend the damage, even in the absence of a continuing
rheumatic process.
Mitral valve disease
|Mitral stenosis
Mitral stenosis is almost always rheumatic in origin, although in
older people it can be caused by heavy calcification of the mitral
valve. There is also a rare form of congenital mitral stenosis.
Pathogenesis
In rheumatic mitral stenosis, the mitral valve orifice is slowly
diminished by progressive fibrosis, calcification of the valve
leaflets, and fusion of the cusps and subvalvular apparatus.
The mitral valve orifice is normally about 5 cm2 in diastole
but can be reduced to <1 cm2 in severe mitral stenosis. The
patient is usually asymptomatic until the orifice is <2 cm2.
As stenosis progresses, left ventricular filling becomes more
dependent on left atrial contraction. There is dilatation and
hypertrophy of the LA and left atrial pressure rises, leading
to pulmonary venous congestion and breathlessness. Any
increase in heart rate shortens diastole when the mitral valve
is open and produces a further rise in left atrial pressure.
Situations that demand an increase in cardiac output, such as
pregnancy and exercise, also increase left atrial pressure and are
poorly tolerated.
Atrial fibrillation is very common due to progressive dilatation of
the LA. Its onset often precipitates pulmonary oedema because
the accompanying tachycardia and loss of atrial contraction
lead to marked haemodynamic deterioration and a rapid rise in
left atrial pressure. In the absence of AF, a more gradual rise
in left atrial pressure may occur. In the presence or absence
of AF, pulmonary hypertension may occur, which can protect
the patient from pulmonary oedema. Pulmonary hypertension
leads to right ventricular hypertrophy and dilatation, tricuspid
regurgitation and right heart failure. Fewer than 20% of patients
16.76 Investigations in acute rheumatic fever
Evidence of a systemic illness
• Leucocytosis, raised erythrocyte sedimentation rate and C-reactive
protein
Evidence of preceding streptococcal infection
• Throat swab culture: group A p-haemolytic streptococci (also from
family members and contacts)
• Antistreptolysin 0 antibodies (AS0 titres): rising titres, or levels of
>200 U (adults) or >300 U (children)
Evidence of carditis
• Chest X-ray: cardiomegaly; pulmonary congestion
• ECG: first- and, rarely, second-degree atrioventricular block;
features of pericarditis; T-wave inversion; reduction in QRS voltages
• Echocardiography: cardiac dilatation and valve abnormalities
518 • CARDIOLOGY
remain in sinus rhythm but many of these have a small fibrotic
LA and severe pulmonary hypertension.
Clinical features
Effort -related dyspnoea is usually the dominant symptom
(Box 16.77). Typically, exercise tolerance diminishes very
slowly over many years until symptoms eventually occur at
rest. Patients frequently do not appreciate the extent of their
disability until the diagnosis is made and their valve disease is
treated. Acute pulmonary oedema or pulmonary hypertension
can lead to haemoptysis. Fatigue is a common symptom due
to a low cardiac output. Thromboembolism is a common
complication, especially in patients with AF. Prior to the
advent of anticoagulant therapy, emboli caused one-quarter
of all deaths.
The physical signs of mitral stenosis are often found before
symptoms develop and their recognition is of particular importance
in pregnancy. The forces that open and close the mitral valve
increase as left atrial pressure rises. The first heart sound (SI)
is therefore loud and can be palpable (tapping apex beat). An
opening snap may be audible and moves closer to the second
sound (S2) as the stenosis becomes more severe and left atrial
pressure rises. However, the first heart sound and opening snap
may be inaudible if the valve is heavily calcified.
Turbulent flow produces the characteristic low-pitched mid¬
diastolic murmur and sometimes a thrill (Fig. 1 6.81). The murmur
is accentuated by exercise and during atrial systole (pre-systolic
accentuation). Early in the disease, a pre-systolic murmur may be
I 16.77 Clinical features of mitral stenosis
Clinical feature
Cause
Symptoms
Breathlessness
Pulmonary congestion, low
cardiac output
Fatigue
Low cardiac output
Oedema, ascites
Right heart failure
Palpitation
Atrial fibrillation
Haemoptysis
Pulmonary congestion, pulmonary
embolism
Cough
Pulmonary congestion
Chest pain
Pulmonary hypertension
Thromboembolism
Atrial stasis and atrial
fibrillation
Signs
Atrial fibrillation
Atrial dilatation
Mitral facies
Auscultation:
Low cardiac output
Loud first heart
sound, opening
snap
Mid-diastolic
murmur
Pressure gradient across the valve
Crepitations
Pulmonary oedema
Pleural effusions
Left heart failure
Right ventricular heave,
loud P2
Pulmonary hypertension
Dilated left
atrium
Stenosed
mitral valve
Systole
Diastolic
gradient
across valve
Loud
Loud
Roll patient towards left to
hear murmur best
(low-pitched, use bell of
stethoscope at apex)
Right ventricular
hypertrophy
Normal left
ventricle
Increased
pulmonary
artery pressure
Fig. 16.81 Mitral stenosis: murmur and the diastolic pressure gradient between left atrium (LA) and left ventricle (LV). (Mean gradient is
reflected by the area between LA and LV in diastole.) The first heart sound is loud, and there is an opening snap (OS) and mid-diastolic murmur (MDM)
with pre-systolic accentuation. [A] Echocardiogram showing reduced opening of the mitral valve in diastole. \B} Colour Doppler showing turbulent flow.
Diseases of the heart valves • 519
16.78 Investigations in mitral stenosis
ECG
• Right ventricular hypertrophy:
tall R waves in \A-V3
Chest X-ray
• Enlarged left atrium and
appendage
• P mitrale or atrial fibrillation
• Signs of pulmonary venous
congestion
Echo
• Thickened immobile cusps
• Reduced rate of diastolic filling
• Reduced valve area
of left ventricle
• Enlarged left atrium
Doppler
• Pressure gradient across
• Left ventricular function
mitral valve
• Pulmonary artery pressure
Cardiac catheterisation
• Coronary artery disease
• Mitral stenosis and
• Pulmonary artery pressure
regurgitation
the only auscultatory abnormality, but in patients with symptoms,
the murmur extends from the opening snap to the first heart
sound. Coexisting mitral regurgitation causes a pansystolic
murmur that radiates towards the axilla.
Pulmonary hypertension may ultimately lead to right ventricular
hypertrophy and dilatation with secondary tricuspid regurgitation,
which causes a systolic murmur and giant V waves’ in the
venous pulse.
Investigations
Doppler echocardiography is the investigation of choice for
evaluation of suspected mitral stenosis (Fig. 16.81). Cardiac
catheterisation may also be required if surgery or valvuloplasty
is being considered, to screen for coexisting conditions such as
CAD. The ECG may show either AF or bifid P waves (P mitrale)
associated with left atrial hypertrophy (Box 16.78). A typical
chest X-ray is shown in Figure 16.9 (p. 451).
Management
Patients with mild symptoms can be treated medically but
intervention by balloon valvuloplasty, mitral valvotomy or
mitral valve replacement should be considered if the patient
remains symptomatic despite medical treatment or if pulmonary
hypertension develops.
Medical management
This consists of anticoagulation to reduce the risk of
systemic embolism, ventricular rate control with digoxin,
(3-blockers or rate-limiting calcium antagonists in AF,
and diuretic to control pulmonary congestion. Antibiotic
prophylaxis against infective endocarditis is no longer routinely
recommended.
Mitral balloon valvuloplasty and valve replacement
Valvuloplasty is the treatment of choice if specific criteria are
fulfilled (Box 16.79 and Fig. 16.82), although surgical closed
or open mitral valvotomy is an acceptable alternative. Patients
who have undergone mitral valvuloplasty or valvotomy should
be followed up at 1-2 -yearly intervals because restenosis may
occur. Clinical symptoms and signs are a guide to the severity
16.79 Criteria for mitral valvuloplasty
• Significant symptoms
• Isolated mitral stenosis
• No (or trivial) mitral regurgitation
• Mobile, non-calcified valve/subvalve apparatus on echo
• Left atrium free of thrombus
*For comprehensive guidelines on valvular heart disease, see www.acc.org.
Fig. 16.82 Mitral valvuloplasty. A guidewire is introduced into the right
atrium (RA) from the femoral vein and the inferior vena cava (IVC). The
inter-atrial septum is punctured, providing access to the left atrium and
mitral valve. A balloon catheter is then advanced over the guidewire across
the mitral valve and the balloon dilated to stretch the valve and reduce the
degree of stenosis.
of mitral restenosis but Doppler echocardiography provides a
more accurate assessment.
Valve replacement is indicated if there is substantial mitral
reflux or if the valve is rigid and calcified (p. 526).
|jVlitral regurgitation
Rheumatic disease is the principal cause in countries where
rheumatic fever is common but elsewhere, including in the UK,
other causes are more important (Box 1 6.80). Mitral regurgitation
may also follow mitral valvotomy or valvuloplasty.
Pathogenesis
Chronic mitral regurgitation causes gradual dilatation of the LA with
little increase in pressure and therefore relatively few symptoms.
Nevertheless, the LV dilates slowly and the left ventricular diastolic
and left atrial pressures gradually increase as a result of chronic
volume overload of the LV. In contrast, acute mitral regurgitation
causes a rapid rise in left atrial pressure (because left atrial
compliance is normal) and marked symptomatic deterioration.
16.80 Causes of mitral regurgitation
• Mitral valve prolapse
• Dilatation of the left ventricle and mitral valve ring (e.g. coronary
artery disease, cardiomyopathy)
• Damage to valve cusps and chordae (e.g. rheumatic heart disease,
endocarditis)
• Ischaemia or infarction of the papillary muscle
• Myocardial infarction
520 • CARDIOLOGY
Pansystolic murmur heard best at apex
and left sternal edge (diaphragm),
radiates to axilla
Dilated left
ventricle
Fig. 16.83 Mitral regurgitation: murmur and systolic wave in left atrial pressure. The first sound is normal or soft and merges with a pansystolic
murmur (PSM) extending to the second heart sound. A third heart sound occurs with severe regurgitation. [A] A transoesophageal echocardiogram shows
mitral valve prolapse, with one leaflet bulging towards the left atrium (LA, arrow). [BThis results in a jet of mitral regurgitation on colour Doppler (arrow).
Mitral valve prolapse
This is also known as ‘floppy’ mitral valve and is a common
cause of mild mitral regurgitation (Fig. 16.83). Some cases are
thought to be due to a developmental abnormality of the mitral
valve and others due to degenerative myxomatous change in a
normal mitral valve. Rarely, mitral valve prolapse may occur in
association with Marfan’s syndrome (p. 508).
In its mildest forms, the valve remains competent but bulges
back into the atrium during systole, causing a mid-systolic
click but no murmur. In the presence of a regurgitant valve, the
click is followed by a late systolic murmur, which lengthens as
the regurgitation becomes more severe. A click is not always
audible and the physical signs may vary with both posture and
respiration. Progressive elongation of the chordae tendineae
leads to increasing mitral regurgitation, and if chordal rupture
occurs, regurgitation suddenly becomes severe. This is rare
before the fifth or sixth decade of life.
Mitral valve prolapse is associated with a variety of typically
benign arrhythmias, atypical chest pain and a very small risk of
embolic stroke or transient ischaemic attack (TIA). Nevertheless,
the overall long-term prognosis is good.
Other causes of mitral regurgitation
Mitral valve function depends on the chordae tendineae and their
papillary muscles; dilatation of the LV distorts the geometry of
these and may cause mitral regurgitation (Box 16.80). Dilated
cardiomyopathy and heart failure from CAD are common causes
of so-called ‘functional’ mitral regurgitation. Endocarditis is an
important cause of acute mitral regurgitation.
Clinical features
Symptoms and signs depend on the underlying cause and how
suddenly the regurgitation develops (Box 16.81). Chronic mitral
regurgitation produces a symptom complex that is similar to that
of mitral stenosis but sudden-onset mitral regurgitation usually
presents with acute pulmonary oedema.
The regurgitant jet causes an apical systolic murmur (Fig.
16.83), which radiates into the axilla and may be accompanied
by a thrill. Increased forward flow through the mitral valve causes
a loud third heart sound and even a short mid-diastolic murmur.
The apex beat feels active and rocking due to left ventricular
volume overload and is usually displaced to the left as a result
of left ventricular dilatation.
Investigations
Echocardiography is a pivotal investigation. The severity of
regurgitation can be assessed by Doppler and information may
also be gained on papillary muscle function and valve prolapse.
An ECG should be performed and commonly shows AF, as
a consequence of atrial dilatation. Cardiac catheterisation is
Diseases of the heart valves • 521
1 16.81 Clinical features of mitral regurgitation
Clinical feature
Cause
Symptoms
Breathlessness
Pulmonary congestion
Fatigue
Low cardiac output
Oedema, ascites
Right heart failure
Palpitation
Atrial fibrillation
Signs
Atrial fibrillation
Atrial dilatation
Displaced apex beat
Cardiomegaly
Auscultation:
Apical pansystolic murmur
Regurgitation of blood from left
ventricle to left atrium
Soft SI
Valve does not close properly
Apical S3
Rapid flow of blood into left ventricle
Crepitations
Pulmonary oedema
Left heart failure
Pleural effusions J
Right ventricular heave
Pulmonary hypertension
Raised jugular venous pressure
Right heart failure
Oedema
Right heart failure
I 16.82 Investigations in mitral regurgitation
ECG
• Left atrial hypertrophy
• Atrial fibrillation
Chest X-ray
• Enlarged left atrium
• Pulmonary venous congestion
• Enlarged left ventricle
• Pulmonary oedema (if acute)
Echo
• Dilated left atrium, left
• Structural abnormalities of
ventricle
mitral valve
• Dynamic left ventricle (unless
myocardial dysfunction
predominates)
Doppler
• Detects and quantifies
regurgitation
Cardiac catheterisation
• Dilated left atrium, dilated left
• Coexisting coronary artery
ventricle, mitral regurgitation
disease
• Pulmonary hypertension
indicated when surgery is being considered (Box 16.82). During
catheterisation, the severity of mitral regurgitation can be assessed
by left ventriculography and by the size of the v (systolic) waves
in the left atrial or pulmonary artery wedge pressure trace.
Management
Mitral regurgitation of moderate severity can be treated medically
with diuretics and vasodilators. Digoxin and anticoagulants should
be given if AF is present (Box 16.83). If systemic hypertension
is present, it should be treated with vasodilators such as ACE
inhibitors or ARBs, since high afterload may worsen the degree of
regurgitation. All patients should be reviewed at regular intervals,
both clinically and by echocardiography. Worsening symptoms,
progressive cardiomegaly or echocardiographic evidence of
deteriorating left ventricular function are indications for mitral valve
replacement or repair. Mitral valve repair is now the treatment
of choice for severe mitral regurgitation, even in asymptomatic
i
• Diuretics
• Vasodilators if hypertension is present
• Digoxin if atrial fibrillation is present
• Anticoagulants if atrial fibrillation is present
patients, because results are excellent and early repair prevents
irreversible left ventricular damage. Mitral regurgitation often
accompanies left ventricular failure associated with CAD. If such
patients are to undergo CABG surgery, it is common practice
to repair the valve and restore mitral valve function by inserting
an annuloplasty ring to overcome annular dilatation and to
bring the valve leaflets closer together. Unfortunately, it can
be difficult to determine whether it is the ventricular dilatation
or the mitral regurgitation that is the predominant problem. If
ventricular dilatation is the underlying cause of mitral regurgitation,
then mitral valve repair or replacement may actually worsen
ventricular function, as the ventricle can no longer empty into
the low-pressure LA.
Aortic valve disease
Aortic stenosis
There are several causes of aortic stenosis but the age at which
patients present can give a clue to the most likely diagnosis
(Box 16.84). In congenital aortic stenosis, obstruction is present
from birth or becomes apparent during infancy. With bicuspid
aortic valves, obstruction may take years to develop as the valve
becomes fibrotic and calcified, and these patients present as
young to middle-aged adults. Rheumatic disease of the aortic
valve presents at a similar age but is usually accompanied
by mitral valve disease. In older people, structurally normal
aortic valves may become stenotic as the result of fibrosis and
calcification. Haemodynamically significant stenosis develops
slowly, typically occurring at 30-60 years in those with rheumatic
disease, 50-60 years in those with bicuspid aortic valves and
70-90 years in those with calcific tricuspid disease.
Pathogenesis
Cardiac output is initially maintained in patients with aortic
stenosis at the cost of a steadily increasing pressure gradient
across the aortic valve. With progression of the stenosis the
LV becomes increasingly hypertrophied and coronary blood
flow may be inadequate to supply the myocardium, such that
i
Infants, children, adolescents
• Congenital aortic stenosis
• Congenital subvalvular aortic stenosis
• Congenital supravalvular aortic stenosis
Young adults to middle-aged
• Calcification and fibrosis of congenitally bicuspid aortic valve
• Rheumatic aortic stenosis
Middle-aged to elderly
• Senile degenerative aortic stenosis
• Calcification of bicuspid valve
• Rheumatic aortic stenosis
16.83 Medical management of mitral regurgitation
16.84 Causes of aortic stenosis
522 • CARDIOLOGY
angina can develop even in the absence of coexisting CAD. The
fixed outflow obstruction limits the increase in cardiac output
required on exercise. Eventually, the LV can no longer overcome
the outflow tract obstruction and LV failure results, leading to
pulmonary oedema.
Clinical features
Aortic stenosis is commonly picked up in asymptomatic patients
at routine clinical examination but the three cardinal symptoms are
angina, breathlessness and syncope (Box 16.85). Angina arises
either because of the increased demands of the hypertrophied LV
working against the high-pressure outflow tract obstruction, or the
presence of coexisting CAD, which affects over 50% of patients.
Exertional breathlessness suggests cardiac decompensation
as a consequence of the excessive pressure overload placed
on the LV. Syncope usually occurs on exertion when cardiac
i
16.85 Clinical features of aortic stenosis
Symptoms
• Mild or moderate stenosis:
•
Exertional syncope
usually asymptomatic
•
Sudden death
• Exertional dyspnoea
•
Episodes of acute pulmonary
• Angina
oedema
Signs
• Ejection systolic murmur
•
Narrow pulse pressure
• Slow-rising carotid pulse
•
Signs of pulmonary venous
• Thrusting apex beat (left
ventricular pressure overload)
congestion
output fails to rise to meet demand, leading to a fall in BP.
Sometimes patients with severe aortic stenosis do not complain
of symptoms. If, on clinical evaluation, this appears to be due to
a sedentary lifestyle, a careful exercise test may reveal symptoms
on modest exertion.
The characteristic clinical signs of severe aortic stenosis are
shown in Box 16.85. A harsh ejection systolic murmur radiates
to the neck, with a soft second heart sound, particularly in
those with calcific valves. The murmur is often likened to a
saw cutting wood and may (especially in older patients) have
a musical quality like the ‘mew’ of a seagull (Fig. 16.84). The
severity of aortic stenosis may be difficult to gauge clinically, as
older patients with a non-compliant ‘stiff arterial system may
have an apparently normal carotid upstroke in the presence
of severe aortic stenosis. Milder degrees of stenosis may be
difficult to distinguish from aortic sclerosis, in which the valve is
thickened or calcified but not obstructed. A careful examination
should be made for other valve lesions, particularly in rheumatic
heart disease, when there is frequently concomitant mitral valve
disease. In contrast to patients with mitral stenosis, which tends
to progress very slowly, patients with aortic stenosis typically
remain asymptomatic for many years but deteriorate rapidly
when symptoms develop; if otherwise untreated, they usually
die within 3-5 years of presentation.
Investigations
Echocardiography is a pivotal investigation in patients suspected
of having aortic stenosis. It can demonstrate restricted valve
opening (Fig. 16.85) and Doppler assessment permits calculation
of the systolic gradient across the aortic valve, from which the
severity of stenosis can be assessed (see Fig. 16.1 1 , p. 451). In
Murmur also heard
at apex
Ejection systolic murmur
radiates to right upper sternal
edge, suprasternal notch
and carotids
mmHg
150
100
Peak-to-peak
systolic gradient
“Diminished
pulse pressure
Systolic
pressure gradient
Post-stenotic
dilatation of
aortic arch
Stenosed
aortic valve
Left ventricular
hypertrophy
Fig. 16.84 Aortic stenosis. Pressure traces
show the systolic gradient between left ventricle
(LV) and aorta. The ‘diamond-shaped’ murmur is
heard best with the diaphragm in the aortic
outflow and also at the apex. An ejection click
(EC) may be present in young patients with a
bicuspid aortic valve but not in older patients
with calcified valves. Aortic stenosis may lead to
left ventricular hypertrophy with a fourth sound
at the apex and post-stenotic dilatation of the
aortic arch. Figure 16.11 (p. 451) shows the
typical Doppler signal with aortic stenosis.
Diseases of the heart valves • 523
Fig. 16.85 Two-dimensional echocardiogram comparing a normal
individual and a patient with calcific aortic stenosis. \k\ Normal individual
in diastole; the aortic leaflets are closed and thin, and a point of coaptation is
seen (arrow). Iff Calcific aortic stenosis in diastole; the aortic leaflets are
thick and calcified (arrow), ff Normal in systole; the aortic leaflets are open
(arrows). \D\ Calcific aortic stenosis in systole; the thickened leaflets have
barely moved (arrows). From Newby D, Grubb N. Cardiology: an illustrated
colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005.
16.86 Investigations in aortic stenosis
ECG
• Left ventricular hypertrophy
• Left bundle branch block
Chest X-ray
• May be normal; sometimes enlarged left ventricle and dilated
ascending aorta on postero-anterior view, calcified valve on
lateral view
Echo
• Calcified valve with restricted opening, hypertrophied left ventricle
Doppler
• Measurement of severity of stenosis
• Detection of associated aortic regurgitation
Cardiac catheterisation
• Mainly to identify associated coronary artery disease
• May be used to measure gradient between left ventricle and aorta
Fig. 16.86 Left ventricular hypertrophy. QRS complexes in limb leads
have increased amplitude with a very large R wave in V6 and S wave in V2.
There is ST depression and T-wave inversion in leads II, III, aVF, V5 and V6:
a ‘left ventricular strain’ pattern.
patients with impaired left ventricular function, velocities across
the aortic valve may be diminished because of a reduced stroke
volume; this is called low-flow aortic stenosis. When marked aortic
regurgitation or elevated cardiac output is present, velocities are
increased because of an increased stroke volume and this may
overestimate stenosis severity on Doppler echocardiography. In
advanced cases, ECG features of hypertrophy (Box 1 6.86) are
often pronounced (Fig. 16.86), and down-sloping ST segments
524 • CARDIOLOGY
16.87 Aortic stenosis in old age
• Incidence: the most common form of valve disease affecting the
very old.
• Symptoms: a common cause of syncope, angina and heart failure
in the very old.
• Signs: because of increasing stiffening in the central arteries, low
pulse pressure and a slow rising pulse may not be present.
• Trans-catheter aortic valve implantation (TAVI): a good option in
older individuals because less invasive than surgery.
• Surgery: can be successful in those aged 80 years or more in the
absence of comorbidity, but with a higher operative mortality. The
prognosis without surgery is poor once symptoms have developed.
• Valve replacement type: a biological valve is often preferable to a
mechanical one because this obviates the need for anticoagulation,
and the durability of biological valves usually exceeds the patient’s
anticipated life expectancy.
and T inversion (‘strain pattern’) are seen in the lateral leads,
reflecting left ventricular fibrosis. Nevertheless, the ECG can
be normal, despite severe stenosis. Imaging with CT and MRI
may be useful in assessing the degree of valve calcification and
stenosis, respectively, and may help where there is uncertainty.
Management
Irrespective of the severity of valve stenosis, patients with
asymptomatic aortic stenosis have a good immediate prognosis
and conservative management is appropriate. Such patients
should be kept under review, as the development of angina,
syncope, symptoms of low cardiac output or heart failure has
a poor prognosis and is an indication for prompt surgery. In
practice, patients with moderate or severe stenosis should be
evaluated every 1-2 years with Doppler echocardiography to
detect evidence of progression in severity. The intervals between
reviews should be more frequent (typically 3-6-monthly) in older
patients with heavily calcified valves.
Patients with symptomatic severe aortic stenosis should
have prompt aortic valve replacement. Delay exposes the
patient to the risk of sudden death or irreversible deterioration
in ventricular function. Old age is not a contraindication to valve
replacement and results are very good in experienced centres,
even for those in their eighties (Box 16.87). This is especially
the case with transcatheter aortic valve implantation (TAVI,
p. 527). Aortic balloon valvuloplasty is useful in congenital aortic
stenosis but has limited value in older patients with calcific aortic
stenosis.
Anticoagulants are required only in patients who have AF or
those who have had a valve replacement with a mechanical
prosthesis.
Aortic regurgitation
This condition can result from either disease of the aortic valve
cusps, infection, trauma or dilatation of the aortic root. The
causes are summarised in Box 16.88.
Pathogenesis
Regurgitation of blood through the aortic value causes the LV to
dilate as cardiac output increases to maintain the demands of
the circulation. The stroke volume of the LV may eventually be
doubled and the major arteries are then conspicuously pulsatile.
As the disease progresses, left ventricular failure develops,
leading to a rise in left ventricular end-diastolic pressure and
pulmonary oedema.
16.89 Clinical features of aortic regurgitation
Symptoms
Mild to moderate aortic regurgitation
• Often asymptomatic
• Palpitations
Severe aortic regurgitation
• Breathlessness
• Angina
Signs
Pulses
• Large-volume or ‘collapsing’ pulse
• Low diastolic and increased pulse pressure
• Bounding peripheral pulses
• Capillary pulsation in nail beds: Quincke’s sign
• Femoral bruit (‘pistol shot’): Duroziez’s sign
• Head nodding with pulse: de Musset’s sign
Murmurs
• Early diastolic murmur
• Systolic murmur (increased stroke volume)
• Austin Flint murmur (soft mid-diastolic)
Other signs
• Displaced, heaving apex beat (volume overload)
• Pre-systolic impulse
• Fourth heart sound
• Crepitations (pulmonary venous congestion)
Clinical features
Until the onset of breathlessness, the only symptom may be
an awareness of the heart beat (Box 16.89), particularly when
lying on the left side, which results from the increased stroke
volume. Paroxysmal nocturnal dyspnoea is sometimes the first
symptom, and peripheral oedema or angina may occur. The
characteristic murmur is best heard to the left of the sternum
during held expiration (Fig. 16.87); a thrill is rare. A systolic murmur
due to the increased stroke volume is common and does not
necessarily indicate stenosis. The regurgitant jet causes fluttering
of the mitral valve and, if severe, causes partial closure of the
anterior mitral leaflet, leading to functional mitral stenosis and a
soft mid-diastolic (Austin Flint) murmur.
Acute severe regurgitation may occur as the result of perforation
of an aortic cusp in endocarditis. In this circumstance, there
may be no time for compensatory left ventricular hypertrophy
and dilatation to develop and the features of heart failure may
predominate. The classical signs of aortic regurgitation in such
patients may be masked by tachycardia and an abrupt rise in
Diseases of the heart valves • 525
Aorta
Lean patient forward with
breath held in expiration
to hear early diastolic
murmur best
Colour jet of aortic
regurgitation
Dilated
aorta
Aortic
valve
Dilated left
ventricle
Increased
pulse
pressure
Fig. 16.87 Aortic regurgitation. The early diastolic murmur is best heard at the left sternal edge and may be accompanied by an ejection systolic (‘to
and fro’) murmur. The aortic arch and left ventricle (L V) may become dilated. The inset shows a Doppler echocardiogram with the regurgitant jet (arrows).
Inset (Colour Doppler echo) From Newby D, Grubb N. Cardiology: an illustrated colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005.
i
ECG
• Initially normal, later left ventricular hypertrophy and T-wave
inversion
Chest X-ray
• Cardiac dilatation, maybe aortic dilatation
• Features of left heart failure
Echo
• Dilated left ventricle • Doppler detects reflux
• Hyperdynamic left ventricle • Fluttering anterior mitral leaflet
Cardiac catheterisation
• Dilated left ventricle • Dilated aortic root
• Aortic regurgitation
*Not always required.
left ventricular end-diastolic pressure. The pulse pressure may
also be normal or near-normal and the diastolic murmur may
be short or even absent.
Investigations
Doppler echocardiography is the investigation of first choice
for detecting regurgitation (Box 16.90). In severe acute aortic
regurgitation, the rapid rise in left ventricular diastolic pressure
may cause premature mitral valve closure. Cardiac catheterisation
and aortography are usually performed to assess the severity of
regurgitation, to determine if there is dilatation of the aorta and
to screen for the presence of coexisting CAD. MRI can also be
useful in assessing the degree and extent of aortic dilatation if
this is suspected on chest X-ray or echocardiography.
Management
Treatment may be required for underlying conditions, such as
endocarditis or syphilis. Aortic valve replacement is indicated
if aortic regurgitation causes symptoms, and this may need to
be combined with aortic root replacement and coronary bypass
surgery. Those with chronic aortic regurgitation can remain
asymptomatic for many years because compensatory ventricular
dilatation and hypertrophy occur, but should be advised to report
the development of any symptoms of breathlessness or angina.
Asymptomatic patients should also be followed up annually with
echocardiography for evidence of increasing ventricular size. If
this occurs or if the end-systolic dimension increases to 55 mm
or more, then aortic valve replacement should be undertaken. If
systemic hypertension is present, vasodilators should be used
to control systolic BP. There is conflicting evidence regarding
the need for aortic valve replacement in asymptomatic patients
with severe aortic regurgitation. When aortic root dilatation is the
cause of aortic regurgitation, as can occur in Marfan’s syndrome,
aortic root replacement is usually necessary.
Tricuspid valve disease
| Tricuspid stenosis
Tricuspid stenosis is usually rheumatic in origin and is rare in
developed countries. Tricuspid disease occurs in fewer than
5% of patients with rheumatic heart disease and then nearly
always occurs in association with mitral and aortic valve disease.
Tricuspid stenosis and regurgitation may also occur in the
carcinoid syndrome (p. 678).
Clinical features and investigations
Although the symptoms of mitral and aortic valve disease
predominate, tricuspid stenosis may cause symptoms of
16.90 Investigations in aortic regurgitation
526 • CARDIOLOGY
right heart failure, including hepatic discomfort and peripheral
oedema.
The main clinical feature is a raised JVP with a prominent a
wave, and a slow y descent due to the loss of normal rapid right
ventricular filling (p. 443). There is also a mid-diastolic murmur,
best heard at the lower left or right sternal edge. This is generally
higher-pitched than the murmur of mitral stenosis and is increased
by inspiration. Right heart failure causes hepatomegaly with pre-
systolic pulsation (large a wave), ascites and peripheral oedema.
The diagnosis can be confirmed by Doppler echocardiography,
which shows similar appearances to those of rheumatic mitral
stenosis.
Management
In patients who require surgery to other valves, either the tricuspid
valve can also be replaced or treated with valvotomy. Balloon
valvuloplasty can be used to treat rare cases of isolated tricuspid
stenosis.
| Tricuspid regurgitation
Tricuspid regurgitation is common, and is most frequently
functional, occurring as a result of right ventricular dilatation
due to right heart failure or biventricular failure. It may
also be the result of other conditions, as summarised in
Box 16.91.
Clinical features
Symptoms are usually non-specific, with tiredness related to
reduced cardiac output, and oedema and hepatic enlargement
due to venous congestion. The most prominent sign is a ‘giant’
v wave in the jugular venous pulse (a cv wave replaces the
normal x descent). Other features include a pansystolic murmur
at the left sternal edge and a pulsatile liver. Echocardiography
may reveal dilatation of the RV. If the valve has been affected
by rheumatic disease, the leaflets will appear thickened and, in
endocarditis, vegetations may be seen.
Management
Tricuspid regurgitation due to right ventricular dilatation often
improves when the cardiac failure is treated. Patients with a
normal pulmonary artery pressure tolerate isolated tricuspid
reflux well, and valves damaged by endocarditis do not
usually need to be replaced. Patients undergoing mitral valve
replacement, who have tricuspid regurgitation due to marked
dilatation of the tricuspid annulus, benefit from valve repair
with an annuloplasty ring to bring the leaflets closer together.
Those with rheumatic damage may require tricuspid valve
replacement.
i
Pulmonary valve disease
| Pulmonary stenosis
This can occur in the carcinoid syndrome but is usually congenital,
in which case it may be isolated or associated with other
abnormalities, such as Fallot’s tetralogy (p. 536).
Clinical features
The principal finding on examination is an ejection systolic murmur,
loudest at the left upper sternum and radiating towards the left
shoulder. There may be a thrill, best felt when the patient leans
forwards and breathes out. The murmur is often preceded
by an ejection sound (click). Delay in right ventricular ejection
may cause wide splitting of the second heart sound. Severe
pulmonary stenosis is characterised by a loud, harsh murmur,
an inaudible pulmonary closure sound (P2), an increased right
ventricular heave, and prominent a waves in the jugular pulse.
Investigations
Doppler echocardiography is the definitive investigation. ECG
may show evidence of right ventricular hypertrophy, and post¬
stenotic dilatation in the pulmonary artery may be observed on
the chest X-ray.
Management
Mild to moderate isolated pulmonary stenosis is relatively common
and does not usually progress or require treatment. Severe
pulmonary stenosis (resting gradient >50 mmHg with a normal
cardiac output) can be treated by percutaneous pulmonary balloon
valvuloplasty or, if this is not available, by surgical valvotomy.
Long-term results are very good. Post-operative pulmonary
regurgitation is common but benign.
| Pulmonary regurgitation
This is rare in isolation and is usually associated with pulmonary
artery dilatation due to pulmonary hypertension. It may complicate
mitral stenosis, producing an early diastolic decrescendo murmur
at the left sternal edge that is difficult to distinguish from aortic
regurgitation (Graham Steell murmur). The pulmonary hypertension
may be secondary to other disease of the left side of the heart,
primary pulmonary vascular disease or Eisenmenger’s syndrome
(p. 532). Trivial pulmonary regurgitation is a frequent finding in
normal individuals and has no clinical significance.
Prosthetic valves
Diseased heart valves can be replaced with mechanical or
biological prostheses. The three most commonly used types
of mechanical prosthesis are the ball and cage, tilting single
disc and tilting bi-leaflet valves. All generate prosthetic sounds
or clicks on auscultation. Pig or allograft valves mounted on a
supporting stent are the most commonly used biological valves.
They generate normal heart sounds. All prosthetic valves used
in the aortic position produce a systolic flow murmur.
All mechanical valves require long-term anticoagulation because
they can cause systemic thromboembolism or may develop valve
thrombosis or obstruction (Box 1 6.92); the prosthetic clicks may
become inaudible if the valve malfunctions. Biological valves have
the advantage of not requiring anticoagulants to maintain proper
function; however, many patients undergoing valve replacement
surgery, especially mitral valve replacement, will have AF that
Primary
• Rheumatic heart disease
• Endocarditis, particularly in intravenous drug-users
• Ebstein’s congenital anomaly (see Box 16.102)
Secondary
• Right ventricular failure
• Right ventricular infarction
• Pulmonary hypertension
16.91 Causes of tricuspid regurgitation
Diseases of the heart valves • 527
16.92 Anticoagulation targets and prosthetic
heart valves
Mechanical valves
Target INR
Ball and cage (e.g. Starr— Ed wards)
3. 0-4.0
Tilting disc (e.g. Bjork-Shiley)
Bi-leaflet (e.g. St Jude)
2. 5-3.0
Biological valves with atrial fibrillation
2. 0-3.0
(INR = international normalised ratio)
Fig. 16.88 Transcatheter aortic valve implantation (TAVI):
bioprosthetic valve.
requires anticoagulation anyway. Biological valves are less durable
than mechanical valves and may degenerate 7 or more years
after implantation, particularly when used in the mitral position.
They are more durable in the aortic position and in older patients,
so are particularly appropriate for patients over 65 undergoing
aortic valve replacement.
| Transcatheter aortic valve implantation
For patients being considered for aortic valve surgery, especially
due to aortic stenosis, transcatheter aortic valve implantation (TAVI)
is an emerging alternative to surgical aortic valve replacement.
The native valve is not removed but is compressed by the new
bioprosthetic valve, which is implanted within it. The bioprosthetic
valve is mounted on a large stent-like structure and is implanted
through a catheter inserted in the femoral artery (Fig. 16.88).
TAVI has several major advantages. It avoids the need for a
sternotomy, is associated with a short recovery period, can
be used in high-risk and otherwise inoperable patients, and
is much better tolerated by elderly patients. Complications
include stroke (2%) and heart block necessitating pacemaker
implantation (5-15%).
Prosthetic valve dysfunction
Symptoms or signs of unexplained heart failure in a patient with
a prosthetic heart valve may be due to valve dysfunction, and
urgent assessment is required. Metallic valves can suffer strut
fracture and fail, causing catastrophic regurgitation. Alternatively,
they may thrombose and cause systemic thromboembolism
or valve obstruction, especially in the presence of inadequate
anticoagulation. Biological valve dysfunction is usually associated
with the development of a regurgitant murmur and may begin
to develop 8-10 years after implantation.
Infective endocarditis
This is caused by microbial infection of a heart valve, the lining of
a cardiac chamber or blood vessel, or by a congenital anomaly.
Both native and prosthetic valves can be affected. The most
common causes of infective endocarditis are streptococci and
staphylococci but other organisms may also be involved.
Epidemiology
The incidence of infective endocarditis in community-based
studies ranges from 5 to 1 5 cases per 1 00000 per annum. More
than 50% of patients are over 60 years of age (Box 1 6.93). In a
large British study, the underlying condition was rheumatic heart
disease in 24% of patients, congenital heart disease in 19%,
and other cardiac abnormalities such as calcified aortic valve or
floppy mitral valve in 25%. The remaining 32% were not thought
to have a pre-existing cardiac abnormality. Bacterial endocarditis
is a serious illness; the case fatality is approximately 20% even
with treatment, and is even higher in those with prosthetic valve
endocarditis and those infected with antibiotic-resistant organisms.
Pathophysiology
Infective endocarditis typically occurs at sites of pre-existing
endocardial damage, but infection with particularly virulent or
aggressive organisms such as Staphylococcus aureus can
cause endocarditis in a previously normal heart. Staphylococcal
endocarditis of the tricuspid valve is a common complication
of intravenous drug use. Many acquired and congenital cardiac
lesions are vulnerable, particularly areas of endocardial damage
caused by a high-pressure jet of blood, such as ventricular
septal defect, mitral regurgitation and aortic regurgitation, many
of which are haemodynamically insignificant. In contrast, the risk
of endocarditis at the site of haemodynamically important low-
pressure lesions, such as a large atrial septal defect, is minimal.
Infection tends to occur at sites of endothelial damage because
they attract deposits of platelets and fibrin that are vulnerable
to colonisation by blood-borne organisms. The avascular valve
tissue and presence of fibrin and platelet aggregates help to
protect proliferating organisms from host defence mechanisms.
When the infection is established, vegetations composed of
organisms, fibrin and platelets grow and may become large
enough to cause obstruction or embolism. Adjacent tissues
are destroyed and abscesses may form. Valve regurgitation
may develop or increase if the affected valve is damaged by
tissue distortion, cusp perforation or disruption of chordae.
Extracardiac manifestations, such as vasculitis and skin lesions,
may occur as the result of either emboli or immune complex
deposition. Mycotic aneurysms may develop in arteries at the
site of infected emboli. In fatal cases, infarction of the spleen
and kidneys and, sometimes, an immune glomerulonephritis
may be found at postmortem.
• Symptoms and signs: may be non-specific, with delirium, weight
loss, malaise and weakness, and the diagnosis may not be
suspected.
• Common causative organisms: often enterococci (from the urinary
tract) and Streptococcus gallolyticus subsp. gallolyticus (from a
colonic source).
• Morbidity and mortality: much higher.
16.93 Endocarditis in old age
528 • CARDIOLOGY
16.94 Microbiology of infective endocarditis
Of prosthetic valve
Of native valve
In injection drug users
Early
Late
Pathogen
(n = 280)
(n = 87)
(n = 15)
(n = 72)
Staphylococci
124 (44%)
60 (69%)
10 (67%)
33 (46%)
Staph, aureus
106 (38%)
60 (69%)
3 (20%)
15(21%)
Coagulase-negative
18 (6%)
0
7 (47%)
18 (25%)
Streptococci
86 (31%)
7 (8%)
0
25 (35%)
Oral
59 (21%)
3 (3%)
0
19 (26%)
Others (non-enterococcal)
27 (10%)
4 (5%)
0
6 (8%)
Enterococcus spp.
21 (8%)
2 (2%)
1 (7%)
5 (7%)
HACEK
12 (4%)
0
0
i d%)
Polymicrobial
6 (2%)
8 (9%)
0
i d%)
Other bacteria
12 (4%)
4 (5%)
0
2 (3%)
Fungi
3(1%)
2 (2%)
0
0
Negative blood culture
16 (6%)
4 (5%)
4 (27%)
5 (7%)
(HACEK = Haemophilus aphrophilus - now known as Aggregatibacter aphrophilus-Aggregatibacter actinomycetemcomitans ; Cardiobacterium hominis ; Eikenella corrodens ;
and Kingella kingae)
Adapted from Moreillon P, Que YA. Infective endocarditis. Lancet 2004; 363:139-149.
Microbiology
Over three-quarters of cases are caused by streptococci or
staphylococci. Viridans streptococci, such as Streptococcus mitis
and Strep, sanguis, which are commensals in the oral cavity, can
enter the blood stream on chewing or tooth-brushing, or at the
time of dental treatment, and are common causes of subacute
endocarditis (Box 1 6.94). Other organisms, including Enterococcus
faecalis, E. faecium and Strep, gallolyticus subsp. gallolyticus
(previously known as Strep, bovis), may enter the blood from the
bowel or urinary tract. Patients who are found to have endocarditis
caused by Strep, gallolyticus should undergo colonoscopy, since
this organism is associated with large-bowel malignancy.
Staph, aureus has now overtaken streptococci as the most
common cause of acute endocarditis. It originates from skin
infections, abscesses or vascular access sites such as intravenous
and central lines, or from intravenous drug use. It is highly
virulent and invasive, usually producing florid vegetations, rapid
valve destruction and abscess formation. Other causes of acute
endocarditis include Strep, pneumoniae and Strep, pyogenes.
Post-operative endocarditis after cardiac surgery may affect
native or prosthetic heart valves or other prosthetic materials. The
most common organisms are coagulase-negative staphylococci
such as Staph, epidermidis, which are part of the normal skin
flora. There is frequently a history of wound infection with the
same organism. Coagulase-negative staphylococci cause
native valve endocarditis in approximately 5% of cases and
this possibility should always be considered before they are
dismissed as blood culture contaminants. Another coagulase-
negative staphylococcus, Staph, lugdenensis, causes a rapidly
destructive acute endocarditis that is associated with previously
normal valves and multiple emboli. Unless accurately identified,
it may also be overlooked as a contaminant.
In Q fever endocarditis due to Coxiella burnetii, the patient
often has a history of contact with farm animals. The aortic valve
is usually affected and there may also be hepatitis, pneumonia
and purpura. Life-long antibiotic therapy may be required.
In about 3-4% of cases, endocarditis may be caused by Gram¬
negative bacteria of the so-called HACEK group (Haemophilus
aphrophilus - now known as Aggregatibacter aphrophilus-
Aggregatibacter actinomycetemcomitans-, Cardiobacterium
hominis ; Eikenella corrodens-, and Kingella kingae). These are
slow-growing, fastidious Gram-negative organisms that are
oropharyngeal commensals. The diagnosis may be revealed
only after prolonged culture and the organisms may be resistant
to penicillin.
Brucella endocarditis is associated with a history of contact
with goats or cattle and often affects the aortic valve.
Yeasts and fungi, such as Candida and Aspergillus, may
attack previously normal or prosthetic valves, particularly in
immunocompromised patients or those with in-dwelling
intravenous catheters. Abscesses and emboli are common,
therapy is difficult, surgery is often required and mortality is high.
Concomitant bacterial infection may be present.
Clinical features
Endocarditis can take either an acute or a more insidious
‘subacute’ form. There is considerable overlap, however, because
the clinical pattern is influenced not only by the organism but
also by the site of infection, prior antibiotic therapy and the
presence of a valve or shunt prosthesis. The subacute form
may abruptly develop acute life-threatening complications, such
as valve disruption or emboli. The Duke criteria for diagnosis of
infective endocarditis are shown in Box 16.95.
Subacute endocarditis
This should be suspected when a patient with congenital or
valvular heart disease develops a persistent fever, complains of
unusual tiredness, night sweats or weight loss, or develops new
signs of valve dysfunction or heart failure. Less often, it presents
as an embolic stroke or peripheral arterial embolism. Other
features (Fig. 16.89) include purpura and petechial haemorrhages
in the skin and mucous membranes, and splinter haemorrhages
under the fingernails or toenails. Osier’s nodes are painful, tender
swellings at the fingertips that are probably the product of
vasculitis; they are rare. Digital clubbing is a late sign. The spleen
is frequently palpable; in Coxiella infections, the spleen and the
Diseases of the heart valves • 529
'Varying' murmurs
(90% new or changed murmur)
Conduction disorder
(10-20%)
Cardiac failure
(40-50%)
Haematuria
(60-70%)
Osier's nodes
(5%)
Petechial rash
(40-50%, may be transient)
Fig. 16.89 Clinical features that may be present in endocarditis. Insets (Petechial rash, nail-fold infarct) From Newby D, Grubb N. Cardiology: an
illustrated colour text. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005.
16.95 Diagnosis of infective endocarditis
Major criteria
Positive blood culture
• Typical organism from two cultures
• Persistent positive blood cultures taken >12 hrs apart
• Three or more positive cultures taken over >1 hr
Endocardial involvement
• Positive echocardiographic findings of vegetations
• New valvular regurgitation
Minor criteria
• Predisposing valvular or cardiac abnormality
• Intravenous drug misuse
• Pyrexia >38°C
• Embolic phenomenon
• Vasculitic phenomenon
• Blood cultures suggestive: organism grown but not achieving major
criteria
• Suggestive echocardiographic findings
*Modified Duke criteria. Patients with two major, or one major and three minor,
or five minor have definite endocarditis. Patients with one major and one minor,
or three minor have possible endocarditis.
liver may be considerably enlarged. Non-visible haematuria is
common. The finding of any of these features in a patient with
persistent fever or malaise is an indication for re-examination to
detect hitherto unrecognised heart disease.
Acute endocarditis
This presents as a severe febrile illness with prominent and
changing heart murmurs and petechiae. Clinical stigmata of
chronic endocarditis are usually absent. Embolic events are
common, and cardiac or renal failure may develop rapidly.
Abscesses may be detected on echocardiography. Partially
treated acute endocarditis behaves like subacute endocarditis.
Post-operative endocarditis
This may present as an unexplained fever in a patient who has
had heart valve surgery. The infection usually involves the valve
ring and may resemble subacute or acute endocarditis, depending
on the virulence of the organism. Morbidity and mortality are high
and revision surgery is often required. The range of organisms is
similar to that seen in native valve disease, but when endocarditis
occurs during the first few weeks after surgery it is usually due
to infection with a coagulase- negative staphylococcus that was
introduced during the perioperative period.
530 • CARDIOLOGY
Investigations
Blood culture (see Fig. 6.6, p. 107) is the pivotal investigation
to identify the organism that is the cause of the infection and
to guide antibiotic therapy. Three to six sets of blood cultures
should be taken prior to commencing therapy and should not
wait for episodes of pyrexia. The first two specimens will detect
bacteraemia in 90% of culture-positive cases. A meticulous aseptic
technique is essential. Taking discrete sets of blood cultures
from peripheral sites at intervals of > 6 hours reduces the risk
of misdiagnosis due to contamination with skin commensals.
Isolation of a typical organism in more than one culture provides
strong evidence in favour of the diagnosis (Box 16.95). An
in-dwelling line should not be used to take cultures. Both aerobic
and anaerobic cultures are required.
Echocardiography is key for detecting and following the
progress of vegetations, for assessing valve damage and for
detecting abscess formation. Vegetations as small as 2-4 mm
can be detected by transthoracic echocardiography, and even
smaller ones (1-1 .5 mm) can be visualised by trans-oesophageal
echocardiography (TOE), which is particularly valuable for identifying
abscess formation and investigating patients with prosthetic heart
valves. Vegetations may be difficult to distinguish in the presence
of an abnormal valve; the sensitivity of transthoracic echo is
approximately 65% but that of TOE is more than 90%. Failure to
detect vegetations does not exclude the diagnosis.
Elevation of the ESR, a normocytic normochromic anaemia,
and leucocytosis are common but not invariable. Measurement of
serum CRP is more reliable than the ESR in monitoring progress.
Proteinuria may occur and non-visible haematuria is usually present.
The ECG may show the development of AV block (due to
aortic root abscess formation) and occasionally infarction due
to emboli. The chest X-ray may show evidence of cardiac failure
and cardiomegaly.
Management
A multidisciplinary approach, with cooperation between the
physician, surgeon and microbiologist, increases the chance
of a successful outcome. Any source of infection should be
removed as soon as possible; for example, a tooth with an
apical abscess should be extracted.
Empirical treatment depends on the mode of presentation,
the suspected organism and the presence of a prosthetic valve
or penicillin allergy. If the presentation is subacute, antibiotic
treatment should ideally be withheld until the results of blood
cultures are available. However, if empirical antibiotic treatment
is considered necessary, amoxicillin (2 g 6 times daily IV) should
be considered (with or without gentamicin). If the presentation
is acute, empirical therapy should be started with vancomycin
(1 g twice daily IV) and gentamicin (1 mg/kg twice daily IV), with
dose adjustment based on antibiotic levels. The same regimen is
used in true penicillin allergy. Patients with suspected prosthetic
valve endocarditis should be treated with vancomycin and
gentamicin at the above-mentioned doses, plus rifampicin orally
in a dose of 300-600 mg twice daily. Following identification of
the causal organism, determination of the minimum inhibitory
concentration (MIC) for the organism helps guide antibiotic
therapy. Recommended regimens for some of the most common
scenarios are shown in Box 16.96. More detailed information
16.96 Antimicrobial treatment of common causative organisms in infective endocarditis
Duration
Antimicrobial susceptibility
Antimicrobial
Dose
Native valve
Prosthetic valve
Streptococci
Penicillin MIC <0.1 25 mg/L
Benzylpenicillin IV
1.2 g 6 times daily
4 weeks1
6 weeks
Penicillin MIC >0.125,
Benzylpenicillin IV and
2.4 g 6 times daily
4 weeks
6 weeks
<0.5 mg/L
gentamicin IV
1 mg/kg twice daily2
2 weeks
2 weeks
Penicillin MIC >0.5mg/L
Vancomycin IV and
1 g twice daily3
4 weeks
6 weeks
gentamicin IV
1 mg/kg twice daily2
4 weeks
6 weeks
Enterococci
Amoxicillin MIC <4 mg/L and
Amoxicillin IV and
2g 6 times daily
4 weeks
6 weeks
gentamicin MIC <128 mg/L
gentamicin IV2
1 mg/kg twice daily2
4 weeks
6 weeks
Amoxicillin MIC >4mg/L and
Vancomycin IV and
1 g twice daily3
4 weeks
6 weeks
gentamicin MIC <128 mg/L
gentamicin IV2
1 mg/kg twice daily2
4 weeks
6 weeks
Staphylococci - native valve
Meticillin-sensitive
Flucloxacillin IV
2g 4-6 times daily4
4 weeks
Meticillin-resistant, vancomycin MIC
Vancomycin IV
1 g twice daily3
4 weeks
-
<2 mg/L, rifampicin-sensitive
Rifampicin orally
300-600 mg twice daily
4 weeks
-
Staphylococci - prosthetic valve
Meticillin-sensitive
Flucloxacillin IV
2g 4-6 times daily
6 weeks
and gentamicin IV
1 mg/kg twice daily2
-
6 weeks
and rifampicin orally
300-600 mg twice daily
-
6 weeks
Meticillin-resistant, vancomycin MIC
Vancomycin IV
1 g twice daily3
-
6 weeks
<2 mg/L, rifampicin-sensitive
and rifampicin orally
300-600 mg twice daily
-
6 weeks
l!When conditions in Box 16.97 are met, 2 weeks of benzylpenicillin and gentamicin (1 mg/kg twice daily) may be sufficient. Ceftriaxone 2g once daily IV/IM can be used
instead of benzylpenicillin for those with non-severe penicillin allergy. 2Pre-dose gentamicin level should be <1 mg/L, post-dose 3-5mg/L. Adjust dose according to levels
and renal function. 3Pre-dose vancomycin level should be 15-20 mg/L. Adjust dose according to levels and renal function.
4Use 6 times daily if weight >85 kg.
(IV = intravenous; MIC = minimum inhibitory concentration)
Adapted from Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the working party of the
British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012; 67:269-289.
Congenital heart disease • 531
16.97 Conditions for the short-course treatment
of endocarditis caused by fully sensitive
streptococci
• Native valve infection
• Minimum inhibitory concentration (MIC) <0.125 mg/L
• No adverse prognostic factors (heart failure, aortic regurgitation,
conduction defect)
• No evidence of thromboembolic disease
• No vegetations >5 mm diameter
• Clinical response within 7 days
16.98 Indications for cardiac surgery in infective
endocarditis
• Heart failure due to valve damage
• Failure of antibiotic therapy (persistent/uncontrolled infection)
• Large vegetations on left-sided heart valves with echo appearance
suggesting high risk of emboli
• Previous evidence of systemic emboli
• Abscess formation
*Patients with prosthetic valve endocarditis or fungal endocarditis often require
cardiac surgery.
can be found in the 2012 British Society for Antimicrobial
Chemotherapy guidelines (see ‘Further reading’).
A 2 -week treatment regimen may be sufficient for fully sensitive
strains of streptococci, provided specific conditions are met
(Box 16.97).
Cardiac surgery with debridement of infected material and
valve replacement may be required in a substantial proportion
of patients, particularly those with Staph, aureus and fungal
infections (Box 16.98). Antimicrobial therapy must be started
before surgery.
Prevention
Until recently, antibiotic prophylaxis was routinely given to
people at risk of infective endocarditis undergoing interventional
procedures. However, as this has not been proven to be effective
and the link between episodes of infective endocarditis and
interventional procedures has not been demonstrated, antibiotic
prophylaxis is no longer offered routinely.
Congenital heart disease
Congenital heart disease can be the result of defects in the
formation of the heart or great vessels or can arise because
the anatomical changes that occur during transition between the
fetus and the newborn child fail to proceed normally. Congenital
heart disease usually presents in childhood but some patients
do not present until adult life. It has been estimated that the
incidence of haemodynamically significant congenital cardiac
abnormalities is about 0.8% of live births (Box 16.99). Defects
that are well tolerated, such as atrial septal defect, may cause
no symptoms until adult life or may be detected incidentally on
routine examination or chest X-ray. Congenital defects that were
previously fatal in childhood can now be corrected, or at least
partially, so that survival to adult life is the norm. Such patients
remain well for many years but subsequently re-present in later
16.99 Incidence and relative frequency of congenital
cardiac malformations
Lesion
% of all congenital
heart defects
Ventricular septal defect
30
Atrial septal defect
10
Persistent ductus arteriosus
10
Pulmonary stenosis
7
Coarctation of aorta
7
Aortic stenosis
6
Tetralogy of Fallot
6
Complete transposition of great arteries
4
Others
20
Bl 16.100 Presentation of congenital heart disease
throughout life
Birth and neonatal period
• Cyanosis
• Heart failure
Infancy and childhood
• Cyanosis
• Murmur
• Heart failure
• Failure to thrive
• Arrhythmia
Adolescence and adulthood
• Heart failure
• Complications of previous
• Murmur
cardiac surgery:
• Arrhythmia
Arrhythmia related to
• Eisenmenger’s syndrome
scarring
• Hypertension
Heart failure secondary to
(coarctation)
scarring
life with related problems such as arrhythmia or heart failure
(Box 16.100).
Pathophysiology
Understanding the fetal circulation helps clarify how some forms
of congenital heart disease occur. Figure 16.90 shows the fetal
circulation and the changes that normally occur immediately
after birth. In the fetus there is little blood flow through the
lungs, which are collapsed because they are not required for
gas exchange. Instead, oxygenated blood from the placenta
passes directly from the right atrium to the left side of the heart
through the foramen ovale without having to flow through the
lungs, and also from the pulmonary artery into the aorta via the
ductus arteriosus.
During early embryonic life, the heart develops as a single
tube that folds back on itself and then divides into two separate
circulations. Failure of septation can cause some forms of atrial
and ventricular septal defect, whereas failure of alignment of the
great vessels with the ventricles contributes to transposition of
the great arteries, tetralogy of Fallot and truncus arteriosus. Atrial
septal defects occur because the foramen ovale fails to close
at birth, as is normal. Similarly, a persistent ductus arteriosus
will remain persistent if it fails to close after birth. Failure of the
aorta to develop at the point of the aortic isthmus and where the
ductus arteriosus attaches can lead to coarctation of the aorta.
Maternal infection and exposure to drugs or toxins are important
causes of congenital heart disease. Maternal rubella infection is
associated with persistent ductus arteriosus, pulmonary valvular
532 • CARDIOLOGY
Fig. 16.90 Changes in the circulation at birth. {K\ In the fetus, oxygenated blood comes through the umbilical vein where it enters the inferior vena
cava (IVC) via the ductus venosus (red). The oxygenated blood streams from the right atrium (RA) through the open foramen ovale to the left atrium (LA)
and via the left ventricle (LV) into the aorta. Venous blood from the superior vena cava (SVC, blue) crosses under the main blood stream into the RA and
then, partly mixed with oxygenated blood (purple), into the right ventricle (R V) and pulmonary artery (PA). The pulmonary vasculature has a high resistance
and so little blood passes to the lungs; most blood passes through the ductus arteriosus to the descending aorta. The aortic isthmus is a constriction in the
aorta that lies in the aortic arch before the junction with the ductus arteriosus and limits the flow of oxygen-rich blood to the descending aorta. This
configuration means that less oxygen-rich blood is supplied to organ systems that take up their function mainly after birth, e.g. the kidneys and intestinal
tract. [§] At birth, the lungs expand with air and pulmonary vascular resistance falls, so that blood now flows to the lungs and back to the LA. The left
atrial pressure rises above right atrial pressure and the flap valve of the foramen ovale closes. The umbilical arteries and the ductus venosus close. In the
next few days, the ductus arteriosus closes under the influence of hormonal changes (particularly prostaglandins) and the aortic isthmus expands. (PV =
pulmonary vein) Adapted from Drews U. Colour atlas of embryology. Stuttgart: Georg Thieme; 1995.
and/or artery stenosis, and atrial septal defect. Maternal alcohol
misuse is associated with septal defects, and maternal lupus
erythematosus with congenital complete heart block. Genetic
or chromosomal abnormalities, such as Down’s syndrome, may
cause septal defects, and gene defects have also been identified
as leading to specific abnormalities, such as Marfan’s syndrome
(p. 508) and DiGeorge’s syndrome (deletion in chromosome 22q).
Clinical features
Symptoms may be absent, or the child may be breathless or
fail to attain normal growth and development. Some defects are
not compatible with extrauterine life and lead to neonatal death.
Clinical signs vary with the anatomical lesion. Murmurs, thrills or
signs of cardiomegaly may be present. In coarctation of the aorta,
radio-femoral delay may be noted (Fig. 16.91) and some female
patients have the features of Turner’s syndrome (p. 659). Features
of other congenital conditions, such as Marfan’s syndrome or
Down’s syndrome, may also be apparent. Cerebrovascular
events and cerebral abscesses may complicate severe cyanotic
congenital disease.
Early diagnosis is important because many types of congenital
heart disease are amenable to surgery, but this opportunity
is lost if secondary changes, such as irreversible pulmonary
hypertension, occur.
Fig. 16.91 Radio-femoral delay. The difference in pulse pressures is
shown.
Central cyanosis and digital clubbing
Central cyanosis of cardiac origin occurs when desatu rated blood
enters the systemic circulation without passing through the lungs
(right-to-left shunting). In the neonate, the most common cause
is transposition of the great arteries, in which the aorta arises
from the RV and the pulmonary artery from the LV in association
with a ventricular septal defect. In older children, cyanosis is
usually the consequence of a ventricular septal defect combined
with severe pulmonary stenosis (as in tetralogy of Fallot) or with
pulmonary vascular disease (Eisenmenger’s syndrome). Prolonged
cyanosis is associated with finger and toe clubbing (p. 442).
Congenital heart disease • 533
Growth retardation and learning difficulties
These may occur with large left-to-right shunts at ventricular or
great arterial level, and also with other defects, especially if they
form part of a genetic syndrome. Major intellectual impairment
is uncommon in children with isolated congenital heart disease;
minor learning difficulties can occur, however. Cerebral function
can also be affected after cardiac surgery if cerebral perfusion
is compromised.
Syncope
In the presence of increased pulmonary vascular resistance
or severe left or right ventricular outflow obstruction, exercise
may provoke syncope as systemic vascular resistance falls
but pulmonary vascular resistance rises, worsening right-to-left
shunting and cerebral oxygenation. Syncope can also occur
because of associated arrhythmias.
Pulmonary hypertension
Persistently raised pulmonary flow with a left-to-right shunt causes
increased pulmonary vascular resistance followed by pulmonary
hypertension. Progressive changes, including obliteration of
distal arterioles, take place and are irreversible. At this stage,
central cyanosis occurs and digital clubbing develops. The chest
X-ray shows enlarged central pulmonary arteries and peripheral
‘pruning’ of the pulmonary vessels. The ECG shows features of
right ventricular hypertrophy.
Eisenmenger’s syndrome
In patients with severe and prolonged pulmonary hypertension
the left-to-right shunt may reverse, resulting in right-to-left shunt
and marked cyanosis. This is termed Eisenmenger’s syndrome.
The cyanosis in Eisenmenger’s syndrome may be more apparent
in the feet and toes than in the upper part of the body, resulting
in so-called differential cyanosis. Eisenmenger’s syndrome is
more common with large ventricular septal defects or persistent
ductus arteriosus than with atrial septal defects. Patients with
Eisenmenger’s syndrome are at particular risk from abrupt
changes in afterload that exacerbate right -to-left shunting, such
as vasodilatation, anaesthesia and pregnancy.
Congenital heart disease in pregnancy
During pregnancy, there is a 50% increase in plasma volume, a
40% increase in whole blood volume and a similar increase in
cardiac output, so problems may arise in women with congenital
heart disease (Box 16.101). Many with palliated or untreated
disease will tolerate pregnancy well, however. Pregnancy is
particularly hazardous in the presence of conditions associated
with cyanosis or severe pulmonary hypertension; maternal mortality
in patients with Eisenmenger’s syndrome is more than 50%.
16.101 Pregnancy in women with congenital
heart disease
Persistent ductus arteriosus
Normally, the ductus arteriosus closes soon after birth but in
this anomaly it fails to do so. Persistence of the ductus is often
associated with other abnormalities and is more common in
females.
Pathophysiology
During fetal life, before the lungs begin to function, most of the
blood from the pulmonary artery passes through the ductus
arteriosus into the aorta (see Fig. 16.90). Persistence of the
ductus causes a continuous AV shunt from the aorta to the
pulmonary artery since pressure in the aorta is higher than
that in the pulmonary circulation. The volume of the shunt
depends on the size of the ductus but as much as 50% of the
left ventricular output may be recirculated through the lungs,
with a consequent increase in the work of the heart (Fig. 1 6.92).
A large left-to-right shunt in infancy may cause a considerable
rise in pulmonary artery pressure and sometimes this leads to
progressive pulmonary vascular damage.
Clinical features
With small shunts there may be no symptoms for years, but
when the ductus is large, growth and development may be
retarded. Usually, there is no disability in infancy but cardiac
failure may eventually ensue, dyspnoea being the first symptom.
A continuous ‘machinery’ murmur is heard with late systolic
accentuation, maximal in the second left intercostal space below
the clavicle (Fig. 16.92). It is frequently accompanied by a thrill.
Pulses are increased in volume.
Enlargement of the pulmonary artery may be detected
radiologically. The ECG is usually normal. If pulmonary vascular
resistance increases, pulmonary artery pressure may rise until it
equals or exceeds aortic pressure. The shunt through the defect
Fig. 16.92 Persistent ductus arteriosus. There is a connection between
the aorta and the pulmonary artery with left-to-right shunting. (LA = left
atrium; LV = left ventricle; PA = pulmonary artery; RA = right atrium;
RV = right ventricle)
• Obstructive lesions: poorly tolerated and associated with
significant maternal morbidity and mortality.
• Cyanotic conditions: especially poorly tolerated. Specialised
pre-conception counselling should explain the increased risks.
• Surgically corrected disease: patients often tolerate
pregnancy well.
• Children of patients with congenital heart disease: 2-5% will
be born with cardiac abnormalities, especially if the mother is
affected. The risk may be up to 20% in babies born of women with
left-sided lesions.
534 • CARDIOLOGY
may then reverse, causing Eisenmenger’s syndrome. The murmur
becomes quieter, may be confined to systole or may disappear.
Investigations
Echocardiography is the investigation of choice although the
persistent ductus requires specific echocardiographic views,
such as from the suprasternal notch, to reveal it. The ECG shows
evidence of right ventricular hypertrophy
Management
A persistent ductus can be closed at cardiac catheterisation with
an implantable occlusive device. Closure should be undertaken
in infancy if the shunt is significant and pulmonary resistance not
elevated, but this may be delayed until later childhood in those
with smaller shunts, for whom closure remains advisable to reduce
the risk of endocarditis. When the ductus is structurally intact, a
prostaglandin synthetase inhibitor (indometacin or ibuprofen) may
be used in the first week of life to induce closure. However, in the
presence of a congenital defect with impaired lung perfusion, such
as occurs in severe pulmonary stenosis and left-to-right shunt
through the ductus, it may be advisable to improve oxygenation
by keeping the ductus open with prostaglandin treatment.
Unfortunately, these treatments do not work if the ductus is
intrinsically abnormal.
Coarctation of the aorta
This condition is twice as common in males and occurs in 1 in
4000 children. It is associated with other abnormalities, most
frequently bicuspid aortic valve and ‘berry’ aneurysms of the
cerebral circulation (p. 1160). Acquired coarctation of the aorta
is rare but may follow trauma or occur as a complication of a
progressive arteritis (Takayasu’s disease, p. 1041).
Pathogenesis
Narrowing of the aorta occurs in the region where the ductus
arteriosus joins the aorta, at the isthmus just below the origin
of the left subclavian artery (see Fig. 16.90). This causes raised
BP affecting vessels of the head and neck proximal to the
coarctation, and reduced BP and impaired circulation distally.
Clinical features
Aortic coarctation is an important cause of cardiac failure in
the newborn but symptoms are often absent in older children
or adults. Headaches may occur from hypertension proximal to
the coarctation, and occasionally weakness or cramps in the
legs may result from decreased circulation in the lower part
of the body. The BP is raised in the upper body but normal
or low in the legs. The femoral pulses are weak and delayed
in comparison with the radial pulse (see Fig. 16.91). A systolic
murmur is usually heard posteriorly, over the coarctation. There
may also be an ejection click and systolic murmur in the aortic
area due to a bicuspid aortic valve. As a result of the aortic
narrowing, collaterals form; they mainly involve the periscapular,
internal mammary and intercostal arteries, and may result in
localised bruits.
Investigations
Imaging by MRI is the investigation of choice (Fig. 16.93). The
chest X-ray in early childhood is often normal but later may show
changes in the contour of the aorta (indentation of the descending
aorta, ‘3 sign’) and notching of the under-surfaces of the ribs
from collaterals. The ECG may show evidence of left ventricular
hypertrophy, which can be confirmed by echocardiography.
Fig. 16.93 MRI scan of coarctation of the aorta. The aorta is severely
narrowed just beyond the arch at the start of the descending aorta (arrow
A). Extensive collaterals have developed; a large internal mammary artery
(arrow B) and several intercostal arteries (arrows C) are shown. Unusually,
in this case, there is also a coarctation of the abdominal aorta (arrow D).
Management
In untreated cases, death may occur from left ventricular failure,
dissection of the aorta or cerebral haemorrhage. Surgical
correction is advisable in all but the mildest cases. If this is
carried out sufficiently early in childhood, persistent hypertension
can be avoided. Patients repaired in late childhood or adult life
often remain hypertensive or develop recurrent hypertension
later on. Recurrence of stenosis may occur as the child grows
and this may be managed by balloon dilatation and sometimes
stenting. The latter may be used as the primary treatment.
Coexistent bicuspid aortic valve, which occurs in over 50% of
cases, may lead to progressive aortic stenosis or regurgitation,
and also requires long-term follow-up.
Atrial septal defect
Atrial septal defect is one of the most common congenital
heart defects and occurs twice as frequently in females. Most
are ‘ostium secundum’ defects, involving the fossa ovalis that,
in utero, was the foramen ovale (see Fig. 16.90). ‘Ostium
primum’ defects result from a defect in the atrioventricular
septum and are associated with a ‘cleft mitral valve’ (split anterior
leaflet).
Pathogenesis
Since the normal RV is more compliant than the LV, a patent
foramen ovale is associated with shunting of blood from the LA to
the RA, and then to the RV and pulmonary arteries (Fig. 16.94).
As a result, there is gradual enlargement of the right side of the
heart and of the pulmonary arteries. Pulmonary hypertension
and shunt reversal sometimes complicate atrial septal defect,
but are less common and tend to occur later in life than with
other types of left-to-right shunt.
Clinical features
Most children are asymptomatic for many years and the condition
is often detected at routine clinical examination or following a chest
X-ray. Symptoms that can occur include dyspnoea, chest infections,
Congenital heart disease • 535
Fig. 16.94 Atrial septal defect. Blood flows across the atrial septum
(arrow) from left to right. The murmur is produced by increased flow
velocity across the pulmonary valve, as a result of left-to-right shunting
and a large stroke volume. The density of shading is proportional to
velocity of blood flow. (LV = left ventricle; PA = pulmonary artery;
RA = right atrium; RV = right ventricle)
cardiac failure and arrhythmias, especially AF. The characteristic
physical signs are the result of the volume overload of the RV:
• wide, fixed splitting of the second heart sound: wide
because of delay in right ventricular ejection (increased
stroke volume and RBBB), and fixed because the septal
defect equalises left and right atrial pressures throughout
the respiratory cycle
• a systolic flow murmur over the pulmonary valve.
In children with a large shunt, there may be a diastolic flow
murmur over the tricuspid valve. Unlike a mitral flow murmur,
this is usually high-pitched.
Investigations
Echocardiography is diagnostic. It directly demonstrates the defect
and typically shows right ventricular dilatation, right ventricular
hypertrophy and pulmonary artery dilatation. The precise size
and location of the defect are best defined by TOE (Fig. 1 6.95).
The chest X-ray typically shows enlargement of the heart and
the pulmonary artery, as well as pulmonary plethora. The ECG
usually demonstrates incomplete RBBB because right ventricular
depolarisation is delayed as a result of ventricular dilatation (with
a ‘primum’ defect, there is also left axis deviation).
Management
Atrial septal defects in which pulmonary flow is increased 50%
above systemic flow (i.e. a flow ratio of 1 .5: 1) are often large
enough to be clinically recognisable and should be closed
surgically. (Smaller defects may be managed conservatively and
patients are monitored with echocardiography.) Closure can also
be accomplished at cardiac catheterisation using implantable
closure devices (Fig. 16.96). The long-term prognosis thereafter
is excellent, unless pulmonary hypertension has developed.
Fig. 16.95 Transoesophageal echocardiogram of an atrial septal
defect. The defect is clearly seen (arrow) between the left atrium above
and right atrium below. Doppler colour-flow imaging shows flow (blue)
across the defect.
Fig. 16.96 Percutaneous closure of atrial septal defect. The closure
device is delivered across the interatrial septum and a disc deployed on
either side to seal the defect. (IVC = inferior vena cava; LV = left ventricle;
PA = pulmonary artery; RA = right atrium; RV = right ventricle)
Severe pulmonary hypertension and shunt reversal are both
contraindications to surgery.
|Ventricular septal defect
Ventricular septal defect is the most common congenital cardiac
defect, occurring once in 500 live births. The defect may be
isolated or part of complex congenital heart disease.
Pathogenesis
Congenital ventricular septal defect occurs as a result of
incomplete septation of the ventricles. Embryologically, the
interventricular septum has a membranous and a muscular
portion, and the latter is further divided into inflow, trabecular and
outflow portions. Most congenital defects are ‘perimembranous’,
occurring at the junction of the membranous and muscular
portions of the septum.
Clinical features
Flow from the high-pressure LV to the low-pressure RV during
systole produces a pansystolic murmur, usually heard best
at the left sternal edge but radiating all over the precordium
(Fig. 16.97). A small defect often produces a loud murmur
(maladie de Roger) in the absence of other haemodynamic
disturbance. Conversely, a large defect produces a softer murmur,
536 • CARDIOLOGY
Fig. 16.97 Ventricular septal defect. In this example, a large
left-to-right shunt (arrows) has resulted in chamber enlargement. (LA = left
atrium; LV = left ventricle; PA = pulmonary artery; RA = right atrium)
particularly if pressure in the RV is elevated. This may be found
immediately after birth, while pulmonary vascular resistance
remains high, or when the shunt is reversed in Eisenmenger’s
syndrome. Congenital ventricular septal defect may present
as cardiac failure in infants, as a murmur with only minor
haemodynamic disturbance in older children or adults, or, rarely,
as Eisenmenger’s syndrome. In a proportion of infants, the murmur
becomes quieter or disappears due to spontaneous closure
of the defect.
If cardiac failure complicates a large defect, it is usually absent
in the immediate postnatal period and becomes apparent only
in the first 4-6 weeks of life. In addition to the murmur, there is
prominent parasternal pulsation, tachypnoea and indrawing of
the lower ribs on inspiration.
Investigations
Doppler echocardiography should be performed since it helps to
identify the small septal defects that are not haemodynamically
significant and are likely to close spontaneously. Patients
with larger defects should be monitored by serial ECG
and echocardiography to screen for signs of pulmonary
hypertension. With larger defects, the chest X-ray shows
pulmonary congestion and the ECG shows bilateral ventricular
hypertrophy.
Management
Small ventricular septal defects require no specific treatment. If
there is cardiac failure in infancy, this should initially be treated
medically with digoxin and diuretics. Persisting failure is an
indication for surgical repair of the defect. Percutaneous closure
devices are under development.
If serial ECG and echocardiography suggest that pulmonary
hypertension is developing, surgical repair should be performed.
Surgical closure is contraindicated in fully developed Eisenmenger’s
syndrome, in which case heart-lung transplantation is the
only effective treatment. The long-term prognosis is generally
very good. An exception is in Eisenmenger’s syndrome,
when death normally occurs in the second or third decade
of life, but a few individuals survive to the fifth decade without
transplantation.
|jetralogy of Fallot
This is complex defect consisting of right ventricular outflow tract
obstruction and right ventricular hypertrophy, a large ventricular
septal defect and an over-riding aorta that, when combined with
the septal defect, allows blood to be pumped directly from the
RV into the aorta. It occurs in about 1 in 2000 births and is
the most common cause of cyanosis in infancy after the first
year of life.
Pathogenesis
Tetralogy of Fallot occurs as the result of abnormal development
of the bulbar septum that separates the ascending aorta from the
pulmonary artery, and which normally aligns and fuses with the
outflow part of the interventricular septum. The right ventricular
outflow obstruction is most often subvalvular (infundibular) but
may be valvular, supravalvular or a combination of these (Fig.
16.98). The subvalvular component of the right ventricular
outflow obstruction is dynamic and may increase suddenly
under adrenergic stimulation. The ventricular septal defect is
usually large and similar in aperture to the aortic orifice. The
combination results in elevated right ventricular pressure and
right-to-left shunting of cyanotic blood across the ventricular
septal defect into the aorta.
Pulmonary stenosis
(infundibular)
(2) Overriding
aorta
(1) Pulmonary
stenosis
(valvular)
(3) Ventricular
septal defect
(4) Right
ventricular
hypertrophy
Fig. 16.98 Tetralogy of Fallot. The tetralogy comprises (1) pulmonary
stenosis, (2) overriding of the ventricular septal defect by the aorta, (3) a
ventricular septal defect and (4) right ventricular hypertrophy. (LA = left
atrium; LV = left ventricle; PA = pulmonary artery; RA = right atrium;
RV = right ventricle)
Congenital heart disease • 537
Clinical features
Children are usually cyanosed but this may not be the case in
the neonate because it is only when right ventricular pressure
rises to equal or exceed left ventricular pressure that a large
right-to-left shunt develops. The affected child may suddenly
become increasingly cyanosed, often after feeding or a crying
attack, and may become apnoeic and unconscious. These
attacks are called ‘Fallot’s spells’. In older children, Fallot’s spells
are uncommon but cyanosis becomes increasingly apparent,
with stunting of growth, digital clubbing and polycythaemia.
Some children characteristically obtain relief by squatting
after exertion, which increases the afterload of the left heart
and reduces the right-to-left shunting. This is called Fallot’s
sign. The natural history before the development of surgical
correction was variable but most patients died in infancy or
childhood.
On examination, the most characteristic feature is the
combination of cyanosis with a loud ejection systolic murmur
in the pulmonary area (as for pulmonary stenosis). Cyanosis
may be absent in the newborn or in patients with only mild right
ventricular outflow obstruction, however. This is called acyanotic
tetralogy of Fallot.
Investigations
Echocardiography is diagnostic and demonstrates that the aorta
is not continuous with the anterior ventricular septum. The ECG
shows right ventricular hypertrophy and the chest X-ray shows
an abnormally small pulmonary artery and a ‘boot-shaped’ heart.
Management
The definitive management is total correction of the defect by
surgical relief of the pulmonary stenosis and closure of the
ventricular septal defect. Primary surgical correction may be
undertaken prior to the age of 5 years. If the pulmonary arteries
are too hypoplastic, then palliation in the form of a Blalock-Taussig
shunt may be performed, with an anastomosis created between
the pulmonary artery and subclavian artery. This improves
pulmonary blood flow and pulmonary artery development, and
may facilitate later definitive correction.
The prognosis after total correction is good, especially if
the operation is performed in childhood. Follow-up is needed
to identify residual shunting, recurrent pulmonary stenosis
and arrhythmias. An implantable defibrillator is sometimes
recommended in adulthood.
I Other causes of cyanotic congenital
heart disease
There are other causes of cyanotic congenital heart disease,
as summarised in Box 16.102. Echocardiography is usually the
definitive diagnostic procedure, supplemented, if necessary, by
cardiac catheterisation.
Adult congenital heart disease
There are increasing numbers of children who have had surgical
correction of congenital defects and who may have further
problems as adults. The transition period between paediatric and
adult care needs to be managed in a carefully planned manner,
addressing many diverse aspects of care (Box 16.103). Those
who have undergone correction of coarctation of the aorta may
develop hypertension in adult life. Those with transposition of
the great arteries who have had a ‘Mustard’ repair, in which
^9 16.102 Other causes of cyanotic congenital
heart disease
Defect
Features
Tricuspid atresia
Absent tricuspid orifice, hypoplastic RV,
RA-to-LA shunt, ventricular septal defect
shunt, other anomalies
Surgical correction may be possible
Transposition of the
great vessels
Aorta arises from the morphological RV,
pulmonary artery from LV
Shunt via atria, ductus and possibly
ventricular septal defect
Palliation by balloon atrial septostomy/
enlargement
Surgical correction possible
Pulmonary atresia
Pulmonary valve atretic and pulmonary
artery hypoplastic
RA-to-LA shunt, pulmonary flow via ductus
Palliation by balloon atrial septostomy
Surgical correction may be possible
Ebstein’s anomaly
Tricuspid valve is dysplastic and displaced
into RV, RV ‘atrial ised’
Tricuspid regurgitation and RA-to-LA shunt
Wide spectrum of severity
Arrhythmias
Surgical repair possible but significant risk
(LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle)
16.103 Congenital heart disease in adolescence
• Patients: a heterogeneous population with residual disease and
sequelae that vary according to the underlying lesion and in
severity; each patient must be assessed individually.
• Management plan: should be agreed with the patient and include
short- and long-term goals and timing of transition to adult care.
• Risks of surgery: non-cardiac surgery for associated congenital
abnormalities carries increased risks and needs to be planned, with
careful pre-operative assessment. Risks include thrombosis,
embolism from synthetic shunts or patches, and volume overload
from fluid shifts. Operative approaches should address cosmetic
concerns, such as site of implantation of abdominal generator.
• Exercise: patients with mild or repaired defects can undertake
moderately vigorous exercise but those with complex defects,
cyanosis, ventricular dysfunction or arrhythmias require specialist
evaluation and individualised advice regarding exercise.
• Genetics: Between 10% and 15% have a genetic basis and this
should be assessed to understand the impact it may have for the
patient’s own future children. A family history, genetic evaluation of
syndromic versus non-syndromic disorders and, sometimes,
cytogenetics are required.
• Education and employment: may be adversely affected and
occupational activity levels need to be assessed.
• End of life: some adolescents with complex disorders may
misperceive and think they have been cured; transition to adult
services may be the first time they receive information about
mortality. Expectations on life expectancy need to be managed and
adolescents are often willing to engage with this and play a role in
decision-making.
blood is redirected at atrial level leaving the RV connected
to the aorta, may develop right ventricular failure in adult life.
This is because the RV is unsuited for function at systemic
pressures and may begin to dilate and fail when patients are in
their twenties or thirties.
538 • CARDIOLOGY
Those who have had surgery involving the atria may develop
atrial arrhythmias, and those who have ventricular scars may
develop ventricular arrhythmias and need consideration for
placement of an ICD. Such patients require careful follow-up
from the teenage years throughout adult life, so that problems
can be identified early and appropriate medical or surgical
treatment instituted. The management of patients with grown-up
congenital heart disease (GUCH) is complex and has developed
as a cardiological subspecialty.
Diseases of the myocardium
Although the myocardium is involved as the result of ischaemia
in CAD and in valvular heart disease, this section focus on
conditions that primarily affect the heart muscle.
Myocarditis
This is an acute inflammatory condition that can have an infectious,
toxic or autoimmune aetiology (Box 16.104). Myocarditis can
complicate many infections in which inflammation may be due
directly to infection of the myocardium or the effects of circulating
toxins. Viral infections are the most common causes, such as
Coxsackie (35 cases per 1 000 infections) and influenza A and B (25
cases per 1 000 infections) viruses. Myocarditis may occur several
weeks after the initial viral symptoms, and susceptibility is increased
by glucocorticoid treatment, immunosuppression, radiation,
previous myocardial damage and exercise. Some bacterial
and protozoal infections may be complicated by myocarditis;
for example, approximately 5% of patients with Lyme disease
(Borrelia burgdorferi, p. 255) develop myopericarditis, which is
often associated with AV block. Toxins such as alcohol and drugs
such as cocaine, lithium and doxorubicin may directly injure the
1 16.104 Some causes of myocarditis
Infections
Viral
• Coxsackie
• Human immunodeficiency
• Adenovirus
virus (HI V)
• Influenza A
• Influenza B
Bacterial
• Borrelia burgdorferi
• Mycoplasma pneumoniae
(Lyme disease)
Protozoal
• Trypanosoma cruzi
• Toxoplasma gondii
(Chagas’ disease)
Fungal
• Aspergillus
Parasitic
• Shistosoma
Drugs/Toxins
• Alcohol
• Cocaine
• Anthracyclines
• Lithium
• Clozapine
Autoimmune
• Systemic lupus erythematosus
• Hypersensitivity reaction to
• Systemic sclerosis
penicillins, sulphonamides,
• Rheumatoid arthritis
lead, carbon monoxide
• Sarcoidosis
myocardium. Other drugs, including penicillins and sulphonamides,
and poisons such as lead and carbon monoxide may cause a
hypersensitivity reaction and associated myocarditis. Occasionally,
autoimmune conditions, such as systemic lupus erythematosus
and rheumatoid arthritis, are associated with myocarditis.
Clinical features
Myocarditis may present in one of four ways:
• Fulminant myocarditis follows a viral prodrome or
influenza-like illness and results in severe heart failure or
cardiogenic shock.
• Acute myocarditis presents over a longer period with heart
failure; it can lead to dilated cardiomyopathy.
• Chronic active myocarditis is rare and associated with
chronic myocardial inflammation.
• Chronic persistent myocarditis is characterised by focal
myocardial infiltrates and can cause chest pain and
arrhythmia without necessarily causing ventricular
dysfunction.
Myocarditis is self-limiting in most patients and the immediate
prognosis is good. Death may, however, occur due to a ventricular
arrhythmia or rapidly progressive heart failure. Myocarditis has
been reported as a cause of sudden and unexpected death in
young athletes. Some forms of myocarditis may lead to chronic
low-grade myocarditis or dilated cardiomyopathy (see below).
For example, in Chagas’ disease (p. 279), the patient frequently
recovers from the acute infection but goes on to develop a
chronic dilated cardiomyopathy 10 or 20 years later.
Investigations
The diagnosis of myocarditis is often made after other more
common causes of cardiac dysfunction have been excluded.
Echocardiography should be performed and may reveal left
ventricular dysfunction that is sometimes regional (due to focal
myocarditis). Cardiac MRI is also useful since it may show
diagnostic patterns of myocardial inflammation or infiltration. The
ECG is frequently abnormal but the changes are non-specific.
Blood should be taken for analysis of troponin I and T, and
creatine kinase. Levels may be elevated in the early phases.
Occasionally, endomyocardial biopsy may be required to confirm
the diagnosis.
Management
Treatment of myocarditis is primarily supportive. Treatment for
cardiac failure or arrhythmias should be given and patients should
be advised to avoid intense physical exertion because there is
some evidence that this can induce potentially fatal ventricular
arrhythmias. There is no evidence of benefit from treatment with
glucocorticoids and immunosuppressive agents.
Specific antimicrobial therapy may be used if a causative
organism has been identified but this is rare. Patients who do
not respond adequately to medical treatment may temporarily
require circulatory support with a mechanical ventricular assist
device. Rarely, cardiac transplantation may be required.
Cardiomyopathy
Cardiomyopathies are primary diseases of the myocardium,
which are classified according to their effects on cardiac structure
and function (Fig. 16.99). They can be inherited or be caused
by infections or exposure to toxins. In some cases no cause
is identified.
Diseases of the myocardium • 539
Fig. 16.99 Types of cardiomyopathy. |Aj Normal heart. [§] Hypertrophic cardiomyopathy: asymmetric septal hypertrophy (ASH) with systolic anterior
motion of the mitral valve (SAM), causing mitral reflux and dynamic left ventricular outflow tract obstruction. [C] Hypertrophic cardiomyopathy: concentric
hypertrophy. [D] Hypertrophic cardiomyopathy: apical hypertrophy. [E] Dilated cardiomyopathy. [F] Arrhythmogenic right ventricular cardiomyopathy.
[G] Obliterative cardiomyopathy. \W\ Restrictive cardiomyopathy.
|J)ilated cardiomyopathy
In North America and Europe, symptomatic dilated cardiomyopathy
has an incidence of 20 per 1 00 000 and a prevalence of 38 per
100000. Men are affected more than twice as often as women.
Pathogenesis
Cardiomyopathy is characterised by dilatation and impaired
contraction of the LV and often the RV. Left ventricular mass is
increased but wall thickness is normal or reduced (Fig. 16.99).
Dilatation of the valve rings can lead to functional mitral and
tricuspid incompetence. Histological changes are variable but
include myofibrillary loss, interstitial fibrosis and T-cell infiltrates.
The term ‘dilated cardiomyopathy’ encompasses a heterogeneous
group of conditions. Alcohol may be an important cause in some
patients. At least 25% of cases are inherited as an autosomal
dominant trait and a variety of single-gene mutations have
been identified. Most of these mutations affect proteins in the
cytoskeleton of the myocytes, such as dystrophin, lamin A and
C, emerin and metavinculin. Many are also associated with
abnormalities of skeletal muscle Conversely, most of the X-linked
inherited skeletal muscular dystrophies, such as Becker and
Duchenne (p. 1143), are associated with cardiomyopathy. Finally,
a late autoimmune reaction to viral myocarditis is thought to
be the cause in a substantial subgroup of patients with dilated
cardiomyopathy; a similar mechanism is believed to be responsible
for the myocardial involvement that occurs in up to 1 0% of patients
with advanced human immunodeficiency virus (HIV) infection.
Clinical features
Most patients present with heart failure or are found to
have the condition during routine investigation. Arrhythmia,
thromboembolism and sudden death may occur at any stage;
sporadic chest pain is a surprisingly frequent symptom. The
differential diagnosis includes ventricular dysfunction due to CAD,
and a diagnosis of dilated cardiomyopathy should be made only
when this has been excluded.
Investigations
Echocardiography and cardiac MRI are the most useful
investigations. Although ECG changes are common, they are
non-specific. Genetic testing is indicated if more than one family
member is diagnosed with the condition.
Management
The focus of management is to control heart failure using the
strategies described earlier in this chapter (p. 464). Although some
patients remain well for many years, the prognosis is variable and
cardiac transplantation may be indicated. Patients with dilated
cardiomyopathy and moderate or severe heart failure are at risk
of sudden arrhythmic death and this can be reduced by rigorous
medical therapy with (3-blockers and either ACE inhibitors or
ARBs. Some patients may be considered for implantation of
a cardiac defibrillator and/or cardiac resynchronisation therapy
(pp. 483 and 484).
Hypertrophic cardiomyopathy
This is the most common form of cardiomyopathy, with a
prevalence of approximately 100 per 100000. It is characterised
by inappropriate and elaborate left ventricular hypertrophy with
malalignment of the myocardial fibres and myocardial fibrosis.
The hypertrophy may be generalised or confined largely to the
interventricular septum (asymmetric septal hypertrophy, Fig.
16.99) or other regions of the heart. A specific variant termed
apical hypertrophic cardiomyopathy is common in the Far East.
540 • CARDIOLOGY
Pathogenesis
Hypertrophic cardiomyopathy is a genetic disorder, usually
with autosomal dominant transmission, a high degree of
penetrance and variable expression. In most patients, it is due
to a single-point mutation in one of the genes that encode
sarcomeric contractile proteins. There are three common groups
of mutation with different phenotypes. Beta-myosin heavy-chain
mutations are associated with elaborate ventricular hypertrophy.
Troponin mutations are associated with little, and sometimes
even no, hypertrophy but marked myocardial fibre disarray,
exercise-induced hypotension and a high risk of sudden death.
Myosin-binding protein C mutations tend to present late in life
and are often associated with hypertension and arrhythmia.
In all subtypes, heart failure may develop because the stiff,
non-compliant LV impedes diastolic filling. Septal hypertrophy
may also cause dynamic left ventricular outflow tract obstruction
(hypertrophic obstructive cardiomyopathy, HOCM) and mitral
regurgitation due to abnormal systolic anterior motion of the
anterior mitral valve leaflet.
Clinical features
Effort -related symptoms, such as angina, breathlessness,
arrhythmia and sudden death, are the dominant clinical
presentations. The symptoms and signs are similar to those of
aortic stenosis, except that, in hypertrophic cardiomyopathy,
the character of the arterial pulse is jerky (Box 16.105). The
annual mortality from sudden death is 2-3% among adults and
4-6% in children and adolescents (Box 16.106). Sudden death
typically occurs during or just after vigorous physical activity and
is thought to be due to ventricular arrhythmias. Hypertrophic
cardiomyopathy is the most common cause of sudden death in
young athletes. In patients who do not suffer fatal arrhythmias, the
natural history is variable but clinical deterioration is often slow.
i
16.105 Clinical features of hypertrophic
cardiomyopathy
Symptoms
• Angina on effort
• Syncope on effort
• Dyspnoea on effort
• Sudden death
Signs
• Jerky pulse* *
• Palpable left ventricular hypertrophy
• Double impulse at the apex (palpable fourth heart sound due to left
atrial hypertrophy)
• Mid-systolic murmur at the base*
• Pansystolic murmur (due to mitral regurgitation) at the apex
Investigations
Echocardiography is the investigation of choice and is usually
diagnostic. Sometimes the diagnosis is more difficult when
another cause of left ventricular hypertrophy is present but
the degree of hypertrophy in hypertrophic cardiomyopathy is
usually greater than in physiological hypertrophy and the pattern
is asymmetrical. The ECG is abnormal and shows features of
left ventricular hypertrophy with a wide variety of often bizarre
abnormalities, including deep T-wave inversion. Genetic testing
can be performed and is helpful in screening relatives of affected
individuals.
Management
Beta-blockers, rate-limiting calcium antagonists and disopyramide
can help to relieve symptoms and prevent syncopal attacks.
Arrhythmias often respond to treatment with amiodarone. No
pharmacological treatment has been identified that can improve
prognosis, however. Outflow tract obstruction can be improved
by partial surgical resection (myectomy) or by iatrogenic infarction
of the basal septum (septal ablation) using a catheter-delivered
alcohol solution. An ICD should be considered in patients with
clinical risk factors for sudden death (Box 16.106). Digoxin and
vasodilators may increase outflow tract obstruction and should
be avoided.
Arrhythmogenic ventricular cardiomyopathy
Arrhythmogenic ventricular cardiomyopathy (AVC) predominantly
affects the myocardium of the right ventricle. It is inherited
in an autosomal dominant manner and has a prevalence of
approximately 10 per 100 000. The genetic defect involves
desmosomal protein genes, most commonly plakophilin 2 (PKP-2),
although current genetic testing protocols will not identify the
culprit gene in many cases. It is characterised by replacement of
patches of the right ventricular myocardium with fibrous and fatty
tissue (see Fig. 16.99). In some cases, the LV is also involved
and this is associated with a poorer prognosis. The diagnosis
is based on a complex set of criteria that take account of the
ECG, structural assessment, genetics and arrhythmias. The
dominant clinical problems are ventricular arrhythmias, sudden
death and right-sided cardiac failure. The ECG typically shows
a slightly broadened QRS complex and inverted T waves in the
right precordial leads. MRI is a helpful diagnostic tool and is used,
along with the 12-lead ECG and ambulatory ECG monitoring,
to screen the first-degree relatives of affected individuals.
Management is based on treating right-sided cardiac failure
with diuretics and cardiac arrhythmias with p-blockers or, in
patients at high risk of sudden death, an implantable defibrillator
can be offered.
|Restrictive cardiomyopathy
In this rare condition, ventricular filling is impaired because
the ventricles are ‘stiff (see Fig. 16.99). This leads to high
atrial pressures with atrial hypertrophy, dilatation and, later, AF.
Amyloidosis is the most common cause in the UK, although
other forms of infiltration due to glycogen storage diseases,
idiopathic perimyocyte fibrosis and a familial form of restrictive
cardiomyopathy can also occur. The diagnosis can be difficult
and requires assessment with Doppler echocardiography, CT
or MRI, and endomyocardial biopsy. Treatment is symptomatic
but the prognosis is usually poor and transplantation may be
indicated.
*Signs of left ventricular outflow tract obstruction may be augmented by standing
up (reduced venous return), inotropes and vasodilators (e.g. sublingual nitrate).
16.106 Risk factors for sudden death in
hypertrophic cardiomyopathy
• A history of previous cardiac arrest or sustained ventricular
tachycardia
• Recurrent syncope
• An adverse genotype and/or family history
• Exercise-induced hypotension
• Non-sustained ventricular tachycardia on ambulatory ECG
monitoring
• Marked increase in left ventricular wall thickness
Diseases of the myocardium • 541
Obliterative cardiomyopathy
This is a rare form of restrictive cardiomyopathy, involving the
endocardium of one or both ventricles; it is characterised by
thrombosis and fibrosis, with gradual obliteration of the ventricular
cavities by fibrous tissue (see Fig. 1 6.99). The mitral and tricuspid
valves become regurgitant. Heart failure and pulmonary and
systemic embolism are prominent features. It can sometimes
be associated with eosinophilia and can occur in eosinophilic
leukaemia and eosinophilic granulomatosis with polyangiitis
(formerly known as Churg-Strauss syndrome, p. 1043). In tropical
countries, the disease can be responsible for up to 10% of
cardiac deaths. Mortality is high: 50% at 2 years. Anticoagulation
and antiplatelet therapy are used, and diuretics may help
symptoms of heart failure. Surgery (tricuspid and/or mitral valve
replacement with decortication of the endocardium) may be helpful
in selected cases.
| Takotsubo cardiomyopathy
Takotsubo cardiomyopathy (Takotsubo syndrome) is a form of
acute left ventricular dysfunction characterised by dilatation of the
left ventricular apex and adjacent myocardium, with associated left
ventricular impairment. The mechanism is poorly understood but
may involve noradrenergic coronary vasoconstriction and acute
left ventricular outflow obstruction. It is often associated with acute
environmental or emotional stress (such as a bereavement) and
presents with chest pain, breathlessness and sometimes cardiac
failure. It occurs more frequently in women than in men. In terms
of both symptoms and the ECG, the condition mimics acute
ST elevation acute coronary syndrome. The diagnosis is usually
made at coronary angiography, when CAD is found to be absent
or minimal. Echocardiography then shows characteristic ‘apical
ballooning’ of the LV. The dilated apex and narrow outflow of the
LV resemble a Japanese octopus trap, or takotsubo (Fig. 1 6.1 00).
Fig. 16.100 Takotsubo cardiomyopathy. Left ventriculogram following
injection of contrast in a patient with Takotsubo cardiomyopathy. The
outline of the dilated left ventricle is indicated by arrows.
i
Infections
Viral
• Coxsackie A and B • HIV
• Influenza
Bacterial
• Diphtheria • Borrelia burgdorferi
Protozoal
• Trypanosomiasis • Toxoplasma gondii
Endocrine and metabolic disorders
• Diabetes
• Hypo- and hyperthyroidism
• Acromegaly
• Carcinoid syndrome
• Phaeochromocytoma
• Inherited storage diseases
Connective tissue diseases
• Systemic sclerosis
• Polyarteritis nodosa
• Systemic lupus erythematosus
Infiltrative disorders
• Haemochromatosis
• Sarcoidosis
• Haemosiderosis
• Amyloidosis
Toxins
• Doxorubicin
• Cocaine
• Alcohol
• Irradiation
Neuromuscular disorders
• Dystrophia myotonica
• Friedreich’s ataxia
Left ventricular dysfunction usually recovers within 4-5 days,
although this can take weeks in some cases. Treatment is with
a (3-blocker, to prevent arrhythmia, and an ACE inhibitor, to treat
left ventricular dysfunction. These drugs are continued only until
cardiac function has recovered.
Secondary causes of cardiomyopathy
Many systemic conditions can produce a picture that is
indistinguishable from dilated cardiomyopathy, including connective
tissue disorders, sarcoidosis, haemochromatosis and alcoholic
heart muscle disease (Box 16.107). In contrast, amyloidosis and
eosinophilic heart disease produce symptoms and signs similar
to those found in restrictive or obliterative cardiomyopathy,
whereas the heart disease associated with Friedreich’s ataxia
(p. 1116) can mimic hypertrophic cardiomyopathy.
Treatment and prognosis are determined by the underlying
disorder. Abstention from alcohol may lead to a dramatic
improvement in patients with alcoholic heart muscle disease.
Cardiac tumours
Primary cardiac tumours are rare (<0.2% of autopsies) but the
heart and mediastinum may be the sites of metastases. Most
primary tumours are benign (75%) and, of these, the majority are
myxomas. The remainder are fibromas, lipomas, fibroelastomas
and haemangiomas.
Atrial myxoma
Myxomas most commonly arise in the LA as single or multiple
polypoid tumours, attached by a pedicle to the interatrial septum.
16.107 Specific diseases of heart muscle
542 • CARDIOLOGY
They are usually gelatinous but may be solid and even calcified,
with superimposed thrombus.
On examination, the first heart sound is usually loud, and there
may be a murmur of mitral regurgitation with a variable diastolic
sound (tumour ‘plop’) due to prolapse of the mass through
the mitral valve. The tumour can be detected incidentally on
echocardiography, or following investigation of pyrexia, syncope,
arrhythmias or emboli. Occasionally, the condition presents with
malaise and features suggestive of a connective tissue disorder,
including a raised ESR.
Treatment is by surgical excision. If the pedicle is removed,
fewer than 5% of tumours recur.
Diseases of the pericardium
The normal pericardial sac contains about 50 mL of fluid, similar to
lymph, which lubricates the surface of the heart. The pericardium
limits distension of the heart, contributes to the haemodynamic
interdependence of the ventricles, and acts as a barrier to
infection. Nevertheless, congenital absence of the pericardium
does not result in significant clinical or functional limitations.
Acute pericarditis
This is due to an acute inflammatory process affecting the
pericardium, which may coexist with myocarditis.
Pathogenesis
A number of causes are recognised (Box 16.108), but in some
cases the cause is unclear. All forms of pericarditis may produce
a pericardial effusion that, depending on the aetiology, may
be fibrinous, serous, haemorrhagic or purulent. A fibrinous
exudate may eventually lead to varying degrees of adhesion
formation, whereas serous pericarditis often produces a large
effusion of turbid, straw-coloured fluid with a high protein content.
A haemorrhagic effusion is often due to malignant disease,
particularly carcinoma of the breast or bronchus, and lymphoma.
Purulent pericarditis is rare and may occur as a complication of
sepsis, by direct spread from an intrathoracic infection, or from
a penetrating injury.
Clinical features
The typical presentation is with chest pain that is retrosternal,
radiates to the shoulders and neck, and is typically aggravated
by deep breathing, movement, a change of position, exercise
and swallowing. A low-grade fever is common. A pericardial
16.108 Causes of acute pericarditis and
pericardial effusion
Infection
• Viral
• Tuberculosis
• Bacterial
Inflammatory
• Rheumatoid arthritis
• Rheumatic fever
• Systemic lupus erythematosus
Other
• Post-myocardial infarction
• Malignancy
• Uraemia
• Trauma
friction rub is a high-pitched, superficial scratching or crunching
noise, produced by movement of the inflamed pericardium, and
is diagnostic of pericarditis; it is usually heard in systole but may
also be audible in diastole and frequently has a ‘to-and-fro’ quality.
Investigations
The diagnosis can often be made on the basis of clinical features
and the ECG; the latter shows ST elevation with upward concavity
(Fig. 16.101) over the affected area, which may be widespread.
PR interval depression is a very specific indicator of acute
pericarditis. Later, there may be T-wave inversion, particularly
if there is a degree of myocarditis. Echocardiography may be
normal or may reveal pericardial effusion, in which case regular
echocardiographic monitoring is recommended.
Management
The pain usually responds to aspirin (600 mg 6 times daily) but a
more potent anti-inflammatory agent, such as indometacin (50 mg
3 times daily), may be required. Colchicine or glucocorticoids
can also suppress symptoms but there is no evidence that they
accelerate cure. In viral pericarditis, recovery usually occurs within
a few days or weeks but there may be recurrences (chronic
relapsing pericarditis). Purulent pericarditis requires treatment
with antimicrobial therapy, pericardiocentesis and, if necessary,
surgical drainage.
Fig. 16.101 ECG in viral pericarditis. Widespread ST elevation (leads I,
II, aVL and V-,— V6) is shown. The upward concave shape of the ST
segments (see leads II and V6) and the unusual distribution of changes
(involving anterior and inferior leads) help to distinguish pericarditis from
acute myocardial infarction.
Diseases of the pericardium • 543
Pericardial effusion
Pericardial effusion often accompanies pericarditis and can have
a number of causes, as shown in Box 16.108.
Clinical features
With the onset of an effusion the heart sounds may become
quieter, and a friction rub, if present, may diminish in intensity but
is not always abolished. Larger effusions may be accompanied
by a sensation of retrosternal oppression. While most effusions
do not have significant haemodynamic effects, large or rapidly
developing effusions may cause cardiac tamponade. This term
is used to describe acute heart failure due to compression of the
heart and is described in detail below. Typical physical findings
are a markedly raised JVP, hypotension, pulsus paradoxus
(p. 448) and oliguria. Atypical presentations may occur when
the effusion is loculated as a result of previous pericarditis or
cardiac surgery.
Investigations
Echocardiography is the definitive investigation and is helpful
in monitoring the size of the effusion and its effect on cardiac
function (Fig. 16.102). The QRS voltages on the ECG are often
reduced in the presence of a large effusion. The QRS complexes
may alternate in amplitude due to a to-and-fro motion of the
heart within the fluid-filled pericardial sac (electrical alternans).
The chest X-ray may show an increase in the size of the cardiac
silhouette and, when there is a large effusion, this has a globular
appearance. Aspiration of the effusion may be required for
diagnostic purposes and, if necessary, for treatment of large
effusions, as described below.
Management
Patients with large effusions that are causing haemodynamic
compromise or cardiac tamponade should undergo aspiration
of the effusion. This involves inserting a needle under
echocardiographic guidance medial to the cardiac apex or
below the xiphoid process, directed upwards towards the left
shoulder. The route of choice will depend on the experience of
Fig. 16.102 Pericardial effusion: echocardiogram (apical view).
Short-axis view of the heart showing a large circumferential pericardial
effusion (arrows). (LV = left ventricle)
the operator, the shape of the patient and the position of the
effusion. A pericardial drain may be placed to provide symptomatic
relief. Complications of pericardiocentesis include arrhythmias,
damage to a coronary artery and bleeding, with exacerbation of
tamponade as a result of injury to the RV. When tamponade is
due to cardiac rupture or aortic dissection, pericardial aspiration
may precipitate further potentially fatal bleeding and, in these
situations, emergency surgery is the treatment of choice. A
viscous, loculated or recurrent effusion may also require formal
surgical drainage.
| Tuberculous pericarditis
Tuberculous pericarditis may complicate pulmonary tuberculosis
but may also be the first manifestation of the infection. In Africa,
a tuberculous pericardial effusion is a common feature of AIDS
(p. 322). The condition typically presents with chronic malaise,
weight loss and a low-grade fever. An effusion usually develops
and the pericardium may become thick and unyielding, leading
to pericardial constriction or tamponade. An associated pleural
effusion is often present.
The diagnosis may be confirmed by aspiration of the fluid
and direct examination or culture for tubercle bacilli. Treatment
requires specific antituberculous chemotherapy (p. 592); in
addition, a 3-month course of prednisolone (initial dose 60 mg
a day, tapering down rapidly) improves outcome.
Chronic constrictive pericarditis
Constrictive pericarditis is due to progressive thickening, fibrosis
and calcification of the pericardium. In effect, the heart is encased
in a solid shell and cannot fill properly. The calcification may extend
into the myocardium, so there may also be impaired myocardial
contraction. The condition often follows an attack of tuberculous
pericarditis but can also complicate haemopericardium, viral
pericarditis, rheumatoid arthritis and purulent pericarditis. It is
often impossible to identify the original insult.
Clinical features
The symptoms and signs of systemic venous congestion are
the hallmarks of constrictive pericarditis. AF is common and
there is often dramatic ascites and hepatomegaly (Box 16.109).
Breathlessness is not a prominent symptom because the lungs
are seldom congested. The condition is sometimes overlooked
but should be suspected in any patient with unexplained right
heart failure and a small heart.
Investigations
A chest X-ray, which may show pericardial calcification (Fig.
16.103), and echocardiography often help to establish the
diagnosis. CT scanning is useful for imaging the pericardial
calcification. Constrictive pericarditis is often difficult to distinguish
i
16.109 Clinical features of constrictive pericarditis
• Fatigue
• Kussmaul’s sign
• Rapid, low-volume pulse
• Hepatomegaly
• Elevated JVP with a rapid
• Ascites
y descent
• Peripheral oedema
• Loud early third heart sound
or ‘pericardial knock’
• Pulsus paradoxus
(JVP =
jugular venous pressure)
544 • CARDIOLOGY
Fig. 16.103 Lateral chest X-ray from a patient with severe heart
failure due to chronic constrictive pericarditis. There is heavy
calcification of the pericardium.
16.110 Clinical features of cardiac tamponade
• Dyspnoea
• Collapse
• Tachycardia
• Hypotension
• Gross elevation of the JVP
• Soft heart sounds with an early third heart sound
• Pulsus paradoxus (a large fall in BP during inspiration, when the
pulse may be impalpable)
• Kussmaul’s sign (a paradoxical rise in JVP during inspiration)
(JVP = jugular venous pressure)
aspiration of the fluid. The ECG may show features of the
underlying disease, such as pericarditis or acute Ml. When there
is a large pericardial effusion, the ECG complexes are small and
there may be electrical alternans: a changing axis with alternate
beats caused by the heart swinging from side to side in the
pericardial fluid. A chest X-ray shows an enlarged globular heart
but can look normal.
from restrictive cardiomyopathy and in such cases complex
echo-Doppler studies and cardiac catheterisation may be
required.
Management
The resulting diastolic heart failure is treated using loop diuretics
and aldosterone antagonists, such as spironolactone. Surgical
resection of the diseased pericardium can lead to a dramatic
improvement but carries a high morbidity, with disappointing
results in up to 50% of patients.
| Cardiac tamponade
Management
Cardiac tamponade is a medical emergency. When the
diagnosis is confirmed, percutaneous pericardiocentesis should
be performed as soon as possible, which usually results in a
dramatic improvement. In some cases, surgical drainage may be
required.
Further information
Websites
This term is used to describe acute heart failure due to
compression of the heart as the result of a large pericardial
effusion. Tamponade may complicate any form of pericarditis but
can be caused by malignant disease, by blood in the pericardial
space following trauma, or by rupture of the free wall of the
myocardium following Ml.
Clinical features
Patients with tamponade are unwell, with hypotension, tachycardia
and a markedly raised JVP. Other clinical features are summarised
in Box 16.1 10.
acc.org American College of Cardiology (ACC): free access to
guidelines for the evaluation and management of many cardiac
conditions.
americanheart.org American Heart Association (AHA): free access to
all the ACC/AHA/ESC guidelines, AHA scientific statements and fact
sheets for patients.
escardio.org European Society of Cardiology (ESC): free access to
guidelines for the diagnosis and management of many cardiac
conditions, and to educational modules.
jbs3risk.com Joint British Societies for the Prevention of Cardiovascular
Disease: risk calculator.
Journal articles
Investigations
The pivotal investigation is echocardiography, which can confirm
the diagnosis and also helps to identify the optimum site for
Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis
and antibiotic treatment of endocarditis in adults: a report of the
working party of the British Society for Antimicrobial Chemotherapy.
J Antimicrob Chemother 2012; 67:269-289.
Respiratory medicine
Clinical examination of the respiratory system 546
Interstitial and infiltrative pulmonary diseases 605
Functional anatomy and physiology 548
Investigation of respiratory disease 550
Imaging 551
Endoscopic examination 553
Immunological and serological tests 554
Microbiological investigations 554
Respiratory function testing 554
Presenting problems in respiratory disease 556
Cough 556
Breathlessness 557
Chest pain 558
Finger clubbing 559
Haemoptysis 559
The incidental pulmonary nodule 560
Pleural effusion 562
Respiratory failure 565
Diffuse parenchymal lung disease 605
Lung diseases due to systemic inflammatory disease 610
Pulmonary eosinophilia and vasculitides 61 1
Lung diseases due to irradiation and drugs 61 2
Rare interstitial lung diseases 61 3
Occupational and environmental lung disease 613
Occupational airway disease 61 3
Pneumoconiosis 614
Lung diseases due to organic dusts 616
Asbestos-related lung and pleural diseases 61 7
Occupational lung cancer 61 8
Occupational pneumonia 61 8
Pulmonary vascular disease 619
Pulmonary embolism 619
Pulmonary hypertension 621
Diseases of the upper airway 622
Obstructive pulmonary diseases 567
Diseases of the nasopharynx 622
Asthma 567
Sleep-disordered breathing 622
Chronic obstructive pulmonary disease 573
Laryngeal disorders 624
Bronchiectasis 578
Tracheal disorders 625
Cystic fibrosis 580
Pleural disease 625
Infections of the respiratory system 581
Diseases of the diaphragm and chest wall 627
Upper respiratory tract infection 581
Disorders of the diaphragm 627
Pneumonia 582
Deformities of the chest wall 628
Tuberculosis 588
Respiratory diseases caused by fungi 596
Tumours of the bronchus and lung 598
Primary tumours of the lung 599
Secondary tumours of the lung 603
Tumours of the mediastinum 603
546 • RESPIRATORY MEDICINE
Clinical examination of the respiratory system
6-9 Thorax
(see opposite)
5 Face, mouth and eyes
Pursed lips
Central cyanosis
Anaemia
Horner’s syndrome
(Ch. 25)
4 Jugular venous pulse
Elevated
Pulsatile
3 Blood pressure
Arterial paradox
2 Radial pulse
Rate
Rhythm
1 Hands
Digital clubbing
Tar staining
Peripheral cyanosis
Signs of occupation
CO2 retention flap
A Finger clubbing
6 Inspection
Deformity
(e.g. pectus excavatum)
Scars
Intercostal indrawing
Symmetry of expansion
Hyperinflation
Paradoxical rib movement
(low flat diaphragm)
A Idiopathic kyphoscoliosis
©
7 Palpation
From the front:
Trachea central
Cricosternal distance
Cardiac apex displaced
Expansion
From behind:
Cervical lymphadenopathy
Expansion
8 Percussion
Resonant or dull
‘Stony dull’ (effusion)
9 Auscultation
Breath sounds:
normal, bronchial, louder or softer
Added sounds:
wheezes, crackles, rubs
Spoken voice (vocal resonance):
absent (effusion), increased
(consolidation)
Whispered voice:
whispering pectoriloquy
10 Leg oedema
Observation
• Respiratory rate
• Cachexia, fever, rash
• Sputum (see below)
• Fetor
Salt and water retention
Cor pulmonale
Venous thrombosis
Locale:
Oxygen delivery
(mask, cannulae)
Nebulisers
Inhalers
Sputum
A Serous/frothy/pink
Pulmonary oedema
A Purulent
Bronchial or pneumonic
infection
A Blood-stained
Cancer, tuberculosis,
bronchiectasis,
pulmonary embolism
A Mucopurulent
Bronchial or pneumonic
infection
Insets (idiopathic kyphoscoliosis) Courtesy of Dr I. Smith, Papworth Hospital, Cambridge; (serous, mucopurulent and purulent sputum) Courtesy of Dr J.
Foweraker, Papworth Hospital, Cambridge.
Clinical examination of the respiratory system • 547
Chronic obstructive pulmonary disease
Use of accessory
muscles
Hyperinflated
‘barrel’ chest
Auscultation
Reduced breath
sounds - wheeze
Heart sounds
loudest in
epigastrium
Pursed lip breathing
Central cyanosis
Prolonged expiration
Reduced cricosternal
distance
Intercostal
indrawing
during
inspiration
Cardiac apex not
palpable
Loss of cardiac
dullness on
percussion
Inward movement
of lower ribs
on inspiration
(low flat diaphragm)
Pulmonary fibrosis
1
- Central cyanosis
Tachypnoea
Small lungs
ff m
X ^ /y
Reduced
\ r
expansion -
^Auscultation
/ /AMcv
/ Fine inspiratory
A crackles at
\ bases
See also Fig. 17.56
Also: raised jugular venous pressure (JVP),
peripheral oedema from salt and
water retention and/or cor pulmonale
Right middle lobe pneumonia
Dull percussion at bases
(high diaphragm)
Also: finger clubbing common in
idiopathic pulmonary fibrosis; raised JVP
and peripheral oedema if cor pulmonale
Right upper lobe collapse
Obscures R heart border
on X-ray
Inspection
Tachypnoea
Central cyanosis (if severe)
Palpation
^Expansion on R
Percussion
Dull R mid-zone and axilla
Auscultation
Bronchial breath sounds
and Tvocal resonance over
consolidation and whispering
pectoriloquy
Pleural rub if pleurisy
X-ray
Deviated trachea (to R)
Elevated horizontal fissure
^Volume R hemithorax
Central (hilar) mass may
be seen
Inspection
^Volume R upper zone
Palpation
Trachea deviated to R
^Expansion R upper zone
Percussion
Dull R upper zone
Auscultation
iBreath sounds with
central obstruction
Right pneumothorax
Large right pleural effusion
Inspection
Tachypnoea (pain, deflation
reflex)
Palpation
^Expansion R side
Percussion
Resonant or hyper-resonant
on R
Auscultation
Absent breath sounds on R
Tension pneumothorax also
causes
Deviation of trachea to
opposite side
Tachycardia and
hypotension
Inspection
Tachypnoea
Palpation
^Expansion on R
Trachea and apex may be
moved to L
Percussion
Stony dull
R mid- and lower zones
Auscultation
Absent breath sounds and
vocal resonance R base
Bronchial breathing or
crackles above effusion
Insets (upper lobe collapse) From http://3. bp.blogspot.com; (pneumothorax) http://chestatlas.com; (pleural effusion) www.ispub.com.
548 • RESPIRATORY MEDICINE
Respiratory disease is responsible for a major burden of morbidity
and untimely death, with conditions such as tuberculosis,
pandemic influenza and pneumonia the most important in world
health terms. The increasing prevalence of allergy, asthma and
chronic obstructive pulmonary disease (COPD) contributes to the
overall burden of chronic disease in the community. By 2025, the
number of cigarette smokers worldwide is anticipated to increase
to 1.5 billion, ensuring a growing burden of tobacco-related
respiratory conditions.
Respiratory disease covers a breadth of pathologies, including
infectious, inflammatory, neoplastic and degenerative processes.
The practice of respiratory medicine thus requires collaboration
with a range of disciplines. Recent advances have improved the
lives of many patients with obstructive lung disease, cystic fibrosis,
obstructive sleep apnoea and pulmonary hypertension, but the
outlook remains poor for lung and other respiratory cancers and
for some of the fibrosing lung conditions.
Functional anatomy and physiology
The lungs occupy the upper two-thirds of the bony thorax,
bounded medially by the spine, the heart and the mediastinum
and interiorly by the diaphragm. During breathing, free movement
of the lung surface relative to the chest wall is facilitated by sliding
contact between the parietal and visceral pleura, which cover the
inner surface of the chest wall and the lung, respectively, and
are normally in close apposition. Inspiration involves downward
contraction of the dome-shaped diaphragm (innervated by
the phrenic nerves originating from C3, 4 and 5) and upward,
outward movement of the ribs on the costovertebral joints, caused
by contraction of the external intercostal muscles (innervated
by intercostal nerves originating from the thoracic spinal
cord). Expiration is largely passive, driven by elastic recoil of
the lungs.
The conducting airways from the nose to the alveoli connect
the external environment with the extensive, thin and vulnerable
alveolar surface. As air is inhaled through the upper airways, it is
filtered in the nose, heated to body temperature and fully saturated
with water vapour; partial recovery of this heat and moisture
occurs on expiration. Total airway cross-section is smallest in
the glottis and trachea, making the central airway particularly
vulnerable to obstruction by foreign bodies and tumours. Normal
breath sounds originate mainly from the rapid turbulent airflow
in the larynx, trachea and main bronchi.
The multitude of small airways within the lung parenchyma
has a very large combined cross-sectional area (over 300 cm2
in the third-generation respiratory bronchioles), resulting in very
slow flow rates. Airflow is virtually silent here and gas transport
occurs largely by diffusion in the final generations. Major bronchial
and pulmonary divisions are shown in Figure 17.1.
The acinus (Fig. 17.2) is the gas exchange unit of the lung
and comprises branching respiratory bronchioles and clusters
of alveoli. Here the air makes close contact with the blood in
the pulmonary capillaries (gas-to-blood distance <0.4 |im), and
oxygen uptake and C02 excretion occur. The alveoli are lined with
flattened epithelial cells (type I pneumocytes) and a few, more
cuboidal, type II pneumocytes. The latter produce surfactant,
which is a mixture of phospholipids that reduces surface tension
and counteracts the tendency of alveoli to collapse under surface
Major bronchial subdivisions
Fig. 17.1 The major bronchial divisions
and the fissures, lobes and segments of
the lungs. The angle of the oblique fissure
means that the left upper lobe is largely
anterior to the lower lobe. On the right, the
transverse fissure separates the upper from
the anteriorly placed middle lobe, which is
matched by the lingular segment on the left
side. The site of a lobe determines whether
physical signs are mainly anterior or
posterior. Each lobe is composed of two or
more bronchopulmonary segments that are
supplied by the main branches of each lobar
bronchus. Bronchopulmonary segments :
Right Upper lobe: (1) Anterior, (2) Posterior,
(3) Apical. Middle lobe : (1) Lateral, (2)
Medial. Lower lobe: (1) Apical, (2) Posterior
basal, (3) Lateral basal, (4) Anterior basal,
(5) Medial basal. Left Upper lobe: (1)
Anterior, (2) Apical, (3) Posterior, (4) Lingular.
Lower lobe: (1) Apical, (2) Posterior basal,
(3) Lateral basal, (4) Anterior basal.
Functional anatomy and physiology • 549
Smooth Terminal
muscle bronchiole
Elastin
fibres
ratory
bronchiole
Alveoli Pores of Kohn
Pulmonary Bronchial Pulmonary
vein
Interlobular Alveolar
septum capillaries
Fig. 17.2 Functional anatomy of the lung. [A] The tapering, branching bronchus is armoured against compression by plates of cartilage. The more
distal bronchioles are collapsible, but held patent by surrounding elastic tissue, [B] The unit of lung supplied by a terminal bronchiole is called an acinus.
The bronchiolar wall contains smooth muscle and elastin fibres. The latter also run through the alveolar walls. Gas exchange occurs in the alveoli, which
are connected to each other by the pores of Kohn. [C] Vascular anatomy of an acinus. Both the pulmonary artery (carrying desaturated blood) and the
bronchial artery (systemic supply to airway tissue) run along the bronchus. The venous drainage to the left atrium follows the interlobular septa. From
www.Netter.com: Illustrations 155 (bronchus, acinus) and 191 (circulation), Elsevier.
tension. Type II pneumocytes can divide to reconstitute type I
pneumocytes after lung injury.
Lung mechanics
Healthy alveolar walls contain a fine network of elastin and
collagen fibres (Fig. 17.2). The volume of the lungs at the end
of a tidal (‘normal’) breath out is called the functional residual
capacity (FRC). At this volume, the inward elastic recoil of the
lungs (resulting from elastin fibres and surface tension in the
alveolar lining fluid) is balanced by the resistance of the chest
wall to inward distortion from its resting shape, causing negative
pressure in the pleural space. Elastin fibres allow the lung to
be easily distended at physiological lung volumes, but collagen
fibres cause increasing stiffness as full inflation is approached,
so that, in health, the maximum inspiratory volume is limited by
the lung (rather than the chest wall). Within the lung, the weight
of tissue compresses the dependent regions and distends the
uppermost parts, so a greater portion of an inhaled breath
passes to the basal regions, which also receive the greatest
blood flow as a result of gravity. Elastin fibres in alveolar walls
maintain small airway patency by radial traction on the airway
walls. Even in health, however, these small airways narrow
during expiration because they are surrounded by alveoli at
higher pressure, but are prevented from collapsing by radial
elastic traction. The volume that can be exhaled is thus limited
purely by the capacity of the expiratory muscles to distort the
chest wall inwards. In emphysema, loss of alveolar walls leaves
the small airways unsupported, and their collapse on expiration
causes air trapping and limits expiration at a high end -expiratory
volume (p. 575).
Control of breathing
The respiratory motor neurons in the posterior medulla oblongata
are the origin of the respiratory cycle. Their activity is modulated
by multiple external inputs in health and in disease (see Fig. 17.9):
• Central chemoreceptors in the ventrolateral medulla sense
the pH of the cerebrospinal fluid (CSF) and are indirectly
stimulated by a rise in arterial PC02.
• The carotid bodies sense hypoxaemia but are mainly
activated by arterial P02 values below 8 kPa (60 mmHg).
They are also sensitised to hypoxia by raised arterial PC02.
• Muscle spindles in the respiratory muscles sense changes
in mechanical load.
• Vagal sensory fibres in the lung may be stimulated by
stretch, by inhaled toxins or by disease processes in the
interstitium.
• Cortical (volitional) and limbic (emotional) influences can
override the automatic control of breathing.
I Ventilation/perfusion matching and the
pulmonary circulation
To achieve optimal gas exchange within the lungs, the regional
distribution of ventilation and perfusion must be matched. At
550 • RESPIRATORY MEDICINE
segmental and subsegmental level, hypoxia constricts pulmonary
arterioles and airway C02 dilates bronchi, helping to maintain good
regional matching of ventilation and perfusion. Lung disease may
create regions of relative under-ventilation or under-perfusion,
which disturb this regional matching, causing respiratory failure
(p. 565). In addition to causing ventilation-perfusion mismatch,
diseases that destroy capillaries or thicken the alveolar capillary
membrane (e.g. emphysema or fibrosis) can impair gas diffusion
directly.
The pulmonary circulation in health operates at low pressure
(approximately 24/9 mmHg) and can accommodate large
increases in flow with minimal rise in pressure, e.g. during
exercise. Pulmonary hypertension occurs when vessels are
destroyed by emphysema, obstructed by thrombus, involved
in interstitial inflammation or thickened by pulmonary vascular
disease. The right ventricle responds by hypertrophy, with
right axis deviation and P pulmonale (tall, peaked p waves)
on the electrocardiogram (ECG), and clinical features of right
heart failure; the term ‘cor pulmonale’ is often used for these
findings.
Lung defences
Upper airway defences
Large airborne particles are trapped by nasal hairs, and
smaller particles settling on the mucosa are cleared towards
the oropharynx by the columnar ciliated epithelium that covers
the turbinates and septum (Fig. 17.3). During cough, expiratory
muscle effort against a closed glottis results in high intrathoracic
pressure, which is then released explosively. The flexible posterior
tracheal wall is pushed inwards by the high surrounding pressure,
which reduces tracheal cross-section and thus maximises the
airspeed to achieve effective expectoration. The larynx also acts
Fig. 17.3 The mucociliary escalator. Scanning electron micrograph of
the respiratory epithelium showing large numbers of cilia (C) overlaid by
the mucus ‘raft’ (M).
as a sphincter, closing to protect the airway during swallowing
and vomiting.
Lower airway defences
The sterility, structure and function of the lower airways are
maintained by close cooperation between the innate and adaptive
immune responses (pp. 62 and 67).
The innate response in the lungs is characterised by
a number of non-specific defence mechanisms. Inhaled
particulate matter is trapped in airway mucus and cleared
by the mucociliary escalator. Cigarette smoke increases
mucus secretion but reduces mucociliary clearance and
predisposes towards lower respiratory tract infections, including
pneumonia. Defective mucociliary transport is also a feature
of several rare diseases, including Kartagener’s syndrome,
Young’s syndrome and ciliary dysmotility syndrome, which
are characterised by repeated sino-pulmonary infections and
bronchiectasis.
Airway secretions contain an array of antimicrobial peptides
(such as defensins, immunoglobulin A (IgA) and lysozyme),
antiproteinases and antioxidants. Many assist with the
opsonisation and killing of bacteria and the regulation of the
powerful proteolytic enzymes secreted by inflammatory cells.
In particular, o^-antitrypsin regulates neutrophil elastase,
and deficiency of this may be associated with premature
emphysema.
Macrophages engulf microbes, organic dusts and other
particulate matter. They are unable to digest inorganic agents,
such as asbestos or silica, which cause their death and lead
to the release of powerful proteolytic enzymes that damage
the lung. Neutrophil numbers in the airway are low but the
pulmonary circulation contains a marginated pool that may be
recruited rapidly in response to bacterial infection. This may
explain the prominence of lung injury in sepsis syndromes and
trauma.
Adaptive immunity is characterised by the specificity of the
response and the development of memory. Lung dendritic cells
facilitate antigen presentation to T and B lymphocytes.
Investigation of respiratory disease
A detailed history, thorough examination and basic haematological
and biochemical tests usually indicate the likely diagnosis and
17.1 Respiratory function in old age
• Reserve capacity: a significant reduction in function can occur
with ageing with only minimal effect on normal breathing, but the
ability to combat acute disease is reduced.
• Decline in FEVy the FEV^FVC (forced expiratory volume/forced vital
capacity, p. 55) ratio falls by around 0.2% per year from 70% at
the age of 40-45 years, due to a decline in elastic recoil in the
small airways with age. Smoking accelerates this decline threefold
on average. Symptoms usually occur only when FE^ drops below
50% of predicted.
• Increasing ventilation-perfusion mismatch: the reduction in
elastic recoil causes a tendency for the small airways to collapse
during expiration, particularly in dependent areas of the lungs, thus
reducing ventilation.
• Reduced ventilatory responses to hypoxia and hypercapnia:
older people may be less tachypnoeic for any given fall in Pa02 or
rise in PaC02.
• Impaired defences against infection: due to reduced numbers of
glandular epithelial cells, which lead to a reduction in protective
mucus.
• Decline in maximum oxygen uptake: due to a combination of
impairments in muscle, and the respiratory and cardiovascular
systems. This leads to a reduction in cardiorespiratory reserve and
exercise capacity.
• Loss of chest wall compliance: due to reduced intervertebral
disc spaces and ossification of the costal cartilages; respiratory
muscle strength and endurance also decline. These changes
become important only in the presence of other respiratory
disease.
Investigation of respiratory disease • 551
differential. A number of other investigations are normally required
to confirm the diagnosis and/or monitor disease activity.
Imaging
| The ‘plain’ chest X-ray
This is performed on the majority of patients suspected of having
chest disease. A posteroanterior (PA) film provides information
on the lung fields, heart, mediastinum, vascular structures and
thoracic cage (Fig. 17.4). Additional information may be obtained
from a lateral film, particularly if pathology is suspected behind the
heart shadow or deep in the diaphragmatic sulci. An approach
to interpreting the chest X-ray is given in Box 17.2 and common
abnormalities are listed in Box 17.3.
Increased shadowing may represent accumulation of fluid,
lobar collapse or consolidation. Uncomplicated consolidation
should not change the position of the mediastinum and the
presence of an air bronchogram means that proximal bronchi
are patent. Collapse (implying obstruction of the lobar bronchus)
is accompanied by loss of volume and displacement of the
mediastinum towards the affected side (Fig. 17.5).
The presence of ring shadows (thickened bronchi seen end-on),
tramline shadows (thickened bronchi side-on) or tubular shadows
(bronchi filled with secretions) suggests bronchiectasis, but
computed tomography is a much more sensitive test than plain
X-ray in bronchiectasis. The presence of pleural fluid is suggested
by a dense basal shadow, which, in the erect patient, ascends
towards the axilla (p. 547). In large pulmonary embolism, relative
oligaemia may cause a lung field to appear abnormally dark.
17.2 How to interpret a chest X-ray
Name, date, Films are posteroanterior (PA) unless marked AP to
orientation denote that they are anteroposterior
Lung fields
Equal translucency?
Check horizontal fissure from right hilum to sixth rib
at the anterior axillary line
Masses? Consolidation? Cavitation?
Lung apices
Check behind the clavicles. Masses? Consolidation?
Cavitation?
Trachea
Central (midway between the clavicular heads)?
Paratracheal mass? Goitre?
Heart
Normal shape?
Cardiothoracic ratio (should be < half the
intrathoracic diameter)
Retrocardiac mass?
Hila
Left should be higher than right
Shape (should be concave laterally; if convex,
consider mass or lymphadenopathy)?
Density?
Diaphragm
Right should be higher than left
Hyperinflation (no more than 10 ribs should be
visible posteriorly above the diaphragm)?
Costophrenic
angles
Acute and well defined (pleural fluid or thickening,
if not)?
Soft tissues
Breast shadows in females
Chest wall for masses or subcutaneous emphysema
Bones
Ribs, vertebrae, scapulae and clavicles
Any fracture visible at bone margins or lucencies?
Lung apex
Trachea
Clavicular heads symmetrical
either side of spine - no rotation
Right hilum
Right atrial
border
Right
costophrenic
angle
Right hemidiaphragm
Medial border
of scapula
Aortic arch
Left hilum
Left ventricular
border
Cardiac apex
Left hemidiaphragm
(normally lower than right)
Right cardiophrenic angle ~ , . .....
a M a Gastric air bubble
Fig. 17.4 The normal chest X-ray. The lung markings consist of branching and tapering lines radiating out from the hila. Where airways and vessels
turn towards the film, they can appear as open or filled circles (see upper pole of right hilum). The scapulae may overlie the lung fields; trace the edge of
bony structures to avoid mistaking them for pleural or pulmonary shadows. To check for hyperinflation, count the ribs; if more than 10 are visible
posteriorly above the diaphragm, the lungs are hyperinflated. From Innes JA. Davidson’s Essentials of medicine. Edinburgh: Churchill Livingstone, Elsevier
Ltd; 2009.
552 • RESPIRATORY MEDICINE
17.3 Common chest X-ray abnormalities
Pulmonary and pleural shadowing
• Consolidation: infection, infarction, inflammation and, rarely,
bronchoalveolar cell carcinoma
• Lobar collapse: mucus plugging, tumour, compression by lymph
nodes
• Solitary nodule: see page 560
• Multiple nodules: miliary tuberculosis (TB), dust inhalation,
metastatic malignancy, healed varicella pneumonia, rheumatoid
disease
• Ring shadows, tramlines and tubular shadows: bronchiectasis
• Cavitating lesions: tumour, abscess, infarct, pneumonia
(; Staphylococcus/Klebsiella ), granulomatosis with polyangiitis
(formerly known as Wegener’s granulomatosis)
• Reticular, nodular and reticulonodular shadows: diffuse parenchymal
lung disease, infection
• Pleural abnormalities: fluid, plaques, tumour
Increased translucency
• Bullae
• Pneumothorax
• Oligaemia
Hilar abnormalities
• Unilateral hilar enlargement: TB, lung cancer, lymphoma
• Bilateral hilar enlargement: sarcoid, lymphoma, TB, silicosis
Other abnormalities
• Hiatus hernia
• Surgical emphysema
Fig. 17.5 Radiological features of lobar collapse caused by bronchial
obstruction. The dotted line in the drawings represents the normal
position of the diaphragm. The dark pink area represents the extent of
shadowing seen on the X-ray.
j Computed tomography
Computed tomography (CT) provides detailed images of the
pulmonary parenchyma, mediastinum, pleura and bony structures.
The displayed range of densities can be adjusted to highlight
different structures, such as the lung parenchyma, the mediastinal
vascular structures or bone. Cross-sectional formatting allows
recognition of the axial distribution of the disease, while coronal
reformation displays the craniocaudal distribution. In cases
of suspected lung cancer, CT is central to both diagnosis
and staging, and facilitates percutaneous needle biopsy. CT
identifies the extent and appearance of pleural thickening (see
Fig. 17.65) and reliably differentiates pleural and pericardial fat
from other pathologies. High-resolution thin-section scanning
provides detailed images of the pulmonary parenchyma and is
particularly useful in assessing diffuse parenchymal lung disease
(see Fig. 17.56), identifying airway thickening, bronchiectasis
(see Fig. 17.29) and emphysema (see Fig. 17.27). The relative
contribution of competing pathologies to a breathless patient may
be assessed. Prone imaging may be used to differentiate the
gravity-induced posterobasal attenuation seen in supine scans.
CT pulmonary angiography (CTPA) has become the investigation
of choice in the diagnosis of pulmonary thromboembolism (see
Fig. 17.68), when it may either confirm the suspected embolism
or highlight an alternative diagnosis. It has largely replaced the
radioisotope-based ventilation-perfusion scan, although the
latter continues to provide useful information in the pre-operative
assessment of patients being considered for lung resection and
in the assessment of pulmonary hypertension. CT may assist
in identifying the cavitation of tuberculosis, fungal infection
(p. 300) and other signs of infection (halo - air crescent). Finally,
CT may be used to assess disease progression, thereby predicting
prognosis, and in screening to detect the earliest signs of disease.
Investigation of respiratory disease • 553
0
Fig. 17.6 Computed tomography and positron emission tomography combined to reveal intrathoracic metastases. [A] In a patient with lung
cancer, CT shows some posterior pleural thickening. [§] PET scanning reveals FDG uptake in two pleural lesions (arrows). [C] The lesions are highlighted in
yellow in the combined PET/CT image. A-C, From http://radiology.rsnajnls.org.
Positron emission tomography
Positron emission tomography (PET) scanners employ the
radiotracer 18F-fluorodeoxyglucose (FDG) to quantify the rate
of glucose metabolism by cells. The 18FDG is rapidly taken up
by metabolically active tissue, where it is phosphorylated and
‘trapped’ in the cell. The assessment of 18FDG uptake may
be qualitative (visual analysis) or semi-quantitative, using the
standardised uptake value (SUV) (Fig. 17.6). PET is useful in
the staging of mediastinal lymph nodes and distal metastatic
disease in patients with lung cancer and in the investigation of
pulmonary nodules. Co-registration of PET and CT (PET-CT)
enhances localisation and characterisation of metabolically
active deposits (Fig. 17.6). PET may also differentiate benign
from malignant pleural disease and can be used to assess the
extent of extrapulmonary disease in sarcoidosis. However, 18FDG
uptake by a lesion is affected by a large number of parameters,
including equipment used, the physics, and biological factors
such as amount of body fat and brown fat uptake and the level
of fasting blood glucose.
|jVlagnetic resonance imaging
Conventional magnetic resonance imaging (MRI) of the lung
parenchyma is seldom useful, although the technique is
increasingly finding a role in the differentiation of benign from
malignant pleural disease, and in delineating invasion of the
chest wall or diaphragm by tumour.
Ultrasound
Transthoracic ultrasound has evolved into a point-of-care
investigation to assess the pleural space (see Fig. 17.15). In
the hands of an experienced operator it can distinguish pleural
fluid from pleural thickening, identify a pneumothorax and, by
directly visualising the diaphragm and solid organs such as
the liver, spleen and kidneys, may be used to guide pleural
aspiration, biopsy and intercostal chest drain insertion safely. It
is also used to guide needle biopsy of superficial lymph node
or chest wall masses and provides useful information on the
shape and movement of the diaphragm.
Endoscopic examination
Laryngoscopy
The larynx may be inspected directly with a fibreoptic laryngoscope
and this is useful in cases of suspected vocal cord dysfunction,
when paradoxical movement of the vocal cords may mimic
asthma. Left-sided lung tumours may involve the left recurrent
laryngeal nerve, paralysing the left vocal cord and leading to a
hoarse voice and a ‘bovine’ cough. Continuous laryngoscopy
during exercise tests allows the identification of exercise- induced
laryngeal obstruction.
Bronchoscopy
The trachea and the first 3-4 generations of bronchi may be
inspected using a flexible bronchoscope. Flexible bronchoscopy
is usually performed under local anaesthesia with sedation, on an
outpatient basis. Abnormal tissue in the bronchial lumen or wall
can be biopsied, and bronchial brushings, washings or aspirates
can be taken for cytological or bacteriological examination. Small
biopsy specimens of lung tissue, taken by forceps passed through
the bronchial wall (transbronchial biopsies), may be helpful in the
diagnosis of bronchocentric disorders such as sarcoidosis and
diffuse malignancy but are generally too small to be of diagnostic
value in other diffuse parenchymal pulmonary disease (p. 605).
Rigid bronchoscopy requires general anaesthesia and is
reserved for specific situations, such as massive haemoptysis
or removal of a foreign body (see Fig. 10.2, p. 179), and can
facilitate endobronchial laser therapy and stenting.
Endobronchial ultrasound
Endobronchial ultrasound (EBUS) allows directed needle aspiration
from peribronchial nodes and is used increasingly to stage lung
cancer. It may also be useful in non-malignant conditions, such
as tuberculosis of the mediastinal lymph nodes or sarcoid.
Lymph nodes down to the main carina can also be sampled
using a mediastinoscope passed through a small incision at the
suprasternal notch under general anaesthetic. Lymph nodes in
the lower mediastinum may be biopsied via the oesophagus
using endoscopic ultrasound (EUS), an oesophageal endoscope
equipped with an ultrasound transducer and biopsy needle.
Thoracoscopy
Thoracoscopy, which involves the insertion of an endoscope
through the chest wall, facilitates biopsy under direct vision
and is performed by surgeons and an increasing number of
physicians. This modality is the gold standard for the evaluation
of the pleural interface, characterisation of complex pleural
effusion, and identification of exudate and haemorrhage, as
well as the analysis of superior sulcus tumours, as it enables
more accurate staging.
554 • RESPIRATORY MEDICINE
Immunological and serological tests
The diagnosis of asthma may be supported by demonstrating an
elevated level of immunoglobulin E (IgE), and the measurement of
IgE directed against specific antigens can be useful in assessing
the contribution of specific allergens to the presentation. Many
autoimmune diseases present with pulmonary involvement and
autoantibodies may be identified in the serum. Serum precipitins
are antibodies that form visible lines of precipitated glycoprotein
when they encounter their specific antigen in an agarose gel
or on an acetate cellulose sheet. They may identify a reaction
to fungi such as Aspergillus (p. 596) or to antigens involved in
hypersensitivity pneumonitis, such as farmer’s lung (p. 616).
IgG enzyme immunoassay may be used interchangeably. The
presence of pneumococcal antigen in sputum, blood or urine may
be of diagnostic importance in pneumonia. Respiratory viruses
can be detected in nose/throat swabs by immunofluorescence
and Legionella infection may diagnosed by detection of the urinary
antigen. The detection of galactomannan, a component of the
cell wall of Aspergillus, may assist in the diagnosis of invasive
aspergillosis, and interferon-gamma release assays are useful
in the detection of latent tuberculosis.
Microbiological investigations
Sputum, pleural fluid, throat swabs, blood, and bronchial washings
and aspirates can be examined for bacteria, fungi and viruses.
The use of hypertonic saline to induce expectoration of sputum
may obviate the need for more invasive procedures, such as
bronchoscopy. Molecular tests are increasingly being used
to provide rapid and accurate identification of many infective
organisms. Nucleic acid amplification tests (NAATs) identify
common respiratory viruses, such as influenza, adenovirus and
respiratory syncytial virus, and have largely replaced paired serology
for Mycoplasma, Legionella and other organisms. NAATs are
increasingly adopted as the first-line investigation for identification
of tuberculosis and rapid identification of drug resistance.
Cytology and histopathology
Cytological examination of exfoliated cells in pleural fluid or
bronchial brushings and washings, or of fine needle aspirates
from lymph nodes or pulmonary lesions, can support a diagnosis
of malignancy but a larger tissue biopsy is often necessary,
particularly as this allows immunohistochemistry using a panel of
antibodies to characterise the tumour. Histopathology may also
allow identification of infective agents such as Mycobacterium
tuberculosis, Pneumocystis jirovecii or fungi. Differential cell
counts in bronchial lavage fluid may help to distinguish pulmonary
changes due to sarcoidosis (p. 608) from those caused by
idiopathic pulmonary fibrosis (p. 605) or hypersensitivity
pneumonitis (p. 616).
Respiratory function testing
Respiratory function tests are used to aid diagnosis, quantify
functional impairment, and monitor treatment or progression
of disease. Airway narrowing, lung volume and gas exchange
capacity are quantified and compared with normal values
[a] Volume \b\ Expiration
Fig. 17.7 Respiratory function tests in health and disease. [A] Volume/time traces from forced expiration in health, chronic obstructive pulmonary
disease (COPD) and fibrosis. COPD causes slow, prolonged and limited exhalation. In fibrosis, forced expiration results in rapid expulsion of a reduced forced
vital capacity (FVC). Forced expiratory volume (FEV^ is reduced in both diseases but disproportionately so, compared to FVC, in COPD. fj] The same data
plotted as flow/volume loops. In COPD, collapse of intrathoracic airways limits flow, particularly during mid- and late expiration. The blue trace illustrates
large airway obstruction, which particularly limits peak flow rates. [C] Lung volume measurement. Volume/time graphs during quiet breathing with a single
maximal breath in and out. COPD causes hyperinflation with increased residual volume. Fibrosis causes a proportional reduction in all lung volumes.
Investigation of respiratory disease • 555
adjusted for age, gender, height and ethnic origin. In diseases
characterised by airway narrowing (e.g. asthma, bronchitis and
emphysema), maximum expiratory flow is limited by dynamic
compression of small intrathoracic airways, some of which may
close completely during expiration, limiting the volume that can
be expired (‘obstructive’ defect). Hyperinflation of the chest
results and can become extreme if elastic recoil is also lost
due to parenchymal destruction, as in emphysema. In contrast,
diseases that cause interstitial inflammation and/or fibrosis lead to
progressive loss of lung volume (‘restrictive’ defect) with normal
expiratory flow rates. Typical laboratory traces are illustrated in
Figure 17.7.
| Measurement of airway obstruction
Airway narrowing is assessed by asking patients to breathe in fully,
then blow out as hard and fast as they can into a peak flow meter
or a spirometer. Peak flow meters are cheap and convenient for
home monitoring of peak expiratory flow (PEF) in the detection
and monitoring of asthma but results are effort-dependent. More
accurate and reproducible measures are obtained by maximum
forced expiration into a spirometer. The forced expired volume
in 1 second (FEVi) is the volume exhaled in the first second, and
the forced vital capacity (FVC) is the total volume exhaled. FEV1
is disproportionately reduced in airflow obstruction, resulting in
FEV/FVC ratios of less than 70%. In this situation, spirometry
should be repeated following inhaled short-acting (32-adrenoceptor
agonists (e.g. salbutamol); an increase of >12% and >200 ml_ in
FEV^ or FVC indicates significant reversibility. A large improvement
in FE\Z^ (>400 ml_) and variability in peak flow over time are
features of asthma (p. 567).
To distinguish large airway narrowing (e.g. tracheal stenosis
or compression; see Fig. 18.12, p. 648) from small airway
narrowing, spirometry data are plotted as flow/volume loops.
These display flow in relation to lung volume (rather than time)
during maximum expiration and inspiration, and the pattern of
flow reveals the site of airflow obstruction (Fig. 17.7B).
Lung volumes
Spirometry can measure only the volume of gas that can be
exhaled; it cannot measure the gas remaining in the lungs after
a maximal expiration. All the gas in the lungs can be measured
by rebreathing an inert non-absorbed gas (usually helium) and
recording how much the test gas is diluted by lung gas at
equilibrium. This measures the volume of intrathoracic gas
that mixes freely with tidal breaths. Alternatively, lung volume
may be measured by body plethysmography (p. 175), which
determines the pressure/volume relationship of the thorax. This
method measures total intrathoracic gas volume, including poorly
ventilated areas such as bullae. The terms used to describe lung
volume are shown in Figure 17.7C.
| Transfer factor
To measure the capacity of the lungs to exchange gas, patients
inhale a test mixture of 0.3% carbon monoxide, which is taken
up avidly by haemoglobin in pulmonary capillaries. After a short
breath-hold, the rate of disappearance of CO into the circulation
is calculated from a sample of expirate, and expressed as the
TLC0 or carbon monoxide transfer factor. Helium is also included
in the test breath to allow calculation of the volume of lung
examined by the test breath. Transfer factor expressed per
unit lung volume is termed Kco. Common respiratory function
abnormalities are summarised in Box 17.4.
0 15 30 45 60 75 90 mmHg
Arterial PaC02
I I Reference range
= 95% Confidence limits
Fig. 17.8 Changes in blood [H+], PaC02 and plasma [HC03~] in
acid-base disorders. The rectangle indicates normal limits for [H+] and
PaC02. The bands represent 95% confidence limits of single disturbances
in human blood. To determine the likely cause of an acid-base disorder,
plot the values of [H+] and PaC02 from an arterial blood gas measurement,.
The diagram indicates whether any acidosis or alkalosis results primarily
from a respiratory disorder of PaC02 or from a metabolic derangement.
Reprinted with permission from Elsevier (Flenley D. Lancet 1971; 1:1921).
Arterial blood gases and oximetry
The measurement of hydrogen ion concentration, Pa02 and
PaC02, and derived bicarbonate concentration in an arterial
blood sample is essential for assessing the degree and type of
respiratory failure and for measuring acid-base status. This is
discussed in detail on pages 363 and 565. Interpretation of results
is made easier by blood gas diagrams (Fig. 1 7.8), which indicate
whether any acidosis or alkalosis is due to acute or chronic
respiratory derangements of PaC02 or to metabolic causes.
Pulse oximeters with finger or ear probes measure the difference
in absorbance of light by oxygenated and deoxygenated blood
and calculate the percentage of haemoglobin that is oxygenated
(the oxygen saturation). This allows non-invasive continuous
556 • RESPIRATORY MEDICINE
assessment of oxygen saturation in patients and its response
to oxygen therapy.
Exercise tests
Resting measurements may be unhelpful in early disease or
in patients complaining only of exercise-induced symptoms.
Exercise testing with spirometry before and after can help to
reveal exercise- induced asthma. Walk tests include the self-paced
6-minute walk and the externally paced incremental ‘shuttle’
test, where patients walk at increasing pace between two cones
1 0 m apart. These provide simple, repeatable assessments of
disability and response to treatment. Cardiopulmonary bicycle
exercise testing, with measurement of metabolic gas exchange,
ventilation and ECG changes, is useful for quantifying exercise
limitation and detecting occult cardiovascular or respiratory
limitation in a breathless patient.
Presenting problems in
respiratory disease
Cough
Cough is the most frequent symptom of respiratory disease and
is caused by stimulation of sensory nerves in the mucosa of the
pharynx, larynx, trachea and bronchi. Acute sensitisation of the
normal cough reflex occurs in a number of conditions and it is
typically induced by changes in air temperature or exposure to
irritants, such as cigarette smoke or perfumes. Distinguishing
characteristics of various causes of cough are detailed in Box 17.5.
The explosive quality of a normal cough is lost in patients with
respiratory muscle paralysis or vocal cord palsy. Paralysis of a
single vocal cord gives rise to a prolonged, low-pitched, inefficient
‘bovine’ cough accompanied by hoarseness. Coexistence of
an inspiratory noise (stridor) indicates partial obstruction of a
major airway (e.g. laryngeal oedema, tracheal tumour, scarring,
compression or inhaled foreign body) and requires urgent
investigation and treatment. Sputum production is common
in patients with acute or chronic cough, and its nature and
appearance can provide clues to the aetiology (p. 546).
Aetiology
Acute transient cough is most commonly caused by viral lower
respiratory tract infection, post-nasal drip resulting from rhinitis or
sinusitis, aspiration of a foreign body, or throat-clearing secondary
to laryngitis or pharyngitis. When cough occurs in the context of
more serious diseases, such as pneumonia, aspiration, congestive
heart failure or pulmonary embolism, it is usually easy to diagnose
from other clinical features.
Patients with chronic cough present more of a challenge,
especially when physical examination, chest X-ray and lung
function studies are normal. In this context, it is most often
explained by cough-variant asthma (where cough may be the
principal or exclusive clinical manifestation), post-nasal drip
secondary to nasal or sinus disease, or gastro-oesophageal
reflux disease (GORD) with aspiration. Diagnosis of the latter
may require oesophageal pH monitoring or a prolonged trial of
anti-reflux therapy (p. 793). Between 10% and 15% of patients
(particularly women) taking angiotensin-converting enzyme (ACE)
inhibitors develop a drug-induced chronic cough. Bordetella
pertussis infection in adults (p. 582) can result in cough lasting
up to 3 months. While most patients with lung cancer have an
abnormal chest X-ray on presentation, fibreoptic bronchos¬
copy or thoracic CT is advisable in most adults (especially
smokers) with otherwise unexplained cough of recent onset,
as this may reveal a small endobronchial tumour or unexpected
foreign body (see Fig. 10.2, p. 179). In a small percentage of
patients, dry cough may be the presenting feature of interstitial
lung disease.
17.5 Cough
Origin
Common causes
Clinical features
Pharynx
Post-nasal drip
History of chronic rhinitis
Larynx
Laryngitis, tumour, whooping cough, croup
Voice or swallowing altered, harsh or painful cough
Paroxysms of cough, often associated with stridor
Trachea
Tracheitis
Raw retrosternal pain with cough
Bronchi
Bronchitis (acute) and chronic obstructive pulmonary
disease (COPD)
Dry or productive, worse in mornings
Asthma
Usually dry, worse at night
Eosinophilic bronchitis
Features similar to asthma but airway hyper- reactivity
absent
Lung cancer
Persistent (often with haemoptysis)
Lung parenchyma
Tuberculosis
Productive (often with haemoptysis)
Pneumonia
Dry initially, productive later
Bronchiectasis
Productive, changes in posture induce sputum
production
Pulmonary oedema
Often at night (may be productive of pink, frothy sputum)
Interstitial fibrosis
Dry and distressing
Drug side-effect
Angiotensin-converting enzyme (ACE) inhibitors
Dry cough
Aspiration
Gastro-oesophageal reflux disease (GORD)
History of acid reflux, heartburn, hiatus hernia
Obesity
Adapted from Munro JF, Campbell IW. Macleod’s Clinical examination, 10th edn. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2000.
Presenting problems in respiratory disease • 557
Breathlessness
Breathlessness or dyspnoea can be defined as the feeling of an
uncomfortable need to breathe. It is unusual among sensations,
as it has no defined receptors, no localised representation in the
brain, and multiple causes both in health (e.g. exercise) and in
diseases of the lungs, heart or muscles.
Pathophysiology
Stimuli to breathing resulting from disease processes are shown
in Figure 17.9. Respiratory diseases can stimulate breathing
and dyspnoea by:
• stimulating intrapulmonary sensory nerves (e.g.
pneumothorax, interstitial inflammation and pulmonary
embolus)
• increasing the mechanical load on the respiratory muscles
(e.g. airflow obstruction or pulmonary fibrosis)
• causing hypoxia, hypercapnia or acidosis, which stimulate
chemoreceptors.
In cardiac failure, pulmonary congestion reduces lung
compliance and can also obstruct the small airways. Reduced
cardiac output also limits oxygen supply to the skeletal muscles
during exercise, causing early lactic acidaemia and further
stimulating breathing via the central chemoreceptors.
Breathlessness and the effects of treatment can be quantified
using a symptom scale. Patients tend to report breathlessness
in proportion to the sum of the above stimuli to breathing.
Individual patients differ greatly in the intensity of breathlessness
reported for a given set of circumstances, but breathlessness
scores during exercise within individuals are reproducible and
can be used to monitor the effects of therapy.
Differential diagnosis
Patients with breathlessness present either with chronic exertional
symptoms or as an emergency with acute breathlessness,
when symptoms are prominent even at rest. The causes can
be classified accordingly (Box 17.6).
Chronic exertional breathlessness
The cause of breathlessness is often apparent from a careful
clinical history. Key questions are detailed below.
How is your breathing at rest and overnight?
In COPD, there is a fixed, structural limit to maximum ventilation,
and a tendency for progressive hyperinflation during exercise.
Breathlessness is apparent mainly when walking and patients
usually report minimal symptoms at rest and overnight. In contrast,
patients with significant asthma are often woken from their sleep
by breathlessness with chest tightness and wheeze.
Orthopnoea is common in COPD, as well as in heart disease,
because airflow obstruction is made worse by cranial displacement
of the diaphragm by the abdominal contents when recumbent,
so many patients choose to sleep propped up. Thus it is not a
useful differentiating symptom unless there is a clear history of
previous angina or infarction to suggest cardiac disease.
Fig. 17.9 Respiratory stimuli contributing to breathlessness. Mechanisms by which disease can stimulate the respiratory motor neurons in the
medulla. Breathlessness is usually felt in proportion to the sum of these stimuli. Further explanation is given on page 179. (CSF = cerebrospinal fluid;
V/Q = ventilation/perfusion match)
558 • RESPIRATORY MEDICINE
I 17.6 Causes of breathlessness
System
Acute dyspnoea
Chronic exertional dyspnoea
Cardiovascular
*Acute pulmonary oedema (p. 463)
Chronic heart failure (p. 463)
Myocardial ischaemia (angina equivalent) (p. 180)
Respiratory
*Acute severe asthma
*Acute exacerbation of COPD
^Pneumothorax
*Pneumonia
^Pulmonary embolus
ARDS
Inhaled foreign body (especially in children)
Lobar collapse
Laryngeal oedema (e.g. anaphylaxis)
*C0PD
^Chronic asthma
Lung cancer
Interstitial lung disease (sarcoidosis, fibrosing alveolitis,
extrinsic allergic alveolitis, pneumoconiosis)
Chronic pulmonary thromboembolism
Lymphangitis carcinomatosis (may cause intolerable
breathlessness)
Large pleural effusion(s)
Others
Metabolic acidosis (e.g. diabetic ketoacidosis, lactic acidosis,
uraemia, overdose of salicylates, ethylene glycol poisoning)
Psychogenic hyperventilation (anxiety- or panic-related)
Severe anaemia
Obesity
Deconditioning
*Denotes a common cause.
(ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease)
How much can you do on a good day?
Noting ‘breathless on exertion’ is not enough; the approximate
distance the patient can walk on the level should be documented,
along with capacity to climb inclines or stairs. Variability within
and between days is a hallmark of asthma; in mild asthma, the
patient may be free of symptoms and signs when well. Gradual,
progressive loss of exercise capacity over months and years,
with consistent disability over days, is typical of COPD. When
asthma is suspected, the degree of variability is best documented
by home peak flow monitoring.
Relentless, progressive breathlessness that is also present at
rest, often accompanied by a dry cough, suggests interstitial
fibrosis. Impaired left ventricular function can also cause chronic
exertional breathlessness, cough and wheeze. A history of angina,
hypertension or myocardial infarction raises the possibility of a
cardiac cause. This may be confirmed by a displaced apex beat, a
raised JVP and cardiac murmurs (although these signs can occur
in severe hypoxic lung disease with fluid retention). The chest
X-ray may show cardiomegaly and an ECG and echocardiogram
may provide evidence of left ventricular disease. Measurement
of arterial blood gases may help, as, in the absence of an
intracardiac shunt or pulmonary oedema, the Pa02 in cardiac
disease is normal and the PaC02 is low or normal.
Did you have breathing problems in childhood or at school?
When present, a history of childhood wheeze increases the
likelihood of asthma, although this history may be absent in
late-onset asthma. A history of atopic allergy also increases the
likelihood of asthma.
Do you have other symptoms along with your breathlessness?
Digital or perioral paraesthesiae and a feeling that ‘I cannot get
a deep enough breath in’ are typical features of psychogenic
hyperventilation but this cannot be diagnosed until investigations
have excluded other potential causes. Additional symptoms
include lightheadedness, central chest discomfort or even
carpopedal spasm due to acute respiratory alkalosis. These
alarming symptoms may provoke further anxiety and exacerbate
hyperventilation. Psychogenic breathlessness rarely disturbs
sleep, frequently occurs at rest, may be provoked by stressful
situations and may even be relieved by exercise. The Nijmegen
17.7 Factors suggesting psychogenic
hyperventilation
• ‘Inability to take a deep breath’
• Frequent sighing/erratic ventilation at rest
• Short breath-holding time in the absence of severe respiratory
disease
• Difficulty in performing and/or inconsistent spirometry measures
• High score (over 26) on Nijmegen questionnaire
• Induction of symptoms during submaximal hyperventilation
• Resting end-tidal C02 <4.5%
• Associated digital and/or perioral paraesthesiae
questionnaire can be used to score some of the typical symptoms
of hyperventilation (Box 17.7). Arterial blood gases show normal
P02, low PC02 and alkalosis.
Pleuritic chest pain in a patient with chronic breathlessness,
particularly if it occurs in more than one site over time, should
raise suspicion of thromboembolic disease. Thromboembolism
may occasionally present as chronic breathlessness with no
other specific features and should always be considered before
a diagnosis of psychogenic hyperventilation is made.
Morning headache is an important symptom in patients with
breathlessness, as it may signal the onset of carbon dioxide
retention and respiratory failure. This is particularly significant
in patients with musculoskeletal disease impairing respiratory
function (e.g. kyphoscoliosis or muscular dystrophy).
Acute severe breathlessness
This is one of the most common and dramatic medical
emergencies. Although respiratory causes are common, it can
result from cardiac disease, metabolic disease or poisoning
causing acidosis, or from psychogenic causes. The approach to
patients with acute severe breathlessness is covered on page 1 79.
Chest pain
Chest pain can result from cardiac, respiratory, oesophageal
or musculoskeletal disorders. The approach to this common
symptom is covered on page 176.
Presenting problems in respiratory disease • 559
Finger clubbing
Finger clubbing describes painless swelling of the soft tissues of
the terminal phalanges, causing increased longitudinal and lateral
convexity of the nail (Fig. 17.10). Upward displacement of the
proximal nail margin causes the anteroposterior diameter of the
finger at that point to exceed that at the distal interphalangeal
joint. It also removes the normal hyponychial angle between
the proximal part of the nail and the adjoining skin. Clubbing
usually affects the fingers symmetrically and commonly also
involves the toes, but can be unilateral if caused by a proximal
Fig. 17.10 Finger clubbing. [A] Anterior view. [§] Lateral view. From
Douglas G, Nicol F, Robertson C. Macleod’s Clinical examination, 13th edn.
Edinburgh: Churchill Livingstone, Elsevier Ltd; 2013.
1 17.8 Differential diagnosis of finger clubbing
Congenital or familial (5-10%)
Acquired
Thoracic (-80%)
• Chronic suppurative
• Tumours:
conditions:
Lung cancer
Pulmonary tuberculosis
Mesothelioma
Bronchiectasis
Fibroma
Lung abscess
• Pulmonary fibrosis
Empyema
Cystic fibrosis
Cardiovascular
• Cyanotic congenital heart
• Arteriovenous shunts and
disease
aneurysms
• Infective endocarditis
Gastrointestinal
• Cirrhosis
• Coeliac disease
• Inflammatory bowel disease
Others
• Thyrotoxicosis (thyroid
• Primary hypertrophic
acropachy)
osteoarthropathy
vascular condition, e.g. arteriovenous shunts for dialysis. It is
sometimes congenital but in over 90% of patients it indicates
a serious underlying disorder. The most common underlying
causes are suppurative or malignant lung disease but a variety
of other conditions can cause clubbing (Box 17.8). Clubbing
may recede if the underlying condition resolves, e.g. following
lung transplantation for cystic fibrosis.
Haemoptysis
Coughing up blood, irrespective of the amount, is an alarming
symptom and patients nearly always seek medical advice.
Care should be taken to establish that it is true haemoptysis
and not haematemesis, or gum or nose bleeding. Haemoptysis
must always be assumed to have a serious cause until this is
excluded (Box 17.9).
Many episodes of haemoptysis remain unexplained, even after
full investigation, and are likely to be due to simple bronchial
infection. A history of repeated small haemoptysis, or blood¬
streaking of sputum, is highly suggestive of lung cancer. Fever,
night sweats and weight loss suggest tuberculosis. Pneumococcal
pneumonia often causes ‘rusty’-coloured sputum but can
cause frank haemoptysis, as can all suppurative pneumonic
infections, including lung abscess (p. 586). Bronchiectasis
(p. 578) and intracavitary mycetoma (p. 597) can cause
catastrophic bronchial haemorrhage, and in these patients there
may be a history of previous tuberculosis or pneumonia in early
life. Finally, pulmonary thromboembolism is a common cause of
haemoptysis and should always be considered.
Physical examination may reveal additional clues. Finger
clubbing suggests lung cancer or bronchiectasis; other
signs of malignancy, such as cachexia, hepatomegaly and
lymphadenopathy, should also be sought. Fever, pleural rub
and signs of consolidation occur in pneumonia or pulmonary
infarction; a minority of patients with pulmonary infarction also
have unilateral leg swelling or pain suggestive of deep venous
n
1 17.9 Causes of haemoptysis
Bronchial disease
• Cancer*
•
Bronchial adenoma
• Bronchiectasis*
• Acute bronchitis*
•
Foreign body
Parenchymal disease
• Tuberculosis*
•
Lung abscess
• Suppurative pneumonia
•
Trauma
• Parasites (e.g. hydatid
•
Actinomycosis
disease, flukes)
•
Mycetoma
Lung vascular disease
• Pulmonary infarction*
•
Polyarteritis nodosa
• Goodpasture’s syndrome
•
Idiopathic pulmonary
(p. 612)
haemosiderosis
Cardiovascular disease
• Acute left ventricular failure*
• Mitral stenosis
•
Aortic aneurysm
Blood disorders
• Leukaemia
• Haemophilia
•
Anticoagulants
*More common causes.
560 • RESPIRATORY MEDICINE
thrombosis. Rashes, haematuria and digital infarcts point to an
underlying systemic disease, such as a vasculitis, which may
be associated with haemoptysis.
Management
In severe acute haemoptysis, the patient should be nursed
upright (or on the side of the bleeding, if this is known), given
high-flow oxygen and resuscitated as required. Bronchoscopy
in the acute phase is difficult and often merely shows blood
throughout the bronchial tree. Infusions of the antifibrinolytic agent
tranexamic acid or the vasopressin precursor terlipressin may help
to limit bleeding but evidence of efficacy is limited. If radiology
shows an obvious central cause, then rigid bronchoscopy under
general anaesthesia may allow intervention to stop bleeding;
however, the source often cannot be visualised. Intubation with a
divided endotracheal tube may allow protected ventilation of the
unaffected lung to stabilise the patient. Bronchial arteriography
and embolisation (Fig. 17.11), or even emergency surgery, can
be life-saving in the acute situation.
In the vast majority of cases, however, the haemoptysis itself
is not life-threatening and a logical sequence of investigations
can be followed:
• chest X-ray, which may provide evidence of a localised
lesion, including tumour (malignant or benign), pneumonia,
mycetoma or tuberculosis
• full blood count (FBC) and clotting screen
• bronchoscopy after acute bleeding has settled, which may
reveal a central lung cancer (not visible on the chest X-ray)
and permit biopsy and tissue diagnosis
• CTPA, which may show underlying pulmonary
thromboembolic disease or alternative causes not seen on
the chest X-ray (e.g. pulmonary arteriovenous malformation
or small or hidden tumours).
Fig. 17.11 Bronchial artery angiography. An angiography catheter has
been passed via the femoral artery and aorta into an abnormally dilated
right bronchial artery (arrows). Contrast is seen flowing into the lung. This
patient had post-tuberculous bronchiectasis and presented with massive
haemoptysis. Bronchial artery embolisation was successfully performed.
The ‘incidental’ pulmonary nodule
A pulmonary nodule may be defined as a well or poorly
circumscribed, approximately rounded structure that appears
on imaging as a focal opacity less than 3 cm in diameter that
is surrounded by aerated lung. The increased use of helical
multi-detector CT (Fig 17.12) has been accompanied by an
epidemic of ‘incidental’ pulmonary nodules. Nodules must
not be dismissed as ‘incidental’, however, until an important
and treatable infective or malignant condition in its earliest
stage is excluded or stability over at least 2 years has been
demonstrated.
The list of potential causes of pulmonary nodules is extensive
and most are benign (Box 17.10). Features on a CT scan
consistent with a benign lesion include being less than 5 mm
in diameter or less than 80 mm3 in volume; diffuse, central,
laminated or popcorn calcification; or the presence of macroscopic
fat. In addition, perifissural lymph nodes and subpleural nodules
with a lentiform or triangular shape do not require any further
investigation.
In cases where a benign lesion cannot be confidently assumed,
further assessment depends on both the appearance of the
nodule and the clinical context. These assessments may be
aided by the use of computer prediction models (Box 17.1 1).
Fig. 17.12 Thoracic CT scan showing a solitary pulmonary nodule
identified in the right upper lobe (arrow).
i
17.10 Causes of pulmonary nodules
Common causes
• Lung cancer
•
Lung abscess
• Single metastasis
•
Tuberculoma
• Localised pneumonia
Uncommon causes
•
Pulmonary infarct
• Benign tumour
•
Pulmonary sequestration
• Lymphoma
•
Pulmonary haematoma
• Arteriovenous malformation
•
‘Pseudotumour’ - fluid
• Hydatid cyst (p. 298)
collection in a fissure
• Bronchogenic cyst
•
Aspergilloma (usually
• Rheumatoid nodule
surrounded by air crescent)
• Granulomatosis with
•
Cryptococcus
polyangiitis (Wegener’s
granulomatosis)
•
Aspergillus nodule
Presenting problems in respiratory disease • 561
17.11 Clinical and radiographic features distinguishing benign from malignant nodules
Feature Risk of malignancy
Feature
Risk of malignancy
Characteristics of nodule
Size
Margin
Calcification
or fat
Location
Nearly all >3 cm but fewer than 1% <4 mm are malignant
Usually smooth in benign lesions
Spiculated suggests malignancy
Laminated or central deposition of calcification suggests
granuloma
‘Popcorn’ pattern suggests hamartoma
Fat may suggest hamartoma or lipoid granuloma
70% of lung cancers occur in upper lobes
Benign lesions are equally distributed throughout upper and
lower lobes
Characteristics of patient
Age Increases with age and is uncommon below age of 40
Smoking history Increases in proportion to duration and amount smoked
Other Increased by history of lung cancer in first-degree
relative and by exposure to asbestos, silica, uranium and
radon
*Linear or sheet-like lung opacities are unlikely to represent neoplasms and do not require follow-up. Some nodular opacities may be sufficiently typical of scarring for
follow-up not to be warranted.
Adapted from MacMahon H, Austin JH, Gamsu G, et at Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner
Society. Radiology 2005; 237:395-400.
Fig. 17.13 Recommendations on the assessment of a solid pulmonary nodule. [A] Initial approach to solid pulmonary nodules. The Brock model is
an online calculator that can also be downloaded as an app (https://brocku.ca/lung-cancer-risk-calculator). The model integrates data on age, sex, family
history of cancer, the presence of emphysema, nodule size, nodule type, nodule position, nodule count and speculation, and calculates the probability that
a nodule will become malignant within a 2- to 4-year follow-up period. Herder is a similar model. ‘Consider positron emission tomography-computed
tomography (PET-CT) for larger nodules in young patients with low risk by Brock score, as this score was developed in a screening cohort (50-75 years)
and so performance in younger patients is unproven. Continues overleaf.
562 • RESPIRATORY MEDICINE
Fig. 17.13, cont’d [§] Solid pulmonary nodule surveillance algorithm. (VDT = volume doubling time) From Callister ME, Baldwin DR, Akram AR, etal.
British Thoracic Society Guidelines on the investigation and management of pulmonary nodules. Thorax 2015; Suppl. 2:ii1-ii54.
A variety of diagnostic approaches may be considered,
including bronchoscopy, percutaneous needle biopsy, PET,
interval CT scanning or even surgical resection of the lesion.
Pulmonary nodules are invariably beyond the vision of the
bronchoscope and, with the notable exception of pulmonary
infection (e.g. tuberculosis), the yield from blind washings is
low, although this may improve as advances in endobronchial
imaging are adopted. If the nodule is favourably located and of
sufficient size, percutaneous needle biopsy under ultrasound or
CT guidance may be employed. The risk of pneumothorax is
approximately 15% and around 7% require intercostal drainage,
so this should be contemplated only in individuals with an FEV1
of more than 35% predicted. Haemorrhage into the lung or
pleural space, air embolism and tumour seeding are rare but
recognised complications.
Where clinical suspicion remains high despite a benign or
indeterminate biopsy or where a nodule is considered to be of
sufficiently high risk for malignancy to merit proceeding straight
to surgery, then surgical resection may be the best management,
as surgery remains the best chance of curing lung cancer. It is
important for the logic underlying this approach to be discussed
with the patient and the consequences of resection of a benign
lesion explained.
PET scanning provides useful information about nodules of at
least 1 cm in diameter. The presence of high metabolic activity
is strongly suggestive of malignancy, while an inactive ‘cold’
nodule is consistent with benign disease. However, a high SUV
is a marker of glucose metabolism, not malignancy, and PET
has significant limitations in regions with high endemic rates
of infectious or granulomatous disease. False-negative results
may occur with neuro-endocrine tumours and minimally invasive
lepidic adenocarcinoma. Detection of neuro-endocrine tumours
may be improved by the use of 68Ga-Dotatoc in place of FDG.
If the nodule is small and inaccessible, interval CT scanning
may be employed. A repeat CT scan at 3 months will reliably
detect growth in larger nodules and may also demonstrate
resolution. Further interval scans may be arranged, depending
on the clinical context (Fig. 17.13).
Particular care must be taken with subsolid nodules, particularly
if further imaging demonstrates the development of a new solid
component, as these may represent a pre-malignant or an early
invasive form of adenocarcinoma.
In cases where the probability of cancer is low, the potential
risk of further scanning must be considered. Subsequent scans
often detect further nodules, increase the risk of false-positive
findings and lead to unnecessary patient anxiety while exposing
the individual to increased radiation.
Pleural effusion
The accumulation of serous fluid within the pleural space is
termed pleural effusion. The accumulation of frank pus is termed
empyema (p. 564), that of blood is haemothorax, and that of
chyle is a chylothorax. In general, pleural fluid accumulates as
a result of either increased hydrostatic pressure or decreased
osmotic pressure (‘transudative’ effusion, as seen in cardiac, liver
or renal failure), or from increased microvascular pressure due to
disease of the pleura or injury in the adjacent lung (‘exudative’
Presenting problems in respiratory disease • 563
effusion). The causes of the majority of pleural effusions (Boxes
17.12 and 1 7.1 3) are identified by a thorough history, examination
and relevant investigations.
Clinical assessment
Symptoms (pain on inspiration and coughing) and signs of pleurisy
(a pleural rub) often precede the development of an effusion,
especially in patients with underlying pneumonia, pulmonary
infarction or connective tissue disease. When breathlessness
is the only symptom, however, the onset may be insidious,
depending on the size and rate of accumulation. The physical
signs are detailed on page 547.
| 17.12 Causes of pleural effusion
Common causes
• Pneumonia (‘parapneumonic
•
Cardiac failure*
effusion’)
•
Subdiaphragmatic disorders
• Tuberculosis
(subphrenic abscess,
• Pulmonary infarction*
• Malignant disease
pancreatitis etc.)
Uncommon causes
• Hypoproteinaemia* (nephrotic
•
Acute rheumatic fever
syndrome, liver failure,
•
Meigs’ syndrome (ovarian
malnutrition)
tumour plus pleural effusion)
• Connective tissue diseases*
•
Myxoedema*
(particularly systemic lupus
•
Uraemia*
erythematosus and rheumatoid
•
Asbestos-related benign
arthritis)
• Post- myocardial infarction
pleural effusion
syndrome
*May cause bilateral effusions.
Investigations
Radiological investigations
The classical appearance of pleural fluid on the erect PA chest film
is of a curved shadow at the lung base, blunting the costophrenic
angle and ascending towards the axilla (p. 547). Fluid appears to
track up the lateral chest wall. In fact, fluid surrounds the whole
lung at this level but casts a radiological shadow only where
the X-ray beam passes tangentially across the fluid against the
lateral chest wall. Around 200 ml_ of fluid is required in order
for it to be detectable on a PA chest X-ray. Previous scarring
or adhesions in the pleural space can cause localised effusions.
Pleural fluid localised below the lower lobe (‘subpulmonary
effusion’) simulates an elevated hemidiaphragm. Pleural fluid
localised within an oblique fissure may produce a rounded
opacity that may be mistaken for a tumour.
Ultrasound is more accurate than plain chest X-ray for
determining the presence of fluid. A clear hypoechoic space
is consistent with a transudate and the presence of moving,
floating densities suggests an exudate. The presence of
septation most likely indicates an evolving empyema or resolving
haemothorax. CT scanning is indicated where malignant disease i
s suspected.
Pleural aspiration and biopsy
In some conditions (e.g. left ventricular failure), it should not be
necessary to sample fluid unless atypical features are present;
appropriate treatment should be administered and the effusion
re-evaluated. In most other circumstances, however, diagnostic
sampling is required. Simple aspiration provides information on
the colour and texture of fluid and these alone may immediately
suggest an empyema or chylothorax. The presence of blood is
consistent with pulmonary infarction or malignancy but may result
from a traumatic tap. Biochemical analysis allows classification into
1 17.13 Pleural effusion: main causes and features
Cause
Appearance of fluid
Type of fluid
Predominant cells in fluid
Other diagnostic features
Tuberculosis
Serous, usually
amber-coloured
Exudate
Lymphocytes (occasionally
polymorphs)
Positive tuberculin test
Isolation of Mycobacterium tuberculosis from pleural
fluid (20%)
Positive pleural biopsy (80%)
Raised adenosine deaminase
Malignant disease
Serous, often
blood-stained
Exudate
Serosal cells and
lymphocytes
Often clumps of malignant
cells
Positive pleural biopsy (40%)
Evidence of malignancy elsewhere
Cardiac failure
Serous, straw-
coloured
Transudate
Few serosal cells
Other signs of cardiac failure
Response to diuretics
Pulmonary
infarction
Serous or
blood-stained
Exudate (rarely
transudate)
Red blood cells
Eosinophils
Evidence of pulmonary infarction
Obvious source of embolism
Factors predisposing to venous thrombosis
Rheumatoid disease
Serous
Turbid if chronic
Exudate
Lymphocytes (occasionally
polymorphs)
Rheumatoid arthritis: rheumatoid factor and
anti-cyclic citrullinated peptide (anti-CCP) antibodies
Cholesterol in chronic effusion; very low glucose in
pleural fluid
Systemic lupus
erythematosus (SLE)
Serous
Exudate
Lymphocytes and serosal
cells
Other signs of SLE
Antinuclear factor or anti-DNA positive
Acute pancreatitis
Serous or
blood-stained
Exudate
No cells predominate
Higher amylase in pleural fluid than in serum
Obstruction of
thoracic duct
Milky
Chyle
None
Chylomicrons
564 • RESPIRATORY MEDICINE
17.14 Light’s criteria for distinguishing pleural
transudate from exudate
Exudate is likely if one or more of the following criteria are met:
• Pleural fluid proteimserum protein ratio >0.5
• Pleural fluid LDH:serum LDH ratio >0.6
• Pleural fluid LDH > two-thirds of the upper limit of normal
serum LDH
(LDH = lactate dehydrogenase)
transudate and exudate (Box 17.14) and Gram stain may suggest
parapneumonic effusion. The predominant cell type provides
useful information and cytological examination is essential. A
low pH suggests infection but may also be seen in rheumatoid
arthritis, ruptured oesophagus or advanced malignancy.
Ultrasound- or CT-guided pleural biopsy provides tissue for
pathological and microbiological analysis. Where necessary,
video-assisted thoracoscopy allows visualisation of the pleura
and direct guidance of a biopsy.
Management
Therapeutic aspiration may be required to palliate breathlessness
but removing more than 1 .5 L at a time is associated with a
small risk of re-expansion pulmonary oedema. An effusion should
never be drained to dryness before establishing a diagnosis,
as biopsy may be precluded until further fluid accumulates.
Treatment of the underlying cause - e.g. heart failure, pneumonia,
pulmonary embolism or subphrenic abscess - will often be
followed by resolution of the effusion. The management of pleural
effusion in pneumonia, tuberculosis and malignancy is dealt
with below.
Empyema
This is a collection of pus in the pleural space, which may be as
thin as serous fluid or so thick that it is impossible to aspirate,
even through a wide-bore needle. Microscopically, neutrophil
leucocytes are present in large numbers. An empyema may involve
the whole pleural space or only part of it (‘loculated’ or ‘encysted’
empyema) and is usually unilateral. It is always secondary to
infection in a neighbouring structure, usually the lung, most
commonly due to the bacterial pneumonias and tuberculosis. Over
40% of patients with community-acquired pneumonia develop
an associated pleural effusion (‘parapneumonic’ effusion) and
about 15% of these become secondarily infected. Other causes
are infection of a haemothorax following trauma or surgery,
oesophageal rupture, and rupture of a subphrenic abscess
through the diaphragm.
Both pleural surfaces are covered with a thick, shaggy,
inflammatory exudate. The pus in the pleural space is often under
considerable pressure, and if the condition is not adequately treated,
pus may rupture into a bronchus, causing a bronchopleural fistula
and pyopneumothorax, or track through the chest wall with the
formation of a subcutaneous abscess or sinus, so-called empyema
necessitans.
Clinical assessment
An empyema should be suspected in patients with pulmonary
infection if there is severe pleuritic chest pain or persisting or
recurrent pyrexia, despite appropriate antibiotic treatment. In
other cases, the primary infection may be so mild that it passes
unrecognised and the first definite clinical features are due to the
17.15 Clinical features of empyema
Systemic features
• Pyrexia, usually high and remittent
• Rigors, sweating, malaise and weight loss
• Polymorphonuclear leucocytosis, high C-reactive protein
Local features
• Pleural pain; breathlessness; cough and sputum, usually because of
underlying lung disease; copious purulent sputum if empyema
ruptures into a bronchus (bronchopleural fistula)
• Clinical signs of pleural effusion
Fig. 17.14 Chest X-ray showing a ‘D’-shaped shadow in the left
mid-zone, consistent with an empyema. In this case, an intercostal
chest drain has been inserted but the loculated collection of pus remains.
empyema itself. Once an empyema has developed, systemic
features are prominent (Box 17.15).
Investigations
Chest X-ray appearances may be indistinguishable from those
of pleural effusion, although pleural adhesions may confine the
empyema to form a ‘D’-shaped shadow against the inside of
the chest wall (Fig. 17.14). When air is present as well as pus
(pyopneumothorax), a horizontal ‘fluid level’ marks the air/liquid
interface. Ultrasound shows the position of the fluid, the extent
of pleural thickening and whether fluid is in a single collection
or multiloculated, containing fibrin and debris (Fig. 17.15). CT
provides information on the pleura, underlying lung parenchyma
and patency of the major bronchi.
Ultrasound or CT is used to identify the optimal site for
aspiration, which is best performed using a wide-bore needle.
If the fluid is thick and turbid pus, empyema is confirmed. Other
features suggesting empyema are a fluid glucose of less than
3.3 mmol/L (60 mg/dL), lactate dehydrogenase (LDH) of more
than 1000 IU/L, or a fluid pH of less than 7.0 (H+ >100 nmol/L).
However, pH measurement should be avoided if pus is thick,
as it damages blood gas machines. The pus is frequently
sterile on culture if antibiotics have already been given. The
distinction between tuberculous and non-tuberculous disease
can be difficult and may require pleural biopsy, histology, culture
and/or a NAAT.
Presenting problems in respiratory disease • 565
Fig. 17.15 Pleural ultrasound showing septation. Courtesy of Dr P.
Sivasothy, Department of Respiratory Medicine, Addenbrooke’s Hospital,
Cambridge.
Management
An empyema will heal only if infection is eradicated and the
empyema space is obliterated, allowing apposition of the visceral
and parietal pleural layers. This can only occur if re-expansion of
the compressed lung is secured at an early stage by removal of
all the pus from the pleural space. When the pus is sufficiently
thin, this is most easily achieved by the insertion of a wide-bore
intercostal tube into the most dependent part of the empyema
space. If the initial aspirate reveals turbid fluid or frank pus, or
if loculations are seen on ultrasound, the tube should be put
on suction (-5 to -10 cmH20) and flushed regularly with 20 ml_
normal saline. If the organism causing the empyema can be
identified, the appropriate antibiotic should be given for 2-4 weeks.
Empirical antibiotic treatment (e.g. intravenous co-amoxiclav or
cefuroxime with metronidazole) should be used if the organism
is unknown. Intrapleural fibrinolytic therapy is of no benefit.
An empyema can often be aborted if these measures are
started early, but if the intercostal tube is not providing adequate
drainage - e.g. when the pus is thick or loculated - surgical
intervention is required to clear the empyema cavity of pus and
break down any adhesions. Surgical ‘decortication’ of the lung
may also be required if gross thickening of the visceral pleura is
preventing re-expansion of the lung. Surgery is also necessary
if a bronchopleural fistula develops.
Despite the widespread availability of antibiotics that are
effective against pneumonia, empyema remains a significant
cause of morbidity and mortality.
Respiratory failure
The term ‘respiratory failure’ is used when pulmonary gas
exchange fails to maintain normal arterial oxygen and carbon
dioxide levels. Its classification into types I and II is defined by
the absence or presence of hypercapnia (raised PaC02).
Pathophysiology
When disease impairs ventilation of part of a lung (e.g. in asthma
or pneumonia), perfusion of that region results in hypoxic and C02-
laden blood entering the pulmonary veins. Increased ventilation of
neighbouring regions of normal lung can increase C02 excretion,
correcting arterial C02 to normal, but cannot augment oxygen
uptake because the haemoglobin flowing through these normal
regions is already fully saturated. Admixture of blood from the
under-ventilated and normal regions thus results in hypoxia with
normocapnia, which is called ‘type I respiratoryfailure’. Diseases
causing this include all those that impair ventilation locally with
sparing of other regions (Box 17.16).
Arterial hypoxia with hypercapnia (type II respiratory failure) is
seen in conditions that cause generalised, severe ventilation-
perfusion mismatch, leaving insufficient normal lung to correct
PaC02, or any disease that reduces total ventilation. The
latter includes not just diseases of the lung but also disorders
affecting any part of the neuromuscular mechanism of ventilation
(Box 17.16).
Management of acute respiratory failure
Prompt diagnosis and management of the underlying cause is
crucial. In type I respiratory failure, high concentrations of oxygen
(40-60% by mask) will usually relieve hypoxia by increasing the
alveolar P02 in poorly ventilated lung units. Occasionally, however
(e.g. severe pneumonia affecting several lobes), mechanical
ventilation may be needed to relieve hypoxia. Patients who need
high concentrations of oxygen for more than a few hours should
receive humidified oxygen.
17.16 How to interpret blood gas abnormalities in respiratory failure
Type I Type II
Hypoxia {Pa02 <8.0 kPa (60 mmHg)) Hypoxia (Pa02 <8.0 kPa (60 mmHg))
Normal or low PaC02 (<6 kPa (45 mmHg)) Raised PaC02 (>6 kPa (45 mmHg))
Acute Chronic Acute Chronic
H+
— >
— >
t
-> or T
Bicarbonate
— >
— >
— >
t
Causes
Acute asthma
Pulmonary oedema
Pneumonia
Lobar collapse
Pneumothorax
Pulmonary embolus
ARDS
C0PD
Lung fibrosis
Lymphangitic carcinomatosis
Right-to-left shunts
Acute severe asthma
Acute exacerbation of C0PD
Upper airway obstruction
Acute neuropathies/paralysis
Narcotic drugs
Primary alveolar hypoventilation
Flail chest injury
C0PD
Sleep apnoea
Kyphoscoliosis
Myopathies/muscular dystrophy
Ankylosing spondylitis
(ARDS = acute respiratory distress syndrome; C0PD
= chronic obstructive pulmonary disease)
566 • RESPIRATORY MEDICINE
Acute type II respiratory failure is an emergency requiring
immediate intervention. It is useful to distinguish between patients
with high ventilatory drive (rapid respiratory rate and accessory
muscle recruitment) who cannot move sufficient air, and those with
reduced or inadequate respiratory effort. In the former, particularly
if inspiratory stridor is present, acute upper airway obstruction
from foreign body inhalation or laryngeal obstruction (angioedema,
carcinoma or vocal cord paralysis) must be considered, as the
Heimlich manoeuvre (p. 625), immediate intubation or emergency
tracheostomy may be life-saving.
More commonly, the problem is in the lungs, with severe
generalised bronchial obstruction from COPD or asthma, acute
respiratory distress syndrome (ARDS) arising from a variety of
insults (p. 198), or occasionally tension pneumothorax (p. 625).
In all such cases, high-concentration (e.g. 60%) oxygen should
be administered, pending a rapid examination of the respiratory
system and measurement of arterial blood gases. Patients with
the trachea deviated away from a silent and resonant hemithorax
are likely to have tension pneumothorax, and air should be
aspirated from the pleural space and a chest drain inserted
as soon as possible. Patients with generalised wheeze, scanty
breath sounds bilaterally or a history of asthma or COPD should
be treated with salbutamol 2.5 mg nebulised with oxygen,
repeated until bronchospasm is relieved. Failure to respond
to initial treatment, declining conscious level and worsening
respiratory acidosis (H+ >50 nmol/L (pH <7. 3), PaC02 >6.6 kPa
(50 mmHg)) on blood gases are all indications that supported
ventilation is required (p. 202).
A small percentage of patients with severe chronic COPD
and type II respiratory failure develop abnormal tolerance to
raised PaC02 and may become dependent on hypoxic drive to
breathe. In these patients only, lower concentrations of oxygen
(24-28% by Venturi mask) should be used to avoid precipitating
worsening respiratory depression (see below). In all cases, regular
monitoring of arterial blood gases is important to assess progress.
Patients with acute type II respiratory failure who have reduced
drive or conscious level may be suffering from sedative poisoning,
C02 narcosis or a primary failure of neurological drive (e.g.
following intracerebral haemorrhage or head injury). History from
a witness may be invaluable, and reversal of specific drugs with
(for example) opiate antagonists is occasionally successful, but
should not delay intubation and supported mechanical ventilation
in appropriate cases.
I Chronic and ‘acute on chronic’ type II
respiratory failure
The most common cause of chronic type II respiratory failure
is severe COPD. Although PaC02 may be persistently raised,
there is no persisting acidaemia because the kidneys retain
bicarbonate, correcting arterial pH to normal. This ‘compensated’
pattern, which may also occur in chronic neuromuscular
disease or kyphoscoliosis, is maintained until there is a further
acute illness (Box 17.16), such as an exacerbation of COPD
that precipitates an episode of ‘acute on chronic’ respiratory
failure, with acidaemia and initial respiratory distress followed
by drowsiness and eventually coma. These patients have lost
their chemosensitivity to elevated PaC02, and so they may
paradoxically depend on hypoxia for respiratory drive and are
at risk of respiratory depression if given high concentrations
of oxygen, e.g. during ambulance transfers or in emergency
departments. Moreover, in contrast to acute severe asthma,
some patients with ‘acute on chronic’ type II respiratory failure
due to COPD may not appear distressed, despite being critically
ill with severe hypoxaemia, hypercapnia and acidaemia. While
the physical signs of C02 retention (delirium, flapping tremor,
bounding pulses and so on) can be helpful if present, they may
not be, so measurement of arterial blood gases is mandatory
in the assessment of initial severity and response to treatment.
Management
The principal aims of treatment in acute on chronic type II
respiratory failure are to achieve a safe Pa02 (>7. 0 kPa (52 mmHg))
without increasing PaC02 and acidosis, while identifying and
treating the precipitating condition. In these patients, it is not
necessary to achieve a normal Pa02; even a small increase will
greatly improve tissue oxygen delivery, since their Pa02 values
are often on the steep part of the oxygen dissociation curve
(see Fig. 10.9, p. 191). The risks of worsening hypercapnia and
coma must be balanced against those of severe hypoxaemia,
which include potentially fatal arrhythmias and hypoxic brain
damage. Immediate treatment is shown in Box 17.17. Patients
who are conscious and have adequate respiratory drive may
benefit from non-invasive ventilation (NIV), which has been shown
to reduce the need for intubation and shorten hospital stay in
acidotic exacerbations of COPD. Patients who are drowsy and
have low respiratory drive require an urgent decision regarding
intubation and ventilation, as this is likely to be the only effective
treatment, even though weaning off the ventilator may be difficult
in severe disease. The decision is challenging, and important
factors to consider include patient and family wishes, presence
of a potentially remediable precipitating condition, prior functional
17.17 Assessment and management of ‘acute on
chronic’ type II respiratory failure
Initial assessment
Patient may not appear distressed, despite being critically ill
• Conscious level (response to commands, ability to cough)
• C02 retention (warm periphery, bounding pulses, flapping tremor)
• Airways obstruction (wheeze, prolonged expiration, hyperinflation,
intercostal indrawing, pursed lips)
• Cor pulmonale (peripheral oedema, raised jugular venous pressure,
hepatomegaly, ascites)
• Background functional status and quality of life
• Signs of precipitating cause (see Box 17.15)
Investigations
• Arterial blood gases (severity of hypoxaemia, hypercapnia,
acidaemia, bicarbonate)
• Chest X-ray
Management
• Maintenance of airway
• Treatment of specific precipitating cause
• Frequent physiotherapy ± pharyngeal suction
• Nebulised bronchodilators
• Controlled oxygen therapy:
Start with 24% Venturi mask
Aim for a Pa02 > 7 kPa (52 mmhlg) (a Pa02 < 5 (37 mmhlg) is
dangerous)
• Antibiotics if evidence of infection
• Diuretics if evidence of fluid overload
Progress
• If PaC02 continues to rise or a safe Pa02 cannot be achieved
without severe hypercapnia and acidaemia, mechanical ventilatory
support may be required
Obstructive pulmonary diseases • 567
capacity and quality of life. The various types of non-invasive
(via a face or nasal mask) or invasive (via an endotracheal tube)
ventilation are detailed on page 202.
Respiratory stimulant drugs, such as doxapram, have been
superseded by intubation and mechanical ventilation in patients
with C02 narcosis.
irradiation are employed to treat obliterative bronchiolitis but late
organ failure remains a significant problem.
The major factor limiting the availability of lung transplantation
is the shortage of donor lungs. To improve organ availability,
techniques to recondition the lungs in vitro after removal from
the donor are being developed.
Home ventilation for chronic respiratory failure
NIV is of great value in the long-term treatment of respiratory
failure due to spinal deformity, neuromuscular disease and central
alveolar hypoventilation. Some patients with advanced lung
disease, e.g. cystic fibrosis, also benefit from NIV for respiratory
failure. In these conditions, type II respiratory failure can develop
slowly and insidiously. Morning headache (due to elevated PaC02)
and fatigue are common symptoms but, in many cases, the
diagnosis is revealed only by sleep studies or morning blood
gas analysis. In the initial stages, ventilation is insufficient for
metabolic needs only during sleep, when there is a physiological
decline in ventilatory drive. Over time, however, C02 retention
becomes chronic, with renal compensation of acidosis. Treatment
by home-based NIV overnight is often sufficient to restore the
daytime PC02 to normal, and to relieve fatigue and headache. In
advanced disease (e.g. muscular dystrophies or cystic fibrosis),
daytime NIV may also be required.
Lung transplantation
Lung transplantation is an established treatment for carefully
selected patients with advanced lung disease unresponsive to
medical treatment (Box 17.18). Single-lung transplantation may
be used for selected patients with advanced emphysema or lung
fibrosis. This is contraindicated in patients with chronic bilateral
pulmonary infection, such as cystic fibrosis and bronchiectasis,
because the transplanted lung is vulnerable to cross-infection in
the context of post-transplant immunosuppression, and for these
individuals bilateral lung transplantation is the standard procedure.
Combined heart-lung transplantation is still occasionally needed
for patients with advanced congenital heart disease, such as
Eisenmenger’s syndrome, and is preferred by some surgeons for
the treatment of primary pulmonary hypertension unresponsive
to medical therapy.
The prognosis following lung transplantation is improving
steadily with modern immunosuppressive drugs: over 50%
10-year survival in some UK centres. Chronic rejection with
obliterative bronchiolitis continues to afflict some recipients,
however. Glucocorticoids are used to manage acute rejection,
but drugs that inhibit cell-mediated immunity specifically, such as
ciclosporin, mycophenolate and tacrolimus (p. 89), are used to
prevent chronic rejection. Azithromycin, statins and total lymphoid
i
17.18 Indications for lung transplantation
Parenchymal lung disease
• Cystic fibrosis
• Langerhans cell histiocytosis
• Emphysema
(p. 613)
• Pulmonary fibrosis
• Lymphangioleiomyomatosis
• Obliterative bronchiolitis
(p. 613)
Pulmonary vascular disease
• Primary pulmonary
• Veno-occlusive disease
hypertension
• Eisenmenger’s syndrome
• Thromboembolic pulmonary
(p. 532)
hypertension
Obstructive pulmonary diseases
Asthma
Asthma is a chronic inflammatory disorder of the airways, in
which many cells and cellular elements play a role. Chronic
inflammation is associated with airway hyper-responsiveness
that leads to recurrent episodes of wheezing, breathlessness,
chest tightness and coughing, particularly at night and in the
early morning. These episodes are usually associated with
widespread but variable airflow obstruction within the lung that
is often reversible, either spontaneously or with treatment.
The prevalence of asthma increased steadily over the latter part
of last century. As asthma affects all age groups, it is one of the
most common and important long-term respiratory conditions in
terms of global years lived with disability (Fig. 17.16).
The development and course of asthma and the response to
treatment are influenced by genetic determinants, while the rapid
rise in prevalence implies that environmental factors are critically
important in the development and expression of the disease. The
potential role of indoor and outdoor allergens, microbial exposure,
diet, vitamins, breastfeeding, tobacco smoke, air pollution and
obesity have been explored but no clear consensus has emerged.
DALYs (per 100000)
Fig. 17.16 The burden of asthma, measured by disability life years
(DALYs) per 100000 population. The burden of asthma is greatest in
children approaching adolescence and the elderly. The burden is similar in
males and females at ages below 30-34 but at older ages the burden is
higher in males. From The Global Asthma Report 2014. Copyright 201 4
The Global Asthma Network.
568 • RESPIRATORY MEDICINE
Increasing concentration of histamine
Fig. 17.17 Airway hyper-reactivity in asthma. This is demonstrated by
bronchial challenge tests with sequentially increasing concentrations of
either histamine, or methacholine or mannitol. The reactivity of the airways
is expressed as the concentration or dose of either chemical required to
produce a specific decrease (usually 20%) in the forced expired volume in
1 second (FEV-j) (PC20 or PD20, respectively).
Pathophysiology
Airway hyper- reactivity (AHR) - the tendency for airways to narrow
excessively in response to triggers that have little or no effect
in normal individuals - is integral to the diagnosis of asthma
and appears to be related, although not exclusively, to airway
inflammation (Fig. 17.17). Other factors likely to be important in
the behaviour of airway smooth muscle include the degree of
airway narrowing and neurogenic mechanisms.
The relationship between atopy (the propensity to produce
IgE) and asthma is well established and in many individuals
there is a clear relationship between sensitisation and allergen
exposure, as demonstrated by skin-prick reactivity or elevated
serum-specific IgE. Common examples of allergens include
house dust mites, pets such as cats and dogs, pests such
as cockroaches, and fungi. Inhalation of an allergen into the
airway is followed by an early and late- phase bronchoconstrictor
response (Fig. 17.18). Allergic mechanisms are also implicated
in some cases of occupational asthma (p. 613).
In cases of aspirin-sensitive asthma, the ingestion of
salicylates results in inhibition of the cyclo-oxygenase enzymes,
preferentially shunting the metabolism of arachidonic acid
through the lipoxygenase pathway with resultant production
of the asthmogenic cysteinyl leukotrienes. In exercise-induced
asthma, hyperventilation results in water loss from the pericellular
lining fluid of the respiratory mucosa, which, in turn, triggers
mediator release. Heat loss from the respiratory mucosa may
also be important.
In persistent asthma, a chronic and complex inflammatory
response ensues, characterised by an influx of numerous
inflammatory cells, the transformation and participation of airway
structural cells, and the secretion of an array of cytokines,
chemokines and growth factors. Examination of the inflammatory
cell profile in induced sputum samples demonstrates that, although
asthma is predominantly characterised by airway eosinophilia,
neutrophilic inflammation predominates in some patients while
in others scant inflammation is observed: so-called ‘pauci-
granulocytic’ asthma.
Peak flow (L/min)
Fig. 17.18 Changes in peak flow following allergen challenge.
A similar biphasic response is observed following a variety of different
challenges. Occasionally, an isolated late response is seen with no early
reaction.
With increasing severity and chronicity of the disease,
remodelling of the airway may occur, leading to fibrosis of the
airway wall, fixed narrowing of the airway and a reduced response
to bronchodilator medication.
Clinical features
Typical symptoms include recurrent episodes of wheezing, chest
tightness, breathlessness and cough. Asthma is commonly
mistaken for a cold or a persistent chest infection (e.g. longer
than 10 days). Classical precipitants include exercise, particularly
in cold weather, exposure to airborne allergens or pollutants,
and viral upper respiratory tract infections. Wheeze apart, there
is often very little to find on examination. An inspection for nasal
polyps and eczema should be performed. Rarely, a vasculitic
rash may suggest eosinophilic granulomatosis with polyangiitis
(formerly known as Churg-Strauss syndrome; p. 1043).
Patients with mild intermittent asthma are usually asymptomatic
between exacerbations. Individuals with persistent asthma report
ongoing breathlessness and wheeze but these are variable, with
symptoms fluctuating over the course of one day, or from day
to day or month to month.
Asthma characteristically displays a diurnal pattern, with
symptoms and lung function being worse in the early morning.
Particularly when poorly controlled, symptoms such as cough
and wheeze disturb sleep. Cough may be the dominant symptom
in some patients, and the lack of wheeze or breathlessness
may lead to a delay in reaching the diagnosis of so-called
‘cough-variant asthma’.
Some patients with asthma have a similar inflammatory
response in the upper airway. Careful enquiry should be made
as to a history of sinusitis, sinus headache, a blocked or runny
nose and loss of sense of smell.
Although the aetiology of asthma is often elusive, an attempt
should be made to identify any agents that may contribute to the
appearance or aggravation of the condition. Particular enquiry
should be made about potential allergens, such as exposure to
a pet cat, guinea pig, rabbit or horse, pest infestation, exposure
to moulds following water damage to a home or building, and
any potential occupational agents (p. 613).
In some circumstances, the appearance of asthma is triggered
by medications. Beta-blockers, even when administered topically
Obstructive pulmonary diseases • 569
as eye drops, may induce bronchospasm, as may aspirin and
other non-steroidal anti-inflammatory drugs (NSAIDs). The classical
aspirin-sensitive patient is female and presents in middle age
with asthma, rhinosinusitis and nasal polyps. Aspirin-sensitive
patients may also report symptoms following alcohol and foods
containing salicylates. Other medications implicated include the
oral contraceptive pill, cholinergic agents and prostaglandin
F2ot. Betel nuts contain arecoline, which is structurally similar to
methacholine and can aggravate asthma. An important minority
of patients develop a particularly severe form of asthma and this
appears to be more common in women. Allergic triggers are
less important and airway neutrophilia predominates.
Diagnosis
The diagnosis of asthma is predominantly clinical and is based
on the combination of the history, lung function and ‘other’ tests,
which allows high, intermediate or low probability of asthma to
emerge. The approach may vary from patient to patient and may
need to be re-evaluated following the introduction of treatment.
Supportive evidence is provided by the demonstration of
variable airflow obstruction, preferably by using spirometry
(Box 17.19) to measure FEV^ and FVC. This identifies the
obstructive defect, defines its severity, and provides a baseline
for bronchodilator reversibility (Fig. 17.19). If spirometry is not
17.19 How to make a diagnosis of asthma
Compatible clinical history plus either/or.
• FEVt >12% (and 200 mL) increase following administration of a
bronchodilator/trial of glucocorticoids. Greater confidence is gained
if the increase is >15% and >400 mL
• >20% diurnal variation on > 3 days in a week for 2 weeks on PEF
diary
• FEVt >15% decrease after 6 mins of exercise
(FEVt = forced expiratory volume in 1 sec; PEF = peak expiratory flow)
Volume
expired (L)
Fig. 17.19 Reversibility test. Forced expiratory manoeuvres before and
20 minutes after inhalation of a p2-adrenoceptor agonist. Note the increase
in forced expiratory volume in 1 second (FEV^ from 1 .0 to 2.5 L.
available, a peak flow meter may be used. Symptomatic patients
should be instructed to record peak flow readings after rising
in the morning and before retiring in the evening. A diurnal
variation in PEF of more than 20% (the lowest values typically
being recorded in the morning) is considered diagnostic, and
the magnitude of variability provides some indication of disease
severity (Fig. 17.20). A trial of glucocorticoids (e.g. 30 mg daily
for 2 weeks) may be useful in establishing the diagnosis, by
demonstrating an improvement in either FEW^ or PEF.
It is not uncommon for patients whose symptoms are
suggestive of asthma to have normal lung function. In these
circumstances, the demonstration of AHR by challenge tests may
be useful to confirm the diagnosis (see Fig. 17.17). AHR has a
high negative predictive value but positive results may be seen
in other conditions, such as COPD, bronchiectasis and cystic
fibrosis. The use of exercise tests is useful when symptoms are
predominantly related to exercise (Fig. 17.21).
The diagnosis may be supported by the presence of atopy
demonstrated by skin-prick tests or measurement of total and
allergen-specific IgE, an FEN0 (a surrogate of eosinophilic airway
inflammation) of >40 parts per billion in a glucocorticoid-naive
adult, or a peripheral blood eosinophilia. Chest X-ray appearances
are often normal but lobar collapse may be seen if mucus occludes
a large bronchus and, if accompanied by the presence of flitting
infiltrates, may suggest that asthma has been complicated by
allergic bronchopulmonary aspergillosis (p. 596). A high-resolution
CT scan (HRCT) may be useful to detect bronchiectasis.
Management
Setting goals
Asthma is a chronic condition but may be controlled with
appropriate treatment in the majority of patients. The goal of
treatment should be to obtain and maintain complete control (Box
1 7.20) but aims may be modified according to the circumstances
Peak flow (L/min)
Fig. 17.20 Serial recordings of peak expiratory flow (PEF) in a
patient with asthma. Note the sharp overnight fall (morning dip)
and subsequent rise during the day. Following the introduction of
glucocorticoids, there is an improvement in PEF rate and reduction of
morning dipping.
570 • RESPIRATORY MEDICINE
1 17.20 Levels of asthma control
Partly controlled (any present
Characteristic
Controlled
in any week)
Uncontrolled
Daytime symptoms
None (< twice/week)
> twice/week ■
Limitations of activities
None
Any
Nocturnal symptoms/awakening
None
Any
> 3 features of partly controlled
Need for rescue/‘reliever’ treatment
None (< twice/week)
> twice/week
asthma present in any week
Lung function (PEF or FEV^
Normal
< 80% predicted or personal best
(if known) on any day ■
Exacerbation
None
> 1/year
1 in any week
(FEV1 = forced expiratory volume in 1 sec; PEF = peak expiratory flow)
FEV1 (L)
Time (minutes)
Fig. 17.21 Exercise-induced asthma. Serial recordings of forced
expiratory volume in 1 second (FEVJ in a patient with bronchial asthma
before and after 6 minutes of strenuous exercise. Note initial rise on
completion of exercise, followed by sudden fall and gradual recovery.
Adequate warm-up exercise or pre-treatment with a p2-adrenoceptor
agonist, nedocromil sodium or a leukotriene antagonist can protect against
exercise-induced symptoms.
and the patient. Unfortunately, surveys consistently demonstrate
that the majority of individuals with asthma report suboptimal
control, perhaps reflecting the poor expectations of patients
and their clinicians.
Whenever possible, patients should be encouraged to take
responsibility for managing their own disease. A full explanation of
the nature of the condition, the relationship between symptoms
and inflammation, the importance of key symptoms such as
nocturnal waking, the different types of medication and, if
appropriate, the use of PEF to guide management decisions
should be given. A variety of tools/questionnaires have been
validated to assist in assessing asthma control. Written action
plans can be helpful in developing self-management skills.
Avoidance of aggravating factors
This is particularly important in the management of occupational
asthma (p. 61 3) but may also be relevant in atopic patients, when
removing or reducing exposure to relevant antigens, such as a
17.21 Asthma in pregnancy
• Clinical course: women with well-controlled asthma usually have
good pregnancy outcomes. Pregnancy in women with more severe
asthma can precipitate worsening control and lead to increased
maternal and neonatal morbidity.
• Labour and delivery: 90% have no symptoms.
• Safety data: good for (32-agonists, inhaled glucocorticoids,
theophyllines, oral prednisolone, and chromones.
• Oral leukotriene receptor antagonists: no evidence that these
harm the fetus and they should not be stopped in women who have
previously demonstrated significant improvement in asthma control
prior to pregnancy.
• Glucocorticoids: women on maintenance prednisolone >7.5 mg/
day should receive hydrocortisone 100 mg 3-4 times daily during
labour.
• Prostaglandin F2a: may induce bronchospasm and should be used
with extreme caution.
• Breastfeeding: use medications as normal.
• Uncontrolled asthma: associated with maternal (hyperemesis,
hypertension, pre-eclampsia, vaginal haemorrhage, complicated
labour) and fetal (intrauterine growth restriction and low birth
weight, preterm birth, increased perinatal mortality, neonatal
hypoxia) complications.
pet, may effect improvement. House dust mite exposure may be
minimised by replacing carpets with floorboards and using mite-
impermeable bedding. So far, improvements in asthma control
following such measures have been difficult to demonstrate. Many
patients are sensitised to several ubiquitous aeroallergens, making
avoidance strategies largely impractical. Measures to reduce
fungal exposure may be applicable in specific circumstances and
medications known to precipitate or aggravate asthma should
be avoided. Smoking cessation (p. 94) is particularly important,
as smoking not only encourages sensitisation but also induces
a relative glucocorticoid resistance in the airway.
The stepwise approach to the management
of asthma
See Figure 17.22.
Step 1 : Occasional use of inhaled short-acting
p2-adrenoreceptor agonist bronchodilators
A variety of different inhaled devices are available and the choice
of device should be guided by patient preference and competence
Obstructive pulmonary diseases • 571
Asthma - suspected
Asthma - diagnosed
Diagnosis and
assessment
Evaluation: • assess symptoms, measure lung function, check inhaler technique and adherence
• adjust dose • update self-management plan • move up and down as appropriate
Consider trials of:
Increasing ICS up to
high dose
Use daily steroid tablet
in the lowest dose
providing adequate
control
Add inhaled LABA to
low-dose ICS (normally
as a combination
inhaler)
If benefit from LABA but
control still inadequate
-continue LABA and
increase ICS to medium
dose
If benefit from LABA but
control still inadequate
-continue LABA and
ICS and consider trial of
other therapy - LTRA,
SR theophylline, LAMA
Addition of a fourth
drug, eg LTRA,
SR theophylline, beta
agonist tablet, LAMA
Maintain high-dose ICS
Consider other
treatments to minimize
use of steroid tablets
Infrequent, short-lived
wheeze
Refer patient for
specialist care
Refer patient for
specialist care
Short-acting |32 agonists as required -consider moving up if using three doses a week or more
Fig. 17.22 Management approach in adults based on asthma control. (ICS = inhaled corticosteroids (glucocorticoids); LABA = long-acting (32-agonist;
LAMA = long-acting muscarinic antagonist; LTRA = leukotriene receptor antagonist; SR = sustained-release) From British Thoracic Society and SIGN
guideline 153: British guideline on the management of asthma (2016).
• Remove the cap and shake the inhaler
• Breathe out gently and place the
mouthpiece into the mouth
• Incline the head backwards to minimise
oropharyngeal deposition
• Simultaneously, begin a slow deep
inspiration, depress the canister and
continue to inhale
• Hold the breath for 1 0 seconds
Fig. 17.23 How to use a metered-dose inhaler.
in its use. The metered-dose inhaler remains the most widely
prescribed (Fig. 17.23).
For patients with mild intermittent asthma (symptoms less
than once a week for 3 months and fewer than two nocturnal
episodes per month), it is usually sufficient to prescribe an inhaled
short-acting (32-agonist, such as salbutamol or terbutaline, to be
used as required. However, many patients (and their physicians)
under-estimate the severity of asthma. A history of a severe
exacerbation should lead to a step-up in treatment.
Step 2: Introduction of regular preventer therapy
Regular anti-inflammatory therapy (preferably inhaled
glucocorticoids (ICS), such as beclometasone, budesonide
(BUD), fluticasone, mometasone or ciclesonide) should be started
in addition to inhaled (32-agonists taken on an as-required basis
for any patient who:
• has experienced an exacerbation of asthma in the last
2 years
• uses inhaled p2-agonists three times a week or more
• reports symptoms three times a week or more
• is awakened by asthma one night per week.
For adults, a reasonable starting dose is 400 pg beclometasone
dipropionate (BDP) or equivalent per day in adults, although
higher doses may be required in smokers. Alternative but much
less effective preventive agents include chromones, leukotriene
receptor antagonists and theophyllines.
Step 3: Add-on therapy
If a patient remains poorly controlled despite regular use of an
inhaled glucocorticoid, a thorough review should be undertaken of
adherence, inhaler technique and ongoing exposure to modifiable
aggravating factors. A further increase in the dose of inhaled
glucocorticoid may benefit some patients but, in general, add-on
therapy should be considered in adults taking 800 pg/day BDP
(or equivalent).
The addition of a long-acting (32-agonist (LABA) to an inhaled
glucocorticoid provides more effective asthma control compared
with increasing the dose of inhaled glucocorticoid alone. Fixed-
combination inhalers of glucocorticoids and LABAs have been
developed; these are more convenient, increase adherence and
prevent patients using a LABA as monotherapy - the latter may
be accompanied by an increased risk of life-threatening attacks
572 • RESPIRATORY MEDICINE
or asthma death. The onset of action of formoterol is similar to
that of salbutamol such that, in carefully selected patients, a
fixed combination of budesonide and formoterol may be used
as both rescue and maintenance therapy.
Oral leukotriene receptor antagonists (e.g. montelukast 10 mg
daily) are generally less effective than U\BAs as add-on therapy
but may facilitate a reduction in the dose of inhaled glucocorticoid
and control exacerbations.
Step 4: Poor control on moderate dose of inhaled glucocorticoid
and add-on therapy: addition of a fourth drug
In adults, the dose of inhaled glucocorticoid may be increased to
2000 pig BDP/BUD (or equivalent) daily. A nasal glucocorticoid
preparation should be used in patients with prominent upper
airway symptoms. Leukotriene receptor antagonists, long-acting
antimuscarinic agents, theophyllines or a slow-release p2-agonist
may be considered. If the trial of add-on therapy is ineffective,
it should be discontinued.
Step 5: Continuous or frequent use of oral glucocorticoids
At this stage, prednisolone therapy (usually administered as a
single daily dose in the morning) should be prescribed in the
lowest amount necessary to control symptoms. Patients who
are on long-term glucocorticoid tablets (>3 months) or are
receiving more than three or four courses per year will be at
risk of systemic side-effects (p. 670). The risk of osteoporosis in
this group can be reduced by giving bisphosphonates (p. 1047).
In patients who continue to experience symptoms and asthma
exacerbation and demonstrate impaired lung function despite
step 5 treatment, omalizumab, a monoclonal antibody directed
against IgE, should be considered for those with a prominent
atopic phenotype, and mepolizumab, a monoclonal antibody that
blocks the binding of IL-5 to its receptor on eosinophils, should
be considered in those with eosinophilic-mediated disease. The
use of immunosuppressants, such as methotrexate, ciclosporin or
oral gold, is less common nowadays, as the response is variable
and the limited benefits may be easily offset by side-effects.
Step-down therapy
Once asthma control is established, the dose of inhaled (or
oral) glucocorticoid should be titrated to the lowest dose at
which effective control of asthma is maintained. Decreasing the
dose of glucocorticoid by around 25-50% every 3 months is a
reasonable strategy for most patients.
Exacerbations of asthma
The course of asthma may be punctuated by exacerbations
with increased symptoms, deterioration in lung function, and an
increase in airway inflammation. Exacerbations are most commonly
precipitated by viral infections but moulds (Altemaria and
Cladosporium), pollens (particularly following thunderstorms) and
air pollution are also implicated. Most attacks are characterised
by a gradual deterioration over several hours to days but some
appear to occur with little or no warning: so-called brittle asthma.
An important minority of patients appear to have a blunted
perception of airway narrowing and fail to appreciate the early
signs of deterioration.
Management of mild to moderate exacerbations
Doubling the dose of inhaled glucocorticoids does not prevent an
impending exacerbation. Short courses of ‘rescue’ glucocorticoids
(prednisolone 30-60 mg daily) are therefore often required to
regain control. Tapering of the dose to withdraw treatment is
not necessary, unless glucocorticoid has been given for more
than 3 weeks.
Indications for ‘rescue’ courses include:
• symptoms and PEF progressively worsening day by day,
with a fall of PEF below 60% of the patient’s personal best
recording
• onset or worsening of sleep disturbance by asthma
• persistence of morning symptoms until midday
• progressively diminishing response to an inhaled
bronchodilator
• symptoms that are sufficiently severe to require treatment
with nebulised or injected bronchodilators.
Management of acute severe asthma
Box 17.22 highlights the immediate assessment requirements
in acute asthma. Measurement of PEF is mandatory, unless
the patient is too ill to cooperate, and is most easily interpreted
when expressed as a percentage of the predicted normal
or of the previous best value obtained on optimal treatment
(Fig. 17.24). Arterial blood gas analysis is essential to determine
the PaC02, a normal or elevated level being particularly dangerous.
A chest X-ray is not immediately necessary, unless pneumothorax
is suspected.
Treatment includes the following measures:
• Oxygen. High concentrations (humidified if possible) should
be administered to maintain the oxygen saturation above
92% in adults. The presence of a high PaC02 should not
be taken as an indication to reduce oxygen concentration
but as a warning sign of a severe or life-threatening attack.
Failure to achieve appropriate oxygenation is an indication
for assisted ventilation.
• High doses of inhaled bronchodilators. Short-acting
p2-agonists are the agent of choice. In hospital, they are
most conveniently given via a nebuliser driven by oxygen,
but delivery of multiple doses of salbutamol via a
metered-dose inhaler through a spacer device provides
equivalent bronchodilatation and can be used in primary
care. Ipratropium bromide provides further bronchodilator
therapy and should be added to salbutamol in acute
severe or life-threatening attacks.
17.22 Immediate assessment of
acute severe asthma
Acute severe asthma
• PEF 33-50% predicted (<200 IVmin)
• Heart rate >110 beats/m in
• Respiratory rate >25 breaths/min
• Inability to complete sentences in 1 breath
Life-threatening features
• PEF <33% predicted
(<100 L/min)
• Sp02 <92% or Pa02 <8 kPa
(60 mmHg) (especially if being
treated with oxygen)
• Normal or raised PaC02
• Silent chest
Near-fatal asthma
• Raised PaC02 and/or requiring mechanical ventilation with raised
inflation pressures
(PEF = peak expiratory flow)
• Cyanosis
• Feeble respiratory effort
• Bradycardia or arrhythmias
• Hypotension
• Exhaustion
• Delirium
• Coma
Obstructive pulmonary diseases • 573
MEASURE PEAK EXPIRATORY FLOW
Convert PEF to % best or % predicted
Life-threatening/acute
_ severe _
Arterial blood gas
Nebulised salbutamol 5 mg or
terbutaline 2.5 mg
6-12 times daily or as required
Oxygen-high-flow/60%
Prednisolone 40 mg orally
(or hydrocortisone 200 mg IV)
Moderate
’ r \
Intravenous access, chest X-ray,
plasma theophylline level, plasma K+
Admit |
• Administer repeat salbutamol
5 mg + ipratropium bromide 500 jug
by oxygen-driven nebuliser
• Consider continuous salbutamol
nebuliser 5-10 mg/hr
• Consider intravenous magnesium
sulphate 1 .2-2.0 g over 20 mins, or
aminophylline 5 mg/kg loading dose
over 20 mins followed by a
continuous infusion at 1 mg/kg/hr
• Correct fluid and electrolytes
(especially K+)
Arterial blood gas
Nebulised salbutamol 5 mg or
terbutaline 2.5 mg
Oxygen -high-flow/60%
Prednisolone 40 mg orally
75% (76%
Wait 30 mins^
_A _
Measure PEF
PEF < 60%
predicted
PEF > 60%
predicted
Mild
100%)
Did patient receive nebulised
therapy before PEF recorded?
(Ytes) (No)
Usual inh
bronchod
I inhaled
bronchodilator
Wait 60 mins
Home I
• Usual treatment
• Return immediately if worse
• Appointment with GP within
48 hours
Home
• Check with senior medical staff
• Prednisolone 40 mg daily for 5 days
• Start or double inhaled
glucocorticoids
• Return immediately if worse
• Appointment with GP within
48 hours
Fig. 17.24 Immediate treatment of patients with acute severe asthma.
• Systemic glucocorticoids. These reduce the inflammatory
response and hasten the resolution of an exacerbation.
They should be administered to all patients with an acute
severe attack. They can usually be administered orally as
prednisolone but intravenous hydrocortisone may be used
in patients who are vomiting or unable to swallow.
There is no evidence base for the use of intravenous fluids
but many patients are dehydrated due to high insensible water
loss and will probably benefit. Potassium supplements may be
necessary, as repeated doses of salbutamol can lower serum
potassium.
If patients fail to improve, a number of further options may
be considered. Intravenous magnesium may provide additional
bronchodilatation in patients whose presenting PEF is below
30% predicted. Some patients appear to benefit from the
use of intravenous aminophylline but cardiac monitoring is
recommended.
PEF should be recorded every 15-30 minutes and then every
4-6 hours. Pulse oximetry should ensure that Sa02 remains
above 92%, but repeat arterial blood gases are necessary if the
initial PaC02 measurements were normal or raised, the Pa02 was
below 8 kPa (60 mmHg) or the patient deteriorates. Box 17.23
lists the indications for endotracheal intubation and intermittent
positive pressure ventilation (IPPV).
Prognosis
The outcome from acute severe asthma is generally good but
a considerable number of deaths occur in young people and
many are preventable. Failure to recognise the severity of an
attack, on the part of either the assessing physician or the
17.23 Indications for assisted ventilation
in acute severe asthma
• Coma
• Respiratory arrest
• Deterioration of arterial blood gas tensions despite optimal therapy:
Pa02 <8 kPa (60 mmHg) and falling
PaC02 >6 kPa (45 mmHg) and rising
pH low and falling (H+ high and rising)
• Exhaustion, delirium, drowsiness
patient, contributes to delay in delivering appropriate therapy
and to under-treatment.
Prior to discharge, patients should be stable on discharge
medication (nebulised therapy should have been discontinued
for at least 24 hours) and the PEF should have reached 75%
of predicted or personal best. The acute attack should prompt
a look for and avoidance of any trigger factors, the delivery of
asthma education and the provision of a written self- management
plan. The patient should be offered an appointment with a GP or
asthma nurse within 2 working days of discharge, and follow-up
at a specialist hospital clinic within a month.
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is defined as a
preventable and treatable disease characterised by persistent
airflow limitation that is usually progressive and associated with
an enhanced chronic inflammatory response in the airways
574 • RESPIRATORY MEDICINE
and the lung to noxious particles or gases. Exacerbations and
co-morbidities contribute to the overall severity in individual
patients. Related diagnoses include chronic bronchitis (cough
and sputum for at least 3 consecutive months in each of 2
consecutive years) and emphysema (abnormal permanent
enlargement of the airspaces distal to the terminal bronchioles,
accompanied by destruction of their walls and without obvious
fibrosis). Extrapulmonary effects include weight loss and skeletal
muscle dysfunction (Fig. 17.25). Commonly associated co-morbid
conditions include cardiovascular disease, cerebrovascular
disease, the metabolic syndrome (p. 730), osteoporosis,
depression and lung cancer.
The prevalence of COPD is directly related to the prevalence
of risk factors in the community, such as tobacco smoking,
coal dust exposure or the use of biomass fuels, and to the age
of the population being studied. Those with the most severe
disease bear the greatest personal impact of the condition and
contribute to its significant social and economic consequences
on society. It is predicted that, by 2030, COPD will represent
the seventh leading cause of disability and fourth most common
cause of death worldwide.
Risk factors are shown in Box 17.24. Cigarette smoking
represents the most significant risk factor for COPD and the
risk of developing the condition relates to both the amount and
duration of smoking. It is unusual to develop COPD with less
than 1 0 pack years (1 pack year = 20 cigarettes/day/year) and
not all smokers develop the condition, suggesting that individual
susceptibility factors are important.
Pathophysiology
COPD has both pulmonary and systemic components (Fig. 1 7.25).
The presence of airflow limitation combined with premature
airway closure leads to gas trapping and hyperinflation, adversely
affecting pulmonary and chest wall compliance. Pulmonary
hyperinflation also results, which flattens the diaphragmatic
muscles and leads to an increasingly horizontal alignment of
the intercostal muscles, placing the respiratory muscles at a
mechanical disadvantage. The work of breathing is therefore
markedly increased - first on exercise, when the time for expiration
is further shortened, but then, as the disease advances, at rest.
17.24 Risk factors for development of chronic
obstructive pulmonary disease
Environmental factors
• Tobacco smoke: accounts for 95% of cases in the UK
• Indoor air pollution: cooking with biomass fuels in confined areas in
developing countries
• Occupational exposures, such as coal dust, silica and cadmium
• Low birth weight: may reduce maximally attained lung function in
young adult life
• Lung growth: childhood infections or maternal smoking may affect
growth of lung during childhood, resulting in a lower maximally
attained lung function in adult life
• Infections: recurrent infection may accelerate decline in FEV-i;
persistence of adenovirus in lung tissue may alter local
inflammatory response, predisposing to lung damage; HIV infection
is associated with emphysema
• Low socioeconomic status
• Cannabis smoking
Host factors
• Genetic factors: -antitrypsin deficiency; other COPD susceptibility
genes are likely to be identified
• Airway hyper- reactivity
(FEV-! = forced expiratory volume in 1 sec)
/ \
Enlargement of mucus-secreting glands
and increase in number of goblet cells,
accompanied by an inflammatory cell
infiltrate, result in increased sputum
production leading to chronic bronchitis
\ _ J
/ I
Pulmonary vascular
remodelling and impaired
cardiac performance
V _ ' _
Loss of elastic tissue, inflammation and
fibrosis in airway wall result in premature
airway closure, gas trapping and dynamic
hyperinflation leading to changes in
pulmonary and chest wall compliance
Unopposed action of
proteases and oxidants
leading to destruction of
alveoli and appearance
of emphysema
Pulmonary
Systemic
Muscular weakness
reflecting deconditioning
and cellular changes
in skeletal muscles
Increased
circulating
inflammatory
markers
Impaired salt and
water excretion
leading to
^ peripheral oedema y
Fig. 17.25 The pulmonary and systemic features of chronic obstructive pulmonary disease.
Obstructive pulmonary diseases • 575
Fig. 17.26 The pathology of emphysema. [A] Normal lung.
\W\ Emphysematous lung, showing gross loss of the normal surface area
available for gas exchange. B, Courtesy of the British Lung Foundation.
Emphysema (Fig. 17.26) may be classified by the pattern of
the enlarged airspaces: centriacinar, panacinar and paraseptal.
Bullae form in some individuals. This results in impaired gas
exchange and respiratory failure.
Clinical features
COPD should be suspected in any patient over the age of
40 years who presents with symptoms of chronic bronchitis
and/or breathlessness. Depending on the presentation, important
differential diagnoses include chronic asthma, tuberculosis,
bronchiectasis and congestive cardiac failure.
Cough and associated sputum production are usually the first
symptoms, and are often referred to as a ‘smoker’s cough’.
Haemoptysis may complicate exacerbations of COPD but should
not be attributed to COPD without thorough investigation.
Breathlessness usually prompts presentation to a health
professional. The level should be quantified for future reference,
often by documenting what the patient can manage before
stopping; scales such as the modified Medical Research
Council (MRC) dyspnoea scale may be useful (Box 17.25). In
advanced disease, enquiry should be made as to the presence
of oedema (which may be seen for the first time during an
exacerbation) and morning headaches (which may suggest
hypercapnia).
Physical signs (p. 546) are non-specific, correlate poorly
with lung function, and are seldom obvious until the disease
is advanced. Breath sounds are typically quiet; crackles may
accompany infection but, if persistent, raise the possibility of
bronchiectasis. Finger clubbing is not a feature of COPD and
should trigger further investigation for lung cancer or fibrosis.
Right heart failure may develop in patients with advanced COPD,
i
17.25 Modified Medical Research Council (MRC)
dyspnoea scale
Grade
Degree of breathlessness related to activities
0
No breathlessness, except with strenuous exercise
1
Breathlessness when hurrying on the level or walking up a
slight hill
2
Walks slower than contemporaries on level ground because
of breathlessness or has to stop for breath when walking at
own pace
3
Stops for breath after walking about 1 00 m or after a few
minutes on level ground
4
Too breathless to leave the house, or breathless when
dressing or undressing
particularly if there is coexisting sleep apnoea or thromboembolic
disease (‘cor pulmonale’). However, even in the absence of heart
failure, COPD patients often have pitting oedema from salt and
water retention caused by renal hypoxia and hypercapnia. The
term ‘cor pulmonale’ is a misnomer in such patients, as they
do not have heart failure. Fatigue, anorexia and weight loss may
point to the development of lung cancer or tuberculosis, but are
common in patients with severe COPD and the body mass index
(BMI) is of prognostic significance. Depression and anxiety are
also common and contribute to morbidity.
Two classical phenotypes have been described: ‘pink puffers’
and ‘blue bloaters’. The former are typically thin and breathless,
and maintain a normal PaC02 until the late stage of disease.
The latter develop (or tolerate) hypercapnia earlier and may
develop oedema and secondary polycythaemia. In practice,
these phenotypes often overlap.
Investigations
Although there are no reliable radiographic signs that correlate
with the severity of airflow limitation, a chest X-ray is essential
to identify alternative diagnoses such as cardiac failure, other
complications of smoking such as lung cancer, and the presence
of bullae. A blood count is useful to exclude anaemia or document
polycythaemia, and in younger patients with predominantly basal
emphysema oq -antitrypsin should be assayed.
The diagnosis requires objective demonstration of airflow
obstruction by spirometry and is established when the post-
bronchodilator FEV^FVC is <70%. The severity of COPD may be
defined in relation to the post-bronchodilator FE\/^ (Box 1 7.26).
Measurement of lung volumes provides an assessment of
hyperinflation. This is generally performed by helium dilution
technique (p. 515); however, in patients with severe COPD, and
in particular large bullae, body plethysmography is preferred
because the use of helium may under-estimate lung volumes.
The presence of emphysema is suggested by a low gas transfer
(p. 515). Exercise tests provide an objective assessment of
exercise tolerance and provide a baseline on which to judge the
response to bronchodilator therapy or rehabilitation programmes;
they may also be valuable when assessing prognosis. Pulse
oximetry may prompt referral for a domiciliary oxygen assessment
if less than 93%.
The assessment of health status by the St George’s Respiratory
Questionnaire (SGRQ) is commonly used for research. In practice,
the COPD Assessment Test and the COPD Control Questionnaire
are easier to administer. HRCT is likely to play an increasing
role in the assessment of COPD, as it allows the detection,
576 • RESPIRATORY MEDICINE
17.26 Spirometric classification of COPD severity
based on post-bronchodilator FEV,
Severity of airflow obstruction
post-bronchodilator
NICE Clinical
PD FEV,/
FVC
FEV/o
predicted
ATS/ERS
(2004)
GOLD
(2008)
Guideline
101 (2010)
<0.7
>80%
Mild
Stage 1 -
mild
Stage 1 -
mild1
<0.7
50-79%
Moderate
Stage II -
moderate
Stage II -
moderate
<0.7
30-49%
Severe
Stage III -
severe
Stage III -
severe
<0.7
<30%
Very
severe
Stage IV -
very severe2
Stage IV -
very severe2
1Mild COPD should not be diagnosed on lung function alone if the patient is
asymptomatic. 20r FE Vt <50% with respiratory failure.
(ATS/ERS = American Thoracic Society/European Respiratory Journal; FE \l^ =
forced expiratory volume in 1 sec; GOLD = Global Initiative for Chronic
Obstructive Lung Disease; PD = post-bronchodilator)
Adapted from National Institute for Health and Care Excellence (NICE) CGI 01
- Chronic obstructive pulmonary disease in over 16s: diagnosis and
management; 2010.
Fig. 17.27 Gross emphysema. High-resolution computed tomogram
showing emphysema, most evident in the right lower lobe.
characterisation and quantification of emphysema (Fig. 17.27)
and is more sensitive than the chest X-ray at detecting bullae. It
is also used to guide lung volume reduction surgery.
Assessment of severity
Stopped
smoking
at 45
Stopped
smoking
at 65
Fig. 17.28 Model of annual decline in FEVt with accelerated decline
in susceptible smokers. When smoking is stopped, subsequent loss is
similar to that in healthy non-smokers. (FEV-i = forced expiratory volume in
1 second)
smokers, and cessation (p. 94) remains the only strategy that
impacts favourably on the natural history of COPD. Complete
cessation is accompanied by an improvement in lung function
and deceleration in the rate of FENA decline (Fig. 17.28). In
regions where the indoor burning of biomass fuels is important,
the introduction of non-smoking cooking devices or alternative
fuels should be encouraged.
Bronchodilators
Bronchodilator therapy is central to the management of
breathlessness. The inhaled route is preferred and a number of
different agents delivered by a variety of devices are available.
Choice should be informed by patient preference and inhaler
assessment. Short-acting bronchodilators may be used for
patients with mild disease but longer-acting bronchodilators
are usually more appropriate for those with moderate to severe
disease. Significant improvements in breathlessness may be
reported despite minimal changes in FEV-,, probably reflecting
improvements in lung emptying that reduce dynamic hyperinflation
and ease the work of breathing. Oral bronchodilator therapy,
such as theophylline preparations, may be contemplated in
patients who cannot use inhaled devices efficiently but their
use may be limited by side-effects, unpredictable metabolism
and drug interactions; hence the requirement to monitor plasma
levels. Orally active, highly selective phosphodiesterase inhibitors
remain under appraisal.
The severity of COPD has traditionally been defined in relation to
the FEV% predicted. However, assessing the impact of COPD
on individual patients in terms of the symptoms and limitations in
activity that they experience and whether they suffer frequent or
significant exacerbations may provide a more clinically relevant
assessment and help guide management.
Management
The management of COPD focuses on improving breathlessness,
reducing the frequency and severity of exacerbations, and
improving health status and prognosis.
Reducing exposure to noxious particles and gases
Sustained smoking cessation in mild to moderate COPD is
accompanied by a reduced decline in FENA compared to persistent
Combined inhaled glucocorticoids and bronchodilators
The fixed combination of an inhaled glucocorticoid and a LABA
improves lung function, reduces the frequency and severity of
exacerbations and improves quality of life. These advantages may
be accompanied by an increased risk of pneumonia, particularly
in the elderly. LABA/inhaled glucocorticoid combinations are
frequently given with a long-acting muscarinic antagonist (LAMA).
LAMAs should be used with caution in patients with significant
heart disease or a history of urinary retention.
Oral glucocorticoids
Oral glucocorticoids are useful during exacerbations but
maintenance therapy contributes to osteoporosis and impaired
skeletal muscle function, and should be avoided. Oral
Obstructive pulmonary diseases • 577
glucocorticoid trials assist in the diagnosis of asthma but do not
predict response to inhaled glucocorticoids in COPD.
Pulmonary rehabilitation
Exercise should be encouraged at all stages and patients
reassured that breathlessness, while distressing, is not dangerous.
Multidisciplinary programmes that incorporate physical training,
disease education and nutritional counselling reduce symptoms,
improve health status and enhance confidence. Most programmes
include two to three sessions per week, last between 6 and
1 2 weeks, and are accompanied by demonstrable and sustained
improvements in exercise tolerance and health status.
Oxygen therapy
Long-term domiciliary oxygen therapy (LTOT) improves survival in
selected patients with COPD complicated by severe hypoxaemia
(arterial Pa02 <7.3 kPa (55 mmHg); Box 17.27). It is most
conveniently provided by an oxygen concentrator and patients
should be instructed to use oxygen for a minimum of 15 hours/
day; greater benefits are seen in those who use it for more than
20 hours/day. The aim of therapy is to increase the Pa02 to at
least 8 kPa (60 mmHg) or Sa02 to at least 90%. Ambulatory
oxygen therapy should be considered in patients who desaturate
on exercise and show objective improvement in exercise capacity
and/or dyspnoea with oxygen. Oxygen flow rates should be
adjusted to maintain Sa02 above 90%.
Surgical intervention
Bullectomy may be considered when large bullae compress
surrounding normal lung tissue. Patients with predominantly upper
lobe emphysema, preserved gas transfer and no evidence of
pulmonary hypertension may benefit from lung volume reduction
surgery (LVRS), in which peripheral emphysematous lung tissue is
resected with the aim of reducing hyperinflation and decreasing the
work of breathing. Both bullectomy and LVRS can be performed
thorascopically, minimising morbidity. Lung transplantation may
benefit carefully selected patients with advanced disease (p. 567).
Other measures
Patients with COPD should be offered an annual influenza
vaccination and, as appropriate, pneumococcal vaccination.
Obesity, poor nutrition, depression and social isolation should
be identified and, if possible, improved. Mucolytic agents are
occasionally used but evidence of benefit is limited.
Palliative care
Addressing end-of-life needs is an important, yet often ignored,
aspect of care in advanced disease. Morphine preparations may
be used for palliation of breathlessness in advanced disease and
benzodiazepines in low dose may reduce anxiety. Decisions
regarding resuscitation should be addressed in advance of
critical illness.
17.27 Prescription of long-term oxygen therapy
in COPD
1 17.28 Calculation of the BODE index
Points on BODE index
Variable
0
1 2
3
FEV,
>65
50-64 36-49
<35
Distance walked in
6 mins (m)
>350
250-349 150-249
<149
MRC dyspnoea scale*
0-1
2 3
4
Body mass index
>21
<21
A patient with a BODE score of 0-2 has a mortality rate of around
1 0% at 52 months, whereas a patient with a BODE score of 7-1 0 has
a mortality rate of around 80% at 52 months.
*See Box 17.25.
(BODE - see text; FE^ =
forced expiratory volume in 1 sec)
Prognosis
COPD has a variable natural history but is usually progressive.
The prognosis is inversely related to age and directly related
to the post-bronchodilator FEV^ Additional poor prognostic
indicators include weight loss and pulmonary hypertension.
A composite score (BODE), comprising the body mass index
(B), the degree of airflow obstruction (O), a measurement of
dyspnoea (D) and exercise capacity (E) may assist in predicting
death from respiratory and other causes (Box 1 7.28). Respiratory
failure, cardiac disease and lung cancer represent common
modes of death.
Acute exacerbations of COPD
Acute exacerbations of COPD are characterised by an increase
in symptoms and deterioration in lung function and health status.
They become more frequent as the disease progresses and are
usually triggered by bacteria, viruses or a change in air quality.
They may be accompanied by the development of respiratory
failure and/or fluid retention and represent an important cause
of death.
Many patients can be managed at home with the use
of increased bronchodilator therapy, a short course of oral
glucocorticoids and, if appropriate, antibiotics. The presence of
cyanosis, peripheral oedema or an alteration in consciousness
should prompt referral to hospital. In other patients, consideration
of comorbidity and social circumstances may influence decisions
regarding hospital admission.
Oxygen therapy
In patients with an exacerbation of severe COPD, high
concentrations of oxygen may cause respiratory depression
and worsening acidosis (p. 566). Controlled oxygen at 24%
or 28% should be used with the aim of maintaining a Pa02 of
more than 8 kPa (60 mmHg) (or an Sa02 of more than 90%)
without worsening acidosis.
Bronchodilators
Nebulised short-acting p2-agonists combined with an
anticholinergic agent (e.g. salbutamol and ipratropium) should
be administered. With careful supervision it is usually safe to
drive nebulisers with oxygen, but if concern exists regarding
oxygen sensitivity, they may be driven by compressed air and
supplemental oxygen delivered by nasal cannula.
Arterial blood gases are measured in clinically stable patients on
optimal medical therapy on at least two occasions 3 weeks apart:
• Pa02 <7.3 kPa (55 mmHg) irrespective of PaC02 and FE \l^ <1.5 L
• Pa02 7.3-8 kPa (55-60 mmHg) plus pulmonary hypertension,
peripheral oedema or nocturnal hypoxaemia
• the patient has stopped smoking
Use at least 15 hrs/day at 2-4 IVmin to achieve a Pa02 >8 kPa
(60 mmHg) without unacceptable rise in PaC02
578 • RESPIRATORY MEDICINE
Glucocorticoids
Oral prednisolone reduces symptoms and improves lung function.
Doses of 30 mg for 1 0 days are currently recommended but
shorter courses may be acceptable. Prophylaxis against
osteoporosis should be considered in patients who receive
repeated courses of glucocorticoids (p. 670).
Antibiotic therapy
The role of bacteria in exacerbations remains controversial and
there is little evidence for the routine administration of antibiotics.
They are currently recommended for patients reporting an increase
in sputum purulence, sputum volume or breathlessness. In most
cases simple regimens are advised, such as an aminopenicillin,
a tetracycline or a macrolide. Co-amoxiclav is only required in
regions where (3-lactamase-producing organisms are known
to be common.
Non-invasive ventilation
Non-invasive ventilation is safe and effective in patients with an
acute exacerbation of COPD complicated by mild to moderate
respiratory acidosis (H+ >45nmol/L, pH <7.3 5), and should be
considered early in the course of respiratory failure to reduce
the need for endotracheal intubation, treatment failure and
mortality. It is not useful in patients who cannot protect their
airway. Mechanical ventilation may be contemplated when there
is a reversible cause for deterioration (e.g. pneumonia) or when
no prior history of respiratory failure has been noted.
Additional therapy
Exacerbations may be accompanied by the development
of peripheral oedema; this usually responds to diuretics.
There has been a vogue for using an infusion of intravenous
aminophylline but evidence for benefit is limited and attention
must be paid to the risk of inducing arrhythmias and drug
interactions. The use of the respiratory stimulant doxapram has
been largely superseded by the development of NIV but it may
be useful for a limited period in selected patients with a low
respiratory rate.
• Asthma: may appear de novo in old age, so airflow obstruction
should not always be assumed to be due to COPD.
• Peak expiratory flow recordings: older people with poor vision
have difficulty reading PEF meters.
• Perception of bronchoconstriction: impaired by age, so an older
patient’s description of symptoms may not be a reliable indicator of
severity.
• Stopping smoking: the benefits on the rate of loss of lung function
decline with age but remain valuable up to the age of 80.
• Metered-dose inhalers: many older people cannot use these
because of difficulty coordinating and triggering the device. Even
mild cognitive impairment virtually precludes their use. Frequent
demonstration and re-instruction in the use of all devices are
required.
• Mortality rates for acute asthma: higher in old age, partly
because patients under-estimate the severity of bronchoconstriction
and also develop a lower degree of tachycardia and pulsus
paradoxus for the same degree of bronchoconstriction.
• Treatment decisions: advanced age in itself is not a barrier to
intensive care or mechanical ventilation in an acute episode of
asthma or COPD, but this decision may be difficult and should be
shared with the patient (if possible), the relatives and the GP.
Discharge
Discharge from hospital may be contemplated once patients are
clinically stable on their usual maintenance medication. Hospital
at-home teams may provide short-term nebuliser loan, improving
discharge rates and providing additional support for the patient.
Bronchiectasis
Bronchiectasis means abnormal dilatation of the bronchi. Chronic
suppurative airway infection with sputum production, progressive
scarring and lung damage occur, whatever the cause.
Aetiology and pathology
Bronchiectasis may result from a congenital defect affecting
airway ion transport or ciliary function, such as cystic fibrosis
(see below), or may be acquired secondary to damage to the
airways by a destructive infection, inhaled toxin or foreign body.
The result is chronic inflammation and infection in the airways.
Box 17.30 shows the common causes, of which tuberculosis
is the most common worldwide.
Localised bronchiectasis may occur due to the accumulation
of pus beyond an obstructing bronchial lesion, such as enlarged
tuberculous hilar lymph nodes, a bronchial tumour or an inhaled
foreign body (e.g. an aspirated peanut).
The bronchiectatic cavities may be lined by granulation tissue,
squamous epithelium or normal ciliated epithelium. There may also
be inflammatory changes in the deeper layers of the bronchial wall
and hypertrophy of the bronchial arteries. Chronic inflammatory
and fibrotic changes are usually found in the surrounding lung
tissue, resulting in progressive destruction of the normal lung
architecture in advanced cases.
Clinical features
The symptoms are shown in Box 17.31 .
Physical signs in the chest may be unilateral or bilateral. If the
bronchiectatic airways do not contain secretions and there is no
associated lobar collapse, there are no abnormal physical signs.
When there are large amounts of sputum in the bronchiectatic
spaces, numerous coarse crackles may be heard over the affected
areas. Collapse with retained secretions blocking a proximal
bronchus may lead to locally diminished breath sounds, while
advanced disease may cause scarring and overlying bronchial
i
Congenital
• Cystic fibrosis
• Ciliary dysfunction syndromes:
Primary ciliary dyskinesia (immotile cilia syndrome)
Kartagener’s syndrome (sinusitis and transposition of the viscera)
• Primary hypogammaglobulinaemia (p. 79)
Acquired: children
• Severe infections in infancy (especially whooping cough, measles)
• Primary tuberculosis
• Inhaled foreign body
Acquired: adults
• Suppurative pneumonia
• Pulmonary tuberculosis
• Allergic bronchopulmonary aspergillosis complicating asthma
(p. 596)
• Bronchial tumours
17.29 Obstructive pulmonary disease in old age
17.30 Causes of bronchiectasis
Obstructive pulmonary diseases • 579
i
Fig. 17.29 Computed tomogram of bronchiectasis. Extensive dilatation
of the bronchi, with thickened walls (arrows) in both lower lobes.
breathing. Acute haemoptysis is an important complication of
bronchiectasis; management is described on page 560.
Investigations
In addition to common respiratory pathogens, sputum culture
may reveal Pseudomonas aeruginosa and Staphylococcus
aureus, fungi such as Aspergillus and various mycobacteria.
Frequent cultures are necessary to ensure appropriate treatment
of resistant organisms.
Bronchiectasis, unless very gross, is not usually apparent
on a chest X-ray. In advanced disease, thickened airway walls,
cystic bronchiectatic spaces and associated areas of pneumonic
consolidation or collapse may be visible. CT is much more
sensitive and shows thickened, dilated airways (Fig. 17.29).
A screening test can be performed in patients suspected
of having a ciliary dysfunction syndrome by measuring the
time taken for a small pellet of saccharin placed in the anterior
chamber of the nose to reach the pharynx, at which point the
patient can taste it. This time should not exceed 20 minutes but
is greatly prolonged in patients with ciliary dysfunction. Ciliary
beat frequency may also be assessed from biopsies taken from
the nose. Structural abnormalities of cilia can be detected by
electron microscopy.
Management
In patients with airflow obstruction, inhaled bronchodilators and
glucocorticoids should be used to enhance airway patency.
Physiotherapy
Patients should be shown how to perform regular daily
physiotherapy to assist the drainage of excess bronchial
secretions. Efficiently executed, this is of great value both in
reducing the amount of cough and sputum, and in preventing
recurrent episodes of bronchopulmonary infection. Patients should
lie in a position in which the lobe to be drained is uppermost.
Deep breathing, followed by forced expiratory manoeuvres (the
‘active cycle of breathing’ technique), helps to move secretions
in the dilated bronchi towards the trachea, from which they
can be cleared by vigorous coughing. Devices that increase
airway pressure either by a constant amount (positive expiratory
pressure mask) or in an oscillatory manner (flutter valve) aid
sputum clearance in some patients and a variety of techniques
should be tried to find the one that suits the individual. The
optimum duration and frequency of physiotherapy depend on the
amount of sputum but 5-10 minutes twice daily is a minimum
for most patients.
Antibiotic therapy
For most patients with bronchiectasis, the appropriate antibiotics
are the same as those used in COPD (p. 578) but larger doses and
longer courses are required, and resolution of symptoms is often
incomplete. When secondary infection occurs with staphylococci
and Gram-negative bacilli, in particular Pseudomonas species,
antibiotic therapy becomes more challenging and should be
guided by the microbiological sensitivities. For Pseudomonas,
oral ciprofloxacin (500-750 mg twice daily) or an intravenous
anti-pseudomonal (3-lactam (e.g. piperacillin-tazobactam or
ceftazidime) will be required. Haemoptysis in bronchiectasis
often responds to treatment of the underlying infection,
although percutaneous embolisation of the bronchial
circulation by an interventional radiologist may be necessary in
severe cases.
Surgical treatment
Excision of bronchiectatic areas is indicated in only a small
proportion of cases. These are usually patients in whom the
bronchiectasis is confined to a single lobe or segment on CT.
Unfortunately, many of those in whom medical treatment proves
unsuccessful are also unsuitable for surgery because of either
extensive bilateral bronchiectasis or coexisting severe airflow
obstruction. In progressive forms of bronchiectasis, resection of
destroyed areas of lung that are acting as a reservoir of infection
should be considered only as a last resort.
Prognosis
The disease is progressive when associated with ciliary dysfunction
and cystic fibrosis, and eventually causes respiratory failure.
In other patients, the prognosis can be relatively good if
physiotherapy is performed regularly and antibiotics are used
aggressively.
Prevention
As bronchiectasis commonly starts in childhood following measles,
whooping cough or a primary tuberculous infection, adequate
prophylaxis for and treatment of these conditions are essential.
Early recognition and treatment of bronchial obstruction are
also important.
17.31 Symptoms of bronchiectasis
• Cough: chronic, daily, persistent
• Sputum: copious, continuously purulent
• Pleuritic pain: when infection spreads to involve pleura, or with
segmental collapse due to retained secretions
• Haemoptysis:
Streaks of blood common, larger volumes with exacerbations of
infection
Massive haemoptysis requiring bronchial artery embolisation
sometimes occurs
• Infective exacerbation: increased sputum volume with fever,
malaise, anorexia
• Halitosis: frequently accompanies purulent sputum
• General debility: difficulty maintaining weight, anorexia, exertional
breathlessness
580 • RESPIRATORY MEDICINE
Cystic fibrosis
Genetics, pathogenesis and epidemiology
Cystic fibrosis (CF) is the most common fatal genetic disease
in Caucasians, with autosomal recessive inheritance, a carrier
rate of 1 in 25, and an incidence of about 1 in 2500 live births
(pp. 40 and 48). It is much less common in people of African
descent and rarer still in Asians. CF is the result of mutations
affecting a gene on the long arm of chromosome 7, which codes
for a chloride channel known as cystic fibrosis transmembrane
conductance regulator (CFTP)\ this influences salt and water
movement across epithelial cell membranes. The most common
CFTR mutation in northern European and American populations
is A F508 but over 2000 mutations of this gene have now been
identified. The genetic defect causes increased sodium and
chloride content in sweat and increased resorption of sodium
and water from respiratory epithelium (Fig. 17.30). Relative
dehydration of the airway epithelium is thought to predispose
to chronic bacterial infection and ciliary dysfunction, leading to
bronchiectasis. The gene defect also causes disorders in the gut
epithelium, pancreas, liver and reproductive tract (see below).
In the 1960s, few patients with CF survived childhood, yet
with aggressive treatment of airway infection and nutritional
support, life expectancy has improved dramatically, so that there
are now more adults than children with CF in many developed
countries. Until recently, the diagnosis was most commonly
made from the clinical picture (bowel obstruction, failure to
thrive, steatorrhoea and/or chest symptoms in a young child),
supported by sweat electrolyte testing and genotyping. Patients
with unusual phenotypes were commonly missed, however, and
late diagnosis led to poorer outcomes. Neonatal screening for
CF using immunoreactive trypsin and genetic testing of newborn
blood samples is now routine in the UK and should reduce
delayed diagnosis and improve outcomes. Pre-implantation
and/or prenatal testing may be offered to those known to be
at high risk (p. 56).
Clinical features
The lungs are macroscopically normal at birth, but bronchiolar
inflammation and infections usually lead to bronchiectasis in
childhood. At this stage, the lungs are most commonly infected
with Staph, aureus ; however, in adulthood, many patients become
colonised with P. aeruginosa, Stenotrophomonas maltophilia
or other Gram-negative bacilli. Recurrent exacerbations of
bronchiectasis, initially in the upper lobes but subsequently
throughout both lungs, cause progressive lung damage,
resulting ultimately in death from respiratory failure. Other clinical
manifestations are shown in Box 17.32. Most men with CF
are infertile due to failure of development of the vas deferens,
but microsurgical sperm aspiration and in vitro fertilisation are
possible. Genotype is a poor predictor of disease severity in
individuals; even siblings with matching genotypes may have
different phenotypes. This suggests that other ‘modifier genes’,
as yet unidentified, influence clinical outcome.
Management
Treatment of CF lung disease
The management of CF lung disease is that of severe bronchiectasis.
All patients with CF who produce sputum should perform chest
physiotherapy daily, and more frequently during exacerbations.
While infections with Staph, aureus can often be managed with
oral antibiotics, intravenous treatment (frequently self-administered
at home through an implanted subcutaneous vascular access
device) is usually needed for Pseudomonas infections.
Unfortunately, the bronchi of many patients with CF eventually
become colonised with pathogens that are resistant to most
antibiotics. Resistant strains of P. aeruginosa, Stenotrophomonas
maltophilia and Burkholderia cepacia are the main culprits and
may require prolonged treatment with unusual combinations
of antibiotics. Aspergillus and non-tuberculous mycobacteria
are also frequently found in the sputum of patients with CF
but in most cases these behave as benign ‘colonisers’ of the
bronchiectatic airways and do not require specific therapy. An
0 Normal
Cystic fibrosis
Airway lumen ■
Fig. 17.30 Cystic fibrosis: basic defect in the pulmonary epithelium. 0 The cystic fibrosis gene (CFTR) codes for a chloride channel (1) in the apical
(luminal) membrane of epithelial cells in the conducting airways. This is normally controlled by cyclic adenosine monophosphate (cAMP) and indirectly by
p-adrenoceptor stimulation, and is one of several apical ion channels that control the quantity and solute content of airway-lining fluid. Normal channels
appear to inhibit the adjacent epithelial sodium channels (2). |§j In cystic fibrosis, one of many cystic fibrosis gene defects causes absence or defective
function of this chloride channel (3). This leads to reduced chloride secretion and loss of inhibition of sodium channels, with excessive sodium resorption
(4) and dehydration of the airway lining. The resulting abnormal airway-lining fluid predisposes to infection by mechanisms still to be fully explained.
Infections of the respiratory system • 581
1 17.32 Complications of cystic fibrosis
Respiratory
• Progressive airway obstruction
•
Haemoptysis
• Infective exacerbations of
•
Lobar collapse due to
bronchiectasis
secretions
• Respiratoryfailure
•
Pulmonary hypertension
• Spontaneous pneumothorax
•
Nasal polyps
Gastrointestinal and hepatic
• Malabsorption and
•
Biliary cirrhosis
steatorrhoea
•
Portal hypertension, varices
• Distal intestinal obstruction
and splenomegaly
syndrome
•
Gallstones
Others
• Diabetes (25% of adults)
•
Psychosocial problems
• Delayed puberty
•
Osteoporosis
• Male infertility
•
Arthropathy
• Stress incontinence due to
•
Cutaneous vasculitis
repeated forced cough
BH 17.33 Treatments that reduce chest exacerbations
and/or improve lung function in cystic fibrosis
Therapy
Patients treated
Nebulised recombinant human DNase
2.5 mg daily
Age >5, FVC >40%
predicted
Nebulised tobramycin
300 mg twice daily, given in alternate
months
Patients colonised with
Pseudomonas aeruginosa
Regular oral azithromycin
500 mg 3 times a week
Patients colonised with
P. aeruginosa
Nebulised hypertonic saline
4 mL 7%, twice daily
Age >6, FEV, > 40%
predicted
(FEV-, = forced expiratory volume in 1 sec; FVC
= forced vital capacity)
exception is Mycobacterium abscessus, which is multi-resistant,
may be transmissible between patients with CF and can cause
progressive lung destruction that is hard to treat.
Some patients have coexistent asthma, which is treated
with inhaled bronchodilators and glucocorticoids; allergic
bronchopulmonary aspergillosis (p. 596) also occurs occasionally
in CF.
Four maintenance treatments have been shown to cause
modest rises in lung function and/or to reduce the frequency of
chest exacerbations in patients with CF (Box 17.33). Individual
responses are variable and should be carefully monitored to
avoid burdening patients with treatments that prove ineffective.
For advanced CF lung disease, home oxygen and NIV
may be necessary to treat respiratory failure. Ultimately, lung
transplantation can produce dramatic improvements but is
limited by donor organ availability.
Treatment of non-respiratory manifestations of CF
There is a clear link between good nutrition and prognosis in
CF. Malabsorption occurs in 85% of patients due to exocrine
pancreatic failure and is treated with oral pancreatic enzymes
and vitamin supplements. The increased calorie requirements
of patients with CF are met by supplemental feeding, including
nasogastric or gastrostomy tube feeding if required. Diabetes
17.34 Cystic fibrosis in adolescence
Issues for the patient
• Move to adult CF centre - loss of trusted paediatric team
• Feelings of being different from peers due to chronic illness
• Demanding treatments that conflict with social and school life
• Pressure to take responsibility for self-care
• Relationship/fertility concerns
Issues for the patient’s parents
• Loss of control over patient’s treatment - feeling excluded
• Loss of trusted paediatric team
• Need to develop trust in adult team
• Feelings of helplessness when adolescent rebels or will not take
treatment
Issues for the CF team
• Reluctance or refusal by patient to engage with transition
• Management of deterioration due to non-adherence
• Motivation of adolescents to self-care
• Provision of adolescent-friendly health-care environment
eventually develops in over 25% of patients and often requires
insulin therapy. Osteoporosis secondary to malabsorption and
chronic ill health should be sought and treated.
Novel therapies for cystic fibrosis
Small molecules designed to correct the function of particular
CFTR defects are being developed. One such drug, ivacaftor
(a CFTR ‘potentiator’), is now an established oral treatment for
the 5% of patients with the G551 D mutation, causing sustained
improvements in FR^ and weight, and normalising the sweat test.
The combination of ivacaftor and lumacaftor (a CFTR ‘corrector’)
has been found to have modest short-term benefit in patients
with DF508 mutations. Improved versions of these treatments
may soon offer similar benefits for these patients. Somatic gene
therapy for CF is also under development. Manufactured normal
copies of the CF gene are ‘packaged’ in liposomes or virus
vectors and administered to the airways by aerosol inhalation.
Trials are under way but more efficient gene delivery methods
are needed to make this practical.
Infections of the respiratory system
Infections of the upper and lower respiratory tract are a major
cause of morbidity and mortality, particularly in patients at the
extremes of age and those with pre-existing lung disease or
immune suppression.
Upper respiratory tract infection
Upper respiratory tract infections (URTIs), such as coryza (the
common cold), acute pharyngitis and acute tracheobronchitis, are
the most common of all communicable diseases and represent
the most frequent cause of short-term absenteeism from work
and school. The vast majority are caused by viruses (p. 249)
and, in adults, are usually short-lived and rarely serious.
Acute coryza is the most common URTI and is usually the
result of rhinovirus infection. In addition to general malaise, acute
coryza typically causes nasal discharge, sneezing and cough.
Involvement of the pharynx results in a sore throat, and that of
582 • RESPIRATORY MEDICINE
the larynx a hoarse or lost voice. If complicated by a tracheitis
or bronchitis, chest tightness and wheeze typical of asthma
occur. Specific investigation is rarely warranted and treatment
with simple analgesics, antipyretics and decongestants is all that
is required. Symptoms usually resolve quickly, but if repeated
URTIs ‘go to the chest’, a more formal diagnosis of asthma
ought to be considered. A variety of viruses causing URTI may
also trigger exacerbations of asthma or COPD and aggravate
other lung diseases.
Bordetella pertussis, the cause of whooping cough, is an
important source of URTI. It is highly contagious and is notifiable
in the UK. Vaccination confers protection and is usually offered
in infancy, but its efficacy wanes in adult life and the infection is
easily spread. Adults usually experience a mild illness similar to
acute coryza but some individuals develop paroxysms of coughing
that can persist for weeks to months, earning whooping cough
the designation of ‘the cough of 100 days’. The diagnosis may
be confirmed by bacterial culture, polymerase chain reaction
(PCR) from a nasopharyngeal swab or serological testing. If
the illness is recognised early in the clinical course, macrolide
antibiotics may ameliorate the course.
Rhinosinusitis typically causes a combination of nasal
congestion, blockage or discharge and may be accompanied by
facial pain/pressure or loss of smell. Examination usually confirms
erythematous swollen nasal mucosa and pus may be evident.
Nasal polyps should be sought and dental infection excluded.
Treatment with topical glucocorticoids, nasal decongestants
and regular nasal douching is usually sufficient and, although
bacterial infection is often present, antibiotics are indicated only
if symptoms persist for more than 5 days. Persistent symptoms
or recurrent episodes should prompt a referral to an ear, nose
and throat specialist.
Influenza is discussed on page 240.
Pneumonia
Pneumonia is as an acute respiratory illness associated with
recently developed radiological pulmonary shadowing that may be
segmental, lobar or multilobar. The context in which pneumonia
develops is highly suggestive of the likely organism(s) involved;
therefore, pneumonias are usually classified as community- or
hospital-acquired, or those occurring in immunocompromised
hosts. ‘Lobar pneumonia’ is a radiological and pathological term
referring to homogeneous consolidation of one or more lung lobes,
often with associated pleural inflammation; bronchopneumonia
refers to more patchy alveolar consolidation associated with
bronchial and bronchiolar inflammation, often affecting both
lower lobes.
Community-acquired pneumonia
Figures from the UK suggest that an estimated 5-11/1000
adults suffer from community-acquired pneumonia (CAP) each
year, accounting for around 5-1 2% of all lower respiratory tract
infections. CAP may affect all age groups but is particularly
common at the extremes of age; for example, worldwide, CAP
continues to kill more children than any other illness and the
propensity to ease the passing of the debilitated and the elderly
led to designation of pneumonia as the ‘old man’s friend’.
Most cases are spread by droplet infection, and while CAP
may occur in previously healthy individuals, several factors may
impair the effectiveness of local defences and predispose to CAP
(Box 1 7.35). Streptococcus pneumoniae (Fig. 1 7.31) remains the
Fig. 17.31 Gram stain of sputum showing Gram-positive diplococci
characteristic of Streptococcus pneumoniae (arrows).
17.35 Factors that predispose to pneumonia
• Cigarette smoking
• Old age
• Upper respiratory tract
• Recent influenza infection
infections
• Pre-existing lung disease
• Alcohol
• HIV
• Glucocorticoid therapy
• Indoor air pollution
i
17.36 Organisms causing community-acquired
pneumonia
Bacteria
• Streptococcus pneumoniae
•
Staphylococcus aureus
• Mycoplasma pneumoniae
•
Chlamydia psittaci
• Legionella pneumophila
•
Coxiella burnetii (Q fever)
• Chlamydia pneumoniae
•
Klebsiella pneumoniae
• Haemophilus influenzae
Viruses
(Freidlander’s bacillus)
• Influenza, parainfluenza
•
Adenovirus
• Measles
•
Cytomegalovirus
• Herpes simplex
•
Coronaviruses (SARS-CoV and
• Varicella
MERS-Co V)
(MERS = Middle East respiratory syndrome; SARS = severe acute respiratory
syndrome)
most common infecting agent, and thereafter the likelihood that
other organisms may be involved depends on the age of the
patient and the clinical context. Viral infections are recognised
as important causes of CAP in children and their contribution
to adult CAP is increasingly recognised. The common causative
organisms are shown in Box 17.36.
Clinical features
Pneumonia, particularly lobar pneumonia, usually presents as an
acute illness. Systemic features, such as fever, rigors, shivering
and malaise, predominate and delirium may be present. The
appetite is invariably lost and headache frequently reported.
Pulmonary symptoms include cough, which at first is
characteristically short, painful and dry, but later is accompanied
by the expectoration of mucopurulent sputum. Rust-coloured
sputum may be produced by patients with Strep, pneumoniae
infection and the occasional patient may report haemoptysis.
Infections of the respiratory system • 583
Any of:
• Confusion*
• Urea > 7 mmol/L
• Respiratory rate > 30/min
• Blood pressure (systolic < 90 mmHg or diastolic < 60 mmHg)
• Age > 65 years
Score 1 point for each feature present
I - ; - 1
CURB-65 score 0 or 1
Likely to be suitable for
home treatment
Consider hospital-supervised
treatment
Options may include
• Short-stay inpatient
• Hospital-supervised outpatient
3 or
more
Manage in hospital as
severe pneumonia
Assess for ICU admission,
especially if CURB-65
score = 4 or 5
Fig. 17.32 Hospital CURB-65. ^Defined as a mental test score of 8 or less, or new disorientation in person, place or time. (ICU = intensive care unit;
urea of 7 mmol/L = 20 mg/dL)
Pleuritic chest pain may be a presenting feature and on occasion
may be referred to the shoulder or anterior abdominal wall. Upper
abdominal tenderness is sometimes apparent in patients with lower
lobe pneumonia or those with associated hepatitis. Less typical
presentations may be seen in the very young and the elderly.
While different organisms often give rise to a similar clinical and
radiological picture, it may be possible to infer the likely agent from
the clinical context. Mycoplasma pneumoniae is more common
in young people and rare in the elderly, whereas Haemophilus
influenzae is more common in the elderly, particularly if underlying
lung disease is present. Legionella pneumophila occurs in local
outbreaks centred on contaminated cooling towers in hotels,
hospitals and other industries. Staph, aureus is more common
following an episode of influenza. Klebsiella pneumonia has
a specific association with alcohol abuse and often presents
with a particularly severe bacteraemic illness. Recent foreign
travel raises the possibility of infections that may otherwise be
unusual in the UK, e.g. MERS-coronavirus (Middle East; p. 249),
melioidosis caused by Burkholderia pseudomallei (South-east
Asia and northern Australia; p. 261) and endemic fungal infection
(North, Central or South America; p. 301). Certain occupations
may be associated with exposure to specific bacteria (p. 618).
Clinical examination should first focus on the respiratory and
pulse rates, blood pressure and an assessment of the mental
state, as these are important in forming a judgement as to
severity of the illness (Fig. 17.32). Chest signs (p. 547) vary,
depending on the inflammatory response, which proceeds through
stages of acute exudation, red and then grey hepatisation, and
finally resolution. When consolidated, the lung is typically dull to
percussion and, as conduction of sound is enhanced, auscultation
reveals bronchial breathing and whispering pectoriloquy; crackles
are heard throughout. An assessment of the state of nutrition
is important, particularly in the elderly. The presence of herpes
labialis may point to streptococcal infection, as may the finding
of ‘rusty’ sputum.
The differential diagnosis of pneumonia is shown in Box 1 7.37.
Investigations
The object of investigations, which are summarised in Box
17.38, is to confirm the diagnosis, assess the severity and
■
I
• Pulmonary infarction
• Pulmonary/pleural tuberculosis
• Pulmonary oedema (can be unilateral)
• Pulmonary eosinophilia (p. 611)
• Malignancy: bronchoalveolar cell carcinoma
• Cryptogenic organising pneumonia/bronchiolitis obliterans organising
pneumonia (C0P/B00P) (p. 606)
identify the development of complications. While many cases
of mild to moderate CAP can be successfully managed without
identification of the organism, a range of microbiological tests
should be performed on patients with severe CAP.
Management
The most important aspects of management include oxygenation,
fluid balance and antibiotic therapy. In severe or prolonged illness,
nutritional support may be required.
Oxygen
Oxygen should be administered to all patients with tachypnoea,
hypoxaemia, hypotension or acidosis with the aim of maintaining
the Pa02 >8 kPa (60 mmHg) or Sa02 >92%. High concentrations
(>35%), preferably humidified, should be used in all patients who
do not have hypercapnia associated with COPD. Continuous
positive airway pressure (CPAP) should be considered in those
who remain hypoxic despite high-concentration oxygen therapy,
and these patients should be managed in a high-dependency
or intensive care environment where mechanical ventilation may
be rapidly employed. Indications for ITU referral are summarised
in Box 17.39.
Fluid balance
Intravenous fluids should be considered in those with severe
illness, in older patients and those with vomiting. It may be
appropriate to discontinue hypertensive agents temporarily.
Otherwise, an adequate oral intake of fluid should be encouraged.
Inotropic support may be required in patients with shock (p. 204).
17.37 Differential diagnosis of pneumonia
584 • RESPIRATORY MEDICINE
17.38 Investigations in community-acquired
pneumonia
Blood
Full blood count
• Very high (>20x109/L) or low (<4x109/L) white cell count: marker
of severity
• Neutrophil leucocytosis >15x1 09/L: suggests bacterial aetiology
• Haemolytic anaemia: occasional complication of Mycoplasma
Urea and electrolytes
• Urea >7 mmol/L (~20 mg/dL): marker of severity
• Hyponatraemia: marker of severity
Liver function tests
• Abnormal if basal pneumonia inflames liver
• Hypoalbuminaemia: marker of severity
Erythrocyte sedimentation rate/C-reactive protein
• Non-specifically elevated
Blood culture
• Bacteraemia: marker of severity
Cold agglutinins
• Positive in 50% of patients with Mycoplasma
Arterial blood gases
• Measure when Sa02 <93% or when clinical features are severe, to
assess ventilatory failure or acidosis
Sputum
Sputum samples
• Gram stain (see Fig. 17.31), culture and antimicrobial sensitivity
testing
Oropharynx swab
• Polymerase chain reaction for Mycoplasma pneumoniae and other
atypical pathogens
Urine
• Pneumococcal and/or Legionella antigen
Chest X-ray
Lobar pneumonia
• Patchy opacification evolves into homogeneous consolidation of
affected lobe
• Air bronchogram (air-filled bronchi appear lucent against
consolidated lung tissue) may be present (Fig. 17.33)
Bronchopneumonia
• Typically patchy and segmental shadowing
Complications
• Para-pneumonic effusion, intrapulmonary abscess or empyema
Staphylococcus aureus
• Suggested by multilobar shadowing, cavitation, pneumatoceles and
abscesses
Pleural fluid
• Always aspirate and culture when present in more than trivial
amounts, preferably with ultrasound guidance
Antibiotic treatment
Prompt administration of antibiotics improves the outcome. The
initial choice of antibiotic is guided by clinical context, severity
assessment, local knowledge of antibiotic resistance patterns and,
at times, epidemiological information. Current regimens are detailed
in Box 17.40. In most patients with uncomplicated pneumonia a
5-day course is adequate, although treatment is usually required
for longer in patients with Legionella, staphylococcal or Klebsiella
pneumonia. Oral antibiotics are usually adequate unless the patient
has a severe illness, impaired consciousness, loss of swallowing
reflex or functional or anatomical reasons for malabsorption.
Fig. 17.33 Pneumonia of the right middle lobe. [A] Posteroanterior
view: consolidation in the right middle lobe with characteristic opacification
beneath the horizontal fissure and loss of normal contrast between the
right heart border and lung. [§] Lateral view: consolidation confined to the
anteriorly situated middle lobe.
17.39 Indications for referral to ITU
• CURB score of 4-5 (see Fig. 17.32), failing to respond rapidly to
initial management
• Persisting hypoxia [Pa02 <8 kPa (60 mmHg)), despite high
concentrations of oxygen
• Progressive hypercapnia
• Severe acidosis
• Circulatory shock
• Reduced conscious level
Treatment of pleural pain
It is important to relieve pleural pain in order to allow the patient
to breathe normally and cough efficiently. For the majority, simple
analgesia with paracetamol, co-codamol or NSAIDs is sufficient.
In some patients, opiates may be required but must be used
with extreme caution in individuals with poor respiratory function.
Physiotherapy
Physiotherapy is not usually indicated in patients with CAP,
although it may be helpful to assist expectoration in patients
who suppress cough because of pleural pain.
Infections of the respiratory system • 585
17.40 Antibiotic treatment for
community-acquired pneumonia
Uncomplicated CAP
• Amoxicillin 500 mg 3 times daily orally
If patient is allergic to penicillin
• Clarithromycin 500 mg twice daily orally or Erythromycin 500 mg 4
times daily orally
If Staphylococcus is cultured or suspected
• Flucloxacillin 1-2 g 4 times daily IV plus
• Clarithromycin 500 mg twice daily IV
If Mycoplasma or Legionella is suspected
• Clarithromycin 500 mg twice daily orally or IV or Erythromycin
500 mg 4 times daily orally IV plus
• Rifampicin 600 mg twice daily IV in severe cases
Severe CAP
• Clarithromycin 500 mg twice daily IV or Erythromycin 500 mg 4
times daily IV plus
• Co-amoxiclav 1.2 g 3 times daily IV or Ceftriaxone 1-2 g daily IV or
Cefuroxime 1 .5 g 3 times daily IV or
• Amoxicillin 1 g 4 times daily IV plus flucloxacillin 2 g 4 times
daily IV
*Antibiotic use in individual patients should take into account local guidance and
antibiotic sensitivity patterns.
Adapted from British Thoracic Society Guidelines.
i
• Para-pneumonic effusion - common
• Empyema (p. 564)
• Retention of sputum causing lobar collapse
• Deep vein thrombosis and pulmonary embolism
• Pneumothorax, particularly with Staphylococcus aureus
• Suppurative pneumonia/lung abscess
• ARDS, renal failure, multi-organ failure (p. 198)
• Ectopic abscess formation [Staph, aureus)
• Hepatitis, pericarditis, myocarditis, meningoencephalitis
• Arrhythmias (e.g. atrial fibrillation)
• Pyrexia due to drug hypersensitivity
(ARDS = acute respiratory distress syndrome)
Prognosis
Most patients respond promptly to antibiotic therapy. Fever may
persist for several days, however, and the chest X-ray often
takes several weeks or even months to resolve, especially in
old age. Delayed recovery suggests either that a complication
has occurred (Box 17.41) or that the diagnosis is incorrect (see
Box 17.37). Alternatively, the pneumonia may be secondary to
a proximal bronchial obstruction or recurrent aspiration. The
mortality rate of adults with non-severe pneumonia is very low
(< 1 %); hospital death rates are typically between 5% and 10%
but may be as high as 50% in severe illness.
Discharge and follow-up
The decision to discharge a hospitalised patient depends on
the home circumstances and the likelihood of complications. A
chest X-ray need not be repeated before discharge in patients
making a satisfactory clinical recovery. Clinical review by GP or
hospital should be arranged around 6 weeks later and a chest
X-ray obtained if there are persistent symptoms, physical signs
or reasons to suspect underlying malignancy.
Prevention
Current smokers should be advised to stop. Influenza and
pneumococcal vaccination should be considered in patients at
highest risk of pneumonia (e.g. those over 65 or with chronic lung,
heart, liver or kidney disease, diabetes or immunosuppression).
Because of the mode of spread, Legionella pneumophila has
important public health implications and usually requires notification
to the appropriate health authority for investigation of potential
sources. In resource-poor settings, tackling malnourishment
and indoor air pollution, and encouraging immunisation against
measles, pertussis and Haemophilus influenzae type b are
particularly important in children.
Hospital-acquired pneumonia
Hospital-acquired pneumonia (HAP) or nosocomial pneumonia
refers to a new episode of pneumonia occurring at least 2 days
after admission to hospital. It is the second most common
hospital-acquired infection (HAI) and the leading cause of HAI-
associated death. The elderly are particularly at risk, as are
patients in intensive care units, especially when mechanically
ventilated; here, the term ventilator-associated pneumonia (VAP)
is applied. Health-care-associated pneumonia (HCAP) refers to
the development of pneumonia in a person who has spent at
least 2 days in hospital within the last 90 days, or has attended
a haemodialysis unit, or received intravenous antibiotics, or been
resident in a nursing home or other long-term care facility. The
factors predisposing to the development of pneumonia in a
hospitalised patient are listed in Box 17.42.
Clinical features and investigation
The diagnosis should be considered in any hospitalised or
ventilated patient who develops purulent sputum (or endotracheal
secretions), new radiological infiltrates, an otherwise unexplained
increase in oxygen requirement, a core temperature >38.3°C, and
a leucocytosis or leucopenia. The clinical features and radiographic
signs are variable and non-specific, however, raising a broad
differential diagnosis that includes pulmonary embolism, ARDS,
pulmonary oedema, pulmonary haemorrhage and drug toxicity.
Therefore, in contrast to CAP, microbiological confirmation should
17.42 Factors predisposing to
hospital-acquired pneumonia
Reduced host defences against bacteria
• Reduced immune defences (e.g. glucocorticoid treatment, diabetes,
malignancy)
• Reduced cough reflex (e.g. post-operative)
• Disordered mucociliary clearance (e.g. anaesthetic agents)
• Bulbar or vocal cord palsy
Aspiration of nasopharyngeal or gastric secretions
• Immobility or reduced conscious level
• Vomiting, dysphagia (N.B. stroke disease), achalasia or severe reflux
• Nasogastric intubation
Bacteria introduced into lower respiratory tract
• Endotracheal intubation/tracheostomy
• Infected ventilators/nebulisers/bronchoscopes
• Dental or sinus infection
Bacteraemia
• Abdominal sepsis
• Intravenous cannula infection
• Infected emboli
17.41 Complications of pneumonia
586 • RESPIRATORY MEDICINE
be sought whenever possible. Adequate sputum samples may
be difficult to obtain in the frail elderly person and physiotherapy
should be considered to aid expectoration. In patients who
are mechanically ventilated, bronchoscopy-directed protected
brush specimens, bronchoalveolar lavage (BAL) or endotracheal
aspirates may be obtained.
Management
The principles of management are similar to those of CAP,
focusing on adequate oxygenation, appropriate fluid balance
and antibiotics. The choice of empirical antibiotic therapy is
considerably more challenging, however, given the diversity of
pathogens and the potential for drug resistance.
The organisms implicated in early-onset HAP (occurring
within 4-5 days of admission) are similar to those involved in
CAP. In patients who have received no previous antibiotics,
co-amoxiclav or cefuroxime represents a sensible choice. If
the patient has received a course of recent antibiotics, then
piperacillin/tazobactam or a third-generation cephalosporin
should be considered.
Late-onset HAP is more often attributable to Gram-negative
bacteria (e.g. Escherichia coli, Pseudomonas aeruginosa,
Klebsiella spp. and Acinetobacter baumannii), Staph, aureus
(including meticillin-resistant Staph, aureus (MRSA)) and
anaerobes, and the choice of antibiotics ought to cover these
possibilities. Antipseudomonal cover may be provided by a
carbapenem (meropenem), an anti-pseudomonal cephalosporin
or piperacillin-tazobactam. MRSA cover may be provided by
glycopeptides such as vancomycin or linezolid. A. baumannii
is usually sensitive to carbapenems but resistant cases may
require nebulised and/or intravenous colistin. The choice of
agents is most appropriately guided by knowledge of local
patterns of microbiology and antibiotic resistance. It is sensible
to commence broad-based cover, discontinuing less appropriate
antibiotics as culture results become available. In the absence
of good evidence, the duration of antibiotic therapy remains
a matter for clinical judgement. Physiotherapy is important to
aid expectoration in the immobile and elderly, and adequate
nutritional support is often required.
Prevention
Despite appropriate management, the mortality from HAP is
high (approximately 30%), mandating prevention whenever
possible. Good hygiene is paramount, particularly with regard
to hand-washing and any equipment used. Steps should be
taken to minimise the chances of aspiration and to limit the use
of stress ulcer prophylaxis with proton pump inhibitors. Oral
antiseptic (chlorhexidine 2%) may be used to decontaminate the
upper airway and some intensive care units employ selective
decontamination of the digestive tract when the anticipated
requirement for ventilation will exceed 48 hours.
I Suppurative pneumonia, aspiration
pneumonia and pulmonary abscess
These conditions are considered together, as their aetiology and
clinical features overlap. Suppurative pneumonia is characterised
by destruction of the lung parenchyma by the inflammatory
process. Although microabscess formation is a characteristic
histological feature, ‘pulmonary abscess’ is usually taken to refer
to lesions in which there is a large localised collection of pus,
or a cavity lined by chronic inflammatory tissue, from which pus
has escaped by rupture into a bronchus.
Suppurative pneumonia and pulmonary abscess often develop
after the inhalation of septic material during operations on the
nose, mouth or throat, under general anaesthesia, or of vomitus
during anaesthesia or coma, particularly if oral hygiene is poor.
Additional risk factors for aspiration pneumonia include bulbar or
vocal cord palsy, achalasia or oesophageal reflux, and alcoholism.
Aspiration tends to localise to dependent areas of the lung, such
as the apical segment of the lower lobe in a supine patient. These
conditions may also complicate local bronchial obstruction from
a neoplasm or foreign body.
Infections are usually due to a mixture of anaerobes and
aerobes in common with the typical flora encountered in the mouth
and upper respiratory tract. Isolates of Prevotella melaninogenica,
Fusobacterium necrophorum, anaerobic or microaerophilic cocci,
and Bacteroides fragilis may be identified. When suppurative
pneumonia or a pulmonary abscess occurs in a previously
healthy lung, the most likely infecting organisms are Staph,
aureus or K. pneumoniae. Actinomyces infections (mostly A.
israelii) cause chronic suppurative pulmonary infections, which
may be associated with poor dental hygiene. Actinomycosis
presents a particular diagnostic challenge because of the slow
growth of actinomycetes.
Bacterial infection of a pulmonary infarct or a collapsed lobe
may also produce a suppurative pneumonia or lung abscess. The
organism(s) isolated from the sputum include Strep, pneumoniae,
Staph, aureus, Streptococcus pyogenes, H. influenzae and, in
some cases, anaerobic bacteria. In many cases, however, no
pathogen can be isolated, particularly when antibiotics have
been given.
Some strains of community-acquired MRSA (CA-MRSA)
produce the cytotoxin Panton-Valentine leukocidin. The organism
is mainly responsible for suppurative skin infection but may
be associated with rapidly progressive severe necrotising
pneumonia.
Lemierre’s syndrome is a rare cause of pulmonary abscesses.
The usual causative agent is the anaerobe Fusobacterium
necrophorum. The illness typically commences as a sore throat,
• Increased risk of and from respiratory infection: because of
reduced immune responses, increased closing volumes, reduced
respiratory muscle strength and endurance, altered mucus layer,
poor nutritional status and the increased prevalence of chronic lung
disease.
• Predisposing factors: other medical conditions may predispose to
infection, e.g. swallowing difficulties due to stroke increase the risk
of aspiration pneumonia.
• Atypical presentation: older patients often present with delirium,
rather than breathlessness or cough.
• Mortality: the vast majority of deaths from pneumonia in developed
countries occur in older people.
• Influenza: has a much higher complication rate, and morbidity and
mortality. Vaccination significantly reduces morbidity and mortality in
old age but uptake is poor.
• Tuberculosis: most cases in old age represent reactivation of
previous, often unrecognised, disease and may be precipitated by
glucocorticoid therapy, diabetes mellitus and the factors above.
Cryptic miliary tuberculosis is an occasional alternative presentation.
Older people more commonly suffer adverse effects from
antituberculous chemotherapy and require close monitoring.
17.43 Respiratory infection in old age
Infections of the respiratory system • 587
i
painful swollen neck, fever, rigor, haemoptysis and dyspnoea;
spread into the jugular veins leads to thrombosis and metastatic
dispersal of the organisms.
Injecting drug-users are at particular risk of developing
haematogenous lung abscess, often in association with
endocarditis affecting the pulmonary and tricuspid valves.
A non-infective form of aspiration pneumonia - exogenous
lipid pneumonia - may follow the aspiration of animal, vegetable
or mineral oils.
The clinical features of suppurative pneumonia are summarised
in Box 17.44.
Investigations
Radiological features of suppurative pneumonia include
homogeneous lobar or segmental opacity consistent with
consolidation or collapse. Abscesses are characterised
by cavitation and a fluid level. Occasionally, a pre-existing
emphysematous bulla becomes infected and appears as a
cavity containing an air-fluid level.
Management
Aspiration pneumonia can usually be treated with amoxicillin
and metronidazole. Co-amoxiclav also has a suitable antibiotic
spectrum but increases the risk of Clostridium difficile infection.
Further modification of antibiotics should be informed by clinical
response and microbiological results. CA-MRSA is usually
susceptible to a variety of oral non-p-lactam antibiotics, such
as trimethoprim/sulfamethoxazole, clindamycin, tetracyclines
and linezolid. Parenteral therapy with vancomycin or linezolid
can also be considered. Fusobacterium necrophorum is highly
susceptible to p-lactam antibiotics and to metronidazole,
clindamycin and third-generation cephalosporins. Prolonged
treatment for 4-6 weeks may be required in some patients with
lung abscess. Established pulmonary actinomycosis requires
6-12 months’ treatment with intravenous or oral penicillin, or
with a tetracycline in penicillin-allergic patients.
Physiotherapy is of great value, especially when suppuration
is present in the lower lobes or when a large abscess cavity has
formed. In most patients there is a good response to treatment,
and although residual fibrosis and bronchiectasis are common
sequelae, these seldom give rise to serious morbidity. Surgery
should be contemplated if no improvement occurs despite
optimal medical therapy. Removal or treatment of any obstructing
endobronchial lesion is essential.
I Pneumonia in the
immunocompromised patient
Patients immunocompromised by drugs or disease (particularly
human immunodeficiency virus (HI V) infection; p. 318) are at
increased risk of pulmonary infection and pneumonia is the most
common cause of death in this group. The majority of infections
are caused by the same pathogens that cause pneumonia in
immunocompetent individuals, but in patients with more profound
immunosuppression less common organisms, or those normally
considered to be of low virulence or non-pathogenic, may
become ‘opportunistic’ pathogens. Depending on the clinical
context, clinicians should consider the possibility of Gram-negative
bacteria, especially P. aeruginosa, viruses, fungi, mycobacteria,
and less common organisms such as Nocardia spp. Infection
is often due to more than one organism.
Clinical features
These typically include fever, cough and breathlessness but
are influenced by the degree of immunosuppression, and
the presentation may be less specific in the more profoundly
immunosuppressed. The onset of symptoms tends to be swift
in those with a bacterial infection but more gradual in patients
with opportunistic organisms such as Pneumocystis jirovecii
and mycobacterial infections (p. 318). In P. jirovecii pneumonia,
symptoms of cough and breathlessness can be present several
days or weeks before the onset of systemic symptoms or the
appearance of radiographic abnormality. The clinical features
of invasive pulmonary aspergillosis are dealt with on page 597.
Investigations
The approach is informed by the clinical context and severity
of the illness. Invasive investigations, such as bronchoscopy,
BAL, transbronchial biopsy or surgical lung biopsy, are often
impractical, as many patients are too ill to undergo these safely;
however, ‘induced sputum’ (p. 554) offers a relatively safe method
of obtaining microbiological samples. HRCT can be helpful:
• focal unilateral airspace opacification favours bacterial
infection, mycobacteria or Nocardia
• bilateral opacification favours P. jirovecii pneumonia, fungi,
viruses and unusual bacteria, e.g. Nocardia
• cavitation may be seen with N. asteroides, mycobacteria
and fungi
• the presence of a ‘halo sign’ (a zone of intermediate
attenuation between the nodule and the lung parenchyma)
may suggest aspergillosis (p. 596)
• pleural effusions suggest pyogenic bacterial infections and
are uncommon in P. jirovecii pneumonia.
Management
In theory, treatment should be based on an established
aetiological diagnosis; in practice, however, the causative agent
is frequently unknown. Factors that favour a bacterial aetiology
include neutropenia, rapid onset and deterioration. In these
circumstances, broad-spectrum antibiotic therapy should be
commenced immediately, e.g. a third-generation cephalosporin,
or a quinolone, plus an antistaphylococcal antibiotic, or an
antipseudomonal penicillin plus an aminoglycoside. Thereafter,
treatment may be tailored according to the results of investigations
and the clinical response. Depending on the clinical context and
response to treatment, antifungal or antiviral therapies may be
added. The management of P. jirovecii infection is detailed on
page 318 and that of invasive aspergillosis on page 596.
17.44 Clinical features of suppurative pneumonia
Symptoms
• Cough with large amounts of sputum, sometimes fetid and
blood-stained
• Pleural pain common
• Sudden expectoration of copious amounts of foul sputum if abscess
ruptures into a bronchus
Clinical signs
• High remittent pyrexia
• Profound systemic upset
• Digital clubbing may develop quickly (10-14 days)
• Consolidation on chest examination; signs of cavitation rarely found
• Pleural rub common
• Rapid deterioration in general health, with marked weight loss if not
adequately treated
588 • RESPIRATORY MEDICINE
Fig. 17.34 Worldwide incidence of tuberculosis
(2014). Estimated new cases (all forms) per 100 000
population. From World Health Organisation. Global
tuberculosis report, 20th edn. Geneva: WHO; 2015.
Tuberculosis
Epidemiology
Tuberculosis (TB) is caused by infection with Mycobacterium
tuberculosis (MTB), which is part of a complex of organisms
including M. bovis (reservoir cattle) and M. africanum (reservoir
humans). The resurgence in TB in the UK observed over the
latter part of the last century has finally halted and notification
of TB has fallen by around 1 .5% per year since 2000. None
the less, its impact on world health remains significant. An
estimated 9.6 million new cases were recorded in 2014, with
the majority presenting in the world’s poorest nations, which
struggle to cover the costs associated with management and
control programmes (Fig. 17.34). In the same year, 1.5 million
men, women and children died of TB, and TB continues to rank
alongside HIV as a leading cause of death worldwide.
Pathology and pathogenesis
M. bovis infection arises mainly drinking non-sterilised milk from
infected cows. M. tuberculosis is spread by the inhalation of
aerosolised droplet nuclei from other infected patients. Once
inhaled, the organisms lodge in the alveoli and initiate the
recruitment of macrophages and lymphocytes. Macrophages
undergo transformation into epithelioid and Langhans cells, which
aggregate with the lymphocytes to form the classical tuberculous
granuloma (Fig. 17.35). Numerous granulomas aggregate to
form a primary lesion or ‘Ghon focus’ (a pale yellow, caseous
nodule, usually a few millimetres to 1-2 cm in diameter), which
is characteristically situated in the periphery of the lung. Spread
of organisms to the hilar lymph nodes is followed by a similar
pathological reaction, and the combination of the primary lesion
and regional lymph nodes is referred to as the ‘primary complex
of Ranke’. Reparative processes encase the primary complex
in a fibrous capsule, limiting the spread of bacilli. If no further
complications ensue, this lesion eventually calcifies and is clearly
seen on a chest X-ray. Lymphatic or haematogenous spread may
occur before immunity is established, however, seeding secondary
foci in other organs, including lymph nodes, serous membranes,
meninges, bones, liver, kidneys and lungs, which may lie dormant
for years. The only clue that infection has occurred may be the
appearance of a cell-mediated, delayed-type hypersensitivity
reaction to tuberculin, demonstrated by tuberculin skin testing
or an interferon gamma release assay (IGRA): so-called latent TB
Fig. 17.35 Tuberculous granuloma. Normal lung tissue is lost and
replaced by a mass of fibrous tissue with granulomatous inflammation
characterised by large numbers of macrophages and multinucleate giant
cells (white arrow). The central area of this focus shows caseous
degeneration (black arrow). Courtesy of Dr William Wallace, Department of
Pathology, Royal Infirmary of Edinburgh.
(p. 594). If these reparative processes fail, primary progressive
disease ensues (Fig. 17.36). The estimated lifetime risk of
developing disease after primary infection is 10%, with roughly
half of this risk occurring in the first 2 years after infection. Factors
predisposing to TB are summarised in Box 1 7.45 and the natural
history of infection with TB is summarised in Box 17.46.
Clinical features: pulmonary disease
Primary pulmonary TB
Primary TB refers to the infection of a previously uninfected
(tuberculin-negative) individual. A few patients develop a self-
limiting febrile illness but clinical disease occurs only if there is
a hypersensitivity reaction or progressive infection (Box 17.47).
Progressive primary disease may appear during the course of
the initial illness or after a latent period of weeks or months.
Miliary TB
Blood-borne dissemination gives rise to miliary TB, which
may present acutely but more frequently is characterised by
2-3 weeks of fever, night sweats, anorexia, weight loss and a
Infections of the respiratory system • 589
Fig. 17.36 Primary pulmonary tuberculosis. (1) Spread from the
primary focus to hilar and mediastinal lymph glands to form the ‘primary
complex’, which heals spontaneously in most cases. (2) Direct extension of
the primary focus - progressive pulmonary tuberculosis. (3) Spread to the
pleura - tuberculous pleurisy and pleural effusion. (4) Blood-borne spread:
few bacilli - pulmonary, skeletal, renal, genitourinary infection, often
months or years later; massive spread - miliary pulmonary tuberculosis
and meningitis.
17.45 Factors increasing the risk of tuberculosis
Patient-related
• Age (children > young adults < elderly)
• First-generation immigrants from high-prevalence countries
• Close contacts of patients with smear-positive pulmonary TB
• Overcrowding (prisons, collective dormitories); homelessness (doss
houses and hostels)
• Chest X-ray evidence of self-healed TB
• Primary infection <1 year previously
• Smoking: cigarettes, bidis (Indian cigarettes made of tobacco
wrapped in temburini leaves) and cannabis
Associated diseases
• Immunosuppression: HIV, anti-tumour necrosis factor (TNF) and
other biologic therapies, high-dose glucocorticoids, cytotoxic agents
• Malignancy (especially lymphoma and leukaemia)
• Diabetes mellitus
• Chronic kidney disease
• Silicosis
• Gastrointestinal disease associated with malnutrition (gastrectomy,
jejuno-ileal bypass, cancer of the pancreas, malabsorption)
• Deficiency of vitamin D or A
• Recent measles in children
Bl 17.46 Natural history of untreated
primary tuberculosis
Time from infection
Manifestations
3-8 weeks
Primary complex, positive tuberculin skin test
3-6 months
Meningeal, miliary and pleural disease
Up to 3 years
Gastrointestinal, bone and joint, and lymph
node disease
Around 8 years
Renal tract disease
From 3 years
onwards
Post-primary disease due to reactivation or
re-infection
Adapted from Davies PDO, ed. Clinical tuberculosis. London: Hodder Arnold;
1998.
17.47 Features of primary tuberculosis
Infection (4-8 weeks)
• Influenza-like illness • Primary complex
• Skin test conversion
Disease
• Lymphadenopathy: hilar (often
unilateral), paratracheal or
mediastinal
• Collapse (especially right
middle lobe)
• Consolidation (especially right
middle lobe)
• Obstructive emphysema
• Cavitation (rare)
• Pleural effusion
• Miliary
• Meningitis
• Pericarditis
Hypersensitivity
• Erythema nodosum • Dactylitis
• Phlyctenular conjunctivitis
17.48 Cryptic tuberculosis
• Age over 60 years
• Intermittent low-grade pyrexia of unknown origin
• Unexplained weight loss, general debility (hepatosplenomegaly in
25-50%)
• Normal chest X-ray
• Blood dyscrasias; leukaemoid reaction, pancytopenia
• Negative tuberculin skin test
• Confirmation by biopsy with granulomas and/or acid-fast bacilli in
liver or bone marrow
dry cough. Hepatosplenomegaly may develop and the presence
of a headache may indicate coexistent tuberculous meningitis.
Auscultation of the chest is frequently normal but in more
advanced disease widespread crackles are evident. Fundoscopy
may show choroidal tubercles. The classical appearances on
chest X-ray are of fine 1-2 mm lesions (‘millet seed’) distributed
throughout the lung fields, although occasionally the appearances
are coarser. Anaemia and leucopenia reflect bone marrow
involvement. ‘Cryptic’ miliary TB is an unusual presentation
sometimes seen in old age (Box 17.48).
Post-primary pulmonary TB
Post-primary disease refers to exogenous (‘new’ infection) or
endogenous (reactivation of a dormant primary lesion) infection
in a person who has been sensitised by earlier exposure. It is
most frequently pulmonary and characteristically occurs in the
apex of an upper lobe, where the oxygen tension favours survival
of the strictly aerobic organism. The onset is usually insidious,
developing slowly over several weeks. Systemic symptoms include
fever, night sweats, malaise and loss of appetite and weight,
and are accompanied by progressive pulmonary symptoms
(Box 17.49). Very occasionally, this form of TB may present
with one of the complications listed in Box 17.50. Radiological
changes include ill-defined opacification in one or both of the
upper lobes, and as progression occurs, consolidation, collapse
and cavitation develop to varying degrees (Fig. 17.37). It is often
difficult to distinguish active from quiescent disease on radiological
criteria alone but the presence of a miliary pattern or cavitation
favours active disease. In extensive disease, collapse may be
marked and results in significant displacement of the trachea and
mediastinum. Occasionally, a caseous lymph node may drain
into an adjoining bronchus, leading to tuberculous pneumonia.
590 • RESPIRATORY MEDICINE
i
17.49 Clinical presentations of pulmonary
tuberculosis
• Chronic cough, often with
• Asymptomatic (diagnosis on
haemoptysis
chest X-ray)
• Pyrexia of unknown origin
• Weight loss, general debility
• Unresolved pneumonia
• Exudative pleural effusion
• Spontaneous pneumothorax
17.50 Complications of chronic pulmonary
tuberculosis
Pulmonary
• Massive haemoptysis
• Aspergilloma/chronic
• Cor pulmonale
aspergillosis
• Fibrosis/emphysema
• Obstructive airways disease
• Atypical mycobacterial
• Bronchiectasis
infection
• Bronchopleural fistula
• Lung/pleural calcification
Non-pulmonary
• Empyema necessitans • Anorectal disease*
• Laryngitis • Amyloidosis
• Enteritis* • Poncet’s polyarthritis
*From swallowed sputum.
Clinical features: extrapulmonary disease
Extrapulmonary TB accounts for 20% of cases in those who
are HIV-negative but is more common in HIV-positive patients.
Lymphadenitis
Lymph nodes are the most common extrapulmonary site of
disease. Cervical and mediastinal glands are affected most
frequently, followed by axillary and inguinal, and more than one
region may be involved. Disease may represent primary infection,
spread from contiguous sites or reactivation. Supraclavicular
lymphadenopathy is often the result of spread from mediastinal
disease. The nodes are usually painless and initially mobile
but become matted together with time. When caseation and
liquefaction occur, the swelling becomes fluctuant and may
discharge through the skin with the formation of a ‘collar-stud’
abscess and sinus formation. Approximately half of cases fail to
show any constitutional features, such as fevers or night sweats.
The tuberculin test is usually strongly positive. During or after
treatment, paradoxical enlargement, development of new nodes
and suppuration may all occur but without evidence of continued
infection; surgical excision is rarely necessary. In non-immigrant
children in the UK, most mycobacterial lymphadenitis is caused by
opportunistic mycobacteria, especially of the M. avium complex.
Gastrointestinal tuberculosis
TB can affect any part of the bowel and patients may present
with a wide range of symptoms and signs (Fig. 17.38). Upper
gastrointestinal tract involvement is rare and is usually an
unexpected histological finding in an endoscopic or laparotomy
specimen. Ileocaecal disease accounts for approximately half of
abdominal TB cases. Fever, night sweats, anorexia and weight
loss are usually prominent and a right iliac fossa mass may be
palpable. Up to 30% of cases present with an acute abdomen.
Ultrasound or CT may reveal thickened bowel wall, abdominal
lymphadenopathy, mesenteric thickening or ascites. Barium
enema and small bowel enema reveal narrowing, shortening and
Consolidation/collapse
Differential diagnosis
• Pneumonia
• Bronchial carcinoma
Cavitation
Differential diagnosis
• Pneumonia/lung abscess
• Lung cancer
• Pulmonary infarct
• Granulomatosis with polyangiitis
(Wegener’s granulomatosis)
• Progressive massive fibrosis
‘Miliary’ diffuse shadowing Pleural effusion/empyema
Differential diagnosis Differential diagnosis
• Sarcoidosis • Bacterial pneumonia
• Malignancy • Pulmonary infarction
• Pneumoconiosis • Carcinoma
• Infection (e.g. histoplasmosis) • Connective tissue disorder
Fig. 17.37 Chest X-ray: major manifestations and differential
diagnosis of pulmonary tuberculosis. Less common manifestations
include pneumothorax, acute respiratory distress syndrome (ARDS; p. 198),
cor pulmonale and localised emphysema.
distortion of the bowel, with caecal involvement predominating.
Diagnosis rests on obtaining histology by either colonoscopy
or mini-laparotomy. The main differential diagnosis is Crohn’s
disease (p. 813). Tuberculous peritonitis is characterised by
abdominal distension, pain and constitutional symptoms. The
ascitic fluid is exudative and cellular, with a predominance of
lymphocytes. Laparoscopy reveals multiple white ‘tubercles’
over the peritoneal and omental surfaces. Low-grade hepatic
dysfunction is common in miliary disease, in which biopsy reveals
granulomas. Occasionally, patients may be frankly icteric, with
a mixed hepatic/cholestatic picture.
Pericardial disease
Disease occurs in two forms (see Fig. 1 7.38 and p. 542): pericardial
effusion and constrictive pericarditis. Fever and night sweats are
rarely prominent and the presentation is usually insidious, with
breathlessness and abdominal swelling. Coexistent pulmonary
disease is very rare, with the exception of pleural effusion. Pulsus
paradoxus, a raised JVP, hepatomegaly, prominent ascites and
peripheral oedema are common to both types. Pericardial effusion
is associated with increased pericardial dullness and a globular
enlarged heart on chest X-ray, and pericardial calcification occurs
in around 25% of cases. Constriction is associated with an early
third heart sound and, occasionally, atrial fibrillation. Diagnosis is
based on the clinical, radiological and echocardiographic findings
(p. 542). The effusion is frequently blood-stained. Open pericardial
biopsy can be performed where there is diagnostic uncertainty.
The addition of glucocorticoids to antituberculosis treatment has
been shown to help both forms of pericardial disease.
Infections of the respiratory system • 591
Headache, vomiting,
seizures, delirium
Lymphocytic meningitis
Hydrocephalus
Space-occupying lesion
(tuberculoma)
Chronic back pain
Kyphosis
Cord compression
Abdominal mass
Psoas abscess
General observation
Weight loss
Fever
Night sweats
Cranial nerve palsy
Lymph node enlargement
Pericardial effusion
Constrictive pericarditis
Exudative ascites
Mesenteric adenitis
Intestinal obstruction
Haematuria/dysuria
Infertility in women
Epididymitis
Monoarthritis
Anorectal ulceration
Fig. 17.38 Systemic presentations of extrapulmonary tuberculosis.
Central nervous system disease
Meningeal disease represents the most important form of central
nervous system TB. Unrecognised and untreated, it is rapidly
fatal. Even when appropriate treatment is prescribed, mortality
rates of 30% have been reported, while survivors may be left
with neurological sequelae. Clinical features, investigations and
management are described on page 1 1 20.
Bone and joint disease
The spine is the most common site for bony TB (Pott’s disease),
which usually presents with chronic back pain and typically
involves the lower thoracic and lumbar spine (see Fig. 17.38).
The infection starts as a discitis and then spreads along the
spinal ligaments to involve the adjacent anterior vertebral bodies,
causing angulation of the vertebrae with subsequent kyphosis.
Paravertebral and psoas abscess formation is common and the
disease may present with a large (cold) abscess in the inguinal
region. CT or MRI is valuable in gauging the extent of disease,
the amount of cord compression, and the site for needle biopsy
or open exploration, if required. The major differential diagnosis is
malignancy, which tends to affect the vertebral body and leave
the disc intact. Important complications include spinal instability
or cord compression.
TB can affect any joint but most frequently involves the hip or
knee. Presentation is usually insidious, with pain and swelling;
fever and night sweats are uncommon. Radiological changes
are often non-specific but, as disease progresses, reduction
in joint space and erosions appear. Poncet’s arthropathy is an
immunologically mediated polyarthritis that usually resolves within
2 months of starting treatment.
Genitourinary disease
Fever and night sweats are rare with renal tract TB and patients
are often only mildly symptomatic for many years. Haematuria,
frequency and dysuria are often present, with sterile pyuria
found on urine microscopy and culture. In women, infertility from
endometritis, or pelvic pain and swelling from salpingitis or a
tubo-ovarian abscess occurs occasionally. In men, genitourinary
TB may present as epididymitis or prostatitis.
Investigations
The presence of an otherwise unexplained cough for more than
2-3 weeks, particularly in regions where TB is prevalent, or
typical chest X-ray or CT changes (Fig. 17.39) should prompt
further investigation (Box 1 7.51). Direct microscopy of a sputum
smear remains the most important first step. At least two sputum
samples (including at least one obtained in the early morning)
from a spontaneously produced deep cough should be obtained.
Induced sputum may be used in those unable to expectorate.
In selected cases, bronchoscopy and lavage or aspiration of a
lymph node by EBUS may be used.
Light-emitting diode fluorescent microscopy with auramine
staining is increasingly replacing the more traditional standard
light microscopy and Ziehl-Neelsen stain (Fig. 17.40) or the use
of mercury-vapour fluorescent microscopy. A positive smear
is sufficient for the presumptive diagnosis of TB but definitive
592 • RESPIRATORY MEDICINE
Fig. 17.39 Typical changes of tuberculosis. The chest X-ray shows
bilateral upper lobe airspace shadowing with cavitation.
i
Specimens required
Pulmonary
• Sputum* (induced with nebulised hypertonic saline if patient not
expectorating)
• Bronchoscopy with washings or BAL
• Gastric washing* (mainly used for children)
Extrapulmonary
• Fluid examination (cerebrospinal, ascitic, pleural, pericardial, joint):
yield classically very low
• Tissue biopsy (from affected site): bone marrow/liver may be
diagnostic in disseminated disease
Diagnostic tests
• Tuberculin skin test: low sensitivity/specificity; useful only in primary
or deep-seated infection
• Stain
Ziehl— Neelsen
Auramine fluorescence
• Nucleic acid amplification
• Culture
Solid media (Lowenstein-Jensen, Middlebrook)
Liquid media (e.g. MGIT)
• Pleural fluid: adenosine deaminase
• Response to empirical antituberculous drugs (usually seen after
5-1 0 days)
Baseline blood tests
• Full blood count, C-reactive protein, erythrocyte sedimentation rate,
urea and electrolytes, liver function tests
*At least two but preferably three, including an early morning sample.
(BAL = bronchoalveolar lavage; MGIT = mycobacteria growth indicator tube)
diagnosis requires culture. The probability of detecting acid-fast
bacilli is proportional to the bacillary burden in the sputum.
Smear-negative sputum should also be cultured, as only 10-100
viable organisms are required for sputum to be culture-positive.
A diagnosis of smear-negative TB may be made in advance of
culture if the chest X-ray appearances are typical of TB.
The slow growth of MTB on solid (typically between 4 and
6 weeks) and automated and semi-automated liquid (typically
around 2 weeks) culture media has prompted the development
Fig. 17.40 Positive Ziehl— Neelsen stain. Mycobacteria (arrow) retain
the red carbol fuchsin stain, despite washing with acid and alcohol.
Courtesy of Adam Hill.
of rapid NAATs (p. 106). For example, Xpert MTB/RIF (a DNA
detection-based NAAT) has the capacity to detect MTB (and
rifampicin resistance) in less than 2 hours. However, while it is
specific to MTB, it is not sufficiently sensitive to have replaced
culture.
The diagnosis of extrapulmonary TB can be more challenging.
There are generally fewer organisms (particularly in meningeal
or pleural fluid), so culture, histopathological examination of
tissue and/or NAAT may be required. Stimulation of T cells by
mycobacterial antigens leads to increased levels of adenosine
deaminase in pleural, pericardial, cerebrospinal and ascitic fluid,
and so may assist in confirming suspected TB.
In the presence of HIV, examination of sputum may still be
useful, as subclinical pulmonary disease is common. Lateral flow
urinary lipoarabinomannan assay (LF-LAM) may be useful in the
severely ill patient with a CD4 count of 100 cells/jiL or less.
Drug sensitivity testing
The rapid detection of drug resistance is central both to the
management of the individual with TB and to control of the
disease in the population. The gold standard remains culture,
in either solid or liquid media, but the use of other phenotypic
tests, such as microscopically observed drug susceptibility
(MODS), colorimetric redox indicator (CRI) methods and nitrate
reductase assay, offer low-cost alternatives, depending on the
resource and expertise available. The potential for molecular
tests to provide rapid drug sensitivity testing (DST) is improving,
particularly with regard to the detection of rifampicin resistance,
which is important because rifampicin forms the cornerstone
of 6-month chemotherapy. Rapid identification of rifampicin
resistance is provided by Xpert MTB/RIF. Line probe assays
(LPAs) use PCR and reverse hybridisation to detect genetic
sequences linked to resistance to both rifampicin and isoniazid,
and increasingly to resistance to pyrazinamide, ethambutol and
other second-line agents.
Management
Chemotherapy
The treatment of TB is based on the principle of an initial intensive
phase to reduce the bacterial population rapidly, followed by
a continuation phase to destroy any remaining bacteria (Box
17.52). Standard treatment involves 6 months’ treatment with
isoniazid and rifampicin, supplemented in the first 2 months with
17.51 Diagnosis of tuberculosis
Infections of the respiratory system • 593
1 17.52 Treatment of new tuberculosis patients (World Health Organisation recommendations)
Intensive phase
Continuation phase
Comments
Standard regimen
2 months of
HRZE
2 months of
HRZE
4 months of HR
4 months of HRE
Applies only in countries with high levels of isoniazid resistance in new TB patients, and where isoniazid
drug susceptibility testing in new patients is not done (or results are unavailable) before the continuation
phase begins
Dosing frequency
Daily*
Daily*
3 times/week
Daily
3 times/week
3 times/week
Optimal
Acceptable alternative for any new patient receiving directly observed therapy
Acceptable alternative, provided that the patient is receiving directly observed therapy and is NOT living
with HIV or living in an HIV-prevalent setting
*Daily (rather than 3 times weekly) intensive-phase dosing may help to prevent acquired drug resistance in TB patients starting treatment with isoniazid resistance.
(H = isoniazid; R = rifampicin; Z = pyrazinamide; E = ethambutol)
Adapted from World Health Organisation. Treatment of tuberculosis guidelines, 4th edn; 2010.
17.53 Main adverse reactions of first-line antituberculous drugs
Isoniazid
Rifampicin
Pyrazinamide
Streptomycin
Ethambutol
Mode of action
Cell wall synthesis
DNA transcription
Unknown
Protein synthesis
Cell wall synthesis
Major adverse
reactions
Peripheral
neuropathy1
Hepatitis2
Rash
Febrile reactions
Hepatitis
Rash
Gastrointestinal
disturbance
Hepatitis
Gastrointestinal
disturbance
Hyperuricaemia
8th nerve damage
Rash
Retrobulbar neuritis3
Arthralgia
Less common adverse
reactions
Lupoid reactions
Seizures
Psychoses
Interstitial nephritis
Thrombocytopenia
Haemolytic anaemia
Rash
Photosensitisation
Gout
Nephrotoxicity
Agranulocytosis
Peripheral neuropathy
Rash
The risk may be reduced by prescribing pyridoxine. 2More common in patients with a slow acetylator status and in alcoholics, deduced visual acuity and colour vision may
be reported with higher doses and are usually reversible.
pyrazinamide and ethambutol. Fixed-dose tablets combining two
or three drugs are preferred. Treatment should be commenced
immediately in any patient who is smear-positive, and in those
who are smear-negative but with typical chest X-ray changes
and no response to standard antibiotics.
Six months of therapy is appropriate for all patients with
new-onset pulmonary TB and most cases of extrapulmonary TB.
However, 1 2 months of therapy is recommended for meningeal
TB, including involvement of the spinal cord in cases of spinal TB;
in these cases, ethambutol may be replaced by streptomycin.
Pyridoxine should be prescribed in pregnant women and
malnourished patients to reduce the risk of peripheral neuropathy
with isoniazid. Where drug resistance is not anticipated, patients
can be assumed to be non-infectious after 2 weeks of appropriate
therapy.
Most patients can be treated at home. Admission to a hospital
unit with appropriate isolation facilities should be considered
where there is uncertainty about the diagnosis, intolerance of
medication, questionable treatment adherence, adverse social
conditions or a significant risk of multidrug-resistant TB (culture¬
positive after 2 months on treatment, or contact with known
multidrug-resistant TB).
Patients treated with rifampicin should be advised that their
urine, tears and other secretions will develop a bright, orange/
red coloration, and women taking the oral contraceptive pill
must be warned that its efficacy will be reduced and alternative
contraception may be necessary. Ethambutol and streptomycin
should be used with caution in renal impairment, with appropriate
dose reduction and monitoring of drug levels. Adverse drug
reactions occur in about 10% of patients but are significantly
more common with HIV co-infection (Box 17.53).
Baseline liver function and regular monitoring are important
for patients treated with standard therapy. Rifampicin may
cause asymptomatic hyperbilirubinaemia but, along with
isoniazid and pyrazinamide, may also cause hepatitis. Mild
asymptomatic increases in transaminases are common but
significant hepatotoxicity only occurs in 2-5%. It is appropriate
to stop treatment and allow any symptoms to subside and the
liver function tests to recover before commencing a stepwise
re-introduction of the individual drugs. Less hepatotoxic regimens
may be considered, including streptomycin, ethambutol and
fluoroquinolones.
Glucocorticoids reduce inflammation and limit tissue damage;
they are currently recommended when treating pericardial
or meningeal disease, and in children with endobronchial
disease. They may confer benefit in TB of the ureter, pleural
effusions and extensive pulmonary disease, and can suppress
hypersensitivity drug reactions. Surgery should be considered in
cases complicated by massive haemoptysis, loculated empyema,
constrictive pericarditis, lymph node suppuration, and spinal
disease with cord compression, but usually only after a full
course of antituberculosis treatment.
The effectiveness of therapy for pulmonary TB is assessed by
further sputum smear at 2 months and at 5 months. Treatment
failure is defined as a positive sputum smear or culture at 5 months
or any patient with a multidrug-resistant strain, regardless of
594 • RESPIRATORY MEDICINE
whether they are smear-positive or negative. Extrapulmonary TB
must be assessed clinically or radiographically, as appropriate.
Control and prevention
TB is preventable, particularly so in those with latent TB.
Supporting the development of laboratory and health-care services
to improve detection and treatment of active and latent TB is
an important component of this goal.
Detection of latent TB
The majority of individuals exposed to MTB harbour the bacteria,
which remain dormant. They do not develop any signs of active
disease and are non-infectious. They are however, at risk of
developing active TB disease and becoming infectious. The
lifetime risk of TB disease for a person with documented latent
TB infection is estimated at 5-15%, with the majority of cases
occurring within the first 5 years after initial infection.
Latent TB may be identified by the presence of immune
responses to M. tuberculosis antigens. Contact tracing is a
legal requirement in many countries. It has the potential to
identify the probable index case, other cases infected by the
same index patient (with or without evidence of disease), and
close contacts who should receive BCG vaccination (see below)
or chemotherapy. Approximately 1 0-20% of close contacts of
patients with smear-positive pulmonary TB and 2-5% of those
with smear-negative, culture-positive disease have evidence of
TB infection.
Cases are commonly identified using the tuberculin skin
test (TST; Fig. 17.41) or an IGRA (Fig. 17.42). An otherwise
Fig. 17.41 The tuberculin skin test. ® The reaction to the intradermal
injection of tuberculin purified protein derivative (PPD) on the inner surface
of the forearm is read between 48 and 72 hours. [S] The diameter of the
indurated area should be measured across the forearm and is positive
when >5 mm.
asymptomatic contact who tests positive but has a normal chest
X-ray may be treated with chemoprophylaxis to prevent infection
from progressing to clinical disease. Chemoprophylaxis should
be offered to adults up to the age of 65 (although age-specific
cut-off varies by country). It should also be considered for
HIV-infected close contacts of a patient with smear-positive
disease. A course of rifampicin and isoniazid for 3 months or
isoniazid for 6 months is effective.
Tuberculin skin testing may be associated with false-positive
reactions in those who have had a BCG vaccination and in
areas where exposure to non-tuberculous mycobacteria is
high. The skin tests may also be falsely negative in the setting
of immunosuppression or overwhelming TB infection.
IGRAs detect the release of interferon-gamma (IFN-y) from
sensitised T cells in response to antigens, such as early secretory
antigenic target (ESAT)-6 or culture filtrate protein (CFP)-1 0, which
are encoded by genes specific to Mycobacterium tuberculosis
and are not shared with BCG or opportunistic mycobacteria (Fig.
17.42). IGRAs are more specific than skin testing and logistically
more convenient, as they require a single blood test rather than
two clinic visits. In the UK, a dual strategy of TST followed by
IGRA is recommended. TST remains the first choice in children,
while IGRA represents the first choice for individuals with HIV.
Directly observed therapy
Poor adherence to therapy is a major factor in prolonged illness,
risk of relapse, and the emergence of drug resistance. Directly
observed therapy (DOT) involves the supervised administration of
therapy 3 times weekly to improve adherence. DOT has become
an important control strategy in resource-poor nations. In the
UK, it is currently recommended for patients thought unlikely to
be adherent to therapy: homeless people and drifters, alcohol or
i
Incubate in
the presence
of antigens
specific to MTB
l
IFN-y
released
t
IFN-y binds to
antibody on base
of ELISPOT wells
Spots counted
I
Incubate in
the presence
of antigens
specific to MTB
t
IFN-y
released
l
Supernatant
removed and
IFN-y measured
by ELISA
Fig. 17.42 The principles of interferon-gamma release assays
(IGRAs). A sample of either (A) purified T cells (T-SPOT.TB test) or (B)
whole blood (QuantiFERON— TB Gold test) is incubated in the presence of
antigens specific to Mycobacterium tuberculosis (MTB). The release of
interferon-gamma (IFN-y) by the cells is measured by enzyme-linked
immunosorbent assay (ELISA). (ELISPOT = enzyme-linked immunosorbent
spot assay)
Infections of the respiratory system • 595
drug users, patients with serious mental illness and those with
a history of non-adherence.
TB and HIV/AIDS
The close links between HIV and TB, particularly in sub-Saharan
Africa, and the potential for both diseases to overwhelm health¬
care funding in resource-poor nations have been recognised, with
the promotion of programmes that link detection and treatment
of TB with detection and treatment of HIV. It is recommended
that all patients with TB should be tested for HIV infection.
Mortality is high and TB is a leading cause of death in HIV
patients. Full discussion of its presentation and management
is given on page 318.
Drug-resistant TB
Drug-resistant TB is defined by the presence of resistance to
any first-line agent. Multidrug-resistant tuberculosis (MDR-TB) is
defined by resistance to at least rifampicin and isoniazid, with or
without other drug resistance. Globally, an estimated 3.3% of new
TB cases and 20% of previously treated cases have MDR-TB. In
2014, an estimated 190000 people died of MDR-TB. Extensively
drug-resistant tuberculosis (XDR-TB) is defined as resistance to
at least rifampicin and isoniazid, in addition to any quinolone and
at least one injectable second-line agent. An estimated 9.7% of
people with MDR-TB have XDR-TB. The prevalence of MDR-TB
is rising, particularly in the former Soviet Union, Central Asia
and Africa. It is more common in individuals with a prior history
of TB, particularly if treatment has been inadequate, and those
with HIV infection. Box 17.54 lists the factors contributing to
the emergence of drug-resistant TB. Diagnosis is challenging,
especially in resource-poor settings, and although cure may
be possible, it requires prolonged treatment with less effective,
more toxic and more expensive therapies. The mortality rate from
MDR-TB is high and that from XDR-TB higher still.
Vaccines
BCG (the Calmette-Guerin bacillus), a live attenuated vaccine
derived from M. bovis, is the most established TB vaccine. It is
administered by intradermal injection and is highly immunogenic.
BCG appears to be effective in preventing disseminated disease,
including tuberculous meningitis, in children, but its efficacy in
adults is inconsistent and new vaccines are urgently needed.
Current vaccination policies vary worldwide according to incidence
and health-care resources, but usually target children and other
high-risk individuals. BCG is very safe, with the occasional
complication of local abscess formation. It should not be
administered to those who are immunocompromised (e.g. by
HIV) or pregnant.
Prognosis
Following successful completion of chemotherapy, cure should
be anticipated in the majority of patients. There is a small (<5%)
and unavoidable risk of relapse. Most relapses occur within
17.54 Factors contributing to the emergence of
drug-resistant tuberculosis
• Drug shortages
• Poor-quality drugs
• Lack of appropriate supervision
• Transmission of drug-resistant strains
• Prior antituberculosis treatment
• Treatment failure (smear-positive at 5 months)
5 months and usually have the same drug susceptibility. In
the absence of treatment, a patient with smear-positive TB
will remain infectious for an average of 2 years; in 1 year, 25%
of untreated cases will die. Death is more likely in those who
are smear-positive and those who smoke. A few patients die
unexpectedly soon after commencing therapy and it is possible
that some have subclinical hypoadrenalism that is unmasked
by a rifampicin-induced increase in glucocorticoid metabolism.
HIV-positive patients have higher mortality rates and a modestly
increased risk of relapse.
Opportunistic mycobacterial infection
Other species of environmental mycobacteria (often termed
‘atypical’) may cause human disease (Box 17.55). The sites
commonly involved are the lungs, lymph nodes, skin and soft
tissues. The most widely recognised of these mycobacteria,
M. avium complex (MAC), is well described in severe HIV
disease (CD4 count <50 cells/mL - p. 324). However, several
others (including MAC) colonise and/or infect apparently
immunocompetent patients with chronic lung diseases such as
COPD, bronchiectasis, pneumoconiosis, old TB, or cystic fibrosis.
The clinical presentation varies from a relatively indolent course
in some to an aggressive course characterised by cavitatory
or nodular disease in others. Radiological appearances may
be similar to classical TB, but in patients with bronchiectasis,
opportunistic infection may present with lower-zone nodules.
The most commonly reported organisms include M. kansasii,
M. malmoense, M. xenopi and M. abscessus but geographical
variation is marked. M. abscessus and M. fortuitum grow rapidly
but the majority grow slowly. More rapid diagnostic systems are
under development, including DNA probes, high-performance
liquid chromatography (HPLC), PCR restriction enzyme analysis
(PRA) and 1 6S rRNA gene sequence analysis. With the exception
of M. kansasii, drug sensitivity testing is usually unhelpful in
predicting treatment response. In the UK, these organisms are
not notifiable to local public health departments as they are
not normally communicable, although there is some evidence
of patient-to-patient transmission of M. abscessus in cystic
fibrosis.
17.55 Site-specific opportunistic
mycobacterial disease
Pulmonary
• M. xenopi
•
MAC
• M. kansasii
•
M. abscessus (in cystic
• M. malmoense
fibrosis)
Lymph node
• MAC
•
M. fortuitum
• M. malmoense
•
M. chelonei
Soft tissue/skin
• M. leprae
•
M. marinum
• M. ulcerans (prevalent in
•
M. fortuitum
Africa, northern Australia and
•
M. chelonae
South-east Asia)
Disseminated
• MAC (HIV-associated)
•
M. fortuitum
• M. haemophilum
•
M. chelonae
• M. genavense
•
BCG
(BCG = bacille Calmette-Guerin; MAC = Mycobacterium avium complex -
M. scrofulaceum, M. intracellulare and M. avium)
596 • RESPIRATORY MEDICINE
17.58 Features of allergic bronchopulmonary
aspergillosis
• Asthma (in the majority of cases)
• Proximal bronchiectasis (inner two-thirds of chest CT field)
• Positive skin test to an extract of Aspergillus fumigatus
• Elevated total serum immunoglobulin E (IgE) >41 7 kll/L
(1000 ng/mL)
• Elevated A. fumigatus- specific IgE or IgG
• Peripheral blood eosinophilia >0.5x109/L
• Presence or history of chest X-ray abnormalities
• Fungal hyphae of A. fumigatus on microscopic examination of
sputum
Respiratory diseases caused by fungi
The majority of fungi encountered by humans are harmless
saprophytes but in certain circumstances (Box 17.56) some
species may cause disease by infecting human tissue, promoting
damaging allergic reactions or producing toxins. ‘Mycosis’ is the
term applied to disease caused by fungal infection. The conditions
associated with Aspergillus species are listed in Box 17.57.
| Allergic bronchopulmonary aspergillosis
Allergic bronchopulmonary aspergillosis (ABPA) occurs as a
result of a hypersensitivity reaction to germinating fungal spores
in the airway wall. The condition may complicate the course
of asthma and cystic fibrosis, and is a recognised cause of
pulmonary eosinophilia (p. 611). The prevalence of ABPA is
approximately 1-2% in asthma and 5-10% in CF. A variety of
human leucocyte antigens (HLAs) convey both an increased and
a decreased risk of developing the condition, suggesting that
genetic susceptibility is important.
Clinical features
Clinical features depend on the stage of the disease. Common
manifestations in the early phases include fever, breathlessness,
cough productive of bronchial casts and worsening of asthmatic
symptoms. The appearance of radiographic infiltrates may cause
ABPA to be mistaken for pneumonia but the diagnosis may also
be suggested by segmental or lobar collapse on chest X-rays of
patients whose asthma symptoms are stable. Diagnostic features
are shown in Box 17.58 and the typical Aspergillus hyphae in
Figure 17.43. If bronchiectasis develops, the symptoms and
complications of that disease often overshadow those of asthma.
Management
ABPA is generally considered an indication for regular therapy
with low-dose oral glucocorticoids (prednisolone 7.5-10 mg
daily) with the aim of suppressing the immunopathological
responses and preventing progressive tissue damage. In some
patients, itraconazole (400 mg/day) facilitates a reduction in oral
17.56 Factors predisposing to pulmonary
fungal disease
17.57 Classification of bronchopulmonary
aspergillosis
• Allergic bronchopulmonary aspergillosis (asthmatic pulmonary
eosinophilia)
• Extrinsic allergic alveolitis ( Aspergillus clavatus)
• Intracavitary aspergilloma
• Invasive pulmonary aspergillosis
• Chronic and subacute pulmonary aspergillosis
Fig. 17.43 Branching Aspergillus hyphae seen in allergic
bronchopulmonary aspergillosis. The figure shows the use of calcofluor
white, a non-specific fluorochrome stain that binds to fungi and fluoresces
when exposed to light of the appropriate wavelength. Aspergillus fumigatus
was subsequently grown on culture. Courtesy of Mr T. Russell and Dr M.
Hanson, Department of Microbiology, NHS Lothian.
glucocorticoids; a 4-month trial is usually recommended to assess
its efficacy. The use of specific anti-lgE monoclonal antibodies is
under consideration. Exacerbations, particularly when associated
with new chest X-ray changes, should be treated promptly with
prednisolone (40-60 mg daily) and physiotherapy. If persistent
lobar collapse occurs, bronchoscopy (usually under general
anaesthetic) should be performed to remove impacted mucus
and ensure prompt re-inflation.
Chronic pulmonary aspergillosis
The term chronic pulmonary aspergillosis (CPA) encompasses
simple aspergilloma, chronic cavitary pulmonary aspergillosis,
chronic fibrosing pulmonary aspergillosis, Aspergillus nodule and
semi-invasive aspergillosis. They are uncommon conditions and
challenging to diagnose and treat.
Simple aspergilloma
Cavities left by diseases such as TB or by damaged bronchi
provide favourable conditions in which inhaled Aspergillus
may lodge and germinate. At the earliest stage, CT scanning
may identify an irregular mucosal wall and, as fungal growth
progresses, this finally collapses into the cavity, forming a fungal
ball that may be identified on imaging (Fig. 17.44).
Simple aspergillomas are often asymptomatic. They can,
however, give rise to a variety of non-specific symptoms, such as
lethargy and weight loss, and may cause recurrent haemoptysis,
which may be life-threatening.
Systemic factors
• Haematological malignancy
• HIV
• Diabetes mellitus
• Chronic alcoholism
• Radiotherapy
Local factors
Glucocorticoids, cytotoxic
chemotherapy, biologic
therapies and other
immunosuppressant
medication
Tissue damage by suppuration or necrosis
Alteration of normal bacterial flora by antibiotic therapy
Infections of the respiratory system • 597
Fig. 17.44 Computed tomogram of aspergilloma in the left upper
lobe. The rounded fungal ball is separated from the wall of the cavity by
an ‘air crescent’ (arrow).
The typical radiological picture is invariably accompanied
by elevated serum precipitins/IgG to A fumigatus. Sputum
microscopy typically demonstrates scanty hyphal fragments
and is usually positive on culture. Less than half exhibit skin
hypersensitivity to extracts of A fumigatus. Rarely, other
filamentous fungi can cause intracavity mycetoma and are
identified by culture.
Asymptomatic cases do not require treatment but haemoptysis
should be controlled by surgery. Tranexamic acid or bronchial
artery embolisation may provide a bridge to surgery or palliate
haemoptysis when surgery is not possible. Instillation of antifungal
agents, such as amphotericin B, via a catheter placed into the
cavity has been reported but is rarely used in the UK.
Chronic cavitary pulmonary aspergillosis and chronic
fibrosing pulmonary aspergillosis
The features of chronic cavitary pulmonary aspergillosis (CCPA)
include cough (with or without haemoptysis), weight loss, anorexia
and fatigue over months or years, with associated fever, night
sweats and elevated inflammatory markers. Radiological features
include thick-walled cavities (predominantly apical), pulmonary
infiltrates and pleural thickening (Fig. 17.45). Once again, diagnosis
rests on a combination of radiological examination, histopathology,
isolation of fungus from the respiratory tract and detection of
Aspergillus IgG in serum. Treatment usually involves prolonged
courses of itraconazole or voriconazole. Cure is unusual and the
most frequent pattern is chronic relapse/remission with gradual
deterioration. Surgical intervention is fraught with complications
and should be avoided. Many patients are malnourished and
require nutritional support. Glucocorticoids should be avoided.
As CCPA progresses, fibrotic destruction of the lung results
and the condition may then be referred to as chronic fibrosing
pulmonary aspergillosis (CFPA).
Aspergillus nodule
The formation of one or more nodules is a less common
manifestation of Aspergillus infection. In addition to lung cancer,
the Aspergillus nodule may mimic TB but cavitation is unusual.
Cryptococcosis or coccidioidomycosis should be considered in
areas where these conditions are endemic.
Subacute invasive aspergillosis
Subacute invasive aspergillosis (SIA) was previously referred to
as chronic necrotising or semi-invasive pulmonary aspergillosis.
Fig. 17.45 Chronic pulmonary aspergillosis. [A] The chest X-ray shows
pleural thickening with loss of lung volume at the left apex (arrow).
fB] High-resolution computed tomography reveals multiple small cavities
and pleural thickening with an aspergilloma and surrounding air crescent
(arrow) in one of the cavities. Courtesy of Professor David Denning,
National Aspergillosis Centre, Manchester, UK.
The clinical and radiological picture is similar to CCPA but lung
biopsy demonstrates invasion of lung tissue by hyphae. The
development of SIA is favoured by mild immunocompromise
and should be suspected in patients with diabetes mellitus,
malnutrition or alcoholism, or with advanced age and in prolonged
glucocorticoid use. It is also seen in the presence of COPD,
non-tuberculous mycobacteria or HIV infection. SIA should be
treated in a similar manner to invasive pulmonary aspergillosis.
| Invasive pulmonary aspergillosis
Invasive pulmonary aspergillosis (IPA) is most commonly a
complication of profound neutropenia caused by drugs (especially
immunosuppressive agents) and/or disease (Box 17.59).
Clinical features
Acute IPA causes a severe necrotising pneumonia and must be
considered in any immunocompromised patient who develops
fever, new respiratory symptoms (particularly pleural pain or
haemoptysis) or a pleural rub. Invasion of pulmonary vessels
causes thrombosis and infarction, and systemic spread may occur
598 • RESPIRATORY MEDICINE
i
17.60 Criteria for the diagnosis of probable invasive
pulmonary aspergillosis
Host factors
• Recent history of neutropenia (< 0.5 x 1 09/L for >10 days)
temporally related to the onset of fungal disease
• Recipient of allogeneic stem cell transplant
• Prolonged use of glucocorticoids (average minimum 0.3 mg/kg/day
prednisolone or equivalent) for >3 weeks (excludes allergic
bronchopulmonary aspergillosis)
• Treatment with other recognised T-cell immune suppressants, such
as ciclosporin, tumour necrosis factor, alpha-blockers, specific
monoclonal antibodies (e.g. alemtuzumab) or nucleoside analogues
during the last 90 days
• Inherited severe immune deficiency, e.g. chronic granulomatous
disease or severe combined immune deficiency (p. 79)
Clinical criteria
• The presence of one of the following on CT:
Dense, well-circumscribed lesion(s) with or without a halo sign
Air crescent sign
Cavity
Tracheobronchitis
• Tracheobronchial ulceration, nodule, pseudomembrane, plaque or
eschar seen on bronchoscopy
Mycological criteria
• Mould in sputum, BAL fluid or bronchial brush, indicated by one of
the following:
Recovery of fungal elements indicating a mould of Aspergillus
Recovery by culture of a mould of Aspergillus
• Indirect tests (detection of antigen or cell wall constituents)
Galactomannan antigen in plasma, serum or BAL fluid
(3-1,3-glucan detected in serum (detects other species of fungi,
as well as Aspergillus f
nMust be consistent with the mycological findings and temporally related to
current episode. 2May be useful as a preliminary screening tool for invasive
aspergillosis.
(BAL = bronchoalveolar lavage)
Adapted from De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of
invasive fungal disease from the European Organisation for Research and
Treatment of Cancer/Mycoses Study Group. Clin Infect Dis 2008;
46:1813-1821.
to the brain, heart, kidneys and others organs. Tracheobronchial
aspergillosis involvement is characterised by the formation of
fungal plaques and ulceration.
HRCT characteristically shows macronodules (usually >1 cm),
which may be surrounded by a ‘halo’ of intermediate attenuation
if captured early (<5 days). Culture or histopathological evidence
of Aspergillus in diseased tissues provides a definitive diagnosis
but the majority of patients are too ill for invasive tests, such
as bronchoscopy or lung biopsy. Other investigations include
detection of Aspergillus cell-wall components (galactomannan
and p-1 ,3-glucan) in blood or BAL fluid and Aspergillus DNA by
PCR. Diagnosis is often inferred from a combination of features
(Box 17.60).
Management and prevention
IPA carries a high mortality rate, especially if treatment is
delayed. The drug of choice is voriconazole. Second-line agents
include liposomal amphotericin, caspofungin, posaconazole and
isavuconazole. Response may be assessed clinically, radiologically
and serologically (by estimation of the circulating galactomannan
level). Recovery is dependent on immune reconstitution, which
may be accompanied by enlargement and/or cavitation of
pulmonary nodules.
Patients at risk of Aspergillus (and other fungal infections) should
be managed in rooms with high -efficiency particulate air (HEPA)
filters and laminar airflow. In areas with high spore counts, patients
are advised to wear a mask if venturing outside their hospital room.
Posaconazole (200 mg 3 times daily) or itraconazole (200 mg/
day) may be prescribed for primary prophylaxis, and patients
with a history of definite or probable IPA should be considered
for secondary prophylaxis before further immunosuppression.
Other fungal infections
Mucormycosis (p. 303) may present with a pulmonary syndrome
that is clinically indistinguishable from acute IPA. Diagnosis
relies on histopathology (where available) and/or culture of the
organism from diseased tissue. The principles of treatment are
as for other forms of mucormycosis: correction of predisposing
factors, antifungal therapy with high-dose lipid amphotericin B or
posaconazole (second line), and surgical debridement.
The endemic mycoses (histoplasmosis, coccidioidomycosis,
blastomycosis and Emergomyces infection) and cryptococcosis
are discussed on pages 302-304. Pneumocystis jirovecii
pneumonia is described on page 318.
Tumours of the bronchus and lung
Lung cancer is the most common cause of death from cancer
worldwide, causing 1.59 million deaths per year (Box 17.61).
Tobacco use is the major preventable cause. Just as tobacco
use and cancer rates are falling in some developed countries,
both smoking and lung cancer are rising in Eastern Europe and
in many developing countries. The great majority of tumours in
the lung are primary lung cancers and, in contrast to many other
tumours, the prognosis remains poor, with fewer than 30% of
patients surviving at 1 year and 6-8% at 5 years.
17.61 The burden of lung cancer
• 1 .8 million new cases worldwide each year
• Most common cancer in men
• Rates rising in women:
Female lung cancer deaths outnumber male in some Nordic
countries
Has overtaken breast cancer in several countries
• More than a threefold increase in deaths since 1950
• More than 50% of cases have metastatic disease at diagnosis
17.59 Risk factors for invasive aspergillosis
• Neutropenia: risk related to duration and degree
• Solid organ or allogeneic stem cell transplantation
• Prolonged high-dose glucocorticoid therapy
• Leukaemia and other haematological malignancies
• Cytotoxic chemotherapy
• Advanced HIV disease
• Severe chronic obstructive pulmonary disease
• Critically ill patients on intensive care units
• Chronic granulomatous disease
Tumours of the bronchus and lung • 599
Primary tumours of the lung
Aetiology
Cigarette smoking is by far the most important cause of lung
cancer. It is thought to be directly responsible for at least 90% of
cases, the risk being proportional to the amount smoked and to
the tar content of cigarettes. The death rate from the disease in
heavy smokers is 40 times that in non-smokers. Risk falls slowly
after smoking cessation but remains above that in non-smokers
for many years. It is estimated that 1 in 2 smokers dies from a
smoking-related disease, about half in middle age. The effect
of ‘passive’ smoking is more difficult to quantify but is currently
thought to be a factor in 5% of all lung cancer deaths. Exposure
to naturally occurring radon is another risk. The incidence of
lung cancer is slightly higher in urban than in rural dwellers,
which may reflect differences in atmospheric pollution (including
tobacco smoke) or occupation, since a number of industrial
materials are associated with lung cancer (p. 1320). In recent
years, the strong link between smoking and ill health has led
many governments to legislate against smoking in public places,
and smoking prevalence and some smoking-related diseases
are already declining in these countries (p. 94).
Lung cancer
The incidence of lung cancer increased dramatically during the
20th century as a direct result of the tobacco epidemic (Fig. 1 7.46).
25-49 —50-59 —60-69 —70-79 —80+
Fig. 17.46 Mortality trends from lung cancer in UK, 1979-2013, by
age and year of death. [A] Males. [1] Females. Note the decline in
mortality from lung cancer in men and increase in mortality in older women
towards the end of this period, reflecting changes in smoking habits. From
Cancer Research UK: http://www.cancerresearchuk.org/health-professional/
cancer-statistics/statistics-by-cancer-type/lung-cancer/mortality. Accessed
January 2017.
In women, smoking prevalence and deaths from lung cancer
continue to increase, and more women now die of lung cancer
than breast cancer in the USA and the UK.
Pathology
Lung cancers arise from the bronchial epithelium or mucous
glands. The common cell types are listed in Box 17.62. When
the tumour occurs in a large bronchus, symptoms arise early
but tumours originating in a peripheral bronchus can grow very
large without producing symptoms, resulting in delayed diagnosis.
Peripheral squamous tumours may undergo central necrosis
and cavitation and may resemble a lung abscess on X-ray
(Fig. 17.47). Lung cancer may involve the pleura directly or by
lymphatic spread and may extend into the chest wall, invading
the intercostal nerves or the brachial plexus and causing pain.
Lymphatic spread to mediastinal and supraclavicular lymph nodes
often occurs before diagnosis. Blood-borne metastases occur
most commonly in liver, bone, brain, adrenals and skin. Even a
small primary tumour may cause widespread metastatic deposits
and this is a particular characteristic of small-cell lung cancers.
Clinical features
Lung cancer presents in many different ways, reflecting local,
metastatic or paraneoplastic tumour effects.
Cough This is the most common early symptom. It is often dry
but secondary infection may cause purulent sputum. A change
in the character of a smoker’s cough, particularly if associated
with other new symptoms, should always raise suspicion of
lung cancer.
Haemoptysis Haemoptysis is common, especially with central
bronchial tumours. Although it may be caused by bronchitic
17.62 Common cell types in lung cancer
Cell type %
Adenocarcinoma 35-40
Squamous 25-30
Small-cell 15
Large-cell 10-15
600 • RESPIRATORY MEDICINE
E
I®
Displacement of
trachea, heart and other
mediastinal
structures to the
Compensatory
emphysema
of left lung
Position of elevated
right hemidiaphragm
(not seen on chest X-ray)
obstruction of
right main bronchus
Fig. 17.48 Collapse of the right lung: effects on neighbouring
structures. [Jj Chest X-ray. [§] The typical abnormalities are highlighted.
infection, haemoptysis in a smoker should always be investigated
to exclude a lung cancer. Occasionally, central tumours invade
large vessels, causing sudden massive haemoptysis that may
be fatal.
Bronchial obstruction This is another common presentation.
The clinical and radiological manifestations (Figs 17.48 and
17.5, p. 552; Box 17.63) depend on the site and extent of the
obstruction, any secondary infection and the extent of coexisting
lung disease. Complete obstruction causes collapse of a lobe
or lung, with breathlessness, mediastinal displacement and
dullness to percussion with reduced breath sounds. Partial
bronchial obstruction may cause a monophonic, unilateral
wheeze that fails to clear with coughing, and may also impair
the drainage of secretions to cause pneumonia or lung abscess
as a presenting problem. Pneumonia that recurs at the same
site or responds slowly to treatment, particularly in a smoker,
should always suggest an underlying lung cancer. Stridor (a harsh
inspiratory noise) occurs when the larynx, trachea or a main
bronchus is narrowed by the primary tumour or by compression
from malignant enlargement of the subcarinal and paratracheal
lymph nodes.
17.63 Causes of large bronchus obstruction
Common
• Lung cancer or adenoma
• Enlarged tracheobronchial lymph nodes (malignant or tuberculous)
• Inhaled foreign bodies (especially right lung)
• Bronchial casts or plugs consisting of inspissated mucus or blood
clot (especially asthma, cystic fibrosis, haemoptysis, debility)
• Collections of mucus or mucopus retained in the bronchi as a result
of ineffective expectoration (especially postoperative following
abdominal surgery)
Rare
• Aortic aneurysm
• Giant left atrium
• Pericardial effusion
• Congenital bronchial atresia
• Fibrous bronchial stricture (e.g. following tuberculosis or bronchial
surgery/lung transplant)
Breathlessness Breathlessness may be caused by collapse or
pneumonia, or by tumour causing a large pleural effusion or
compressing a phrenic nerve and leading to diaphragmatic
paralysis.
Pain and nerve entrapment Pleural pain may indicate malignant
pleural invasion, although it can occur with distal infection.
Intercostal nerve involvement causes pain in the distribution
of a thoracic dermatome. Cancer in the lung apex may cause
Horner’s syndrome (ipsilateral partial ptosis, enophthalmos,
miosis and hypohidrosis of the face; p. 1 091) due to involvement
of the sympathetic nerves to the eye at or above the stellate
ganglion. Pancoast’s syndrome (pain in the inner aspect of the
arm, sometimes with small muscle wasting in the hand) indicates
malignant destruction of the T1 and C8 roots in the lower part
of the brachial plexus by an apical lung tumour.
Mediastinal spread Involvement of the oesophagus may cause
dysphagia. If the pericardium is invaded, arrhythmia or pericardial
effusion may occur. Superior vena cava obstruction by malignant
nodes causes suffusion and swelling of the neck and face,
conjunctival oedema, headache and dilated veins on the chest
wall and is most commonly due to lung cancer. Involvement of
the left recurrent laryngeal nerve by tumours at the left hilum
causes vocal cord paralysis, voice alteration and a ‘bovine’ cough
(lacking the normal explosive character). Supraclavicular lymph
nodes may be palpably enlarged or identified using ultrasound; if
so, a needle aspirate may provide a simple means of cytological
diagnosis.
Metastatic spread This may lead to focal neurological defects,
epileptic seizures, personality change, jaundice, bone pain or
skin nodules. Lassitude, anorexia and weight loss usually indicate
metastatic spread.
Finger clubbing Overgrowth of the soft tissue of the terminal
phalanx, leading to increased nail curvature and nail bed
fluctuation, is often seen (p. 546).
Hypertrophic pulmonary osteoarthropathy (HPOA) This is a painful
periostitis of the distal tibia, fibula, radius and ulna, with local
tenderness and sometimes pitting oedema over the anterior
shin. X-rays reveal subperiosteal new bone formation. While
Tumours of the bronchus and lung • 601
17.64 Non-metastatic extrapulmonary manifestations
of lung cancer
Endocrine (Ch. 18)
• Inappropriate antidiuretic hormone (ADH, vasopressin) secretion,
causing hyponatraemia
• Ectopic adrenocorticotrophic hormone secretion
• Hypercalcaemia due to secretion of parathyroid hormone-related
peptides
• Carcinoid syndrome (p. 678)
• Gynaecomastia
Neurological (Ch. 25)
• Polyneuropathy
• Myelopathy
• Cerebellar degeneration
• Myasthenia (Lambert-Eaton syndrome, p. 1142)
Other
• Digital clubbing
• Hypertrophic pulmonary osteoarthropathy
• Nephrotic syndrome
• Polymyositis and dermatomyositis
• Eosinophilia
most frequently associated with lung cancer, HPOA can occur
with other tumours.
Non-metastatic extrapulmonary effects (Box 1 7.64) The syndrome
of inappropriate antidiuretic hormone secretion (SIADH, p. 357)
and ectopic adrenocorticotrophic hormone secretion (p. 670) are
usually associated with small-cell lung cancer. Hypercalcaemia
may indicate malignant bone destruction or production of
hormone-like peptides by a tumour. Associated neurological
syndromes may occur with any type of lung cancer.
Investigations
The main aims of investigation are to confirm the diagnosis,
establish the histological cell type and define the extent of the
disease.
Imaging
Lung cancer produces a range of appearances on chest X-ray,
from lobar collapse (see Fig. 17.5, p. 552) to mass lesions,
effusion or malignant rib destruction (Fig. 17.49). CT should
be performed early, as it may reveal mediastinal or metastatic
spread and is helpful for planning biopsy procedures, e.g. in
establishing whether a tumour is accessible by bronchoscopy
or percutaneous CT-guided biopsy.
Biopsy and histopathology
Over half of primary lung tumours can be visualised and sampled
directly by biopsy and brushing using a flexible bronchoscope.
Bronchoscopy also allows an assessment of operability, from
the proximity of central tumours to the main carina (Fig. 17.50).
For tumours that are too peripheral to be accessible by
bronchoscope, the yield of ‘blind’ bronchoscopic washings
and brushings from the radiologically affected area is low and
percutaneous needle biopsy under CT or ultrasound guidance
is a more reliable way to obtain a histological diagnosis. There
is a small risk of iatrogenic pneumothorax, which may preclude
the procedure if there is extensive coexisting COPD. In patients
with a peripheral tumour and enlarged hilar or paratracheal lymph
nodes on CT, bronchoscopy with EBUS-guided node sampling
may allow both diagnosis and staging. In those who are unfit
Fig. 17.49 Common radiological presentations of lung cancer.
(1) Unilateral hilar enlargement suggests a central tumour or hilar glandular
involvement. However, a peripheral tumour in the apex of a lower lobe
can look like an enlarged hilar shadow on the posteroanterior X-ray.
(2) Peripheral pulmonary opacity (p. 560) is usually irregular but well
circumscribed, and may contain irregular cavitation. It can be very large.
(3) Lung, lobe or segmental collapse is usually caused by tumour occluding
a proximal bronchus. Collapse may also be due to compression of a
bronchus by enlarged lymph glands. (4) Pleural effusion usually indicates
tumour invasion of the pleural space or, very rarely, infection in collapsed
lung tissue distal to a lung cancer. (5) Paratracheal lymphadenopathy may
cause widening of the upper mediastinum. (6) A malignant pericardial
effusion may cause enlargement of the cardiac shadow. (7) A raised
hemidiaphragm may be caused by phrenic nerve palsy. Screening will
show paradoxical upward movement when the patient sniffs. (8) Osteolytic
rib destruction indicates direct invasion of the chest wall or metastatic
spread.
Fig. 17.50 Bronchoscopic view of a lung cancer. There is distortion of
mucosal folds, partial occlusion of the airway lumen and abnormal tumour
tissue.
for invasive investigation, sputum cytology may reveal malignant
cells, although the yield is low.
In patients with pleural effusions, pleural aspiration and biopsy
is the preferred investigation. Where facilities exist, thoracoscopy
increases yield by allowing targeted biopsies under direct vision.
In patients with metastatic disease, the diagnosis can often
be confirmed by needle aspiration or biopsy of affected lymph
nodes, skin lesions, liver or bone marrow.
602 • RESPIRATORY MEDICINE
Tumour stage
Lymph node spread
NO
N1
N2
N3
(None)
(Ipsilateral hilar)
(Ipsilateral mediastinal
or subcarinal)
(Contralateral or
supraclavicular)
T1 a (< 1 cm)
IA1 (92%)
Tib (>1 to <2 cm)
IA2 (83%)
Tic (>2 to <3 cm)
IA3 (77%)
MB (53%)
IIIA (36%)
NIB (26%)
T2a (>3 to <4 cm)
IB (68%)
T2b (>4 cm to <5 cm)
IIA (60%)
T3 (>5 cm)
MB (53%)
T4 (>7 cm or invading heart,
vessels, oesophagus, carina etc.)
IIIA (36%)
NIB (26%)
NIC (13%)
Mia Lung metastasis/effusion
IVA (10%)
Mlb Single extrathoracic metastasis
Mic Multiple extrathoracic metastases
IVB (0%)
Fig. 17.51 Tumour stage and 5-year survival in non-small-cell lung cancer. The figure shows the relationship between tumour extent (size, lymph
node status and metastases) and prognosis (% survival at 5 years for each clinical stage). Based on data from Detterbeck FC, Boffa DJ, Kim AW, Tanoue
T. The eighth edition lung cancer stage classification. Chest 2017; 151:193-203.
Staging to guide treatment
The propensity of small-cell lung cancer to metastasise early means
these patients are usually not suitable for surgical intervention. In
non-small-cell lung cancer (NSCLC), treatment and prognosis are
determined by disease extent, so careful staging is required. CT
is used early to detect obvious local or distant spread. Enlarged
upper mediastinal nodes may be sampled using an EBUS-
equipped bronchoscope or by mediastinoscopy. Nodes in the
lower mediastinum can be sampled through the oesophageal
wall using endoscopic ultrasound. Combined CT and whole-body
PET (see Fig. 17.6, p. 553) is commonly used to detect occult
but metabolically active metastases. Head CT, radionuclide bone
scanning, liver ultrasound and bone marrow biopsy are generally
reserved for patients with clinical, haematological or biochemical
evidence of tumour spread to these sites. Information on tumour
size and nodal and metastatic spread is then collated to assign
the patient to one of seven staging groups that determine optimal
management and prognosis (Fig. 17.51). Detailed physiological
testing is required to assess whether respiratory and cardiac
function is sufficient to allow aggressive treatment.
Management
Surgical resection carries the best hope of long-term survival but
some patients treated with radical radiotherapy and chemotherapy
also achieve prolonged remission or cure. In over 75% of cases,
treatment with the aim of cure is not possible or is inappropriate
due to extensive spread or comorbidity. Such patients are offered
palliative therapy and best supportive care. Radiotherapy and,
in some cases, chemotherapy can relieve symptoms.
Surgical treatment
Accurate pre-operative staging, coupled with improvements in
surgical and post-operative care, now offers 5-year survival rates
of over 75% in stage I disease (NO, tumour confined within visceral
pleura) and 55% in stage II disease, which includes resection in
patients with ipsilateral peribronchial or hilar node involvement.
Radiotherapy
While much less effective than surgery, radical radiotherapy can
offer long-term survival in selected patients with localised disease
in whom comorbidity precludes surgery. Radical radiotherapy
is usually combined with chemotherapy when lymph nodes are
involved (stage III). Highly targeted (stereotactic) radiotherapy
may be given in 3-5 treatments for small lesions.
The greatest value of radiotherapy, however, is in the palliation
of distressing complications, such as superior vena cava
obstruction, recurrent haemoptysis, and pain caused by chest
wall invasion or by skeletal metastatic deposits. Obstruction of
the trachea and main bronchi can also be relieved temporarily.
Radiotherapy can be used in conjunction with chemotherapy in
the treatment of small-cell carcinoma and is particularly efficient
at preventing the development of brain metastases in patients
who have had a complete response to chemotherapy (p. 1331).
Chemotherapy
The treatment of small-cell carcinoma with combinations of
cytotoxic drugs, sometimes with radiotherapy, can increase
median survival from 3 months to well over a year. The use of
combinations of chemotherapeutic drugs requires considerable
skill and should be overseen by multidisciplinary teams of clinical
oncologists and specialist nurses. Combination chemotherapy
leads to better outcomes than single-agent treatment. Regular
cycles of therapy, including combinations of intravenous
cyclophosphamide, doxorubicin and vincristine or intravenous
cisplatin and etoposide, are commonly used.
In NSCLC chemotherapy is less effective, though platinum-
based chemotherapy regimens offer 30% response rates and
a modest increase in survival, and are widely used. Some
non-small-cell lung tumours, particularly adenocarcinomas in
non-smokers, carry detectable mutations, e.g. in the epidermal
growth factor receptor (EGFR) gene. Tyrosine kinase inhibitors,
such as erlotinib and monoclonal antibodies to EGFR (e.g.
bevacizumab), show improved treatment responses in metastatic
Tumours of the bronchus and lung • 603
NSCLC and EGFR mutations, and similar approaches are being
developed to target other known genetic abnormalities.
In NSCLC there is some evidence that chemotherapy
given before surgery may increase survival and can effectively
‘down-stage’ disease with limited nodal spread. Post-operative
chemotherapy is now proven to enhance survival rates when
operative samples show nodal involvement by tumour.
Nausea and vomiting are common side-effects of chemotherapy
and are best treated with 5-HT3 receptor antagonists (p. 1353).
Laser therapy and stenting
Palliation of symptoms caused by major airway obstruction can be
achieved in selected patients using bronchoscopic laser treatment
to clear tumour tissue and allow re-aeration of collapsed lung.
The best results are achieved in tumours of the main bronchi.
Endobronchial stents can be used to maintain airway patency
in the face of extrinsic compression by malignant nodes.
other sarcomas. These secondary deposits are usually multiple
and bilateral. Often there are no respiratory symptoms and the
diagnosis is incidental on X-ray. Breathlessness may occur if
a considerable amount of lung tissue has been replaced by
metastatic tumour. Endobronchial deposits are uncommon but
can cause haemoptysis and lobar collapse.
Lymphatic infiltration may develop in carcinoma of the
breast, stomach, bowel, pancreas or bronchus. ‘Lymphangitic
carcinomatosis’ causes severe, rapidly progressive breathlessness
with marked hypoxaemia. The chest X-ray shows diffuse
pulmonary shadowing radiating from the hilar regions, often with
septal lines, and CT shows characteristic polygonal thickened
interlobular septa. Palliation of breathlessness with opiates may
help (p. 1353).
Tumours of the mediastinum
General aspects of management
The best outcomes are obtained when lung cancer is managed in
specialist centres by multidisciplinary teams, including oncologists,
thoracic surgeons, respiratory physicians and specialist nurses.
Effective communication, pain relief and attention to diet
are important. Lung tumours can cause clinically significant
depression and anxiety, and these may need specific therapy.
The management of non-metastatic endocrine manifestations is
described in Chapter 18. When a malignant pleural effusion is
present, an attempt should be made to drain the pleural cavity
using an intercostal drain; provided that the lung fully re-expands,
pleurodesis with a sclerosing agent, such as talc, should be
performed to prevent recurrent effusion.
Prognosis
The overall prognosis in lung cancer is very poor, 70% of patients
dying within a year of diagnosis and only 6-8% surviving 5 years
after diagnosis. The best prognosis is with well-differentiated
squamous cell tumours that have not metastasised and are
amenable to surgical resection. The clinical features and prognosis
of some less common tumours are given in Box 17.65.
Secondary tumours of the lung
Blood-borne metastatic deposits in the lungs may be derived
from many primary carcinomas, in particular breast, kidney,
uterus, ovary, testes and thyroid, and also from osteogenic and
Figure 1 7.52 shows the major compartments of the mediastinum
and Box 17.66 lists likely causes of a mediastinal mass.
I 17.66 Causes of a mediastinal mass
Superior mediastinum
• Retrosternal goitre
•
Thymic tumour
• Persistent left superior vena
•
Dermoid cyst
cava
•
Lymphoma
• Prominent left subclavian
•
Aortic aneurysm
artery
Anterior mediastinum
• Retrosternal goitre
•
Germ cell tumour
• Dermoid cyst
•
Pericardial cyst
• Thymic tumour
•
Hiatus hernia through the
• Lymphoma
diaphragmatic foramen of
• Aortic aneurysm
Morgagni
Posterior mediastinum
• Neurogenic tumour
•
Aortic aneurysm
• Paravertebral abscess
• Oesophageal lesion
Middle mediastinum
•
Foregut duplication
• Lung cancer
•
Bronchogenic cyst
• Lymphoma
• Sarcoidosis
•
Hiatus hernia
1 17.65 Rare types of lung tumour
Tumour
Status
Histology
Typical presentation
Prognosis
Adenosquamous carcinoma
Malignant
Tumours with areas of unequivocal
squamous and adeno-differentiation
Peripheral or central
lung mass
Stage-dependent
Neuro-endocrine (carcinoid)
tumour (p. 678)
Low-grade malignant
Neuro-endocrine differentiation
Bronchial obstruction,
cough
95% 5-year survival
with resection
Bronchial gland adenoma
Benign
Salivary gland differentiation
Tracheobronchial
irritation/obstruction
Local resection curative
Bronchial gland carcinoma
Low-grade malignant
Salivary gland differentiation
Tracheobronchial
irritation/obstruction
Local recurrence
Hamartoma
Benign
Mesenchymal cells, cartilage
Peripheral lung nodule
Local resection curative
Bronchoalveolar carcinoma
Malignant
Tumour cells line alveolar spaces
Alveolar shadowing,
productive cough
Variable, worse if
multifocal
604 • RESPIRATORY MEDICINE
Retrosternal thyroid
Thymus
Lower border of
manubrium sterni
Teratoma
Dermoid
Pleuropericardial cyst
Fig. 17.52 The divisions of the mediastinum. (1) Superior mediastinum. (2) Anterior mediastinum. (3) Middle mediastinum. (4) Posterior mediastinum.
Sites of the more common mediastinal tumours are also illustrated. From Johnson N McL. Respiratory medicine. Oxford: Blackwell Science; 1986.
17.67 Clinical features of malignant
mediastinal invasion
Trachea and main bronchi
• Stridor, breathlessness, cough, pulmonary collapse
Oesophagus
• Dysphagia, oesophageal displacement or obstruction on barium
swallow examination
Phrenic nerve
• Diaphragmatic paralysis
Left recurrent laryngeal nerve
• Paralysis of left vocal cord with hoarseness and ‘bovine’
cough
Sympathetic trunk
• Horner’s syndrome
Superior vena cava
• SVC obstruction: non-pulsatile distension of neck veins,
subconjunctival oedema, and oedema and cyanosis of head,
neck, hands and arms; dilated anastomotic veins on chest
wall
Pericardium
• Pericarditis and/or pericardial effusion
Benign tumours and cysts in the mediastinum are often
diagnosed when a chest X-ray is undertaken for some other
reason. In general, they do not invade vital structures but may
cause symptoms by compressing the trachea or the superior
vena cava. A dermoid cyst may very occasionally rupture into a
bronchus.
Malignant mediastinal tumours are distinguished by
their power to invade, as well as compress, surrounding
structures. As a result, even a small malignant tumour can
produce symptoms, although, more commonly, the tumour
has attained a considerable size before this happens (Box
17.67). The most common cause is mediastinal lymph node
metastasis from lung cancer but lymphomas, leukaemia,
malignant thymic tumours and germ-cell tumours can cause
similar features. Aortic and innominate aneurysms have
destructive features resembling those of malignant mediastinal
tumours.
Fig. 17.53 Intrathoracic goitre (arrows) extending from right upper
mediastinum.
Investigations
A benign mediastinal tumour generally appears on chest X-ray as
a sharply circumscribed mediastinal opacity encroaching on one
or both lung fields (Fig. 17.53). CT (or MRI) is the investigation
of choice for mediastinal tumours (e.g. see Fig. 18.12, p. 648).
A malignant mediastinal tumour seldom has a clearly defined
margin and often presents as a general broadening of the
mediastinum.
Bronchoscopy may reveal a primary lung cancer causing
mediastinal lymphadenopathy. EBUS may be used to guide
sampling of peribronchial masses. The posterior mediastinum can
be imaged and biopsied via the oesophagus using endoscopic
ultrasound (p. 553).
Mediastinoscopy under general anaesthetic can be used
to visualise and biopsy masses in the superior and anterior
mediastinum but surgical exploration of the chest, with removal of
part or all of the tumour, is often required to obtain a histological
diagnosis.
Interstitial and infiltrative pulmonary diseases • 605
Management
Benign mediastinal tumours should be removed surgically
because most produce symptoms sooner or later. Cysts may
become infected, while neural tumours have the potential to
undergo malignant transformation. The operative mortality is
low in the absence of coexisting cardiovascular disease, COPD
or extreme age.
Interstitial and infiltrative
pulmonary diseases
Diffuse parenchymal lung disease
The diffuse parenchymal lung diseases (DPLDs) are a
heterogeneous group of conditions affecting the pulmonary
parenchyma (interstitium) and/or alveolar lumen, which are
frequently considered collectively as they share a sufficient number
of clinical physiological and radiographic similarities (Box 17.68).
17.68 Features common to the diffuse parenchymal
lung diseases
Clinical presentation
• Cough: usually dry, persistent and distressing
• Breathlessness: usually slowly progressive; insidious onset; acute in
some cases
Examination findings
• Crackles: typically bilateral and basal
• Clubbing: common in idiopathic pulmonary fibrosis but also seen in
other types, e.g. asbestosis
• Central cyanosis and signs of right heart failure in advanced disease
Radiology
• Chest X-ray: typically small lung volumes with reticulonodular
shadowing but may be normal in early or limited disease
• High-resolution computed tomography: combinations of ground
glass changes, reticulonodular shadowing, honeycomb cysts and
traction bronchiectasis, depending on stage of disease
Pulmonary function
• Typically restrictive ventilatory defect with reduced lung volumes
and impaired gas transfer; exercise tests assess exercise tolerance
and exercise-related fall in Sa02
They often present with cough, which is typically dry and
distressing, and breathlessness, which is often insidious in onset
but thereafter relentlessly progressive. Physical examination reveals
the presence of inspiratory crackles and in many cases digital
clubbing develops. Pulmonary function tests typically show a
restrictive ventilatory defect in the presence of small lung volumes
and reduced gas transfer. The typical radiographic findings
include, in the earliest stages, ground glass and reticulonodular
shadowing, with progression to honeycomb cysts and traction
bronchiectasis. While these appearances may be seen on a
‘plain’ chest X-ray, they are most easily appreciated on HRCT,
which has assumed a central role in the evaluation of DPLD (Fig.
17.54). The current classification is shown in Figure 17.55 and
the potential differential diagnoses in Box 17.69.
|jdiopathic interstitial pneumonias
The idiopathic interstitial pneumonias represent a major subgroup
of DPLD that are grouped together as a result of their unknown
aetiology (Box 17.70). They are often distinguished by the
predominant histological pattern on tissue biopsy; hence they
are frequently referred to by their pathological description, e.g.
usual interstitial pneumonia (UIP) or non-specific interstitial
pneumonia (NSIP). The most important of these is idiopathic
pulmonary fibrosis.
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis is defined as a progressive fibrosing
interstitial pneumonia of unknown cause, occurring in adults
and associated with the histological or radiological pattern of
UIP. Important differentials include fibrosing diseases caused
i
17.69 Conditions that mimic diffuse parenchymal
lung disease
Infection
• Viral pneumonia
• Tuberculosis
• Pneumocystis jirovecii
• Parasite, e.g. filariasis
• Mycoplasma pneumoniae
• Fungal infection
Malignancy
• Leukaemia and lymphoma
• Multiple metastases
• Lymphangitic carcinomatosis
• Bronchoalveolar carcinoma
Pulmonary oedema
Aspiration pneumonitis
Clinical assessment including chest X-ray, pulmonary function tests, haematology,
biochemical and immunological investigations
High-resolution CT
i
r
Appearances consistent
with usual interstitial
pneumonia
\r
Inconsistent clinical or
CT appearances
Appearances consistent
with another diffuse
parenchymal lung disease,
e.g. sarcoid
i i i
Diagnose idiopathic
pulmonary fibrosis
Further investigations, e.g.
bronchoalveolar lavage,
transbronchial biopsy,
surgical biopsy
Diagnose and treat
accordingly
Fig. 17.54 Algorithm for the investigation of patients with interstitial lung disease following initial clinical and chest X-ray examination.
606 • RESPIRATORY MEDICINE
Diffuse parenchymal lung disease (DPLD)
r
DPLD of known cause,
e.g. drugs or association
with connective tissue
disease
T
Idiopathic interstitial
pneumonia
Granulomatous DPLD,
e.g. sarcoidosis
Other forms of DPLD, e.g.
lymphangioleiomyomatosis,
histiocytosis X etc.
Idiopathic pulmonary
fibrosis
Idiopathic interstitial
pneumonia other
than idiopathic
pulmonary fibrosis
Desquamative interstitial
pneumonia
Acute interstitial
pneumonia
Non-specific interstitial
pneumonia
Respiratory bronchiolitis
interstitial lung disease
Cryptogenic organising
pneumonia
Lymphocytic interstitial
pneumonia
Fig. 17.55 Classification of diffuse parenchymal lung disease.
1 17.70 Idiopathic interstitial pneumonias
Clinical diagnosis
Notes
Usual interstitial pneumonia (UIP)
Idiopathic pulmonary fibrosis - see text
Non-specific interstitial pneumonia (NSIP)
See page 608
Respiratory bronchiolitis-interstitial lung
disease
More common in men and smokers. Usually presents at age 40-60 years. Smoking cessation may
lead to improvement. Natural history unclear
Acute interstitial pneumonia
Often preceded by viral upper respiratory tract infection. Severe exertional dyspnoea, widespread
pneumonic consolidation and diffuse alveolar damage on biopsy. Prognosis often poor
Desquamative interstitial pneumonia (DIP)
More common in men and smokers. Presents at age 40-60 years. Insidious onset of dyspnoea.
Clubbing in 50%. Biopsy shows increased macrophages in alveolar space, septal thickening and
type II pneumocyte hyperplasia. Prognosis generally good
Cryptogenic organising pneumonia
(‘bronchiolitis obliterans organising
pneumonia’ - B00P)
Presents as clinical and radiological pneumonia. Systemic features and markedly raised erythrocyte
sedimentation rate common. Finger clubbing absent. Biopsy shows florid proliferation of immature
collagen (Masson bodies) and fibrous tissue. Response to glucocorticoids classically excellent
Lymphocytic interstitial pneumonia (LIP)
More common in women, slow onset over years. Investigate for associations with connective tissue
disease or HIV. Unclear whether glucocorticoids are helpful
by occupational exposure, medication or connective tissue
diseases, which must be excluded by careful history, examination
and investigation.
The histological features of the condition are suggestive of
repeated episodes of focal damage to the alveolar epithelium
consistent with an autoimmune process but the aetiology remains
elusive: speculation has included exposure to viruses (e.g.
Epstein-Barr virus), occupational dusts (metal or wood), drugs
(antidepressants) or chronic gastro-oesophageal reflux. Familial
cases are rare but genetic factors that control the inflammatory
and fibrotic response are likely to be important. There is a strong
association with cigarette smoking.
Clinical features
IPF usually presents in the older adult and is uncommon
before the age of 50 years. With the advent of widespread
CT scanning it may present as an incidental finding in an
otherwise asymptomatic individual but more typically presents
with progressive breathlessness (which may have been insidious)
and a non-productive cough. Constitutional symptoms are
unusual. Clinical findings include finger clubbing and the presence
of bi-basal fine late inspiratory crackles likened to the unfastening
of Velcro.
Investigations
These are summarised in Box 17.71. Established IPF will
be apparent on chest X-ray as a bilateral lower lobe and
subpleural reticular shadowing. The chest X-ray may be normal
in individuals with early or limited disease, however. HRCT typically
demonstrates a patchy, predominantly peripheral, subpleural
and basal reticular pattern and, in more advanced disease, the
presence of honeycombing cysts and traction bronchiectasis
Interstitial and infiltrative pulmonary diseases • 607
17.71 Investigations in diffuse parenchymal
lung disease
Laboratory investigations
• Full blood count: lymphopenia in sarcoid; eosinophilia in pulmonary
eosinophilias and drug reactions; neutrophilia in hypersensitivity
pneumonitis
• Ca2+: may be elevated in sarcoid
• Lactate dehydrogenase: may be elevated in active alveolitis
• Serum angiotensin-converting enzyme: non-specific indicator of
disease activity in sarcoid
• Erythrocyte sedimentation rate and C-reactive protein: non-
specifically raised
• Autoimmune screen: anti-cyclic citrullinated peptide (anti-CCP) and
other autoantibodies may suggest connective tissue disease
Radiology
• See Box 17.68
Pulmonary function
• See Box 17.68
Bronchoscopy
• Bronchoalveolar lavage: differential cell counts may point to sarcoid
and drug-induced pneumonitis, pulmonary eosinophilias,
hypersensitivity pneumonitis or cryptogenic organising pneumonia;
useful to exclude infection
• Transbronchial biopsy: useful in sarcoid and differential of
malignancy or infection
• Bronchial biopsy: occasionally useful in sarcoid
Video-assisted thoracoscopic lung biopsy (in selected cases)
• Allows pathological classification: presence of asbestos bodies may
suggest asbestosis; silica in occupational fibrosing lung disease
Others
• Liver biopsy: may be useful in sarcoidosis
• Urinary calcium excretion: may be useful in sarcoidosis
(Fig. 1 7.56). When these features are present, HRCT has a high
positive predictive value for the diagnosis of IPF and recourse to
biopsy is seldom necessary. FIRCT appearances may also be
sufficiently characteristic to suggest an alternative diagnosis such
as hypersensitivity pneumonitis (p. 616) or sarcoidosis (p. 608).
The presence of pleural plaques may suggest asbestosis (p. 618).
Pulmonary function tests classically show a restrictive
defect with reduced lung volumes and gas transfer. However,
lung volumes may be preserved in patients with concomitant
emphysema. Dynamic tests are useful to document exercise
tolerance and demonstrate exercise- induced arterial hypoxaemia,
but as IPF advances, arterial hypoxaemia and hypocapnia are
present at rest.
Bronchoscopy is seldom indicated unless there is serious
consideration of differential diagnoses of infection or a malignant
process; lymphocytosis may suggest chronic hypersensitivity
pneumonitis. The tissue samples obtained by transbronchial lung
biopsy are invariably insufficient to be of value, and if tissue is
required, a surgical lung biopsy should be sought. Lung biopsy
should be considered in cases of diagnostic uncertainty or with
atypical features. UIP is the histological pattern predominantly
encountered in IPF (Fig. 17.57); however, it is also found in
asbestosis, hypersensitivity pneumonitis, connective tissue
diseases and drug reactions.
It is not uncommon to identify a mildly positive antinuclear
antibody (ANA) or anti-cyclic citrullinated peptide 2 (anti-CCP2)
and repeat serological testing may be performed, as lung disease
may precede the appearance of connective tissue disease.
E
E
Fig. 17.56 Idiopathic pulmonary fibrosis. Typical high-resolution CT
images demonstrate the bilateral, predominantly basal and peripheral
reticular opacities, accompanied by honeycombing in the later stages.
[A] Anteroposterior view. [§] Transverse section. Courtesy of Dr Andrew
Baird, Consultant Radiologist, NHS Lothian, Edinburgh, UK.
Management
The management options for IPF are improving. If the vital
capacity is between 50% and 80% predicted, patients may be
offered either pirfenidone (an antifibrotic agent) or nintedanib
(a tyrosine kinase inhibitor). Both of these agents have been
shown to reduce the rate of decline in lung function. Patients
taking pirfenidone should be advised to avoid direct exposure
to sunlight and use photoprotective clothing and high-protection
sunscreens. Nintedanib may be accompanied by diarrhoea.
Neither drug improves cough or breathlessness and treatment
should be discontinued if lung function declines by more than
10% over the first year of treatment. Medication to control
gastro-oesophageal reflux may improve the cough. Current
smokers should be apprised of the increased risk of lung cancer
and advised to stop. Influenza and pneumococcal vaccination
should be recommended. Patients should be encouraged
to exercise and participate in pulmonary rehabilitation using
ambulatory oxygen if appropriate. Domiciliary oxygen should
be considered for palliation of breathlessness in severe cases.
Where appropriate, lung transplantation should be considered.
The optimum treatment for acute exacerbations is unknown.
Treatment is largely supportive. Broad-spectrum antibiotics may
608 • RESPIRATORY MEDICINE
Fig. 17.57 Pathology of usual interstitial pneumonia. [A] Lung tissue showing subpleural scarring, most prominently down the posterior edge of the
lower lobe. This distribution of fibrosis is typical of usual interstitial pneumonitis. The fibrosis may be associated with prominent cystic change known as
‘honeycomb lung’. \W\ Histology showing severe interstitial fibrosis with loss of the normal alveolar architecture and the development of ‘honeycomb’ cysts.
Courtesy of Dr William Wallace, Department of Pathology, Royal Infirmary of Edinburgh.
be combined with glucocorticoids and sometimes additional
immunosuppression but there are few data to support this
approach.
Prognosis
The natural history is usually one of steady decline; however,
some patients are prone to exacerbations accompanied by an
acute deterioration in breathlessness, disturbed gas exchange,
and new ground glass changes or consolidation on HRCT. In
advanced disease, central cyanosis is detectable and patients
may develop pulmonary hypertension and features of right heart
failure. A median survival of 3 years is widely quoted; the rate of
disease progression varies considerably, however, from death
within a few months to survival with minimal symptoms for many
years. Serial lung function testing may provide useful prognostic
information, relative preservation of lung function suggesting
longer survival and significantly impaired gas transfer and/or
desaturation on exercise heralding a poorer prognosis. The
finding of high numbers of fibroblastic foci on biopsy suggests
a more rapid deterioration.
Non-specific interstitial pneumonia
The clinical picture of fibrotic NSIP is similar to that of IPF,
although patients tend to be women and younger in age. As
with UIP, the condition may present as an isolated idiopathic
pulmonary condition, but an NSIP pattern is often associated with
connective tissue disease, certain drugs, chronic hypersensitivity
pneumonitis or HIV infection and care must be taken to exclude
these possibilities. As with UIP, the pulmonary condition may
precede the appearance of connective tissue disease. HRCT
findings are less specific than with IPF and lung biopsy may be
required. The prognosis is significantly better than that of IPF,
particularly in the cellular form of the condition, and the 5-year
mortality rate is typically less than 15%.
Sarcoidosis
Sarcoidosis is a multisystem granulomatous disorder of unknown
aetiology that is characterised by the presence of non-caseating
granulomas (Fig. 17.58). The condition is more frequently
described in colder parts of northern Europe. It also appears
to be more common and more severe in those from a West
Indian or Asian background; Eskimos, Arabs and Chinese are
Fig. 17.58 Sarcoidosis of the lung. Histology showing non-caseating
granulomas (arrows). Courtesy of Dr William Wallace, Department of
Pathology, Royal Infirmary of Edinburgh.
rarely affected. The tendency for sarcoid to present in the spring
and summer has led to speculation about the role of infective
agents, including mycobacteria, propionibacteria and viruses, but
the cause remains elusive. Genetic susceptibility is supported
by familial clustering; a range of class II HLA alleles confer
protection from, or susceptibility to, the condition. Sarcoidosis
occurs less frequently in smokers. It may be associated with
common variable immunodeficiency (p. 79).
Clinical features
Sarcoidosis is considered with other DPLDs, as over 90% of
cases affect the lungs, but the condition can involve almost any
organ (Fig. 17.59 and Box 17.72). Lofgren’s syndrome - an
acute illness characterised by erythema nodosum, peripheral
arthropathy, uveitis, bilateral hilar lymphadenopathy (BHL),
lethargy and occasionally fever - is often seen in young women.
Alternatively, BHL may be detected in an otherwise asymptomatic
individual undergoing a chest X-ray for other purposes. Pulmonary
disease may also present in a more insidious manner with
cough, exertional breathlessness and radiographic infiltrates;
chest auscultation is often surprisingly unremarkable. Fibrosis
Interstitial and infiltrative pulmonary diseases • 609
Fig. 17.59 Possible systemic involvement in sarcoidosis. Inset (Erythema nodosum): From Savin JA, Hunter JAA, Hepburn NC. Skin signs in clinical
medicine. London: Mosby-Wolfe; 1997.
17.72 Presentation of sarcoidosis
occurs in around 20% of cases of pulmonary sarcoidosis and
may cause a silent loss of lung function. Pleural disease is
uncommon and finger clubbing is not a feature. Complications
such as bronchiectasis, aspergilloma, pneumothorax, pulmonary
hypertension and cor pulmonale have been reported but are rare.
Investigations
Lymphopenia is characteristic and liver function tests may be
mildly deranged. Hypercalcaemia may be present (reflecting
increased formation of calcitriol - 1 ,25-dihydroxyvitamin D - by
alveolar macrophages), particularly if the patient has been exposed
to strong sunlight. Hypercalciuria may also be seen and may lead
to nephrocalcinosis. Serum angiotensin-converting enzyme (ACE)
17.73 Chest X-ray changes in sarcoidosis
Stage I: BHL (usually symmetrical); paratracheal nodes
often enlarged
• Often asymptomatic but may be associated with erythema nodosum
and arthralgia. The majority of cases resolve spontaneously within
1 year
Stage II: BHL and parenchymal infiltrates
• Patients may present with breathlessness or cough. The majority of
cases resolve spontaneously
Stage III: parenchymal infiltrates without BHL
• Disease less likely to resolve spontaneously
Stage IV: pulmonary fibrosis
• Can cause progression to ventilatory failure, pulmonary hypertension
and cor pulmonale
(BHL = bilateral hilar lymphadenopathy)
may provide a non-specific marker of disease activity and can
assist in monitoring the clinical course. Chest radiography has
been used to stage sarcoid (Box 1 7.73). In patients with pulmonary
infiltrates, pulmonary function testing may show a restrictive
defect accompanied by impaired gas exchange. Exercise tests
• Asymptomatic: abnormal routine chest X-ray (-30%) or abnormal
liver function tests
• Respiratory and constitutional symptoms (20-30%)
• Erythema nodosum and arthralgia (20-30%)
• Ocular symptoms (5-10%)
• Skin sarcoid (including lupus pernio) (5%)
• Superficial lymphadenopathy (5%)
• Other (1%), e.g. hypercalcaemia, diabetes insipidus, cranial nerve
palsies, cardiac arrhythmias, nephrocalcinosis
610 • RESPIRATORY MEDICINE
may reveal oxygen desaturation. Bronchoscopy may demonstrate
a ‘cobblestone’ appearance of the mucosa, and bronchial and
transbronchial biopsies usually show non-caseating granulomas,
as may samples from the mediastinal nodes obtained by EBUS.
Bronchoalveolar lavage fluid typically contains an increased
CD4:CD8 T-cell ratio. Characteristic HRCT appearances include
reticulonodular opacities that follow a perilymphatic distribution
centred on bronchovascular bundles and the subpleural areas.
PET scanning can detect extrapul monary disease.
The occurrence of erythema nodosum with BHL on chest X-ray
is often sufficient for a confident diagnosis, without recourse to a
tissue biopsy. Similarly, atypical presentation with classical HRCT
features may also be accepted. In other instances, however, the
diagnosis should be confirmed by histological examination of the
involved organ. The presence of anergy (e.g. to tuberculin skin
tests) may support the diagnosis.
Management
Patients who present with acute illness and erythema nodosum
should receive NSAIDs and, on occasion, a short course of
glucocorticoids. The majority of patients enjoy spontaneous
remission and so, if there is no evidence of organ damage,
systemic glucocorticoid therapy can be withheld for 6 months.
However, prednisolone (at a starting dose of 20-40 mg/
day) should be commenced immediately in the presence of
hypercalcaemia, pulmonary impairment, renal impairment and
uveitis. Topical glucocorticoids may be useful in cases of mild
uveitis, and inhaled glucocorticoids have been used to shorten
the duration of systemic glucocorticoid use in asymptomatic
parenchymal sarcoid. Patients should be warned that strong
sunlight may precipitate hypercalcaemia and endanger renal
function.
Features suggesting a less favourable outlook include age
over 40, Afro-Caribbean ethnicity, persistent symptoms for more
than 6 months, the involvement of more than three organs,
lupus pernio (see Fig. 17.59) and a stage lll/IV chest X-ray. In
patients with severe disease, methotrexate (10-20 mg/week),
azathioprine (50-150 mg/day) and specific tumour necrosis
factor alpha (TNF-a) inhibitors (p. 1006) have been effective.
Chloroquine, hydroxychloroquine and low-dose thalidomide
may be useful in cutaneous sarcoid with limited pulmonary
involvement. Selected patients may be referred for consideration
of single lung transplantation. The overall mortality is low (1-5%)
and usually reflects cardiac involvement or pulmonary fibrosis.
Lung diseases due to systemic
inflammatory disease
The acute respiratory distress syndrome
See page 1 98.
I Respiratory involvement in connective
tissue disorders
Pulmonary complications of connective tissue disease are
common, affecting the airways, alveoli, pulmonary vasculature,
diaphragm and chest wall muscles, and the chest wall itself.
In some instances, pulmonary disease may precede the
appearance of the connective tissue disorder (Box 17.74).
Indirect associations between connective tissue disorders and
respiratory complications include those due to disease in other
organs, e.g. thrombocytopenia causing haemoptysis; pulmonary
toxic effects of drugs used to treat the connective tissue disorder
(e.g. gold and methotrexate); and secondary infection due to the
disease itself, neutropenia or immunosuppressive drug regimens.
Rheumatoid disease
Pulmonary involvement in rheumatoid disease is important,
accounting for around 10-20% of the mortality associated with
the condition (p. 1021). The majority of cases occur within 5 years
of the rheumatological diagnosis but pulmonary manifestations
may precede joint involvement in 10-20%. Pulmonary fibrosis
is the most common pulmonary manifestation. All forms of
interstitial disease have been described but NSIP is probably
the most common. A rare variant of localised upper lobe fibrosis
and cavitation is occasionally seen.
Pleural effusion is common, especially in men with seropositive
disease. Effusions are usually small and unilateral, but can be
large and bilateral. Most resolve spontaneously. Biochemical
testing shows an exudate with markedly reduced glucose levels
and raised lactate dehydrogenase (LDH). Effusions that fail to
resolve spontaneously may respond to a short course of oral
prednisolone (30-40 mg daily) but some become chronic.
Rheumatoid pulmonary nodules are usually asymptomatic
and detected incidentally on imaging. They are most often
multiple and subpleural in site (Fig. 17.60). Solitary nodules
can mimic primary lung cancer; when multiple, the differential
1 17.74 Respiratory complications of connective tissue disorders
Disorder
Airways
Parenchyma
Pleura
Diaphragm and chest wall
Rheumatoid arthritis
Bronchitis, obliterative bronchiolitis,
bronchiectasis, crico-arytenoid
arthritis, stridor
Pulmonary fibrosis, nodules,
upper lobe fibrosis, infections
Pleurisy, effusion,
pneumothorax
Poor healing of intercostal
drain sites
Systemic lupus
erythematosus
-
Pulmonary fibrosis,
‘vasculitic’ infarcts
Pleurisy, effusion
Diaphragmatic weakness
(shrinking lungs)
Systemic sclerosis
Bronchiectasis
Pulmonary fibrosis, aspiration
pneumonia
-
Cutaneous thoracic restriction
(hidebound chest)
Dermatomyositis/
polymyositis
Lung cancer
Pulmonary fibrosis
-
Intercostal and diaphragmatic
myopathy
Granulomatosis with
polyangiitis
Epistaxis, nasal discharge crusting,
subglottic stenosis
Pulmonary nodules that may
cavitate
Pleurisy, effusion
-
Interstitial and infiltrative pulmonary diseases • 611
Fig. 17.60 Rheumatoid (necrobiotic) nodules. Thoracic CT just below
the level of the main carina, showing the typical appearance of peripheral
pleural-based nodules (arrows). The nodule in the left lower lobe shows
characteristic cavitation.
diagnoses include pulmonary metastatic disease. Cavitation
raises the possibility of TB and predisposes to pneumothorax.
The combination of rheumatoid nodules and pneumoconiosis
is known as Caplan’s syndrome (p. 615).
Bronchitis and bronchiectasis are both more common in
rheumatoid patients. Rarely, the potentially fatal condition called
obliterative bronchiolitis may develop. Bacterial lower respiratory
tract infections are frequent. Treatments given for rheumatoid
arthritis may also be relevant: glucocorticoid therapy predisposes
to infections, methotrexate may cause pulmonary fibrosis, and
anti-TNF therapy has been associated with the reactivation of TB.
Systemic lupus erythematosus
Pleuropulmonary involvement is more common in lupus than in
any other connective tissue disorder and may be a presenting
problem, when it is sometimes attributed incorrectly to infection or
pulmonary embolism. Up to two-thirds of patients have repeated
episodes of pleurisy, with or without effusions. Effusions may
be bilateral and may also involve the pericardium.
The most serious manifestation of lupus is an acute alveolitis
that may be associated with diffuse alveolar haemorrhage.
This condition is life-threatening and requires either immediate
immunosuppression with glucocorticoids or a step-up in
immunosuppressive treatment, if already started.
Pulmonary fibrosis is a relatively uncommon manifestation of
systemic lupus erythematosus (SLE). Some patients with SLE
present with exertional dyspnoea and orthopnoea but without
overt signs of pulmonary fibrosis. The chest X-ray reveals elevated
diaphragms and pulmonary function testing shows reduced lung
volumes. This condition has been described as ‘shrinking lungs’
and has been attributed to diaphragmatic myopathy.
SLE patients with antiphospholipid antibodies are at increased
risk of venous and pulmonary thromboembolism and require
life-long anticoagulation.
Systemic sclerosis
Most patients with systemic sclerosis (p. 1 037) eventually develop
diffuse pulmonary fibrosis; at necropsy more than 90% have
evidence of lung fibrosis. In some patients it is indolent, but when
progressive, as in IPF, the median survival time is around 4 years.
Pulmonary fibrosis is rare in the CREST variant of progressive
systemic sclerosis but isolated pulmonary hypertension may
develop.
Other pulmonary complications include recurrent aspiration
pneumonias secondary to oesophageal disease. Rarely, sclerosis
of the skin of the chest wall may be so extensive and cicatrising as
to restrict chest wall movement - the so-called ‘hidebound chest’.
Pulmonary eosinophilia and vasculitides
Pulmonary eosinophilia refers to the association of radiographic
(usually pneumonic) abnormalities and peripheral blood
eosinophilia. The term encompasses a group of disorders of
different aetiology (Box 17.75). Eosinophils are the predominant
cell recovered in sputum or BAL, and eosinophil products are
likely to the prime mediators of tissue damage.
Acute eosinophilic pneumonia
Acute eosinophilic pneumonia is an acute febrile illness (of less
than 5 days’ duration), characterised by diffuse pulmonary
infiltrates and hypoxic respiratory failure. The pathology is usually
that of diffuse alveolar damage. Diagnosis is confirmed by
BAL, which characteristically demonstrates >25% eosinophils.
The condition is usually idiopathic but drug reactions should
be considered. Glucocorticoids invariably induce prompt and
complete resolution.
Chronic eosinophilic pneumonia
Chronic eosinophilic pneumonia typically presents in an insidious
manner with malaise, fever, weight loss, breathlessness and
unproductive cough. It is more common in middle-aged females.
The classical chest X-ray appearance has been likened to the
photographic negative of pulmonary oedema with bilateral,
peripheral and predominantly upper lobe parenchymal shadowing.
The peripheral blood eosinophil count is almost always very high,
and the erythrocyte sedimentation rate (ESR) and total serum
IgE are elevated. BAL reveals a high proportion of eosinophils
i
Extrinsic (cause known)
• Helminths: e.g. Ascaris, Toxocara, Filaria
• Drugs: nitrofurantoin, para-aminosalicylic acid (PAS), sulfasalazine,
imipramine, chlorpropamide, phenylbutazone
• Fungi: e.g. Aspergillus fumigatus causing allergic bronchopulmonary
aspergillosis (p. 596)
Intrinsic (cause unknown)
• Cryptogenic eosinophilic pneumonia
• Eosinophilic granulomatosis with polyangiitis (formerly Churg—
Strauss syndrome), diagnosed on the basis of four or more of the
following features:
Asthma
Peripheral blood eosinophilia >1.5x1 09/L (or >10% of a total
white cell count)
Mononeuropathy or polyneuropathy
Pulmonary infiltrates
Paranasal sinus disease
Eosinophilic vasculitis on biopsy of an affected site
• Hypereosinophilic syndrome
• Polyarteritis nodosa (p. 1 042; rare)
17.75 Pulmonary eosinophilia
612 • RESPIRATORY MEDICINE
in the lavage fluid. Response to prednisolone (20-40 mg daily)
is usually dramatic. Prednisolone can usually be withdrawn after
a few weeks without relapse but long-term, low-dose therapy
is occasionally necessary.
| Tropical pulmonary eosinophilia
Tropical pulmonary eosinophilia occurs as a result of a mosquito-
borne filarial infection with Wuchereria bancrofti or Brugia malayi
(p. 290). The condition presents with fever, weight loss, dyspnoea
and asthma-like symptoms. The peripheral blood eosinophilia
is marked, as is the elevation of total IgE. High antifilarial
antibody titres are seen. The diagnosis may be confirmed by a
response to treatment with diethylcarbamazine (6 mg/kg/day for
3 weeks). Tropical pulmonary eosinophilia must be distinguished
from infection with Strongyloides stercoralis (p. 289) as, in
strongyloidiasis, glucocorticoids may cause a life-threatening
hyperinfection syndrome. Ascariasis (‘larva migrans’) and other
hookworm infestation are covered in Chapter 1 1 .
Granulomatosis with polyangiitis
Granulomatosis with polyangiitis (formerly referred to as Wegener’s
granulomatosis) is a rare vasculitic and granulomatous condition
(p. 1 041). The lung is commonly involved in systemic forms of the
disease but a limited pulmonary form may also occur. Respiratory
symptoms include cough, haemoptysis and chest pain. Associated
upper respiratory tract manifestations include nasal discharge
and crusting, and otitis media. Fever, weight loss and anaemia
are common. Radiological features include multiple nodules and
cavitation that may resemble primary or metastatic carcinoma,
or a pulmonary abscess. Tissue biopsy confirms the distinctive
pattern of necrotising granulomas and necrotising vasculitis.
Other respiratory complications include tracheal subglottic
stenosis and saddle nose deformity. The differential diagnoses
include mycobacterial and fungal infection and other forms of
pulmonary vasculitis, including polyarteritis nodosa (pulmonary
infarction), microscopic polyangiitis, eosinophilic granulomatosis
with polyangiitis (formerly Churg-Strauss syndrome: marked tissue
eosinophilia and association with asthma), necrotising sarcoid,
bronchocentric granulomatosis and lymphomatoid granulomatosis.
Goodpasture’s disease
This describes the association of pulmonary haemorrhage and
glomerulonephritis, in which IgG antibodies bind to the glomerular
or alveolar basement membranes (p. 401). Pulmonary disease
usually precedes renal involvement and includes radiographic
infiltrates and hypoxia with or without haemoptysis. It occurs
more commonly in men and almost exclusively in smokers.
Lung diseases due to irradiation and drugs
Radiotherapy
Targeting radiotherapy to certain tumours is inevitably accompanied
by irradiation of normal lung tissue. Although delivered in divided
doses, the effects are cumulative. Acute radiation pneumonitis
is typically seen within 6-12 weeks and presents with cough
and dyspnoea. This may resolve spontaneously but responds to
glucocorticoid treatment. Chronic interstitial fibrosis may present
several months later with symptoms of exertional dyspnoea and
cough. Changes are often confined to the area irradiated but may
be bilateral. Established post-irradiation fibrosis does not usually
respond to glucocorticoid treatment. The pulmonary effects of
radiation (p. 1 332) are exacerbated by treatment with cytotoxic
drugs, and the phenomenon of ‘recall pneumonitis’ describes
the appearance of radiation injury in a previously irradiated area
when chemotherapy follows radiotherapy. If the patient survives,
there are long-term risks of lung cancer.
Drugs
Drugs may cause a variety of pulmonary conditions (Box 1 7.76).
Pulmonary fibrosis may occur in response to a variety of drugs but
is seen most frequently with bleomycin, methotrexate, amiodarone
and nitrofurantoin. Eosinophilic pulmonary reactions can also
be caused by drugs. The pathogenesis may be an immune
reaction similar to that in hypersensitivity pneumonitis, which
specifically attracts large numbers of eosinophils into the lungs.
This type of reaction is well described as a rare reaction to a
variety of antineoplastic agents (e.g. bleomycin), antibiotics (e.g.
sulphonamides), sulfasalazine and the anticonvulsants phenytoin
and carbamazepine. Patients usually present with breathlessness,
cough and fever. The chest X-ray characteristically shows patchy
shadowing. Most cases resolve completely on withdrawal of
the drug, but if the reaction is severe, rapid resolution can be
obtained with glucocorticoids.
Drugs may also cause other lung diseases, such as asthma,
pulmonary haemorrhage, pleural effusion and, rarely, pleural
thickening. An ARDS-like syndrome of acute non-cardiogenic
pulmonary oedema may present with dramatic onset of
breathlessness, severe hypoxaemia and signs of alveolar oedema
i
Non-cardiogenic pulmonary oedema (ARDS)
• Hydrochlorothiazide
• Thrombolytics (streptokinase)
• Intravenous (3-adrenoceptor agonists (e.g. for premature labour)
• Aspirin and opiates (in overdose)
Non-eosinophilic alveolitis
• Amiodarone, flecainide, gold, nitrofurantoin, cytotoxic agents
- especially bleomycin, busulfan, mitomycin C, methotrexate,
sulfasalazine
Pulmonary eosinophilia
• Antimicrobials (nitrofurantoin, penicillin, tetracyclines,
sulphonamides, nalidixic acid)
• Drugs used in joint disease (gold, aspirin, penicillamine, naproxen)
• Cytotoxic drugs (bleomycin, methotrexate, procarbazine)
• Psychotropic drugs (chlorpromazine, dosulepin, imipramine)
• Anticonvulsants (carbamazepine, phenytoin)
• Others (sulfasalazine, nadolol)
Pleural disease
• Bromocriptine, amiodarone, methotrexate, methysergide
• Induction of systemic lupus erythematosus - phenytoin, hydralazine,
isoniazid
Asthma
• Pharmacological mechanisms ((3-blockers, cholinergic agonists,
aspirin and NSAIDs)
• Idiosyncratic reactions (tamoxifen, dipyridamole)
(ARDS = acute respiratory distress syndrome; NSAIDs = non-steroidal
anti-inflammatory drugs)
17.76 Drug-induced respiratory disease
Occupational and environmental lung disease • 613
on the chest X-ray. This syndrome has been reported most
frequently in cases of opiate overdose in drug addicts (p. 142) but
also after salicylate overdose, and there are occasional reports
of its occurrence after therapeutic doses of drugs, including
hydrochlorothiazides and some cytotoxic agents.
i£\
• Idiopathic pulmonary fibrosis: the most common interstitial lung
disease, with a poor prognosis.
• Chronic aspiration pneumonitis: must always be considered in
elderly patients presenting with bilateral basal shadowing on a chest
X-ray.
• Granulomatosis with polyangiitis (Wegener’s granulomatosis):
a rare condition but more common in old age. Renal involvement is
more common at presentation and upper respiratory problems are
fewer.
• Asbestosis: symptoms may appear only in old age because of the
prolonged latent period between exposure and disease.
• Drug-induced interstitial lung disease: more common,
presumably because of the increased chance of exposure to
multiple drugs.
• Rarer interstitial disease: sarcoidosis, idiopathic pulmonary
haemosiderosis, alveolar proteinosis and eosinophilic pneumonia
rarely present.
• Increased dyspnoea: coexistent muscle weakness, chest wall
deformity (e.g. thoracic kyphosis) and deconditioning may all
exacerbate dyspnoea associated with interstitial lung disease.
• Surgical lung biopsy: often inappropriate in the very frail. A
diagnosis therefore frequently depends on clinical and high-
resolution computed tomography findings alone.
Rare interstitial lung diseases
See Box 17.78.
Occupational and environmental
lung disease
The role of occupation and environmental exposure in lung
disease is a particularly important area of respiratory medicine.
Occupational lung disease is common and, in addition to the
challenges of its diagnosis and management, often involves
discussions about the workplace and, in some circumstances,
litigation. Many countries encourage the registration of cases of
occupational lung disease.
Occupational airway disease
Occupational asthma
Occupational asthma should be considered in any individual
of working age who develops new-onset asthma, particularly if
the individual reports improvement in asthma symptoms during
periods away from work, e.g. at weekends and on holidays.
Workers in certain occupations appear to be at particularly
high risk (Box 17.79) and the condition is more common in
smokers and atopic individuals. Depending on the intensity
of exposure, asthmatic symptoms usually develop within the
first few years of employment but are classically preceded by
a latent period. Symptoms of rhinoconjunctivitis often precede
17.77 Interstitial lung disease in old age
1 17.78 Rare interstitial lung diseases
Disease
Presentation
Chest X-ray
Course
Idiopathic pulmonary
haemosiderosis
Haemoptysis, breathlessness,
anaemia
Bilateral infiltrates, often perihilar
Diffuse pulmonary fibrosis
Rapidly progressive in children
Slow progression or remission in adults
Death from massive pulmonary
haemorrhage or cor pulmonale and
respiratory failure
Alveolar proteinosis
Breathlessness and cough
Occasionally fever, chest pain
and haemoptysis
Diffuse bilateral shadowing, often
more pronounced in the hilar
regions
Air bronchogram
Spontaneous remission in one-third
Whole-lung lavage or granulocyte-
macrophage colony-stimulating factor
(GM-CSF) therapy may be effective
Langerhans cell histiocytosis
(histiocytosis X)
Breathlessness, cough,
pneumothorax
Diffuse interstitial shadowing
progressing to honeycombing
Course unpredictable but may progress
to respiratory failure
Smoking cessation may be followed by
significant improvement
Poor response to immunosuppressive
treatment
Neurofibromatosis
Breathlessness and cough in a
patient with multiple organ
involvement with neurofibromas,
including skin
Bilateral reticulonodular shadowing
of diffuse interstitial fibrosis
Slow progression to death from
respiratory failure
Poor response to glucocorticoid therapy
Alveolar microlithiasis
May be asymptomatic
Breathlessness and cough
Diffuse calcified micronodular
shadowing more pronounced in
the lower zones
Slowly progressive to cor pulmonale
and respiratory failure
May stabilise in some
Lymphangioleiomyomatosis
Haemoptysis, breathlessness,
pneumothorax and chylous
effusion in females
Diffuse bilateral shadowing
CT shows characteristic
thin-walled cysts with well-defined
walls throughout both lungs
Progressive to death within 10 years
Oestrogen ablation and progesterone
therapy of doubtful value
Consider lung transplantation
Pulmonary tuberous sclerosis
Very similar to lymphangioleiomyomatosis, except occasionally occurs in men
614 • RESPIRATORY MEDICINE
Fig. 17.61 Peak flow readings in occupational asthma. In this example, an individual with suspected occupational asthma has performed serial peak
flow recording both at and away from work. The maximum, mean and minimum values are plotted daily. Days at work are indicated by the shaded areas.
The diurnal variation is displayed at the top. Here, a period away from work is followed by a marked improvement in peak flow readings and a reduction in
diurnal variation. (PEF = peak expiratory flow)
i
Most frequently reported causative agents
• Isocyanates • Animals
• Flour and grain dust • Aldehydes
• Colophony and fluxes • Wood dust
• Latex
Workers most commonly reported to occupational
asthma schemes
• Paint sprayers • Nurses
• Bakers and pastry-makers • Chemical workers
the development of asthma. When occupational asthma follows
exposure to high-molecular-weight proteins, sensitisation may
be demonstrated by skin testing or measurement of specific IgE
to the agent in question. Confirmation of occupational asthma
should be sought from lung function tests. This usually involves
serial recording of peak flow at work at least four times per day
for a minimum of 3 weeks and, if possible, including a period
away from work (Fig. 17.61). In certain circumstances, specific
challenge tests are required to confirm the diagnosis.
It may be possible to remove the worker from the implicated
agent, but when this cannot be done, consideration of personal
protective equipment and workplace hygiene may allow the
worker to retain their job and livelihood. Specialist follow-up
in such situations is highly advisable. A favourable prognosis
is indicated by a short history of symptoms and normal lung
function at diagnosis. Where reduction or avoidance of exposure
fails to bring about resolution, the management is identical to
that of any patient with asthma (p. 569).
Reactive airways dysfunction syndrome
Reactive airways dysfunction syndrome or acute irritant-induced
asthma refers to the development of a persistent asthma-like
syndrome following the inhalation of an airway irritant: typically,
a single, specific exposure to a gas, smoke, fume or vapour in
very high concentrations. Pulmonary function tests show airflow
obstruction and airway hyper-reactivity, and the management is
similar to that of asthma. Once developed, the condition often
persists but it is common for symptoms to improve over years.
Chronic obstructive pulmonary disease
While tobacco smoking remains the most important preventable
cause of COPD, there is increasing recognition that other noxious
particles and gases can cause, or aggravate, the condition.
Occupational COPD is recognised in workers exposed to
coal dust, crystalline silica and cadmium. In many parts of
the developing world, indoor air pollution from the burning of
biomass fuels in confined spaces used for cooking contributes
to the development of COPD.
Byssinosis
Byssinosis occurs in workers of cotton and flax mills exposed
to cotton brack (dried leaf and plant debris). An acute form of
the disease may occur, but more typically, byssinosis develops
after 20-30 years’ exposure. Typical symptoms include chest
tightness or breathlessness accompanied by a drop in lung
function; classically, these are most severe on the first day of
the working week (‘Monday fever’) or on return to work following
a period away. As the week progresses, symptoms improve
and the fall in lung function becomes less dramatic. Continued
exposure leads to the development of persistent symptoms and
a progressive decline in FEV^ similar to that observed in COPD.
Pneumoconiosis
Pneumoconiosis may be defined as a permanent alteration of
lung structure due to the inhalation of mineral dust and the
tissue reactions of the lung to its presence, excluding bronchitis
and emphysema (Box 17.80). Not all dusts are pathogenic. For
example, silica is highly fibrogenic, whereas iron (siderosis), tin
(stannosis) and barium (baritosis) are almost inert. Beryllium causes
an interstitial granulomatous disease similar to sarcoidosis. In
17.79 Occupational asthma
Occupational and environmental lung disease • 615
1 17.80 Lung diseases caused by exposure to inorganic dusts
Cause
Occupation
Description
Characteristic pathological features
Coal dust
Silica
Coal mining
Mining, quarrying, stone dressing, metal grinding,
pottery, boiler scaling
Coal worker’s pneumoconiosis
Silicosis
i Focal and interstitial fibrosis, centrilobular
emphysema, progressive massive fibrosis
Asbestos
Demolition, ship breaking, manufacture of fireproof
insulating materials, pipe and boiler lagging
Asbestos-related disease
Pleural plaques, diffuse pleural thickening,
acute benign pleurisy, carcinoma of lung,
interstitial fibrosis, mesothelioma
Iron oxide
Arc welding
Siderosis
Mineral deposition only
Tin oxide
Tin mining
Stannosis
Tin-laden macrophages
Beryllium
Aircraft, atomic energy and electronics industries
Berylliosis
Granulomas, interstitial fibrosis
many types of pneumoconiosis, a long period of dust exposure
is required before radiological changes appear and these may
precede clinical symptoms. The most important pneumoconioses
include coal worker’s pneumoconiosis, silicosis and asbestosis.
| Coal worker’s pneumoconiosis
Coal worker’s pneumoconiosis (CWP) follows prolonged inhalation
of coal dust. Dust-laden alveolar macrophages aggregate to form
macules in or near the centre of the secondary pulmonary lobule
and a fibrotic reaction ensues, resulting in the appearance of
scattered discrete fibrotic lesions. Classification is based on the
size and extent of radiographic nodularity. Simple coal worker’s
pneumoconiosis (SCWP) refers to the appearance of small
radiographic nodules in an otherwise asymptomatic individual.
SCWP does not impair lung function and, once exposure
ceases, will seldom progress. Progressive massive fibrosis
(PMF ) refers to the formation of conglomerate masses (mainly
in the upper lobes), which may cavitate. The development of
PMF is usually associated with cough, sputum that may be black
(melanoptysis) and breathlessness. The chest X-ray appearances
may be confused with lung cancer, TB and granulomatosis with
polyangiitis. PMF may progress, even after coal dust exposure
ceases, and in extreme cases leads to respiratory failure and
right ventricular failure.
Caplan’s syndrome describes the coexistence of rheumatoid
arthritis and rounded fibrotic nodules 0.5-5 cm in diameter.
They show pathological features similar to a rheumatoid nodule,
including central necrosis, palisading histiocytes, and a peripheral
rim of lymphocytes and plasma cells. This syndrome may also
occur in other types of pneumoconiosis.
^ Silicosis
Silicosis results from the inhalation of crystalline silica, usually in
the form of quartz, by workers cutting, grinding and polishing
stone. Classic silicosis is most common and usually manifests
after 10-20 years of continuous silica exposure, during which
time the patient remains asymptomatic. Accelerated silicosis
is associated with a much shorter duration of dust exposure
(typically 5-10 years), may present as early as after 1 year of
exposure and, as the name suggests, follows a more aggressive
course. Intense exposure to very fine crystalline silica dust can
cause a more acute disease: silicoproteinosis, similar to alveolar
proteinosis (see Box 17.78).
Radiological features are similar to those of CWP, with multiple
well-circumscribed 3-5 mm nodular opacities predominantly in
the mid- and upper zones. As the disease progresses, PMF
Fig. 17.62 Silicosis, jj] A chest X-ray from a patient with silicosis,
showing the presence of small rounded nodules, predominantly seen in the
upper zones. [§] High-resolution computed tomogram from the same
patient, demonstrating conglomeration of nodules with posterior bias.
may develop (Fig. 17.62). Enlargement of the hilar glands with
an ‘egg-shell’ pattern of calcification is said to be characteristic
but is non-specific. Silica is highly fibrogenic and the disease
is usually progressive, even when exposure ceases; hence
the affected worker should invariably be removed from further
exposure. Individuals with silicosis are at increased risk of TB
616 • RESPIRATORY MEDICINE
(silicotuberculosis), lung cancer and COPD; associations with
renal and connective tissue disease have also been described.
Berylliosis
Exposure to beryllium is encountered in the aerospace,
engineering, telecommunications and biomedical industries.
The presence of cough, progressive breathlessness, night sweats
and arthralgia in a worker exposed to dusts, fumes or vapours
containing beryllium should raise suspicion of berylliosis. The
radiographic appearances are similar in type and distribution to
those of sarcoid and biopsy shows sarcoid-like granulomas. The
diagnosis may be confirmed by specialised tests of lymphocyte
function.
Less common pneumoconioses
Siderosis refers to the development of a benign iron oxide
pneumoconiosis in welders and other iron foundry workers.
Baritosis may be seen in barium process workers and stannosis
in tin refining. Haematite lung occurs in iron ore miners and
resembles silicosis but stains the lung red. Diamond polishers
may develop hard metal disease, which is similar to UIP but the
pathology shows a giant-cell interstitial pneumonia. Workers
exposed to aluminium oxide develop bauxite pneumoconiosis,
sometimes referred to as shaver’s disease. Popcorn worker’s
lung is a form of obliterative bronchiolitis following ingestion of
diacetyl used in butter flavouring.
Lung diseases due to organic dusts
A wide range of organic agents may cause respiratory disorders
(Box 17.81). Disease results from a local immune response to
animal proteins or fungal antigens in mouldy vegetable matter.
Hypersensitivity pneumonitis is the most common of these
conditions.
1 1 17 81 Examples of lung diseases caused by
organic dusts
Disorder
Source
Antigen/agent
Farmer’s lung*
Mouldy hay, straw,
grain
Saccharopolyspora
rectivirgula (formerly
Micropolyspora faeni)
Aspergillus fumigatus
Bird fancier’s
lung*
Avian excreta,
proteins and feathers
Avian serum proteins
Malt worker’s
lung*
Mouldy maltings
Aspergillus clavatus
Cheese worker’s
lung*
Mouldy cheese
Aspergillus clavatus
Penicillium case i
Maple bark
stripper’s lung*
Bark from stored
maple
Cryptostroma corticate
Saxophone
player’s lung
Reed of any wind
instrument
Fusarium spp.
Penicillium spp.
Cladosporium spp.
Byssinosis
Textile industries
Cotton, flax, hemp dust
Inhalation
(‘humidifier’) fever
Contamination of air
conditioning
Thermophilic
actinomycetes
*Presents as hypersensitivity pneumonitis.
Hypersensitivity pneumonitis
Hypersensitivity pneumonitis (HP; also called extrinsic allergic
alveolitis) results from the inhalation of a wide variety of organic
antigens that give rise to a diffuse immune complex reaction in
the walls of alveoli and bronchioles. Common causes include
farmer’s lung and bird fancier’s lung. Other examples are shown
in Box 1 7.81 . HP is not exclusively occupational or environmental
and other important causes include medications (see Box 17.76).
The pathology of HP is consistent with both type III and type IV
immunological mechanisms (p. 83). Precipitating IgG antibodies
may be detected in the serum and a type III Arthus reaction is
believed to occur in the lung, where the precipitation of immune
complexes results in activation of complement and an inflammatory
response in the alveolar walls, characterised by the influx of
mononuclear cells and foamy histiocytes. The presence of poorly
formed non-caseating granulomas in the alveolar walls suggests
that type IV responses are also important. The distribution of the
inflammatory infiltrate is predominantly peribronchiolar. Chronic
forms of the disease may be accompanied by fibrosis. For
reasons that remain uncertain, there is a lower incidence of HP
in smokers compared to non-smokers.
Clinical features
The presentation of HP varies from an acute form to a more
indolent pattern in accordance with the antigen load. For example,
the farmer exposed to mouldy hay, as occurs when the hay
is gathered and stored damp during a wet summer, or the
pigeon fancier cleaning a large pigeon loft will, within a few
hours, report influenza-like symptoms accompanied by cough,
breathlessness and wheeze. The individual with low-level antigen
exposure, however, such as the owner of an indoor pet bird,
will typically present in a more indolent fashion with slowly
progressive breathlessness; in some cases, established fibrosis
may be present by the time the disease is recognised. Chest
auscultation typically reveals widespread end-inspiratory crackles
and squeaks.
Investigations
In cases of acute HP, the chest X-ray typically shows ill-defined
patchy airspace shadowing, which, given the systemic features,
may be confused with pneumonia. HRCT is more likely to show
bilateral ground-glass shadowing and areas of consolidation
superimposed on small centrilobar nodular opacities with an
upper and middle lobe predominance (Fig. 17.63). In more chronic
disease, features of fibrosis, such as volume loss, linear opacities
and architectural distortion, appear. In common with other fibrotic
diseases, pulmonary function tests show a restrictive ventilatory
defect with reduced lung volumes and impaired gas transfer,
dynamic tests may detect oxygen desaturation and, in more
advanced disease, type I respiratory failure is present at rest.
Diagnosis
The diagnosis of HP is usually based on the characteristic
clinical and radiological features, together with the identification
of a potential source of antigen at the patient’s home or place
of work (Box 17.82). It may be supported by a positive serum
precipitin test or by more sensitive serological investigations. It is
important, however, to be aware that the presence of precipitins
in the absence of other features does not make the diagnosis;
the great majority of farmers with positive precipitins do not
have farmer’s lung, and up to 15% of pigeon breeders may
have positive serum precipitins yet remain healthy.
Occupational and environmental lung disease • 617
Fig. 17.63 Hypersensitivity pneumonitis. \E\ High-resolution computed
tomogram showing typical patchy ground-glass opacification. [§] Histology
shows evidence of an interstitial inflammatory infiltrate in the lung, and
expanding alveolar walls, with a peribronchial distribution. Within the
infiltrate, there are foci of small, poorly defined non-caseating granulomas
(inset), which often lie adjacent to the airways. In this case, there is little in
the way of established lung fibrosis but this can be marked. A, Courtesy of
DrS. Jackson, Western General Hospital, Edinburgh. B, Courtesy of Dr
William Wallace, Dept of Pathology, Royal Infirmary of Edinburgh.
17.82 Predictive factors in the identification of
hypersensitivity pneumonitis
• Exposure to a known offending antigen
• Positive precipitating antibodies to offending antigen
• Recurrent episodes of symptoms
• Inspiratory crackles on examination
• Symptoms occurring 4-8 hours after exposure
• Weight loss
Where HP is suspected but the cause is not readily apparent,
a visit to the patient’s home or workplace should be arranged.
Occasionally, such as when an agent previously unrecognised as
causing HP is suspected, provocation testing may be necessary
to prove the diagnosis; if positive, inhalation of the relevant
antigen is followed after 3-6 hours by pyrexia and a reduction
in vital capacity and gas transfer factor. BAL fluid usually shows
an increase in the number of CD8+ T lymphocytes and
transbronchial biopsy can occasionally provide sufficient tissue
for a confident diagnosis; however, open lung biopsy may be
necessary.
Management
If it is practical, the patient should cease exposure to the inciting
agent. In some cases this may be difficult, however, because
of either implications for livelihood (e.g. farmers) or addiction to
hobbies (e.g. pigeon breeders). Dust masks with appropriate filters
may minimise exposure and may be combined with methods
of reducing levels of antigen (e.g. drying hay before storage).
In acute cases, prednisolone should be given for 3-4 weeks,
starting with an oral dose of 40 mg per day. Severely hypoxaemic
patients may require high-concentration oxygen therapy initially.
Most patients recover completely, but if unchecked, fibrosis may
progress to cause severe respiratory disability, hypoxaemia,
pulmonary hypertension, cor pulmonale and eventually death.
| Inhalation (‘humidifier’) fever
Inhalation fever shares similarities with HP. It occurs as a result of
contaminated humidifiers or air-conditioning units that release a
fine spray of microorganisms into the atmosphere. The illness is
characterised by self-limiting fever and breathlessness; permanent
sequelae are unusual. An identical syndrome can also develop
after disturbing an accumulation of mouldy hay, compost or
mulch. So-called ‘hot tub lung’ appears to be attributable
to Mycobacterium avium. Outbreaks of HP in workers using
metalworking fluids appear to be linked to Acinetobacter or
Ochrobactrum.
Asbestos-related lung and pleural diseases
Asbestos is a naturally occurring silicate. Asbestos fibres may be
classified as either chrysotile (white asbestos), which accounts
for 90% of the world’s production, or serpentine (crocidolite or
blue asbestos, and amosite or brown asbestos). The favourable
thermal and chemical insulation properties led to its extensive
use by the shipbuilding and construction industries throughout
the latter part of the 20th century. Exposure to asbestos may
be followed, after a lengthy latent period, by the development
of both pleural and pulmonary disease.
Pleural plaques
Pleural plaques are the most common manifestation of past
asbestos exposure, being discrete circumscribed areas of
hyaline fibrosis situated on the parietal pleura of the chest wall,
Fig. 17.64 Asbestos-related benign pleural plaques. Chest X-ray
showing extensive calcified pleural plaques (‘candle wax’ appearance -
arrows), particularly marked on the diaphragm and lateral pleural surfaces.
618 • RESPIRATORY MEDICINE
diaphragm, pericardium or mediastinum. They are virtually always
asymptomatic, usually being identified as an incidental finding
on a chest X-ray (Fig. 17.64) or thoracic CT scan, particularly
when partially calcified. They do not cause impairment of lung
function and are benign.
Acute benign asbestos pleurisy
Benign asbestos pleurisy is estimated to occur in around 20%
of asbestos workers but many episodes are subclinical and pass
unreported. When symptomatic, patients present with features
of pleurisy, including mild fever and systemic disturbance. The
diagnosis therefore necessitates the exclusion of other known
causes of pleurisy and pleural effusion. Repeated episodes
may be followed by the development of diffuse (visceral) pleural
thickening.
| Diffuse pleural thickening
Diffuse pleural thickening (DPT) refers to thickening of the visceral
pleura. In contrast to pleural plaques, if this is sufficiently extensive,
it may cause restrictive lung function impairment, exertional
breathlessness and, occasionally, persistent chest pain. The typical
appearances of DPT on chest X-ray include thickening of the
pleura along the chest wall and obliteration of the costophrenic
angles. Earlier manifestations detected by CT scanning include
parenchymal bands (Fig. 17.65) and ‘round atelectasis’. There
is no treatment and the condition may be progressive in around
one-third of individuals. In exceptionally severe cases, surgical
decortication may be considered. A pleural biopsy may be
required to exclude mesothelioma.
Fig. 17.65 Thoracic CT scan showing right-sided pleural thickening
and an associated parenchymal band.
Asbestosis
Fibrosis of the lung following asbestos exposure generally
requires substantial exposure over several years and is rarely
associated with low-level or bystander exposure. In common
with other fibrosing lung diseases, asbestosis usually presents
with exertional breathlessness and fine, late inspiratory crackles
over the lower zones. Finger clubbing may be present. Pulmonary
function tests and HRCT appearances are similar to those of
UIP. These features, accompanied by a history of substantial
asbestos exposure, are generally sufficient to establish the
diagnosis and lung biopsy is rarely necessary. When biopsy is
performed, asbestosis may be diagnosed when alveolar septal
fibrosis is accompanied by an average of at least two asbestos
bodies per square centimetre of lung tissue. In some cases,
asbestos fibre counts may be performed on lung biopsy material
to establish the diagnosis.
Asbestosis is usually slowly progressive and has a better
prognosis than IPF, but in advanced cases respiratory failure,
pulmonary hypertension and cor pulmonale may still develop.
About 40% of patients (who usually smoke) develop lung cancer
and 1 0% may develop mesothelioma.
Mesothelioma
Mesothelioma is a malignant tumour affecting the pleura or, less
commonly, the peritoneum. Its occurrence almost invariably
suggests past asbestos exposure, which may be low-level.
There is typically a long latent interval between first exposure
and the onset of clinical manifestations, and this accounts for
the continued increasing incidence many years after control
measures have been implemented. Around 1 in 170 of all British
men born in the 1940s will die of mesothelioma.
Pleural mesothelioma typically presents with increasing
breathlessness resulting from pleural effusion or unremitting
chest pain, reflecting involvement of the chest wall. As the
tumour progresses, it encases the underlying lung and may
invade the parenchyma, the mediastinum and the pericardium.
Metastatic disease, although not often clinically detectable in
life, is a common finding on postmortem.
Mesothelioma is almost invariably fatal. Highly selected patients
may be considered for radical surgery but, in the majority of
patients, therapy is invariably directed towards palliation of
symptoms. The use of chemotherapy may improve quality of life
and is accompanied by a small survival benefit, typically regarded
as being around 3 months. Radiotherapy can be used to control
pain and limit the risk of tumour seeding at biopsy sites. Pleural
effusions are managed with drainage and pleurodesis. Typical
figures for survival from onset of symptoms are around 1 6 months
for epithelioid tumours, 1 0 months for sarcomatoid tumours and
1 5 months for biphasic tumours, with only a minority of patients
surviving for longer periods.
Occupational lung cancer
Individuals exposed to substantial quantities of asbestos are at
increased risk of lung cancer, particularly if they smoke tobacco.
Increased risks of lung cancer have also been reported in workers
who develop silicosis and those exposed to radon gas, beryllium,
diesel exhaust fumes, cadmium, chromium, and dust and fumes
from coke plants.
Occupational pneumonia
Occupational and environmental exposures may be linked
to the development of pneumonia. Pneumococcal vaccine is
recommended for welders. Farm workers, abattoir workers and
hide factory workers may be exposed to Coxiella burnetii, the
causative agent of Q fever. The organisms are excreted from
milk, urine, faeces and amniotic fluid; they may be transmitted
by cattle ticks or contaminated dust from the milking floor, or
by drinking milk that is inadequately pasteurised. Birds (often
parrots) or budgerigars infected with Chlamydia psittaci can
cause psittacosis. Sewage workers, farmers, animal handlers and
vets run an increased risk of leptospiral pneumonia, and contact
Pulmonary vascular disease • 619
with rabbits, hares, muskrats and ground squirrels is associated
with tularaemic pneumonia, caused by Francisella tularensis.
Anthrax (wool -sorter’s disease) may occur in workers exposed
to infected hides, hair, bristle, bonemeal and animal carcases.
Pulmonary vascular disease
Pulmonary embolism
The majority of pulmonary emboli arise from the propagation of
lower limb deep vein thrombosis (p. 186). Rare causes include
septic emboli (from endocarditis affecting the tricuspid or pulmonary
valves), tumour (especially choriocarcinoma), fat following fracture
of long bones such as the femur, air, and amniotic fluid, which
may enter the mother’s circulation following delivery.
Clinical features
The diagnosis of pulmonary embolism (PE) may be aided by
asking three questions:
• Is the clinical presentation consistent with PE?
• Does the patient have risk factors for PE?
• Are there any alternative diagnoses that can explain the
patient’s presentation?
Clinical presentation varies, depending on number, size and
distribution of emboli and on underlying cardiorespiratory reserve
(Box 1 7.83). A recognised risk factor is present in 80-90% (see
Box 23.65, p. 975). The presence of one or more risk factors
increases the risk further still.
Investigations
A variety of non-specific radiographic appearances have been
described (Fig. 17.66) but the chest X-ray is most useful in
17.83 Features of pulmonary thromboemboli
Acute massive PE
Acute small/medium PE
Chronic PE
Pathophysiology
Major haemodynamic effects: icardiac
output; acute right heart failure
Occlusion of segmental pulmonary
artery -> infarction ± effusion
Chronic occlusion of pulmonary
microvasculature, right heart failure
Symptoms
Faintness or collapse, crushing central
chest pain, apprehension, severe
dyspnoea
Pleuritic chest pain, restricted
breathing, haemoptysis
Exertional dyspnoea
Late: symptoms of pulmonary
hypertension or right heart failure
Signs
Major circulatory collapse: tachycardia,
hypotension, tJVP, RV gallop rhythm,
loud P2, severe cyanosis, iurinary output
Tachycardia, pleural rub, raised
hemidiaphragm, crackles, effusion
(often blood-stained), low-grade fever
Early: may be minimal
Later: RV heave, loud P2
Terminal: signs of right heart failure
Chest X-ray
Usually normal; may be subtle oligaemia
Pleuropulmonary opacities, pleural
effusion, linear shadows, raised
hemidiaphragm
Enlarged pulmonary artery trunk,
enlarged heart, prominent right
ventricle
Electrocardiogram
S>^0313 anterior T-wave inversion, RBBB
Sinus tachycardia
RV hypertrophy and strain
Arterial blood gases
Markedly abnormal with iPa02 and
iPaC02, metabolic acidosis
May be normal or iPa02 or iPaC02
Exertional iPa02 or desaturation on
formal exercise testing
Alternative diagnoses
Myocardial infarction, pericardial
tamponade, aortic dissection
Pneumonia, pneumothorax,
musculoskeletal chest pain
Other causes of pulmonary
hypertension
(JVP = jugular venous pressure; PE = pulmonary embolism; RBBB = right bundle branch block; RV = right ventricular)
Pulmonary opacities
(any size or shape,
rarely lobar or segmental,
can cavitate)
Wedge-shaped opacity
Horizontal linear opacities
(bilateral and usually in
lower zones)
Pleural effusion
(usually blood-stained
on aspiration)
Fig. 17.66 Features of pulmonary thromboembolism/infarction on chest X-ray.
Oligaemia of lung field
Enlarged pulmonary
artery
Elevated
hemidiaphragm
620 • RESPIRATORY MEDICINE
excluding key differential diagnoses, e.g. pneumonia or
pneumothorax. Normal appearances in an acutely breathless
and hypoxaemic patient should raise the suspicion of PE, as
should bilateral changes in anyone presenting with unilateral
pleuritic chest pain.
The ECG is often normal but is useful in excluding other
important differential diagnoses, such as acute myocardial
infarction and pericarditis. The most common findings in PE
include sinus tachycardia and anterior T-wave inversion but
these are non-specific; larger emboli may cause right heart strain
revealed by an SiQ3T3 pattern, ST-segment and T-wave changes,
or the appearance of right bundle branch block.
Arterial blood gases typically show a reduced Pa02 and a
normal or low PaC02, and an increased alveolar-arterial oxygen
gradient, but may be normal in a significant minority. A metabolic
acidosis may be seen in acute massive PE with cardiovascular
collapse.
An elevated D-dimer (see Fig. 10.6, p. 187) is of limited value,
as it may be raised in a variety of other conditions, including
myocardial infarction, pneumonia and sepsis. However, low
levels, particularly in the context of a low clinical risk, have a
high negative predictive value and further investigation is usually
unnecessary (Fig. 1 7.67). The result of the D-dimer assay should
be disregarded in high-risk patients, as further investigation is
mandatory even when normal. The serum troponin I (see Box
10.3, p. 179) may be elevated, reflecting right heart strain.
CTPA is the first-line diagnostic test (Fig. 17.68). It has the
advantage of visualising the distribution and extent of the emboli
or highlighting an alternative diagnosis, such as consolidation,
pneumothorax or aortic dissection. The sensitivity of CT scanning
may be increased by simultaneous visualisation of the femoral
and popliteal veins, although this is not widely practised. As
the contrast media may be nephrotoxic, care should be taken
in patients with renal impairment, and CTPA avoided in those
with a history of allergy to iodinated contrast media. In these
cases, either V/Q scanning or ventilation/perfusion single photon
emission computed tomography (V/Q SPECT) may be considered.
Venous thromboembolism
suspected
Fig. 17.67 Algorithm for the investigation of patients with suspected
pulmonary thromboembolism. Clinical risk is based on the presence of
risk factors for venous thromboembolism and the probability of another
diagnosis. (DVT = deep vein thrombosis; PE = pulmonary embolism)
Colour Doppler ultrasound of the leg veins may be used in
patients with suspected PE, particularly if there are clinical signs
in a limb, as many will have identifiable proximal thrombus in
the leg veins.
Bedside echocardiography is extremely helpful in the differential
diagnosis and assessment of acute circulatory collapse (p. 199).
Acute dilatation of the right heart is usually present in massive
PE, and thrombus (embolism in transit) may be visible. Important
differential diagnoses, including left ventricular failure, aortic
dissection and pericardial tamponade, can also be identified.
Conventional pulmonary angiography is still useful in selected
settings or for the delivery of catheter-based therapies.
Management
General measures
Prompt recognition and treatment are potentially life-saving.
Sufficient oxygen should be given to hypoxaemic patients to
maintain arterial oxygen saturation above 90%. Circulatory shock
should be treated with intravenous fluids or plasma expander, but
inotropic agents are of limited value as the hypoxic dilated right
ventricle is already close to maximally stimulated by endogenous
catecholamines. Diuretics and vasodilators should also be avoided,
as they will reduce cardiac output. Opiates may be necessary
to relieve pain and distress but should be used with caution
Fig. 17.68 CT pulmonary angiogram. The arrow points to a saddle
embolism in the bifurcation of the pulmonary artery.
17.84 Pulmonary embolism in pregnancy
• Maternal mortality: venous thromboembolism is the leading direct
cause in the UK.
• CT pulmonary angiography: may be performed safely (0.01—
0.06 mGy). It is important to consider the risk of radiation to breast
tissue (particularly if there is a family history of breast carcinoma).
• V/Q scanning: greater radiation dose to fetus (0.11-0.22 mGy) but
significantly less to maternal breast tissue.
• In utero radiation exposure: estimated incidence of childhood
malignancy is about 1 in 16 000 per mGy.
• Warfarin: teratogenic, so pulmonary embolism should be treated
with low-molecular-weight heparin during pregnancy.
Pulmonary vascular disease • 621
in the hypotensive patient. External cardiac massage may be
successful in the moribund patient by dislodging and breaking
up a large central embolus.
Anticoagulation
The main principle of treatment for PE is anticoagulation, which
is discussed for PE and other forms of VTE on page 975.
Thrombolytic and surgical therapy
Thrombolysis is indicated in any patient presenting with acute
massive PE accompanied by cardiogenic shock. In the absence
of shock, the benefits are less clear but thrombolysis may be
considered in those presenting with right ventricular dilatation
and hypokinesis or severe hypoxaemia. Patients must be
screened carefully for haemorrhagic risk, as there is a high risk
of intracranial haemorrhage. Surgical pulmonary embolectomy may
be considered in selected patients but carries a high mortality.
Caval filters
A patient in whom anticoagulation is contraindicated, who has
suffered massive haemorrhage on anticoagulation, or recurrent
VTE despite anticoagulation, should be considered for an inferior
vena caval filter. Retrievable caval filters are particularly useful in
individuals with temporary risk factors. The caval filter should be
used only until anticoagulation can be safely initiated, at which
time the filter should be removed if possible.
Prognosis
Immediate mortality is greatest in those with echocardiographic
evidence of right ventricular dysfunction or cardiogenic shock.
Once anticoagulation is commenced, however, the risk of
mortality rapidly falls. The risk of recurrence is highest in the
first 6-1 2 months after the initial event, and at 1 0 years around
one-third of individuals will have suffered a further event.
Pulmonary hypertension
Pulmonary hypertension (PH) is defined as a mean pulmonary
artery pressure (PAP) of at least 25 mmHg at rest, as measured
by right heart catheterisation. The definition may be further refined
by consideration of the pulmonary wedge pressure (PWP), the
cardiac output and the transpulmonary pressure gradient (mean
PAP - mean PWP). The clinical classification of PH is shown
in Box 17.85. Further classification is based on the degree of
functional disturbance, assessed using the New York Heart
Association (NYHA) grades I— IV. Although respiratory failure due
to intrinsic pulmonary disease is the most common cause of PH,
severe PH may occur as a primary disorder, as a complication
of connective tissue disease (e.g. systemic sclerosis), or as a
result of chronic thromboembolic events.
Primary pulmonary hypertension (PPH) is a rare but important
disease that predominantly affects women aged between 20
and 30 years. Familial disease is rarer still but is known to be
associated with mutations in the gene encoding type II bone
morphogenetic protein receptor (BMPR2), a member of the
transforming growth factor beta (TGF-p) superfamily. Mutations
in this gene have been identified in some patients with sporadic
PH. Pathological features include hypertrophy of both the media
and the intima of the vessel wall and a clonal expansion of
endothelial cells, which take on the appearance of plexiform
lesions. There is marked narrowing of the vessel lumen and
this, together with the frequently observed in situ thrombosis,
leads to an increase in pulmonary vascular resistance and PH.
i
Pulmonary arterial hypertension
• Primary pulmonary hypertension: sporadic and familial
• Secondary to: connective tissue disease (limited cutaneous systemic
sclerosis), congenital systemic to pulmonary shunts, portal
hypertension, HIV infection, exposure to various drugs or toxins, and
persistent pulmonary hypertension of the newborn
Pulmonary venous hypertension
• Left-sided atrial or ventricular heart disease
• Left-sided valvular heart disease
• Pulmonary veno-occlusive disease
• Pulmonary capillary haemangiomatosis
Pulmonary hypertension associated with disorders of the
respiratory system and/or hypoxaemia
• Chronic obstructive pulmonary disease
• Diffuse parenchymal lung disease
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Neonatal lung disease
• Alveolar capillary dysplasia
• Severe kyphoscoliosis
Pulmonary hypertension caused by chronic thromboembolic
disease
• Thromboembolic obstruction of the proximal pulmonary arteries
• In situ thrombosis
• Sickle-cell disease
Miscellaneous
• Inflammatory conditions
• Extrinsic compression of central pulmonary veins
Adapted from Dana Point 2008. Simonneau G, Robbins IM, Beghetti M, et al.
Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol
2009; 54:S43-S54.
Clinical features
PH presents insidiously and is often diagnosed late. Typical
symptoms include breathlessness, chest pain, fatigue, palpitation
and syncope. Important signs include elevation of the JVP (with
a prominent ‘a’ wave if in sinus rhythm), a parasternal heave
(right ventricular hypertrophy), accentuation of the pulmonary
component of the second heart sound and a right ventricular
third heart sound. Signs of interstitial lung disease or cardiac, liver
or connective tissue disease may suggest the underlying cause.
Investigations
PH is suspected if an ECG shows a right ventricular ‘strain’ pattern
or a chest X-ray shows enlarged pulmonary arteries, peripheral
pruning and right ventricle enlargement (Fig. 17.69). Doppler
assessment of the tricuspid regurgitant jet by transthoracic
echocardiography provides a non-invasive estimate of the PAP,
which is equal to 4 x (tricuspid regurgitation velocity)2. Further
assessment should be by right heart catheterisation to assess
pulmonary haemodynamics, measure vasodilator responsiveness
and thus guide further therapy.
Management
Specialist centres should direct the management of PH. Diuretic
therapy should be prescribed for patients with right heart failure.
Supplemental oxygen should be given to maintain resting Pa02
17.85 Classification of pulmonary hypertension
622 • RESPIRATORY MEDICINE
Fig. 17.69 Chest X-ray showing the typical appearance in
pulmonary hypertension.
above 8 kPa (60 mmHg). Anticoagulation should be considered
unless there is an increased risk of bleeding. Digoxin may be useful
in patients who develop atrial tachyarrhythmias. Pregnancy carries
a very high risk of death and women of child-bearing age should
be counselled appropriately. Excessive physical activity that leads
to distressing symptoms should be avoided but otherwise patients
should be encouraged to remain active. Pneumococcal and
influenza vaccination should be recommended. Nitrates should
be avoided owing to the risk of hypotension, and p-blockers
are poorly tolerated. Cyclizine can aggravate PH and should
also be avoided.
Disease-targeted strategies have focused on replacing
endogenous prostacyclins with infusions of epoprostenol or
treprostinil or nebulised iloprost; blocking endothelin-mediated
vasoconstriction with agents such as bosentan, ambrisentan
or macitentan; or enhancing endogenous nitric oxide-mediated
vasodilatation with phosphodiesterase V inhibitors, such as
sildenafil or tadalafil, or the guanylate cyclase stimulator riociguat.
High-dose calcium channel blockers may be appropriate in those
with an acute vasodilator response.
Selected patients are referred for double-lung transplantation,
and pulmonary thrombo-endarterectomy may be contemplated
in those with chronic proximal pulmonary thromboembolic
disease. Atrial septostomy (the creation of a right-to-left shunt)
decompresses the right ventricle and improves haemodynamic
performance; it may be used as a bridge to transplantation or
as a palliative measure.
Diseases of the upper airway
Diseases of the nasopharynx
Allergic rhinitis
This is a disorder in which there are episodes of nasal congestion,
watery nasal discharge and sneezing. It may be seasonal or
perennial, and is due to an immediate hypersensitivity reaction
in the nasal mucosa. Seasonal antigens include pollens from
grasses, flowers, weeds or trees. Grass pollen is responsible
for hay fever, the most common type of seasonal allergic rhinitis
in northern Europe, which is at its peak between May and July.
This is a worldwide problem, however, which may be aggravated
during harvest seasons.
Perennial allergic rhinitis may be a specific reaction to antigens
derived from house dust, fungal spores or animal dander, but
similar symptoms can be caused by physical or chemical irritants,
e.g. pungent odours or fumes, including strong perfumes, cold
air and dry atmospheres. The phrase ‘vasomotor rhinitis’ is
often used in this context, as the term ‘allergic’ is a misnomer.
Clinical features
In the seasonal type, there are frequent sudden attacks of sneezing,
with profuse watery nasal discharge and nasal obstruction. These
attacks last for a few hours and are often accompanied by
smarting and watering of the eyes and conjunctival irritation. In
perennial rhinitis, the symptoms are similar but more continuous
and usually less severe. Skin hypersensitivity tests with the
relevant antigen are usually positive in seasonal allergic rhinitis
but are less useful in perennial rhinitis.
Management
In those sensitised to house dust, simple measures, such as
thorough dust removal from the bed area, leaving a window
open and renewing old pillows, are often helpful. Avoidance of
pollen and antigens from domestic pets, however desirable and
beneficial, is usually impractical.
The following medications, singly or in combination, are usually
effective in both seasonal and perennial allergic rhinitis:
• an antihistamine such as loratadine
• sodium cromoglicate nasal spray
• glucocorticoid nasal spray, e.g. beclometasone
dipropionate, fluticasone, mometasone or budesonide.
When symptoms are very severe, resistant to usual treatments
and seriously interfering with school, business or social activities,
immunotherapy (desensitisation) is also used but carries the risk
of serious reactions and must be managed in specialist centres.
Vasomotor rhinitis is often difficult to treat but may respond to
ipratropium bromide, administered into each nostril 3 times daily.
Sleep-disordered breathing
A variety of respiratory disorders affect sleep or are affected by
sleep. Cough and wheeze disturbing sleep are characteristic
of asthma, while the hypoventilation that accompanies normal
sleep can precipitate respiratory failure in patients with disordered
ventilation due to kyphoscoliosis, diaphragmatic paralysis or
muscle disease (e.g. muscular dystrophy).
In contrast, a small but important group of disorders cause
problems only during sleep. Patients may have normal lungs
and daytime respiratory function, but during sleep have either
abnormalities of ventilatory drive (central sleep apnoea) or upper
airway obstruction (obstructive sleep apnoea). Of these, the
obstructive sleep apnoea/hypopnoea syndrome is by far the
most common and important. When this coexists with COPD,
severe respiratory failure can result, even if the COPD is mild.
The sleep apnoea/hypopnoea syndrome
Recurrent upper airway obstruction during sleep, sufficient to
cause sleep fragmentation and daytime sleepiness, is thought to
affect 2% of women and 4% of men aged 30-60 in Caucasian
populations. Daytime sleepiness, especially in monotonous
situations, results in a threefold increased risk of road traffic
accidents and a ninefold increased risk of single-vehicle accidents.
Diseases of the upper airway • 623
Aetiology
Sleep apnoea results from recurrent occlusion of the pharynx
during sleep, usually at the level of the soft palate. Inspiration
results in negative pressure within the pharynx. During wakefulness,
upper airway dilating muscles, including palatoglossus and
genioglossus, contract actively during inspiration to preserve
airway patency. During sleep, muscle tone declines, impairing
the ability of these muscles to maintain pharyngeal patency. In
a minority of people, a combination of an anatomically narrow
palatopharynx and under-activity of the dilating muscles during
sleep results in inspiratory airway obstruction. Incomplete
obstruction causes turbulent flow, resulting in snoring (44%
of men and 28% of women aged 30-60 snore). More severe
obstruction triggers increased inspiratory effort and transiently
wakes the patient, allowing the dilating muscles to re-open the
airway. These awakenings are so brief that patients have no
recollection of them. After a series of loud deep breaths that
may wake their bed partner, the patient rapidly returns to sleep,
snores and becomes apnoeic once more. This cycle of apnoea
and awakening may repeat itself many hundreds of times per
night and results in severe sleep fragmentation and secondary
variations in blood pressure, which may predispose over time
to cardiovascular disease.
Predisposing factors to the sleep apnoea/hypopnoea syndrome
include male gender, which doubles the risk, and obesity, which
is found in about 50% because parapharyngeal fat deposits
tend to narrow the pharynx. Nasal obstruction or a recessed
mandible can further exacerbate the problem. Acromegaly
and hypothyroidism also predispose by causing submucosal
infiltration and narrowing of the upper airway. Sleep apnoea
is often familial, where the maxilla and mandible are back-set,
narrowing the upper airway. Alcohol and sedatives predispose
to snoring and apnoea by relaxing the upper airway dilating
muscles. As a result of marked sympathetic activation during
apnoea, sleep-disordered breathing is associated over time
with sustained hypertension and an increased risk of coronary
events and stroke. Associations have also been described
with insulin resistance, the metabolic syndrome and type 2
diabetes. Treatment of sleep apnoea reduces sympathetic drive
and blood pressure, and may also improve these associated
metabolic disorders.
Clinical features
Excessive daytime sleepiness is the principal symptom and
snoring is virtually universal. The patient usually feels that he or
she has been asleep all night but wakes unrefreshed. Bed partners
report loud snoring in all body positions and often have noticed
multiple breathing pauses (apnoeas). Difficulty with concentration,
impaired cognitive function and work performance, depression,
irritability and nocturia are other features.
Investigations
Provided that the sleepiness does not result from inadequate
time in bed or from shift work, anyone who repeatedly falls
asleep during the day when not in bed, who complains that
his or her work is impaired by sleepiness, or who is a habitual
snorer with multiple witnessed apnoeas should be referred for a
sleep assessment. A more quantitative assessment of daytime
sleepiness can be obtained by questionnaire (Box 17.86).
Overnight studies of breathing, oxygenation and sleep quality
are diagnostic (Fig. 17.70) but the level of investigation depends
on local resources and the probability of the diagnosis. The current
i
How likely are you to doze off or fall asleep in the situations described
below? Choose the most appropriate number for each situation from
the following scale:
0 = would never doze
1 = slight chance of dozing
2 = moderate chance of dozing
3 = high chance of dozing
• Sitting and reading
• Watching TV
• Sitting inactive in a public place (e.g. a theatre or a meeting)
• As a passenger in a car for an hour without a break
• Lying down to rest in the afternoon when circumstances permit
• Sitting and talking to someone
• Sitting quietly after a lunch without alcohol
• In a car, while stopped for a few minutes in the traffic
Normal subjects average 5.9 (SD 2.2) and patients with severe
obstructive sleep apnoea average 16.0 (SD 4.4).
Oxygen
saturation
(%) Baseline night CPAP night
loo-.
' 2400 0100 0200 0300 0400 T 1 2400 0100 0200 0300 0400 '
Time (hrs) Time (hrs)
Fig. 17.70 Sleep apnoea/hypopnoea syndrome: overnight oxygen
saturation trace. The left-hand panel shows the trace of a patient who had
53 apnoeas plus hypopnoeas/hour, 55 brief awakenings/hour and marked
oxygen desaturation. The right-hand panel shows the effect of continuous
positive airway pressure (CPAP) of 1 0 cmH20 delivered through a
tight-fitting nasal mask: it abolished his breathing irregularity and
awakenings, and improved oxygenation. Courtesy of Professor N.J. Douglas.
threshold for diagnosing moderate sleep apnoea/hypopnoea
syndrome is 15 or more apnoeas/hypopnoeas per hour of
sleep, where an apnoea is defined as a 10-second or longer
breathing pause and a hypopnoea a 1 0-second or longer 50%
reduction in breathing.
Several other conditions can cause daytime sleepiness but can
usually be excluded by a careful history (Box 17.87). Narcolepsy
is a rare cause of sudden-onset sleepiness, occurring in 0.05%
of the population (p. 1105). Idiopathic hypersomnolence occurs in
younger individuals and is characterised by long nocturnal sleeps.
Management
The major hazard to patients and those around them is traffic
accidents, so drivers must be strongly advised not to drive
until treatment has relieved their sleepiness. In a minority, relief
of nasal obstruction or the avoidance of alcohol may prevent
obstruction. Advice to obese patients to lose weight is often
unheeded and the majority of patients need to use continuous
17.86 Epworth sleepiness scale
624 • RESPIRATORY MEDICINE
17.87 Differential diagnosis of
persistent sleepiness
positive airway pressure (CPAP) delivered by a nasal mask
every night to splint the upper airway open. When CPAP is
tolerated, the effect is often dramatic (Fig. 17.70), with relief of
somnolence and improved daytime performance, quality of life
and survival. Unfortunately, 30-50% of patients do not tolerate
CPAP. Mandibular advancement devices that fit over the teeth
and hold the mandible forward, thus opening the pharynx, are
an alternative that is effective in some patients. There is no
evidence that palatal surgery is of benefit.
Laryngeal disorders
The larynx is commonly affected by acute self-limiting infections
(p. 581). Other disorders include chronic laryngitis, laryngeal
tuberculosis, laryngeal paralysis and laryngeal obstruction.
Tumours of the larynx are relatively common, particularly in
smokers. For further details, the reader should refer to an
otolaryngology text.
| Chronic laryngitis
The common causes are listed in Box 1 7.88. The chief symptoms
are hoarseness or loss of voice (aphonia). There is irritation of the
throat and a spasmodic cough. The disease pursues a chronic
course, frequently uninfluenced by treatment, and the voice
may become permanently impaired. Other causes of chronic
hoarseness include use of inhaled glucocorticoid treatment,
tuberculosis, laryngeal paralysis or tumour.
In some patients, a chest X-ray may reveal an unsuspected
lung cancer or pulmonary tuberculosis. If these are not found,
laryngoscopy should be performed to exclude a local structural
cause.
When no specific treatable cause is found, the voice must be
rested completely. This is particularly important in public speakers
and singers. Smoking should be avoided. Some benefit may be
obtained from frequent inhalations of medicated steam.
Laryngeal paralysis
Interruption of the motor nerve supply of the larynx is nearly
always unilateral and, because of the intrathoracic course of
i
• Repeated attacks of acute laryngitis
• Excessive use of the voice, especially in dusty atmospheres
• Heavy tobacco smoking
• Mouth-breathing from nasal obstruction
• Chronic infection of nasal sinuses
i
• Inflammatory or allergic oedema, or exudate
• Spasm of laryngeal muscles
• Inhaled foreign body
• Inhaled blood clot or vomitus in an unconscious patient
• Tumours of the larynx
• Bilateral vocal cord paralysis
• Fixation of both cords in rheumatoid disease
the left recurrent laryngeal nerve, usually left-sided. One or both
recurrent laryngeal nerves may be damaged by thyroidectomy,
carcinoma of the thyroid or anterior neck injury. Rarely, the vagal
trunk itself is involved by tumour, aneurysm or trauma.
Clinical features and management
Hoarseness always accompanies laryngeal paralysis, whatever its
cause. Paralysis of organic origin is seldom reversible, but when
only one vocal cord is affected, hoarseness may improve or even
disappear after a few weeks, as the normal cord compensates
by crossing the midline to approximate with the paralysed cord
on phonation.
‘Bovine cough’ is a characteristic feature of organic laryngeal
paralysis, and lacks the explosive quality of normal coughing
because the cords fail to close the glottis. Sputum clearance
may also be impaired. A normal cough in patients with partial
loss of voice or aphonia virtually excludes laryngeal paralysis.
Stridor is occasionally present but seldom severe, except when
laryngeal paralysis is bilateral.
Laryngoscopy is required to establish the diagnosis of laryngeal
paralysis. The paralysed cord lies in the so-called ‘cadaveric’
position, midway between abduction and adduction.
The cause should be treated, if possible. In unilateral paralysis,
persistent dysphonia may be improved by the injection of Teflon
into the affected vocal cord. In bilateral organic paralysis, tracheal
intubation, tracheostomy or plastic surgery on the larynx may
be necessary.
Psychogenic hoarseness and aphonia
Psychogenic causes of hoarseness or aphonia may be suggested
by associated symptoms in the history (p. 1187). Laryngoscopy
may be necessary, however, to exclude a physical cause. In
psychogenic aphonia, only the voluntary movement of adduction
of the vocal cords is seen to be impaired. Speech therapy may
be helpful.
Laryngeal obstruction
Laryngeal obstruction is more liable to occur in children than in
adults because of the smaller size of the glottis. Important causes
are given in Box 17.89. Sudden complete laryngeal obstruction
by a foreign body produces the clinical picture of acute asphyxia:
Lack of sleep
• Inadequate time in bed
• Extraneous sleep disruption (e.g. babies/children)
• Shiftwork
• Excessive caffeine intake
• Physical illness (e.g. pain)
Sleep disruption
• Sleep apnoea/hypopnoea syndrome
• Periodic limb movement disorder (recurrent limb movements during
non-REM sleep, frequent nocturnal awakenings; p. 1106)
Sleepiness with relatively normal sleep
• Narcolepsy
• Idiopathic hypersomnolence (rare)
• Neurological lesions (e.g. hypothalamic or upper brainstem infarcts
or tumours)
• Drugs
Psychological/psychiatric
• Depression
17.88 Causes of chronic laryngitis
17.89 Causes of laryngeal obstruction
Pleural disease • 625
violent but ineffective inspiratory efforts with indrawing of the
intercostal spaces and the unsupported lower ribs, accompanied
by cyanosis. Unrelieved, the condition progresses to coma
and death within a few minutes. When, as in most cases, the
obstruction is incomplete at first, the main clinical features are
progressive breathlessness accompanied by stridor and cyanosis.
Urgent treatment to prevent complete obstruction is needed.
Management
Transient laryngeal obstruction due to exudate and spasm, which
may occur with acute pharyngitis in children and with whooping
cough, is potentially dangerous but can usually be relieved by
steam inhalation. Laryngeal obstruction from all other causes
carries a high mortality and demands prompt treatment.
When a foreign body causes laryngeal obstruction in children,
it can often be dislodged by turning the patient head downwards
and squeezing the chest vigorously. In adults, a sudden forceful
compression of the upper abdomen (Heimlich manoeuvre) may
be effective. Otherwise, the cause of the obstruction should be
investigated by direct laryngoscopy, which may also permit the
removal of an unsuspected foreign body or the insertion of a
tube past the obstruction into the trachea. Tracheostomy must
be performed without delay if these procedures fail to relieve
obstruction but, except in dire emergencies, this should be
performed in theatre by a surgeon.
In diphtheria, antitoxin should be administered, and for
other infections the appropriate antibiotic should be given.
In angioedema, complete laryngeal occlusion can usually be
prevented by treatment with adrenaline (epinephrine; 0.5-1 mg
(0.5-1 mL of 1 : 1000) IM), chlorphenamine maleate (10-20 mg
by slow intravenous injection) and intravenous hydrocortisone
sodium succinate (200 mg).
Tracheal disorders
| Tracheal obstruction
External compression by lymph nodes containing metastases,
usually from a lung cancer, is a more frequent cause of tracheal
obstruction than primary benign or malignant tumours. The
trachea may also be compressed by a retrosternal goitre (see
Fig. 18.12, p. 648). Rare causes include an aneurysm of the
aortic arch and (in children) tuberculous mediastinal lymph nodes.
Tracheal stenosis is an occasional complication of tracheostomy,
prolonged intubation, granulomatosis with polyangiitis (Wegener’s
granulomatosis; p. 1041) or trauma.
Clinical features and management
Stridor can be detected in every patient with severe tracheal
narrowing. Bronchoscopic examination of the trachea should
be undertaken without delay to determine the site, degree and
nature of the obstruction.
Localised tumours of the trachea can be resected but
reconstruction after resection may be technically difficult.
Endobronchial laser therapy, bronchoscopically placed tracheal
stents, chemotherapy and radiotherapy are alternatives to surgery.
The choice of treatment depends on the nature of the tumour
and the general health of the patient. Benign tracheal strictures
can sometimes be dilated but may require resection.
iJTacheo-oesophageal fistula
This may be present in newborn infants as a congenital
abnormality. In adults, it is usually due to malignant lesions in
the mediastinum, such as carcinoma or lymphoma, eroding
both the trachea and oesophagus to produce a communication
between them. Swallowed liquids enter the trachea and bronchi
through the fistula and provoke coughing.
Surgical closure of a congenital fistula, if undertaken promptly,
is usually successful. There is usually no curative treatment for
malignant fistulae, and death from overwhelming pulmonary
infection rapidly supervenes.
Pleural disease
Pleurisy, pleural effusion, empyema and asbestos-associated
pleural disease have been described above.
Pneumothorax
Pneumothorax is the presence of air in the pleural space, which
can either occur spontaneously, or result from iatrogenic injury or
trauma to the lung or chest wall (Box 1 7.90). Primary spontaneous
pneumothorax occurs in patients with no history of lung disease.
Smoking, tall stature and the presence of apical subpleural blebs
are risk factors. Secondary pneumothorax affects patients with
pre-existing lung disease and is associated with higher mortality
rates (Fig. 17.71).
Where the communication between the airway and the pleural
space seals off as the lung deflates and does not re-open, the
i
Spontaneous
Primary
• No evidence of overt lung disease; air escapes from the lung into
the pleural space through rupture of a small pleural bleb, or the
pulmonary end of a pleural adhesion
Secondary
• Underlying lung disease, most commonly chronic obstructive
pulmonary disease and tuberculosis; also seen in asthma, lung
abscess, pulmonary infarcts, lung cancer and all forms of fibrotic
and cystic lung disease
Traumatic
• Iatrogenic (e.g. following thoracic surgery or biopsy) or chest wall
injury
Patient age (years)
Fig. 17.71 Bimodal age distribution for hospital admissions for
pneumothorax in England. The incidence of primary spontaneous
pneumothorax peaks in males aged 15-30 years. Secondary spontaneous
pneumothorax occurs mainly in males over 55 years.
17.90 Classification of pneumothorax
626 • RESPIRATORY MEDICINE
s s si
negative atmospheric positive, mediastinal shift
to opposite side
Fig. 17.72 Types of spontaneous pneumothorax. [A] Closed type. \W\ Open type. [C] Tension (valvular) type.
pneumothorax is referred to as ‘closed’ (Fig. 17.72A). The mean
pleural pressure remains negative, spontaneous reabsorption
of air and re-expansion of the lung occur over a few days or
weeks, and infection is uncommon. This contrasts with an ‘open’
pneumothorax, where the communication fails to seal and air
continues to pass freely between the bronchial tree and pleural
space (Fig. 17.72B). An example of the latter is a bronchopleural
fistula, which can facilitate the transmission of infection from
the airways into the pleural space, leading to empyema. An
open pneumothorax is commonly seen following rupture of an
emphysematous bulla, tuberculous cavity or lung abscess into
the pleural space.
Occasionally, the communication between the airway and
the pleural space acts as a one-way valve, allowing air to
enter the pleural space during inspiration but not to escape on
expiration. This is a tension pneumothorax. Large amounts of
trapped air accumulate progressively in the pleural space and
the intrapleural pressure rises to well above atmospheric levels.
This causes mediastinal displacement towards the opposite side,
with compression of the opposite normal lung and impairment
of systemic venous return, causing cardiovascular compromise
(Fig. 1 7.72C).
Clinical features
The most common symptoms are sudden-onset unilateral pleuritic
chest pain or breathlessness. In those individuals with underlying
lung disease, breathlessness can be severe and may not resolve
spontaneously. In patients with a small pneumothorax, physical
examination may be normal. A larger pneumothorax (>15% of
the hemithorax) results in decreased or absent breath sounds
(p. 547). The combination of absent breath sounds and a resonant
percussion note is diagnostic of pneumothorax.
By contrast, in tension pneumothorax there is rapidly
progressive breathlessness associated with a marked tachycardia,
hypotension, cyanosis and tracheal displacement away from the
side of the silent hemithorax. Occasionally, tension pneumothorax
may occur without mediastinal shift, if malignant disease or
scarring has splinted the mediastinum.
Investigations
The chest X-ray shows the sharply defined edge of the deflated
lung with complete translucency (no lung markings) between this
and the chest wall (p. 547). Care must be taken to differentiate
between a large pre-existing emphysematous bulla and a
if
• Spontaneous pneumothorax: invariably associated with underlying
lung disease in old age and has a significant mortality. Surgical or
chemical pleurodesis is advised in all such patients.
• Rib fracture: common cause of pleural-type pain; may be
spontaneous (due to coughing), traumatic or pathological.
Underlying osteomalacia may contribute to poor healing, especially
in the housebound with no exposure to sunlight.
• Tuberculosis: should always be considered and actively excluded
in any elderly patient presenting with a unilateral pleural effusion.
• Mesothelioma: more common in older individuals than younger
people due to a long latency period between asbestos exposure
(often more than 20 years) and the development of disease.
• Analgesia: frail older people are particularly sensitive to the
respiratory depressant effects of opiate-based analgesia and careful
monitoring is required when using these agents for pleural pain.
pneumothorax. CT is used in difficult cases to avoid misdirected
attempts at aspiration. X-rays may also show the extent of any
mediastinal displacement and reveal any pleural fluid or underlying
pulmonary disease.
Management
Primary pneumothorax, in which the lung edge is less than
2 cm from the chest wall and the patient is not breathless,
normally resolves without intervention. In young patients presenting
with a moderate or large spontaneous primary pneumothorax,
percutaneous needle aspiration of air is a simple and well -tolerated
alternative to intercostal tube drainage, with a 60-80% chance of
avoiding the need for a chest drain (Fig. 17.73). In patients with
significant underlying chronic lung disease, however, secondary
pneumothorax may cause respiratory distress. In these individuals,
the success rate of aspiration is much lower, and intercostal
tube drainage and inpatient observation are usually required,
particularly in those over 50 years old and those with respiratory
compromise. If there is a tension pneumothorax, immediate
release of the positive pressure by insertion of a blunt cannula
into the pleural space may be beneficial, allowing time to prepare
for chest drain insertion.
When needed, intercostal drains are inserted in the fourth, fifth
or sixth intercostal space in the mid-axillary line, connected to an
underwater seal or one-way Heimlich valve, and secured firmly
17.91 Pleural disease in old age
Diseases of the diaphragm and chest wall • 627
Fig. 17.73 Management of spontaneous pneumothorax. (1)
Immediate decompression prior to insertion of the intercostal drain. (2)
Aspirate in the second intercostal space anteriorly in the mid-clavicular line
using a 16F cannula; discontinue if resistance is felt, the patient coughs
excessively, or more than 2.5 L of air are removed. (3) The post-aspiration
chest X-ray is not a reliable indicator of whether a pleural leak remains,
and all patients should be told to attend again immediately in the event of
deterioration.
to the chest wall. Clamping of an intercostal drain is potentially
dangerous and rarely indicated. The drain should be removed
the morning after the lung has fully re-inflated and bubbling has
stopped. Continued bubbling after 5-7 days is an indication
for surgery. If bubbling in the drainage bottle stops before full
re-inflation, the tube is either blocked or kinked or displaced.
Supplemental oxygen may speed resolution, as it accelerates
the rate at which nitrogen is reabsorbed by the pleura.
Patients with a closed pneumothorax should be advised not
to fly, as the trapped gas expands at altitude. After complete
resolution, there is no clear evidence to indicate how long
patients should avoid flying for, although British Thoracic Society
guidelines suggest that waiting 1-2 weeks, with confirmation
of full inflation prior to flight, is prudent. Patients should also
be advised to stop smoking and informed about the risks of a
recurrent pneumothorax. Diving is potentially dangerous after
pneumothorax, unless a surgical pleurodesis has sealed the
lung to the chest wall.
Recurrent spontaneous pneumothorax
After primary spontaneous pneumothorax, recurrence occurs
within a year of either aspiration or tube drainage in approximately
25% of patients and should prompt definitive treatment. Surgical
pleurodesis is recommended in all patients following a second
pneumothorax and should be considered following the first
episode of secondary pneumothorax if low respiratory reserve
makes recurrence hazardous. Pleurodesis can be achieved
by pleural abrasion or parietal pleurectomy at thoracotomy or
thoracoscopy.
Diseases of the diaphragm
and chest wall
Disorders of the diaphragm
| Congenital disorders
Diaphragmatic hernias
Congenital defects of the diaphragm can allow herniation of
abdominal viscera. Posteriorly situated hernias through the
foramen of Bochdalek are more common than anterior hernias
through the foramen of Morgagni.
Eventration of the diaphragm
Abnormal elevation or bulging of one hemidiaphragm, more
often the left, results from total or partial absence of muscular
development of the septum transversum. Most eventrations are
asymptomatic and are detected by chance on X-ray in adult life
but severe respiratory distress can be caused in infancy if the
diaphragmatic muscular defect is extensive.
Acquired disorders
Elevation of a hemidiaphragm may result from paralysis or
other structural causes (Box 17.92). The phrenic nerve may be
damaged by lung cancer, disease of cervical vertebrae, tumours
of the cervical cord, shingles, trauma (including road traffic and
birth injuries), surgery, and stretching of the nerve by mediastinal
masses and aortic aneurysms. Idiopathic diaphragmatic paralysis
occasionally occurs in otherwise fit patients. Paralysis of one
hemidiaphragm results in loss of around 20% of ventilatory
capacity but may not be noticed by otherwise healthy individuals.
Ultrasound screening can be used to demonstrate paradoxical
upward movement of the paralysed hemidiaphragm on sniffing.
CT of the chest and neck is the best way to exclude occult
disease affecting the phrenic nerve.
Bilateral diaphragmatic weakness occurs in peripheral
neuropathies of any type, including Guillain-Barre syndrome
(p. 1140); in disorders affecting the anterior horn cells, e.g.
poliomyelitis (p. 1123); in muscular dystrophies; and in connective
tissue disorders, such as SLE and polymyositis (pp. 1034
and 1039).
Hiatus hernia is common (p. 791). Diaphragmatic rupture
is usually caused by a crush injury and may not be detected
until years later. Respiratory disorders that cause pulmonary
hyperinflation, e.g. emphysema, and those that result in small stiff
lungs, e.g. diffuse pulmonary fibrosis, compromise diaphragmatic
function and predispose to fatigue.
| 17.92 Causes of elevation of a hemidiaphragm
• Phrenic nerve paralysis
• Pulmonary infarction
• Eventration of the diaphragm
• Subphrenic abscess
• Decrease in volume of one
• Large volume of gas in the
lung (e.g. lobectomy, unilateral
stomach or colon
pulmonary fibrosis)
• Large tumours or cysts of the
• Severe pleuritic pain
liver
628 • RESPIRATORY MEDICINE
Deformities of the chest wall
Thoracic kyphoscoliosis
Abnormalities of alignment of the dorsal spine and their consequent
effects on thoracic shape may be caused by:
• congenital abnormality
• vertebral disease, including tuberculosis, osteoporosis and
ankylosing spondylitis
• trauma
• neuromuscular disease, such as poliomyelitis.
Simple kyphosis (increased anterior curvature of the thoracic
spine) causes less pulmonary embarrassment than kyphoscoliosis
(anteroposterior and lateral curvature). Kyphoscoliosis, if severe,
restricts and distorts expansion of the chest wall and impairs
diaphragmatic function, causing ventilation-perfusion mismatch
in the lungs. Patients with severe deformity may develop type
II respiratory failure (initially manifest during sleep), pulmonary
hypertension and right ventricular failure. They can often be
successfully treated with non-invasive ventilatory support
(p. 202).
Pectus excavatum
Pectus excavatum (funnel chest) is an idiopathic condition in
which the body of the sternum, usually only the lower end, is
curved inwards. The heart is displaced to the left and may be
compressed between the sternum and the vertebral column but
only rarely is there associated disturbance of cardiac function.
The deformity may restrict chest expansion and reduce vital
capacity. Operative correction is rarely performed, and then
only for cosmetic reasons.
|Pectus carinatum
Pectus carinatum (pigeon chest) is frequently caused by severe
asthma during childhood. Very occasionally, this deformity can
be produced by rickets or be idiopathic.
Further information
Websites
brit-thoracic.org.uk British Thoracic Society: access to guidelines on a
range of respiratory conditions.
ersnet.org European Respiratory Society: provides information on
education and research, and patient information.
ginasthma.com Global Initiative for Asthma: comprehensive overview of
asthma.
goldcopd.org Global Initiative for Chronic Obstructive Lung Disease:
comprehensive overview of COPD.
thoracic.org American Thoracic Society: provides information on
education and research, and patient information.
MWJ Strachan
JDC Newell-Price
Us
Endocrinology
Clinical examination in endocrine disease 630
An overview of endocrinology 632
Functional anatomy and physiology 632
Endocrine pathology 632
Investigation of endocrine disease 633
Presenting problems in endocrine disease 633
The thyroid gland 634
Functional anatomy, physiology and investigations 634
Presenting problems in thyroid disease 635
Thyrotoxicosis 635
Hypothyroidism 639
Asymptomatic abnormal thyroid function tests 642
Thyroid lump or swelling 642
Autoimmune thyroid disease 643
Transient thyroiditis 646
Iodine-associated thyroid disease 647
Simple and multinodular goitre 648
Thyroid neoplasia 649
Congenital thyroid disease 650
The reproductive system 651
Functional anatomy, physiology and investigations 651
Presenting problems in reproductive disease 653
Delayed puberty 653
Precocious puberty 654
Amenorrhoea 654
Male hypogonadism 655
Infertility 656
Gynaecomastia 657
Hirsutism 657
Polycystic ovarian syndrome 658
Turner’s syndrome 659
Klinefelter’s syndrome 660
The parathyroid glands 661
Functional anatomy, physiology and investigations 661
Presenting problems in parathyroid disease 661
Hypercalcaemia 661
Hypocalcaemia 662
Primary hyperparathyroidism 663
Familial hypocalciuric hypercalcaemia 664
Hypoparathyroidism 664
The adrenal glands 665
Functional anatomy and physiology 665
Presenting problems in adrenal disease 666
Cushing’s syndrome 666
Therapeutic use of glucocorticoids 670
Adrenal insufficiency 671
Incidental adrenal mass 673
Primary hyperaldosteronism 674
Phaeochromocytoma and paraganglioma 675
Congenital adrenal hyperplasia 676
The endocrine pancreas and gastrointestinal tract 676
Presenting problems in endocrine pancreas disease 676
Spontaneous hypoglycaemia 676
Gastroenteropancreatic neuro-endocrine tumours 678
The hypothalamus and the pituitary gland 679
Functional anatomy, physiology and investigations 679
Presenting problems in hypothalamic and pituitary disease 681
Hypopituitarism 681
Pituitary tumour 683
Hyperprolactinaemia/galactorrhoea 684
Prolactinoma 684
Acromegaly 685
Craniopharyngioma 687
Diabetes insipidus 687
Disorders affecting multiple endocrine glands 688
Multiple endocrine neoplasia 688
Autoimmune polyendocrine syndromes 689
Late effects of childhood cancer therapy 689
630 • ENDOCRINOLOGY
Clinical examination in endocrine disease
Endocrine disease causes clinical
syndromes with symptoms and signs
involving many organ systems. The
emphasis of the clinical examination
depends on the gland or hormone that
is thought to be abnormal.
Diabetes mellitus (described in detail in
Ch. 20) and thyroid disease are the most
common endocrine disorders.
5 Blood pressure
Hypertension in Cushing’s
and Conn’s syndromes,
phaeochromocytoma
Hypotension in adrenal
insufficiency
4 Pulse
Atrial fibrillation
Sinus tachycardia
Bradycardia
3 Skin
Hair distribution
Dry/greasy
Pigmentation/pallor
Bruising
Vitiligo
Striae
Thickness
A Vitiligo in organ-specific
autoimmune disease
2 Hands
Palmar erythema
Tremor
Acromegaly
Carpal tunnel syndrome
A Pigmentation of creases
due to high ACTH levels
in Addison’s disease
A Acromegalic hands. Note soft
tissue enlargement causing
‘spade-like’ changes
1 Height and weight
6 Head
A Prognathism in
acromegaly
Eyes
Graves’ disease
(see opposite)
Diplopia
Visual field defect
(see opposite)
Hair
Alopecia
Frontal balding
Observation
• Most examination in endocrinology
is by observation
• Astute observation can often yield
‘spot’ diagnosis of endocrine
disorders
• The emphasis of examination
varies depending on which gland
or hormone is thought to be
involved
Facial features
Mental state
Hypothyroid
Lethargy
Hirsutism
Depression
Acromegaly
Delirium
Cushing’s
Libido
7 Neck
Voice
Hoarse, e.g. hypothyroid
Virilised
Thyroid gland (see opposite)
Goitre
Nodules
8 Breasts
Galactorrhoea
Gynaecomastia
9 Body fat
Central obesity in Cushing’s
syndrome and growth hormone
deficiency
10 Bones
Fragility fractures (e.g. of
vertebrae, neck of femur or
distal radius)
11 Genitalia
Virilisation
Pubertal development
Testicular volume
12 Legs
Proximal myopathy
Myxoedema
A Pretibial myxoedema
in Graves' disease
Clinical examination in endocrine disease • 631
6 Examination of the visual
fields by confrontation
• Sit opposite patient
• You and patient cover opposite
eyes
• Bring red pin (or wiggling finger)
slowly into view from extreme of
your vision, as shown
• Ask patient to say ‘now’ when it
comes into view
• Continue to move pin into centre
of vision and ask patient to tell
you if it disappears
• Repeat in each of four quadrants
• Repeat in other eye
A bitemporal hemianopia is the
classical finding in pituitary
macroadenomas (p. 683)
6 Examination in Graves’ ophthalmopathy
Inspect from front and side
Periorbital oedema (Fig. 18.8)
Conjunctival inflammation
(chemosis)
Corneal ulceration
Proptosis (exophthalmos)*
Lid retraction*
Range of eye movements
Lid lag on descending gaze*
Diplopia on lateral gaze
Pupillary reflexes
Afferent defect (pupils constrict
further on swinging light to
unaffected eye, Box 25.22)
Normal
Proptosis
Lid
retraction
0
Normal
0
Normal
Lid lag
descent
descent
0
0
0
• Vision Right proptosis and afferent pupillary defect
Visual acuity impaired
Loss of colour vision
Visual field defects
• Ophthalmoscopy
Optic disc pallor
Papilloedema
*Note position of eyelids relative to iri
7 Examination of the thyroid gland
• Inspect from front to side
• Palpate from behind
Thyroid moves on swallowing
Check if lower margin is palpable
Cervical lymph nodes
Tracheal deviation
• Auscultate for bruit
Ask patient to hold breath
If present, check for
radiating murmur
• Percuss for retrosternal thyroid
• Consider systemic signs of
thyroid dysfunction (Box 18.7)
incl. tremor, palmar erythema,
warm peripheries, tachycardia,
lid lag
• Consider signs of Graves’
disease incl. ophthalmopathy,
pretibial myxoedema
• Check for Pemberton’s sign,
i.e. facial engorgement when
arms raised above head
Abnormal findings
Diffuse soft goitre with bruit
Graves’ disease (p. 643)
Diffuse firm goitre
Hashimoto’s thyroiditis (p. 646)
Diffuse tender goitre
Subacute thyroiditis (p. 646)
Multinodular goitre (p. 648)
± Retrosternal extension,
tracheal compression
Solitary nodule (p. 642)
Adenoma, cyst or carcinoma
Cervical lymphadenopathy
Suggests carcinoma
632 • ENDOCRINOLOGY
Endocrinology concerns the synthesis, secretion and action
of hormones. These are chemical messengers released from
endocrine glands that coordinate the activities of many different
cells. Endocrine diseases can therefore affect multiple organs and
systems. This chapter describes the principles of endocrinology
before dealing with the function and diseases of each gland
in turn.
Some endocrine disorders are common, particularly those
of the thyroid, parathyroid glands, reproductive system and p
cells of the pancreas (Ch. 20). For example, thyroid dysfunction
occurs in more than 10% of the population in areas with iodine
deficiency, such as the Himalayas, and 4% of women aged
20-50 years in the UK. Less common endocrine syndromes
are described later in the chapter.
Few endocrine therapies have been evaluated by randomised
controlled trials, in part because hormone replacement therapy
(e.g. with levothyroxine) has obvious clinical benefits and placebo-
controlled trials would be unethical. Where trials have been
performed, they relate mainly to use of therapy that is ‘optional’
and/or more recently available, such as oestrogen replacement
in post-menopausal women, androgen therapy in older men and
growth hormone replacement.
An overview of endocrinology
Functional anatomy and physiology
Some endocrine glands, such as the parathyroids and pancreas,
respond directly to metabolic signals, but most are controlled
by hormones released from the pituitary gland. Anterior pituitary
hormone secretion is controlled in turn by substances produced
in the hypothalamus and released into portal blood, which drains
directly down the pituitary stalk (Fig. 18.1). Posterior pituitary
hormones are synthesised in the hypothalamus and transported
down nerve axons, to be released from the posterior pituitary.
Hormone release in the hypothalamus and pituitary is regulated
by numerous stimuli and through feedback control by hormones
produced by the target glands (thyroid, adrenal cortex and
gonads). These integrated endocrine systems are called ‘axes’
and are listed in Figure 18.2.
A wide variety of molecules can act as hormones, including
peptides such as insulin and growth hormone, glycoproteins such
as thyroid-stimulating hormone, and amines such as noradrenaline
(norepinephrine). The biological effects of hormones are mediated
by binding to receptors. Many receptors are located on the
cell surface. These interact with various intracellular signalling
molecules on the cytosolic side of the plasma membrane to
affect cell function, usually through changes in gene expression.
Some hormones, most notably steroids, triiodothyronine (T3) and
vitamin D, bind to specific intracellular receptors. The hormone/
receptor complex forms a ligand-activated transcription factor,
which regulates gene expression directly (p. 39).
The classical model of endocrine function involves hormones
synthesised in endocrine glands, which are released into the
circulation and act at sites distant from those of secretion (as
in Fig. 18.1). However, additional levels of regulation are now
recognised. Many other organs secrete hormones or contribute
to the peripheral metabolism and activation of prohormones. A
notable example is the production of oestrogens from adrenal
androgens in adipose tissue by the enzyme aromatase. Some
hormones, such as neurotransmitters, act in a paracrine fashion
Fig. 18.1 An archetypal endocrine axis. Regulation by negative
feedback and direct control is shown, along with the equilibrium between
active circulating free hormone and bound or metabolised hormone.
to affect adjacent cells, or act in an autocrine way to affect
behaviour of the cell that produces the hormone.
Endocrine pathology
For each endocrine axis or major gland, diseases can be classified
as shown in Box 18.1. Pathology arising within the gland is
often called ‘primary’ disease (e.g. primary hypothyroidism in
Hashimoto’s thyroiditis), while abnormal stimulation of the gland is
often called ‘secondary’ disease (e.g. secondary hypothyroidism
in patients with a pituitary tumour and thyroid-stimulating hormone
i
Hormone excess
• Primary gland over-production
• Secondary to excess trophic substance
Hormone deficiency
• Primary gland failure
• Secondary to deficient trophic hormone
Hormone hypersensitivity
• Failure of inactivation of hormone
• Target organ over-activity/hypersensitivity
Hormone resistance
• Failure of activation by hormone
• Target organ resistance
Non-functioning tumours
• Benign
• Malignant
18.1 Classification of endocrine disease
An overview of endocrinology • 633
Regulation
Hypothalamus
Pituitary
Glands/targets
Target
hormones
Function
Oestrogen
Progesterone
Androgen
Prolactin
Inhibin
♦
GnRH
4
LH
FSH
I
Gonads:
testes or
ovaries
4
Oestrogen
Progesterone
Androgen
#
Reproduction
T3
Oestrogen
Stress
1
4
TRH
Dopamine
rvi
TSH
Prolactin
Anterior
*
Thyroid
1
f
Breast
■
I
T4
t3
4
Metabolism
I
Lactation
IGF-1
I
GHRH
Somatostatin
«
GH
i
Liver
1
IGF-1
IGF-BP3
4
Growth
Circadian
rhythm
Stress
Cortisol
4
CRH
Osmolality
Intravascular
volume
I
Vasopressin Oxytocin
Adrenal Distal Uterus
cortex nephron Breast
Stress
Metabolism
Water Parturition
balance Lactation
Fig. 18.2 The principal endocrine ‘axes’. Some major endocrine glands are not controlled by the pituitary. These include the parathyroid glands
(regulated by calcium concentrations, p. 661), the adrenal zona glomerulosa (regulated by the renin-angiotensin system, p. 665) and the endocrine
pancreas (Ch. 20). Italics show negative regulation. (ACTH = adrenocorticotropic hormone; CRH = corticotrophin-releasing hormone; FSH = follicle-
stimulating hormone; GH = growth hormone; GHRH = growth hormone-releasing hormone; GnRH = gonadotrophin-releasing hormone; IGF-1 = insulin-like
growth factor-1 ; IGF-BP3 = IGF-binding protein-3; LH = luteinising hormone: T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotrophin-releasing hormone;
TSH = thyroid-stimulating hormone; vasopressin = antidiuretic hormone (ADH))
deficiency). Some pathological processes can affect multiple
endocrine glands (p. 688); these may have a genetic basis
(such as organ-specific autoimmune endocrine disorders and
the multiple endocrine neoplasia (MEN) syndromes) or be a
consequence of therapy for another disease (e.g. following
treatment of childhood cancer with chemotherapy and/or
radiotherapy).
Investigation of endocrine disease
Biochemical investigations play a central role in endocrinology.
Most hormones can be measured in blood but the circumstances
in which the sample is taken are often crucial, especially for
hormones with pulsatile secretion, such as growth hormone;
those that show diurnal variation, such as cortisol; or those
that demonstrate monthly variation, such as oestrogen or
progesterone. Some hormones are labile and need special
collection, handling and processing requirements, e.g. collection
in a special tube and/or rapid transportation to the laboratory
on ice. Local protocols for hormone measurement should be
carefully followed. Other investigations, such as imaging and
biopsy, are more frequently reserved for patients who present
with a tumour. The principles of investigation are shown in Box
18.2. The choice of test is often pragmatic, taking local access
to reliable sampling facilities and laboratory measurements into
account.
Presenting problems in endocrine disease
Endocrine diseases present in many different ways and to
clinicians in many different disciplines. Classical syndromes are
described in relation to individual glands in the following sections.
Often, however, the presentation is with non-specific symptoms
(Box 1 8.3) or with asymptomatic biochemical abnormalities. In
18.2 Principles of endocrine investigation
Timing of measurement
• Release of many hormones is rhythmical (pulsatile, circadian or
monthly), so random measurement may be invalid and sequential or
dynamic tests may be required
Choice of dynamic biochemical test
• Abnormalities are often characterised by loss of normal regulation of
hormone secretion
• If hormone deficiency is suspected, choose a stimulation test
• If hormone excess is suspected, choose a suppression test
• The more tests there are to choose from, the less likely it is that
any single test is infallible, so avoid interpreting one result in
isolation
Imaging
• ‘Functional’ as well as conventional ‘structural’ imaging can be
performed as secretory endocrine cells can also take up labelled
substrates, e.g. radio-labelled iodine or octreotide
• Most endocrine glands have a high prevalence of ‘incidentalomas’,
so do not scan unless the biochemistry confirms endocrine
dysfunction or the primary problem is a tumour
Biopsy
• Many endocrine tumours are difficult to classify histologically (e.g.
adrenal carcinoma and adenoma)
addition, endocrine diseases are encountered in the differential
diagnosis of common complaints discussed in other chapters of
this book, including electrolyte abnormalities (Ch. 14), hypertension
(Ch. 16), obesity (Ch. 19) and osteoporosis (Ch. 24). Although
diseases of the adrenal glands, hypothalamus and pituitary
are relatively rare, their diagnosis often relies on astute clinical
observation in a patient with non-specific complaints, so it is
important that clinicians are familiar with their key features.
634 • ENDOCRINOLOGY
KM 18.3 Examples of non-specific presentations of
endocrine disease
Symptom
Most likely endocrine disorder(s)
Lethargy and depression
Hypothyroidism, diabetes mellitus,
hyperparathyroidism, hypogonadism,
adrenal insufficiency, Cushing’s
syndrome
Weight gain
Hypothyroidism, Cushing’s syndrome
Weight loss
Thyrotoxicosis, adrenal insufficiency,
diabetes mellitus
Polyuria and polydipsia
Diabetes mellitus, diabetes insipidus,
hyperparathyroidism, hypokalaemia
(Conn’s syndrome)
Heat intolerance
Thyrotoxicosis, menopause
Palpitation
Thyrotoxicosis, phaeochromocytoma
Headache
Acromegaly, pituitary tumour,
phaeochromocytoma
Muscle weakness
(usually proximal)
Thyrotoxicosis, Cushing’s syndrome,
hypokalaemia (e.g. Conn’s syndrome),
hyperparathyroidism, hypogonadism
Coarsening of features
Acromegaly, hypothyroidism
The thyroid gland
Diseases of the thyroid, summarised in Box 18.4, predominantly
affect females and are common, occurring in about 5% of the
population. The thyroid axis is involved in the regulation of cellular
differentiation and metabolism in virtually all nucleated cells, so
that disorders of thyroid function have diverse manifestations.
Structural diseases of the thyroid gland, such as goitre, commonly
occur in patients with normal thyroid function.
Functional anatomy, physiology and
investigations
Thyroid physiology is illustrated in Figure 18.3. The parafollicular
C cells secrete calcitonin, which is of no apparent physiological
significance in humans. The follicular epithelial cells synthesise
thyroid hormones by incorporating iodine into the amino acid
tyrosine on the surface of thyroglobulin (Tg), a protein secreted
into the colloid of the follicle. Iodide is a key substrate for thyroid
hormone synthesis; a dietary intake in excess of 100 |ig/day
is required to maintain thyroid function in adults. The thyroid
secretes predominantly thyroxine (T4) and only a small amount of
triiodothyronine (T3); approximately 85% of T3 in blood is produced
from T4 by a family of monodeiodinase enzymes that are active in
many tissues, including liver, muscle, heart and kidney. Selenium
is an integral component of these monodeiodinases. T4 can be
regarded as a prohormone, since it has a longer half-life in blood
than T3 (approximately 1 week compared with approximately
18 hours), and binds and activates thyroid hormone receptors
less effectively than T3. T4 can also be converted to the inactive
metabolite, reverse T3.
T3 and T4 circulate in plasma almost entirely (>99%) bound to
transport proteins, mainly thyroxine-binding globulin (TBG). It is
the unbound or free hormones that diffuse into tissues and exert
diverse metabolic actions. Some laboratories use assays that
measure total T4 and T3 in plasma but it is increasingly common
to measure free T4 and free T3. The theoretical advantage of the
1 18.4 Classification of thyroid disease
Primary
Secondary
Hormone excess
Graves’ disease
Multinodular goitre
Adenoma
Subacute thyroiditis
TSHoma
Hormone deficiency
Hashimoto’s thyroiditis
Atrophic hypothyroidism
Hypopituitarism
Hormone
hypersensitivity
-
Hormone resistance
Thyroid hormone
resistance syndrome
5'-monodeiodinase
deficiency
Non-functioning
tumours
Differentiated carcinoma
Medullary carcinoma
Lymphoma
free hormone measurements is that they are not influenced by
changes in the concentration of binding proteins. For example,
TBG levels are increased by oestrogen (such as in the combined
oral contraceptive pill) and this will result in raised total T3 and
T4, although free thyroid hormone levels are normal.
Production of T3 and T4 in the thyroid is stimulated by thyrotrophin
(thyroid-stimulating hormone, TSH), a glycoprotein released from
the thyrotroph cells of the anterior pituitary in response to the
hypothalamic tripeptide, thyrotrophin-releasing hormone (TRH).
A circadian rhythm of TSH secretion can be demonstrated with
a peak at 0100 hrs and trough at 1100 hrs, but the variation is
small so that thyroid function can be assessed reliably from a
single blood sample taken at any time of day and does not usually
require any dynamic stimulation or suppression tests. There is a
negative feedback of thyroid hormones on the hypothalamus and
pituitary such that in thyrotoxicosis, when plasma concentrations
of T3 and T4 are raised, TSH secretion is suppressed. Conversely,
in hypothyroidism due to disease of the thyroid gland, low T3 and
T4 are associated with high circulating TSH levels. The relationship
between TSH and T4 is classically described as inverse log-linear
(Fig. 18.4). The anterior pituitary is, though, very sensitive to
minor changes in thyroid hormone levels within the reference
range. For example, in an individual whose free T4 level is usually
15 pmol/L (1.17 ng/dL), a rise or fall of 5 pmol/L (0.39 ng/dL)
would be associated on the one hand with undetectable TSH,
and on the other hand with a raised TSH. For this reason,
TSH is usually regarded as the most useful investigation of
thyroid function. However, interpretation of TSH values without
considering thyroid hormone levels may be misleading in patients
with pituitary disease; for example, TSH is inappropriately low or
‘normal’ in secondary hypothyroidism (see Box 18.5 and Box
18.53, p. 680). Moreover, TSH may take several weeks to ‘catch
up’ with T4 and T3 levels; for example, levothyroxine therapy will
raise T4 and T3 levels within approximately 2 weeks but it may
take 4-6 weeks for the TSH to reach a steady state. Heterophilic
antibodies (host antibodies with affinity to the animal antibodies
used in biological assays, p. 242) can also interfere with the
TSH assay and cause a spurious high or low measurement.
Common patterns of abnormal thyroid function test results and
their interpretation are shown in Box 18.5.
Other modalities commonly employed in the investigation
of thyroid disease include measurement of antibodies against
The thyroid gland • 635
Tyrosine
nh2
HO VcH2-CH-COOH
f
Monoiodotyrosine (MIT)
I NH?
HO
CHo-CH-COOH
Diiodotyrosine (DIT)
I NHo
HO
ch2-ch-cooh
T
Triiodothyronine (T3)
i i nh2
HO
^ ini ^
ch2-ch-cooh
Thyroxine (T4)
ho -{yojy
nh2
ch2-ch-cooh
Reverse T3 (rT3)
ho -cyo-cy
nh2
I
ch2-ch-cooh
Colloid DJT
MIT-
DIT
Parafollicular (C) cells
Colloid
Follicular
epithelium
Target tissues
jrrl3
Increased metabolic rate
(
Mimic p-adrenergic action,
e.g. on heart rate, gut motility
Tv4 .
%y
CNS activation
Bone demineralisation
Cellular differentiation
J5tc. )
Protein-bound
T4> T3 (>99%)
Fig. 18.3 Structure and function of the thyroid gland. (1) Thyroglobulin (Tg) is synthesised and secreted into the colloid of the follicle. (2) Inorganic
iodide (l~) is actively transported into the follicular cell (‘trapping’). (3) Iodide is transported on to the colloidal surface by a transporter (pendrin, defective
in Pendred’s syndrome, p. 650) and ‘organified’ by the thyroid peroxidase enzyme, which incorporates it into the amino acid tyrosine on the surface of Tg
to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). (4) lodinated tyrosines couple to form T3 and T4. (5) Tg is endocytosed. (6) Tg is cleaved by
proteolysis to free the iodinated tyrosine and thyroid hormones. (7) lodinated tyrosine is dehalogenated to recycle the iodide. (8) T4 is converted to T3 by
5'-monodeiodinase.
Fig. 18.4 The relationship between serum thyroid-stimulating
hormone (TSH) and free T4. Due to the classic negative feedback
loop between T4 and TSH, there is an inverse relationship between
serum free T4 and the log of serum TSH. To convert pmol/L to ng/dL,
divide by 12.87.
the TSH receptor or other thyroid antigens (see Box 18.8),
radioisotope imaging, fine needle aspiration biopsy and ultrasound.
Their use is described below.
Presenting problems in thyroid disease
The most common presentations are hyperthyroidism
(thyrotoxicosis), hypothyroidism and enlargement of the thyroid
(goitre or thyroid nodule). Widespread availability of thyroid
function tests has led to the increasingly frequent identification
of patients with abnormal results who either are asymptomatic
or have non-specific complaints such as tiredness and
weight gain.
| Thyrotoxicosis
Thyrotoxicosis describes a constellation of clinical features arising
from elevated circulating levels of thyroid hormone. The most
common causes are Graves’ disease, multinodular goitre and
autonomously functioning thyroid nodules (toxic adenoma) (Box
18.6). Thyroiditis is more common in parts of the world where
relevant viral infections occur, such as North America.
Clinical assessment
The clinical manifestations of thyrotoxicosis are shown in
Box 18.7 and an approach to differential diagnosis is given in
636 • ENDOCRINOLOGY
18.5 How to interpret thyroid function test results
TSH
t4
T3
Most likely interpretation(s)
U.D.
Raised
Raised
Primary thyrotoxicosis
U.D. or low
Raised
Normal
Over-treatment of hypothyroidism with levothyroxine
Factitious thyrotoxicosis
U.D.
Normal1
Raised
Primary T3 toxicosis
U.D.
Normal1
Normal1
Subclinical thyrotoxicosis
U.D. or low
Raised
Low or
Non-thyroidal illness
normal
Amiodarone therapy
U.D. or low
Low
Raised
Over-treatment of hypothyroidism with liothyronine (T3)
U.D.
Low
Low
Secondary hypothyroidism4
Transient thyroiditis in evolution
Normal
Low
Low2
Secondary hypothyroidism4
Mildly elevated 5—20 mlU/L
Low
Low2
Primary hypothyroidism
Secondary hypothyroidism4
Elevated > 20 mlU/L
Low
Low2
Primary hypothyroidism
Mildly elevated 5—20 mlU/L
Normal3
Normal2
Subclinical hypothyroidism
Elevated 20-500 mlU/L
Normal
Normal
Artefact
Heterophilic antibodies (host antibodies with affinity to the animal
antibodies used in TSH assays)
Elevated
Raised
Raised
Non-adherence to levothyroxine replacement - recent ‘loading’ dose
Secondary thyrotoxicosis4
Thyroid hormone resistance
Usually upper part of reference range. 2T3 is not a sensitive indicator of hypothyroidism and should not be requested. 3Usually lower part of reference range. 4i.e. Secondary
to pituitary or hypothalamic disease. Note that TSH assays may report detectable TSH.
(TSH = thyroid-stimulating hormone; U.D. = undetectable)
KM 18.6 Causes of thyrotoxicosis and their relative
frequencies
Cause
Frequency (%)
Graves’ disease
76
Multinodular goitre
14
Solitary thyroid adenoma
5
Thyroiditis
Subacute (de Quervain’s)2
3
Post-partum2
0.5
Iodide-induced
Drugs (amiodarone)2
1
Radiographic contrast media2
-
Iodine supplementation programme2
-
Extrathyroidal source of thyroid hormone
Factitious thyrotoxicosis2
0.2
Struma ovarii2'3
-
TSH-induced
TSH-secreting pituitary adenoma
0.2
Choriocarcinoma and hydatidiform mole4
-
Follicular carcinoma ± metastases
0.1
In a series of 2087 patients presenting to the Royal Infirmary of Edinburgh over
a 10-year period. Characterised by negligible radioisotope uptake. 3i.e. Ovarian
teratoma containing thyroid tissue. 4Human chorionic gonadotrophin has
thyroid-stimulating activity.
(TSH = thyroid-stimulating hormone)
Figure 18.5. The most common symptoms are weight loss with
a normal or increased appetite, heat intolerance, palpitations,
tremor and irritability. Tachycardia, palmar erythema and lid lag
are common signs. Not all patients have a palpable goitre, but
experienced clinicians can discriminate the diffuse soft goitre of
Graves’ disease from the irregular enlargement of a multinodular
goitre. All causes of thyrotoxicosis can cause lid retraction and lid
lag, due to potentiation of sympathetic innervation of the levator
palpebrae muscles, but only Graves’ disease causes other features
of ophthalmopathy, including periorbital oedema, conjunctival
irritation, exophthalmos and diplopia. Pretibial myxoedema
(p. 646) and the rare thyroid acropachy (a periosteal hypertrophy,
indistinguishable from finger clubbing) are also specific to Graves’
disease.
Investigations
The first-line investigations are serum T3, T4 and TSH. If abnormal
values are found, the tests should be repeated and the abnormality
confirmed in view of the likely need for prolonged medical
treatment or destructive therapy. In most patients, serum T3 and
T4 are both elevated, but T4 is in the upper part of the reference
range and T3 is raised (T3 toxicosis) in about 5%. Serum TSH is
undetectable in primary thyrotoxicosis, but values can be raised
in the very rare syndrome of secondary thyrotoxicosis caused
by a TSH-producing pituitary adenoma. When biochemical
thyrotoxicosis has been confirmed, further investigations should
be undertaken to determine the underlying cause, including
measurement of TSH receptor antibodies (TRAb, elevated in
Graves’ disease; Box 18.8) and radioisotope scanning, as shown
in Figure 18.5. Other non-specific abnormalities are common
The thyroid gland • 637
1 18.7 Clinical features of thyroid dysfunction
Thyrotoxicosis
Hypothyroidism
Symptoms
Signs
Symptoms
Signs
Common
Weight loss despite normal or
Weight loss
Weight gain
Weight gain
increased appetite
Tremor
Cold intolerance
Heat intolerance, sweating
Palmar erythema
Fatigue, somnolence
Palpitations, tremor
Sinus tachycardia
Dry skin
Dyspnoea, fatigue
Lid retraction, lid lag
Dry hair
Irritability, emotional lability
Menorrhagia
Less common
Osteoporosis (fracture, loss of
Goitre with bruit1
Constipation
Hoarse voice
height)
Atrial fibrillation2
Hoarseness
Facial features:
Diarrhoea, steatorrhoea
Systolic hypertension/increased
Carpal tunnel syndrome
Purplish lips
Angina
pulse pressure
Alopecia
Malar flush
Ankle swelling
Cardiac failure2
Aches and pains
Periorbital oedema
Anxiety, psychosis
Hyper-reflexia
Muscle stiffness
Loss of lateral eyebrows
Muscle weakness
Ill-sustained clonus
Deafness
Anaemia
Periodic paralysis (predominantly
Proximal myopathy
Depression
Carotenaemia
in Chinese and other Asian
Bulbar myopathy2
Infertility
Erythema ab igne
groups)
Bradycardia hypertension
Pruritus, alopecia
Delayed relaxation of reflexes
Amenorrhoea/oligomenorrhoea
Dermal myxoedema
Infertility, spontaneous abortion
Loss of libido, impotence
Excessive lacrimation
Rare
Vomiting
Gynaecomastia
Psychosis (myxoedema madness)
Ileus, ascites
Apathy
Spider naevi
Galactorrhoea
Pericardial and pleural effusions
Anorexia
Onycholysis
Impotence
Cerebellar ataxia
Exacerbation of asthma
Pigmentation
Myotonia
In Graves’ disease only. 2Features found particularly in elderly patients.
18.8 Prevalence of thyroid autoantibodies (%)
Antibodies to:
Thyroid peroxidase1
Thyroglobulin
TSH receptor
Normal population
8-27
5-20
0
Graves’ disease
50-80
50-70
80-95
Autoimmune hypothyroidism
90-100
80-90
10-20
Multinodular goitre
-30-40
-30-40
0
Transient thyroiditis
-30-40
-30-40
0
Thyroid peroxidase (IPO) antibodies are the principal component of what was previously measured as thyroid ‘microsomal’ antibodies. Thyroid-stimulating hormone
receptor antibodies (TRAb) can be agonists (stimulatory, causing Graves’ thyrotoxicosis) or antagonists (‘blocking’, causing hypothyroidism).
(Box 18.9). An electrocardiogram (ECG) may demonstrate sinus
tachycardia or atrial fibrillation.
Radio-iodine uptake tests measure the proportion of isotope that
is trapped in the whole gland but have been largely superseded by
99mtechnetiurn scintigraphy scans, which also indicate trapping, are
quicker to perform with a lower dose of radioactivity, and provide
a higher-resolution image. In low-uptake thyrotoxicosis, the cause
is usually a transient thyroiditis (p. 646). Occasionally, patients
induce ‘factitious thyrotoxicosis’ by consuming excessive amounts
of a thyroid hormone preparation, most often levothyroxine. The
exogenous levothyroxine suppresses pituitary TSH secretion
and hence iodine uptake, serum thyroglobulin and release of
endogenous thyroid hormones. The T4:T3 ratio (typically 30:1 in
conventional thyrotoxicosis) is increased to above 70:1 because
circulating T3 in factitious thyrotoxicosis is derived exclusively
from the peripheral monodeiodination of T4 and not from thyroid
secretion. The combination of negligible iodine uptake, high
T4:T3 ratio and a low or undetectable thyroglobulin is diagnostic.
Management
Definitive treatment of thyrotoxicosis depends on the underlying
cause and may include antithyroid drugs, radioactive iodine or
surgery. A non-selective p-adrenoceptor antagonist ((3-blocker),
such as propranolol (160 mg daily) or nadolol (40-80 mg daily),
will alleviate but not abolish symptoms in most patients within
24-48 hours. Beta-blockers should not be used for long-term
638 • ENDOCRINOLOGY
r
Clinically thyrotoxic
ITSH and tT3 ± T4
T
Scenario?
Possible non-thyroidal illness
Repeat when acute
illness has resolved
Any features of Graves’ disease?
• Diffuse goitre with bruit
• Ophthalmopathy1
• Pretibial myxoedema
• Positive TSH receptor antibodies2
Yes
No
Any features of non-Graves’
thyrotoxicosis?
• Recent (< 6 months) pregnancy
• Neck pain/flu-like illness
• Drugs (amiodarone, T4)3
• Palpable multinodular goitre
or solitary nodule
1
No
Yes
▼
Thyroid scintigraphy4
Low-uptake thyrotoxicosis
• Transient thyroiditis
• Extrathyroidal T4 source
Toxic
adenoma
Toxic
multinodular goitre
Graves’
disease
Fig. 18.5 Establishing the differential diagnosis in thyrotoxicosis. Graves’ ophthalmopathy refers to clinical features of exophthalmos and periorbital
and conjunctival oedema, not simply the lid lag and lid retraction that can occur in all forms of thyrotoxicosis. 2Thyroid-stimulating hormone (TSH) receptor
antibodies are very rare in patients without autoimmune thyroid disease but occur in only 80-95% of patients with Graves’ disease; a positive test is
therefore confirmatory but a negative test does not exclude Graves’ disease. Other thyroid antibodies (e.g. anti-peroxidase and anti-thyroglobulin antibodies)
are unhelpful in the differential diagnosis since they occur frequently in the population and are found with several of the disorders that cause thyrotoxicosis.
3Scintigraphy is not necessary in most cases of drug-induced thyrotoxicosis. 4 99mTechnetiurn pertechnetate scans of patients with thyrotoxicosis. In
low-uptake thyrotoxicosis, most commonly due to a viral, post-partum or iodine-induced thyroiditis, there is negligible isotope detected in the region of the
thyroid, although uptake is apparent in nearby salivary glands (not shown here). In a toxic adenoma there is lack of uptake of isotope by the rest of the
thyroid gland due to suppression of serum TSH. In multinodular goitre there is relatively low, patchy uptake within the nodules; such an appearance is not
always associated with a palpable thyroid. In Graves’ disease there is diffuse uptake of isotope.
18.9 Non-specific laboratory abnormalities in thyroid
dysfunction
Thyrotoxicosis
• Serum enzymes: raised alanine aminotransferase, y-glutamyl
transferase (GGT), and alkaline phosphatase from liver and
bone
• Raised bilirubin
• Mild hypercalcaemia
• Glycosuria: associated diabetes mellitus, ‘lag storage’
glycosuria
Hypothyroidism
• Serum enzymes: raised creatine kinase, aspartate aminotransferase,
lactate dehydrogenase (LDH)
• Hypercholesterolemia
• Anaemia: normochromic normocytic or macrocytic
• Hyponatraemia
*These abnormalities are not useful in differential diagnosis, so the tests should
be avoided and any further investigation undertaken only if abnormalities persist
when the patient is euthyroid.
treatment of thyrotoxicosis but are extremely useful in the
short term, while patients are awaiting hospital consultation or
following 131 1 therapy. Verapamil may be used as an alternative
to p-blockers, e.g. in patients with asthma, but usually is only
effective in improving tachycardia and has little effect on the
other systemic manifestations of thyrotoxicosis.
Atrial fibrillation in thyrotoxicosis
Atrial fibrillation occurs in about 1 0% of patients with thyrotoxicosis.
The incidence increases with age, so that almost half of all males
with thyrotoxicosis over the age of 60 are affected. Moreover,
subclinical thyrotoxicosis (p. 642) is a risk factor for atrial fibrillation.
Characteristically, the ventricular rate is little influenced by digoxin
but responds to the addition of a p-blocker. Thromboembolic
vascular complications are particularly common in thyrotoxic
atrial fibrillation so that anticoagulation is required, unless
contraindicated. Once thyroid hormone and TSH concentrations
have been returned to normal, atrial fibrillation will spontaneously
revert to sinus rhythm in about 50% of patients but cardioversion
may be required in the remainder.
The thyroid gland • 639
18.10 The Burch-Wartofsky scoring system for
thyrotoxic crisis
Diagnostic parameters
Score
Temperature (°C)
<37.1
0
37.2-37.7
5
37.8-38.2
10
38.3-38.8
15
38.9-39.2
20
39.3-39.9
25
>40.0
30
Central nervous system
Absent
0
Mild (agitation)
10
Moderate (delirium, psychosis, extreme lethargy)
20
Severe (seizures, coma)
30
Gastrointestinal system
Absent
0
Moderate (diarrhoea, nausea, vomiting, abdominal pain)
10
Severe (unexplained jaundice)
20
Cardiovascular system: pulse rate (beats/min)
<89
0
90-109
5
110-119
10
120-129
15
130-139
20
>140
25
Atrial fibrillation
Absent
0
Present
10
Congestive heart failure
Absent
0
Mild (peripheral oedema)
5
Moderate (bi -basal crepitations)
10
Severe (pulmonary oedema)
20
Precipitant history
Absent
Present
0
10
Scores should be totalled.
Score >45 = likely thyrotoxic crisis; 25-44 = impending
thyrotoxic crisis; <25 = unlikely to represent thyroid crisis.
Adapted from Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid
storm. Endocrinol Metab Clin N Am 1993; 22:263-277.
Thyrotoxic crisis (‘thyroid storm’)
This is a rare but life-threatening complication of thyrotoxicosis.
The most prominent signs are fever, agitation, delirium, tachycardia
or atrial fibrillation and, in the older patient, cardiac failure. The
Burch-Wartofsky system may be used to help establish the
diagnosis (Box 18.10). Thyrotoxic crisis is a medical emergency
and has a mortality of 10% despite early recognition and
treatment. It is most commonly precipitated by infection in a
patient with previously unrecognised or inadequately treated
thyrotoxicosis. It may also develop in known thyrotoxicosis
shortly after thyroidectomy in an ill-prepared patient or within a
few days of 131 1 therapy, when acute radiation damage may lead
to a transient rise in serum thyroid hormone levels.
Patients should be rehydrated and given propranolol, either
orally (80 mg 4 times daily) or intravenously (1-5 mg 4 times
daily). Sodium ipodate (500 mg per day orally) will restore
serum T3 levels to normal in 48-72 hours. This is a radiographic
contrast medium that not only inhibits the release of thyroid
hormones but also reduces the conversion of T4 to T3, and
is therefore more effective than potassium iodide or Lugol’s
solution. Dexamethasone (2 mg 4 times daily) and amiodarone
have similar effects. Oral carbimazole 40-60 mg daily (p. 644)
should be given to inhibit the synthesis of new thyroid hormone.
If the patient is unconscious or uncooperative, carbimazole can
be administered rectally with good effect but no preparation is
available for parenteral use. After 1 0-1 4 days the patient can
usually be maintained on carbimazole alone.
| Hypothyroidism
Hypothyroidism is a common condition with various causes (Box
18.11), but autoimmune disease (Hashimoto’s thyroiditis) and
thyroid failure following 131 1 or surgical treatment of thyrotoxicosis
account for over 90% of cases, except in areas where iodine
deficiency is endemic. Women are affected approximately six
times more frequently than men.
Clinical assessment
The clinical presentation depends on the duration and severity
of the hypothyroidism. Those in whom complete thyroid failure
has developed insidiously over months or years may present with
many of the clinical features listed in Box 1 8.7. A consequence of
prolonged hypothyroidism is the infiltration of many body tissues
by the mucopolysaccharides hyaluronic acid and chondroitin
1 8.1 1 Causes of hypothyroidism
Anti-TPO
Causes
antibodies1
Goitre
Autoimmune
Hashimoto’s thyroiditis
++
±
Spontaneous atrophic hypothyroidism
-
-
Graves’ disease with TSH receptor¬
blocking antibodies
+
±
Iatrogenic
Radioactive iodine ablation
+
+
Thyroidectomy
Drugs:
+
—
Carbimazole, methimazole,
propylthiouracil
+
±
Amiodarone
+
+
Lithium
-
+
Transient thyroiditis
Subacute (de Quervain’s) thyroiditis
+
±
Post-partum thyroiditis
+
±
Iodine deficiency
e.g. In mountainous regions
_
++
Congenital
Dyshormonogenesis
++
Thyroid aplasia
-
-
Infiltrative
Amyloidosis, Riedel’s thyroiditis,
sarcoidosis etc.
+
++
Secondary hypothyroidism
TSH deficiency
-
-
!As shown in Box 18.8, thyroid autoantibodies are common in the healthy
population, so might be present in anyone. ++ high titre; + more likely to be
detected than in the healthy population; -
± may be present; ++ characteristic.
not especially likely. 2Goitre:
- absent;
(TP0 = thyroid peroxidase; TSH = thyroid-stimulating hormone)
640 • ENDOCRINOLOGY
Fig. 18.6 An approach to adults with suspected primary hypothyroidism. This scheme ignores congenital causes of hypothyroidism (see Box 18.11),
such as thyroid aplasia and dyshormonogenesis (associated with nerve deafness in Pendred’s syndrome, p. 650), which are usually diagnosed in
childhood, 1m mu no reactive thyroid-stimulating hormone (TSH) may be detected at normal or even modestly elevated levels in patients with pituitary failure;
unless T4 is only marginally low, TSH should be > 20 mlll/L to confirm the diagnosis of primary hypothyroidism. 2The usual abnormality in sick euthyroidism
is a low TSH but any pattern can occur. 3Thyroid peroxidase (TPO) antibodies are highly sensitive but not very specific for autoimmune thyroid disease (see
Boxes 18.8 and 18.11). Specialist advice is most appropriate where indicated. Secondary hypothyroidism is rare, but is suggested by deficiency of
pituitary hormones or by clinical features of pituitary tumour such as headache or visual field defect (p. 683). Rare causes of hypothyroidism with goitre
include dyshormonogenesis and infiltration of the thyroid (see Box 18.1 1).
sulphate, resulting in a low-pitched voice, poor hearing, slurred
speech due to a large tongue, and compression of the median
nerve at the wrist (carpal tunnel syndrome). Infiltration of the
dermis gives rise to non-pitting oedema (myxoedema), which
is most marked in the skin of the hands, feet and eyelids.
The resultant periorbital puffiness is often striking and may be
combined with facial pallor due to vasoconstriction and anaemia,
or a lemon-yellow tint to the skin caused by carotenaemia, along
with purplish lips and malar flush. Most cases of hypothyroidism
are not clinically obvious, however, and a high index of suspicion
needs to be maintained so that the diagnosis is not overlooked
in individuals complaining of non-specific symptoms such as
tiredness, weight gain, depression or carpal tunnel syndrome.
The key discriminatory features in the history and examination
are highlighted in Figure 18.6. Care must be taken to identify
patients with transient hypothyroidism, in whom life-long
levothyroxine therapy is inappropriate. This is often observed
during the first 6 months after thyroidectomy or 131 1 treatment
of Graves’ disease, in the post-thyrotoxic phase of subacute
thyroiditis and in post-partum thyroiditis. In these conditions,
levothyroxine treatment is not always necessary, as the patient
may be asymptomatic during the short period of thyroid failure.
Investigations
In the vast majority of cases, hypothyroidism results from an
intrinsic disorder of the thyroid gland (primary hypothyroidism).
In this situation, serum T4 is low and TSH is elevated, usually in
excess of 20mlU/L. Measurements of serum T3 are unhelpful
since they do not discriminate reliably between euthyroidism and
hypothyroidism. Secondary hypothyroidism is rare and is caused
by failure of TSH secretion in an individual with hypothalamic
or anterior pituitary disease. Other non-specific abnormalities
are shown in Box 18.9. In severe, prolonged hypothyroidism,
the ECG classically demonstrates sinus bradycardia with low-
voltage complexes and ST-segment and T-wave abnormalities.
Measurement of thyroid peroxidase antibodies is helpful but
further investigations are rarely required (Fig. 18.6).
Management
Treatment is with levothyroxine replacement. It is customary to
start with a low dose of 50 \ig per day for 3 weeks, increasing
thereafter to 1 00 jig per day for a further 3 weeks and finally to
a maintenance dose of 100-150 jig per day. In younger patients,
it is safe to initiate levothyroxine at a higher dose (e.g. 100 jig
per day), to allow a more rapid normalisation of thyroid hormone
levels. Levothyroxine has a half-life of 7 days so it should always
be taken as a single daily dose and at least 6 weeks should pass
before repeating thyroid function tests (as TSH takes several
weeks to reach a steady state) and adjusting the dose. Patients
feel better within 2-3 weeks. Reduction in weight and periorbital
puffiness occurs quickly but the restoration of skin and hair
texture and resolution of any effusions may take 3-6 months. As
illustrated in Figure 18.6, most patients do not require specialist
review but will need life-long levothyroxine therapy.
The dose of levothyroxine should be adjusted to maintain serum
TSH within the reference range. To achieve this, serum T4 often
needs to be in the upper part of the reference range because
the T3 required for receptor activation is derived exclusively from
conversion of T4 within the target tissues, without the usual
contribution from thyroid secretion. Some physicians advocate
The thyroid gland • 641
18.12 Situations in which an adjustment of the dose
of levothyroxine may be necessary
Increased dose required
Use of other medication
• Increase T4 clearance: phenobarbital, phenytoin, carbamazepine,
rifampicin, sertraline*, chloroquine*
• Interfere with intestinal T4 absorption: colestyramine, sucralfate,
aluminium hydroxide, ferrous sulphate, dietary fibre supplements,
calcium carbonate
Pregnancy or oestrogen therapy
• Increases concentration of serum thyroxine-binding globulin
After surgical or 131l ablation of Graves’ disease
• Reduces thyroidal secretion with time
Malabsorption
Decreased dose required
Ageing
• Decreases T4 clearance
Graves’ disease developing in patient with long-standing primary
hypothyroidism
• Switch from production of blocking to stimulating TSH receptor
antibodies
*Mechanism not fully established.
combined replacement with T4 (levothyroxine) and T3 (liothyronine)
or preparations of animal thyroid extract but this approach remains
controversial and is not supported by robust evidence. Some
patients remain symptomatic despite normalisation of TSH and
may wish to take extra levothyroxine, which suppresses TSH.
However, suppressed TSH is a risk factor for osteoporosis and
atrial fibrillation (see below; subclinical thyrotoxicosis), so this
approach cannot be recommended.
It is important to measure thyroid function every 1-2 years once
the dose of levothyroxine is stabilised. This encourages adherence
to therapy and allows adjustment for variable underlying thyroid
activity and other changes in levothyroxine requirements (Box
18.12). Some patients have a persistent elevation of serum TSH
despite an ostensibly adequate replacement dose of levothyroxine;
most commonly, this is a consequence of suboptimal adherence
to therapy. There may be differences in bioavailability between
the numerous generic preparations of levothyroxine and so, if an
individual is experiencing marked changes in serum TSH despite
optimal adherence, the prescription of a branded preparation of
levothyroxine could be considered. There is some limited evidence
that suggests levothyroxine absorption may be better when the
drug is taken before bed and can be further optimised by adding
a vitamin C supplement; such strategies may be considered
in patients with malabsorption. In some poorly compliant
patients, levothyroxine is taken diligently or even in excess
for a few days prior to a clinic visit, resulting in the seemingly
anomalous combination of a high serum T4 and high TSH (see
Box 18.5).
Levothyroxine replacement in ischaemic heart disease
Hypothyroidism and ischaemic heart disease are common
conditions that often occur together. Although angina may remain
unchanged in severity or paradoxically disappear with restoration
of metabolic rate, exacerbation of myocardial ischaemia, infarction
and sudden death are recognised complications of levothyroxine
replacement, even using doses as low as 25 \ig per day. In
patients with known ischaemic heart disease, thyroid hormone
replacement should be introduced at low dose and increased very
slowly under specialist supervision. It has been suggested that
T3 has an advantage over T4, since T3 has a shorter half-life and
any adverse effect will reverse more quickly, but the more distinct
peak in hormone levels after each dose of T3 is a disadvantage.
Coronary intervention may be required if angina is exacerbated
by levothyroxine replacement therapy.
Hypothyroidism in pregnancy
Women with hypothyroidism usually require an increased dose of
levothyroxine in pregnancy; inadequately treated hypothyroidism
in pregnancy has been associated with impaired cognitive
development in the fetus. This is discussed in more detail on
page 1279 (see also Box 18.18).
Myxoedema coma
This is a very rare presentation of hypothyroidism in which there
is a depressed level of consciousness, usually in an elderly patient
who appears myxoedematous. Body temperature may be as
low as 25°C, convulsions are not uncommon, and cerebrospinal
fluid (CSF) pressure and protein content are raised. The mortality
rate is 50% and survival depends on early recognition and
treatment of hypothyroidism and other factors contributing to the
altered consciousness level, such as medication, cardiac failure,
pneumonia, dilutional hyponatraemia and respiratory failure.
Myxoedema coma is a medical emergency and treatment
must begin before biochemical confirmation of the diagnosis.
Suspected cases should be treated with an intravenous injection
of 20 jig liothyronine, followed by further injections of 20 |ig
3 times daily until there is sustained clinical improvement. In
survivors, there is a rise in body temperature within 24 hours
and, after 48-72 hours, it is usually possible to switch patients to
oral levothyroxine in a dose of 50 jig daily. Unless it is apparent
that the patient has primary hypothyroidism, the thyroid failure
should also be assumed to be secondary to hypothalamic or
pituitary disease and treatment given with hydrocortisone 100 mg
IM 3 times daily, pending the results of T4, TSH and cortisol
measurement (p. 680). Other measures include slow rewarming
(p. 166), cautious use of intravenous fluids, broad-spectrum
antibiotics and high-flow oxygen.
Symptoms of hypothyroidism with normal thyroid
function tests
The classic symptoms of hypothyroidism are, by their very
nature, non-specific (see Box 18.3). There is a wide differential
diagnosis for symptoms such as ‘fatigue’, ‘weight gain’ and ‘low
mood’. As has been noted, outside the context of pituitary and
hypothalamic disease, serum TSH is an excellent measure of an
individual’s thyroid hormone status. However, some individuals
believe that they have hypothyroidism despite normal serum
TSH concentrations. There are a large number of websites that
claim that serum TSH is not a good measure of thyroid hormone
status and suggest that other factors, such as abnormalities
of T4 to T3 conversion, may lead to low tissue levels of active
thyroid hormones. Such websites often advocate a variety of
tests of thyroid function of dubious scientific validity, including
measurement of serum reverse T3, 24-hour urine T3, basal body
temperature, skin iodine absorption, and levels of selenium in
blood and urine. Individuals who believe they have hypothyroidism,
despite normal conventional tests of thyroid function, can be
difficult to manage. They require reassurance that their symptoms
are being taken seriously and that organic disease has been
carefully considered; if their symptoms persist, referral to a
642 • ENDOCRINOLOGY
team specialising in medically unexplained symptoms should
be considered.
I Asymptomatic abnormal thyroid
function tests
One of the most common problems in medical practice is how
to manage patients with abnormal thyroid function tests who
have no obvious signs or symptoms of thyroid disease. These
can be divided into three categories.
Subclinical thyrotoxicosis
Serum TSH is undetectable and serum T3 and T4 are at the
upper end of the reference range. This combination is most often
found in older patients with multinodular goitre. These patients
are at increased risk of atrial fibrillation and osteoporosis, and
hence the consensus view is that they have mild thyrotoxicosis
and require therapy, usually with 131 1 . Otherwise, annual review
is essential, as the conversion rate to overt thyrotoxicosis with
elevated T4 and/or T3 concentrations is 5% each year.
Subclinical hypothyroidism
Serum TSH is raised and serum T3 and T4 concentrations are at
the lower end of the reference range. This may persist for many
years, although there is a risk of progression to overt thyroid
failure, particularly if antibodies to thyroid peroxidase are present
or if the TSH rises above lOmlll/L In patients with non-specific
symptoms, a trial of levothyroxine therapy may be appropriate.
In those with positive autoantibodies or a TSH greater than
lOmIU/L, it is better to treat the thyroid failure early rather than
risk loss to follow-up and subsequent presentation with profound
hypothyroidism. Levothyroxine should be given in a dose sufficient
to restore the serum TSH concentration to normal.
Non-thyroidal illness (‘sick euthyroidism’)
This typically presents with a low serum TSH, raised T4 and
normal or low T3 in a patient with systemic illness who does not
have clinical evidence of thyroid disease. These abnormalities
are caused by decreased peripheral conversion of T4 to T3 (with
conversion instead to reverse T3), altered levels of binding proteins
and their affinity for thyroid hormones, and often reduced secretion
of TSH. During convalescence, serum TSH concentrations may
increase to levels found in primary hypothyroidism. As thyroid
function tests are difficult to interpret in patients with non-thyroidal
illness, it is wise to avoid performing thyroid function tests unless
there is clinical evidence of concomitant thyroid disease. If an
abnormal result is found, treatment should only be given with
specialist advice and the diagnosis should be re-evaluated
after recovery.
Thyroid lump or swelling
A lump or swelling in the thyroid gland can be a source of
considerable anxiety for patients. There are numerous causes
but, broadly speaking, a thyroid swelling is either a solitary
nodule, a multinodular goitre or a diffuse goitre (Box 18.13).
Nodular thyroid disease is more common in women and occurs
in approximately 30% of the adult female population. The majority
of thyroid nodules are impalpable but may be identified when
imaging of the neck is performed for another reason, such
as during Doppler ultrasonography of the carotid arteries or
computed tomographic pulmonary angiography. Increasingly,
thyroid nodules are identified during staging of patients with
cancer with computed tomography (CT), magnetic resonance
18.13 Causes of thyroid enlargement
Diffuse goitre
• Simple goitre
• Hashimoto’s thyroiditis1
• Graves’ disease
• Drugs: iodine, amiodarone, lithium
• Iodine deficiency (endemic goitre)1
• Suppurative thyroiditis2
Multinodular goitre
Solitary nodule
• Colloid cyst
• Hyperplastic nodule
• Follicular adenoma
• Papillary carcinoma
• Follicular carcinoma
• Transient thyroiditis2
• Dyshormonogenesis1
• Infiltrative: amyloidosis,
sarcoidosis etc.
• Riedel’s thyroiditis2
• Medullary cell carcinoma
• Anaplastic carcinoma
• Lymphoma
• Metastasis
1Goitre likely to shrink with levothyroxine therapy. 2Usually tender.
imaging (MRI) or positron emission tomography (PET) scans.
Palpable thyroid nodules occur in 4-8% of adult women and
1-2% of adult men, and classically present when the individual
(or a friend or relative) notices a lump in the neck. Multinodular
goitre and solitary nodules sometimes present with acute painful
enlargement due to haemorrhage into a nodule.
Patients with thyroid nodules often worry that they have cancer
but the reality is that only 5-1 0% of thyroid nodules are malignant.
A nodule presenting in childhood or adolescence, particularly
if there is a past history of head and neck irradiation, or one
presenting in an elderly patient should heighten suspicion of a
primary thyroid malignancy (p. 649). The presence of cervical
lymphadenopathy also increases the likelihood of malignancy.
Rarely, a secondary deposit from a renal, breast or lung carcinoma
presents as a painful, rapidly growing, solitary thyroid nodule.
Thyroid nodules identified on PET scanning have an approximately
33% chance of being malignant.
Clinical assessment and investigations
Swellings in the anterior part of the neck most commonly originate
in the thyroid and this can be confirmed by demonstrating that
the swelling moves on swallowing (p. 631). It is often possible
to distinguish clinically between the three main causes of thyroid
swelling. There is a broad differential diagnosis of anterior neck
swellings, which includes lymphadenopathy, branchial cysts,
dermoid cysts and thyroglossal duct cysts (the latter are classically
located in the midline and move on protrusion of the tongue).
An ultrasound scan should be performed urgently, if there is any
doubt as to the aetiology of an anterior neck swelling.
Serum T3, T4 and TSH should be measured in all patients with
a goitre or solitary thyroid nodule. The finding of biochemical
thyrotoxicosis or hypothyroidism (both of which may be
subclinical) should lead to investigations, as already described on
pages 636 and 640.
Thyroid scintigraphy
Thyroid scintigraphy with 99mtechnetiurn should be performed
in an individual with a low serum TSH and a nodular thyroid
to confirm the presence of an autonomously functioning (‘hot’)
nodule (see Fig. 18.5). In such circumstances, further evaluation
is not necessary. ‘Cold’ nodules on scintigraphy have a much
higher likelihood of malignancy, but the majority are benign and
so scintigraphy is not routinely used in the evaluation of thyroid
nodules when TSH is normal.
The thyroid gland • 643
Thyroid ultrasound
If thyroid function tests are normal, an ultrasound scan will often
determine the nature of the thyroid swelling. Ultrasound can
establish whether there is generalised or localised swelling of
the thyroid. Inflammatory disorders causing a diffuse goitre, such
as Graves’ disease and Hashimoto’s thyroiditis, demonstrate a
diffuse pattern of hypoechogenicity and, in the case of Graves’
disease, increased thyroid blood flow may be seen on colour-flow
Doppler. The presence of thyroid autoantibodies will support the
diagnosis of Graves’ disease or Hashimoto’s thyroiditis, while
their absence in a younger patient with a diffuse goitre and
normal thyroid function suggests a diagnosis of ‘simple goitre’
(p. 648).
Ultrasound can readily determine the size and number of
nodules within the thyroid and can distinguish solid nodules from
those with a cystic element. Ultrasound is used increasingly as
the key investigation in defining the risk of malignancy in a nodule.
Size of the nodule is not a predictor of the risk of malignancy but
there are other ultrasound characteristics that are associated with
a higher likelihood of malignancy. These include hypoechoicity,
intranodular vascularity, the presence of microcalcification and
irregular or lobulated margins. A purely cystic nodule is highly
unlikely to be malignant and a ‘spongiform’ appearance is also
highly predictive of a benign aetiology. Individual nodules within
a multinodular goitre have the same risk of malignancy as a
solitary nodule. Thyroid ultrasonography is a highly specialised
investigation and the accurate stratification of risk of malignancy
of a thyroid nodule requires skill and expertise.
Fine needle aspiration cytology
Fine needle aspiration cytology is recommended for thyroid
nodules that are suspicious for malignancy or are radiologically
indeterminate. Fine needle aspiration of a thyroid nodule can
be performed in the outpatient clinic, usually under ultrasound
guidance. Aspiration may be therapeutic for a cyst, although
recurrence on more than one occasion is an indication for surgery.
Fine needle aspiration cytology cannot differentiate between a
follicular adenoma and a follicular carcinoma, and in 10-20%
of cases an inadequate specimen is obtained.
Management
Nodules with a benign appearance on ultrasound may be
observed in an ultrasound surveillance programme; when the
suspicion of malignancy is very low, the patient may be reassured
and discharged. In parts of the world with borderline low iodine
intake, there is evidence that levothyroxine therapy, in doses that
suppress serum TSH, may reduce the size of some nodules. This
should not be routine practice in iodine-sufficient populations.
Nodules that are suspicious for malignancy are treated by
surgical excision, by either lobectomy or thyroidectomy. Nodules
that are radiologically and/or cytologically indeterminate are
more of a management challenge and often end up being
surgically excised. Molecular techniques may, in the future,
improve the diagnostic accuracy of thyroid cytology and allow a
more conservative strategy for individuals with an indeterminate
biopsy. Nodules in which malignancy is confirmed by formal
histology are treated as described on page 649.
A diffuse or multinodular goitre may also require surgical
treatment for cosmetic reasons or if there is compression of
local structures (resulting in stridor or dysphagia). 131 1 therapy
may also cause some reduction in size of a multinodular goitre.
Levothyroxine therapy may shrink the goitre of Hashimoto’s
disease, particularly if serum TSH is elevated.
Autoimmune thyroid disease
Thyroid diseases are amongst the most prevalent antibody-
mediated autoimmune diseases and are associated with other
organ-specific autoimmunity (Ch. 4 and p. 689). Autoantibodies
may produce inflammation and destruction of thyroid tissue,
resulting in hypothyroidism, goitre (in Hashimoto’s thyroiditis)
or sometimes even transient thyrotoxicosis (‘Hashitoxicosis’),
or they may stimulate the TSH receptor to cause thyrotoxicosis
(in Graves’ disease). There is overlap between these conditions,
since some patients have multiple autoantibodies.
Graves’ disease
Graves’ disease can occur at any age but is unusual before
puberty and most commonly affects women aged 30-50 years.
The most common manifestation is thyrotoxicosis with or without
a diffuse goitre. The clinical features and differential diagnosis
are described on page 635. Graves’ disease also causes
ophthalmopathy and, rarely, pretibial myxoedema (p. 646).
These extrathyroidal features usually occur in thyrotoxic patients
but can arise in the absence of thyroid dysfunction.
Graves’ thyrotoxicosis
Pathophysiology
The thyrotoxicosis results from the production of immunoglobulin
G (IgG) antibodies directed against the TSH receptor on the
thyroid follicular cell, which stimulate thyroid hormone production
and proliferation of follicular cells, leading to goitre in the majority
of patients. These antibodies are termed thyroid-stimulating
immunoglobulins or TSH receptor antibodies (TRAb) and can be
detected in the serum of 80-95% of patients with Graves’ disease.
The concentration of TRAb in the serum is presumed to fluctuate
to account for the natural history of Graves’ thyrotoxicosis (Fig.
18.7). Thyroid failure seen in some patients may result from the
presence of blocking antibodies against the TSH receptor, and
from tissue destruction by cytotoxic antibodies and cell-mediated
immunity.
0
0
0
0 1 2 3 4 5
Time in years
Thyrotoxic Euthyroid Hypothyroid
Fig. 18.7 Natural history of the thyrotoxicosis of Graves’ disease.
[ A] and 0U The majority (60%) of patients have either prolonged periods of
thyrotoxicosis of fluctuating severity, or periods of alternating relapse and
remission. [C] It is the minority who experience a single short-lived episode
followed by prolonged remission and, in some cases, by the eventual onset
of hypothyroidism.
644 • ENDOCRINOLOGY
Graves’ disease has a strong genetic component. There is
50% concordance for thyrotoxicosis between monozygotic twins
but only 5% concordance between dizygotic twins. Genome¬
wide association studies have identified polymorphisms at the
MHC, CTLA4, PTPN22, TSHR1 and FCRL3 loci as predisposing
genetic variants. Many of these loci have been implicated in the
pathogenesis of other autoimmune diseases.
A suggested trigger for the development of thyrotoxicosis in
genetically susceptible individuals may be infection with viruses
or bacteria. Certain strains of the gut organisms Escherichia coli
and Yersinia enterocolitica possess cell membrane TSH receptors
and it has been suggested that antibodies to these microbial
antigens may cross-react with the TSH receptors on the host
thyroid follicular cell. In regions of iodine deficiency (p. 647),
iodine supplementation can precipitate thyrotoxicosis, but only
in those with pre-existing subclinical Graves’ disease. Smoking
is weakly associated with Graves’ thyrotoxicosis but strongly
linked with the development of ophthalmopathy.
Management
Symptoms of thyrotoxicosis respond to (3-blockade (p. 637) but
definitive treatment requires control of thyroid hormone secretion.
The different options are compared in Box 18.14. Some clinicians
adopt an empirical approach of prescribing a course of antithyroid
drug therapy and then recommending 131 1 or surgery if relapse
occurs. In many centres, however, 131 1 is used extensively as
a first-line therapy, given the high risk of relapse following a
course of antithyroid drugs. A number of observational studies
have linked therapeutic 131 1 with increased incidence of some
malignancies, particularly of the thyroid and gastrointestinal tract,
but the results have been inconsistent; the association may be
with Graves’ disease rather than its therapy, and the magnitude
of the effect, if any, is small. Experience from the disaster at the
Chernobyl nuclear power plant in 1986 suggests that younger
people are more sensitive to radiation-induced thyroid cancer.
Antithyroid drugs The most commonly used are carbimazole
and its active metabolite, methimazole (not available in the
UK). Propylthiouracil is equally effective. These drugs reduce
the synthesis of new thyroid hormones by inhibiting the
iodination of tyrosine (see Fig. 18.3). Carbimazole also has an
immunosuppressive action, leading to a reduction in serum TRAb
concentrations, but this is not enough to influence the natural
history of the thyrotoxicosis significantly.
Antithyroid drugs should be introduced at high doses
(carbimazole 40-60 mg daily or propylthiouracil 400-600 mg
daily). Usually, this results in subjective improvement within
1 0-1 4 days and renders the patient clinically and biochemically
euthyroid at 6-8 weeks. At this point, the dose can be reduced
and titrated to maintain T4 and TSH within their reference range.
In most patients, carbimazole is continued at 5-20 mg per
day for 12-18 months in the hope that remission will occur.
Between 50% and 70% of patients with Graves’s disease
will subsequently relapse, usually within 2 years of stopping
treatment. Risk factors for relapse include younger age, male sex,
presence of a goitre, and higher TRAb titres at both diagnosis
and cessation of antithyroid therapy. Rarely, T4 and TSH levels
fluctuate between those of thyrotoxicosis and hypothyroidism at
successive review appointments, despite good drug adherence,
presumably due to rapidly changing concentrations of TRAb. In
these patients, satisfactory control can be achieved by blocking
thyroid hormone synthesis with carbimazole 30-40 mg daily and
adding levothyroxine 100-150 jig daily as replacement therapy
(a ‘block and replace’ regime).
Antithyroid drugs can have adverse effects. The most common is
a rash. Agranulocytosis is a rare but potentially serious complication
that cannot be predicted by routine measurement of white blood
cell count but which is reversible on stopping treatment. Patients
should be warned to stop the drug and seek medical advice
immediately, should a severe sore throat or fever develop while
on treatment. Propylthiouracil is associated with a small but
definite risk of hepatotoxicity, which, in some instances, has
resulted in liver failure requiring liver transplantation, and even in
death. It should therefore be considered second-line therapy to
carbimazole and be used only during pregnancy or breastfeeding
(p. 1279), or if an adverse reaction to carbimazole has occurred.
18.14 Comparison of treatments for the thyrotoxicosis of Graves’ disease
Management
Common indications
Contraindications
Disadvantages/complications
Antithyroid drugs
(carbimazole, propylthiouracil)
First episode in patients <40 years
Breastfeeding (propylthiouracil
suitable)
Hypersensitivity rash 2%
Agranulocytosis 0.2%
Hepatotoxicity (with propylthiouracil)
- very rare but potentially fatal
>50% relapse rate usually within
2 years of stopping drug
Subtotal thyroidectomy
Large goitre
Poor drug adherence, especially in
young patients
Recurrent thyrotoxicosis after course
of antithyroid drugs in young patients
Previous thyroid surgery
Dependence on voice, e.g. opera
singer, lecturer2
Hypothyroidism (-25%)
Transient hypocalcaemia (10%)
Permanent hypoparathyroidism (1 %)
Recurrent laryngeal nerve palsy2 (1 %)
Radio-iodine
Patients >40 years3
Recurrence following surgery
irrespective of age
Other serious comorbidity
Pregnancy or planned pregnancy
within 6 months of treatment
Active Graves’ ophthalmopathy4
Hypothyroidism: -40% in first year,
80% after 1 5 years
Most likely treatment to result in
exacerbation of ophthalmopathy4
^ near-total thyroidectomy is now the favoured operation for Graves’ thyrotoxicosis in many institutions and is associated with a higher risk of some complications, including
hypothyroidism (nearly 100%), but a reduced risk of persistent or recurrent thyrotoxicosis. 2lt is not only vocal cord palsy due to recurrent laryngeal nerve damage that alters
the voice following thyroid surgery; the superior laryngeal nerves are frequently transected and this results in minor changes in voice quality. 3ln many institutions, 131l is
used more liberally and is prescribed for much younger patients. 4The extent to which radio-iodine exacerbates ophthalmopathy is controversial and practice varies; some
use prednisolone to reduce this risk.
The thyroid gland • 645
Thyroid surgery Patients should be rendered euthyroid with
antithyroid drugs before operation. Oral potassium iodide, 60 mg
three times daily, is often added for 10 days before surgery to
inhibit thyroid hormone release and reduce the size and vascularity
of the gland, making surgery technically easier. Traditionally, a
‘subtotal’ thyroidectomy is performed, in which a portion of one
lobe of the thyroid is left in situ, with the aim of rendering the
patient euthyroid. While complications of surgery are rare and
80% of patients are euthyroid, 15% are permanently hypothyroid
and 5% remain thyrotoxic. As a consequence, many endocrine
surgeons now opt to perform a ‘near-total’ thyroidectomy, leaving
behind only a small portion of gland adjacent to the recurrent
laryngeal nerves. This strategy invariably results in permanent
hypothyroidism and is probably associated with a higher risk
of hypoparathyroidism, but maximises the potential for cure of
thyrotoxicosis.
Radioactive iodine 131 1 is administered orally as a single dose and
is trapped and organised in the thyroid (see Fig. 18.3). 131l emits
both p and y radiation and, although it decays within a few weeks,
it has long-lasting inhibitory effects on survival and replication of
follicular cells. The variable radio-iodine uptake and radiosensitivity
of the gland means that the choice of dose is empirical; in
most centres, approximately 400-600 MBq (approximately
10-15 mCi) is administered. This regimen is effective in 75% of
patients within 4-12 weeks. During the lag period, symptoms
can be controlled by a p-blocker or, in more severe cases, by
carbimazole. However, carbimazole reduces the efficacy of 131 1
therapy because it prevents organification of 131 1 in the gland,
and so should be avoided until 48 hours after radio-iodine
administration. If thyrotoxicosis persists after 6 months, a further
dose of 131 1 can be given. The disadvantage of 131 1 treatment is
that the majority of patients eventually develop hypothyroidism.
131 1 is usually avoided in patients with Graves’ ophthalmopathy
and evidence of significant active orbital inflammation. It can be
administered with caution in those with mild or ‘burnt-out’ eye
disease, when it is customary to cover the treatment with a 6-week
tapering course of oral prednisolone. In women of reproductive
age, pregnancy must be excluded before administration of 131 1
and avoided for 6 months thereafter; men are also advised against
fathering children for 6 months after receiving 131 1 .
Thyrotoxicosis in pregnancy
Thyrotoxicosis in pregnancy may be associated with significant
maternal and fetal morbidity. Management is very specialised
and is discussed on page 1279 (see also Box 18.18).
Thyrotoxicosis in adolescence
Thyrotoxicosis can occasionally occur in adolescence and is
almost always due to Graves’ disease. The presentation may
be atypical and management challenging, as summarised in
Box 18.15.
Graves’ ophthalmopathy
This condition is immunologically mediated but the autoantigen
has not been identified. Within the orbit (and the dermis) there
is cytokine-mediated proliferation of fibroblasts that secrete
hydrophilic glycosaminoglycans. The resulting increase in interstitial
fluid content, combined with a chronic inflammatory cell infiltrate,
causes marked swelling and ultimately fibrosis of the extraocular
muscles (Fig. 18.8) and a rise in retrobulbar pressure. The eye
is displaced forwards (proptosis, exophthalmos, p. 631) and in
severe cases there is optic nerve compression.
m
• Presentation: may present with a deterioration in school
performance or symptoms suggestive of attention deficit
hyperactivity disorder.
• Antithyroid drug therapy: prolonged courses may be required
because remission rates following an 18-month course of therapy
are much lower than in adults.
< Adherence: adherence to antithyroid drug therapy is often
suboptimal, resulting in poor disease control that may adversely
affect performance at school.
• Radio-iodine therapy: usually avoided in adolescents because of
concerns about risk of future malignancy.
Fig. 18.8 Graves’ disease. [A] Bilateral ophthalmopathy in a 42-year-old
man. The main symptoms were diplopia in all directions of gaze and
reduced visual acuity in the left eye. The periorbital swelling is due to
retrobulbar fat prolapsing into the eyelids, and increased interstitial fluid as
a result of raised intraorbital pressure. [¥] Transverse CT of the orbits,
showing the enlarged extraocular muscles. This is most obvious at the
apex of the left orbit (arrow), where compression of the optic nerve caused
reduced visual acuity.
Ophthalmopathy, like thyrotoxicosis (see Fig. 18.7), typically
follows an episodic course and it is helpful to distinguish patients
with active inflammation (periorbital oedema and conjunctival
inflammation with changing orbital signs) from those in whom
the inflammation has ‘burnt out’. Eye disease is detectable in
up to 50% of thyrotoxic patients at presentation, but active
ocular inflammation may occur before or after thyrotoxic
episodes (exophthalmic Graves’ disease). It is more common
in cigarette smokers and is exacerbated by poor control of
thyroid function, especially hypothyroidism. The most frequent
presenting symptoms are related to increased exposure of the
cornea, resulting from proptosis and lid retraction. There may
be excessive lacrimation made worse by wind and bright light,
a ‘gritty’ sensation in the eye, and pain due to conjunctivitis
or corneal ulceration. In addition, there may be reduction of
18.15 Thyrotoxicosis in adolescence
646 • ENDOCRINOLOGY
visual acuity and/or visual fields as a consequence of corneal
oedema or optic nerve compression. Other signs of optic nerve
compression include reduced colour vision and a relative afferent
pupillary defect (pp. 631 and 1088). If the extraocular muscles
are involved and do not act in concert, diplopia results.
The majority of patients require no treatment other than
reassurance. Smoking cessation should be actively encouraged.
Methylcellulose eye drops and gel counter the gritty discomfort
of dry eyes, and tinted glasses or side shields attached to
spectacle frames reduce the excessive lacrimation triggered by
sun or wind. In patients with mild Graves’ ophthalmopathy, oral
selenium (1 00 jig twice daily for 6 months) improves quality of life,
reduces ocular involvement and slows progression of disease;
the mechanism of action is not known but may relate to an
antioxidant effect. More severe inflammatory episodes are treated
with glucocorticoids (e.g. pulsed intravenous methylprednisolone)
and sometimes orbital radiotherapy. There is also an increasing
trend to use alternative immunosuppressive therapies, such as
rituximab and ciclosporin. Loss of visual acuity is an indication for
urgent surgical decompression of the orbit. In ‘burnt-out’ disease,
surgery to the extraocular muscles, and later the eyelids, may
improve diplopia, conjunctival exposure and cosmetic appearance.
Pretibial myxoedema
This infiltrative dermopathy occurs in fewer than 5% of patients
with Graves’ disease and has similar pathological features as
occur in the orbit. It takes the form of raised pink-coloured or
purplish plaques on the anterior aspect of the leg, extending
on to the dorsum of the foot (p. 630). The lesions may be itchy
and the skin may have a ‘peau d’orange’ appearance with
growth of coarse hair; less commonly, the face and arms are
affected. Treatment is rarely required but in severe cases topical
glucocorticoids may be helpful.
Hashimoto’s thyroiditis
Hashimoto’s thyroiditis is characterised by destructive lymphoid
infiltration of the thyroid, ultimately leading to a varying degree
of fibrosis and thyroid enlargement. There is an increased risk
of thyroid lymphoma (p. 650), although this is exceedingly
rare. The nomenclature of autoimmune hypothyroidism is
confusing. Some authorities reserve the term ‘Hashimoto’s
thyroiditis’ for the condition of patients with positive antithyroid
peroxidase autoantibodies and a firm goitre who may or may
not be hypothyroid, and use the term ‘spontaneous atrophic
hypothyroidism’ for the condition of hypothyroid patients without
a goitre in whom TSH receptor-blocking antibodies may be more
important than antithyroid peroxidase antibodies. However, these
syndromes can both be considered as variants of the same
underlying disease process.
Hashimoto’s thyroiditis increases in incidence with age and
affects approximately 3.5 per 1 000 women and 0.8 per 1 000 men
each year. Many present with a small or moderately sized diffuse
goitre, which is characteristically firm or rubbery in consistency.
Around 25% of patients are hypothyroid at presentation. In the
remainder, serum T4 is normal and TSH normal or raised, but
these patients are at risk of developing overt hypothyroidism
in future years. Antithyroid peroxidase antibodies are present
in the serum in more than 90% of patients with Hashimoto’s
thyroiditis. In those under the age of 20 years, antinuclear factor
(ANF) may also be positive.
Levothyroxine therapy is indicated as treatment for
hypothyroidism (p. 640) and also to shrink an associated goitre.
In this context, the dose of levothyroxine should be sufficient to
suppress serum TSH to low but detectable levels.
Transient thyroiditis
Subacute (de Quervain’s) thyroiditis
In its classical painful form, subacute thyroiditis is a transient
inflammation of the thyroid gland occurring after infection with
Coxsackie, mumps or adenoviruses. There is pain in the region
of the thyroid that may radiate to the angle of the jaw and the
ears, and is made worse by swallowing, coughing and movement
of the neck. The thyroid is usually palpably enlarged and tender.
Systemic upset is common. Affected patients are usually females
aged 20-40 years. Painless transient thyroiditis can also occur
after viral infection and in patients with underlying autoimmune
disease. The condition can also be precipitated by drugs, including
interferon-a and lithium.
Irrespective of the clinical presentation, inflammation in the
thyroid gland occurs and is associated with release of colloid and
stored thyroid hormones, but also with damage to follicular cells
and impaired synthesis of new thyroid hormones. As a result, T4
and T3 levels are raised for 4-6 weeks until the pre-formed colloid
is depleted. Thereafter, there is usually a period of hypothyroidism
of variable severity before the follicular cells recover and normal
thyroid function is restored within 4-6 months (Fig. 18.9). In
the thyrotoxic phase, the iodine uptake is low because the
damaged follicular cells are unable to trap iodine and because
TSH secretion is suppressed. Low-titre thyroid autoantibodies
appear transiently in the serum, and the erythrocyte sedimentation
rate (ESR) is usually raised. High-titre autoantibodies suggest an
underlying autoimmune pathology and greater risk of recurrence
and ultimate progression to hypothyroidism.
The pain and systemic upset usually respond to simple
measures such as non-steroidal anti-inflammatory drugs
(NSAIDs). Occasionally, however, it may be necessary to prescribe
prednisolone 40 mg daily for 3-4 weeks. The thyrotoxicosis is mild
and treatment with a (3-blocker is usually adequate. Antithyroid
drugs are of no benefit because thyroid hormone synthesis is
impaired rather than enhanced. Careful monitoring of thyroid
function and symptoms is required so that levothyroxine can be
prescribed temporarily in the hypothyroid phase. Care must be
taken to identify patients presenting with hypothyroidism who
Thyrotoxic Hypothyroid Euthyroid
Months
Fig. 18.9 Thyroid function tests in an episode of transient thyroiditis.
This pattern might be observed in classical subacute (de Quervain’s)
thyroiditis, painless thyroiditis or post-partum thyroiditis. The duration of
each phase varies between patients.
The thyroid gland • 647
are in the later stages of a transient thyroiditis, since they are
unlikely to require life-long levothyroxine therapy (see Fig. 18.6).
Post-partum thyroiditis
The maternal immune response, which is modified during
pregnancy to allow survival of the fetus, is enhanced after delivery
and may unmask previously unrecognised subclinical autoimmune
thyroid disease. Surveys have shown that transient biochemical
disturbances of thyroid function occur in 5-1 0% of women within
6 months of delivery (see Box 18.18). Those affected are likely
to have antithyroid peroxidase antibodies in the serum in early
pregnancy. Symptoms of thyroid dysfunction are rare and there
is no association between postnatal depression and abnormal
thyroid function tests. However, symptomatic thyrotoxicosis
presenting for the first time within 12 months of childbirth is
likely to be due to post-partum thyroiditis and the diagnosis
is confirmed by a negligible radio-isotope uptake. The clinical
course and treatment are similar to those of painless subacute
thyroiditis (see above). Post-partum thyroiditis tends to recur after
subsequent pregnancies, and eventually patients progress over
a period of years to permanent hypothyroidism.
Iodine-associated thyroid disease
|Jodine deficiency
Iodine is an essential micronutrient and is a key component of
T4 and T3. The World Health Organisation (WHO) recommends a
daily intake of iodine of 150 jig/day for adult men and women;
higher levels are recommended for pregnant women (p. 1279).
Dietary sources of iodine include seafood, dairy products, eggs
and grains. Dietary iodine deficiency is a major worldwide public
health issue, with an estimated one-third of the world population
living in areas of iodine insufficiency. Iodine deficiency is particularly
common in Central Africa, South-east Asia and the Western
Pacific. It is associated with the development of thyroid nodules
and goitre (endemic goitre); the reduced substrate available for
thyroid hormone production increases thyroid activity to maximise
iodine uptake and recycling, and this acts as a potent stimulus
for enlargement of the thyroid and nodule formation. Most
affected patients are euthyroid with normal or raised TSH levels,
although hypothyroidism can occur with severe iodine deficiency.
Suspected iodine deficiency can be assessed by measuring
iodine in urine (either a 24-hour collection or a spot sample).
Endemic goitre can be treated by iodine supplementation, and a
reduction in nodule and goitre size can be seen, particularly if it is
commenced in childhood. Iodine deficiency is not associated with
an increased risk of Graves’ disease or thyroid cancer, but the
high prevalence of nodular autonomy does result in an increased
risk of thyrotoxicosis and this risk may be further increased by
iodine supplementation. Conversely, iodine supplementation may
also increase the prevalence of subclinical hypothyroidism and
autoimmune hypothyroidism. These complex effects of iodine
supplementation are further discussed below.
In pregnancy, iodine deficiency is associated with impaired
brain development, and severe deficiency can cause cretinism.
Worldwide, iodine deficiency is the most common cause
of preventable impaired cognitive development in children
(p. 1279). The WHO and other international organisations have
made reversal of iodine deficiency a priority and have helped
organise national supplementation programmes. These have
mainly involved the iodisation of table salt, but have also included
schemes to administer oral or intramuscular iodised oil to at-risk
populations and the addition of iodine to wells supplying water
to local communities. These schemes have been extremely
effective in reducing the prevalence of iodine deficiency, but
lower consumption of table salt has actually led to an increase
in iodine deficiency in some developed countries like Australia
and New Zealand.
|jodine-induced thyroid dysfunction
Iodine has complex effects on thyroid function. Very high
concentrations of iodine inhibit thyroid hormone synthesis and
release (known as the Wolff-Chaikoff effect) and this forms
the rationale for iodine treatment in thyroid crisis (p. 637) and
prior to thyroid surgery for thyrotoxicosis (p. 645). This is an
autoregulatory response to protect the body from the sudden
release of large amounts of thyroid hormone in response to the
ingestion of a substantial load of iodine. This effect only lasts
for about 10 days, after which it is followed by an ‘escape
phenomenon’: essentially, the return to normal organification of
iodine and thyroid peroxidase action (see Fig. 18.3). Therefore,
if iodine is given to prepare an individual with Graves’ disease
for surgery, the operation must happen within 10-14 days;
otherwise, a significant relapse of the thyrotoxicosis could occur.
Iodine deficiency and underlying thyroid disease can both
moderate the effects of iodine on thyroid function. In iodine-
deficient parts of the world, transient thyrotoxicosis may be
precipitated by prophylactic iodinisation programmes. In
iodine-sufficient areas, thyrotoxicosis can be precipitated by
iodine-containing radiographic contrast medium or expectorants
in individuals who have underlying thyroid disease predisposing
to thyrotoxicosis, such as multinodular goitre or Graves’ disease
in remission. Induction of thyrotoxicosis by iodine is called the
Jod-Basedow effect. Chronic excess iodine administration can
also result in hypothyroidism; this is, in effect, a failure to escape
from the Wolff-Chaikoff effect and usually occurs in the context
of prior insult to the thyroid by, for example, autoimmune disease,
thyroiditis, lithium, antithyroid drugs or surgery.
Amiodarone
The anti-arrhythmic agent amiodarone has a structure that is
analogous to that of T4 (Fig. 18.10) and contains huge amounts
of iodine; a 200 mg dose contains 75 mg iodine. Amiodarone
also has a cytotoxic effect on thyroid follicular cells and inhibits
conversion of T4 to T3 (increasing the ratio of T4:T3). Most patients
receiving amiodarone have normal thyroid function but up to
20% develop hypothyroidism or thyrotoxicosis, and so thyroid
function should be monitored regularly. TSH provides the best
indicator of thyroid function.
The thyrotoxicosis can be classified as either:
• type /: iodine-induced excess thyroid hormone synthesis in
patients with an underlying thyroid disorder, such as
Fig. 18.10 The structure of amiodarone. Note the similarities to T4 (see
Fig. 18.3).
648 • ENDOCRINOLOGY
nodular goitre or latent Graves’ disease (an example of the
Jod-Basedow effect).
• type //: thyroiditis due to a direct cytotoxic effect of
amiodarone administration.
These patterns can overlap and may be difficult to distinguish
clinically, as iodine uptake is low in both. There is no widely
accepted management algorithm, although the iodine excess
renders the gland resistant to 131 1. Antithyroid drugs may be
effective in patients with the type I form but are ineffective in type
II thyrotoxicosis. Prednisolone is beneficial in the type II form.
A pragmatic approach is to commence combination therapy
with an antithyroid drug and glucocorticoid in patients with
significant thyrotoxicosis. A rapid response (within 1-2 weeks)
usually indicates a type II picture and permits withdrawal of
the antithyroid therapy; a slower response suggests a type
I picture, in which case antithyroid drugs may be continued
and prednisolone withdrawn. Potassium perchlorate can also
be used to inhibit iodine trapping in the thyroid. If the cardiac
state allows, amiodarone should be discontinued, but it has a
long half-life (50-60 days) and so its effects are long-lasting.
To minimise the risk of type I thyrotoxicosis, thyroid function
should be measured in all patients prior to commencement
of amiodarone therapy, and amiodarone should be avoided if
TSH is suppressed.
Hypothyroidism should be treated with levothyroxine, which
can be given while amiodarone is continued.
Simple and multinodular goitre
These terms describe diffuse or multinodular enlargement of the
thyroid, which occurs sporadically and is of unknown aetiology.
| Simple diffuse goitre
This form of goitre usually presents between the ages of 15 and
25 years, often during pregnancy, and tends to be noticed by
friends and relatives rather than the patient. Occasionally, there
is a tight sensation in the neck, particularly when swallowing. The
goitre is soft and symmetrical, and the thyroid enlarged to two
or three times normal. There is no tenderness, lymphadenopathy
or overlying bruit. Concentrations of T3, T4 and TSH are normal
and no thyroid autoantibodies are detected in the serum. No
treatment is necessary and the goitre usually regresses. In
some, however, the unknown stimulus to thyroid enlargement
persists and, as a result of recurrent episodes of hyperplasia and
involution during the following 10-20 years, the gland becomes
multinodular with areas of autonomous function.
| Multinodular goitre
The natural history is shown in Figure 1 8.1 1 . Patients with thyroid
enlargement in the absence of thyroid dysfunction or positive
autoantibodies (i.e. with ‘simple goitre’; see above) as young
adults may progress to develop nodules. These nodules grow
at varying rates and secrete thyroid hormone ‘autonomously’,
thereby suppressing TSH-dependent growth and function in
the rest of the gland. Ultimately, complete suppression of TSH
occurs in about 25% of cases, with T4 and T3 levels often within
the reference range (subclinical thyrotoxicosis, p. 642), but
sometimes elevated (toxic multinodular goitre; see Fig. 18.5).
Clinical features and investigations
Multinodular goitre is usually diagnosed in patients presenting with
thyrotoxicosis, a large goitre with or without tracheal compression,
Age (in years)
15-25
26-55
>55
Goitre
Diffuse
Nodular
Nodular
Tracheal
compression/
deviation
No
Minimal
Yes
t3.t4
Normal
Normal
Raised
TSH
Normal
Normal or
undetectable
Undetectable
Fig. 18.11 Natural history of simple goitre.
Fig. 18.12 Computed tomogram showing retrosternal multinodular
goitre (black arrow). This is causing acute severe breathlessness and
stridor due to tracheal compression (white arrow).
or sudden painful swelling caused by haemorrhage into a nodule
or cyst. The goitre is nodular or lobulated on palpation and may
extend retrosternal ly; however, not all multinodular goitres causing
thyrotoxicosis are easily palpable. Very large goitres can cause
mediastinal compression with stridor (Fig. 18.12), dysphagia
and obstruction of the superior vena cava. Hoarseness due
to recurrent laryngeal nerve palsy can occur but is far more
suggestive of thyroid carcinoma.
The diagnosis can be confirmed by ultrasonography and/or
thyroid scintigraphy (see Fig. 18.5). In patients with large goitres,
a flow-volume loop is a good screening test for significant
tracheal compression (see Fig. 17.7, p. 554). If intervention
is contemplated, a CT or MRI of the thoracic inlet should be
performed to quantify the degree of tracheal displacement or
compression and the extent of retrosternal extension. Nodules
should be evaluated for the possibility of thyroid neoplasia, as
described on page 649.
Management
If the goitre is small, no treatment is necessary but annual thyroid
function testing should be arranged, as the natural history is
progression to a toxic multinodular goitre. Thyroid surgery is
indicated for large goitres that cause mediastinal compression
The thyroid gland • 649
or that are cosmetically unattractive. 131 1 can result in a significant
reduction in thyroid size and may be of value in elderly patients.
Levothyroxine therapy is of no benefit in shrinking multinodular
goitres in iodine-sufficient countries and may simply aggravate
any associated thyrotoxicosis.
In toxic multinodular goitre, treatment is usually with 131 1 . The
iodine uptake is lower than in Graves’ disease, so a higher dose
may be administered (up to 800 Mbq (approximately 20 mCi))
and hypothyroidism is less common. In thyrotoxic patients with
a large goitre, thyroid surgery may be indicated. Long-term
treatment with antithyroid drugs is not usually employed, as
relapse is invariable after drug withdrawal; drug therapy is normally
reserved for frail older patients in whom surgery or 131 1 is not an
appropriate option.
Asymptomatic patients with subclinical thyrotoxicosis (p. 642)
are increasingly being treated with 131 1 on the grounds that a
suppressed TSH is a risk factor for atrial fibrillation and, particularly
in post-menopausal women, osteoporosis.
Thyroid neoplasia
Patients with thyroid tumours usually present with a solitary
nodule (p. 642). Most are benign and a few of these, called
‘toxic adenomas’, secrete excess thyroid hormones. Primary
thyroid malignancy is rare, accounting for less than 1%
of all carcinomas, and has an incidence of 25 per million
per annum. As shown in Box 18.16, it can be classified
according to the cell type of origin. With the exception of
medullary carcinoma, thyroid cancer is more common in
females.
| Toxic adenoma
A solitary toxic nodule is the cause of less than 5% of all cases
of thyrotoxicosis. The nodule is a follicular adenoma, which
autonomously secretes excess thyroid hormones and inhibits
endogenous TSH secretion, with subsequent atrophy of the
rest of the thyroid gland. The adenoma is usually greater than
3 cm in diameter.
Most patients are female and over 40 years of age. Although
many nodules are palpable, the diagnosis can be made with
certainty only by thyroid scintigraphy (see Fig. 18.5). The
i
18.16 Malignant thyroid tumours
Type of tumour
Frequency
(%)
Age at
presentation
(years)
10-year
survival (%)
Follicular cells
Differentiated
carcinoma:
Papillary
75-85
20-40
98
Follicular
10-20
40-60
94
Anaplastic
<5
>60
9
Parafollicular C cells
Medullary carcinoma
5-8
>40*
78
Lymphocytes
Lymphoma
<5
>60
45
*Patients with medullary carcinoma as part of multiple endocrine neoplasia (MEN)
types 2 and 3 (p. 688) may present in childhood.
thyrotoxicosis is usually mild and in almost 50% of patients the
plasma T3 alone is elevated (T3 thyrotoxicosis). 131 1 (400-800 MBq
(1 0-20 mCi)) is highly effective and is an ideal treatment since
the atrophic cells surrounding the nodule do not take up iodine
and so receive little or no radiation. For this reason, permanent
hypothyroidism is unusual. Hemithyroidectomy is an alternative
management option.
| Differentiated carcinoma
Papillary carcinoma
This is the most common of the malignant thyroid tumours and
accounts for 90% of radiation-induced thyroid cancer. It may be
multifocal and spread is initially to regional lymph nodes. Some
patients present with cervical lymphadenopathy and no apparent
thyroid enlargement; in such instances, the primary lesion may
be less than 10 mm in diameter.
Follicular carcinoma
This is usually a single encapsulated lesion. Spread to cervical
lymph nodes is rare. Metastases are blood-borne and are most
often found in bone, lungs and brain.
Management
The management of thyroid cancers should be individualised
and planned in multidisciplinary team meetings that include all
specialists involved in the service; this should include thyroid
surgeons, endocrinologists, oncologists, pathologists, radiologists
and nurse specialists. Large tumours, those with adverse
histological features and/or tumours with metastatic disease at
presentation are usually managed by total thyroidectomy followed
by a large dose of 131 1 (1100 or 3700 MBq (approximately 30 or
1 00 mCi)) to ablate any remaining normal or malignant thyroid
tissue. Thereafter, long-term treatment with levothyroxine in a
dose sufficient to suppress TSH (usually 1 50-200 pig daily) is
given, as there is evidence that growth of differentiated thyroid
carcinomas is TSH-dependent. Smaller tumours with no adverse
histological features may require only thyroid lobectomy.
Follow-up involves measurement of serum thyroglobulin,
which should be undetectable in patients whose normal thyroid
has been ablated and who are taking a suppressive dose of
levothyroxine. Thyroglobulin antibodies may interfere with the
assay and, depending on the method employed, may result in a
falsely low or high result. Detectable thyroglobulin, in the absence
of assay interference, is suggestive of tumour recurrence or
metastases, particularly if the thyroglobulin titre is rising across
serial measurements. Local recurrence or metastatic disease
may be localised by ultrasound, CT, MRI and/or whole-body
scanning with 131 1, and may be treated with further surgery
and/or 131 1 therapy. 131 1 treatment in thyroid cancer and isotope
scanning both require serum TSH concentrations to be elevated
(>20mlU/L). This may be achieved by stopping levothyroxine
for 4-6 weeks, inducing symptomatic hypothyroidism, or by
administering intramuscular injections of recombinant human
TSH. Patients usually find the latter approach preferable but it
is more expensive. Those with locally advanced or metastatic
papillary and follicular carcinoma that is refractive to 131 1 may be
considered for therapy with sorafenib or lenvatinib. These drugs
are multi-targeted tyrosine kinase inhibitors and have been shown
in trials to prolong progression -free survival by between 5 and
14 months. They have multiple toxicities, however, including
poor appetite, weight loss, fatigue, diarrhoea, mucositis, rashes,
hypertension and blood dyscrasias. The potential benefits of
650 • ENDOCRINOLOGY
if
Thyrotoxicosis
• Causes: commonly due to multinodular goitre.
• Clinical features: apathy, anorexia, proximal myopathy, atrial
fibrillation and cardiac failure predominate.
• Non-thyroidal illness: thyroid function tests are performed more
frequently in the elderly but interpretation may be altered by
intercurrent illness.
Hypothyroidism
• Clinical features: non-specific features, such as physical and
mental slowing, are often attributed to increasing age and the
diagnosis is delayed.
• Myxoedema coma (p. 641): more likely in the elderly.
• Levothyroxine dose: to avoid exacerbating latent or established
heart disease, the starting dose should be 25 jig daily.
Levothyroxine requirements fall with increasing age and few patients
need more than 1 00 jig daily.
• Other medication (see Box 18.12): may interfere with absorption
or metabolism of levothyroxine, necessitating an increase in dose.
18.17 The thyroid gland in old age
therapy therefore have to be carefully weighed against side-effects
that can significantly impair quality of life.
Prognosis
Most patients with papillary and follicular thyroid cancer will
be cured with appropriate treatment. Adverse prognostic
factors include older age at presentation, the presence of
distant metastases, male sex and certain histological subtypes.
However, 131 1 therapy can be effective in treating those with distant
metastases, particularly small-volume disease in the lungs, and
so prolonged survival is quite common.
Anaplastic carcinoma and lymphoma
These two conditions are difficult to distinguish clinically but are
distinct cytologically and histologically. Patients are usually over
60 years of age and present with rapid thyroid enlargement
over 2-3 months. The goitre is hard and there may be stridor
due to tracheal compression and hoarseness due to recurrent
laryngeal nerve palsy. There is no effective treatment for anaplastic
carcinoma, although surgery and radiotherapy may be considered
in some circumstances. In older patients, median survival is
only 7 months.
The prognosis for lymphoma, which may arise from pre¬
existing Hashimoto’s thyroiditis, is better (p. 961), with a median
survival of 9 years. Some 98% of tumours are non-Hodgkin’s
lymphomas, usually the diffuse large B-cell subtype. Treatment is
with combination chemotherapy and external beam radiotherapy
(p. 965).
|Medullary carcinoma
This tumour arises from the parafollicular C cells of the thyroid. In
addition to calcitonin, the tumour may secrete 5-hydroxytryptamine
(5-HT, serotonin), various peptides of the tachykinin family,
adrenocorticotrophic hormone (ACTH) and prostaglandins. As
a consequence, carcinoid syndrome (p. 678) and Cushing’s
syndrome (p. 666) may occur.
Patients usually present in middle age with a firm thyroid
mass. Cervical lymph node involvement is common but distant
metastases are rare initially. Serum calcitonin levels are raised and
are useful in monitoring response to treatment. Despite the very
high levels of calcitonin found in some patients, hypocalcaemia is
extremely rare; however, hypercalcitoninaemia can be associated
with severe, watery diarrhoea.
Treatment is by total thyroidectomy with removal of regional
cervical lymph nodes. Since the C cells do not concentrate
iodine and are not responsive to TSH, there is no role for 131 1
therapy or TSH suppression with levothyroxine. External beam
radiotherapy may be considered in some patients at high risk
of local recurrence. Vandetanib and cabozantinib are tyrosine
kinase inhibitors licensed for patients with progressive advanced
medullary cancer. The prognosis is less good than for papillary
and follicular carcinoma, but individuals can live for many decades
with persistent disease that behaves in an indolent fashion.
Medullary carcinoma of the thyroid occurs sporadically
in 70-90% cases; in 10-30% of cases, there is a genetic
predisposition that is inherited in an autosomal dominant fashion
and is due to an activating mutation in the RET gene. This inherited
tendency normally forms part of one of the MEN syndromes (MEN
2 (also known as MEN 2a) or MEN 3 (also known as MEN 2b),
p. 688) but, occasionally, susceptibility to medullary carcinoma
is the only inherited trait (familial medullary thyroid cancer).
|Riedel’s thyroiditis
This is not a form of thyroid cancer but the presentation is
similar and the differentiation can usually be made only by
thyroid biopsy. It is an exceptionally rare condition of unknown
aetiology, in which there is extensive infiltration of the thyroid
and surrounding structures with fibrous tissue. There may be
associated mediastinal and retroperitoneal fibrosis. Presentation is
with a slow-growing goitre that is irregular and stony-hard. There
is usually tracheal and oesophageal compression necessitating
partial thyroidectomy. Other recognised complications include
recurrent laryngeal nerve palsy, hypoparathyroidism and eventually
hypothyroidism.
Congenital thyroid disease
Early treatment with levothyroxine is essential to prevent
irreversible brain damage in children (cretinism) with congenital
hypothyroidism. Routine screening of TSH levels in heel-prick
blood samples obtained 5-7 days after birth (as part of the
Guthrie test) has revealed an incidence of approximately 1 in
3000, resulting from thyroid agenesis, ectopic or hypoplastic
glands, or dyshormonogenesis. Congenital hypothyroidism
is thus six times more common than phenylketonuria. It is
now possible to start levothyroxine replacement therapy within
2 weeks of birth. Developmental assessment of infants treated
at this early stage has revealed no differences between cases
and controls in most children.
Dyshormonogenesis
Several autosomal recessive defects in thyroid hormone synthesis
have been described; the most common results from deficiency
of the intrathyroidal peroxidase enzyme. Homozygous individuals
present with congenital hypothyroidism; heterozygotes present in
the first two decades of life with goitre, normal thyroid hormone
levels and a raised TSH. The combination of dyshormonogenetic
goitre and nerve deafness is known as Pendred’s syndrome
and is due to mutations in pendrin, the protein that
transports iodide to the luminal surface of the follicular cell
(see Fig. 18.3).
The reproductive system • 651
18.18 Thyroid disease in pregnancy
Normal pregnancy
• Trimester-specific reference ranges: should be used to interpret
thyroid function test results in pregnancy.
Iodine deficiency
• Iodine requirements: increased in pregnancy. The World Health
Organisation (WHO) recommends a minimum intake of 250 jig/day.
• Iodine deficiency: the major cause of preventable impaired
cognitive development in children worldwide.
Hypothyroidism
• Impaired cognitive development in the offspring: may be
associated with hypothyroidism that is not adequately treated.
• Levothyroxine replacement therapy dose requirements:
increase by 30-50% from early in pregnancy. Monitoring to
maintain TSH results within the trimester-specific reference range is
recommended in early pregnancy and at least once in each
trimester.
Thyrotoxicosis
• Gestational thyrotoxicosis: associated with multiple pregnancies
and hyperemesis gravidarum. Transient and usually does not
require antithyroid drug treatment.
• Graves’ disease: the most common cause of sustained
thyrotoxicosis in pregnancy
• Antithyroid drugs: propylthiouracil should be used in the first
trimester, with carbimazole substituted in the second and third
trimesters.
Post-partum thyroiditis
• Screening: not recommended for every woman, but thyroid function
should be tested 4-6 weeks post-partum in those with a personal
history of thyroid disease, goitre or other autoimmune disease
including type 1 diabetes, in those known to have positive
antithyroid peroxidase antibodies, or when there is clinical suspicion
of thyroid dysfunction.
| Thyroid hormone resistance
This is a rare disorder in which the pituitary and hypothalamus
are resistant to feedback suppression of TSH by T3, sometimes
due to mutations in the thyroid hormone receptor p or because
of defects in monodeiodinase activity. The result is high levels
of TSH, T4 and T3, often with a moderate goitre that may not
be noted until adulthood. Thyroid hormone signalling is highly
complex and involves different isozymes of both monodeiodinases
and thyroid hormone receptors in different tissues. For that
reason, other tissues may or may not share the resistance to
thyroid hormone and there may be features of thyrotoxicosis
(e.g. tachycardia). This condition can be difficult to distinguish
from an equally rare TSH-producing pituitary tumour (TSHoma;
see Box 18.5, p. 636); administration of TRH results in elevation
of TSH in thyroid hormone resistance and not in TSHoma, but
an MRI scan of the pituitary may be necessary to exclude a
macroadenoma.
The reproductive system
Clinical practice in reproductive medicine is shared between
several specialties, including gynaecology, urology, paediatrics,
psychiatry and endocrinology. The following section is focused
on disorders managed by endocrinologists.
• Facial, axillary and body hair growth
• Scalp balding
• Skin sebum production
• Penis and scrotal development
• Prostate development and function
• Laryngeal enlargement
• Muscle power
• Bone metabolism/epiphyseal closure
• Libido
• Aggression
Fig. 18.13 Male reproductive physiology. (FSH = follicle-stimulating
hormone; LH = luteinising hormone)
Functional anatomy, physiology and
investigations
The physiology of male and female reproductive function is
illustrated in Figures 18.13 and 18.14, respectively. Pathways
for synthesis of sex steroids are shown in Figure 18.19
(p. 667).
The male
In the male, the testis serves two principal functions: synthesis
of testosterone by the interstitial Leydig cells under the control
of luteinising hormone (LH), and spermatogenesis by Sertoli cells
under the control of follicle-stimulating hormone (FSH) (but also
requiring adequate testosterone). Negative feedback suppression
of LH is mediated principally by testosterone, while secretion
of another hormone by the testis, inhibin, suppresses FSH.
The axis can be assessed easily by a random blood sample
for testosterone, LH and FSH. Testosterone levels are higher
in the morning and therefore, if testosterone is marginally low,
sampling should be repeated with the patient fasted at 0900 hrs.
Testosterone is largely bound in plasma to sex hormone-binding
globulin and this can also be measured to calculate the ‘free
androgen index’ or the ‘bioavailable’ testosterone. Testicular
function can also be tested by semen analysis.
There is no equivalent of the menopause in men, although
testosterone concentrations decline slowly from the fourth decade
onwards.
652 • ENDOCRINOLOGY
Ovulation
Follicular phase j Luteal phase
Oestradiol Oestradiol
Oestradiol Oestradiol Progesterone Progesterone
Primary Dominant Mature Haemorrhagic Mature Regressing
vesicular
Follicle Corpus luteum
Oestradiol
• Endometrial
proliferation
• Genital
development
and lubrication
• Breast
proliferation
• Bone epiphyseal
closure and
mineral content
• Brain
• Body fat
distribution
• Skin sebum
Progesterone
• Endometrial
secretory change
• Increased
myometrial
contractility
• Thermogenesis
• Breast swelling
Fig. 18.14 Female reproductive physiology and the normal menstrual cycle. (FSH = follicle-stimulating hormone; LH = luteinising hormone)
The female
In the female, physiology varies during the normal menstrual
cycle. FSH stimulates growth and development of ovarian
follicles during the first 14 days after the menses. This leads to
a gradual increase in oestradiol production from granulosa cells,
which initially suppresses FSH secretion (negative feedback) but
then, above a certain level, stimulates an increase in both the
frequency and amplitude of gonadotrophin-releasing hormone
(GnRH) pulses, resulting in a marked increase in LH secretion
(positive feedback). The mid-cycle ‘surge’ of LH induces ovulation.
After release of the ovum, the follicle differentiates into a corpus
luteum, which secretes progesterone. Unless pregnancy occurs
during the cycle, the corpus luteum regresses and the fall in
progesterone levels results in menstrual bleeding. Circulating
levels of oestrogen and progesterone in pre-menopausal women
are, therefore, critically dependent on the time of the cycle.
The most useful ‘test’ of ovarian function is a careful menstrual
history: if menses are regular, measurement of gonadotrophins
and oestrogen is not necessary. In addition, ovulation can be
confirmed by measuring plasma progesterone levels during the
luteal phase (‘day 21 progesterone’).
Cessation of menstruation (the menopause) occurs at an
average age of approximately 50 years in developed countries.
In the 5 years before, there is a gradual increase in the number
of anovulatory cycles and this is referred to as the climacteric.
Oestrogen and inhibin secretion falls and negative feedback
results in increased pituitary secretion of LH and FSH (both
typically to levels above 30 IU/L (3.3 |ig/L)).
The pathophysiology of male and female reproductive
dysfunction is summarised in Box 18.19.
KWi 18.19 Classification of diseases of the
reproductive system
Primary
Secondary
Hormone
excess
Polycystic ovarian
syndrome
Granulosa cell tumour
Leydig cell tumour
Teratoma
Pituitary
gonadotrophinoma
Hormone
deficiency
Menopause
Hypogonadism (see
Box 18.20)
Turner’s syndrome
Klinefelter’s syndrome
Hypopituitarism
Kallmann’s syndrome
(isolated GnRH
deficiency)
Severe systemic
illness, including
anorexia nervosa
Hormone
hypersensitivity
Idiopathic hirsutism
Hormone
resistance
Androgen resistance
syndromes
Complete (‘testicular
feminisation’)
Partial (Reifenstein’s
syndrome)
5a-reductase type 2
deficiency
Non-functioning
tumours
Ovarian cysts
Carcinoma
Teratoma
Seminoma
(GnRH = gonadotrophin-releasing hormone)
The reproductive system • 653
Presenting problems in reproductive
disease
|J)elayed puberty
Normal pubertal development is discussed on page 1290.
Puberty is considered to be delayed if the onset of the physical
features of sexual maturation has not occurred by a chronological
age that is 2.5 standard deviations (SD) above the national
average. In the UK, this is by the age of 14 in boys and 13 in
girls. Genetic factors have a major influence in determining the
timing of the onset of puberty, such that the age of menarche
(the onset of menstruation) is often comparable within sibling
and mother-daughter pairs and within ethnic groups. However,
because there is also a threshold for body weight that acts
as a trigger for normal puberty, the onset of puberty can be
influenced by other factors including nutritional status and chronic
illness (p. 694).
Clinical assessment
The differential diagnosis is shown in Box 18.20. The key
issue is to determine whether the delay in puberty is simply
because the ‘clock is running slow’ (constitutional delay of
puberty) or because there is pathology in the hypothalamus/
pituitary (hypogonadotrophic hypogonadism) or the gonads
(hypergonadotrophic hypogonadism). A general history and
physical examination should be performed with particular reference
to previous or current medical disorders, social circumstances
and family history. Body proportions, sense of smell and pubertal
stage should be carefully documented and, in boys, the presence
or absence of testes in the scrotum noted. Current weight and
height may be plotted on centile charts, along with parental
heights. Previous growth measurements in childhood, which can
i
Constitutional delay
Hypogonadotrophic hypogonadism
• Structural hypothalamic/pituitary disease (see Box 18.54, p. 681)
• Functional gonadotrophin deficiency:
Chronic systemic illness (e.g. asthma, malabsorption, coeliac
disease, cystic fibrosis, renal failure)
Psychological stress
Anorexia nervosa
Excessive physical exercise
Hyperprolactinaemia
Other endocrine disease (e.g. Cushing’s syndrome, primary
hypothyroidism)
• Isolated gonadotrophin deficiency (Kallmann’s syndrome)
Hypergonadotrophic hypogonadism
• Acquired gonadal damage:
Chemotherapy/radiotherapy to gonads
Trauma/surgery to gonads
Autoimmune gonadal failure
Mumps orchitis
Tuberculosis
Haemochromatosis
• Developmental/congenital gonadal disorders:
Steroid biosynthetic defects
Anorchidism/cryptorchidism in males
Klinefelter’s syndrome (47XXY, male phenotype)
Turner’s syndrome (45X0, female phenotype)
usually be obtained from health records, are extremely useful.
Healthy growth usually follows a centile. Usually, children with
constitutional delay have always been small but have maintained
a normal growth velocity that is appropriate for bone age. Poor
linear growth, with ‘crossing of the centiles’, is more likely to
be associated with acquired disease. Issues that are commonly
encountered in the management of adolescents with delayed
puberty are summarised in Box 18.21.
Constitutional delay of puberty
This is the most common cause of delayed puberty, but is a
much more frequent explanation for lack of pubertal development
in boys than in girls. Affected children are healthy and have
usually been more than 2SD below the mean height for their
age throughout childhood. There is often a history of delayed
puberty in siblings or parents. Since sex steroids are essential for
fusion of the epiphyses, ‘bone age’ can be estimated by X-rays
of epiphyses, usually in the wrist and hand; in constitutional delay,
bone age is lower than chronological age. Constitutional delay
of puberty should be considered as a normal variant, as puberty
will commence spontaneously. However, affected children can
experience significant psychological distress because of their
lack of physical development, particularly when compared with
their peers.
Hypogonadotrophic hypogonadism
This may be due to structural, inflammatory or infiltrative disorders
of the pituitary and/or hypothalamus (see Box 18.54, p. 681). In
such circumstances, other pituitary hormones, such as growth
hormone, are also likely to be deficient.
‘Functional’ gonadotrophin deficiency is caused by a variety of
factors, including low body weight, chronic systemic illness (as
a consequence of the disease itself or secondary malnutrition),
endocrine disorders and profound psychosocial stress.
Isolated gonadotrophin deficiency is usually due to a genetic
abnormality that affects the synthesis of either GnRH or
gonadotrophins. The most common form is Kallmann’s syndrome,
in which there is primary GnRH deficiency and, in most affected
individuals, agenesis or hypoplasia of the olfactory bulbs, resulting
in anosmia or hyposmia. If isolated gonadotrophin deficiency is
left untreated, the epiphyses fail to fuse, resulting in tall stature
with disproportionately long arms and legs relative to trunk height
(eunuchoid habitus).
Cryptorchidism (undescended testes) and gynaecomastia
are commonly observed in all forms of hypogonadotrophic
hypogonadism.
• Aetiology: in boys the most common cause is constitutional delay,
whereas in girls there is inevitably a structural hypothalamic/pituitary
abnormality or a factor that affects their function.
• Psychological effects: whatever the underlying cause, delayed
puberty is often associated with substantial psychological distress.
< Investigations: a karyotype should be performed in all adolescents
with hypergonadotrophic hypogonadism, to exclude Turner’s and
Klinefelter’s syndromes, unless there is an obvious precipitating
cause.
• Medical induction of puberty: if this is being considered, it needs
to be managed carefully and carried out in a controlled fashion, to
avoid premature fusion of the epiphyses.
18.20 Causes of delayed puberty and hypogonadism
18.21 Delayed puberty
654 • ENDOCRINOLOGY
Hypergonadotrophic hypogonadism
Hypergonadotrophic hypogonadism associated with delayed
puberty is usually due to Klinefelter’s syndrome in boys and
Turner’s syndrome in girls (pp. 659 and 660). Other causes of
primary gonadal failure are shown in Box 18.20.
Investigations
Key measurements are LH and FSH, testosterone (in boys) and
oestradiol (in girls). Chromosome analysis should be performed
if gonadotrophin concentrations are elevated. If gonadotrophin
concentrations are low, then the differential diagnosis lies between
constitutional delay and hypogonadotrophic hypogonadism. A
plain X-ray of the wrist and hand may be compared with a set
of standard films to obtain a bone age. Full blood count, renal
function, liver function, thyroid function and coeliac disease
autoantibodies (p. 806) should be measured, but further tests
may be unnecessary if the blood tests are normal and the
child has all the clinical features of constitutional delay. If
hypogonadotrophic hypogonadism is suspected, neuroimaging
and further investigations are required (p. 680).
Management
Puberty can be induced using low doses of oral oestrogen in
girls (e.g. ethinylestradiol 2 jig daily) or testosterone in boys
(testosterone gel or depot testosterone esters). Fligher doses carry
a risk of early fusion of epiphyses. This therapy should be given
in a specialist clinic where the progress of puberty and growth
can be carefully monitored. In children with constitutional delay,
this ‘priming’ therapy can be discontinued when endogenous
puberty is established, usually in less than a year. In children
with hypogonadism, the underlying cause should be treated
and reversed if possible. If hypogonadism is permanent, sex
hormone doses are gradually increased during puberty and full
adult replacement doses given when development is complete.
Precocious puberty
Precocious puberty (PP) is the early development of any
secondary sexual characteristics before the age of 9 years in
a boy and 6-8 years of age in a girl. Central PP is due to the
early maturation of the hypothalamic-pituitary-gonadal axis and
thus is gonadotrophin-dependent. It is more common in girls
than boys and often no structural cause is identified, i.e. ‘the
physiological clock is running fast’. Structural causes are found
more commonly in younger children and in boys and include:
• central nervous system (CNS) tumours such as
astrocytomas, germ-cell tumours secreting human
chorionic gonadotrophin (hCG) and hypothalamic
harmartomas
• CNS injury caused by infection, inflammation or trauma/
surgery
• congenital CNS structural abnormalities.
Pseudo (or peripheral) PP is much less common, and is due to
excess sex steroids in the absence of pituitary gonadotrophins,
with causes including congenital adrenal hyperplasia and
McCune-Albright syndrome (p. 1055).
Investigations
Measurement of basal and GnRH-stimulated gonadotrophin
levels will allow categorisation into central or peripheral PP, with
gonadotrophin levels rising in central PP. Imaging of the CNS
is required in cases of central PP, while adrenal and ovarian
imaging is indicated in peripheral PP.
Management
Social and psychological difficulties may accompany the onset
of PP and the premature closure of the epiphyses can result in
reduced final height. In central PP, development can be arrested
with long-acting GnRH analogues. In both central and peripheral
PP, treatment of any underlying cause is indicated.
Amenorrhoea
Primary amenorrhoea may be diagnosed in a female who has
never menstruated; this usually occurs as a manifestation of
delayed puberty but may also be a consequence of anatomical
defects of the female reproductive system, such as endometrial
hypoplasia or vaginal agenesis. Secondary amenorrhoea describes
the cessation of menstruation in a female who has previously
had periods. The causes of this common presentation are
shown in Box 18.22. In non-pregnant women, secondary
amenorrhoea is almost invariably a consequence of either ovarian
or hypothalamic/pituitary dysfunction. Premature ovarian failure
(premature menopause) is defined, arbitrarily, as occurring before
40 years of age. Rarely, endometrial adhesions (Asherman’s
syndrome) can form after uterine curettage, surgery or infection
with tuberculosis or schistosomiasis, preventing endometrial
proliferation and shedding.
Clinical assessment
The underlying cause can often be suspected from associated
clinical features and the patient’s age. Hypothalamic/pituitary
disease and premature ovarian failure result in oestrogen
deficiency, which causes a variety of symptoms usually associated
with the menopause (Box 18.23). A history of galactorrhoea
should be sought. Significant weight loss of any cause can
cause amenorrhoea by suppression of gonadotrophins. Weight
gain may suggest hypothyroidism, Cushing’s syndrome or,
very rarely, a hypothalamic lesion. Hirsutism, obesity and
long-standing irregular periods suggest polycystic ovarian
1 18.22 Causes of secondary amenorrhoea
Physiological
• Pregnancy
• Menopause
Hypogonadotrophic hypogonadism (see Box 18.20)
Ovarian dysfunction
• Hypergonadotrophic
• Polycystic ovarian syndrome
hypogonadism (see Box
18.20)
• Androgen-secreting tumours
Uterine dysfunction
• Asherman’s syndrome
1 18.23 Symptoms of oestrogen deficiency
Vasomotor effects
• Hot flushes
• Sweating
Psychological
• Anxiety
• Irritability
• Emotional lability
Genitourinary
• Dyspareunia
• Urgency of micturition
• Vaginal infections
The reproductive system • 655
syndrome (PCOS, p. 658). The presence of other autoimmune
disease raises the possibility of autoimmune premature
ovarian failure.
Investigations
Pregnancy should be excluded in women of reproductive age
by measuring urine or serum hCG. Serum LH, FSH, oestradiol,
prolactin, testosterone, T4 and TSH should be measured and,
in the absence of a menstrual cycle, can be taken at any time.
Investigation of hyperprolactinaemia is described on page 684.
High concentrations of LH and FSH with low or low-normal
oestradiol suggest primary ovarian failure. Ovarian autoantibodies
may be positive when there is an underlying autoimmune aetiology,
and a karyotype should be performed in younger women to
exclude mosaic Turner’s syndrome. Elevated LH, prolactin and
testosterone levels with normal oestradiol are common in PCOS.
Low levels of LH, FSH and oestradiol suggest hypothalamic or
pituitary disease and a pituitary MRI is indicated.
There is some overlap in gonadotrophin and oestrogen
concentrations between women with hypogonadotrophic
hypogonadism and PCOS. If there is doubt as to the underlying
cause of secondary amenorrhoea, then the response to 5 days
of treatment with an oral progestogen (e.g. medroxyprogesterone
acetate 10 mg twice daily) can be assessed. In women with
PCOS, the progestogen will cause maturation of the endometrium
and menstruation will occur a few days after the progestogen
is stopped. In women with hypogonadotrophic hypogonadism,
menstruation does not occur following progestogen withdrawal
because the endometrium is atrophic as a result of oestrogen
deficiency. If doubt persists in distinguishing oestrogen deficiency
from a uterine abnormality, the capacity for menstruation can
be tested with 1 month of treatment with cyclical oestrogen
and progestogen (usually administered as a combined oral
contraceptive pill).
Assessment of bone mineral density by dual X-ray
absorptiometry (DXA, p. 989) may be appropriate in patients
with low androgen and oestrogen levels.
Management
Where possible, the underlying cause should be treated. For
example, women with functional amenorrhoea due to excessive
exercise and low weight should be encouraged to reduce their
exercise and regain some weight. The management of structural
pituitary and hypothalamic disease is described on page 684
and that of PCOS on page 658.
In oestrogen-deficient women, replacement therapy may be
necessary to treat symptoms and/or to prevent osteoporosis.
Women who have had a hysterectomy can be treated with
oestrogen alone but those with a uterus should be treated with
combined oestrogen/progestogen therapy, since unopposed
oestrogen increases the risk of endometrial cancer. Cyclical
hormone replacement therapy (HRT) regimens typically involve
giving oestrogen on days 1-21 and progestogen on days
14-21 of the cycle, and this can be conveniently administered
as the oral contraceptive pill. If oestrogenic side-effects (fluid
retention, weight gain, hypertension and thrombosis) are a
concern, then lower-dose oral or transdermal HRT may be more
appropriate.
The timing of the discontinuation of oestrogen replacement
therapy is still a matter of debate. In post-menopausal women,
HRT has been shown to relieve menopausal symptoms and to
prevent osteoporotic fractures but is associated with adverse
effects, which are related to the duration of therapy and to the
patient’s age. In patients with premature menopause, HRT
should be continued up to the age of around 50 years, but
continued beyond this age only if there are continued symptoms
of oestrogen deficiency on discontinuation.
Management of infertility in oestrogen-deficient women is
described on page 656.
| Male hypogonadism
The clinical features of both hypo- and hypergonadotrophic
hypogonadism include loss of libido, lethargy with muscle
weakness, and decreased frequency of shaving. Patients may
also present with gynaecomastia, infertility, delayed puberty,
osteoporosis or anaemia of chronic disease. The causes of
hypogonadism are listed in Box 18.20. Mild hypogonadism may
also occur in older men, particularly in the context of central
adiposity and the metabolic syndrome (p. 730). Postulated
mechanisms are complex and include reduction in sex hormone¬
binding globulin by insulin resistance and reduction in GnRH and
gonadotrophin secretion by cytokines or oestrogen released by
adipose tissue. Testosterone levels also fall gradually with age in
men (see Box 18.30) and this is associated with gonadotrophin
levels that are low or inappropriately within the ‘normal’ range.
There is an increasing trend to measure testosterone in older
men, typically as part of an assessment of erectile dysfunction
and lack of libido.
Investigations
Male hypogonadism is confirmed by demonstrating a low fasting
0900-hr serum testosterone level. The distinction between
hypo- and hypergonadotrophic hypogonadism is by measurement
of random LH and FSH. Patients with hypogonadotrophic
hypogonadism should be investigated as described for pituitary
disease on page 680. Patients with hypergonadotrophic
hypogonadism should have the testes examined for cryptorchidism
or atrophy, and a karyotype should be performed (to identify
Klinefelter’s syndrome).
Management
Testosterone replacement is clearly indicated in younger men
with significant hypogonadism to prevent osteoporosis and to
restore muscle power and libido. Debate exists as to whether
replacement therapy is of benefit in mild hypogonadism associated
with ageing and central adiposity, particularly in the absence of
structural pituitary/hypothalamic disease or other pituitary hormone
deficiency. In such instances, a therapeutic trial of testosterone
therapy may be considered if symptoms are present (e.g. low
libido and erectile dysfunction), but the benefits of therapy must
be carefully weighed against the potential for harm.
Routes of testosterone administration are shown in Box
18.24. First-pass hepatic metabolism of testosterone is
highly efficient, so bioavailability of ingested preparations is
poor. Doses of systemic testosterone can be titrated against
symptoms; circulating testosterone levels may provide only a
rough guide to dosage because they may be highly variable
(Box 18.24). Testosterone therapy can aggravate prostatic
carcinoma; prostate-specific antigen (PSA) should be measured
before commencing testosterone therapy in men older than
50 years and monitored annually thereafter. Haemoglobin
concentration should also be monitored in older men, as androgen
replacement can cause polycythaemia. Testosterone replacement
inhibits spermatogenesis; treatment for fertility is described
below.
656 • ENDOCRINOLOGY
18.24 Options for androgen replacement therapy
Route of
administration
Preparation
Dose
Frequency
Comments
Intramuscular
Testosterone enantate
50-250 mg
Every 3-4 weeks
Produces peaks and troughs of testosterone levels that are
outside the physiological range and may be symptomatic
Testosterone undecanoate
1000 mg
Every 3 months
Smoother profile than testosterone enantate, with less
frequent injections
Subcutaneous
Testosterone pellets
600-800 mg
Every
Smoother profile than testosterone enantate but
4-6 months
implantation causes scarring and infection
Transdermal
Testosterone patch
5-1 0 mg
Daily
Stable testosterone levels but high incidence of skin
hypersensitivity
Testosterone gel
50-1 00 mg
Daily
Stable testosterone levels; transfer of gel can occur
following skin-to-skin contact with another person
Oral
Testosterone undecanoate
40-1 20 mg
Twice daily
Very variable testosterone levels; risk of hepatotoxicity
| Infertility
Infertility affects around 1 in 7 couples of reproductive age,
often causing psychological distress. The main causes are
listed in Box 18.25. In women, it may result from anovulation or
abnormalities of the reproductive tract that prevent fertilisation
or embryonic implantation, often damaged Fallopian tubes from
previous infection. In men, infertility may result from impaired
sperm quality (e.g. reduced motility) or reduced sperm number.
Azoospermia or oligospermia is usually idiopathic but may be a
consequence of hypogonadism (see Box 18.20). Microdeletions
of the Y chromosome are increasingly recognised as a cause
of severely abnormal spermatogenesis. In many couples, more
than one factor causing subfertility is present, and in a large
proportion no cause can be identified.
i
Female factor (35-40%)
• Ovulatory dysfunction:
Polycystic ovarian syndrome
Hypogonadotrophic hypogonadism (see Box 18.20)
Hypergonadotrophic hypogonadism (see Box 18.20)
• Tubular dysfunction:
Pelvic inflammatory disease (chlamydia, gonorrhoea)
Endometriosis
Previous sterilisation
Previous pelvic or abdominal surgery
• Cervical and/or uterine dysfunction:
Congenital abnormalities
Fibroids
Treatment for cervical carcinoma
Asherman’s syndrome
Male factor (35-40%)
• Reduced sperm quality or production:
Y chromosome microdeletions
Varicocele
Hypergonadotrophic hypogonadism (see Box 18.20)
Hypogonadotrophic hypogonadism (see Box 18.20)
• Tubular dysfunction:
Varicocele
Congenital abnormality of vas deferens/epididymis
Previous sexually transmitted infection (chlamydia, gonorrhoea)
Previous vasectomy
Unexplained or mixed factor (20-35%)
Clinical assessment
A history of previous pregnancies, relevant infections and surgery
is important in both men and women. A sexual history must
be explored sensitively, as some couples have intercourse
infrequently or only when they consider the woman to be ovulating,
and psychosexual difficulties are common. Irregular and/or
infrequent menstrual periods are an indicator of anovulatory
cycles in the woman, in which case causes such as PCOS
should be considered. In men, the testes should be examined
to confirm that both are in the scrotum and to identify any
structural abnormality, such as small size, absent vas deferens
or the presence of a varicocele.
Investigations
Investigations should generally be performed after a couple has
failed to conceive despite unprotected intercourse for 12 months,
unless there is an obvious abnormality like amenorrhoea. Both
partners need to be investigated. The male partner needs a
semen analysis to assess sperm count and quality. Home testing
for ovulation (by commercial urine dipstick kits, temperature
measurement, or assessment of cervical mucus) is not
recommended, as the information is often counterbalanced by
increased anxiety if interpretation is inconclusive. In women with
regular periods, ovulation can be confirmed by an elevated serum
progesterone concentration on day 21 of the menstrual cycle.
Transvaginal ultrasound can be used to assess uterine and ovarian
anatomy. Tubal patency may be examined at laparoscopy or by
hysterosalpingography (HSG; a radio-opaque medium is injected
into the uterus and should normally outline the Fallopian tubes).
In vitro assessments of sperm survival in cervical mucus may
be done in cases of unexplained infertility but are rarely helpful.
Management
Couples should be advised to have regular sexual intercourse,
ideally every 2-3 days throughout the menstrual cycle. It is not
uncommon for ‘spontaneous’ pregnancies to occur in couples
undergoing investigations for infertility or with identified causes
of male or female subfertility.
In women with anovulatory cycles secondary to PCOS
(p. 658), clomifene, which has partial anti -oestrogen action, blocks
negative feedback of oestrogen on the hypothalamus/pituitary,
causing gonadotrophin secretion and thus ovulation. In women
with gonadotrophin deficiency or in whom anti -oestrogen therapy
is unsuccessful, ovulation may be induced by direct stimulation
of the ovary by daily injection of FSH and an injection of hCG to
18.25 Causes of infertility
The reproductive system • 657
induce follicular rupture at the appropriate time. In hypothalamic
disease, pulsatile GnRH therapy with a portable infusion pump
can be used to stimulate pituitary gonadotrophin secretion
(note that non-pulsatile administration of GnRH or its analogues
paradoxically suppresses LH and FSH secretion). Whatever
method of ovulation induction is employed, monitoring of response
is essential to avoid multiple ovulation. For clomifene, ultrasound
monitoring is recommended for at least the first cycle. During
gonadotrophin therapy, closer monitoring of follicular growth
by transvaginal ultrasonography and blood oestradiol levels is
mandatory. ‘Ovarian hyperstimulation syndrome’ is characterised
by grossly enlarged ovaries and capillary leak with circulatory
shock, pleural effusions and ascites. Anovulatory women who fail
to respond to ovulation induction or who have primary ovarian
failure may wish to consider using donated eggs or embryos,
surrogacy and adoption.
Surgery to restore Fallopian tube patency can be effective but
in vitro fertilisation (IVF) is normally recommended. IVF is widely
used for many causes of infertility and in unexplained cases of
prolonged (>3 years) infertility. The success of IVF depends on
age, with low success rates in women over 40 years.
Men with hypogonadotrophic hypogonadism who wish
fertility are usually given injections of hCG several times a
week (recombinant FSH may also be required in men with
hypogonadism of pre-pubertal origin); it may take up to 2 years
to achieve satisfactory sperm counts. Surgery is rarely an option
in primary testicular disease but removal of a varicocele can
improve semen quality. Extraction of sperm from the epididymis
for IVF, and intracytoplasmic sperm injection (ICSI, when single
spermatozoa are injected into each oocyte) are being used
increasingly in men with oligospermia or poor sperm quality who
have primary testicular disease. Azoospermic men may opt to
use donated sperm but this may be in short supply.
reach adult levels before testosterone) and in elderly men (due
to decreasing testosterone concentrations). Prolactin excess
alone does not cause gynaecomastia (p. 684).
Clinical assessment
A drug history is important. Gynaecomastia is often asymmetrical
and palpation may allow breast tissue to be distinguished from
the prominent adipose tissue (lipomastia) around the nipple that
is often observed in obesity. Features of hypogonadism should
be sought (see above) and the testes examined for evidence of
cryptorchidism, atrophy or a tumour.
Investigations
If a clinical distinction between gynaecomastia and adipose
tissue cannot be made, then ultrasonography or mammography
is required. A random blood sample should be taken for
testosterone, LH, FSH, oestradiol, prolactin and hCG. Elevated
oestrogen concentrations are found in testicular tumours and
hCG-producing neoplasms.
Management
An adolescent with gynaecomastia who is progressing normally
through puberty may be reassured that the gynaecomastia will
usually resolve once development is complete. If puberty does not
proceed normally, then there may be an underlying abnormality
that requires investigation (p. 653). Gynaecomastia may cause
significant psychological distress, especially in adolescent boys,
and surgical excision may be justified for cosmetic reasons.
Androgen replacement will usually improve gynaecomastia in
hypogonadal males and any other identifiable underlying cause
should be addressed if possible. The anti -oestrogen tamoxifen
may also be effective in reducing the size of the breast tissue.
Hirsutism
Hirsutism refers to the excessive growth of terminal hair (the thick,
pigmented hair usually associated with the adult male chest) in
an androgen-dependent distribution in women (upper lip, chin,
chest, back, lower abdomen, thigh, forearm) and is one of the
most common presentations of endocrine disease. It should be
distinguished from hypertrichosis, which is generalised excessive
growth of vellus hair (the thin, non-pigmented hair that is typically
found all over the body from childhood onwards). The aetiology
of androgen excess is shown in Box 18.27.
Clinical assessment
The severity of hirsutism is subjective. Some women suffer
profound embarrassment from a degree of hair growth that
others would not consider remarkable. Important observations
are a drug and menstrual history, calculation of body mass index,
measurement of blood pressure, and examination for virilisation
(clitoromegaly, deep voice, male-pattern balding, breast atrophy)
and associated features, including acne vulgaris or Cushing’s
syndrome (p. 666). Hirsutism of recent onset associated with
virilisation is suggestive of an androgen-secreting tumour but
this is rare.
Investigations
A random blood sample should be taken for testosterone,
prolactin, LH and FSH. If there are clinical features of Cushing’s
syndrome, further investigations should be performed (p. 667).
If testosterone levels are more than twice the upper limit of
normal for females, idiopathic hirsutism and PCOS are less
likely, especially if LH and FSH levels are low. Under these
Gynaecomastia
Gynaecomastia is the presence of glandular breast tissue in males.
Normal breast development in women is oestrogen-dependent,
while androgens oppose this effect. Gynaecomastia results from
an imbalance between androgen and oestrogen activity, which
may reflect androgen deficiency or oestrogen excess. Causes
are listed in Box 18.26. The most common are physiological: for
example, in the newborn baby (due to maternal and placental
oestrogens), in pubertal boys (in whom oestradiol concentrations
18.26 Causes of gynaecomastia
Idiopathic
Physiological
Drug-induced
• Cimetidine
• Digoxin
• Anti-androgens (cyproterone acetate, spironolactone)
• Some exogenous anabolic steroids (diethylstilbestrol)
• Cannabis
Hypogonadism (see Box 18.20)
Androgen resistance syndromes
Oestrogen excess
• Liver failure (impaired steroid metabolism)
• Oestrogen-secreting tumour (e.g. of testis)
• Human chorionic gonadotrophin-secreting tumour (e.g. of testis
or lung)
658 • ENDOCRINOLOGY
18.27 Causes of hirsutism
Cause
Clinical features
Investigation findings
Treatment
Idiopathic
Often familial
Mediterranean or Asian background
Normal
Cosmetic measures
Anti-androgens
Polycystic ovarian
syndrome
Obesity
Oligomenorrhoea or secondary
amenorrhoea
Infertility
LH:FSH ratio > 2.5:1
Minor elevation of androgens*
Mild hyperprolactinaemia
Weight loss
Cosmetic measures
Anti-androgens
(Metformin, glitazones may be
useful)
Congenital adrenal
hyperplasia
(95% 21 -hydroxylase
deficiency)
Pigmentation
History of salt-wasting in childhood,
ambiguous genitalia, or adrenal
crisis when stressed
Jewish background
Elevated androgens* that suppress with
dexamethasone
Abnormal rise in 1 7-OH-progesterone
with ACTH
Glucocorticoid replacement
administered in reverse rhythm
to suppress early morning ACTH
Exogenous androgen
administration
Athletes
Virilisation
Low LH and FSH
Analysis of urinary androgens may detect
drug of misuse
Stop steroid misuse
Androgen-secreting tumour
of ovary or adrenal cortex
Rapid onset
Virilisation: clitoromegaly, deep
voice, balding, breast atrophy
High androgens* that do not suppress
with dexamethasone
Low LH and FSH
CT or MRI usually demonstrates a tumour
Surgical excision
Cushing’s syndrome
Clinical features of Cushing’s
syndrome (p. 667)
Normal or mild elevation of adrenal
androgens*
See investigations (p. 667)
Treat the cause (p. 667)
*e.g. Serum testosterone levels in women: <2 nmol/L (<58 ng/dL) is normal; 2-5 nmol/L (58-144 ng/dL) is minor elevation; >5 nmol/L (>144 ng/dL) is high and requires
further investigation.
(ACTH = adrenocorticotropic hormone; CT = computed tomography; FH = follicle-stimulating hormone; LH = luteinising hormone; MRI = magnetic resonance imaging)
circumstances, other causes of androgen excess should be
sought. Congenital adrenal hyperplasia due to 21 -hydroxylase
deficiency is diagnosed by a short ACTH stimulation test with
measurement of 1 7-OH-progesterone (p. 676). In patients
with androgen-secreting tumours, serum testosterone does
not suppress following a 48-hour low-dose dexamethasone
suppression test. The tumour should then be sought by CT or
MRI of the adrenals and ovaries.
Management
This depends on the cause (Box 1 8.27). Options for the treatment
of PCOS and idiopathic hirsutism are similar and are described
below.
Polycystic ovarian syndrome
Polycystic ovarian syndrome (PCOS) affects up to 1 0% of women
of reproductive age. It is a heterogeneous disorder (Box 18.28),
often associated with obesity, for which the primary cause remains
uncertain. Genetic factors probably play a role, since PCOS
often affects several family members. The severity and clinical
features of PCOS vary markedly between individual patients but
diagnosis is usually made during the investigation of hirsutism
(p. 657) or amenorrhoea/oligomenorrhoea (p. 655). Infertility
may also be present (p. 656). There is no universally accepted
definition but it has been recommended that a diagnosis of PCOS
requires the presence of two of the following three features:
• menstrual irregularity
• clinical or biochemical androgen excess
• multiple cysts in the ovaries (most readily detected by
transvaginal ultrasound; Fig. 18.15).
1 18.28 Features of polycystic ovarian syndrome
Mechanisms
Manifestations
Pituitary dysfunction
High serum LH
High serum prolactin
Anovulatory menstrual cycles
Oligomenorrhoea
Secondary amenorrhoea
Cystic ovaries
Infertility
Androgen excess
Hirsutism
Acne
Obesity
Hyperglycaemia
Elevated oestrogens
Insulin resistance
Dyslipidaemia
Hypertension
*These mechanisms are interrelated; it is not known which, if any, is primary.
PCOS probably represents the common endpoint of several different pathologies.
(LH = luteinising hormone)
Women with PCOS are at increased risk of glucose intolerance
and some authorities recommend screening for type 2 diabetes
and other cardiovascular risk factors associated with the metabolic
syndrome (p. 730).
Management
This should be directed at the presenting complaint but all
PCOS patients who are overweight should be encouraged to
lose weight, as this can improve several symptoms, including
menstrual irregularity, and reduces the risk of type 2 diabetes.
The reproductive system • 659
18.29 Anti-androgen therapy
Mechanism of action
Drug
Dose
Hazards
Androgen receptor antagonism
Cyproterone acetate
2, 50 or 100 mg on days 1-11
Hepatic dysfunction
of 28-day cycle with
Feminisation of male fetus
ethinylestradiol 30 pig on days
Progesterone receptor agonist
1-21
Dysfunctional uterine bleeding
Spironolactone
100-200 mg daily
Electrolyte disturbance
Flutamide
Not recommended
Hepatic dysfunction
5a-reductase inhibition
Finasteride
5 mg daily
Limited clinical experience; possibly less
(prevent conversion of testosterone
to active di hydrotestosterone)
efficacious than other treatments
Suppression of ovarian steroid
Oestrogen
See combination with cyproterone
Venous thromboembolism
production and elevation of sex
acetate above
Hypertension
hormone-binding globulin
or
Weight gain
Conventional oestrogen-containing
Dyslipidaemia
contraceptive
Increased breast and endometrial carcinoma
Fig. 18.15 Polycystic ovary. A transvaginal ultrasound scan showing
multiple cysts (some indicated by small arrows) in the ovary (highlighted by
bigger arrows) of a woman with polycystic ovarian syndrome.
Menstrual irregularity and infertility
Most women with PCOS have oligomenorrhoea, with irregular,
heavy menstrual periods. This may not require treatment
unless fertility is desired. Metformin (p. 746), by reducing insulin
resistance, may restore regular ovulatory cycles in overweight
women, although it is less effective than clomifene (p. 656)
at restoring fertility as measured by successful pregnancy.
Thiazolidinediones (p. 747) also enhance insulin sensitivity and
restore menstrual regularity in PCOS but are contraindicated in
women planning pregnancy.
In women who have very few periods each year or are
amenorrhoeic, the high oestrogen concentrations associated
with PCOS can cause endometrial hyperplasia. Progestogens can
be administered on a cyclical basis to induce regular shedding
of the endometrium and a withdrawal bleed, or a progestogen-
impregnated intrauterine coil can be fitted.
Hirsutism
For hirsutism, most patients will have used cosmetic measures,
such as shaving, bleaching and waxing, before consulting a
doctor. Electrolysis and laser treatment are effective for small
areas like the upper lip and for chest hair but are expensive.
Eflornithine cream inhibits ornithine decarboxylase in hair follicles
and may reduce hair growth when applied daily to affected
areas of the face.
If conservative measures are unsuccessful, anti-androgen
therapy is given (Box 18.29). The life cycle of a hair follicle is at
least 3 months and no improvement is likely before this time,
when follicles have shed their hair and replacement hair growth
has been suppressed. Metformin and thiazolidinediones are
less effective at treating hirsutism than at restoring menstrual
regularity. Unless weight is lost, hirsutism will return if therapy is
discontinued. The patient should know that prolonged exposure
to some agents may not be desirable and they should be stopped
before pregnancy.
Turner’s syndrome
Turner’s syndrome affects around 1 in 2500 females. It is
classically associated with a 45X0 karyotype but other cytogenetic
abnormalities may be responsible, including mosaic forms
(e.g. 45XO/46XX or 45XO/46XY) and partial deletions of an X
chromosome.
Clinical features
These are shown in Figure 18.16.
Individuals with Turner’s syndrome invariably have short stature
from an early age and this is often the initial presenting symptom.
It is probably due to haploinsufficiency of the SHOX gene, one
copy of which is found on both the X and Y chromosomes,
which encodes a protein that is predominantly found in bone
fibroblasts.
The genital tract and external genitalia in Turner’s syndrome
are female in character, since this is the default developmental
outcome in the absence of testes. Ovarian tissue develops
normally until the third month of gestation, but thereafter there
is gonadal dysgenesis with accelerated degeneration of oocytes
and increased ovarian stromal fibrosis, resulting in ‘streak ovaries’.
The inability of ovarian tissue to produce oestrogen results
in loss of negative feedback and elevation of FSH and LH
concentrations.
There is a wide variation in the spectrum of associated somatic
abnormalities. The severity of the phenotype is, in part, related to
660 • ENDOCRINOLOGY
Short stature
Fish-like mouth
High-arched palate
Autoimmune thyroid disease (20%)
Coarctation of aorta
Bicuspid aortic valve
Aortic root dilatation
Coronary artery disease
Hypertension
Abnormal LFTs (30-80%)
Streak gonads
Gonadoblastoma (XY mosaic)
Psychological problems
Impaired visuospatial processing
Reduced IQ (ring chromosome X)
Low-set ears
Sensorineural/conduction
hearing loss
Webbing of neck (25-40%)
Widely spaced nipples
Shield chest
Wide carrying angle of elbows
Type 2 diabetes/IGT (10-30%)
Inflammatory bowel
disease (0.2-0.3%)
Horseshoe kidneys and other
renal and collecting system
abnormalities
Reduced bone mineral density
- Lymphoedema of hands
and feet (30%)
Fig. 18.16 Clinical features of Turner’s syndrome (45X0). (IGT = impaired glucose tolerance; LFTs = liver function tests)
the underlying cytogenetic abnormality. Mosaic individuals may
have only mild short stature and may enter puberty spontaneously
before developing gonadal failure.
Diagnosis and management
The diagnosis of Turner’s syndrome can be confirmed by
karyotype analysis. Short stature, although not directly due
to growth hormone deficiency, responds to high doses of
growth hormone. Prophylactic gonadectomy is recommended
for individuals with 45XO/46XY mosaicism because there is
an increased risk of gonadoblastoma. Pubertal development
can be induced with oestrogen therapy but causes fusion of
the epiphyses and cessation of growth. The timing of pubertal
induction therefore needs to be carefully planned. Adults with
Turner’s syndrome require long-term oestrogen replacement
therapy and should be monitored periodically for the development
of aortic root dilatation, hearing loss and other somatic
complications.
Klinefelter’s syndrome
Klinefelter’s syndrome affects approximately 1 in 1000 males
and is usually associated with a 47XXY karyotype. However,
other cytogenetic variants may be responsible, especially
46XY/47XXY mosaicism. The principal pathological abnormality
is dysgenesis of the seminiferous tubules. This is evident from
infancy (and possibly even in utero) and progresses with age.
By adolescence, hyalinisation and fibrosis are present within
the seminiferous tubules and Leydig cell function is impaired,
resulting in hypogonadism.
£
• Post-menopausal osteoporosis: a major public health issue due
to the high incidence of associated fragility fractures, especially
of hip.
• Hormone replacement therapy: should be prescribed only above
the age of 50 for the short-term relief of symptoms of oestrogen
deficiency.
• Sexual activity: many older people remain sexually active.
• ‘Male menopause’: does not occur, although testosterone
concentrations do fall with age. Testosterone therapy in mildly
hypogonadal men may be of benefit for body composition, muscle
and bone. Large randomised trials are required to determine
whether benefits outweigh potentially harmful effects on the
prostate and cardiovascular system.
• Androgens in older women: hirsutism and balding occur. In those
rare patients with elevated androgen levels, this may be
pathological, e.g. from an ovarian tumour.
Clinical features
The diagnosis is typically made in adolescents who have
presented with gynaecomastia and failure to progress normally
through puberty. Affected individuals usually have small, firm
testes. Tall stature is apparent from early childhood, reflecting
characteristically long leg length associated with 47XXY, and may
be exacerbated by androgen deficiency with lack of epiphyseal
closure in puberty. Other clinical features may include learning
difficulties and behavioural disorders, as well as an increased risk
of breast cancer and type 2 diabetes in later life. The spectrum
of clinical features is wide and some individuals, especially
18.30 Gonadal function in old age
The parathyroid glands • 661
those with 46XY/47XXY mosaicism, may pass through puberty
normally and be identified only during investigation for infertility.
Diagnosis and management
Klinefelter’s syndrome is suggested by the typical phenotype in
a patient with hypergonadotrophic hypogonadism and can be
confirmed by karyotype analysis. Individuals with clinical and
biochemical evidence of androgen deficiency require androgen
replacement (see Box 18.24). There are reports of successful
pregnancy occurring following ICSI therapy where spermatocytes
have been retrieved from the gonads of men with Klinefelter’s
syndrome.
The parathyroid glands
Parathyroid hormone (PTH) plays a key role in the regulation of
calcium and phosphate homeostasis and vitamin D metabolism,
as shown in Figure 24.61 (p. 1051). The consequences of altered
function of this axis in gut and renal disease are covered on
pages 783 and 418, respectively. Other metabolic bone
diseases are explored on page 1044. Here, the investigation
of hypercalcaemia and hypocalcaemia and disorders of the
parathyroid glands are discussed.
Functional anatomy, physiology and
investigations
The four parathyroid glands lie behind the lobes of the thyroid
and weigh between 25 and 40 mg. The parathyroid chief cells
respond directly to changes in calcium concentrations via a
G protein-coupled cell surface receptor (the calcium-sensing
receptor) located on the cell surface (see Fig. 25.55). When
serum ionised calcium levels fall, PTH secretion rises. PTH is
a single-chain polypeptide of 84 amino acids. It acts on the
renal tubules to promote reabsorption of calcium and reduce
reabsorption of phosphate, and on the skeleton to increase
osteoclastic bone resorption and bone formation. PTH also
promotes the conversion of 25-hydroxyvitamin D to the active
metabolite, 1 ,25-dihydroxyvitamin D; the 1 ,25-dihydroxyvitamin
D, in turn, enhances calcium absorption from the gut.
More than 99% of total body calcium is in bone. Prolonged
exposure of bone to high levels of PTH is associated with
increased osteoclastic activity and new bone formation, but
the net effect is to cause bone loss with mobilisation of calcium
into the extracellular fluid. In contrast, pulsatile release of PTH
causes net bone gain, an effect that is exploited therapeutically
in the treatment of osteoporosis (p. 1048).
The differential diagnosis of disorders of calcium metabolism
requires measurement of calcium phosphate, alkaline
phosphatase, renal function, PTH and 25-hydroxyvitamin D.
Although the parathyroid glands detect and respond to ionised
calcium levels, most clinical laboratories measure only total serum
calcium levels. About 50% of total calcium is bound to organic
ions, such as citrate or phosphate, and to proteins, especially
albumin. Accordingly, if the serum albumin level is reduced,
total calcium concentrations should be ‘corrected’ by adjusting
the value for calcium upwards by 0.02 mmol/L (0.08 mg/dL)
for each 1 g/L reduction in albumin below 40 g/L. If albumin
concentrations are significantly low, as in severe acute illness
and other chronic illness such as liver cirrhosis, this correction
is less accurate and measurement of ionised calcium is needed.
Calcitonin is secreted from the parafollicular C cells of the
thyroid gland. Although it is a useful tumour marker in medullary
carcinoma of thyroid (p. 650) and can be given therapeutically in
Paget’s disease of bone (p. 1053), its release from the thyroid
is of no clinical relevance to calcium homeostasis in humans.
Disorders of the parathyroid glands are summarised in
Box 18.31.
Presenting problems in parathyroid disease
Hypercalcaemia
Hypercalcaemia is one of the most common biochemical
abnormalities and is often detected during routine biochemical
analysis in asymptomatic patients. However, it can present with
chronic symptoms, as described below, and occasionally as an
acute emergency with severe hypercalcaemia and dehydration.
18.31 Classification of diseases of the parathyroid glands
Primary
Secondary
Hormone excess
Primary hyperparathyroidism
Parathyroid adenoma
Parathyroid carcinoma1
Parathyroid hyperplasia2
Tertiary hyperparathyroidism
Following prolonged secondary hyperparathyroidism
Secondary hyperparathyroidism
Chronic kidney disease
Malabsorption
Vitamin D deficiency
Hormone deficiency
Hypoparathyroidism
Post-surgical
Autoimmune
Inherited
Hormone hypersensitivity
Autosomal dominant hypercalciuric hypocalcaemic (CASR-activating mutation)
Hormone resistance
Pseudohypoparathyroidism
Familial hypocalciuric hypercalcaemia
Non-functioning tumours
Parathyroid carcinoma1
Parathyroid carcinomas may or may not produce parathyroid hormone. 2ln multiple endocrine neoplasia (MEN) syndromes (p. 688).
(CASR = calcium-sensing receptor)
662 • ENDOCRINOLOGY
Causes of hypercalcaemia are listed in Box 18.32. Of these,
primary hyperparathyroidism and malignant hypercalcaemia are
by far the most common. Familial hypocalciuric hypercalcaemia
(FHH) is a rare but important cause that needs differentiation
from primary hyperparathyroidism (HPT). Lithium may cause
hyperparathyroidism by reducing the sensitivity of the calcium¬
sensing receptor.
Clinical assessment
Symptoms and signs of hypercalcaemia include polyuria and
polydipsia, renal colic, lethargy, anorexia, nausea, dyspepsia
and peptic ulceration, constipation, depression, drowsiness and
impaired cognition. Patients with malignant hypercalcaemia can
have a rapid onset of symptoms and may have clinical features
that help to localise the tumour.
The classic symptoms of primary hyperparathyroidism are
described by the adage ‘bones, stones and abdominal groans’,
but few patients present in this way nowadays and the disorder
is most often picked up as an incidental finding on biochemical
testing. About 50% of patients with primary hyperparathyroidism
are asymptomatic while others have non-specific symptoms
such as fatigue, depression and generalised aches and pains.
Some present with renal calculi and it has been estimated that
i
With normal or elevated parathyroid hormone (PTH) levels
• Primary or tertiary hyperparathyroidism
• Lithium-induced hyperparathyroidism
• Familial hypocalciuric hypercalcaemia
With low PTH levels
• Malignancy (lung, breast, myeloma, renal, lymphoma, thyroid)
• Elevated 1 ,25-dihydroxyvitamin D (vitamin D intoxication,
sarcoidosis, human immunodeficiency virus, other granulomatous
disease)
• Thyrotoxicosis
• Paget’s disease with immobilisation
• Milk-alkali syndrome
• Thiazide diuretics
• Glucocorticoid deficiency
5% of first stone formers and 1 5% of recurrent stone formers
have primary hyperparathyroidism (p. 663). Hypertension is a
common feature of hyperparathyroidism. Parathyroid tumours
are almost never palpable.
A family history of hypercalcaemia raises the possibility of
FHH or MEN (p. 688).
Investigations
The most discriminatory investigation is measurement of PTH. If PTH
levels are detectable or elevated in the presence of hypercalcaemia,
then primary hyperparathyroidism is the most likely diagnosis. High
plasma phosphate and alkaline phosphatase accompanied by renal
impairment suggest tertiary hyperparathyroidism. Hypercalcaemia
may cause nephrocalcinosis and renal tubular impairment, resulting
in hyperuricaemia and hyperchloraemia.
Patients with FHH can present with a similar biochemical
picture to primary hyperparathyroidism but typically have low
urinary calcium excretion (a ratio of urinary calcium clearance
to creatinine clearance of <0.01). The diagnosis of FHH can be
confirmed by screening family members for hypercalcaemia and/
or identifying an inactivating mutation in the gene encoding the
calcium-sensing receptor.
If PTH is low and no other cause is apparent, then malignancy
with or without bony metastases is likely. PTH-related peptide,
which is often responsible for the hypercalcaemia associated with
malignancy, is not detected by PTH assays, but can be measured
by a specific assay (although this is not usually necessary).
Unless the source is obvious, the patient should be screened
for malignancy with a chest X-ray, myeloma screen (p. 967) and
CT as appropriate.
Management
Treatment of severe hypercalcaemia and primary hyper¬
parathyroidism is described on pages 663 and 1327, respectively.
FHH does not require any specific intervention.
Hypocalcaemia
Aetiology
Hypocalcaemia is much less common than hypercalcaemia. The
differential diagnosis is shown in Box 18.33. The most common
18.32 Causes of hypercalcaemia
18.33 Differential diagnosis of hypocalcaemia
Total serum
calcium
Ionised serum
calcium
Serum
phosphate
Serum PTH
Comments
Hypoalbuminaemia
4-
Adjust calcium upwards by 0.02 mmol/L
(0.1 mg/dL) for every 1 g/L reduction in
albumin below 40 g/L
Alkalosis
4.
<-» or T
p. 366
Vitamin D deficiency
4-
4.
4.
t
p. 1049
Chronic renal failure
1
i
t
t
Due to impaired vitamin D hydroxylation
Serum creatinine T
Hypoparathyroidism
1
i
t
i
See text
Pseudohypoparathyroidism
4-
4.
t
t
Characteristic phenotype (see text)
Acute pancreatitis
1
1
o or i
t
Usually clinically obvious
Serum amylase T
Hypomagnesaemia
1
1
Variable
or >
Treatment of hypomagnesaemia may correct
hypocalcaemia
(T = levels increased; i = levels reduced; = levels normal)
The parathyroid glands • 663
cause of hypocalcaemia is a low serum albumin with normal
ionised calcium concentration. Conversely, ionised calcium may
be low in the face of normal total serum calcium in patients with
alkalosis: for example, as a result of hyperventilation.
Hypocalcaemia may also develop as a result of magnesium
depletion and should be considered in patients with malabsorption,
those on diuretic or proton pump inhibitor therapy, and/or those
with a history of alcohol excess. Magnesium deficiency causes
hypocalcaemia by impairing the ability of the parathyroid glands
to secrete PTH (resulting in PTH concentrations that are low or
inappropriately in the reference range) and may also impair the
actions of PTH on bone and kidney.
Clinical assessment
Mild hypocalcaemia is often asymptomatic but, with more
profound reductions in serum calcium, tetany can occur. This
is characterised by muscle spasms due to increased excitability
of peripheral nerves.
Children are more liable to develop tetany than adults
and present with a characteristic triad of carpopedal spasm,
stridor and convulsions, although one or more of these may
be found independently of the others. In carpopedal spasm,
the hands adopt a characteristic position with flexion of the
metacarpophalangeal joints of the fingers and adduction of
the thumb (‘main d’accoucheur’). Pedal spasm can also occur
but is less frequent. Stridor is caused by spasm of the glottis.
Adults can also develop carpopedal spasm in association with
tingling of the hands and feet and around the mouth, but stridor
and fits are rare.
Latent tetany may be detected by eliciting Trousseau’s sign:
inflation of a sphygmomanometer cuff on the upper arm to
more than the systolic blood pressure is followed by carpal
spasm within 3 minutes. Less specific is Chvostek’s sign, in
which tapping over the branches of the facial nerve as they
emerge from the parotid gland produces twitching of the facial
muscles.
Hypocalcaemia can cause papilloedema and prolongation of the
ECG QT interval, which may predispose to ventricular arrhythmias.
Prolonged hypocalcaemia and hyperphosphataemia (as in
hypoparathyroidism) may cause calcification of the basal ganglia,
grand mal epilepsy, psychosis and cataracts. Hypocalcaemia
associated with hypophosphataemia, as in vitamin D deficiency,
causes rickets in children and osteomalacia in adults (p. 1049).
Management
Emergency management of hypocalcaemia associated with tetany
is given in Box 18.34. Treatment of chronic hypocalcaemia is
described on page 1051.
18.34 Management of severe hypocalcaemia
Immediate management
• 10-20 mL 10% calcium gluconate IV over 10-20 mins
• Continuous IV infusion may be required for several hours (equivalent
of 10 mL 10% calcium gluconate/hr)
• Cardiac monitoring is recommended
If associated with hypomagnesaemia
• 50 mmol (1 .23 g) magnesium chloride IV over 24 hrs
• Most parenteral magnesium will be excreted in the urine, so further
doses may be required to replenish body stores
Primary hyperparathyroidism
Primary hyperparathyroidism is caused by autonomous secretion
of PTH, usually by a single parathyroid adenoma, which can vary
in diameter from a few millimetres to several centimetres. It should
be distinguished from secondary hyperparathyroidism, in which
there is a physiological increase in PTH secretion to compensate
for prolonged hypocalcaemia (such as in vitamin D deficiency,
p. 1049), and from tertiary hyperparathyroidism, in which
continuous stimulation of the parathyroids over a prolonged
period of time results in adenoma formation and autonomous PTH
secretion (Box 18.35). This is most commonly seen in individuals
with advanced chronic kidney disease (p. 418).
The prevalence of primary hyperparathyroidism is about 1
in 800 and it is 2-3 times more common in women than men;
90% of patients are over 50 years of age. It also occurs in the
familial MEN syndromes (p. 688), in which case hyperplasia or
multiple adenomas of all four parathyroid glands are more likely
than a solitary adenoma.
Clinical and radiological features
The clinical presentation of primary hyperparathyroidism is
described on page 667. Parathyroid bone disease is now rare
due to earlier diagnosis and treatment. Osteitis fibrosa results
from increased bone resorption by osteoclasts with fibrous
replacement in the lacunae. This may present as bone pain
and tenderness, fracture and deformity. Chondrocalcinosis can
occur due to deposition of calcium pyrophosphate crystals
within articular cartilage. It typically affects the menisci at the
knees and can result in secondary degenerative arthritis or
predispose to attacks of acute pseudogout (p. 1016). Skeletal
X-rays are usually normal in mild primary hyperparathyroidism,
but in patients with advanced disease characteristic changes
are observed. In the early stages there is demineralisation, with
subperiosteal erosions and terminal resorption in the phalanges.
A ‘pepper-pot’ appearance may be seen on lateral X-rays of the
skull. Reduced bone mineral density, resulting in either osteopenia
or osteoporosis, is now the most common skeletal manifestation
of hyperparathyroidism. This is usually not evident radiographically
and requires assessment by DXA (p. 989).
In nephrocalcinosis, scattered opacities may be visible within
the renal outline. There may be soft tissue calcification in arterial
walls and hands and in the cornea.
Investigations
The diagnosis can be confirmed by finding a raised PTH level in
the presence of hypercalcaemia, provided that FHH is excluded
18.35 Hyperparathyroidism
Type
Serum calcium
PTH
Primary
Single adenoma (90%)
Multiple adenomas (4%)
Nodular hyperplasia (5%)
Carcinoma (1%)
Raised
Not suppressed
Secondary
Chronic renal failure
Malabsorption
Osteomalacia and rickets
Low
Raised
Tertiary
Raised
Not suppressed
664 • ENDOCRINOLOGY
Fig. 18.17 99mTc-sestamibi scan of a
patient with primary hyperparathyroidism
secondary to a parathyroid adenoma.
[A~| After 1 hour, there is uptake in the thyroid
gland (thick arrow) and the enlarged left inferior
parathyroid gland (thin arrow), [8] After 3 hours,
uptake is evident only in the parathyroid (thin
arrow).
(p. 664). Parathyroid scanning by 99mTc-sestamibi scintigraphy
(MIBI; Fig. 18.17) and an ultrasound examination can be
performed prior to surgery, in an attempt to localise an adenoma;
a concordant finding of tissue consistent with a parathyroid
gland and uptake on the MIBI scan allows a targeted resection.
Negative imaging does not exclude the diagnosis, however, and
four-gland exploration may be needed.
Management
The treatment of choice for primary hyperparathyroidism is
surgery, with excision of a solitary parathyroid adenoma or
hyperplastic glands. Experienced surgeons will identify solitary
tumours in more than 90% of cases. Patients with parathyroid
bone disease run a significant risk of developing hypocalcaemia
post-operatively but the risk of this can be reduced by correcting
vitamin D deficiency pre-operatively.
Surgery is usually indicated for individuals aged less than
50 years, with clear-cut symptoms or documented complications
(such as renal stones, renal impairment or osteoporosis), and
(in asymptomatic patients) significant hypercalcaemia (corrected
serum calcium >2.85 mmol/L (>11.4 mg/dL)). Patients who
are treated conservatively without surgery should have calcium
biochemistry and renal function checked annually and bone
density monitored periodically. They should be encouraged to
maintain a high oral fluid intake to avoid renal stones.
Occasionally, primary hyperparathyroidism presents with severe
life-threatening hypercalcaemia. This is often due to dehydration
and should be managed medically with intravenous fluids and
bisphosphonates, as described on page 1327. If this is not
effective, then urgent parathyroidectomy should be considered.
Cinacalcet (p. 419) is a calcimimetic that enhances the
sensitivity of the calcium-sensing receptor, so reducing PTH
levels, and is licensed for tertiary hyperparathyroidism and as
a treatment for patients with primary hyperparathyroidism who
are unwilling to have surgery or are medically unfit.
Familial hypocalciuric hypercalcaemia
This autosomal dominant disorder is caused by an inactivating
mutation in one of the alleles of the calcium-sensing receptor
gene, which reduces the ability of the parathyroid gland to ‘sense’
ionised calcium concentrations. As a result, higher than normal
calcium levels are required to suppress PTH secretion. The typical
presentation is with mild hypercalcaemia with PTH concentrations
that are ‘inappropriately’ at the upper end of the reference range
or are slightly elevated. Calcium-sensing receptors in the renal
tubules are also affected and this leads to increased renal tubular
reabsorption of calcium and hypocalciuria (as measured in the
vitamin D-replete individual by a fractional calcium excretion
or 24-hour calcium excretion). The hypercalcaemia of FHH is
always asymptomatic and complications do not occur. The
main risk of FHH is that of the patient being subjected to an
unnecessary (and ineffective) parathyroidectomy if misdiagnosed
as having primary hyperparathyroidism. Testing of family members
for hypercalcaemia is helpful in confirming the diagnosis and
it is also possible to perform genetic testing. No treatment
is necessary.
Hypoparathyroidism
The most common cause of hypoparathyroidism is damage
to the parathyroid glands (or their blood supply) during thyroid
surgery. Rarely, hypoparathyroidism can occur as a result of
infiltration of the glands with iron in haemochromatosis (p. 895)
or copper in Wilson’s disease (p. 896).
There are a number of rare congenital or inherited forms of
hypoparathyroidism. One form is associated with autoimmune
polyendocrine syndrome type 1 (p. 689) and another with DiGeorge
syndrome (p. 79). Autosomal dominant hypoparathyroidism is the
mirror image of FHH (see above), in that an activating mutation
in the calcium-sensing receptor reduces PTH levels, resulting
in hypocalcaemia and hypercalciuria.
Pseudohypoparathyroidism
In this disorder, the individual is functionally hypoparathyroid
but, instead of PTH deficiency, there is tissue resistance to the
effects of PTH, such that PTH concentrations are markedly
elevated. The PTH receptor itself is normal but the downstream
signalling pathways are defective due to mutations that affect
GNAS1 , which encodes the Gsa protein, a molecule involved
in signal transduction downstream of the PTH receptor and
other G protein-coupled receptors. There are several subtypes
but the most common (pseudohypoparathyroidism type 1 a) is
characterised by hypocalcaemia and hyperphosphataemia, in
association with short stature, short fourth metacarpals and
metatarsals, rounded face, obesity and subcutaneous calcification;
these features are collectively referred to as Albright’s hereditary
osteodystrophy (AHO). Type 1 a pseudohypoparathyroidism occurs
only when the GNAS1 mutation is inherited on the maternal
chromosome (maternal imprinting, p. 49).
The term pseudopseudohypoparathyroidism is used to describe
patients who have clinical features of AHO but normal serum
calcium and PTH concentrations; it occurs when the GNAS1
mutation is inherited on the paternal chromosome. The inheritance
of these disorders is an example of genetic imprinting (p. 49).
The difference in clinical features occurs as a result of the fact
that renal cells exclusively express the maternal GNAS1 allele,
whereas both maternal and paternal alleles are expressed in other
cell types; this explains why maternal inheritance is associated
with hypocalcaemia and resistance to PTH (which regulates
The adrenal glands • 665
serum calcium and phosphate levels largely by an effect on the
renal tubule), and why paternal inheritance is associated with
skeletal and other abnormalities in the absence of hypocalcaemia
and raised PTH values.
Management of hypoparathyroidism
Persistent hypoparathyroidism and pseudohypoparathyroidism
are treated with oral calcium salts and vitamin D analogues,
either 1 a-hydroxycholecalciferol (alfacalcidol) or 1,25-
dihydroxycholecalciferol (calcitriol). This therapy needs careful
monitoring because of the risks of iatrogenic hypercalcaemia,
hypercalciuria and nephrocalcinosis. Recombinant PTH is
available as subcutaneous injection therapy for osteoporosis
(p. 1048) and, although not currently licensed, has been used
in hypoparathyroidism (but not in pseudohypoparathyroidism). It
is much more expensive than calcium and vitamin D analogue
therapy but has the advantage that it is less likely to cause
hypercalciuria. There is no specific treatment for AHO other than
to try to maintain calcium levels within the reference range using
active vitamin D metabolites.
if
• Osteoporosis: always exclude osteomalacia and
hyperparathyroidism by checking vitamin D and calcium
concentrations.
• Primary hyperparathyroidism: more common with ageing. Older
people can often be observed without surgical intervention.
• Hypercalcaemia: may cause delirium.
• Vitamin D deficiency: common because of limited exposure to the
sun and reduced ability of older skin to synthesise cholecalciferol.
The adrenal glands
The adrenals comprise several separate endocrine glands within
a single anatomical structure. The adrenal medulla is an extension
of the sympathetic nervous system that secretes catecholamines
into capillaries rather than synapses. Most of the adrenal cortex is
made up of cells that secrete cortisol and adrenal androgens, and
form part of the hypothalamic-pituitary-adrenal (HPA) axis. The
small outer glomerulosa of the cortex secretes aldosterone under
the control of the renin-angiotensin system. These functions are
important in the integrated control of cardiovascular, metabolic
and immune responses to stress.
There is increasing evidence that subtle alterations in adrenal
function contribute to the pathogenesis of common diseases
such as hypertension, obesity and type 2 diabetes mellitus.
However, classical syndromes of adrenal hormone deficiency
and excess are relatively rare.
Functional anatomy and physiology
Adrenal anatomy and function are shown in Figure 18.18.
Histologically, the cortex is divided into three zones, but these
function as two units (zona glomerulosa and zonae fasciculata/
reticularis) that produce corticosteroids in response to humoral
stimuli. Pathways for the biosynthesis of corticosteroids are shown
in Figure 18.19. Investigation of adrenal function is described
under specific diseases below. The different types of adrenal
disease are shown in Box 18.37.
Glucocorticoids
Cortisol is the major glucocorticoid in humans. Levels are highest
in the morning on waking and lowest in the middle of the night.
Cortisol rises dramatically during stress, including any illness.
This elevation protects key metabolic functions (such as the
maintenance of cerebral glucose supply during starvation) and
inhibits potentially damaging inflammatory responses to infection
and injury. The clinical importance of cortisol deficiency is,
therefore, most obvious at times of stress.
More than 95% of circulating cortisol is bound to protein,
principally cortisol-binding globulin, which is increased by
oestrogens. It is the free fraction that is biologically active.
Cortisol regulates cell function by binding to glucocorticoid
receptors that regulate the transcription of many genes. Cortisol
can also activate mineralocorticoid receptors, but it does not
normally do so because most cells containing mineralocorticoid
receptors also express an enzyme called 1 1 p-hydroxysteroid
dehydrogenase type 2 (1 1 p-HSD2), which inactivates cortisol
by converting it to cortisone. Inhibitors of 1 1 p-HSD2 (such as
liquorice) or mutations in the gene that encodes 1 1 p-HSD2
cause cortisol to act as a mineralocorticoid, resulting in sodium
retention and hypertension (see Box 18.46).
18.36 The parathyroid glands in old age
18.37 Classification of diseases of the adrenal glands
Primary
Secondary
Hormone excess
Non-ACTH-dependent
ACTH-dependent
Cushing’s syndrome
Cushing’s syndrome
Primary hyperaldosteronism
Phaeochromocytoma
Secondary hyperaldosteronism
Hormone deficiency
Addison’s disease
Congenital adrenal hyperplasia
Hypopituitarism
Hormone hypersensitivity
1 1 p-hydroxysteroid dehydrogenase type 2 deficiency
Liddle’s syndrome
Hormone resistance
Pseudohypoaldosteronism
Glucocorticoid resistance syndrome
Non-functioning tumours
Adenoma
Carcinoma (usually functioning)
Metastatic tumours
(ACTH = adrenocorticotropic hormone)
666 • ENDOCRINOLOGY
Sympathetic nervous system
Sympathetic nervous
system
Hypothalamic - pituitary- adrenal axis
Adrenal medulla
1
( * X
Adrenaline Noradrenaline
(epinephrine) (norepinephrine)
(3-adrenoceptor a-adrenoceptor
Vasodilatation Vasoconstriction
Tachycardia
Insulin resistance
Adrenal cortex
Zonae fasciculata
and reticularis
' — £ -
Negative feedback
Adrenal
gland
Adrenal cortex
Zona glomerulosa
Low renal perfusion
Low filtered Na
Sympathetic
activation
Na retention
K wasting <
Metabolic
alkalosis
ACTH
i
< —
Androgens
4
Androgen
receptor
4
Pubic and
axillary hair
Libido, especially
females
Angiotensinogen
Cortex
Zonae fasciculata
and reticularis
—II
Angiotensin I
Angiotensin II
Cortex
Zona
glomerulosa
4
Aldosterone
J
Renin - angiotensin - aldosterone axis
— x
Cortisol . .
4
Glucocorticoid
receptor
4
Protein catabolism
Insulin resistance
Immune response
Hypertension
Increased appetite
Memory
Fig. 18.18 Structure and function of the adrenal glands. (ACE = angiotensin-converting enzyme; ACTH = adrenocorticotrophic hormone; JGA =
juxtaglomerular apparatus; MR = mineralocorticoid receptor)
Mineralocorticoids
Aldosterone is the most important mineralocorticoid. It binds to
mineralocorticoid receptors in the kidney and causes sodium
retention and increased excretion of potassium and protons
(p. 351). The principal stimulus to aldosterone secretion is angiotensin
II, a peptide produced by activation of the renin-angiotensin system
(see Fig. 18.18). Renin activity in the juxtaglomerular apparatus of
the kidney is stimulated by low perfusion pressure in the afferent
arteriole, low sodium filtration leading to low sodium concentrations
at the macula densa, or increased sympathetic nerve activity.
As a result, renin activity is increased in hypovolaemia and renal
artery stenosis, and is approximately doubled when standing up
from a recumbent position.
Catecholamines
In humans, only a small proportion of circulating noradrenaline
(norepinephrine) is derived from the adrenal medulla; much
more is released from sympathetic nerve endings. Conversion of
noradrenaline to adrenaline (epinephrine) is catalysed by catechol
O-methyltransferase (COMT), which is induced by glucocorticoids.
Blood flow in the adrenal is centripetal, so that the medulla is
bathed in high concentrations of cortisol and is the major source
of circulating adrenaline. However, after surgical removal of the
adrenal medullae, there appear to be no clinical consequences
attributable to deficiency of circulating catecholamines.
Adrenal androgens
Adrenal androgens are secreted in response to ACTH and are the
most abundant steroids in the blood stream. They are probably
important in the initiation of puberty (adrenarche). The adrenals
are also the major source of androgens in adult females and
may be important in female libido.
Presenting problems in adrenal disease
Cushing’s syndrome
Cushing’s syndrome is caused by excessive activation of
glucocorticoid receptors. It is most commonly iatrogenic, due
to prolonged administration of synthetic glucocorticoids such as
The adrenal glands • 667
Cholesterol
Corticosterone
► Cortisol
Dihydro¬
testosterone
► Aldosterone
Key
Glucocorticoids
Mineralocorticoids
Androgens
Oestrogens
Progesterone
^ Enzymes in
^^^^the adrenal
^^Enzymes outside 'n
^^^^the adrenal — ^
Fig. 18.19 The major pathways of synthesis of steroid hormones. (DHEAS = dehydroepiandrosterone sulphate; HSD = hydroxysteroid dehydrogenase)
prednisolone. Endogenous Cushing’s syndrome is uncommon but
is caused by chronic over-production of cortisol by the adrenal
glands, either as the result of an adrenal tumour or because of
excessive production of ACTH by a pituitary tumour or ectopic
ACTH production by other tumours.
Aetiology
The causes are shown in Box 18.38. Amongst endogenous
causes, pituitary-dependent cortisol excess (by convention, called
Cushing’s disease) accounts for approximately 80% of cases.
Both Cushing’s disease and cortisol-secreting adrenal tumours
are four times more common in women than men. In contrast,
ectopic ACTH syndrome (often due to a small-cell carcinoma
of the bronchus) is more common in men.
Clinical assessment
The diverse manifestations of glucocorticoid excess are shown
in Figure 18.20. Many of these are not specific to Cushing’s
syndrome and, because spontaneous Cushing’s syndrome is rare,
the positive predictive value of any single clinical feature alone is
low. Moreover, some common disorders can be confused with
Cushing’s syndrome because they are associated with alterations
in cortisol secretion, e.g. obesity and depression (Box 18.38).
Features that favour Cushing’s syndrome in an obese patient
are bruising, myopathy and thin skin. Any clinical suspicion of
cortisol excess is best resolved by further investigation.
It is vital to exclude iatrogenic causes in all patients with
Cushing’s syndrome since even inhaled or topical glucocorticoids
can induce the syndrome in susceptible individuals. A careful drug
history must therefore be taken before embarking on complex
investigations. An 0800-0900-hr serum cortisol of <100 nmol/L
(3.6 pig/dL) in a patient with a normal sleep-wake pattern and
Cushingoid appearance is consistent with exogenous synthetic
glucocorticoid use (common) or cyclical secretion of cortisol from
endogenous Cushing’s (uncommon).
Some clinical features are more common in ectopic ACTH
syndrome. While ACTH -secreting pituitary tumours retain some
negative feedback sensitivity to cortisol, this is absent in tumours
that produce ectopic ACTH, typically resulting in higher levels
of both ACTH and cortisol than are observed in pituitary-driven
disease. The high ACTH levels are associated with marked
18.38 Classification of endogenous Cushing’s
syndrome
ACTH-dependent - 80%
• Pituitary adenoma secreting ACTH (Cushing’s disease) - 70%
• Ectopic ACTH syndrome (bronchial carcinoid, small-cell lung
carcinoma, other neuro-endocrine tumour) - 10%
Non-ACTH-dependent - 20%
• Adrenal adenoma - 1 5%
• Adrenal carcinoma - 5%
• ACTH-independent macronodular hyperplasia; primary pigmented
nodular adrenal disease; McCune-Albright syndrome (together
<1%)
Hypercortisolism due to other causes (also referred to as
pseudo-Cushing’s syndrome)
• Alcohol excess (biochemical and clinical features)
• Major depressive illness (biochemical features only, some clinical
overlap)
• Primary obesity (mild biochemical features, some clinical overlap)
(ACTH = adrenocorticotropic hormone)
pigmentation because of binding to melanocortin 1 receptors
on melanocytes in the skin. The high cortisol levels also overcome
the capacity of 1 1 (3-HSD2 to inactivate cortisol in the kidney
(p. 665), causing hypokalaemic alkalosis that aggravates myopathy
and hyperglycaemia (by inhibiting insulin secretion). When the
tumour that is secreting ACTH is malignant, then the onset is usually
rapid and may be associated with cachexia. For these reasons,
the classical features of Cushing’s syndrome are less common
in ectopic ACTH syndrome; if present, they suggest that a less
aggressive tumour, such as a bronchial carcinoid, is responsible.
In Cushing’s disease, the pituitary tumour is usually a
microadenoma (< 1 0 mm in diameter); hence other features
of a pituitary macroadenoma (hypopituitarism, visual failure or
disconnection hyperprolactinaemia, p. 684) are rare.
Investigations
The large number of tests available for Cushing’s syndrome
reflects the fact that each one has limited specificity and sensitivity
668 • ENDOCRINOLOGY
Psychosis
Cataracts
Mild exophthalmos
Hypertension
Centripetal obesity
Striae
Decreased skin
thickness
Wasting and weakness
of proximal thigh
muscles
Bruising
Fig. 18.20 Cushing’s syndrome. [A] Clinical features common to all causes. Q§J A patient with Cushing’s disease before treatment. [C] The same patient
1 year after the successful removal of an ACTH-secreting pituitary microadenoma by trans-sphenoidal surgery.
in isolation. Accordingly, several tests are usually combined to
establish the diagnosis. Testing for Cushing’s syndrome should
be avoided under conditions of stress, such as an acute illness,
because this activates the HPA axis, causing potentially spurious
results. The diagnosis of Cushing’s is a two-step process:
1 . to establish whether the patient has Cushing’s syndrome
(Fig. 18.21)
2. to define its cause (Fig. 18.22).
Some additional tests are useful in all cases of Cushing’s
syndrome, including plasma electrolytes, glucose, glycosylated
haemoglobin and bone mineral density measurement.
Establishing the presence of Cushing’s syndrome
In patients where there is appropriate clinical suspicion, Cushing’s
syndrome is confirmed by using two of three main tests:
1 . failure to suppress serum cortisol with low doses of oral
dexamethasone
2. loss of the normal circadian rhythm of cortisol, with
inappropriately elevated late-night serum or salivary
cortisol
3. increased 24-hour urine free cortisol (see Fig. 18.21).
Dexamethasone is used for suppression testing because it
does not cross-react in immunoassays for cortisol. An overnight
dexamethasone suppression test (ONDST) involves administration
of 1 mg dexamethasone at 2300 hrs and measurement of
serum cortisol at 0900 hrs the following day. In a low-dose
dexamethasone suppression test (LDDST), serum cortisol is
measured following administration of 0.5 mg dexamethasone
4 times daily for 48 hours. For either test, a normal response is
a serum cortisol of <50 nmol/L (1.8 pg/dL). It is important for
any oestrogens to be stopped for 6 weeks prior to investigation
to allow corticosteroid-binding globulin (CBG) levels to return to
normal and to avoid false-positive responses, as most cortisol
assays measure total cortisol, including that bound to CBG.
Cyclicity of cortisol secretion is a feature of all types of Cushing’s
syndrome and, if very variable, can confuse diagnosis. Use of
multiple salivary cortisol samples over weeks or months can be
helpful in diagnosis but an elevated salivary cortisol alone should
not be taken as proof of diagnosis. In iatrogenic Cushing’s
syndrome, cortisol levels are low unless the patient is taking
a glucocorticoid (such as prednisolone) that cross-reacts in
immunoassays with cortisol.
Determining the underlying cause
Once the presence of Cushing’s syndrome is confirmed,
measurement of plasma ACTH is the key to establishing
the differential diagnosis; it is best measured in the morning
around 0900 hrs. In the presence of excess cortisol secretion,
an undetectable ACTH (< 1 .1 pmol/L (5 ng/L)) indicates an
adrenal cause, while ACTH levels of >3.3 pmol/L (15 ng/L)
suggest a pituitary cause or ectopic ACTH. ACTH levels between
these values represent a ‘grey area’ and further evaluation by a
specialist is required. Tests to discriminate pituitary from ectopic
sources of ACTH rely on the fact that pituitary tumours, but not
ectopic tumours, retain some features of normal regulation of
The adrenal glands • 669
Fig. 18.21 Sequence of investigations in suspected spontaneous Cushing’s syndrome. A serum cortisol of 50 nmol/L is equivalent to 1 .8 jig/dL.
(LDDST = low-dose dexamethasone suppression test; ONDST = overnight dexamethasone suppression test; UFC = urinary free cortisol)
ACTH secretion. Thus, in pituitary-dependent Cushing’s disease,
ACTH secretion is suppressed by high-dose dexamethasone
and ACTH is stimulated by corticotrophin-releasing hormone
(CRH). In a high-dose dexamethasone suppression test (HDDST),
serum cortisol is measured before and after administration of
2 mg of dexamethasone 4 times daily for 48 hours.
Techniques for localisation of tumours secreting ACTH or
cortisol are listed in Figure 18.22. MRI detects around 60% of
pituitary microadenomas secreting ACTH. If available, bilateral
inferior petrosal sinus sampling (BIPSS) with measurement of
ACTH is the best means of confirming Cushing’s disease, unless
MRI shows a tumour bigger than 6 mm, in which case it may not
be needed. CT or MRI detects most adrenal tumours; adrenal
carcinomas are usually large (>5 cm) and have other features
of malignancy (p. 673).
Management
Untreated severe Cushing’s syndrome has a 50% 5-year mortality.
Most patients are treated surgically, but medical therapy may
be given in severe cases for a few weeks prior to operation to
improve the clinical state. A number of drugs are available that
inhibit glucocorticoid biosynthesis, including metyrapone and
ketoconazole. The dose of these agents is best titrated against
serum cortisol levels or 24-hour urine free cortisol.
Cushing’s disease
Trans-sphenoidal surgery carried out by an experienced surgeon
with selective removal of the adenoma is the treatment of choice,
with approximately 70% of patients going into immediate
remission. Around 20% of patients suffer a recurrence, often
years later, emphasising the need for life-long follow-up.
Laparoscopic bilateral adrenalectomy performed by an expert
surgeon effectively cures ACTH -dependent Cushing’s syndrome,
but in patients with pituitary-dependent Cushing’s syndrome
this can result in Nelson’s syndrome. In Nelson’s syndrome,
the loss of negative feedback from endogenous cortisol results
in growth of the pituitary tumour, often leading to an invasive
pituitary macroadenoma (which causes local mass effects) and
very high ACTH levels (which cause pigmentation). The risk of
Nelson’s syndrome is reported as being reduced by pituitary
irradiation in some series, but not all.
The somatostatin analogue pasireotide is also licensed for the
treatment of Cushing’s disease and works by suppressing ACTH
secretion by the tumour. It may cause tumour shrinkage but
cortisol levels are likely to return to pre-treatment levels following
cessation of therapy. Pasireotide has to be administered by
twice-daily subcutaneous injection and is relatively expensive. It
is an alternative to drugs that inhibit glucocorticoid biosynthesis
in patients who are not suitable for a surgical approach.
Adrenal tumours
Laparoscopic adrenal surgery is the treatment of choice for
adrenal adenomas. Surgery offers the only prospect of cure for
adrenocortical carcinomas but, in general, prognosis is poor
with high rates of recurrence, even in patients with localised
disease at presentation. Radiotherapy to the tumour bed reduces
670 • ENDOCRINOLOGY
Fig. 18.22 Determining the cause of confirmed Cushing’s syndrome. To convert pmol/L to ng/L, multiply by 4.541 . (ACTH = adrenocorticotrophic
hormone; AIMAH = ACTH-independent macronodular adrenal hyperplasia; BIPSS = bilateral inferior petrosal sinus sampling; hCRH = human corticotrophin-
releasing hormone; HDDST = high-dose dexamethasone suppression test; PPNAD = primary pigmented nodular adrenal disease)
the risk of local recurrence; systemic therapy consists of the
adrenolytic drug mitotane and chemotherapy, but responses are
often poor.
Ectopic ACTH syndrome
Localised tumours, such as bronchial carcinoid, should be
removed surgically. In patients with incurable malignancy, it is
important to reduce the severity of the Cushing’s syndrome
using medical therapy (see above) or, if appropriate, bilateral
adrenalectomy.
| Therapeutic use of glucocorticoids
The remarkable anti-inflammatory properties of glucocorticoids
have led to their use in a wide variety of clinical conditions but
the hazards are significant. Equivalent doses of commonly used
glucocorticoids are listed in Box 18.39. Topical preparations
(dermal, rectal and inhaled) can also be absorbed into the
systemic circulation, and although this rarely occurs to a sufficient
degree to produce clinical features of Cushing’s syndrome, it
can result in significant suppression of endogenous ACTH and
cortisol secretion. Severe Cushing’s syndrome can result if there
is concomitant administration of inhaled glucocorticoids and
strong inhibitors of the liver enzyme CYP450 3A4, such as the
antiretroviral drug ritonavir (p. 324).
18.39 Approximate equivalent doses of
glucocorticoids
• Hydrocortisone: 20 mg
• Cortisone acetate: 25 mg
• Prednisolone: 5 mg
• Dexamethasone: 0.5 mg
Adverse effects of glucocorticoids
The clinical features of glucocorticoid excess are illustrated in
Figure 18.20. Adverse effects are related to dose, duration of
therapy, and pre-existing conditions that might be worsened by
glucocorticoid therapy, such as diabetes mellitus or osteoporosis.
Osteoporosis is a particularly important problem because,
for a given bone mineral density, the fracture risk is greater
in glucocorticoid-treated patients than in post-menopausal
osteoporosis. Therefore, when systemic glucocorticoids are
prescribed and the anticipated duration of steroid therapy is more
than 3 months, bone-protective therapy should be considered,
as detailed on page 1005. Rapid changes in glucocorticoid levels
can also lead to marked mood disturbances, including depression,
mania and insomnia. Glucocorticoid use also increases the white
blood cell count (predominantly neutrophils), which must be taken
into account when assessing patients with possible infection.
The adrenal glands • 671
The anti-inflammatory effect of glucocorticoids may mask signs
of disease. For example, perforation of a viscus may be masked
and the patient may show no febrile response to an infection.
Although there is debate about whether or not glucocorticoids
increase the risk of peptic ulcer when used alone, they act
synergistically with NSAIDs, including aspirin, to increase the risk
of serious gastrointestinal adverse effects. Latent tuberculosis
may be reactivated and patients on glucocorticoids are at risk
of severe varicella zoster virus infection, so should avoid contact
with chickenpox or shingles if they are non-immune.
Management of glucocorticoid withdrawal
All glucocorticoid therapy, even if inhaled or applied topically, can
suppress the HPA axis. In practice, this is likely to result in a crisis
due to adrenal insufficiency on withdrawal of treatment only if
glucocorticoids have been administered orally or systemically for
longer than 3 weeks, if repeated courses have been prescribed
within the previous year, or if the dose is higher than the equivalent
of 7.5 mg prednisolone per day. In these circumstances, the
drug, when it is no longer required for the underlying condition,
must be withdrawn slowly at a rate dictated by the duration of
treatment. If glucocorticoid therapy has been prolonged, then it
may take many months for the HPA axis to recover. All patients
must be advised to avoid sudden drug withdrawal. They should
be issued with a steroid card and/or wear an engraved bracelet
(Box 18.40).
Recovery of the HPA axis is aided if there is no exogenous
glucocorticoid present during the nocturnal surge in ACTH
secretion. This can be achieved by giving glucocorticoid in the
morning. Giving ACTH to stimulate adrenal recovery is of no
value, as the pituitary remains suppressed.
In patients who have received glucocorticoids for longer
than a few weeks, especially if the period is months to years,
it is often valuable to confirm that the HPA axis is recovering
during glucocorticoid withdrawal. Withdrawal has to be very
slow, usually by a dose reduction equivalent of prednisolone
1 mg per month or slower. Once the dose of glucocorticoid
is reduced to a minimum (e.g. 5 mg prednisolone or 0.5 mg
18.40 Advice to patients on glucocorticoid
replacement therapy
Intercurrent stress
• Febrile illness: double dose of hydrocortisone
Surgery
• Minor operation: hydrocortisone 100 mg IM with pre-medication
• Major operation: hydrocortisone 100 mg 4 times daily for 24 hrs,
then 50 mg IM 4 times daily until ready to take tablets
Vomiting
• Patients must have parenteral hydrocortisone if unable to take it by
mouth
Steroid card
• Patient should carry this at all times; it should give information
regarding diagnosis, steroid, dose and doctor
Bracelet and emergency pack
• Patients should be encouraged to buy a bracelet and have it
engraved with the diagnosis, current treatment and a reference
number for a central database
• Patients should be given a hydrocortisone emergency pack and
trained in the self-administration of hydrocortisone 100 mg IM; they
should be advised to take the pack on holidays/trips abroad
dexamethasone per day), then serum cortisol can be measured
at 0900 hrs before the next dose. If this is < 1 00 nmol/L (3.6 pig/
dL), slow reduction should be continued with a repeat 0900 hrs
serum cortisol when the dose of prednisolone is 3 mg per day.
Once 0900 hrs serum cortisol is >100 nmol/L, then an ACTH
stimulation test should be performed (see Box 18.43) to confirm
if glucocorticoids can be withdrawn completely. Even when
glucocorticoids have been successfully withdrawn, short-term
replacement therapy is often advised during significant intercurrent
illness occurring in subsequent months, as the HPA axis may
not be able to respond fully to severe stress.
Adrenal insufficiency
Adrenal insufficiency results from inadequate secretion of cortisol
and/or aldosterone. It is potentially fatal and notoriously variable in
its presentation. A high index of suspicion is therefore required in
patients with unexplained fatigue, hyponatraemia or hypotension.
Causes are shown in Box 18.41. The most common is ACTH
deficiency (secondary adrenocortical failure), usually because of
inappropriate withdrawal of chronic glucocorticoid therapy or a
pituitary tumour (p. 683). Congenital adrenal hyperplasia and
Addison’s disease (primary adrenocortical failure) are rare causes.
Clinical assessment
The clinical features of adrenal insufficiency are shown in
Box 18.42. In Addison’s disease, either glucocorticoid or
mineralocorticoid deficiency may come first, but eventually all
patients fail to secrete both classes of corticosteroid.
Patients may present with chronic features and/or in acute
circulatory shock. With a chronic presentation, initial symptoms are
often misdiagnosed as chronic fatigue syndrome or depression. In
primary adrenal insufficiency, weight loss is a uniform presenting
feature. Adrenocortical insufficiency should also be considered in
patients with hyponatraemia, even in the absence of symptoms
(p. 357).
Features of an acute adrenal crisis include circulatory shock
with severe hypotension, hyponatraemia, hyperkalaemia and, in
some instances, hypoglycaemia and hypercalcaemia. Muscle
cramps, nausea, vomiting, diarrhoea and unexplained fever
18.41 Causes of adrenocortical insufficiency
Secondary (iACTH)
• Withdrawal of suppressive glucocorticoid therapy
• Hypothalamic or pituitary disease
Primary (TACTH)
Addison’s disease
Common causes
Rare causes
• Autoimmune:
• Lymphoma
Sporadic
• Intra-adrenal haemorrhage
Polyglandular
(Waterhouse-Friderichsen
syndromes (p. 688)
syndrome following
• Tuberculosis
meningococcal sepsis)
• HIV/AIDS
• Amyloidosis
• Metastatic carcinoma
• Flaemochromatosis
• Bilateral adrenalectomy
Corticosteroid biosynthetic enzyme defects
• Congenital adrenal hyperplasias
• Drugs: metyrapone, ketoconazole, etomidate
(ACTH = adrenocorticotropic hormone)
672 • ENDOCRINOLOGY
18.42 Clinical and biochemical features of adrenal insufficiency
Glucocorticoid
insufficiency
Mineralocorticoid
insufficiency
ACTH excess
Adrenal androgen
insufficiency
Withdrawal of exogenous
glucocorticoid
+
-
-
+
Hypopituitarism
+
-
-
+
Addison’s disease
+
+
+
+
Congenital adrenal hyperplasia
(21 -hydroxylase deficiency)
+
+
+
-
Clinical features
Weight loss, anorexia
Malaise, weakness
Nausea, vomiting
Diarrhoea or constipation
Postural hypotension
Shock
Hypoglycaemia
Hyponatraemia (dilutional)
Hypercalcaemia
Hypotension
Shock
Hyponatraemia (depletional)
Hyperkalaemia
Pigmentation of:
Sun-exposed areas
Pressure areas (e.g.
elbows, knees)
Palmar creases,
knuckles
Mucous membranes
Conjunctivae
Recent scars
Decreased body hair
and loss of libido,
especially in females
(ACTH = adrenocorticotropic hormone)
18.43 How and when to do an ACTH stimulation test
Use
• Diagnosis of primary or secondary adrenal insufficiency
• Assessment of HPA axis in patients taking suppressive
glucocorticoid therapy
• Relies on ACTH-dependent adrenal atrophy in secondary adrenal
insufficiency, so may not detect acute ACTH deficiency (e.g. in
pituitary apoplexy, p. 683)
Dose
• 250 pig ACTH1_24 (Synacthen) by IM injection at any time of day
Blood samples
• 0 and 30 mins for plasma cortisol
• 0 mins also for ACTH (on ice) if Addison’s disease is being
considered (patient not known to have pituitary disease or to be
taking exogenous glucocorticoids)
Results
• Normal subjects: plasma cortisol >500 nmol/L (approximately
18 jig/dL)* either at baseline or at 30 mins
• Incremental change in cortisol is not a criterion
*The exact cortisol concentration depends on the cortisol assay being used.
(ACTH = adrenocorticotropic hormone; HPA = hypothalamic-pituitary-adrenal)
may be present. The crisis is often precipitated by intercurrent
disease, surgery or infection.
Vitiligo occurs in 10-20% of patients with autoimmune
Addison’s disease (p. 630).
Investigations
Treatment should not be delayed to wait for results in patients
with suspected acute adrenal crisis. Here, a random blood
sample should be stored for subsequent measurement of serum
cortisol and, if possible, plasma ACTH; if the patient’s clinical
condition permits, it may be appropriate to spend 30 minutes
performing a short ACTH stimulation test (Box 18.43) before
administering hydrocortisone, but delays must be avoided if there
is circulatory compromise. Investigations should be performed
before treatment is given in patients who present with features
suggestive of chronic adrenal insufficiency.
Assessment of glucocorticoids
Random plasma cortisol is usually low in patients with
adrenal insufficiency but it may be within the reference range,
yet inappropriately low, for a seriously ill patient. Random
measurement of normal levels of plasma cortisol cannot therefore
be used to confirm or refute the diagnosis, unless the value
is above 500 nmol/L (>18 pig/dL), which effectively excludes
adrenal insufficiency.
More useful is the short ACTH stimulation test (also called the
tetracosactrin or short Synacthen test) described in Box 18.43.
Cortisol levels fail to increase in response to exogenous ACTH in
patients with primary or secondary adrenal insufficiency. These
can be distinguished by measurement of ACTH (which is low in
ACTH deficiency and high in Addison’s disease).
Assessment of mineralocorticoids
Mineralocorticoid secretion in patients with suspected Addison’s
disease cannot be adequately assessed by electrolyte
measurements since hyponatraemia occurs in both aldosterone
and cortisol deficiency (see Box 1 8.42 and p. 357). Hyperkalaemia
is common, but not universal, in aldosterone deficiency. Plasma
renin and aldosterone should be measured in the supine position.
In mineralocorticoid deficiency, plasma renin activity is high, with
plasma aldosterone being either low or in the lower part of the
reference range.
Assessment of adrenal androgens
This is not necessary in men because testosterone from the testes
is the principal androgen. In women, dehydroepiandrosterone
sulphate (DHEAS) and androstenedione may be measured in a
random specimen of blood, though levels are highest in the morning.
Other tests to establish the cause
Patients with unexplained secondary adrenocortical insufficiency
should be investigated as described on page 680. In patients
with elevated ACTH, further tests are required to establish
The adrenal glands • 673
the cause of Addison’s disease. Adrenal autoantibodies are
frequently positive in autoimmune adrenal failure. If antibody tests
are negative, imaging of the adrenal glands with CT or MRI is
indicated. Tuberculosis causes adrenal calcification, visible on plain
X-ray or ultrasound scan. A human immunodeficiency virus (HI V)
test should be performed if risk factors for infection are present
(p. 310). Adrenal metastases are a rare cause of adrenal
insufficiency. Patients with evidence of autoimmune adrenal
failure should be screened for other organ-specific autoimmune
diseases, such as thyroid disease, pernicious anaemia and type
1 diabetes.
Management
Patients with adrenocortical insufficiency always need
glucocorticoid replacement therapy and usually, but not always,
mineralocorticoid therapy. There is some evidence that adrenal
androgen replacement may also be beneficial in women. Other
treatments depend on the underlying cause. The emergency
management of adrenal crisis is described in Box 18.44.
Glucocorticoid replacement
Adrenal replacement therapy consists of oral hydrocortisone
(cortisol) 15-20 mg daily in divided doses, typically 10 mg on
waking and 5 mg at around 1500 hrs. These are physiological
replacement doses that should not cause Cushingoid side-effects.
The dose may need to be adjusted for the individual patient but
this is subjective. Excess weight gain usually indicates over¬
replacement, while persistent lethargy or hyperpigmentation may
be due to an inadequate dose or lack of absorption. Measurement
of serum cortisol levels is not usually helpful. Advice to patients
dependent on glucocorticoid replacement is given in Box 1 8.40.
Mineralocorticoid replacement
Fludrocortisone (9a-fluoro-hydrocortisone) is administered at the
usual dose of 0.05-0.15 mg daily, and adequacy of replacement
may be assessed by measurement of blood pressure, plasma
electrolytes and plasma renin. It is indicated for virtually every
patient with primary adrenal insufficiency but is not needed in
secondary adrenal insufficiency.
18.44 Management of adrenal crisis
Correct volume depletion
• IV saline as required to normalise blood pressure and pulse
• In severe hyponatraemia (<125 mmol/L) avoid increases of plasma
Na >10 mmol/L/day to prevent pontine demyelination (p. 358)
• Fludrocortisone is not required during the acute phase of treatment
Replace glucocorticoids
• IV hydrocortisone succinate 100 mg stat, and 100 mg 4 times daily
for first 12-24 hrs
• Continue parenteral hydrocortisone (50-100 mg IM 4 times daily)
until patient is well enough for reliable oral therapy
Correct other metabolic abnormalities
• Acute hypoglycaemia: IV 10% glucose
• Hyperkalaemia: should respond to volume replacement but
occasionally requires specific therapy (see Box 14.17, p. 363)
Identify and treat underlying cause
• Consider acute precipitant, such as infection
• Consider adrenal or pituitary pathology (see Box 18.41)
(fv
• Adrenocortical insufficiency: often insidious and may present with
tiredness, drowsiness, delirium, falls, immobility and orthostatic
hypotension.
• Glucocorticoid therapy: especially hazardous in older people, who
are already relatively immunocompromised and susceptible to
osteoporosis, diabetes, hypertension and other complications.
• ‘Physiological’ glucocorticoid replacement therapy: increased
risk of adrenal crisis because adherence may be poor and there is
a greater incidence of intercurrent illness. Patient and carer
education, with regular reinforcement of the principles described in
Box 18.40, is crucial.
Androgen replacement
Androgen replacement with DHEAS (50 mg/day) is occasionally
given to women with primary adrenal insufficiency who have
symptoms of reduced libido and fatigue, but the evidence in
support of this is not robust and treatment may be associated
with side-effects such as acne and hirsutism.
| Incidental adrenal mass
It is not uncommon for a mass in the adrenal gland to be
identified on a CT or MRI scan of the abdomen that has been
performed for another indication. Such lesions are known as
adrenal ‘incidentalomas’. The prevalence increases with age and
they are present in up to 1 0% of adults aged 70 years and older.
Eighty-five per cent of adrenal incidentalomas are non¬
functioning adrenal adenomas. The remainder includes functional
tumours of the adrenal cortex (secreting cortisol, aldosterone
or androgens), phaeochromocytomas, primary and secondary
carcinomas, hamartomas and other rare disorders, including
granulomatous infiltrations.
Clinical assessment and investigations
There are two key questions to be resolved: is the lesion secreting
hormones, and is it benign or malignant?
Patients with an adrenal incidentaloma are usually asymptomatic.
However, clinical signs and symptoms of excess glucocorticoids
(p. 665), mineralocorticoids (see below), catecholamines (p. 666)
and, in women, androgens (p. 666) should be sought. Investigations
should include a dexamethasone suppression test, urine or
plasma metanephrines and, in virilised women, measurement
of serum testosterone, DHEAS and androstenedione. Patients
with hypertension should be investigated for mineralocorticoid
excess, as described below. In bilateral masses consistent
with adrenocortical lesions, 17-OH-progesterone should also
be measured.
CT and MRI are equally effective in assessing the malignant
potential of an adrenal mass, using the following parameters:
• Size. The larger the lesion, the greater the malignant
potential. Around 90% of adrenocortical carcinomas are
over 4 cm in diameter, but specificity is poor since only
approximately 25% of such lesions are malignant.
• Configuration. Homogeneous and smooth lesions are
more likely to be benign. The presence of metastatic
lesions elsewhere increases the risk of malignancy, but as
many as two-thirds of adrenal incidentalomas in patients
with cancer are benign.
• Presence of lipid. Adenomas are usually lipid-rich, resulting
in an attenuation of below 10 Hounsfield units (HU) on
18.45 Glucocorticoids in old age
674 • ENDOCRINOLOGY
an unenhanced CT, and in signal dropout on chemical
shift MRI.
• Enhancement. Benign lesions demonstrate rapid washout
of contrast, whereas malignant lesions tend to retain
contrast.
Histology in a sample obtained by CT-guided biopsy is rarely
indicated, and is not useful in distinguishing an adrenal adenoma
from an adrenocortical carcinoma. Biopsy is occasionally helpful in
confirming adrenal metastases from other cancers, but should be
avoided if either phaeochromocytoma or primary adrenal cancer
is suspected in order to avoid precipitation of a hypertensive
crisis or seeding of tumour cells, respectively.
Management
In patients with radiologically benign, non-functioning lesions
of less than 4 cm in diameter, surgery is required only if serial
imaging suggests tumour growth. Functional lesions and tumours
of more than 4 cm in diameter should be considered for surgery,
though many centres will not operate on tumours of more than
4 cm if all other characteristics suggest benign disease. Optimal
management of patients with low-grade cortisol secretion, as
demonstrated by the dexamethasone suppression test, remains
to be established.
Primary hyperaldosteronism
Estimates of the prevalence of primary hyperaldosteronism vary
according to the screening tests employed, but it may occur
in as many as 10% of people with hypertension. Indications
to test for mineralocorticoid excess in hypertensive patients
include hypokalaemia (including hypokalaemia induced by thiazide
diuretics), poor control of blood pressure with conventional
therapy, a family history of early-onset hypertension, or
presentation at a young age.
Causes of excessive activation of mineralocorticoid receptors
are shown in Box 18.46. It is important to differentiate primary
hyperaldosteronism, caused by an intrinsic abnormality of the
adrenal glands resulting in aldosterone excess, from secondary
i
With renin high and aldosterone high (secondary
hyperaldosteronism)
• Inadequate renal perfusion (diuretic therapy, cardiac failure, liver
failure, nephrotic syndrome, renal artery stenosis)
• Renin-secreting renal tumour (very rare)
With renin low and aldosterone high (primary
hyperaldosteronism)
• Adrenal adenoma secreting aldosterone (Conn’s syndrome)
• Idiopathic bilateral adrenal hyperplasia
• Glucocorticoid-suppressible hyperaldosteronism (rare)
With renin low and aldosterone low (non-aldosterone-dependent
activation of mineralocorticoid pathway)
• Ectopic ACTH syndrome
• Liquorice misuse (inhibition of 1 1 (3-HSD2)
• Liddle’s syndrome
• 1 1 -deoxycorticosterone-secreting adrenal tumour
• Rare forms of congenital adrenal hyperplasia and 1 1 (3-HSD2
deficiency
(1 1 (3-HSD2 = 1 1 (3 - hy d roxyste ro i d dehydrogenase type 2; ACTH =
adrenocorticotropic hormone)
hyperaldosteronism, which is usually a consequence of enhanced
activity of renin in response to inadequate renal perfusion and
hypotension. Most individuals with primary hyperaldosteronism
have bilateral adrenal hyperplasia (idiopathic hyperaldosteronism),
while only a minority have an aldosterone-producing adenoma
(APA; Conn’s syndrome). Glucocorticoid-suppressible
hyperaldosteronism is a rare autosomal dominant condition
in which aldosterone is secreted ‘ectopically’ from the adrenal
zonae fasciculata/reticularis in response to ACTH. Rarely, the
mineralocorticoid receptor pathway in the distal nephron is
activated, even though aldosterone concentrations are low.
Clinical features
Individuals with primary hyperaldosteronism are usually
asymptomatic but may have features of sodium retention or
potassium loss. Sodium retention may cause oedema, while
hypokalaemia may cause muscle weakness (or even paralysis,
especially in South-east Asian populations), polyuria (secondary
to renal tubular damage, which produces nephrogenic diabetes
insipidus) and occasionally tetany (because of associated
metabolic alkalosis and low ionised calcium). Blood pressure is
elevated but accelerated phase hypertension is rare.
Investigations
Biochemical
Routine blood tests may show a hypokalaemic alkalosis. Sodium
is usually at the upper end of the reference range in primary
hyperaldosteronism, but is characteristically low in secondary
hyperaldosteronism (because low plasma volume stimulates
vasopressin (antidiuretic hormone, ADH) release and high
angiotensin II levels stimulate thirst). The key measurements are
plasma renin and aldosterone (Box 18.46), and in many centres
the aldosterone : renin ratio (ARR) is employed as a screening test
for primary hyperaldosteronism in hypertensive patients. Almost all
antihypertensive drugs interfere with this ratio (p-blockers inhibit
while diuretics stimulate renin secretion). Thus, individuals with an
elevated ARR require further testing after stopping antihypertensive
drugs for at least 4 weeks. If necessary, antihypertensive agents
that have minimal effects on the renin-angiotensin system, such
as calcium antagonists and a-blockers, may be substituted.
Oral potassium supplementation may also be required, as
hypokalaemia itself suppresses renin activity. If, on repeat testing,
plasma renin is low and aldosterone concentrations are elevated,
then further investigation under specialist supervision may include
suppression tests (sodium loading) and/or stimulation tests
(captopril or furosemide administration) to differentiate angiotensin
ll-dependent aldosterone secretion in idiopathic hyperplasia from
autonomous aldosterone secretion typical of an APA.
Imaging and localisation
Imaging with CT or MRI will identify most APAs (Fig. 18.23) but it
is important to recognise the risk of false positives (non-functioning
adrenal adenomas are common) and false negatives (imaging
may have insufficient resolution to identify adenomas with a
diameter of less than 0.5 cm). If the imaging is inconclusive
and there is an intention to proceed with surgery on the basis
of strong biochemical evidence of an APA, then adrenal vein
catheterisation with measurement of aldosterone (and cortisol to
confirm positioning of the catheters) is required. In some centres,
this is performed even in the presence of a unilateral ‘adenoma’,
to avoid inadvertent removal of an incidental non-functioning
adenoma contralateral to a radiologically inapparent cause of
aldosterone excess.
18.46 Causes of mineralocorticoid excess
The adrenal glands • 675
Fig. 18.23 Aldosterone-producing adenoma causing Conn’s
syndrome. [A] CT scan of left adrenal adenoma (arrow). [§] The tumour is
‘canary yellow’ because of intracellular lipid accumulation.
Management
Mineralocorticoid receptor antagonists (spironolactone and
eplerenone) are valuable in treating both hypokalaemia and
hypertension in all forms of mineralocorticoid excess. Up to 20%
of males develop gynaecomastia on spironolactone. Amiloride
(10-40 mg/day), which blocks the epithelial sodium channel
regulated by aldosterone, is an alternative.
In patients with an APA, medical therapy is usually given
for a few weeks to normalise whole-body electrolyte balance
before unilateral adrenalectomy. Laparoscopic surgery cures the
biochemical abnormality but, depending on the pre-operative
duration, hypertension remains in as many as 70% of cases,
probably because of irreversible damage to the systemic
microcirculation.
Phaeochromocytoma and paraganglioma
These are rare neuro-endocrine tumours that may secrete
catecholamines (adrenaline/epinephrine, noradrenaline/
norepinephrine). Approximately 80% of these tumours occur in
the adrenal medulla (phaeochromocytomas), while 20% arise
elsewhere in the body in sympathetic ganglia (paragangliomas).
Most are benign but approximately 1 5% show malignant features.
Around 40% are associated with inherited disorders, including
neurofibromatosis (p. 1131), von Hippel-Lindau syndrome
(p. 1132), MEN 2 and MEN 3 (p. 688). Paragangliomas
are particularly associated with mutations in the succinate
i
18.47 Clinical features of phaeochromocytoma
• Hypertension (usually
• Abdominal pain, vomiting
paroxysmal; often postural
• Constipation
drop of blood pressure)
• Weight loss
• Paroxysms of:
Pallor (occasionally
• Glucose intolerance
flushing)
Palpitations, sweating
Headache
Anxiety (angor animi)
dehydrogenase B, C and D genes. Other genetic causes include
mutations in SDHA, SDHAF2, TMEN127 and MAX.
Clinical features
These depend on the pattern of catecholamine secretion and
are listed in Box 18.47.
Some patients present with hypertension, although it has
been estimated that phaeochromocytoma accounts for less
than 0.1% of cases of hypertension. The presentation may be
with a complication of hypertension, such as stroke, myocardial
infarction, left ventricular failure, hypertensive retinopathy or
accelerated phase hypertension. The apparent paradox of
postural hypotension between episodes is explained by ‘pressure
natriuresis’ during hypertensive episodes so that intravascular
volume is reduced. There may also be features of the familial
syndromes associated with phaeochromocytoma. Paragangliomas
are often non-functioning.
Investigations
Excessive secretion of catecholamines can be confirmed by
measuring metabolites in plasma and/or urine (metanephrine
and normetanephrine). There is a high ‘false-positive’ rate, as
misleading metanephrine concentrations may be seen in stressed
patients (during acute illness, following vigorous exercise or
severe pain) and following ingestion of some drugs such as
tricyclic antidepressants. For this reason, a repeat sample should
usually be requested if elevated levels are found, although, as a
rule, the higher the concentration of metanephrines, the more
likely the diagnosis of phaeochromocytoma/paraganglioma.
Serum chromogranin A is often elevated and may be a useful
tumour marker in patients with non-secretory tumours and/or
metastatic disease. Genetic testing should be considered in
individuals with other features of a genetic syndrome, in those
with a family history of phaeochromocytoma/paraganglioma,
and in those presenting under the age of 50 years.
Localisation
Phaeochromocytomas are usually identified by abdominal CT or
MRI (Fig. 18.24). Localisation of paragangliomas may be more
difficult. Scintigraphy using meta-iodobenzyl guanidine (MIBG)
can be useful, particularly if combined with CT, for adrenal
phaeochromocytoma but is often negative in paraganglioma.
18F-deoxyglucose PET is especially useful for detection of
malignant disease and for confirming an imaging abnormality
as a paraganglioma in an individual with underlying risk due to
genetic mutation. Less widely available, 68gallium dotatate PET/
CT imaging has high sensitivity for paraganglioma.
Management
In functioning tumours, medical therapy is required to prepare
the patient for surgery, preferably for a minimum of 6 weeks,
676 • ENDOCRINOLOGY
Fig. 18.24 CT scan of abdomen showing large left adrenal
phaeochromocytoma. The normal right adrenal (white arrow) contrasts
with the large heterogeneous phaeochromocytoma arising from the left
adrenal gland (black arrow).
to allow restoration of normal plasma volume. The most useful
drug in the face of very high circulating catecholamines is the
a-blocker phenoxybenzamine (1 0-20 mg orally 3-4 times daily)
because it is a non-competitive antagonist, unlike prazosin or
doxazosin. If a-blockade produces a marked tachycardia, then
a p-blocker such as propranolol can be added. On no account
should a p-blocker be given before an a-blocker, as this may
cause a paradoxical rise in blood pressure due to unopposed
a-mediated vasoconstriction.
During surgery, sodium nitroprusside and the short-acting
a-antagonist phentolamine are useful in controlling hypertensive
episodes, which may result from anaesthetic induction or
tumour mobilisation. Post-operative hypotension may occur and
require volume expansion and, very occasionally, noradrenaline
(norepinephrine) infusion, but is uncommon if the patient has
been prepared with phenoxybenzamine.
Metastatic tumours may behave in an aggressive or a very
indolent fashion. Management options include debulking surgery,
radionuclide therapy with 131 l-MIBG, chemotherapy and (chemo)
embolisation of hepatic metastases; some may respond to
tyrosine kinase and angiogenesis inhibitors.
Congenital adrenal hyperplasia
Pathophysiology and clinical features
Inherited defects in enzymes of the cortisol biosynthetic pathway
(see Fig. 18.19) result in insufficiency of hormones downstream
of the block, with impaired negative feedback and increased
ACTH secretion. ACTH then stimulates the production of steroids
upstream of the enzyme block. This produces adrenal hyperplasia
and a combination of clinical features that depend on the severity
and site of the defect in biosynthesis. All of these enzyme
abnormalities are inherited as autosomal recessive traits.
The most common enzyme defect is 21 -hydroxylase deficiency.
This results in impaired synthesis of cortisol and aldosterone, and
accumulation of 17-OH-progesterone, which is then diverted to
form adrenal androgens. In about one-third of cases, this defect is
severe and presents in infancy with features of glucocorticoid and
mineralocorticoid deficiency (see Box 1 8.42) and androgen excess,
such as ambiguous genitalia in girls. In the other two-thirds,
mineralocorticoid secretion is adequate but there may be features
of cortisol insufficiency and/or ACTH and androgen excess,
including precocious pseudo-puberty, which is distinguished from
‘true’ precocious puberty by low gonadotrophins. Sometimes
the mildest enzyme defects are not apparent until adult life,
when females may present with amenorrhoea and/or hirsutism
(pp. 762 and 763). This is called ‘non-classical’ or ‘late-onset’
congenital adrenal hyperplasia.
Defects of all the other enzymes in Figure 18.19 are rare. Both
17- hydroxylase and lip-hydroxylase deficiency may produce
hypertension due to excess production of 1 1 -deoxycorticosterone,
which has mineralocorticoid activity.
Investigations
Circulating 17-OH-progesterone levels are raised in 21 -hydroxylase
deficiency but this may be demonstrated only after ACTH
administration in late-onset cases. To avoid salt-wasting crises
in infancy, 17-OH-progesterone can be routinely measured in
heelprick blood spot samples taken from all infants in the first
week of life. Assessment is otherwise as described for adrenal
insufficiency on page 672.
In siblings of affected children, antenatal genetic diagnosis
can be made by amniocentesis or chorionic villus sampling.
This allows prevention of virilisation of affected female fetuses
by administration of dexamethasone to the mother to suppress
ACTH levels.
Management
The aim is to replace deficient corticosteroids and to suppress
ACTH-driven adrenal androgen production. A careful balance
is required between adequate suppression of adrenal androgen
excess and excessive glucocorticoid replacement resulting in
features of Cushing’s syndrome. In children, growth velocity is an
important measurement, since either under- or over-replacement
with glucocorticoids suppresses growth. In adults, there is no
uniformly agreed adrenal replacement regime, and clinical features
(menstrual cycle, hirsutism, weight gain, blood pressure) and
biochemical profiles (plasma renin, 17-OH-progesterone and
testosterone levels) provide a guide.
Women with late-onset 21 -hydroxylase deficiency may not
require corticosteroid replacement. If hirsutism is the main
problem, anti-androgen therapy may be just as effective (p. 659).
The endocrine pancreas and
gastrointestinal tract
A series of hormones are secreted from cells distributed
throughout the gastrointestinal tract and pancreas. Functional
anatomy and physiology are described on pages 723 and 848.
Diseases associated with abnormalities of these hormones are
listed in Box 18.48. Most are rare, with the exception of diabetes
mellitus (Ch. 20).
Presenting problems in endocrine
pancreas disease
Spontaneous hypoglycaemia
Hypoglycaemia most commonly occurs as a side-effect of
treatment with insulin or sulphonylurea drugs in people with
The endocrine pancreas and gastrointestinal tract • 677
18.48 Classification of endocrine diseases of the
pancreas and gastrointestinal tract
Primary
Secondary
Hormone
excess
Insulinoma
Gastrinoma (Zollinger—
Ellison syndrome, p. 802)
Carcinoid syndrome
(secretion of 5-HT)
Glucagonoma
VIPoma
Somatostatinoma
Hypergastrinaemia
of achlorhydria
Hyperinsulinaemia
after bariatric
surgery
Hormone
deficiency
Diabetes mellitus
Hormone
resistance
Insulin resistance
syndromes (e.g. type 2
diabetes mellitus,
lipodystrophy, Donohue’s
syndrome)
Non-functioning
tumours
Pancreatic carcinoma
Pancreatic neuro-endocrine
tumour
(5-HT = 5-hydroxytryptamine, serotonin)
diabetes mellitus. In non-diabetic individuals, symptomatic
hypoglycaemia is rare, but it is not uncommon to detect venous
blood glucose concentrations below 3.0 mmol/L (54 mg/dL)
in asymptomatic patients. For this reason, and because the
symptoms of hypoglycaemia are non-specific, a hypoglycaemic
disorder should be diagnosed only if all three conditions of
Whipple’s triad are met (Fig. 18.25). There is no specific blood
glucose concentration at which spontaneous hypoglycaemia
can be said to occur, although the lower the blood glucose
concentration, the more likely it is to have pathological
significance. Investigations are unlikely to be needed unless
glucose concentrations below 3.0 mmol/L are observed, many
patients with true hypoglycaemia demonstrating glucose levels
below 2.2 mmol/L (40 mg/dL).
Clinical assessment
The clinical features of hypoglycaemia are described in the section
on insulin-induced hypoglycaemia on page 738. Individuals with
chronic spontaneous hypoglycaemia often have attenuated
autonomic responses and ‘hypoglycaemia unawareness’, and
may present with a wide variety of features of neuroglycopenia,
including odd behaviour and convulsions. The symptoms are
usually episodic and relieved by consumption of carbohydrate.
Symptoms occurring while fasting (such as before breakfast) or
following exercise are much more likely to be representative of
pathological hypoglycaemia than those that develop after food
(post-prandial or ‘reactive’ symptoms). Hypoglycaemia should be
considered in all comatose patients, even if there is an apparently
obvious cause, such as hemiplegic stroke or alcohol intoxication.
Investigations
Does the patient have a hypoglycaemic disorder?
Patients who present acutely with delirium, coma or convulsions
should be tested for hypoglycaemia at the bedside with a capillary
blood sample and an automated meter. While this is sufficient
to exclude hypoglycaemia, blood glucose meters are relatively
inaccurate in the hypoglycaemic range and the diagnosis should
Whipple’s triad confirmed
Patient had symptoms of hypoglycaemia
Low blood glucose measured at the time of symptoms
Symptoms resolved on correction of hypoglycaemia
Fig. 18.25 Differential diagnosis of spontaneous hypoglycaemia.
Measurement of insulin and C-peptide concentrations during an episode is
helpful in determining the underlying cause.
always be confirmed by a laboratory-based glucose measurement.
At the same time, a sample should be taken for later measurement
of alcohol, insulin, C-peptide, cortisol and sulphonylurea levels,
if hypoglycaemia is confirmed. Taking these samples during an
acute presentation prevents subsequent unnecessary dynamic
tests and is of medico-legal importance in cases where poisoning
is suspected.
Patients who attend the outpatient clinic with episodic symptoms
suggestive of hypoglycaemia present a more challenging problem.
The main diagnostic test is the prolonged (72-hour) fast. If
symptoms of hypoglycaemia develop during the fast, then blood
samples should be taken to confirm hypoglycaemia and for later
measurement of insulin and C-peptide. Hypoglycaemia is then
corrected with oral or intravenous glucose and Whipple’s triad
completed by confirmation of the resolution of symptoms. The
absence of clinical and biochemical evidence of hypoglycaemia
during a prolonged fast effectively excludes the diagnosis of a
hypoglycaemic disorder.
What is the cause of the hypoglycaemia?
In the acute setting, the underlying diagnosis is often obvious.
In non-diabetic individuals, alcohol excess is the most common
cause of hypoglycaemia in the UK but other drugs - e.g. salicylates,
quinine and pentamidine - may also be implicated. Hypoglycaemia
is one of many metabolic derangements that occur in patients with
hepatic failure, renal failure, adrenal insufficiency, sepsis or malaria.
Hypoglycaemia in the absence of insulin, or any insulin-like
factor, in the blood indicates impaired gluconeogenesis and/or
availability of glucose from glycogen in the liver. Hypoglycaemia
associated with high insulin and low C-peptide concentrations
is indicative of administration of exogenous insulin, either
factitiously or feloniously. Adults with high insulin and C-peptide
concentrations during an episode of hypoglycaemia are most
likely to have an insulinoma but sulphonylurea ingestion should
also be considered (particularly in individuals with access to
such medication, such as health-care professionals or family
members of someone with type 2 diabetes). Suppressed
plasma (3-hydroxybutyrate helps confirm inappropriate insulin
secretion during fasting. Usually, insulinomas in the pancreas
678 • ENDOCRINOLOGY
18.49 Spontaneous hypoglycaemia in old age
• Presentation: may present with focal neurological abnormality.
Blood glucose should be checked in all patients with acute
neurological symptoms and signs, especially stroke, as these will
reverse with early treatment of hypoglycaemia.
are small (<5 mm diameter) but can be identified by CT, MRI or
ultrasound (endoscopic or laparoscopic). Imaging should include
the liver since around 1 0% of insulinomas are malignant and may
metastasise to the liver. Rarely, large non-pancreatic tumours,
such as sarcomas, may cause recurrent hypoglycaemia because
of their ability to produce excess pro-insulin-like growth factor-2
(pro-IGF-2), which has considerable structural homology to insulin.
Management
Treatment of acute hypoglycaemia should be initiated as soon
as laboratory blood samples have been taken and should not be
deferred until formal laboratory confirmation has been obtained.
Intravenous dextrose (5% or 10%) is effective in the short term
in the obtunded patient and should be followed on recovery
with oral unrefined carbohydrate (starch). Continuous dextrose
infusion may be necessary, especially in sulphonylurea poisoning.
Intramuscular glucagon (1 mg) stimulates hepatic glucose release
but is ineffective in patients with depleted glycogen reserves,
such as in alcohol excess or liver disease.
Chronic recurrent hypoglycaemia in insulin-secreting tumours
can be treated by regular consumption of oral carbohydrate
combined with agents that inhibit insulin secretion (diazoxide or
somatostatin analogues). Insulinomas are resected when benign,
providing the individual is fit enough to undergo surgery. Metastatic
malignant insulinomas may be incurable and are managed along
the same lines as other metastatic neuro-endocrine tumours
(see below).
Gastroenteropancreatic neuro-endocrine
tumours
Neuro-endocrine tumours (NETs) are a heterogeneous group
derived from neuro-endocrine cells in many organs, including
the gastrointestinal tract, lung, adrenals (phaeochromocytoma,
p. 675) and thyroid (medullary carcinoma, p. 650). Most NETs
occur sporadically but a proportion are associated with genetic
cancer syndromes, such as MEN 1 , 2 and 3 and neurofibromatosis
type 1 (pp. 688 and 1131). NETs may secrete hormones into
the circulation.
Gastroenteropancreatic NETs arise in organs that are
derived embryologically from the gastrointestinal tract. Most
commonly, they occur in the small bowel but they can also arise
elsewhere in the bowel, pancreas, thymus and bronchi. The
term ‘carcinoid’ is often used when referring to non-pancreatic
gastroenteropancreatic NETs because, when initially described,
they were thought to behave in an indolent fashion compared
with conventional cancers. It is now recognised that there is a
wide spectrum of malignant potential for all NETs; some are
benign (most insulinomas and appendiceal carcinoid tumours),
while others have an aggressive clinical course with widespread
metastases (small-cell carcinoma of the lung). The majority
of gastroenteropancreatic NETs behave in an intermediate
manner, with relatively slow growth but a propensity to invade
and metastasise to remote organs, especially the liver.
18.50 Pancreatic neuro-endocrine tumours
Tumour
Hormone
Effects
Gastrinoma
Gastrin
Peptic ulcer and
steatorrhoea (Zollinger—
Ellison syndrome,
p. 802)
Insulinoma
Insulin
Recurrent
hypoglycaemia (see
above)
VIPoma
Vasoactive intestinal
peptide (VIP)
Watery diarrhoea and
hypokalaemia
Glucagonoma
Glucagon
Diabetes mellitus,
necrolytic migratory
erythema
Somatostatinoma
Somatostatin
Diabetes mellitus and
steatorrhoea
18.51 Clinical features of the carcinoid syndrome
• Episodic flushing, wheezing and diarrhoea
• Facial telangiectasia
• Cardiac involvement (tricuspid regurgitation, pulmonary stenosis,
right ventricular endocardial plaques) leading to heart failure
Clinical features
Patients with gastroenteropancreatic NETs often have a history
of abdominal pain over many years prior to diagnosis and usually
present with local mass effects, such as small-bowel obstruction,
appendicitis, and pain from hepatic metastases. Thymic and
bronchial carcinoids occasionally present with ectopic ACTH
syndrome (p. 667). Pancreatic NETs can also cause hormone excess
(Box 18.50) but most are non-functional. The classic ‘carcinoid
syndrome’ (Box 18.51) occurs when vasoactive hormones reach
the systemic circulation. In the case of gastrointestinal carcinoids,
this invariably means that the tumour has metastasised to the liver
or there are peritoneal deposits, which allow secreted hormones
to gain access to the systemic circulation; hormones secreted
by the primary tumour into the portal vein are metabolised and
inactivated in the liver. The features of Zollinger— Ellison syndrome
are described on page 802.
Investigations
A combination of imaging with ultrasound, CT, MRI and/or
radio-labelled somatostatin analogue (Fig. 18.26) will usually
identify the primary tumour and allow staging, which is crucial
for determining prognosis. Biopsy of the primary tumour or a
metastatic deposit is required to confirm the histological type.
NETs demonstrate immunohistochemical staining for the proteins
chromogranin A and synaptophysin, and the histological grade
provides important prognostic information: the higher the Ki67
proliferation index, the worse the prognosis.
Carcinoid syndrome is confirmed by measuring elevated
concentrations of 5-hydroxyindoleacetic acid (5-HIAA), a
metabolite of serotonin, in a 24-hour urine collection. False
positives can occur, particularly if the individual has been
eating certain foods, such as avocado and pineapple. Plasma
chromogranin A can be measured in a fasting blood sample,
along with the hormones listed in Box 18.50. All of these can
be useful as tumour markers.
The hypothalamus and the pituitary gland • 679
0
0
Fig. 18.26 Octreotide scintigraphy in a metastatic neuro-endocrine tumour. [A] Coronal CT scan showing hepatomegaly and a mass inferior to the
liver (at the intersection of the horizontal and vertical red lines). Jj Octreotide scintogram showing patches of increased uptake in the upper abdomen.
[C] When the octreotide and CT scans are superimposed, it shows that the areas of increased uptake are in hepatic metastases and in the tissue mass,
which may be lymph nodes or a primary tumour.
Management
Treatment of solitary tumours is by surgical resection. If metastatic
or multifocal primary disease is present, then surgery is usually not
indicated, unless there is a complication such as gastrointestinal
obstruction. Diazoxide can reduce insulin secretion in insulinomas,
and high doses of proton pump inhibitors suppress acid production
in gastrinomas. Somatostatin analogues are effective in reducing
the symptoms of carcinoid syndrome and of excess glucagon and
vasoactive intestinal peptide (VIP) production. The slow-growing
nature of NETs means that conventional cancer therapies, such as
chemotherapy and radiotherapy, have limited efficacy, but use of
somatostatin analogues is associated with improved progression-
free survival. Other treatments, such as interferon, targeted
radionuclide therapy with 131I-MIBG and radio-labelled somatostatin
analogues (which may be taken up by NET metastases), and
resection/embolisation/ablation of hepatic metastases, may have a
role in the palliation of symptoms but debate exists as to whether
this prolongs life. The tyrosine kinase inhibitor sunitinib and the
mammalian target of rapamycin (mTOR) inhibitor everolimus have
shown significant improvements in progression-free survival in
patients with advanced and progressive pancreatic and lung NETS
that are not poorly differentiated, and should be considered as
part of standard therapy.
The hypothalamus and the
pituitary gland
Diseases of the hypothalamus and pituitary have an annual
incidence of approximately 3:1 00000 and a prevalence of 30-70
per 100000. The pituitary plays a central role in several major
endocrine axes, so that investigation and treatment invariably
involve several other endocrine glands.
Functional anatomy, physiology
and investigations
The anatomical relationships of the pituitary are shown in Figure
18.27 and its numerous functions are shown in Figure 18.2
(p. 633). The pituitary gland is enclosed in the sella turcica and
bridged over by a fold of dura mater called the diaphragma
sellae, with the sphenoidal air sinuses below and the optic chiasm
above. The cavernous sinuses are lateral to the pituitary fossa
and contain the 3rd, 4th and 6th cranial nerves and the internal
0
m
Fig. 18.27 Anatomical relationships of the normal pituitary gland
and hypothalamus. See also Figure 18.2 (p. 633). [A] Sagittal MRI.
Ml Coronal MRI. (AP = anterior pituitary; CS = cavernous sinus; FI =
hypothalamus; 1C = internal carotid artery; OC = optic chiasm; PP =
posterior pituitary; PS = pituitary stalk; SS = sphenoid sinus; TV = third
ventricle)
carotid arteries. The gland is composed of two lobes, anterior
and posterior, and is connected to the hypothalamus by the
infundibular stalk, which has portal vessels carrying blood from
the median eminence of the hypothalamus to the anterior lobe
and nerve fibres to the posterior lobe.
680 • ENDOCRINOLOGY
I 18.52 Classification of diseases of the pituitary and hypothalamus
Primary
Secondary
Non-functioning tumours
Pituitary adenoma
Craniopharyngioma
Metastatic tumours
Hormone excess
Anterior pituitary
Prolactinoma
Acromegaly
Cushing’s disease
Rare TSH-, LH- and FSH-secreting adenomas
Disconnection hyperprolactinaemia
Hypothalamus and posterior pituitary
Syndrome of inappropriate antidiuretic
hormone (SIADH, p. 357)
Hormone deficiency
Anterior pituitary
Hypopituitarism
GnRH deficiency
Hypothalamus and posterior pituitary
Cranial diabetes insipidus
(Kallmann’s syndrome)
Hormone resistance
Growth hormone resistance (Laron dwarfism)
Nephrogenic diabetes insipidus
(FSH = follicle-stimulating hormone; GnRH
= gonadotrophin-releasing hormone; LH = luteinising hormone; TSH =
thyroid-stimulating hormone)
Diseases of the hypothalamus and pituitary are classified in
Box 18.52. By far the most common disorder is an adenoma
of the anterior pituitary gland.
Investigation of patients with pituitary disease
Although pituitary disease presents with diverse clinical
manifestations (see below), the approach to investigation is
similar in all cases (Box 18.53).
The approach to testing for hormone deficiency is outlined
in Box 18.53. Details are given in the sections on individual
glands elsewhere in this chapter. Tests for hormone excess vary
according to the hormone in question. For example, prolactin is
not secreted in pulsatile fashion, although it rises with significant
psychological stress. Assuming that the patient was not distressed
by venepuncture, a random measurement of serum prolactin is
sufficient to diagnose hyperprolactinaemia. In contrast, growth
hormone is secreted in a pulsatile fashion. A high random level
does not confirm acromegaly; the diagnosis is confirmed only by
failure of growth hormone to be suppressed during an oral glucose
tolerance test, and a high serum insulin-like growth factor-1
(IGF-1). Similarly, in suspected ACTH-dependent Cushing’s
disease (p. 666), random measurement of plasma cortisol is
unreliable and the diagnosis is usually made by a dexamethasone
suppression test.
The most common local complication of a large pituitary tumour
is compression of the optic pathway. The resulting visual field
defect can be documented using a Goldman’s perimetry chart.
MRI reveals ‘abnormalities’ of the pituitary gland in as many
as 10% of ‘healthy’ middle-aged people. It should therefore be
performed only if there is a clear biochemical abnormality or if a
patient presents with clinical features of pituitary tumour (see below).
A pituitary tumour may be classified as either a macroadenoma
(> 1 0 mm diameter) or a microadenoma (< 1 0 mm diameter).
Surgical biopsy is usually only performed as part of a
therapeutic operation. Conventional histology identifies tumours
as chromophobe (usually non-functioning), acidophil (typically
prolactin- or growth hormone-secreting) or basophil (typically
ACTH-secreting); immunohistochemistry may confirm their
secretory capacity but is poorly predictive of growth potential
of the tumour.
18.53 How to investigate patients with suspected
pituitary hypothalamic disease
Identify pituitary hormone deficiency
ACTH deficiency
• Short ACTH stimulation test (see Box 1 8.43)
• Insulin tolerance test (see Box 18.56): only if there is uncertainty in
interpretation of short ACTH stimulation test (e.g. acute
presentation)
LH/FSH deficiency
• In the male, measure random serum testosterone, LH and
FSH
• In the pre-menopausal female, ask if the menses are
regular
• In the post-menopausal female, measure random serum LH
and FSH (FSH normally >30 IU/L and LH >20 IU/L)
TSH deficiency
• Measure random serum T4
• Note that TSH is often detectable in secondary hypothyroidism
Growth hormone deficiency
Only investigate if growth hormone replacement therapy is being
contemplated (p. 682)
• Measure immediately after exercise
• Consider other stimulatory tests (see Box 18.55)
Cranial diabetes insipidus
Only investigate if patient complains of polyuria/polydipsia, which may
be masked by ACTH or TSH deficiency
• Exclude other causes of polyuria with blood glucose, potassium and
calcium measurements
• Water deprivation test (see Box 18.61) or 5% saline infusion
test
Identify hormone excess
• Measure random serum prolactin
• Investigate for acromegaly (glucose tolerance test) or Cushing’s
syndrome (p. 667) if there are clinical features
Establish the anatomy and diagnosis
• Consider visual field testing
• Image the pituitary and hypothalamus by MRI or CT
(ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; LH =
luteinising hormone; TSH = thyroid-stimulating hormone)
The hypothalamus and the pituitary gland • 681
Presenting problems in hypothalamic and
pituitary disease
The clinical features of pituitary disease are shown in Figure
18.28. Younger women with pituitary disease most commonly
present with secondary amenorrhoea (p. 654) or galactorrhoea
(in hyperprolactinaemia). Post-menopausal women and men of
any age are less likely to report symptoms of hypogonadism and
so are more likely to present late with larger tumours causing
visual field defects. Nowadays, many patients present with the
incidental finding of a pituitary tumour on a CT or MRI scan.
Hypopituitarism
Hypopituitarism describes combined deficiency of any of the
anterior pituitary hormones. The clinical presentation is variable
and depends on the underlying lesion and the pattern of resulting
hormone deficiency. The most common cause is a pituitary
macroadenoma but other causes are listed in Box 18.54.
Clinical assessment
The presentation is highly variable. For example, following
radiotherapy to the pituitary region, there is a characteristic
sequence of loss of pituitary hormone secretion. Growth hormone
secretion is often the earliest to be lost. In adults, this produces
lethargy, muscle weakness and increased fat mass but these
features are not obvious in isolation. Next, gonadotrophin (LH and
FSH) secretion becomes impaired with loss of libido in the male
and oligomenorrhoea or amenorrhoea in the female. Later, in the
male there may be gynaecomastia and decreased frequency of
shaving. In both sexes, axillary and pubic hair eventually become
^9 18.54 Causes of anterior pituitary hormone
deficiency
Structural
• Primary pituitary tumour
•
Chordoma
• Adenoma* *
•
Germinoma (pinealoma)
• Carcinoma (exceptionally rare)
•
Arachnoid cyst
• Craniopharyngioma*
•
Rathke’s cleft cyst
• Meningioma*
• Secondary tumour (including
•
Haemorrhage (apoplexy)
leukaemia and lymphoma)
Inflammatory/infiltrative
• Sarcoidosis
•
Lymphocytic hypophysitis
• Infections, e.g. pituitary
•
Haemochromatosis
abscess, tuberculosis,
syphilis, encephalitis
•
Langerhans cell histiocytosis
Congenital deficiencies
• GnRH (Kallmann’s syndrome)*
•
TRH
• GHRH*
•
CRH
Functional
• Chronic systemic illness
• Anorexia nervosa
•
Excessive exercise
Other
• Head injury*
•
Post-partum necrosis
• (Para)sellar surgery*
(Sheehan’s syndrome)
• (Para)sellar radiotherapy*
•
Opiate analgesia
*The most common causes of pituitary hormone deficiency.
(CRH = corticotrophin-releasing hormone; GHRH = growth hormone-releasing
hormone; GnRH = gonadotrophin-releasing hormone; TRH = thyrotrophin¬
releasing hormone)
Local complications
• Headache
• Visual field defect
• Disconnection hyperprolactinaemia
• Diplopia (cavernous sinus involvement)
• Acute infarction/expansion (pituitary apoplexy)
Hormone excess
Hypopituitarism
Hyperprolactinaemia
• Galactorrhoea
• Amenorrhoea
• Hypogonadism
Acromegaly
• Headache
• Sweating
• Change in shoe
and ring size
Cushing’s disease
• Weight gain
• Bruising
• Myopathy
• Hypertension
• Striae
• Depression
Macroadenoma (arrows)
V > 10 mm diameter y
*
Growth hormone
• Lethargy
Gonadotrophins
• Lethargy
• Loss of libido
• Hair loss
• Amenorrhoea
ACTH
• Lethargy
• Postural hypotension
• Pallor
• Hair loss
TSH
• Lethargy
Vasopressin
(usually post-surgical)
• Thirst and polyuria
Fig. 18.28 Common symptoms and signs to consider in a patient with suspected pituitary disease. (ACTH = adrenocorticotropic hormone; TSH =
thyroid-stimulating hormone)
682 • ENDOCRINOLOGY
i
GH levels are commonly undetectable, so a choice from the range of
‘stimulation’ tests is required:
• Insulin-induced hypoglycaemia
• Arginine (may be combined with GHRH)
• Glucagon
• Clonidine (in children)
(GH = growth hormone; GHRH = growth hormone-releasing hormone)
sparse or even absent and the skin becomes characteristically finer
and wrinkled. Chronic anaemia may also occur. The next hormone
to be lost is usually ACTH, resulting in symptoms of cortisol
insufficiency (including postural hypotension and a dilutional
hyponatraemia). In contrast to primary adrenal insufficiency
(p. 671), angiotensin ll-dependent zona glomerulosa function
is not lost and hence aldosterone secretion maintains normal
plasma potassium. In contrast to the pigmentation of Addison’s
disease due to high levels of circulating ACTH acting on the skin
melanocytes, a striking degree of pallor is usually present. Finally,
TSH secretion is lost with consequent secondary hypothyroidism.
This contributes further to apathy and cold intolerance. In contrast
to primary hypothyroidism, frank myxoedema is rare, presumably
because the thyroid retains some autonomous function. The
onset of all of the above symptoms is notoriously insidious.
However, patients sometimes present acutely unwell with
glucocorticoid deficiency. This may be precipitated by a mild
infection or injury, or may occur secondary to pituitary apoplexy
(p. 683).
Other features of pituitary disease may be present (Fig. 18.28).
Investigations
The strategy for investigation of pituitary disease is described
in Box 18.53. In acutely unwell patients, the priority is to
diagnose and treat cortisol deficiency (p. 672). Other tests
can be undertaken later. Specific dynamic tests for diagnosing
hormone deficiency are described in Boxes 18.43 and 18.55.
More specialised biochemical tests, such as insulin tolerance
tests (Box 18.56), GnRH and TRH tests, are rarely required. All
patients with biochemical evidence of pituitary hormone deficiency
should have an MRI or CT scan to identify pituitary or hypothalamic
tumours. If a tumour is not identified, then further investigations
are indicated to exclude infectious or infiltrative causes.
Management
Treatment of acutely ill patients is similar to that described for
adrenocortical insufficiency on page 673, except that sodium
depletion is not an important component to correct. Chronic
hormone replacement therapies are described below. Once the
cause of hypopituitarism is established, specific treatment - of
a pituitary macroadenoma, for example (see below) - may be
required.
Cortisol replacement
Hydrocortisone should be given if there is ACTH deficiency.
Suitable doses are described in the section on adrenal disease
on page 672. Mineralocorticoid replacement is not required.
Thyroid hormone replacement
Levothyroxine 50-1 50 jig once daily should be given as described
on page 640. Unlike in primary hypothyroidism, measuring
18.56 How and when to do an insulin tolerance test
Use
• Assessment of the HPA axis
• Assessment of GH deficiency
• Indicated when there is doubt after the other tests in Box 1 8.53
• Usually performed in specialist centres, especially in children
• IV glucose and hydrocortisone must be available for resuscitation
Contraindications
• Ischaemic heart disease
• Epilepsy
• Severe hypopituitarism (0800 hrs plasma cortisol <180 nmol/L
(6.6 pig/dL))
Dose
• 0.15 U/kg body weight soluble insulin IV
Aim
• To produce adequate hypoglycaemia (tachycardia and sweating with
blood glucose <2.2 mmol/L (40 mg/dL))
Blood samples
• 0, 30, 45, 60, 90, 120 mins for blood glucose, plasma cortisol and
growth hormone
Results
• Normal subjects: GH > 6.7 |ig/L (20mlU/L)*
• Normal subjects: cortisol >550 nmol/L (approximately 20.2 jig/dL)*
The precise cut-off figure for a satisfactory cortisol and GH response depends
on the assay used and so varies between centres.
(GH = growth hormone; HPA = hypothalamic-pituitary-adrenal)
TSH is not helpful in adjusting the replacement dose because
patients with hypopituitarism often secrete glycoproteins that
are measured in the TSH assays but are not bioactive. The
aim is to maintain serum T4 in the upper part of the reference
range. It is dangerous to give thyroid replacement in adrenal
insufficiency without first giving glucocorticoid therapy, since
this may precipitate adrenal crisis.
Sex hormone replacement
This is indicated if there is gonadotrophin deficiency in women
under the age of 50 and in men to restore normal sexual function
and to prevent osteoporosis (p. 1044).
Growth hormone replacement
Growth hormone (GH) is administered by daily subcutaneous
self-injection to children and adolescents with GH deficiency and,
until recently, was discontinued once the epiphyses had fused.
However, although hypopituitary adults receiving ‘full’ replacement
with hydrocortisone, levothyroxine and sex steroids are usually
much improved by these therapies, some individuals remain
lethargic and unwell compared with a healthy population. Some
of these patients feel better, and have objective improvements
in their fat:muscle mass ratio and other metabolic parameters,
if they are also given GH replacement. Treatment with GH may
also help young adults to achieve a higher peak bone mineral
density. The principal side-effect is sodium retention, manifest
as peripheral oedema or carpal tunnel syndrome if given in
excess. For this reason, GH replacement should be started at
a low dose, with monitoring of the response by measurement
of serum IGF-1 .
18.55 Tests of growth hormone secretion
The hypothalamus and the pituitary gland • 683
Pituitary tumour
Pituitary tumours produce a variety of mass effects, depending on
their size and location, but also present as incidental findings on
CT or MRI, or with hypopituitarism, as described above. A wide
variety of disorders can present as mass lesions in or around
the pituitary gland (see Box 18.54). Most intrasellar tumours
are pituitary macroadenomas (most commonly non-functioning
adenomas; see Fig. 18.28), whereas suprasellar masses may be
craniopharyngiomas (see Fig. 18.31). The most common cause
of a parasellar mass is a meningioma.
Clinical assessment
Clinical features are shown in Figure 18.28. A common but
non-specific presentation is with headache, which may be the
consequence of stretching of the diaphragma sellae. Although
the classical abnormalities associated with compression of
the optic chiasm are bitemporal hemianopia (see Fig. 18.29)
or upper quadrantanopia, any type of visual field defect can
result from suprasellar extension of a tumour because it may
compress the optic nerve (unilateral loss of acuity or scotoma)
or the optic tract (homonymous hemianopia). Optic atrophy may
be apparent on ophthalmoscopy. Lateral extension of a sellar
mass into the cavernous sinus with subsequent compression
of the 3rd, 4th or 6th cranial nerve may cause diplopia and
strabismus, but in anterior pituitary tumours this is an unusual
presentation.
Occasionally, pituitary tumours infarct or there is bleeding into
cystic lesions. This is termed ‘pituitary apoplexy’ and may result
in sudden expansion with local compression symptoms and
acute-onset hypopituitarism. Non-haemorrhagic infarction can
also occur in a normal pituitary gland; predisposing factors include
catastrophic obstetric haemorrhage (Sheehan’s syndrome),
diabetes mellitus and raised intracranial pressure.
Investigations
Patients suspected of having a pituitary tumour should undergo
MRI or CT. While some lesions have distinctive neuro-radiological
features, the definitive diagnosis is made on histology after
surgery. All patients with (para)sellar space-occupying lesions
should have pituitary function assessed as described in
Box 18.53.
Management
Modalities of treatment of common pituitary and hypothalamic
tumours are shown in Box 18.57. Associated hypopituitarism
should be treated as described above.
Urgent treatment is required if there is evidence of pressure
on visual pathways. The chances of recovery of a visual field
defect are proportional to the duration of symptoms, with full
recovery unlikely if the defect has been present for longer than
4 months. In the presence of a sellar mass lesion, it is crucial
that serum prolactin is measured before emergency surgery
is performed. If the prolactin is over 5000mlU/L (236 ng/mL),
then the lesion is likely to be a macroprolactinoma and should
respond to a dopamine agonist with shrinkage of the lesion,
making surgery unnecessary (see Fig. 18.29).
Most operations on the pituitary are performed using the
trans-sphenoidal approach via the nostrils, while transfrontal
surgery via a craniotomy is reserved for suprasellar tumours
and is much less frequently needed. It is uncommon to be
able to resect lateral extensions into the cavernous sinuses,
although with modern endoscopic techniques this is more
feasible. All operations on the pituitary carry a risk of damaging
normal endocrine function; this risk increases with the size of
the primary lesion.
Pituitary function (see Box 1 8.53) should be retested 4-6 weeks
following surgery, primarily to detect the development of any
new hormone deficits. Rarely, the surgical treatment of a sellar
lesion can result in recovery of hormone secretion that was
deficient pre-operatively.
Following surgery, usually after 3-6 months, imaging should be
repeated. If there is a significant residual mass and the histology
confirms an anterior pituitary tumour, external radiotherapy may
be given to reduce the risk of recurrence but the risk: benefit
ratio needs careful individualised discussion. Radiotherapy is
not useful in patients requiring urgent therapy because it takes
many months or years to be effective and there is a risk of
acute swelling of the mass. Fractionated radiotherapy carries
a life-long risk of hypopituitarism (50-70% in the first 1 0 years)
and annual pituitary function tests are obligatory. There is also
concern that radiotherapy might impair cognitive function, cause
vascular changes and even induce primary brain tumours, but
these side-effects have not been quantified reliably and are likely
I 18.57 Therapeutic modalities for functioning and non-functioning hypothalamic and pituitary tumours
Surgery
Radiotherapy
Medical
Comment
Non-functioning
pituitary macroadenoma
1st line
2nd line
-
Prolactinoma
2nd line
2nd line
1st line
Dopamine agonists
Dopamine agonists usually cause macroadenomas
to shrink
Acromegaly
1st line
2nd line
2nd line
Somatostatin analogues
Dopamine agonists
GH receptor antagonists
Medical therapy does not reliably cause
macroadenomas to shrink
Radiotherapy and medical therapy are used in
combination for inoperable tumours
Cushing’s disease
1st line
2nd line
2nd line
Steroidogenesis inhibitors
Pasireotide
Radiotherapy may take many years to reduce ACTH
excess and medical therapies may be used as a
bridge. Bilateral adrenalectomy may also be
considered if the pituitary tumour is not completely
resectable
Craniopharyngioma
1st line
2nd line
-
(ACTH = adrenocorticotropic hormone; GH = growth hormone)
684 • ENDOCRINOLOGY
to be rare. Stereotactic radiosurgery allows specific targeting of
residual disease in a more focused fashion.
Non-functioning tumours should be followed up by repeated
imaging at intervals that depend on the size of the lesion and
on whether or not radiotherapy has been administered. For
smaller lesions that are not causing mass effects, therapeutic
surgery may not be indicated and the lesion may simply be
monitored by serial neuroimaging without a clear-cut diagnosis
having been established.
Hyperprolactinaemia/galactorrhoea
Hyperprolactinaemia is a common abnormality that usually
presents with hypogonadism and/or galactorrhoea (lactation in
the absence of breastfeeding). Since prolactin stimulates milk
secretion but not breast development, galactorrhoea rarely
occurs in men and only does so if gynaecomastia has been
induced by hypogonadism (p. 655). The differential diagnosis
of hyperprolactinaemia is shown in Box 18.58. Many drugs,
especially dopamine antagonists, elevate prolactin concentrations.
Pituitary tumours can cause hyperprolactinaemia by directly
secreting prolactin (prolactinomas, see below), or by compressing
the infundibular stalk and thus interrupting the tonic inhibitory effect
of hypothalamic dopamine on prolactin secretion (‘disconnection’
hyperprolactinaemia).
Prolactin usually circulates as a free (monomeric) hormone
in plasma but, in some individuals, prolactin becomes bound
to an IgG antibody. This complex is known as macroprolactin
and such patients have macroprolactinaemia (not to be
confused with macroprolactinoma, a prolactin-secreting pituitary
tumour of more than 1 cm in diameter). Since macroprolactin
cannot cross blood-vessel walls to reach prolactin receptors
i
18.58 Causes of hyperprolactinaemia
Physiological
• Stress (e.g. post-seizure)
• Sleep
• Pregnancy
• Coitus
• Lactation
• Exercise
• Nipple stimulation
• Baby crying
Drug-induced
Dopamine antagonists
• Antipsychotics (phenothiazines
and butyrophenones)
• Antidepressants
Dopamine-depleting drugs
• Reserpine
Oestrogens
• Oral contraceptive pill
• Antiemetics (e.g.
metoclopramide, domperidone)
• Methyldopa
Pathological
Common
• Disconnection
• Primary hypothyroidism
hyperprolactinaemia (e.g.
• Polycystic ovarian syndrome
non-functioning pituitary
• Macroprolactinaemia
macroadenoma)
• Prolactinoma (usually
microadenoma)
Uncommon
• Pituitary tumour secreting
• Hypothalamic disease
prolactin and growth hormone
• Renal failure
Rare
Chest wall reflex (e.g. post herpes zoster)
in target tissues, it is of no pathological significance. Some
commercial prolactin assays do not distinguish prolactin from
macroprolactin and so macroprolactinaemia is a cause of spurious
hyperprolactinaemia. Identification of macroprolactin requires
gel filtration chromatography or polyethylene glycol precipitation
techniques, and one of these tests should be performed in all
patients with hyperprolactinaemia if the prolactin assay is known
to cross-react.
Clinical assessment
In women, in addition to galactorrhoea, hypogonadism associated
with hyperprolactinaemia causes secondary amenorrhoea and
anovulation with infertility (p. 654). Important points in the history
include drug use, recent pregnancy and menstrual history. The
quantity of milk produced is variable and it may be observed only
by manual expression. In men there is decreased libido, reduced
shaving frequency and lethargy (p. 655). Unilateral galactorrhoea
may be confused with nipple discharge, and breast examination
to exclude malignancy or fibrocystic disease is important. Further
assessment should address the features in Figure 18.28.
Investigations
Pregnancy should first be excluded before further investigations
are performed in women of child-bearing potential. The upper limit
of normal for many assays of serum prolactin is approximately
500mlU/L (24 ng/mL). In non-pregnant and non-lactating
patients, monomeric prolactin concentrations of 500-1 000 mlU/L
(24-47 ng/mL) are likely to be induced by stress or drugs, and
a repeat measurement is indicated. Levels between 1000 and
5000mlU/L (47-236 ng/mL) are likely to be due to either drugs,
a microprolactinoma or ‘disconnection’ hyperprolactinaemia.
Levels above 5000mlU/L (236 ng/mL) are highly suggestive of
a macroprolactinoma.
Patients with prolactin excess should have tests of gonadal
function (p. 651), and T4 and TSH should be measured to
exclude primary hypothyroidism causing TRH-induced prolactin
excess. Unless the prolactin falls after withdrawal of relevant
drug therapy, a serum prolactin consistently above the reference
range is an indication for MRI or CT scan of the hypothalamus
and pituitary. Patients with a macroadenoma also need tests
for hypopituitarism (see Box 18.53).
Management
If possible, the underlying cause should be corrected (e.g.
cessation of offending drugs and giving levothyroxine replacement
in primary hypothyroidism). If dopamine antagonists are the
cause, then dopamine agonist therapy is contraindicated;
if gonadal dysfunction is the primary concern, sex steroid
replacement therapy may be indicated. Troublesome physiological
galactorrhoea can also be treated with dopamine agonists (see
Box 18.59). Management of prolactinomas is described below.
Prolactinoma
Most prolactinomas in pre-menopausal women are
microadenomas because the symptoms of prolactin excess
usually result in early presentation. Prolactin-secreting cells of
the anterior pituitary share a common lineage with GH-secreting
cells, so occasionally prolactinomas can secrete excess GH
and cause acromegaly. In prolactinomas there is a relationship
between prolactin concentration and tumour size: the higher
the level, the bigger the tumour. Some macroprolactinomas
can elevate prolactin concentrations above lOOOOOmIU/L
The hypothalamus and the pituitary gland • 685
(4700 ng/mL). The investigation of prolactinomas is the same
as for other pituitary tumours (see above).
Management
As shown in Box 18.57, several therapeutic modalities can be
employed in the management of prolactinomas.
Medical
Dopamine agonist drugs are first-line therapy for the majority
of patients (Box 18.59). They usually reduce serum prolactin
concentrations and cause significant tumour shrinkage after
several months of therapy (Fig. 18.29), but visual field defects,
if present, may improve within days of first administration. It is
possible to withdraw dopamine agonist therapy without recurrence
of hyperprolactinaemia after a few years of treatment in some
Fig. 18.29 Shrinkage of a macroprolactinoma following treatment
with a dopamine agonist. [A] MRI scan showing a pituitary
macroadenoma (T) compressing the optic chiasm (C). [§] MRI scan of
the same tumour following treatment with a dopamine agonist. The
macroadenoma, which was a prolactinoma, has decreased in size
substantially and is no longer compressing the optic chiasm.
patients with a microadenoma. Also, after the menopause,
suppression of prolactin is required in microadenomas only
if galactorrhoea is troublesome, since hypogonadism is then
physiological and tumour growth unlikely. In patients with
macroadenomas, drugs can be withdrawn only after curative
surgery or radiotherapy and under close supervision.
Ergot-derived dopamine agonists (bromocriptine and
cabergoline) can bind to 5-HT2B receptors in the heart and
elsewhere and have been associated with fibrotic reactions,
particularly tricuspid valve regurgitation, when used in high
doses in patients with Parkinson’s disease. At the relatively
low doses used in prolactinomas most data suggest that
systematic screening for cardiac fibrosis is unnecessary, but
if dopamine agonist therapy is prolonged, periodic screening
by echocardiography or use of non-ergot agents (quinagolide)
may be indicated.
Surgery and radiotherapy
Surgical decompression is usually necessary only when a
macroprolactinoma has failed to shrink sufficiently with dopamine
agonist therapy, and this may be because the tumour has a
significant cystic component. Surgery may also be performed in
patients who are intolerant of dopamine agonists. Microadenomas
can be removed selectively by trans-sphenoidal surgery with a
cure rate of about 80%, but recurrence is possible; the cure rate
for surgery in macroadenomas is substantially lower.
External irradiation may be required for some macroadenomas
to prevent regrowth if dopamine agonists are stopped.
Pregnancy
Hyperprolactinaemia often presents with infertility, so dopamine
agonist therapy may be followed by pregnancy. Patients with
microadenomas should be advised to withdraw dopamine
agonist therapy as soon as pregnancy is confirmed. In contrast,
macroprolactinomas may enlarge rapidly under oestrogen
stimulation and these patients should continue dopamine agonist
therapy and need measurement of prolactin levels and visual
fields during pregnancy. All patients should be advised to report
headache or visual disturbance promptly.
Acromegaly
Acromegaly is caused by growth hormone (GH) secretion from
a pituitary tumour, usually a macroadenoma, and carries an
approximate twofold excess mortality when untreated.
18.59 Dopamine agonist therapy: drugs used to treat prolactinomas
Drug
Oral dose
Advantages
Disadvantages
Bromocriptine
2.5-15 mg/day
2-3 times daily
Available for parenteral use
Short half-life; useful in treating infertility
Proven long-term efficacy
Ergotamine-like side-effects (nausea, headache,
postural hypotension, constipation)
Frequent dosing so poor adherence
Rare reports of fibrotic reactions in various tissues
Cabergoline
250-1 000 jig/week
2 doses/week
Long-acting, so missed doses less important
Reported to have fewer ergotamine-like
side-effects
Limited data on safety in pregnancy
Associated with cardiac valvular fibrosis in
Parkinson’s disease
Quinagolide
50-1 50 pig/day
Once daily
A non-ergot with few side-effects in patients
intolerant of the above
Limited data on safety in pregnancy
*Tolerance develops for the side-effects. All of these agents, especially bromocriptine, must be introduced at low dose and increased slowly. If several doses of
bromocriptine are missed, the process must start again.
686 • ENDOCRINOLOGY
Skull growth -prominent
supraorbital ridges with
large frontal sinuses
Prognathism
(growth of lower jaw)
Increased sweating
Thickened skin
IGT (25%)/type 2
diabetes (10%)
Colonic cancer
(2-3 x t)
Enlargement of hands
Arthropathy
Carpal tunnel syndrome
Enlargement of feet
Increased heel pad thickness
Clinical features
If GH hypersecretion occurs before puberty, then the presentation
is with gigantism. More commonly, GH excess occurs in adult
life and presents with acromegaly. If hypersecretion starts in
adolescence and persists into adult life, then the two conditions
may be combined. The clinical features are shown in Figure 18.30.
The most common complaints are headache and sweating.
Additional features include those of any pituitary tumour (see
Fig. 18.28).
Investigations
The clinical diagnosis must be confirmed by measuring GH levels
during an oral glucose tolerance test and measuring serum IGF-1 .
In normal subjects, plasma GH suppresses to below 0.5 pg/L
(approximately 2 m IU/L). In acromegaly, GH does not suppress
and in about 30% of patients there is a paradoxical rise; IGF-1 is
also elevated. The rest of pituitary function should be investigated
as described in Box 18.53. Prolactin concentrations are elevated
in about 30% of patients due to co-secretion of prolactin from
the tumour. Additional tests in acromegaly may include screening
for colonic neoplasms with colonoscopy.
Management
The main aims are to improve symptoms and to normalise serum
GH and IGF-1 to reduce morbidity and mortality. Treatment is
summarised in Box 18.57.
Surgical
Trans-sphenoidal surgery is usually the first line of treatment
and may result in cure of GH excess, especially in patients
with microadenomas. More often, surgery serves to debulk the
tumour and further second-line therapy is required, according
to post-operative imaging and glucose tolerance test results.
Radiotherapy
External radiotherapy is usually employed as second-line treatment
if acromegaly persists after surgery, to stop tumour growth and
lower GH levels. However, GH levels fall slowly (over many years)
and there is a risk of hypopituitarism.
Medical
If acromegaly persists after surgery, medical therapy is usually
employed to lower GH levels to below 1 .0 pg/L (approximately
3mlU/L) and to normalise IGF-1 concentrations. Medical
therapy may be discontinued after several years in patients
who have received radiotherapy. Somatostatin analogues (such
as octreotide, lanreotide or pasireotide) can be administered as
slow-release injections every few weeks. Somatostatin analogues
can also be used as primary therapy for acromegaly either as
an alternative or in advance of surgery, given evidence that
they can induce modest tumour shrinkage in some patients.
Dopamine agonists are less effective at lowering GH but may
sometimes be helpful, especially with associated prolactin excess.
The hypothalamus and the pituitary gland • 687
Pegvisomant is a peptide GH receptor antagonist administered
by daily self-injection and may be indicated in some patients
whose GH and IGF-1 concentrations fail to suppress sufficiently
following somatostatin analogue therapy.
Craniopharyngioma
Craniopharyngiomas are benign tumours that develop in cell rests
of Rathke’s pouch, and may be located within the sella turcica, or
commonly in the suprasellar space. They are often cystic, with a
solid component that may or may not be calcified (Fig. 18.31). In
young people, they are diagnosed more commonly than pituitary
adenomas. They may present with pressure effects on adjacent
structures, hypopituitarism and/or cranial diabetes insipidus. Other
clinical features directly related to hypothalamic damage may
also occur. These include hyperphagia and obesity, loss of the
sensation of thirst and disturbance of temperature regulation, and
these features can be significant clinical challenges to manage.
Craniopharyngiomas can be treated by the trans-sphenoidal
route but surgery may also involve a craniotomy, with a relatively
high risk of hypothalamic damage and other complications. If the
Fig. 18.31 Craniopharyngioma. [A] This developmental tumour
characteristically presents in younger patients; it is often cystic and
calcified, as shown in this MRI scan (arrows). Jj] Pathology specimen.
tumour has a large cystic component, it may be safer to place
in the cyst cavity a drain that is attached to a subcutaneous
access device, rather than attempt a resection. Whatever form
it takes, surgery is unlikely to be curative and radiotherapy may
often be given to reduce the risk of relapse. Unfortunately,
craniopharyngiomas often recur, requiring repeated surgery. They
often cause considerable morbidity, usually from hypothalamic
obesity, water balance problems and/or visual failure.
Diabetes insipidus
This uncommon disorder is characterised by the persistent
excretion of excessive quantities of dilute urine and by thirst. It
is classified into two types:
• cranial diabetes insipidus, in which there is deficient
production of vasopressin by the hypothalamus
• nephrogenic diabetes insipidus, in which the renal tubules
are unresponsive to vasopressin.
The underlying causes are listed in Box 18.60.
Clinical features
The most marked symptoms are polyuria and polydipsia. The
patient may pass 5-20 L or more of urine in 24 hours. This is
of low specific gravity and osmolality. If the patient has an intact
thirst mechanism, is conscious and has access to oral fluids, then
he or she can maintain adequate fluid intake. However, in an
unconscious patient or a patient with damage to the hypothalamic
thirst centre, diabetes insipidus is potentially lethal. If there is
associated cortisol deficiency, then diabetes insipidus may not
be manifest until glucocorticoid replacement therapy is given.
The most common differential diagnosis is primary polydipsia,
caused by drinking excessive amounts of fluid in the absence
of a defect in vasopressin or thirst control.
18.60 Causes of diabetes insipidus
Cranial
Structural hypothalamic or high stalk lesion
• See Box 18.54
Idiopathic
Genetic defect
• Dominant (Al/Pgene mutation)
• Recessive (DIDMOAD syndrome - association of diabetes insipidus
with diabetes mellitus, optic atrophy, deafness)
Nephrogenic
Genetic defect
• V2 receptor mutation
• Aquaporin-2 mutation
• Cystinosis
Metabolic abnormality
• Hypokalaemia
• Hypercalcaemia
Drug therapy
• Lithium
• Demeclocycline
Poisoning
• Heavy metals
Chronic kidney disease
• Polycystic kidney disease
• Sickle-cell anaemia
• Infiltrative disease
688 • ENDOCRINOLOGY
18.61 How and when to do a water deprivation test
Use
• To establish a diagnosis of diabetes insipidus and to differentiate
cranial from nephrogenic causes
Protocol
• No coffee, tea or smoking on the test day
• Free fluids until 0730 hrs on the morning of the test, but
discourage patients from ‘stocking up’ with extra fluid in anticipation
of fluid deprivation
• No fluids from 0730 hrs
• Attend at 0830 hrs for measurement of body weight and plasma
and urine osmolality
• Record body weight, urine volume, urine and plasma osmolality and
thirst score on a visual analogue scale every 2 hrs for up to 8 hrs
• Stop the test if the patient loses 3% of body weight
• If plasma osmolality reaches >300 mOsmol/kg and urine osmolality
<600 mOsmol/kg, then administer DDAVP (see text) 2 pg IM
Interpretation
• Diabetes insipidus is confirmed by a plasma osmolality
>300 mOsmol/kg with a urine osmolality <600 mOsmol/kg
• Cranial diabetes insipidus is confirmed if urine osmolality rises by at
least 50% after DDAVP
• Nephrogenic diabetes insipidus is confirmed if DDAVP does not
concentrate the urine
• Primary polydipsia is suggested by low plasma osmolality at the
start of the test
Investigations
Diabetes insipidus can be confirmed if serum vasopressin is
undetectable (although the assay for this is not widely available) or
the urine is not maximally concentrated (i.e. <600 mmol/kg) in the
presence of increased plasma osmolality (i.e. >300 mOsmol/kg).
Sometimes, the diagnosis can be confirmed or refuted by random
simultaneous samples of blood and urine, but more often a
dynamic test is required. The water deprivation test described in
Box 1 8.61 is widely used, but an alternative is to infuse hypertonic
(5%) saline and measure vasopressin secretion in response to
increasing plasma osmolality. Thirst can also be assessed during
these tests on a visual analogue scale. Anterior pituitary function
and suprasellar anatomy should be assessed in patients with
cranial diabetes insipidus (see Box 18.53).
In primary polydipsia, the urine may be excessively dilute
because of chronic diuresis, which ‘washes out’ the solute
gradient across the loop of Henle, but plasma osmolality is low
rather than high. DDAVP (see below) should not be administered
to patients with primary polydipsia, since it will prevent excretion
of water and there is a risk of severe water intoxication if the
patient continues to drink fluid to excess.
In nephrogenic diabetes insipidus, appropriate further tests
may include plasma electrolytes, calcium, ultrasound of the
kidneys and urinalysis.
Management
Treatment of cranial diabetes insipidus is with des-amino-des-
aspartate-arginine vasopressin (desmopressin, DDAVP), an
analogue of vasopressin that has a longer half-life. For chronic
replacement therapy DDAVP may be administered intranasally and
orally, although the latter formulation has variable bioavailability.
In sick patients, DDAVP should be given by intramuscular
injection. The dose of DDAVP should be adjusted on the basis
if
• Late presentation: often with large tumours causing visual
disturbance, because early symptoms such as amenorrhoea and
sexual dysfunction do not occur or are not recognised.
• Coincidentally discovered pituitary tumours: may not require
surgical intervention if the visual apparatus is not involved, because
of slow growth.
• Hyperprolactinaemia: less impact in post-menopausal women who
are already ‘physiologically’ hypogonadal. Macroprolactinomas,
however, require treatment because of their potential to cause mass
effects.
of serum sodium concentrations and/or osmolality. The principal
hazard is excessive treatment, resulting in water intoxication
and hyponatraemia. Conversely, inadequate treatment results in
thirst and polyuria. The ideal dose prevents nocturia but allows a
degree of polyuria from time to time before the next dose (e.g.
DDAVP nasal dose 5 pg in the morning and 1 0 jug at night).
The polyuria in nephrogenic diabetes insipidus is improved
by thiazide diuretics (e.g. bendroflumethiazide 5-10 mg/day),
amiloride (5-10 mg/day) and NSAIDs (e.g. indometacin 15 mg 3
times daily), although the last of these carries a risk of reducing
glomerular filtration rate.
Disorders affecting multiple
endocrine glands
Multiple endocrine neoplasia
Multiple endocrine neoplasias (MEN) are rare autosomal dominant
syndromes characterised by hyperplasia and formation of
adenomas or malignant tumours in multiple glands. They fall into
four groups, as shown in Box 1 8.63. Some other genetic diseases
also have an increased risk of endocrine tumours; for example,
phaeochromocytoma is associated with von Hippel-Lindau
syndrome (p. 1132) and neurofibromatosis type 1 (p. 1131).
The MEN syndromes should be considered in all patients with
two or more endocrine tumours and in patients with solitary
tumours who report other endocrine tumours in their family.
Inactivating mutations in MEN 1 (MENIN), a tumour suppressor
gene on chromosome 1 1 , cause MEN 1 , whereas MEN 2 and
3 (also known as MEN 2a and 2b, respectively) are caused
by gain-of-function mutations in the RET proto-oncogene on
chromosome 10. These cause constitutive activation of the
membrane-associated tyrosine kinase RET, which controls
the development of cells that migrate from the neural crest. In
contrast, loss-of-function mutations of the RET kinase cause
Hirschsprung’s disease (p. 834). MEN 4 is extremely rare and
is associated with loss-of-function mutations in the CDNK1B
gene on chromosome 12; this gene codes for the protein p27,
which has putative tumour suppressor activity. Predictive genetic
testing can be performed on relatives of individuals with MEN
syndromes, after appropriate counselling (p. 59).
Individuals who carry mutations associated with MEN should
be entered into a surveillance programme. In MEN 1 , this typically
involves annual history, examination and measurements of serum
calcium and prolactin, and MRI of the pituitary and pancreas every
2 years; some centres also perform regular CT or MRI scans
18.62 The pituitary and hypothalamus in old age
Further information • 689
18.63 Multiple endocrine neoplasia (MEN) syndromes
MEN 1 (Wermer’s syndrome)
• Primary hyperparathyroidism
• Pituitary tumours
• Pancreatic neuro-endocrine tumours (e.g. non-functioning,
insulinoma, gastrinoma)
• Bronchial and thymic carcinoids
• Adrenal tumours
• Cutaneous lesions (e.g. lipomas, collagenomas, angiofibromas)
MEN 2 (also known as MEN 2a or Sipple’s syndrome)
• Primary hyperparathyroidism
• Medullary carcinoma of thyroid
• Phaeochromocytoma
MEN 3 (also known as MEN 2b)
• As for MEN 2 above (though medullary thyroid cancer occurs
earlier, even within the first year of life)
• Marfanoid habitus
• Skeletal abnormalities (e.g. craniosynostosis)
• Abnormal dental enamel
• Multiple mucosal neuromas
MEN 4
• Primary hyperparathyroidism
• Pituitary tumours
• Possible tumours in the adrenals, reproductive organs, kidneys
• Possible pancreatic, gastric, bronchial and cervical neuro-endocrine
tumours
of the chest. In individuals with MEN 2 and 3, annual history,
examination and measurement of serum calcium, calcitonin and
urinary or plasma catecholamine metabolites should be performed.
Because the penetrance of medullary carcinoma of the thyroid
approaches 100% in individuals with a RET mutation, prophylactic
thyroidectomy should be performed in early childhood in most
patients. The precise timing of surgery in childhood should be
guided by the specific mutation in the RET gene.
Autoimmune polyendocrine syndromes
Two distinct autoimmune polyendocrine syndromes are known:
APS types 1 and 2.
The most common is APS type 2 (Schmidt’s syndrome), which
typically presents in women between the ages of 20 and 60. It
is usually defined as the occurrence in the same individual of
two or more autoimmune endocrine disorders, some of which
are listed in Box 18.64. The mode of inheritance is autosomal
dominant with incomplete penetrance and there is a strong
association with HLA-DR3 and CTL4-4.
Much less common is APS type 1 , which is also termed
autoimmune poly-endocrinopathy-candidiasis-ectodermal
18.64 Autoimmune polyendocrine syndromes (APS)*
Type 1 (APECED)
• Addison’s disease
• Chronic mucocutaneous
• Hypoparathyroidism
candidiasis
• Type 1 diabetes
• Nail dystrophy
• Primary hypothyroidism
• Dental enamel hypoplasia
Type 2 (Schmidt’s syndrome)
• Addison’s disease
• Type 1 diabetes
• Primary hypothyroidism
• Vitiligo
• Graves’ disease
• Coeliac disease
• Pernicious anaemia
• Myasthenia gravis
• Primary hypogonadism
In both types of APS, the precise pattern of disease varies between affected
individuals.
(APECED = autoimmune poly-endocrinopathy-candidiasis-ectodermal dystrophy)
dystrophy (APECED). This is inherited in an autosomal recessive
fashion and is caused by loss-of-function mutations in the
autoimmune regulator gene AIRE, which is responsible for the
presentation of self-antigens to thymocytes in utero. This is
essential for the deletion of thymocyte clones that react against
self-antigens and hence for the development of immune tolerance
(p. 82). The most common clinical features are described in Box
1 8.64, although the pattern of presentation is variable and other
autoimmune disorders are often observed.
Late effects of childhood cancer therapy
The therapies used to treat cancers in children and adolescents,
including radiotherapy and chemotherapy, may cause long-term
endocrine dysfunction (p. 1298).
Further information
Websites
british-thyroid-association.org British Thyroid Association: provider of
guidelines, e.g. treatment of hypothyroidism and the investigation
and management of thyroid cancer.
btf-thyroid.org British Thyroid Foundation: a resource for patient
leaflets and support for patients with thyroid disorders.
endocrinology.org British Society for Endocrinology: useful online
education resources and links to patient support group.
endo-society.org American Endocrine Society: provider of clinical
practice guidelines.
pituitary.org.uk Pituitary Foundation: a resource for patient and general
practitioner leaflets and further information.
thyroid.org American Thyroid Association: provider of clinical practice
guidelines.
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AG Shand
JPH Wilding
Nutritional factors in disease
Clinical examination in nutritional disorders 692
Clinical assessment and investigation of nutritional status 693
Nutritional factors and disease 694
Physiology of nutrition 694
Disorders of altered energy balance 698
Obesity 698
Under-nutrition 704
Micronutrients, minerals and their diseases 711
Vitamins 71 1
Inorganic micronutrients 71 6
692 • NUTRITIONAL FACTORS IN DISEASE
Clinical examination in nutritional disorders
3 Hands
Muscle wasting (dorsal interossei,
thenar eminences)
Finger clubbing
Leukonychia (low albumin)
Koilonychia (iron deficiency)
A Koilonychia
2 Simple anthropometries
(see right)
Body mass index
Triceps skin fold thickness
Waist circumference
1 Observation
Signs of weight loss:
Prominent ribs
Muscle wasting
iSkin turgor
A Scaphoid abdomen
A Clinical effects of short bowel
syndrome after multiple
resection in Crohn’s disease
4 Eyes
Sunken eyes
Pallor
Jaundice
Bitot spots (ivitamin A;
see Fig. 19.12)
5 Affect
Fatigue
Depression
Dementia
6 Mouth
Pallor
Angular stomatitis folate,
iron)
Glossitis (vLBi2, folate, iron)
Gingivitis, bleeding gums
(^vitamin C; see Fig. 19.14)
Poorly fitting dentures
A Gingivitis
7 Skin
Dry, flaky skin or dermatitis (see
Fig. 19.13)
Flair loss
Specific abnormalities:
Petechiae, corkscrew hairs
(ivitamin C)
Dermatitis of pellegra (iniacin)
A Corkscrew hairs
8 Legs
Pitting oedema
Ulcers
Insets (Scaphoid abdomen) From Chandra A, Quinones-Baldrich WJ. Chronic mesenteric ischemia: How to select patients for invasive treatment. Sem Vase
Surg 2010; 23:21-28; (Koilonychia) Habif TP. Clinical Dermatology, 6th edn. Philadelphia: Saunders, Elsevier Inc.; 2016; (Gingivitis) Newman MG, Takei H,
Klokkevold PR, etal. Carranza’s Clinical Periodontology, 12th edn. Philadelphia: Saunders, Elsevier Inc.; 2015; (Corkscrew hairs) Bolognia JL, Jorizzo JL,
Schaffer JV, etal. Dermatology, 3rd edn. Philadelphia: Saunders, Elsevier Inc.; 2012.
Clinical assessment and investigation of nutritional status • 693
Clinical assessment and investigation of nutritional status
Under-nutrition can go unnoticed in
patients with multiple comorbidities. It is
vital to be aware of under-nutrition as a
potential reason for any acute medical
presentation or as a modifier of it. Early
nutritional assessment is crucial and a
dietary history provides useful information
(especially when taken by a dietitian). Points
to note include past medical and surgical
history (e.g. abdominal or intestinal surgery),
Important elements of the
diet history
Ask about weight
• Current weight
• Weight 2 weeks, 1 month and 6 months
ago
• Assessment of degree of change
Ask about current food intake
• Quantity of food and if any change
• Quality of food taken
• Whether normal food is being eaten
• Avoidance of specific food types (e.g.
solids)
• Any nutritional supplements
• Reliance on supplements/tube feeding
• Any change in appetite or interest in
food
• Any taste disturbance
Ask about symptoms that interfere
with eating
• Oral ulcers or oral pain
• Difficulties swallowing
• Nausea/vomiting
• Early satiety
• Alteration in bowel habit
• Abdominal (or other) pain
Ask about activity levels/performance
status
• Normal activity
• Slightly reduced activity
• Inactive <50% of the time
• Inactive most of the time
a drug history and a specific diet history.
Evidence of recent weight loss and muscle
wasting should be sought. Simple, validated
tools are available to screen patients for
nutritional problems. Body composition
reflects energy balance and is assessed
by clinical anthropomorphic measurements.
More sophisticated techniques may be used
to assess body composition or functional
capacity if required.
2 Body mass index (BMI)
Example: an adult of 70 kg with a height of
1 .75 m has a BMI of 70/1 ,752=22.9 kg/m2
• BMI is a useful way of identifying under- or
over-nutrition but cannot discriminate
between lean body or muscle mass and fat
mass
• Fat mass is also subject to ethnic variation;
for the same BMI, Asians tend to have
more body fat than Europeans
• If height cannot be determined (e.g. in older
people or those unable to stand),
measurement of the femoral length or ‘knee
height’ is a good surrogate
Measurement of knee height.
2 Measures of body composition
and nutritional status
Body composition
• Anthropometry (see below)
• Bioelectrical impedance
• Dual X-ray absorptiometry (DXA)
Muscle function and global
nutritional status
• Hand grip strength (dynamometer test)
- poor grip associated with increased
mortality
Obesity and fat distribution (android
vs gynoid)
• Waist:hip ratio (circumferences measured
midway between superior iliac crest and
lower border of rib cage, and at greater
trochanters, respectively)
Body fat content and muscle mass
• Triceps skinfold thickness (when combined
with mid-/upper arm circumference
estimates muscle mass)
Triceps skinfold thickness. Lean patients
6-12 mm; obese patients 40-50 mm.
Screening hospitalised patients for risk of malnutrition. Acute illnesses include decompensated liver disease, cancer cachexia or being kept ‘nil by
mouth’. Adapted from the British Association of Parenteral and Enteral Nutrition Malnutrition Universal Screening Tool (www.bapen.org.uk).
694 • NUTRITIONAL FACTORS IN DISEASE
Nutritional factors and disease
Obtaining adequate nutrition is a fundamental requirement for
the survival of every individual and species. The politics of food
provision for humans are complex and constitute a prominent
factor in wars, natural disasters and the global economy. In recent
decades, economic success has been rewarded by plentiful
nutrition unknown to previous generations, which has led to
a pandemic of obesity and its consequences for health, yet in
many parts of the world, famine and under-nutrition still represent
a huge burden. Quality, as well as quantity, of food influences
health, with governmental advice on healthy diets maximising
fruit and vegetable intakes (Fig. 19.1). Inappropriate diets have
been linked to diseases such as coronary heart disease and
cancer. Deficiencies of vitamins or minerals lead to avoidable
conditions, such as anaemia due to iron deficiency or blindness
due to severe vitamin A deficiency. A proper understanding
of nutrition is therefore essential in dealing with the needs of
individual patients and in informing the planning of public policy.
Physiology of nutrition
Nutrients in the diet can be classified into ‘macronutrients’, which
are eaten in relatively large amounts to provide fuel for energy,
and ‘micronutrients’ (e.g. vitamins and minerals), which do not
contribute to energy balance but are required in small amounts
because they are not synthesised in the body.
Energy balance
The laws of thermodynamics dictate that energy balance is
achieved when energy intake = energy expenditure (Fig. 19.2).
Energy expenditure has several components. The basal metabolic
rate (BMR) describes the obligatory energy expenditure required
to maintain metabolic functions in tissues and hence sustain
life. It is most closely predicted by fat-free mass (i.e. total body
mass minus fat mass), which is lower in females and older
people (Fig. 19.2B). Extra metabolic energy is consumed during
growth, pregnancy and lactation, and when febrile. Metabolic
Bread, rice,
Fig. 19.1 Proportion of key food groups recommended for a healthy,
well-balanced diet. Crown copyright. Department of Health in association
with the Welsh Government, the Scottish Government and the Food
Standards Agency in Northern Ireland.
energy is also required for thermal regulation, and expenditure
is higher in cold or hot environments. The energy required for
digestion of food (diet-induced thermogenesis; Fig. 19. 2D)
accounts for approximately 10% of total energy expenditure,
with protein requiring more energy than other macronutrients.
Another component of energy expenditure is governed by the
level of muscular activity, which can vary considerably with
occupation and lifestyle (Fig. 19.2C). Physical activity levels are
usually defined as multiples of BMR.
Energy intake is determined by the ‘macronutrient’ content
of food. Carbohydrates, fat, protein and alcohol provide fuel for
oxidation in the mitochondria to generate energy (as adenosine
triphosphate (ATP); p. 49). The energy provided by each of
these elements differs:
• carbohydrates (1 6 kJ/g)
• fat (37 kJ/g)
• protein (17 kJ/g)
• alcohol (29 kJ/g).
Regulation of energy balance
Energy intake and expenditure are highly regulated (Fig. 19.3). A
link with reproductive function ensures that pregnancy is most
likely to occur during times of nutritional plenty, when both mother
and baby have a better chance of survival. Improved nutrition is
thought to be the reason for the increasingly early onset of puberty
in many societies. At the other extreme, anorexia nervosa and
excessive exercise can lead to amenorrhoea (p. 654).
Regulation of energy balance is coordinated in the hypothal¬
amus, which receives afferent signals that indicate nutritional
status in the short term (e.g. the stomach hormone ghrelin,
which falls immediately after eating and rises gradually thereafter,
to suppress satiety and signal that it is time for the next meal)
and the long term (e.g. the adipose hormone leptin, which
increases with growing fat mass and may also link fat mass to
reproductive function). The hypothalamus responds with changes
in many local neurotransmitters that alter activity in a number
of pathways that influence energy balance (Fig. 19.3), including
hormones acting on the pituitary gland (see Fig. 18.2, p. 633),
and neural control circuits that connect with the cerebral cortex
and autonomic nervous system.
Responses to under- and over-nutrition
These complex regulatory pathways allow adaptation to
variations in nutrition. In response to starvation, reproductive
function is suppressed, BMR is reduced, and there are profound
psychological effects, including energy conservation through
lethargy. These adjustments can ‘defend’ body weight within
certain limits. In the low-insulin state of starvation (see Fig. 20.5,
p. 725), however, fuels are liberated from stores initially in glycogen
(in liver and muscle), then in triglyceride (lipolysis in adipose tissue,
with excess free fatty acid supply to the liver leading to ketosis)
and finally in protein (proteolysis in muscle). In those with a high
glucose requirement, such as neonates and women who are
pregnant or breastfeeding, starvation can result in ketoacidosis
associated with normal or low blood glucose (p. 365).
In response to over-nutrition, BMR is increased, and extra
energy is consumed in the work of carrying increased fat stores,
so that body weight is again ‘defended’ within certain limits. In
the high-insulin state of over-nutrition, excess energy is invested
in fatty acids and stored as triglycerides; these are deposited
principally in adipose tissue but they may also accumulate in
the liver (non-alcoholic fatty liver disease; p. 882) and skeletal
muscle. If hypothalamic function is abnormal (e.g. in those with
Nutritional factors and disease • 695
Energy expenditure
Vi
1 megajoule (MJ)
= 239 kilocalorie (kcal)
= energy stored in ~ 34 g fat
Fig. 19.2 Determinants of energy balance. [A] Energy intake is shown as national averages, highlighting the differences in sources of energy in
different countries (but obscuring substantial regional variations). The targets are recommendations as a percentage of food energy only (Source: Dept of
Health 1991). For WHO targets, see Box 19.4. In the UK, it is assumed that 5% of energy intake will be derived from alcohol. [§] Data for normal basal
metabolic rate (BMR) were obtained from healthy men and women in various countries. BMR declines from middle age and is lower in women, even after
adjustment for body size because of differences in fat-free mass. [C] Energy is required for movement and activity. Physical activity level (PAL) is the
multiple of BMR by which total energy expenditure is increased by activity. [D] Energy is consumed in order to digest food. ^Leisure or sport activity
increases PAL by ~0.3 for each 30-60 minutes of moderate exercise performed 4-5 times per week. The UK population median for PAL is 1 .6, with
estimates of 1 .5 for the ‘less active’ and 1 .8 for the ‘more active’.
craniopharyngioma; see Fig. 18.31, p. 687) or in rare patients
with mutations in relevant genes (e.g. in leptin or melanocortin-4
receptors), loss of response to satiety signals, together with loss
of adaptive changes in energy expenditure, result in relentless
weight gain.
| Macronutrients (energy-yielding nutrients)
Carbohydrates
Types of carbohydrate and their dietary sources are listed in
Box 19.1. The ‘available’ carbohydrates (starches and sugars)
are broken down to monosaccharides before absorption from
the gut (p. 768), and supply over half the energy in a normal,
well-balanced diet (see Fig. 19.2A). No individual carbohydrate
is an essential nutrient, as carbohydrates can be synthesised
de novo from glycerol or protein. If the available carbohydrate
intake is less than 1 00 g per day, however, increased lipolysis
leads to ketosis (see Fig. 20.7, p. 730).
Dietary guidelines do not restrict the intake of intrinsic sugars
in fruit and vegetables or the sugars in milk. However, intake
of non-milk extrinsic sugars (sucrose, maltose, fructose), which
increase the risk of dental caries and diabetes mellitus, should
696 • NUTRITIONAL FACTORS IN DISEASE
Stomach
Pancreas-
Small bowel
Habit
Hedonic
response
to food
e. Insulin Ghrelin Leptin
ide vi /
Nil/
Hypothalamus
Satiety
nr
Neuro-endocrine responses
(growth hormone, cortisol, thyroxine)
Autonomic nervous system
I
Energy expenditure/storage
Adipose tissue
Reproductive
hormones
Muscle Adipose tissue
Fig. 19.3 Regulation of energy balance and its link with reproduction. © indicates factors that are stimulated by eating and induce satiety.
© indicates factors that are suppressed by eating and inhibit satiety.
19.1 Dietary carbohydrates
Class
Components
Examples
Source
Free sugars
Monosaccharides
Disaccharides
Glucose, fructose
Sucrose, lactose, maltose
Intrinsic: fruits, milks, vegetables
Extrinsic (extracted, refined): beet or cane sucrose,
high-fructose corn syrup
Short-chain carbohydrates
Oligosaccharides
Maltodextrins, fructo-oligosaccharides
Starch polysaccharides
Rapidly digestible
Slowly digestible
Resistant
Cereals (wheat, rice), root vegetables (potato),
legumes (lentils, beans, peas)
Non-starch polysaccharides
(NSPs; dietary fibre)
Fibrous
Viscous
Cellulose
Hemicellulose
Pectins
Gums
Plants
Sugar alcohols
Sorbitol, xylitol
Sorbitol: stone fruits (apples, peaches, prunes)
Xylitol: maize, berry fruits
Both used as low-calorie sugar alternatives
be limited. Individuals who do not produce lactase (‘lactose-
intolerant’) are advised to avoid or limit dairy products and foods
with added lactose. Starches in cereal foods, root foods and
legumes provide the largest proportion of energy in most diets
around the world. All starches are polymers of glucose, linked by
the same 1-4 glycosidic linkages. Some starches are digested
promptly by salivary and then pancreatic amylase, however,
producing rapid delivery of glucose to the blood. Other starches
are digested more slowly, either because they are protected in
the structure of the food, or because of their crystal structure, or
because the molecule is unbranched (amylose). These differences
are the basis for the ‘glycaemic index’ of foods. This is the area
under the curve of the rise in blood glucose concentration in the
2 hours following ingestion of 50 g carbohydrate, expressed as
a percentage of the response to 50 g anhydrous glucose. There
is evidence linking high glycaemic index foods, particularly foods
containing large amounts of sugars such as glucose, sucrose
or fructose (e.g. in soft drinks) with obesity and type 2 diabetes
Nutritional factors and disease • 697
(p. 932). Sugar alcohols (e.g. sorbitol) that are not absorbed
form the gut and are used as replacement sweeteners can
cause diarrhoea if eaten in large amounts.
Dietary fibre
Dietary fibre is plant food that is not digested by human enzymes
in the gastrointestinal tract. Most dietary fibre is known as
‘non-starch polysaccharides’ (NSPs) (see Box 19.1). A small
percentage of ‘resistant’ dietary starch may also pass unchanged
into the large intestine. Dietary fibre can be broken down by
the resident bacteria in the colon to produce short-chain fatty
acids. This is essential fuel for the enterocytes and contributes
to bowel health. The extent of flatus formed is dependent on
the food source.
Some types of NSP, notably the hemicellulose of wheat,
increase the water-holding capacity of colonic contents and
the bulk of faeces. They relieve simple constipation, appear to
prevent diverticulosis and may reduce the risk of cancer of the
colon. Other viscous, indigestible polysaccharides like pectin and
guar gum are important in the upper gastrointestinal tract, where
they slow gastric emptying, contribute to satiety, and reduce
bile salt absorption and hence plasma cholesterol concentration.
Fats
Fat has the highest energy density of the macronutrients (37 kJ/g)
and excessive consumption may be an insidious cause of obesity
(see Fig. 19.2A). Free fatty acids are absorbed in chylomicrons
(pp. 371 and 372; see Fig. 21.5, p. 768), allowing access of
complex molecules into the circulation. Fatty acid structures
are shown in Figure 19.4. The principal polyunsaturated fatty
acid (PUFA) in plant seed oils is linoleic acid (18:2 oo6). This
and a-linolenic acid (18:3 co3) are the ‘essential’ fatty acids,
which humans cannot synthesise de novo. They undergo further
desaturation and elongation, to produce, for example, y-linolenic
acid (18:3 co6) and arachidonic acid (20:4 co6). These are
precursors of prostaglandins and eicosanoids, and form part of
the structure of lipid membranes in all cells. Fish oils are rich in
co3 PUFA (e.g. eicosapentaenoic (20:5 co3) and docosahexaenoic
(22 : 6 co3), which promote the anti-inflammatory cascade of
prostaglandin production and occur in the lipids of the human
brain and retina. They inhibit thrombosis by competitively
antagonising thromboxane A2 formation. Replacing saturated
1
CH3-
14
COOH
Saturated fatty acid, e.g. myristic acid (14:0 )
□ CH2
■ CH
18
Monounsaturated fatty acid, e.g. oleic acid (18:1 co9)
CH3-
COOH
Polyunsaturated fatty acid, e.g. linoleic acid (18:2 co6)
Fig. 19.4 Schematic representation of fatty acids. Standard
nomenclature specifies the number of carbon atoms and indicates the
number and position of the double bond(s) relative to the methyl (— CH3, co)
end of the molecule after a colon.
fat (i.e. from animal sources: butter, ghee or lard) with PUFA in
the diet can lower the concentration of circulating low-density
lipoprotein (LDL) cholesterol and may help prevent coronary
heart disease. High intakes of trans fatty acids (TFAs; isomers of
the natural cis fatty acids) reflect the use of oils that have been
partially hydrogenated in the food industry. It is recommended
that TFAs are limited to less than 2% of the dietary fat intake,
as they are associated with cardiovascular disease. Changes in
industrial practice in the UK and US have meant that TFA intake
is now below 1%, with the residual amounts coming from milk
as a result of ruminant digestion.
Cholesterol is also absorbed directly from food in chylomicrons
and is an important substrate for steroid and sterol synthesis,
but not an important source of energy.
Proteins
Proteins are made up of some 20 different amino acids, of which
nine are ‘essential’ (Box 19.2), i.e. they cannot be synthesised
in humans but are required for synthesis of important proteins.
Another group of five amino acids are termed ‘conditionally
essential’, meaning that they can be synthesised from other amino
acids, provided there is an adequate dietary supply. The remaining
amino acids can be synthesised in the body by transamination,
provided there is a sufficient supply of amino groups.
The nutritive or ‘biological’ value of different proteins depends
on the relative proportions of essential amino acids they contain.
Proteins of animal origin, particularly from eggs, milk and meat,
are generally of higher biological value than proteins of vegetable
origin, which are low in one or more of the essential amino acids.
When two different vegetable proteins are eaten together (e.g.
a cereal and a legume), however, their amino acid contents are
complementary and produce an adequate mix, an important
principle in vegan diets.
Dietary recommendations for macronutrients
Recommendations for energy intake (Box 19.3) and proportions
of macronutrients (Box 19.4) have been calculated to provide a
balance of essential nutrients and minimise the risks of excessive
refined sugar (dental caries, high glycaemic index/diabetes
mellitus), saturated fat or trans fat (obesity, coronary heart disease).
Recommended dietary fibre intake is based on avoiding risks
of colonic disease. The usual recommended protein intake for
a healthy man doing light work is 65-1 00 g/day. The minimum
requirement is around 40 g of protein with a high proportion of
essential amino acids or a high biological value.
1 19.2 Amino acids
Essential amino acids
• Tryptophan
• Valine
• Histidine
• Phenylalanine
• Methionine
• Lysine
• Threonine
• Leucine
• Isoleucine
Conditionally essential amino acids and their precursors
• Cysteine: methionine, serine
• Tyrosine: phenylalanine
• Arginine: glutamine/glutamate, aspartate
• Proline: glutamate
• Glycine: serine, choline
698 • NUTRITIONAL FACTORS IN DISEASE
I 19.3 Daily adult energy requirements in health
Daily requirements
Circumstances
Females
Males
At rest (basal
metabolic rate)
5.4 MJ (1300 kcal)
6.7 MJ (1600 kcal)
Less active
8.0 MJ (1900 kcal)
9.9 MJ (2400 kcal)
Population median
8.8 MJ (2100 kcal)
10.8 MJ (2600 kcal)
More active
9.6 MJ (2300 kcal)
11.8 MJ (2800 kcal)
*These are based on a healthy target body mass index (BMI) of 22.5 kg/m2. For
a female, height is 162 cm and weight 59.0 kg; for a male, height is 175 cm
and weight 68.8 kg. Previous average recommendations of 8.1 MJ (1950 kcal,
usually rounded up to 2000 kcal) for females and 10.7 MJ (2500 kcal) for males
should continue to be used, as these fall within experimental error.
19.4 WHO recommended population
macronutrient goals
Nutrient (% of total energy
unless indicated)
Target limits for average
population intakes
Lower
Upper
Total fat
15
30
Saturated fatty acids
0
10
Polyunsaturated fatty acids
6
10
Trans fatty acids
0
2
Dietary cholesterol (mg/day)
0
300
Total carbohydrate
55
75
Free sugars
0
10
Complex carbohydrate
50
70
Dietary fibre (g/day):
As non-starch polysaccharides
16
24
As total dietary fibre
27
40
Protein
10
15
Disorders of altered energy balance
Obesity
Obesity is regarded as a pandemic, with potentially disastrous
consequences for human health. Over 25% of adults in the UK
were obese (i.e. BMI > 30 kg/m2) in 2015, compared with 7%
in 1980 and 16% in 1995. Moreover, almost 66% of the UK
adult population are overweight (BMI > 25 kg/m2), although
there is considerable regional and age group variation. In
developing countries, average national rates of obesity are low,
but these figures may disguise high rates of obesity in urban
communities; for example, nearly 25% of women in urban India
are overweight.
There is increasing public awareness of the health implications
of obesity. Many will seek medical help for their obesity, others
will present with complications of obesity, and increasing numbers
are being identified during health screening examinations.
Complications
Obesity has adverse effects on both mortality and morbidity (Fig.
19.5). Changes in mortality are difficult to analyse due to the
confounding effects of lower body weight in cigarette smokers and
those with other illnesses (such as cancer). It is clear, however,
that the lowest mortality rates are seen in Europeans in the BMI
range 18.5-24 kg/m2 (and at lower BMI in Asians). It is suggested
that obesity at age 40 years can reduce life expectancy by up to
7 years for non-smokers and by 13 years for smokers. Coronary
heart disease (Fig. 19.6) is the major cause of death but cancer
rates are also increased in the overweight, especially colorectal
cancer in males and cancer of the gallbladder, biliary tract,
breast, endometrium and cervix in females. Obesity has little
effect on life expectancy above 70 years of age, but the obese
do spend a greater proportion of their active life disabled. The
Psychosocial
Eating disorders
Poor self-esteem
Body image disorder
Social isolation and stigmatisation
Depression
Pulmonary
Exercise intolerance
Obstructive sleep apnoea
Asthma
Gastrointestinal
Gallstones
Gastro-oesophageal reflux
Non-alcoholic fatty liver disease
Colon cancer
Renal
Glomerulosclerosis
Renal cancer
Musculoskeletal
Ankle sprains
Flat feet
Tibia vara
Osteoarthritis
Back pain
Neurological
Pseudotumour cerebri
(idiopathic intracranial
hypertension)
Cardiovascular
Hypertension
Dyslipidaemia
Coagulopathy
Chronic inflammation
Endothelial dysfunction
Endocrine
Insulin resistance
Impaired fasting glucose
or glucose intolerance
Type 2 diabetes
Precocious puberty
Menstrual irregularities
Polycystic ovary
syndrome (females)
Hormone-related cancers
(breast, endometrium, prostate)
Fig. 19.5 Complications of obesity.
Disorders of altered energy balance • 699
4
3
2
1
0
10
9
8
7
6
5
4
3
2
1
0
<25 25-30 >30
Normal weight Overweight Obese
Body mass index (kg/m2)
Fig. 19.6 Risks of diabetes and cardiovascular disease in
overweight and obese women. Data are from the Nurses’ Health Study
in the USA, and mostly relate to Caucasian women. In some ethnic groups
(e.g. South Asians, Native Americans) and in people with higher waist
circumference, the metabolic complications are even more severe at a
given level of body mass index.
<21 21-22.9 23-24.9 25-28.9 >29
rise in obesity has been accompanied by an epidemic of type
2 diabetes (p. 732) and osteoarthritis, particularly of the knee.
Although an increased body size results in greater bone density
through increased mechanical stress, it is not certain whether this
translates to a lower incidence of osteoporotic fractures (p. 1 044).
Obesity may have profound psychological consequences,
compounded by stigmatisation of the obese in many societies.
Body fat distribution
For some complications of obesity, the distribution rather than
the absolute amount of excess adipose tissue appears to
be important. Increased intra-abdominal fat causes ‘central’
(‘abdominal’, ‘visceral’, ‘android’ or ‘apple-shaped’) obesity,
which contrasts with subcutaneous fat accumulation causing
‘generalised’ (‘gynoid’ or ‘pear-shaped’) obesity; the former is
more common in men and is more closely associated with type
2 diabetes, the metabolic syndrome and cardiovascular disease
(see Fig. 19.5). The key difference between these depots of
fat may lie in their vascular anatomy, with intra-abdominal fat
draining into the portal vein and thence directly to the liver. Thus
many factors that are released from adipose tissue (including
free fatty acids; ‘adipokines’, such as tumour necrosis factor
alpha, adiponectin and resistin) may be at higher concentration
KM 19.5 Some reasons for the increasing prevalence of
obesity - the ‘obesogenic’ environment
Increasing energy intake
• T Portion sizes
• T Energy-dense food (fat and
• T Snacking and loss of
sugars)
regular meals
• T Affluence
Decreasing energy expenditure
• T Car ownership
• i Sports in schools
• i Walking to school/work
• T Time spent on computer
• T Automation; i manual
games and watching TV
labour
• T Central heating
in the liver and muscle, and hence induce insulin resistance and
promote type 2 diabetes. Recent research has also highlighted the
importance of fat deposition within specific organs, especially the
liver, as an important determinant of metabolic risk in the obese.
Aetiology
Accumulation of fat results from a discrepancy between
energy consumption and energy expenditure that is too large
to be defended by the hypothalamic regulation of BMR. A
continuous small daily positive energy balance of only
0.2-0. 8 MJ (50-200 kcal; <10% of intake) would lead to weight
gain of 2-20 kg over a period of 4-1 0 years. Given the cumulative
effects of subtle energy excess, body fat content shows ‘tracking’
with age, such that obese children usually become obese adults.
Weight tends to increase throughout adult life, as BMR and
physical activity decrease (see Fig. 19.2).
The pandemic of obesity reflects changes in both energy
intake and expenditure (Box 19.5), although both are difficult to
measure reliably. The estimated average global daily supply of
food energy per person increased from approximately 9.8 MJ
(2350 kcal) in the 1960s to approximately 1 1 .7 MJ (2800 kcal)
in the 1990s, but its delivery is unequal. For example, in India
it is estimated that 5% of the population receives 40% of the
available food energy, leading to obesity in the urban population in
parallel with under-nutrition in some rural communities. In affluent
societies, a significant proportion of this food supply is discarded.
In the USA, men’s average daily energy intake reportedly rose
from 10.2 MJ (2450 kcal) in 1971 to 1 1 .0 MJ (2618 kcal) in
2000. Portion sizes, particularly of energy-dense foods such
as drinks with highly refined sugar content and salty snacks,
have increased. However, UK data suggest that energy intakes
have declined (which may in part be due to deliberate restriction
or ‘dieting’), but this is apparently insufficient to compensate
for the decrease in physical activity in recent years. Obesity is
correlated positively with the number of hours spent watching
television, and inversely with levels of physical activity (e.g. stair
climbing). It is suggested that minor activities such as fidgeting,
also termed non-exercise activity thermogenesis (NEAT), may
contribute to energy expenditure and protect against obesity.
Susceptibility to obesity
Susceptibility to obesity and its adverse consequences
undoubtedly varies between individuals. It is not true that obese
subjects have a ‘slow metabolism’, since their BMR is higher
than that of lean subjects. Twin and adoption studies confirm a
genetic influence on obesity. The pattern of inheritance suggests
a polygenic disorder, with small contributions from a number of
different genes, together accounting for 25-70% of variation in
weight. Recent results from ‘genome-wide’ association studies
of polymorphisms in large numbers of people (p. 45) have
700 • NUTRITIONAL FACTORS IN DISEASE
identified a handful of genes that influence obesity, some of
which encode proteins known to be involved in the control of
appetite or metabolism and some of which have an unknown
function. These genes account for less than 5% of the variation
in body weight, however. Genes also influence fat distribution
and therefore the risk of the metabolic consequences of obesity,
such as type 2 diabetes and fatty liver disease.
A few rare single-gene disorders have been identified that
lead to severe childhood obesity. These include mutations
of the melanocortin-4 receptor (MC4R), which account for
approximately 5% of severe early-onset obesity; defects in the
enzymes processing propiomelanocortin (POMC, the precursor
for adrenocorticotrophic hormone (ACTH)) in the hypothalamus;
and mutations in the leptin gene (see Fig. 19.3). The latter can
be treated by leptin injections. Additional genetic conditions in
which obesity is a feature include Prader-Willi (see Box 3.8,
p. 51) and Lawrence-Moon-Biedl syndromes.
Reversible causes of obesity and weight gain
In a small minority of patients presenting with obesity, specific
causal factors can be identified and treated (Box 19.6). These
patients are distinguished from those with idiopathic obesity by
their short history, with a recent marked change in the trajectory
of their adult weight gain.
Clinical features and investigations
In assessing an individual presenting with obesity, the aims are to:
• quantify the problem
• exclude an underlying cause
• identify complications
• reach a management plan.
1 19.6 Potentially reversible causes of weight gain
Endocrine factors
• Hypothyroidism
• Hypothalamic tumours
• Cushing’s syndrome
or injury
• Insulinoma
Drug treatments
• Atypical antipsychotics
• Pizotifen
(e.g. olanzapine)
• Glucocorticoids
• Sulphonylureas,
• Sodium valproate
thiazolidinediones, insulin
• p-blockers
Severity of obesity can be quantified using the BMI and
waist circumference. The risk of metabolic and cardiovascular
complications of obesity is higher in those with a high waist
circumference; lower levels of BMI and waist circumference
indicate higher risk in Asian populations (Box 19.7).
A dietary history may be helpful in guiding dietary advice
(p. 693) but is notoriously susceptible to under-reporting of food
consumption. It is important to consider ‘pathological’ eating
behaviour (such as binge eating, nocturnal eating or bulimia;
p. 1204), which may be the most important issue to address in
some patients. Alcohol is an important source of energy intake
and should be considered in detail.
The history of weight gain may help diagnose underlying causes.
A patient who has recently gained substantial weight or has
gained weight at a faster rate than previously, and is not taking
relevant drugs (see Box 19.6), is more likely to have an underlying
disorder such as hypothyroidism (p. 639) or Cushing’s syndrome
(p. 666). All obese patients should have thyroid function tests
performed on one occasion, and an overnight dexamethasone
suppression test or 24-hour urine free cortisol if Cushing’s
syndrome is suspected. Monogenic and ‘syndromic’ causes
of obesity are usually relevant only in children presenting with
severe obesity.
Assessment of the diverse complications of obesity (see Fig.
19.5) requires a thorough history, examination and screening
investigations. The impact of obesity on the patient’s life and work
is a major consideration. Assessment of other cardiovascular risk
factors is important. Blood pressure should be measured with a
large cuff, if required (p. 510). Associated type 2 diabetes and
dyslipidaemia are detected by measurement of blood glucose
or HbA1c and a serum lipid profile, ideally in a fasting morning
sample. Elevated serum transaminases occur in patients with
non-alcoholic fatty liver disease (p. 884).
Management
The health risks of obesity are largely reversible if identified and
treated early. Interventions proven to reduce weight in obese
patients also ameliorate cardiovascular risk factors. Lifestyle
advice that lowers body weight and increases physical exercise
reduces the incidence of type 2 diabetes (p. 743). Given the
high prevalence of obesity and the large magnitude of its risks,
population strategies to prevent and reverse obesity are high
on the public health priority list for many countries. Initiatives
include promoting healthy eating in schools, enhancing walking
19.7 Quantifying obesity with BMI and waist circumference for risk of type 2 diabetes and cardiovascular disease
Waist circumference2
BMI (weight in kg/height in m2)
Classification
Men <94 cm
Women <80 cm
Men 94-102 cm
Women 80-88 cm
Men >102 cm
Women >88 cm
18.5-24.9
Reference range
Negligible
Mildly increased
Moderate
25.0-29.9
Overweight
Negligible
Moderate
Severe
>30.0
Obese
30.0-34.9
Class 1
Moderate
Severe
Very severe
35.0-39.9
Class II
-
Very severe
Very severe
>40.0
Class III
-
Very severe
Very severe
Classification of the World Health Organisation (WHO) and International Obesity Task Force. The Western Pacific Region Office of WHO recommends that, among Asians,
BMI >23.0 is overweight and >25.0 is obese. Lower cut-offs for waist circumference have also been proposed for Asians but have not been validated. 2When BMI is
>35 kg/m2, waist circumference does not add to the increased risk.
Disorders of altered energy balance • 701
and cycling options for commuters, and liaising with the food
industry to reduce energy, sugar and fat content and to label
foods appropriately; taxes on high-sugar drinks have also been
introduced in some countries. Unfortunately, ‘low-fat’ foods are
often still energy-dense, and current lifestyles with labour-saving
devices, sedentary work and passive leisure activities have
much lower energy requirements than the manual labour and
household duties of previous generations.
Most patients seeking assistance with obesity are motivated
to lose weight but have attempted to do so previously without
long-term success. Often weight will have oscillated between
periods of successful weight loss and then regain of weight.
These patients may hold misconceptions that they have an
underlying disease, inaccurate perceptions of their energy intake
and expenditure, and an unrealistic view of the target weight that
they would regard as a ‘success’. An empathetic explanation
of energy balance, which recognises that some individuals are
more susceptible to obesity than others and may find it more
difficult to lose body weight and sustain this loss, is important.
Exclusion of underlying ‘hormone imbalance’ with simple tests
is reassuring and shifts the focus on to consideration of energy
balance. Appropriate goals for weight loss should be agreed,
recognising that the slope of the relationship between obesity
and many of its complications becomes steeper with increasing
BMI, so that a given amount of weight loss achieves greater risk
reduction at higher levels of BMI. A reasonable goal for most
patients is to lose 5-1 0% of body weight.
The management plan will vary according to the severity of
the obesity (see Box 19.7) and the associated risk factors and
complications. It will also be influenced by availability of resources;
health-care providers and regulators have generally been careful
not to recommend expensive interventions (especially long-term
drug therapy and surgery) for everyone who is overweight. Instead,
most guidelines focus resources on short-term interventions in
those who have high health risks and comorbidities associated
with their obesity, and who have demonstrated their capacity to
alter their lifestyle to achieve weight loss (Fig. 19.7).
Lifestyle advice
Behavioural modification to avoid some of the effects of the
‘obesogenic’ environment (see Box 19.5) is the cornerstone of
long-term control of weight. Adopting regular eating patterns
and maximising physical activity are advised, with reference to
the modest extra activity required to increase physical activity
level (PAL) ratios (see Fig. 19.2C). Where possible, this should
be incorporated in the daily routine (e.g. walking rather than
driving to work), as this is more likely to be sustained. Alternative
exercise (e.g. swimming) may be considered if musculoskeletal
complications prevent walking. Changes in eating behaviour
(including food selection, portion size control, avoidance of
snacking, regular meals to encourage satiety, and substitution
of sugar with artificial sweeteners) should be discussed. Regular
support from a dietitian or attendance at a weight loss group
may be helpful.
Weight loss diets
In overweight people, adherence to the lifestyle advice given
above may gradually induce weight loss. In obese patients,
more active intervention is usually required to lose weight before
conversion to the ‘weight maintenance’ advice given above. A
significant industry has developed in marketing diets for weight
loss. These vary substantially in their balance of macronutrients
(Box 19.8) but there is little evidence that they vary in their
medium-term (1 -year) efficacy. Most involve recommending a
reduction of daily total energy intake of -2.5 MJ (600 kcal) from
the patient’s normal consumption. Modelling data that take into
account the reduced energy expenditure as weight is lost suggest
that a reduction of energy intake of 100 kJ per day will lead to
an eventual body weight change of about 1 kg, with half of the
weight change being achieved in about 1 year and 95% of the
weight change in about 3 years. Weight loss is highly variable and
patient adherence is the major determinant of success. There is
some evidence that weight loss diets are most effective in their
early weeks and that adherence is improved by novelty of the
diet; this provides some justification for switching to a different
dietary regimen when weight loss slows on the first diet. Vitamin
Fig. 19.7 Therapeutic options for obesity. Relevant comorbidities
include type 2 diabetes, hypertension, cardiovascular disease, sleep
apnoea, and waist circumference of >102 cm in men or 88 cm in women.
This is an approximate consensus of the numerous national guidelines,
which vary slightly in their recommendations and are revised every few
years.
19.8 Low-calorie diet therapy for obesity
Diet
% Carbohydrate
% Fat
% Protein
Comments
Normal (typical developed country)
50
30
15
Moderate fat (e.g. Weight Watchers)
60
25
15
Maintains balance in macronutrients and micronutrients
while reducing energy-dense fats
Low carbohydrate (e.g. Atkins)
10
60
30
Induction of ketosis may suppress hunger
High protein (e.g. Zone)
43
30
27
Protein has greater satiety effect than other macronutrients
Low fat (e.g. Ornish)
70
13
17
702 • NUTRITIONAL FACTORS IN DISEASE
supplementation is wise in those diets in which macronutrient
balance is markedly disturbed.
In some patients, more rapid weight loss is required, e.g.
in preparation for surgery. There is no role for starvation diets,
which risk profound loss of muscle mass and the development
of arrhythmias (and even sudden death) secondary to elevated
free fatty acids, ketosis and deranged electrolytes. Very-low-
calorie diets (VLCDs) can be considered for short-term rapid
weight loss, producing losses of 1 .5-2.5 kg/week, compared to
0.5 kg/week on conventional regimens, but require the supervision
of an experienced physician and nutritionist. The composition of
the diet should ensure a minimum of 50 g of protein each day
for men and 40 g for women to minimise muscle degradation.
Energy content should be a minimum of 1 .65 MJ (400 kcal) for
women of height <1.73 m, and 2.1 MJ (500 kcal) for all men
and for women taller than 1 .73 m. Side-effects are a problem in
the early stages and include orthostatic hypotension, headache,
diarrhoea and nausea.
Drugs
A huge investment has been made by the pharmaceutical
industry in finding drugs for obesity. The side-effect profile has
limited the use of many agents, with notable withdrawals from
clinical use of sibutramine (increased cardiovascular events) and
rimonabant (psychiatric side-effects) in recent years. Orlistat
has been available for many years, and four drugs or drug
combinations have recently been approved in the USA and two
of these in Europe. There is no role for diuretics, or for thyroxine
therapy without biochemical evidence of hypothyroidism. Drug
therapy should always be used as an adjunct to lifestyle advice
and support, which should be continued throughout treatment.
Orlistat inhibits pancreatic and gastric lipases and thereby
decreases the hydrolysis of ingested triglycerides, reducing dietary
fat absorption by approximately 30%. The drug is not absorbed
and adverse side-effects relate to the effect of the resultant fat
malabsorption on the gut: namely, loose stools, oily spotting,
faecal urgency, flatus and the potential for malabsorption of
fat-soluble vitamins. Orlistat at the standard dose of 120 mg is
taken with each of the three main meals of the day; a lower dose
(60 mg) is available without prescription in some countries. Its
efficacy is shown in Figure 19.8; these effects may be explained
because patients taking orlistat adhere better to low-fat diets in
order to avoid unpleasant gastrointestinal side-effects.
The combination of low-dose phentermine and topiramate
extended release has been approved in the USA; this results in
weight loss of approximately 6% greater than placebo and benefits
lipids and glucose concentrations. Concerns over teratogenicity of
topiramate and cardiovascular effects of phentermine have so far
H \b\
Years of follow-up Years of follow-up
Fig. 19.8 Effects of orlistat (A), liraglutide
(B) and bariatric surgery (C) on weight loss.
For the bariatric surgery data, each obese
subject undergoing surgery was matched with a
control subject whose obesity was managed
according to the standard of care for
non-operative interventions. Note that the
maximum weight loss achieved with orlistat and
liraglutide was approximately 10 kg, and that
the follow-up period is relatively short; surgery
achieves much more substantial and prolonged
weight loss. A, Data from Torgerson JS
Hauptman J, Boldrin MS, et al. A randomized
study of orlistat as an adjunct to lifestyle
changes for the prevention of type 2 diabetes
in obese patients. Diabetes Care 2004;
27:155-161. B, Data from le Roux CW, Astrup
A, Fujioka K, etal. 3 years of liraglutide versus
placebo for type 2 diabetes risk reduction and
weight management in individuals with
prediabetes: a randomised, double-blind trial.
Lancet; published online 22 Feb 2017. C, Data
from Sjbstrdm L, Narbro K, Sjbstrdm D, et al.
Effects of bariatric surgery on mortality in
Swedish obese subjects. N Engl J Med 2007;
357:741-752.
Disorders of altered energy balance • 703
precluded its approval in Europe. The 5-HT2c inhibitor lorcaserin
is also approved in the USA; it is moderately effective and has a
relatively low rate of adverse effects. The combination of the opioid
antagonist naltrexone and the noradrenaline (norepinephrine)/
dopamine re-uptake inhibitor bupropion is also effective. The
main adverse effects are dry mouth and constipation. Finally, a
higher dose of the injectable glucagon-like peptide-1 (GLP-1)
receptor agonist liraglutide (3 mg) is also approved for use and
has been shown to reduce the risk of diabetes in patients with
pre-diabetes.
Drug therapy is usually reserved for patients with high risk
of complications from obesity (see Fig. 19.7), and its optimum
timing and duration are controversial. There is evidence that those
patients who demonstrate early weight loss (usually defined as
5% after 1 2 weeks on the optimum dose) achieve greater and
longer-term weight loss, and this is reflected in most guidelines
for the use of drugs for obesity. Treatment can be stopped
in non-responders at this point and an alternative treatment
considered. Although life-long therapy is advocated for many
drugs that reduce risk on the basis of relatively short-term
research trials (e.g. drugs for hypertension and osteoporosis),
some patients who continue to take anti-obesity drugs tend to
regain weight with time; this may partly reflect age-related weight
gain, but significant weight gain should prompt reinforcement of
lifestyle advice and, if this is unsuccessful, drug therapy should
be discontinued (see Fig. 19.8).
Surgery
‘Bariatric’ surgery is by far the most effective long-term treatment
for obesity (see Fig. 1 9.8 and Box 1 9.9) and is the only anti-obesity
intervention that has been associated with reduced mortality.
Bariatric surgery should be contemplated in motivated patients
who have very high risks of complications of obesity (see Fig. 1 9.7),
when extensive dietary and drug therapy has been insufficiently
effective. It is usually reserved for those with severe obesity (BMI
>40 kg/m2), or those with a BMI >35 kg/m2 and significant
complications, such as type 2 diabetes or obstructive sleep
apnoea, although some evidence-based guidelines now suggest
surgery can be considered at a lower weight in people with
recent-onset diabetes and a BMI >30 kg/m2. Only experienced
specialist surgeons should undertake these procedures, in
collaboration with a multidisciplinary team. Several approaches
are used (Fig. 19.9) and all can be performed laparoscopically.
The mechanism of weight loss may not simply relate to limiting
the stomach or absorptive capacity, but rather in disrupting the
release of ghrelin from the stomach or promoting the release of
other peptides from the small bowel, thereby enhancing satiety
signalling in the hypothalamus. Diabetes may improve rapidly
HS 19.9 Effectiveness and adverse effects of
laparoscopic bariatric surgical procedures
Procedure
Expected weight
loss (% excess
weight)
Adverse effects
Gastric
banding
50-60%
Band slippage, erosion, stricture
Port site infection
Mortality <0.2% in experienced
centres
Sleeve
gastrectomy
50-60%
Iron deficiency
Vitamin B12 deficiency
Mortality <0.2% in experienced
centres
Roux-en-Y
gastric
bypass
70-80%
Internal hernia
Stomal ulcer
Dumping syndrome
Hypoglycaemia
Iron deficiency
Vitamin B12 deficiency
Vitamin D deficiency
Mortality 0.5%
Duodenal
switch
Up to 100%
Steatorrhoea
Protein-calorie malnutrition
Iron deficiency
Vitamin B12 deficiency
Calcium, zinc, copper deficiency
Mortality 1%
Fig. 19.9 Bariatric surgical procedures. [A] Laparoscopic banding, with the option of a reservoir band and subcutaneous access to restrict the stomach
further after compensatory expansion has occurred. [§] Sleeve gastrectomy. [C] Roux-en-Y gastric bypass. [D] Biliopancreatic diversion with duodenal
switch.
704 • NUTRITIONAL FACTORS IN DISEASE
after surgery, particularly after gastric bypass, and although this
may be attributed to severe energy restriction in the perioperative
period, it is possible that increased release of incretin hormones
such as GLP-1 may contribute to the improvement in glucose
control. Complications depend on the approach. Mortality is low
in experienced centres but post-operative respiratory problems,
wound infection and dehiscence, staple leaks, stomal stenosis,
marginal ulcers and venous thrombosis may occur. Additional
problems may arise at a later stage, such as pouch and distal
oesophageal dilatation, persistent vomiting, ‘dumping’ (p. 801),
hypoglycaemia and micronutrient deficiencies, particularly of
folate, vitamin B12 and iron, which are of special concern to
women contemplating pregnancy; this should be delayed for
at least 2 years following surgery.
Cosmetic surgical procedures may be considered in obese
patients after successful weight loss. Apronectomy is usually
advocated to remove an overhang of abdominal skin, especially if
infected or ulcerated. This operation is of no value for long-term
weight reduction if food intake remains unrestricted.
Treatment of additional risk factors
Obesity must not be treated in isolation and other risk factors must
be addressed, including smoking, excess alcohol consumption,
diabetes mellitus, hyperlipidaemia, hypertension and obstructive
sleep apnoea. Treatment of these is discussed in the relevant
chapters.
Under-nutrition
Starvation and famine
There remain regions of the world, particularly rural Africa, where
under-nutrition due to famine is endemic, the prevalence of
BMI of less than 18.5 kg/m2 (Box 19.10) in adults is as high
as 20%, and growth retardation due to under-nutrition affects
50% of children. The World Health Organisation (WHO) reports
that chronic under-nutrition is responsible for more than half
of all childhood deaths worldwide. Starvation is manifest as
marasmus (malnutrition with marked muscle wasting) or, when
additive complications such as oxidative stress come into play,
malnourished children can develop kwashiorkor (malnutrition
with oedema). Growth retardation is due to deficiencies of key
nutrients (protein, zinc, potassium, phosphate and sulphur).
Treatment of these childhood conditions is not discussed in
this adult medical textbook. In adults, starvation is the result
of chronic sustained negative energy (calorie) balance. Causes
are shown in Box 19.1 1 . Causes of weight loss are considered
further on page 785.
Clinical features
In starvation, the severity of malnutrition can be assessed by
anthropometric measurements, such as BMI (see p. 693 and Box
19.10). Demispan and mid-arm circumference measurements
are most useful in monitoring progress during treatment. The
clinical features of severe under-nutrition in adults are listed in
Box 19.12.
Under-nutrition often leads to vitamin deficiencies, especially
of thiamin, folate and vitamin C (see below). Diarrhoea can lead
to depletion of sodium, potassium and magnesium. The high
mortality rate in famine situations is often due to outbreaks of
infection, such as typhus or cholera, but the usual signs of
infection may not be apparent. In advanced starvation, patients
become completely inactive and may assume a flexed, fetal
position. In the last stage of starvation, death comes quietly
and often quite suddenly. The very old are most vulnerable. All
organs are atrophied at necropsy, except the brain, which tends
to maintain its weight.
Investigations
In a famine, laboratory investigations may be impractical but
will show that plasma free fatty acids are increased and there
is ketosis and a mild metabolic acidosis. Plasma glucose is low
19.11 Causes of under-nutrition and weight loss
in adults
Decreased energy intake
• Famine
• Persistent regurgitation or vomiting
• Anorexia, including depression and anorexia nervosa
• Malabsorption (e.g. small intestinal disease)
• Maldigestion (e.g. pancreatic exocrine insufficiency)
Increased energy expenditure
• Increased basal metabolic rate (thyrotoxicosis, trauma, fever,
cancer, cachexia)
• Excessive physical activity (e.g. marathon runners)
• Energy loss (e.g. glycosuria in diabetes)
• Impaired energy storage (e.g. Addison’s disease,
phaeochromocytoma)
19.12 Clinical features of severe under-nutrition
in adults
• Weight loss
• Thirst, craving for food, weakness and feeling cold
• Nocturia, amenorrhoea or impotence
• Lax, pale, dry skin with loss of turgor and, occasionally, pigmented
patches
• Cold and cyanosed extremities, pressure sores
• Hair thinning or loss (except in adolescents)
• Muscle-wasting, best demonstrated by the loss of the temporalis
and periscapular muscles and reduced mid-arm circumference
• Loss of subcutaneous fat, reflected in reduced skinfold thickness
and mid-arm circumference
• Hypothermia, bradycardia, hypotension and small heart
• Oedema, which may be present without hypoalbuminaemia (‘famine
oedema’)
• Distended abdomen with diarrhoea
• Diminished tendon jerks
• Apathy, loss of initiative, depression, introversion, aggression if food
is nearby
• Susceptibility to infections (Box 19.13)
KM 19.10 Classification of under-nutrition in adults by
body mass index (weight/height2)
BMI (kg/m2)
Classification
>20
Adequate nutrition
18.5-20
Marginal
<18.5
Under-nutrition
17-18.4
Mild
16-17
Moderate
<16
Severe
Disorders of altered energy balance • 705
i
• Gastroenteritis and Gram-negative sepsis
• Respiratory infections, especially bronchopneumonia
• Certain viral diseases, especially measles and herpes simplex
• Tuberculosis
• Streptococcal and staphylococcal skin infections
• Helminthic infestations
but albumin concentration is often maintained because the liver
still functions normally. Insulin secretion is diminished, glucagon
and cortisol tend to increase, and reverse T3 replaces normal
triiodothyronine (p. 634). The resting metabolic rate falls, partly
because of reduced lean body mass and partly because of
hypothalamic compensation (see Fig. 19.2). The urine has a fixed
specific gravity and creatinine excretion becomes low. There
may be mild anaemia, leucopenia and thrombocytopenia. The
erythrocyte sedimentation rate is normal unless there is infection.
Tests of delayed skin hypersensitivity, e.g. to tuberculin, are
falsely negative. The electrocardiogram shows sinus bradycardia
and low voltage.
Management
Whether in a famine or in wasting secondary to disease, the
severity of under-nutrition is graded according to BMI (see Box
19.10). People with mild starvation are in no danger; those with
moderate starvation need extra feeding; and those who are
severely underweight need hospital care.
In severe starvation, there is atrophy of the intestinal epithelium
and of the exocrine pancreas, and the bile is dilute. It is critical for
the condition to be managed by experts. When food becomes
available, it should be given by mouth in small, frequent amounts
at first, using a suitable formula preparation (Box 19.14). Individual
energy requirements can vary by 30%. During rehabilitation,
more concentrated formula can be given with additional food
that is palatable and similar to the usual staple meal. Salt should
be restricted and micronutrient supplements (e.g. potassium,
magnesium, zinc and multivitamins) may be essential. Between
6.3 and 8.4 MJ/day (1 500-2000 kcal/day) will arrest progressive
under-nutrition but additional energy may be required for regain
of weight. During refeeding, a weight gain of 5% body weight per
month indicates satisfactory progress. Other care is supportive
and includes attention to the skin, adequate hydration, treatment
of infections and careful monitoring of body temperature, since
thermoregulation may be impaired.
Circumstances and resources are different in every famine
but many problems are non-medical and concern organisation,
infrastructure, liaison, politics, procurement, security and ensuring
that food is distributed on the basis of need. Lastly, plans must
be made for the future for prevention and/or earlier intervention
if similar circumstances prevail.
Under-nutrition in hospital
It is a paradox that, in spite of record levels of access to food in
the developed economies of the world, under-nutrition remains a
serious issue in many sectors of society, particularly the elderly
and less independent. While the scale of the problem does not
match that seen in the developing world, the issues pertaining to
poor or impaired health are similar. In the general UK population,
30% of those requiring acute admission to hospital show evidence
of serious under-nutrition and 65% of those admitted will lose an
i
19.14 WHO recommended diets for refeeding
Nutrient (per 100 mL)
F-75 diet
F-100 diet2
Energy
315 kJ
420 kJ (100 kcal)
(75 kcal)
Protein (g)
0.9
2.9
Lactose (g)
1.3
4.2
Potassium (mmol)
3.6
5.9
Sodium (mmol)
0.9
1.9
Magnesium (mmol)
0.43
0.73
Zinc (mg)
2.0
2.3
Copper (mg)
0.25
0.25
Percentage of energy from:
Protein
5
12
Fat
32
53
Osmolality (mOsmol/kg)
333
419
Dose
170 kJ/kg
630-920 kJ/kg
(40 kcal/kg)
(150-220 kcal/kg)
Rate of feeding by mouth
2.2 (mL/kg/hr)
Gradual increase
in volume, 6 times
daily
T-75 is prepared from milk powder (25 g), sugar (70 g), cereal flour (35 g),
vegetable oil (27 g) and vitamin and mineral supplements, made up to 1 L with
water.
2F-1 00 (1 L) contains milk powder (80 g), sugar (50 g), vegetable oil
(60 g) and vitamin and mineral supplements (no cereal).
average of 5% of their total body weight during that admission.
In the older population, levels of under-nutrition and vitamin
deficiencies parallel levels of independent living. In Scotland,
33% of those aged over 65 who are living in their own home
are deficient in folic acid and 1 0% are deficient in vitamin C. The
prevalence of vitamin deficiencies rises further in less independent
groups in residential or nursing homes.
Under-nutrition is poorly recognised in hospitals and has serious
consequences. Physical effects include impaired immunity and
muscle weakness, which in turn affect cardiac and respiratory
function, and delayed wound healing after surgery with increased
risks of post-operative infection. The under-nourished patient
is often withdrawn and this may be mistaken for depressive
illness. Engagement with treatment and rehabilitation can be
adversely affected. Much of this can be avoided through better
awareness of the prevalence of under-nutrition, prompt nutritional
assessment and monitoring with appropriate intervention. Scoring
systems, such as the MUST tool (p. 693), raise awareness
across multidisciplinary teams, and encourage staff to assess
and monitor food intake and weigh patients regularly.
Causes are often complex (see Box 19.11). Social issues
impact on food choices and may cause or exacerbate disease.
Social isolation, low levels of disposable income and a lack of
knowledge or interest in healthy eating may increase reliance on
calorie-dense convenience foods of poor nutritional quality. In
turn, the non-specific effects of chronic inflammation, infection
or malignancy, as well as specific gastrointestinal disorders,
may adversely affect appetite, reducing food intake. Patients
may report avoidance of certain foods that exacerbate their
symptoms (often fibre-rich, otherwise healthy foods).
A loss of appetite is not specific to gastrointestinal disease and
may be seen as a non-specific response to myriad other conditions
or their treatments. The most common reported side-effects
19.13 Infections associated with starvation
706 • NUTRITIONAL FACTORS IN DISEASE
19.15 Factors affecting adequacy of nutritional
intake in hospitalised patients
of many prescription drugs are nausea and gastrointestinal
disturbance. Surgical resection of the gastrointestinal tract can
have major nutritional sequelae in the years following, ranging from
intolerance of normal volumes of food to intestinal failure (where
there is partial or complete failure of the intestine to perform its
vital functions). There may be no single problem impacting on the
intake of adequate nutrition but it helps to consider systematically
where the problem(s) might lie (Box 19.15).
Specific issues arising after intestinal surgery
Gastrectomy or partial gastrectomy
There may be a loss of gastric capacity, leading to intolerance of
larger volumes of food and early satiety or vomiting. Vagotomy and
gastroenterostomy may cause symptoms of dumping syndrome
(p. 801), which can lead to food avoidance and weight loss.
Many patients who have had gastric surgery will develop iron
deficiency (and, less commonly, vitamin D and vitamin B12
deficiency) unless adequately supplemented post-operatively.
Proximal small bowel surgery
Those who have had roux-en-Y reconstruction or have blind¬
ending or excluded loops of small bowel are prone to small
intestinal bacterial overgrowth. This may impair absorption
of iron, folic acid and vitamin B12. Very rarely, it can cause
hyperammonaemia and metabolic coma, in which bacterial
metabolism of amino acids leads to a lack of citrulline and
impairment of the urea cycle.
Pancreatic resection/Whipple’s operation
Without adequate post-operative supplementation, this can be a
very serious insult to the digestive tract. There is loss of pancreatic
exocrine function (causing steatorrhoea and malabsorption of
protein, fats and fat-soluble vitamins), as well as the potential
for small intestinal bacterial overgrowth (malabsorption of iron,
folic acid and vitamin B12).
Ileal resection
Ileal resection (p. 810) may give rise to vitamin B12 deficiency and,
rarely, to steatorrhoea and malabsorption of fat-soluble vitamins.
Massive small bowel resection
This may cause short bowel syndrome and intestinal failure, with
impaired ability to absorb fluids, electrolytes and macronutrients
adequately without parenteral support.
An approach to assisted nutrition in hospital patients
Once the problems leading to under-nutrition have been
recognised, it is important to make an individualised plan to
address these issues specifically. In most cases, this means a
decision to intervene to tackle and reverse nutritional difficulties.
This may involve simply ensuring that adequate supplies of
food are delivered and prepared regularly or that dentures fit
properly, but may require an assessment of a patient’s ability
to swallow or of the intestine’s ability to digest foods. This must
include consideration of the potential for disruption of the normal
physiology of absorption and digestion in the context of the
patient’s medical and surgical history. Whenever possible, it is best
to use the most physiological means of feeding, reserving more
invasive interventions for when normal physiological mechanisms
of swallowing and digestion are impaired or absent. Enteral feeding
is preferred to parenteral, provided the intestine is accessible
and functioning.
Refeeding syndrome
In severely malnourished individuals, attempts at rapid correction of
malnutrition switch the body from a reliance on fat to carbohydrate
metabolism. Release of insulin is triggered, shifting potassium,
phosphate and magnesium into cells (with water following the
osmotic gradient) and causing potentially fatal shifts of fluids and
electrolytes from the extracellular to the intracellular compartment.
Rapid depletion of (already low) thiamin exacerbates the condition.
Clinical features include nausea, vomiting, muscle weakness,
seizures, respiratory depression, cardiac arrest and sudden
death. The risks of refeeding are greatest in those who are
most malnourished (especially chronic alcoholics), but even
those who have gone without food for 5 days can be at risk and
restitution of feeding should always be done slowly, with careful
monitoring of serum potassium, phosphate and magnesium in
the first 3-5 days.
Oral nutritional supplements
Poor appetite, immobility, poor dentition or even being kept ‘nil
by mouth’ for hospital procedures all contribute to weight loss. As
a first step, patients should be encouraged and helped to eat an
adequate amount of normal food. Where swallow and intestinal
function remain intact, the simplest form of assisted nutrition is
the use of oral nutritional supplements. Most branded products
are nutritionally complete (fortified with the daily requirements of
vitamins, minerals and trace elements). They most often come
in the form of liquid drinks but various formulations and textures
exist, including ‘shakes’ and ‘puddings’ with a thicker consistency.
They are cost-effective and very useful for people who may require
just a small number of additional calories each day to maintain
or gain weight in the short or longer term. However, in spite of
their nutritional value, small volume and range of flavours, many
people find them unpalatable or difficult to tolerate.
Factors affecting appetite
• Altered taste
• Nausea and/or vomiting
• Non-specific effects of illness and/or drugs
Issues of quantity
• Is there enough food on the plate?
• Social, cultural, financial, general and mental health issues may all
be relevant, individually or in combination
Getting the food from the plate to the mouth
• Generalised reduced mobility
• Reduced manual dexterity
• Loss of limb function
Difficulties chewing the food
• Poorly fitting dentures
• Pain in the oral cavity
Specific problems with the gastrointestinal tract
• Obstruction
• Ischaemia
• Inflammation
• Malabsorption
Cultural issues
• Is the food provided appropriate to the patient’s beliefs?
More general evidence of self-neglect
• Evidence of chronic coexisting illness
• Evidence of mental health problems - low mood may be ‘cause’ or
‘effect’ in under-nutrition
Disorders of altered energy balance • 707
Enteral feeding
Where swallowing or food ingestion is impaired but intestinal
function remains intact, more invasive forms of assisted feeding
may be necessary. Enteral tube feeding is usually the intervention
of choice. In enteral feeding, nutrition is delivered to and absorbed
by the functioning intestine. Delivery usually means bypassing
the mouth and oesophagus (or sometimes the stomach and
proximal small bowel) by means of a feeding tube (naso-enteral,
gastrostomy or jejunostomy feeding). There are a number of
theoretical advantages to enteral, as opposed to parenteral,
feeding, which have achieved almost mythical status. These
include:
• preservation of intestinal mucosal architecture, gut-
associated lymphoid tissue, and hepatic and pulmonary
immune function
• reduced levels of systemic inflammation and
hyperglycaemia
• interference with pathogenicity of gut micro-organisms.
However, the areas in which advantage has been consistently
proven are:
• fewer episodes of infection
• reduced cost
• earlier return to intestinal function
• reduced length of hospital stay.
Complications
The risks of enteral feeding are those related to tube insertion
(Box 19.16) and diarrhoea (Box 19.17).
Route of access
Nasogastric tube feeding This is simple, readily available,
comparatively low-cost and most suitable for short-term feeding
(up to 4 weeks). Insertion of a nasogastric tube requires care
and training (see Box 21.41, p. 805), as potentially serious
complications can arise (Box 19.16). Patients with reduced
conscious level may pull at tubes and displace them. This can
be minimised in the short term by the use of a nasal ‘bridle’
19.16 Complications of nasogastric tube feeding
• Tube misplacement, e.g. tracheal or bronchial placement ( rarely ,
intracranial placement)
• Reflux of gastric contents and pulmonary aspiration
• Interrupted feeding or inadequate feed volumes
• Refeeding syndrome
19.17 Diarrhoea related to enteral feeding
Factors contributing to diarrhoea
• Fibre-free feed may reduce short-chain fatty acid production in
colon
• Fat malabsorption
• Inappropriate osmotic load
• Pre-existing primary gut problem (e.g. lactose intolerance)
• Infection
Management
• Often responds well to a fibre-containing feed or a switch to an
alternative feed
• Simple antidiarrhoeal agents (e.g. loperamide) can be very effective
device, which fixes the tube around the nasal septum. Although
these devices are very effective, there is a risk of damage to the
nasal septum (especially bleeding) if a patient persists in pulling
forcibly on the tube.
Gastrostomy feeding Gastrostomy is a more invasive insertion
technique with higher costs initially. It is most suitable for
when longer-term feeding (more than 4 weeks) is required.
Gastrostomies are less liable to displacement than nasogastric
tubes and the presence of the gastrostomy in the stomach allows
for fewer feed interruptions, meaning that more of the prescribed
feeds can be administered. Tubes were placed at the time of
open surgery until the 1980s, when an endoscopic, minimally
invasive technique was developed. A variety of techniques for
radiological insertion have also been introduced subsequently.
Both endoscopic and radiological gastrostomy insertion involve
inflating the stomach, thus apposing it to the anterior abdominal
wall. The stomach is then punctured percutaneously and a suitable
tube placed (Fig. 19.10). Tubes vary in design but each has an
internal retainer device (plastic ‘bumper’ or balloon) that sits
snugly against the gastric mucosa, and an external retainer that
limits movement. These retainers hold the gastric wall against the
abdominal wall, effectively creating a controlled gastrocutaneous
fistula that matures over 2-4 weeks. Radiological gastrostomy
placement also utilises percutaneous ‘stay sutures’, which
provide further temporary anchorage and assist in placement.
There is no evidence to recommend one technique over another,
although the radiological method has advantages in patients with
cancers of the head and neck undergoing potentially curative
therapy (less chance of tumour ‘seeding’) and in those with poor
respiratory reserve (such as motor neuron disease) since there
is no endoscope to compress the upper airways. Reported
outcomes are broadly similar for both and the choice of technique
should be based on indications and contraindications, operator
experience and facilities available. Most important is rigorous
patient assessment and selection prior to gastrostomy placement,
which should be done by a multidisciplinary nutrition support
team, and avoided when the procedure may be too hazardous
or the benefits are outweighed by the risks (see Boxes 19.18
and Box 19.27 below).
Post-pyloric feeding In patients with a high risk of pulmonary
aspiration or gastroparesis, it may be preferable to feed into the
jejunum (via a nasojejunal tube, gastrostomy with jejunal extension
or direct placement into jejunum by radiological, endoscopic or
laparoscopic means).
Parenteral nutrition
This is usually reserved for clinical situations where the absorptive
functioning of the intestine is severely impaired. In parenteral
feeding, nutrition is delivered directly into a large-diameter systemic
vein, completely bypassing the intestine and portal venous
system. As well as being more invasive, more expensive and
19.18 Complications of gastrostomy tube feeding
• Reflux of gastric contents and pulmonary aspiration (same as
nasogastric tube)
• Risks of insertion (pain, damage to intra-abdominal structures,
intestinal perforation, pulmonary aspiration, infection, death)
• Risk of tumour ‘seeding’ if an endoscopic ‘pull-through’ technique
is used in head and neck or oesophageal cancer patients
• Refeeding syndrome
708 • NUTRITIONAL FACTORS IN DISEASE
Fig. 19.10 Percutaneous endoscopic gastrostomy (PEG) placement. [A] Finger pressure on the anterior abdominal wall is noted by the endoscopist.
[§] Following insertion of a cannula through the anterior abdominal wall into the stomach, a guidewire is threaded through the cannula and grasped by
the endoscopic forceps or snare. [C] The endoscope is withdrawn with the guidewire. The gastrostomy tube is then attached to the guidewire. [6] The
guidewire and tube are pulled back through the mouth, oesophagus and stomach to exit on the anterior abdominal wall, and the endoscope is repassed to
confirm the site of placement of the retention device. The latter closely abuts the gastric mucosa; its position is maintained by an external fixation device
(see inset). It is also possible to place PEG tubes using fluoroscopic guidance when endoscopy is difficult (radiologically inserted gastrostomy).
19.19 Complications of parenteral nutrition
Intravenous catheter complications
• Insertion (pneumothorax, haemothorax, arterial puncture)
• Catheter infection (sepsis, discitis, pulmonary or cerebral abscess)
• Central venous thrombosis
Metabolic complications
• Refeeding syndrome
• Electrolyte imbalance
• Hyperglycaemia
• Hyperalimentation
• Fluid overload
• Hepatic steatosis/fibrosis/cirrhosis
less physiological than the enteral route, parenteral nutrition
is associated with many more complications (Box 19.19),
mainly infective and metabolic (disturbances of electrolytes,
hyperglycaemia). Strict adherence to aseptic practice in handling
catheters and careful monitoring of clinical (pulse, blood pressure
and temperature) and biochemical (urea, electrolytes, glucose
and liver function tests) parameters are necessary to minimise
risk to the patient (Box 19.20).
The parenteral route may be indicated for patients who
are malnourished or at risk of becoming so, and who have
an inadequate or unsafe oral intake and a poorly functioning
or non-functioning or perforated intestine or an intestine that
cannot be accessed by tube feeding. In practice, it is most
often required in acutely ill patients with multi-organ failure or
in severely under-nourished patients undergoing surgery. It
may offer a benefit over oral or enteral feeding prior to surgery
in those who are severely malnourished when other routes of
feeding have been inadequate. Parenteral nutrition following
surgery should be reserved for when enteral nutrition is not
tolerated or feasible or where complications (especially sepsis)
19.20 Parameters for monitoring parenteral nutrition
in hospital
Parameter
Monitoring requirement
Electrolytes (sodium, potassium,
magnesium)
Bone profile (calcium, phosphate)
Liver function tests (bilirubin,
alanine aminotransferase, alkaline
phosphatase, y-glutamyl transferase)
Markers of inflammation
(C-reactive protein, leucocyte count)
Daily until stable and then
2-3 times per week
Blood glucose
At least twice daily until stable
and then daily
Cholesterol and triglycerides
Weekly initially, reducing to
every 3 months when stable
impair gastrointestinal function, such that oral or enteral feeding
is not possible for at least 7 days.
Intestinal failure (‘short bowel syndrome’)
Intestinal failure (IF) is defined as a reduction in the function of
the gut below the minimum necessary for the absorption of
macronutrients and/or water and electrolytes such that intravenous
supplementation is required to support health and/or growth.
The term can be used only when there is both:
• a major reduction in absorptive capacity and
• an absolute need for intravenous fluid support.
IF can be further classified according to its onset, metabolic
consequences and expected outcome.
• Type 1 IF: an acute-onset, usually self-limiting condition
with few long-term sequelae. It is most often seen
following abdominal surgery or in the context of critical
illness. Intravenous support may be required for a few
days to weeks.
Disorders of altered energy balance • 709
• Type 2 IF\ far less common. The onset is also usually
acute, following some intra-abdominal catastrophic event
(ischaemia, volvulus, trauma or perioperative complication).
Septic and metabolic problems are seen, along with
complex nutritional issues. It requires multidisciplinary input
(nursing, dietetic, medical, biochemical, surgical,
radiological and microbiological) and support may be
necessary for weeks to months.
• Type 3 IF : a chronic condition in which patients are
metabolically stable but intravenous support is required
over months to years. It may or may not be reversible.
Management
IF is a complex clinical problem with profound and wide-ranging
physiological and psychological effects, which is best cared for
by a dedicated multidisciplinary team. The majority of IF results
from short bowel syndrome (Box 19.21), with chronic intestinal
dysmotility and chronic intestinal pseudo-obstruction accounting
for most of the remainder. The severity of the physiological upset
correlates well with how much functioning intestine remains
(rather than how much has been removed). Measurement of
the remaining small bowel (from the duodeno-jejunal flexure) at
the time of surgery is essential for planning future therapy (Box
19.22). The aims of treatment are to:
• provide nutrition, water and electrolytes to maintain health
with normal body weight (and allow normal growth in
affected children)
• utilise the enteral or oral routes as much as possible
• minimise the burden of complications of the underlying
disease, as well as the IF and its treatment
• allow a good quality of life.
If the ileum and especially the ileum and colon remain intact,
long-term nutritional support can usually be avoided. Unlike the
jejunum, the ileum can adapt to increase absorption of water
and electrolytes over time. The presence of the colon (part or
wholly intact) further improves fluid absorption and can generate
energy through production of short-chain fatty acids. It is therefore
useful to classify patients with a short gut according to whether
or not they have any residual colon.
Jejunum-colon patients
Those with an anastomosis between jejunum and residual colon
(jejunum-colon patients) may look well in the days or initial weeks
19.21 Causes of short bowel syndrome in adults
• Mesenteric ischaemia
• Post-operative complications
• Crohn’s disease
• Trauma
• Neoplasia
• Radiation enteritis
following the acute insult but develop protein-energy malnutrition
and significant weight loss, becoming seriously under-nourished
over weeks to months.
Stool volume is determined by oral intake, with higher intakes
causing more diarrhoea and the potential for dehydration, sodium
and magnesium depletion and acute renal failure. The absence
of the ileum leads to deficiencies of vitamin B12 and fat-soluble
vitamins. The absorption of various drugs, including thyroxine,
digoxin and warfarin, can be reduced. Approximately 45%
of patients will develop gallstones due to disruption of the
enterohepatic circulation of bile acids, and 25% may develop
calcium oxalate renal stones due to increased colonic absorption
of oxalate (see Fig. 21 .43, p. 810).
Jejunostomy patients
Patients left with a stoma (usually a jejunostomy) behave very
differently, although stool volumes are again determined by oral
intake. The jejunum is intrinsically highly permeable, and in the
absence of the ileum and its net absorptive role, high losses
of fluid, sodium and magnesium dominate the clinical picture
from the outset. Dehydration, hyponatraemia, hypomagnesaemia
and acute renal failure are the most immediate problems but
protein-energy malnutrition will also develop. The jejunum has
no real potential for adaptation in terms of absorption, so it is
essential to recognise and address the issues of dehydration
and electrolyte disturbance early and not expect the problems
to improve with time (Box 19.23).
19.23 Management of short bowel patients
(and ‘high-output’ stoma)
Accurate charting of fluid intake and losses
• Vital: oral intake determines stool volume and should be restricted
rather than encouraged
Dehydration and hyponatraemia
• Must first be corrected intravenously to restore circulating volume
and reduce thirst
• Stool volume should be minimised and any ongoing fluid imbalance
between oral intake and stool losses replenished intravenously
Measures to reduce stool volume losses
• Restrict oral fluid intake to <500 mL724 hrs
• Give a further 1 000 mL oral fluid as oral rehydration solution
containing 90-120 mmol Na/L (St Mark’s solution or Glucodrate,
Nestle)
• Slow intestinal transit (to maximise opportunities for absorption):
Loperamide, codeine phosphate
• Reduce volume of intestinal secretions:
Gastric acid: omeprazole 20 mg/day orally
Other secretions: octreotide 50-100 jig 3 times daily by
subcutaneous injection
Measures to increase absorption
• Teduglutide (a recombinant glucagon-like peptide 2) significantly
reduces requirements for intravenous fluid and nutritional support
19
il
19.22 Likely requirements for support according to length of intact residual small bowel
Residual length of jejunum (cm) Oral fluid restriction
Oral glucose/electrolyte solution
Intravenous fluids
Parenteral nutrition
<200
Yes
Yes
May avoid
May avoid
<100
Yes
Yes
Yes
May avoid
<75
Yes
Yes
Yes
Yes
710 • NUTRITIONAL FACTORS IN DISEASE
Small bowel and multivisceral transplantation
Long-term intravenous nutritional support remains the mainstay
of therapy for chronic IF but has its own morbidity and mortality.
The 1 0-year survival for patients on long-term home parenteral
nutrition is approximately 90%. The majority of deaths are due
to the underlying disease process but 5-1 1 % will die from direct
complications of parenteral nutrition itself (especially catheter-
related sepsis). A minority of patients with chronic IF, for whom
the safe administration of parenteral nutrition has become difficult
or impossible, may benefit from small bowel transplantation
(Box 19.24). The first successful small bowel transplant was
carried out in 1988. The introduction of tacrolimus allowed a
satisfactory balance of immunosuppression, avoiding rejection
while minimising sepsis. Since then, over 2000 transplants have
been performed worldwide. Survival rates continue to improve,
for both isolated small bowel and multivisceral transplantation
(small bowel along with a combination of liver and/or kidney and/
or pancreas), although major complications are still frequent (Box
19.25). Current 5-year survival rates are 50-80%, with better
outcomes for younger patients and those receiving isolated
small bowel procedures.
Further developments in treatment of intestinal failure
Teduglutide is a long-acting recombinant human GLP-2. It
enhances intestinal absorption by:
• increasing intestinal blood flow to the intestine
• increasing portal blood flow away from the intestine
• slowing intestinal transit times
• reducing gastric acid secretion.
In patients with short bowel syndrome and IF, the increased
intestinal absorptive function induced by teduglutide can
significantly reduce the volumes of parenteral fluids and
nutrition required, and may allow some patients to regain
independence of parenteral support. Recognised side-effects
19.24 Potential indications for small bowel
transplantation
Complications of central venous catheters
• Central venous thrombosis leading to loss of two or more
intravenous access points
• Severe or recurrent line sepsis
• Recurrent severe acute kidney injury related to dehydration
Metabolic complications of parenteral nutrition
include abdominal cramps and distension (seen in 50%),
peristomal swelling, pain, nausea, vomiting and local injection
site reactions. Since teduglutide stimulates proliferation of the
intestinal epithelium, it should be avoided in those with a history
of gastrointestinal malignancy in the past 5 years or a current
malignancy. In those patients with a colon, a pre-treatment
screening colonoscopy should be undertaken to detect and
remove any polyps. Use of teduglutide is currently limited by
high costs.
19.27 Ethical and legal considerations in the
management of artificial nutritional support
• Care of the sick involves the duty of providing adequate fluid and
nutrients
• Food and fluid should not be withheld from a patient who expresses
a desire to eat and drink, unless there is a medical contraindication
(e.g. risk of aspiration)
• A treatment plan should include consideration of nutritional issues
and should be agreed by all members of the health-care team
• In the situation of palliative care, tube feeding should be instituted
only if it is needed to relieve symptoms
• Tube feeding is usually regarded in law as a medical treatment.
Like other treatments, the need for such support should be
reviewed on a regular basis and changes made in the light of
clinical circumstances
• A competent adult patient must give consent for any invasive
procedures, including passage of a nasogastric tube or insertion of
a central venous cannula
• If a patient is unable to give consent, the health-care team should
act in that person’s best interests, taking into account any wishes
previously expressed by the patient and the views of family
• Under certain specified circumstances (e.g. anorexia nervosa), it is
appropriate to provide artificial nutritional support to the unwilling
patient
Adapted from British Association for Parenteral and Enteral Nutrition guidelines
(www.bapen.org.uk).
• Parenteral nutrition-related liver fibrosis, cirrhosis and liver failure
19.25 Complications of small bowel/multivisceral
transplantation
• Sepsis:
Enteric bacterial species
Staphylococci
Fungal species
• Cytomegalovirus infection
• Post-transplantation lymphoproliferative disease (PTLD)
• Graft-versus-host disease
• Acute and chronic rejection
• Chronic renal impairment
| Artificial nutrition at the end of life
Rarely, assisted nutrition may not result in the expected outcomes
of reversal of weight loss or improved quality and duration of life.
It very seldom reverses other underlying health issues, although
it may be used as a short term ‘bridge’ to help through a patient
through a particular crisis.
Such scenarios may present when someone is approaching
the end of life, or in the face of weight loss due to advanced
if
• Body composition: muscle mass is decreased and percentage of
body fat increased.
• Energy expenditure: with the fall in lean body mass, basal
metabolic rate is decreased and energy requirements are reduced.
• Weight loss: after weight gain throughout adult life, weight often
falls beyond the age of 80 years. This may reflect decreased
appetite, loss of smell and taste, and decreased interest in and
financial resources for food preparation, especially after loss of a
partner.
• BMI: less reliable in old age as height is lost (due to kyphosis,
osteoporotic crush fractures, loss of intervertebral disc spaces).
Alternative measurements include arm demispan and knee height
(p. 693), which can be extrapolated to estimate height.
19.26 Energy balance in old age
Micronutrients, minerals and their diseases • 711
respiratory or cardiac failure, malignancy or dementia. In selected
cases, a decision not to intervene may be appropriate. An
intervention that merely prolongs life without preserving or adding
to its quality is seldom justified, particularly if the intervention is
not without risk itself. Such decisions are not taken lightly and
careful scrutiny of each case is necessary. There should be
a thoughtful and sensitive discussion explaining what artificial
nutrition can and cannot achieve involving the multidisciplinary
team looking after the patient as well as next of kin and, in some
cases, legal representatives (Box 19.27).
Nutrition and dementia
Weight loss is seen commonly in people with dementia, and
nutritional and eating problems are a significant source of concern
for those caring for them. It is appropriate to:
• screen for malnutrition (e.g. MUST, see above)
• assess specific eating difficulties (e.g. Edinburgh Feeding
Evaluation in Dementia questionnaire)
• monitor and document body weight
• encourage adequate intake of food
• use oral nutritional supplements.
However, the evidence that artificial nutritional support beyond
oral supplementation improves overall functioning or prolongs life in
dementia is absent or weak. There may be specific circumstances
where a trial of such feeding can be justified (see Box 19.27).
Success is more likely in those with mild to moderate dementia,
when a temporary and reversible crisis has been precipitated
by some acute event. It is important to remember that there is
strong evidence to avoid tube feeding in those with advanced
dementia because this improves neither the quality nor the
duration of life (Fig. 19.11).
Frailty
Sarcopenia
Dementia
Cognitive
impairment
Age-related
changes and
diseases
Weight loss
Nutritional
deficiencies
Intake^
Fig. 19.11 Malnutrition in dementia - a vicious circle. From Volkert
D, Chourdakis M, Faxen-lrving G, et al. ESPEN guidelines on nutrition in
dementia. Clin Nutr 2015; 34:1052-1073.
Micronutrients, minerals and
their diseases
Vitamins
Vitamins are organic substances with key roles in certain metabolic
pathways, and are categorised into those that are fat-soluble
(vitamins A, D, E and K) and those that are water-soluble (vitamins
of the B complex group and vitamin C).
Recommended daily intakes of micronutrients (Box 19.28) vary
between countries and the nomenclature has become potentially
confusing. In the UK, the ‘reference nutrient intake’ (RNI) has
been calculated as the mean plus two standard deviations
(SD) of daily intake in the population, which therefore describes
normal intake for 97.5% of the population. The lower reference
19.28 Summary of clinically important vitamins
Sources
Vitamin
Rich
Important
Reference nutrient intake (RNI)
Fat-soluble
A (retinol)
Liver
Milk and milk products, eggs, fish oils
700 pig men
600 pig women
D (cholecalciferol)
Fish oils
Ultraviolet exposure to skin
10 pig if >65 years or no
Egg yolks, margarine, fortified cereals
sunlight exposure
E (tocopherol)
Sunflower oil
Vegetables, nuts, seed oils
No RNI. Safe intake:
4 mg men
3 mg women
K (phylloquinone, menaquinone)
Soya oil, menaquinones
produced by intestinal bacteria
Green vegetables
No RNI. Safe intake: 1 pig/kg
Water-soluble
Eh (thiamin)
Pork
Cereals, grains, beans
0.8 mg per 9.68 MJ (2000 kcal)
energy intake
B2 (riboflavin)
Milk
Milk and milk products, breakfast
1.3 mg men
cereals, bread
1.1 mg women
B3 (niacin, nicotinic acid,
Meat, cereals
17 mg men
nicotinamide)
13 mg women
B6 (pyridoxine)
Meat, fish, potatoes, bananas
Vegetables, intestinal microflora synthesis
1 .4 mg men
1 .2 mg women
Folate
Liver
Green leafy vegetables, fortified breakfast
cereals
200 pig
B12 (cobalamin)
Animal products
Bacterial colonisation
1.5 pig
Biotin
Egg yolk
Intestinal flora
No RNI. Safe intake: 10-200 pig
C (ascorbic acid)
Citrus fruit
Fresh fruit, fresh and frozen vegetables
40 mg
*Rich sources contain the nutrient in high concentration but are not generally eaten in large amounts; important sources contain less but contribute most because larger
amounts are eaten.
712 • NUTRITIONAL FACTORS IN DISEASE
19.29 Nutrition in pregnancy and lactation
• Energy requirements: increased in both mother and fetus but can
be met through reduced maternal energy expenditure.
• Micronutrient requirements: adaptive mechanisms ensure
increased uptake of minerals in pregnancy, but extra increments of
some are required during lactation (see Box 19.32). Additional
increments of some vitamins are recommended during pregnancy
and lactation:
Vitamin A. for growth and maintenance of the fetus, and to
provide some reserve (important in some countries to prevent
blindness associated with vitamin A deficiency). Teratogenic in
excessive amounts.
Vitamin D. to ensure bone and dental development in the infant.
Higher incidences of hypocalcaemia, hypoparathyroidisim and
defective dental enamel have been seen in infants of women not
taking vitamin D supplements at >50° latitude.
Folate, taken pre-conceptually and during the first trimester,
reduces the incidence of neural tube defects by 70%.
Vitamin B12: in lactation only.
Thiamin, to meet increased fetal energy demands.
Riboflavin, to meet extra demands.
Niacin, in lactation only.
Vitamin 0. for the last trimester to maintain maternal stores as
fetal demands increase.
Iodine in countries with high consumption of staple foods
(e.g. brassicas, maize, bamboo shoots) that contain goitrogens
(thiocyanates or perchlorates) that interfere with iodine uptake,
supplements prevent infants being born with cretinism.
(fv
• Requirements: although requirements for energy fall with age,
those for micronutrients do not. If dietary intake falls, a vitamin-rich
diet is required to compensate.
• Vitamin D: levels are commonly low due to reduced dietary intake,
decreased sun exposure and less efficient skin conversion. This
leads to bone loss and fractures. Supplements should be given to
those at risk of falls in institutional care - the group at highest risk
and most likely to benefit.
• Vitamin B12 deficiency: a causal relationship with dementia has
not been identified, but it does produce neuropsychiatric effects and
should be checked in all those with declining cognitive function.
19.30 Vitamin deficiency in old age
nutrient intake (LRNI) is the mean minus 2 SD, below which
would be considered deficient in most of the population. These
dietary reference values (DRV) have superseded the terms RDI
(recommended daily intake) and RDA (recommended daily
amount). Other countries use different terminology. Additional
amounts of some micronutrients may be required in pregnancy
and lactation (Box 19.29).
Vitamin deficiency diseases are most prevalent in developing
countries but still occur in developed countries. Older people
(Box 19.30) and alcoholics are at risk of deficiencies in B vitamins
and in vitamins D and C. Nutritional deficiencies in pregnancy
can affect either the mother or the developing fetus, and extra
increments of vitamins are recommended in the UK (see Box
19.29). Darker-skinned individuals living at higher latitude, and
those who cover up or do not go outside are at increased risk
of vitamin D deficiency due to inadequate sunlight exposure.
Dietary supplements are recommended for these ‘at-risk’ groups.
Some nutrient deficiencies are induced by diseases or drugs.
Deficiencies of fat-soluble vitamins are seen in conditions of fat
malabsorption (Box 19.31).
19.31 Gastrointestinal disorders that may be
associated with malabsorption of fat-soluble vitamins
• Biliary obstruction
• Pancreatic exocrine insufficiency
• Coeliac disease
• Ileal inflammation or resection
Biochemical assessment of vitamin status
Nutrient
Biochemical assessments of deficiency or excess
Vitamin A
Serum retinol may be low in deficiency
Serum retinyl esters: when vitamin A toxicity is
suspected
Vitamin D
Plasma/serum 25-hydroxyvitamin D (25(0H)D):
reflects body stores (liver and adipose tissue)
Plasma/serum 1 ,25(0H)2D: difficult to interpret
Vitamin E
Serum tocopherol cholesterol ratio
Vitamin K
Coagulation assays (e.g. prothrombin time)
Plasma vitamin K
Vitamin
(thiamin)
Red blood cell transketolase activity or whole-blood
vitamin
Vitamin B2
(riboflavin)
Red blood cell glutathione reductase activity or
whole-blood vitamin B2
Vitamin B3
(niacin)
Urinary metabolites: 1-methyl-2-pyridone-5-
carboxamide, 1 -methylnicotinamide
Vitamin B6
Plasma pyridoxal phosphate or erythrocyte
transaminase activation coefficient
Vitamin B12
Plasma B12: poor measure of overall vitamin B12
status but will detect severe deficiency
Alternatives (methylmalonic acid and
holotranscobalamin) are not used routinely
Folate
Red blood cell folate
Plasma folate: reflects recent intake but also detects
unmetabolised folic acid from foods and supplements
Vitamin C
Leucocyte ascorbic acid: assesses vitamin C tissue
stores
Plasma ascorbic acid: reflects recent (daily) intake
Some vitamins also have pharmacological actions when given
at supraphysiological doses, such as the use of vitamin A for acne
(p. 1242). Taking vitamin supplements is fashionable in many
countries, although there is no evidence of benefit. Toxic effects
are most serious with high dosages of vitamins A, B6 and D.
Investigation of suspected vitamin deficiency or excess may
involve biochemical assessment of body stores (Box 19.32).
Measurements in blood should be interpreted carefully, however,
in conjunction with the clinical presentation.
| Fat-soluble vitamins
Vitamin A (retinol)
Pre-formed retinol is found only in foods of animal origin. Vitamin
A can also be derived from carotenes, which are present in
green and coloured vegetables and some fruits. Carotenes
provide most of the total vitamin A in the UK and constitute
the only supply in vegans. Retinol is converted to several other
important molecules:
• 1 1 -cis-retinaldehyde is part of the photoreceptor complex
in rods of the retina.
Micronutrients, minerals and their diseases • 713
• Retinoic acid induces differentiation of epithelial cells by
binding to specific nuclear receptors, which induce
responsive genes. In vitamin A deficiency, mucus-secreting
cells are replaced by keratin-producing cells.
• Retinoids are necessary for normal growth, fetal
development, fertility, haematopoiesis and immune
function.
Globally, the most important consequence of vitamin A
deficiency is irreversible blindness in young children. Asia is most
notably affected and the problem is being addressed through
widespread vitamin A supplementation programmes. Adults
are not usually at risk because liver stores can supply vitamin A
when foods containing vitamin A are unavailable.
Early deficiency causes impaired adaptation to the dark (night
blindness). Keratinisation of the cornea (xerophthalmia) gives rise
to characteristic Bitot’s spots and progresses to keratomalacia,
with corneal ulceration, scarring and irreversible blindness (Fig.
19.12). In countries where vitamin A deficiency is endemic,
pregnant women should be advised to eat dark green, leafy
vegetables and yellow fruits (to build up stores of retinol in
the fetal liver), and infants should be fed the same. The WHO
Fig. 19.12 Eye signs of vitamin A deficiency. [A] Bitot’s spots
in xerophthalmia, showing the white triangular plaques (arrows).
[B Keratomalacia in a 14-month-old child. There is liquefactive necrosis
affecting the greater part of the cornea, with typical sparing of the superior
aspect. A, Courtesy of Institute of Ophthalmology, Moorfields Eye Hospital,
London. B, From WHO. Report of a joint WHO/USAID meeting, vitamin A
deficiency and xerophthalmia (WHO technical report series no. 5 W); 1976.
is according high priority to prevention in communities where
xerophthalmia occurs, giving single prophylactic oral doses of
60 mg retinyl palmitate (providing 200000 U retinol) to pre-school
children. This also reduces mortality from gastroenteritis and
respiratory infections.
Repeated moderate or high doses of retinol can cause liver
damage, hyperostosis and teratogenicity. Women in countries
where deficiency is not endemic are therefore advised not to
take vitamin A supplements in pregnancy. Retinol intake may also
be restricted in those at risk of osteoporosis. Acute overdose
leads to nausea and headache, increased intracranial pressure
and skin desquamation. Excessive intake of carotene can cause
pigmentation of the skin (hypercarotenosis); this gradually fades
when intake is reduced.
Vitamin D
The natural form of vitamin D, cholecalciferol or vitamin D3,
is formed in the skin by the action of ultraviolet (U V) light on
7-dehydrocholesterol, a metabolite of cholesterol. Few foods
contain vitamin D naturally and skin exposure to sunlight is the
main source. Moving away from the equator, the intensity of UV
light decreases, so that at a latitude above 50° (including northern
Europe) vitamin D is not synthesised in winter, and even above
30° there is seasonal variation. The body store accumulated
during the summer is consumed during the winter. Vitamin D is
converted in the liver to 25-hydroxyvitamin D (25(OH)D), which
is further hydroxylated in the kidneys to 1 ,25-dihydroxyvitamin
D (1 ,25(OH)2D), the active form of the vitamin (see Fig. 24.61 ,
p. 1051). This 1 ,25(OH)2D activates specific intracellular receptors
that influence calcium metabolism, bone mineralisation and tissue
differentiation. The synthetic form, ergocalciferol or vitamin D2, is
considered to be less potent than endogenous D3.
Recommended dietary intakes aim to improve musculoskeletal
health, preventing rickets and osteomalacia, enhancing muscle
strength and reducing the risks of falls in the elderly. Adequate
levels of vitamin D may also be important in non-musculoskeletal
conditions and may improve immune function (p. 1309). Marga¬
rines are fortified with vitamin D in the UK, and milk is fortified
in some parts of Europe and in North America. However, the
combination of low dietary intake and limited sunlight exposure
in the UK has led to recommendations that everyone over the
age of 5 should take 1 0 jig of vitamin D daily. The individuals at
highest risk of vitamin D deficiency are those who have limited
exposure to sunshine. People who are confined indoors, those
who habitually cover up their skin when outdoors and those
with darker skins should take 10 jig of vitamin D per day all
year round. Other groups may require such supplementation
only in the winter months of October to March.
The effects of vitamin D deficiency (calcium deficiency, rickets
and osteomalacia) are described on page 1 049. An analogue of
vitamin D (calcipotriol) is used for treatment of skin conditions such
as psoriasis. Excessive doses of cholecalciferol, ergocalciferol
or the hydroxylated metabolites cause hypercalcaemia (p. 661).
Vitamin E
There are eight related fat-soluble substances with vitamin E
activity. The most important dietary form is a-tocopherol. Vitamin
E has many direct metabolic actions:
• It prevents oxidation of polyunsaturated fatty acids in cell
membranes by free radicals.
• It helps maintain cell membrane structure.
• It affects DNA synthesis and cell signalling.
• It is involved in the anti-inflammatory and immune systems.
714 • NUTRITIONAL FACTORS IN DISEASE
Human deficiency is rare and has been described only in
premature infants and in malabsorption. It can cause a mild
haemolytic anaemia, ataxia and visual scotomas. Vitamin E intakes
of up to 3200 mg/day (1 000-fold greater than recommended
intakes) are considered safe. Diets rich in vitamin E are consumed
in countries with lower rates of coronary heart disease,
although randomised controlled trials have not demonstrated
cardioprotective effects of vitamin E or other antioxidants.
Vitamin K
Vitamin K is supplied in the diet mainly as vitamin (phylloquinone)
in the UK, or as vitamin K2 (menaquinone) from fermented
products in parts of Asia. Vitamin K2 is also synthesised by
bacteria in the colon. Vitamin K is a co-factor for carboxylation
reactions: in particular, the production of y-carboxyglutamate
(gla). Gla residues are found in four of the coagulation factor
proteins (II, VII, IX and X; p. 918), conferring their capacity to
bind to phospholipid surfaces in the presence of calcium. Other
important gla proteins are osteocalcin and matrix gla protein,
which are important in bone mineralisation.
Vitamin K deficiency leads to delayed coagulation and bleeding.
In obstructive jaundice, dietary vitamin K is not absorbed and it
is essential to administer the vitamin in parenteral form before
surgery. Warfarin and related anticoagulants (p. 939) act by
antagonising vitamin K. Vitamin K is given routinely to newborn
babies to prevent haemorrhagic disease. Symptoms of excess
have been reported only in infants, with synthetic preparations
linked to haemolysis and liver damage.
Water-soluble vitamins
Thiamin (vitamin BJ
Thiamin is widely distributed in foods of both vegetable and
animal origin. Thiamin pyrophosphate (TPP) is a co-factor for
enzyme reactions involved in the metabolism of macronutrients
(carbohydrate, fat and alcohol), including:
• decarboxylation of pyruvate to acetyl -co-enzyme A, which
bridges between glycolysis and the tricarboxylic acid
(Krebs) cycle
• transketolase activity in the hexose monophosphate shunt
pathway
• decarboxylation of a-ketoglutarate to succinate in the
Krebs cycle.
In thiamin deficiency, cells cannot metabolise glucose
aerobically to generate energy as ATP. Neuronal cells are most
vulnerable because they depend almost exclusively on glucose
for energy requirements. Impaired glucose oxidation also causes
an accumulation of pyruvic and lactic acids, which produce
vasodilatation and increased cardiac output.
Deficiency - beri-beri
In the developed world, thiamin deficiency is mainly encountered
in chronic alcoholics. Poor diet, impaired absorption, storage
and phosphorylation of thiamin in the liver, and the increased
requirements for thiamin to metabolise ethanol all contribute. In
the developing world, deficiency usually arises as a consequence
of a diet based on polished rice. The body has very limited stores
of thiamin, so deficiency is manifest after only 1 month on a
thiamin-free diet. There are two forms of the disease in adults:
• Dry (or neurological) beri-beri manifests with chronic
peripheral neuropathy and with wrist and/or foot drop, and
may cause Korsakoff’s psychosis and Wernicke’s
encephalopathy (p. 1195).
• Wet (or cardiac) beri-beri causes generalised oedema
due to biventricular heart failure with pulmonary
congestion.
In dry beri-beri, response to thiamin administration is not
uniformly good. Multivitamin therapy seems to produce some
improvement, however, suggesting that other vitamin deficiencies
may be involved. Wernicke’s encephalopathy and wet beri-beri
should be treated without delay with intravenous vitamin B and C
mixture (Pabrinex, p. 1195). Korsakoff’s psychosis is irreversible
and does not respond to thiamin treatment.
Riboflavin (vitamin BJ
Riboflavin is required for the flavin co-factors involved in
oxidation-reduction reactions. It is widely distributed in animal
and vegetable foods. Levels are low in staple cereals but
germination increases its content. It is destroyed under alkaline
conditions by heat and by exposure to sunlight. Deficiency is
rare in developed countries. It mainly affects the tongue and
lips and manifests as glossitis, angular stomatitis and cheilosis.
The genitals may be involved, as well as the skin areas rich in
sebaceous glands, causing nasolabial or facial dyssebacea. Rapid
recovery usually follows administration of riboflavin 10 mg daily
by mouth.
Niacin (vitamin B3)
Niacin encompasses nicotinic acid and nicotinamide. Nicotinamide
is an essential part of the two pyridine nucleotides, nicotinamide
adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide
phosphate (NADP), which play a key role as hydrogen acceptors
and donors for many enzymes. Niacin can be synthesised in
the body in limited amounts from the amino acid tryptophan.
Deficiency - pellagra
Pellagra was formerly endemic among poor people who subsisted
chiefly on maize, which contains niacytin, a form of niacin that
the body is unable to utilise. Pellagra can develop in only
8 weeks in individuals eating diets that are very deficient in niacin
and tryptophan. It remains a problem in parts of Africa, and
is occasionally seen in alcoholics and in patients with chronic
small intestinal disease in developed countries. Pellagra can
occur in Hartnup’s disease, a genetic disorder characterised by
impaired absorption of several amino acids, including tryptophan.
It is also seen occasionally in carcinoid syndrome (p. 678),
when tryptophan is consumed in the excessive production of
5-hydroxytryptamine (5-HT, serotonin). Pellagra has been called
the disease of the three Ds:
• Dermatitis. Characteristically, there is erythema resembling
severe sunburn, appearing symmetrically over the parts of
the body exposed to sunlight, particularly the limbs and
especially on the neck but not the face (Casal’s necklace,
Fig. 19.13). The skin lesions may progress to vesiculation,
cracking, exudation and secondary infection.
• Diarrhoea. This is often associated with anorexia, nausea,
glossitis and dysphagia, reflecting the presence of a
non-infective inflammation that extends throughout the
gastrointestinal tract.
• Dementia. In severe deficiency, delirium occurs acutely
and dementia develops in chronic cases.
Treatment is with nicotinamide, given in a dose of 100 mg 3
times daily orally or parenterally. The response is usually rapid.
Within 24 hours the erythema diminishes, the diarrhoea ceases
and a striking improvement occurs in the patient’s mental state.
Micronutrients, minerals and their diseases • 715
v-
&
Fig. 19.13 Dermatitis due to pellagra (niacin deficiency). The lesions
appear on those parts of the body exposed to sunlight. The classic ‘Casal’s
necklace’ can be seen around the neck and upper chest. From Karthikeyan
K, Thappa DM. Pellagra and skin. Int J Dermatol 2002; 41:476-481.
Toxicity
Excessive intakes of niacin may lead to reversible hepatotoxicity.
Nicotinic acid is a lipid-lowering agent but at doses above
200 mg a day gives rise to vasodilatory symptoms (‘flushing’
and/or hypotension).
Pyridoxine (vitamin B6)
Pyridoxine, pyridoxal and pyridoxamine are different forms of
vitamin B6 that undergo phosphorylation to produce pyridoxal
5-phosphate (PLP). PLP is the co-factor for a large number of
enzymes involved in the metabolism of amino acids. Vitamin B6
is available in most foods.
Deficiency is rare, although certain drugs, such as isoniazid
and penicillamine, act as chemical antagonists to pyridoxine.
Pyridoxine administration is effective in isoniazid-induced peripheral
neuropathy and some cases of sideroblastic anaemia. Large doses
of vitamin B6 have an antiemetic effect in radiotherapy-induced
nausea. Although vitamin B6 supplements have become popular
in the treatment of nausea in pregnancy, carpal tunnel syndrome
and pre-menstrual syndrome, there is no convincing evidence of
benefit. Very high doses of vitamin B6 taken for several months
can cause a sensory polyneuropathy.
Biotin
Biotin is a co-enzyme in the synthesis of fatty acids, isoleucine
and valine, and is also involved in gluconeogenesis. Deficiency
results from consuming very large quantities of raw egg whites
(>30% energy intake) because the avidin they contain binds to
and inactivates biotin in the intestine. It may also be seen after
long periods of total parenteral nutrition. The clinical features of
deficiency include scaly dermatitis, alopecia and paraesthesia.
Folate (folic acid)
Folates exist in many forms. The main circulating form is
5-methyltetrahydrofolate. The natural forms are prone to oxidation.
Folic acid is the stable synthetic form. Folate works as a methyl
donor for cellular methylation and protein synthesis. It is directly
involved in DNA and RNA synthesis, and requirements increase
during embryonic development.
Folate deficiency may cause three major birth defects (spina
bifida, anencephaly and encephalocele) resulting from imperfect
closure of the neural tube, which takes place 3-4 weeks after
conception. The UK Department of Health advises that women
who have experienced a pregnancy affected by a neural tube
defect should take 5 mg of folic acid daily from before conception
and throughout the first trimester; this reduces the incidence
of these defects by 70%. All women planning a pregnancy are
advised to include good sources of folate in their diet, and to
take folate supplements throughout the first trimester. Liver is
the richest source of folate but an alternative source (e.g. leafy
vegetables) is advised in early pregnancy because of the high
vitamin A content of liver (p. 712). Folate deficiency has also
been associated with heart disease, dementia and cancer. There
is mandatory fortification of flour with folic acid in the USA and
voluntary fortification of many foods across Europe. There are
now concerns that this may contribute to the increased incidence
of colon cancer through promotion of the growth of polyps.
Hydroxycobaiamin (vitamin B12)
Vitamin B12 is a co-factor in folate co-enzyme recycling and nerve
myelination. Vitamin B12 and folate are particularly important in
DNA synthesis in red blood cells (p. 943). The haematological
disorders (macrocytic or megaloblastic anaemias) caused by their
deficiency are discussed on pages 943-945. Vitamin B12, but
not folate, is needed for the integrity of myelin, so that vitamin
B12 deficiency is also associated with neurological disease (see
Box 23.33, p. 944).
Neurological consequences of vitamin B12 deficiency
In older people and chronic alcoholics, vitamin B12 deficiency arises
from insufficient intake and/or from malabsorption. Several drugs,
including neomycin, can render vitamin B12 inactive. Adequate
intake of folate maintains erythropoiesis and there is a concern
that fortification of foods with folate may mask underlying vitamin
B12 deficiency. In severe deficiency there is insidious, diffuse and
uneven demyelination. It may be clinically manifest as peripheral
neuropathy or spinal cord degeneration affecting both posterior
and lateral columns (‘subacute combined degeneration of the
spinal cord’; p. 1138), or there may be cerebral manifestations
(resembling dementia) or optic atrophy. Vitamin B12 therapy
improves symptoms in most cases.
Vitamin C (ascorbic acid)
Ascorbic acid is the most active reducing agent in the aqueous
phase of living tissues and is involved in intracellular electron
transfer. It takes part in the hydroxylation of proline and lysine
in protocollagen to hydroxyproline and hydroxylysine in mature
collagen. It is very easily destroyed by heat, increased pH and
light, and is very soluble in water; hence many traditional cooking
methods reduce or eliminate it. Claims that high-dose vitamin C
improves immune function (including resistance to the common
cold) and cholesterol turnover remain unsubstantiated.
Deficiency - scurvy
Vitamin C deficiency causes defective formation of collagen with
impaired healing of wounds, capillary haemorrhage and reduced
platelet adhesiveness (normal platelets are rich in ascorbate) (Fig.
19.14). Precipitants and clinical features of scurvy are shown
716 • NUTRITIONAL FACTORS IN DISEASE
Fig. 19.14 Scurvy. [A] Gingival swelling and bleeding. [§] Perifollicular hyperkeratosis. A and B, From Ho V, Prinsloo P, Ombiga J. Persistent anaemia
due to scurvy. J New Zeal Med Assoc 2007; 120:62. Reproduced with permission.
19.33 Scurvy - vitamin C deficiency
Precipitants
Increased requirement
• Trauma, surgery, burns,
infections
• Smoking
• Drugs (glucocorticoids, aspirin,
indometacin, tetracycline)
Clinical features
• Swollen gums that bleed
easily
• Perifollicular and petechial
haemorrhages
• Ecchymoses
Dietary deficiency
• Lack of dietary fruit and
vegetables for >2 months
• Infants fed exclusively on
boiled milk
• Haemarthrosis
• Gastrointestinal bleeding
• Anaemia
• Poor wound healing
in Box 19.33. A dose of 250 mg vitamin C 3 times daily by
mouth should saturate the tissues quickly. The deficiencies of
the patient’s diet also need to be corrected and other vitamin
supplements given if necessary. Daily intakes of more than
1 g/day have been reported to cause diarrhoea and the formation
of renal oxalate stones.
Other dietary organic compounds
There are a number of non-essential organic compounds
with purported health benefits, such as reducing risk of heart
disease or cancer. Groups of compounds such as the flavonoids
and phytoestrogens show bioactivity through their respective
antioxidant and oestrogenic or anti-oestrogenic activities.
Flavonoids (of which there are a number of different classes
of compound) are found in fruit and vegetables, tea and wine;
phytoestrogens are found in soy products (with higher intakes
in parts of Asia compared to Europe and the USA) and pulses.
Caffeine from tea and coffee and carbonated beverages affects
the nervous system and can improve mental performance in the
short term, with adverse effects seen at higher intakes. Intake
of non-carbonic organic acids (which are not metabolised to
carbon dioxide), e.g. oxalates, may be restricted in individuals
prone to kidney stones.
Inorganic micronutrients
A number of inorganic elements are essential dietary constituents
for humans (Box 19.34). Deficiency is seen when there is
inadequate dietary intake of minerals or excessive loss from
the body. Toxic effects have also been observed from self-
medication and disordered absorption or excretion. Examples
of clinical toxicity include excess of iron (haemochromatosis or
haemosiderosis), fluoride (fluorosis; p. 149), copper (Wilson’s
disease) and selenium (selenosis, seen in parts of China). For most
minerals, the available biochemical markers do not accurately
reflect dietary intake and dietary assessment is required.
Calcium and phosphorus
Calcium is the most abundant cation in the body and powerful
homeostatic mechanisms control circulating ionised calcium
levels (pp. 661 and 1050). The WHO’s dietary guidelines for
calcium differ between countries, with higher intakes usually
recommended in places with higher fracture prevalence. Between
20% and 30% of calcium in the diet is absorbed, depending
on vitamin D status and food source. Calcium requirements
depend on phosphorus intakes, with an optimum molar ratio
(Ca:P) of 1 : 1 . Excessive phosphorus intakes (e.g. 1-1 .5 g/day)
with a Ca:P of 1 :3 have been shown to cause hypocalcaemia
and secondary hyperparathyroidism (p. 662).
Calcium absorption may be impaired in vitamin D deficiency
(pp. 661 and 1050) and in malabsorption secondary to small
intestinal disease. Calcium deficiency causes impaired bone
mineralisation and can lead to osteomalacia in adults. The potential
benefits of high calcium intake in osteoporosis are discussed on
page 1048. Too much calcium can lead to constipation, and
toxicity has been observed in ‘milk-alkali syndrome’ (p. 662).
Dietary deficiency of phosphorus is rare (except in older
people with limited diets) because it is present in nearly all foods
and phosphates are added to a number of processed foods.
Phosphate deficiency in adults occurs:
• in patients with renal tubular phosphate loss (p. 405)
• in patients receiving a prolonged high dosage of aluminium
hydroxide (p. 419)
• in alcoholics sometimes when they are fed with high-
carbohydrate foods
• in patients receiving parenteral nutrition if inadequate
phosphate is provided.
Deficiency causes hypophosphataemia (p. 368) and muscle
weakness secondary to ATP deficiency.
|jron
Iron is involved in the synthesis of haemoglobin and is required
for the transport of electrons within cells and for a number of
enzyme reactions. Non-haem iron in cereals and vegetables is
Micronutrients, minerals and their diseases • 717
19.34 Summary of clinically important minerals
Sources
Mineral
Rich
Important
Reference nutrient intake (RNI)
Calcium
Milk and milk products, tofu
Milk, boned fish, green vegetables, beans
700 mg2
Phosphorus
Most foods contain phosphorus
Marmite and dry-roasted peanuts Milk, cereal products, bread and meat
550 mg2
Magnesium
Whole grains, nuts
Unprocessed and wholegrain foods
300 mg men
270 mg women2
Iron
Liver, red meat (haem iron)
Non-haem iron from vegetables,
wholemeal bread
8.7 mg
14.8 mg women <50 years
Zinc
Red meat, seafood
Dairy produce, wholemeal bread
9.5 mg men
7 mg women2
Iodine
Edible seaweeds
Milk and dairy products
140 |ig
Selenium
Fish, wheat grown in selenium-rich soils
Fish
75 pig men
60 pig women2
Copper
Shellfish, liver
Bread, cereal products, vegetables
1 .2 mg2
Fluoride
Drinking water, tea
No RNI. Safe intake: 0.5 mg/kg
Potassium
Dried fruit, potatoes, coffee
Fresh fruit, vegetables, milk
3500 mg
Sodium
Table salt, anchovies
Processed foods, bread, bacon
1600 mg
1Rich sources contain the nutrient in high concentration but are not generally eaten in large amounts; important sources contain less but contribute most because larger
amounts are eaten, increased amounts are required in women during lactation.
poorly absorbed but makes the greater contribution to overall
intake, compared to the well-absorbed haem iron from animal
products. Fruits and vegetables containing vitamin C enhance
iron absorption, while the tannins in tea reduce it. Dietary calcium
reduces iron uptake from the same meal, which may precipitate
iron deficiency in those with borderline iron stores. There is no
physiological mechanism for excretion of iron, so homeostasis
depends on the regulation of iron absorption (see Fig. 23.18,
p. 942). This is regulated at the level of duodenal enterocytes by
hepcidin (a peptide secreted by hepatocytes in the duodenum).
The expression of hepcidin is suppressed when body iron is low,
leading to enhanced efflux of iron into the circulation. The normal
daily loss of iron is 1 mg, arising from desquamated surface
cells and intestinal losses. A regular loss of only 2 ml_ of blood
per day doubles the iron requirement. On average, an additional
20 mg of iron is lost during menstruation, so pre-menopausal
women require about twice as much iron as men (and more if
menstrual losses are heavy).
The major consequence of iron deficiency is anaemia (p. 940).
This is one of the most important nutritional causes of ill health
in all parts of the world. In the UK, it is estimated that 10%
women are iron-deficient. Dietary iron overload is occasionally
observed and results in iron accumulation in the liver and, rarely,
cirrhosis. Haemochromatosis results from an inherited increase
in iron absorption (p. 895).
|jodine
Iodine is required for synthesis of thyroid hormones (p. 634).
It is present in sea fish, seaweed and most plant foods grown
near the sea. The amount of iodine in soil and water influences
the iodine content of most foods. Iodine is lacking in the highest
mountainous areas of the world (e.g. the Alps and the Himalayas)
and in the soil of frequently flooded plains (e.g. Bangladesh).
About a billion people in the world are estimated to have an
inadequate iodine intake and hence are at risk of iodine deficiency
disorder. Goitre is the most common manifestation, affecting
about 200 million people (p. 648).
In those areas where most women have endemic goitre, 1 %
or more of babies are born with cretinism (characterised by
mental and physical retardation). There is a higher than usual
prevalence of deafness, slowed reflexes and poor learning in
the remaining population. The best way of preventing neonatal
cretinism is to ensure adequate levels of iodine during pregnancy.
This can be achieved by intramuscular injections with 1-2 mL
of iodised poppy seed oil (475-950 mg iodine) to women of
child-bearing age every 3-5 years, by administration of iodised
oil orally at 6-monthly or yearly intervals to adults and children,
or by provision of iodised salt for cooking.
|Zinc
Zinc is present in most foods of vegetable and animal origin. It
is an essential component of many enzymes, including carbonic
anhydrase, alcohol dehydrogenase and alkaline phosphatase.
Acute zinc deficiency has been reported in patients receiving
prolonged zinc-free parenteral nutrition and causes diarrhoea,
mental apathy, a moist, eczematoid dermatitis, especially around
the mouth, and loss of hair. Chronic zinc deficiency occurs in
dietary deficiency, malabsorption syndromes, alcoholism and its
associated hepatic cirrhosis. It causes the clinical features seen
in the very rare congenital disorder known as acrodermatitis
enteropathica (growth retardation, hair loss and chronic diarrhoea).
Zinc deficiency is thought to be responsible for one-third of
the world’s population not reaching their optimal height. In
the Middle East, chronic deficiency has been associated with
dwarfism and hypogonadism. In starvation, zinc deficiency causes
thymic atrophy; zinc supplements may accelerate the healing
of skin lesions, promote general well-being, improve appetite
and reduce the morbidity associated with the under-nourished
state, and lower the mortality associated with diarrhoea and
pneumonia in children.
718 • NUTRITIONAL FACTORS IN DISEASE
Selenium
The family of seleno-enzymes includes glutathione peroxidase,
which helps prevent free radical damage to cells, and mono-
deiodinase, which converts thyroxine to triiodothyronine
(p. 634). North American soil has a higher selenium content than
European and Asian soil, and the decreasing reliance of Europe
on imported American food in recent decades has resulted in a
decline in dietary selenium intake.
Selenium deficiency can cause hypothyroidism, cardiomyopathy
in children (Keshan’s disease) and myopathy in adults. Excess
selenium can cause heart disease.
^Fluoride
Fluoride helps prevent dental caries because it increases the
resistance of the enamel to acid attack. It is a component of bone
mineral and some studies have shown anti-fracture effects at low
doses, but excessive intakes may compromise bone structure.
If the local water supply contains more than 1 part per million
(ppm) of fluoride, the incidence of dental caries is low. Soft
waters usually contain no fluoride, while very hard waters may
contain over 10 ppm. The benefit of fluoride is greatest when
it is taken before the permanent teeth erupt, while their enamel
is being laid down. The addition of traces of fluoride (at 1 ppm)
to public water supplies is now a widespread practice. Chronic
fluoride poisoning is occasionally seen where the water supply
contains >10 ppm fluoride. It can also occur in workers handling
cryolite (aluminium sodium fluoride), used in smelting aluminium.
Fluoride poisoning is described on page 149. Pitting of teeth is
a result of too much fluoride as a child.
Sodium, potassium and magnesium
Western diets are high in sodium due to the sodium chloride
(salt) that is added to processed food. In the UK, it is suggested
that daily salt intakes are kept well below 6 g. The roles of
sodium, potassium and magnesium, along with the disease states
associated with abnormal intakes or disordered metabolism, are
discussed in Chapter 14.
Other essential inorganic nutrients
These include chloride (a counter-ion to sodium and potassium),
cobalt (required for vitamin B12), sulphur (a constituent of
methionine and cysteine), manganese (needed for or activates
many enzymes) and chromium (necessary for insulin action).
Deficiency of chromium presents as hyperglycaemia and has
been reported in adults as a rare complication of prolonged
parenteral nutrition.
Copper metabolism is abnormal in Wilson’s disease (p. 896).
Deficiency occasionally occurs but only in young children, causing
microcytic hypochromic anaemia, neutropenia, retarded growth,
skeletal rarefaction and dermatosis.
Further information
Websites
bapen.org.uk British Society for Parenteral and Enteral Nutrition;
includes the MUST tool.
bsg.org.uk British Society of Gastroenterology: guidelines on
management of patients with a short bowel, enteral feeding for
adult hospital patients and the provision of a percutaneously placed
enteral tube feeding service.
espen.org European Society for Parenteral and Enteral Nutrition:
guidelines for adult parenteral nutrition; perioperative care in
elective colonic and rectal/pelvic surgery; nutrition in dementia;
acute and chronic intestinal failure in adults; and nutrition in cancer
patients.
nice.org.uk National Institute for Health and Care Excellence: guidance
for nutritional support in adults.
Diabetes mellitus
Clinical examination of the patient with diabetes 720
Management of diabetes 741
Functional anatomy and physiology 723
Patient education, diet and lifestyle 743
Investigations 725
Drugs to reduce hyperglycaemia 745
Insulin therapy 748
Establishing the diagnosis of diabetes 727
Transplantation 752
Aetiology and pathogenesis of diabetes 728
Management of diabetes in special situations 752
Presenting problems in diabetes mellitus 734
Complications of diabetes 755
Hyperglycaemia 734
Diabetic retinopathy 757
Presentation with the complications of diabetes 735
Diabetic nephropathy 757
Diabetes emergencies 735
Diabetic neuropathy 758
Diabetic ketoacidosis 735
The diabetic foot 761
Hyperglycaemic hyperosmolar state 738
Hypoglycaemia 738
720 • DIABETES MELLITUS
Clinical examination of the patient with diabetes
6 Head
Xanthelasma
Cranial nerve palsy/eye
movements/ptosis
5 Neck
Carotid pulse
Bruits
Thyroid enlargement
4 Axillae
A Acanthosis nigricans
in insulin resistance
3 Blood pressure
2 Skin
Bullae
Pigmentation
Granuloma annulare
Vitiligo
1 Hands
(see opposite)
A ‘Prayer sign’
7 Eyes (see opposite)
Visual acuity
Cataract/lens opacity
Fundoscopy
A Exudative maculopathy
Observation
• Weight loss in insulin deficiency
• Obesity in type 2 diabetes
• Mucosal candidiasis
• Dehydration- dry mouth,
itissue turgor
• Air hunger- Kussmaul breathing
in ketoacidosis
8 Insulin injection sites
(see opposite)
9 Abdomen
Hepatomegaly
(fatty infiltration of liver)
10 Legs
Muscle-wasting
Sensory abnormality
Hair loss
Tendon reflexes
^Necrobiosis lipoidica
1 1 Feet (see opposite)
Inspection
Peripheral pulses
Sensation
ACharcot neuroarthropathy
Insets (Acanthosis nigricans) From Urn E (ed.). Medicine and surgery: an integrated textbook. Edinburgh: Elsevier Ltd; 2007. (Exudative maculopathy)
Courtesy of Dr A. I/I/. Patrick and Dr I. W. Campbell.
Clinical examination of the patient with diabetes • 721
Diabetes can affect every system in the
body. In routine clinical practice, exam¬
ination of the patient with diabetes is
focused on hands, blood pressure, axillae,
neck, eyes, insulin injection sites and feet.
7 Examination of the eyes
Visual acuity
• Check distance vision using Snellen chart
at 6 m
• Check near vision using standard reading
chart
• Note that visual acuity can alter reversibly
with acute hyperglycaemia due to osmotic
changes affecting the lens. Most patients
with retinopathy do not have altered
visual acuity, except after a vitreous
haemorrhage or in some cases of
maculopathy
Lens opacification
• Look for the red reflex using the
ophthalmoscope held 30 cm from
the eye
Fundal examination
• Either use a three-field retinal camera or
dilate pupils with a mydriatic (e.g.
tropicamide) and examine with an
ophthalmoscope in a darkened room
• Note features of diabetic retinopathy
(p. 1174), including photocoagulation
scars from previous laser treatment
Background retinopathy. Courtesy of Dr
A. I N. Patrick and Dr I. W. Campbell.
Proliferative retinopathy. Courtesy of Dr
A. I N. Patrick and Dr I. W. Campbell.
i Examination of the hands
Several abnormalities are more common in
diabetes:
• Limited joint mobility (‘cheiroarthropathy’)
causes painless stiffness. The inability to
extend (to 1 80°) the metacarpophalangeal
or interphalangeal joints of at least one
finger bilaterally can be demonstrated in
the ‘prayer sign’
• Dupuytren’s contracture (p. 1059) causes
nodules or thickening of the skin and
knuckle pads
• Carpal tunnel syndrome (p. 1139)
presents with wrist pain radiating into
the hand
• Trigger finger (flexor tenosynovitis) may
be present
• Muscle-wasting/sensory changes may be
present in peripheral sensorimotor
neuropathy, although this is more
common in the lower limbs
8 Insulin injection sites
Main areas used
• Anterior abdominal wall
• Upper thighs/buttocks
• Upper outer arms
Inspection
• Bruising
• Subcutaneous fat deposition
(lipohypertrophy)
• Subcutaneous fat loss (lipoatrophy;
associated with injection of unpurified
animal insulins - now rare)
• Erythema, infection (rare)
Lipohypertrophy of the upper arm.
ii Examination of the feet
Inspection
• Look for evidence of callus formation on
weight-bearing areas, clawing of the toes
(in neuropathy), loss of the plantar arch,
discoloration of the skin (ischaemia),
localised infection and ulcers
• Deformity may be present, especially in
Charcot neuroarthropathy
• Fungal infection may affect skin between
toes, and nails
Circulation
• Peripheral pulses, skin temperature and
capillary refill may be abnormal
Sensation
• This is abnormal in stocking distribution in
typical peripheral sensorimotor neuropathy
• Testing light touch with monofilaments is
sufficient for risk assessment; test other
sensation modalities (vibration, pain,
proprioception) only when neuropathy is
being evaluated
Reflexes
• Ankle reflexes are lost in typical
sensorimotor neuropathy
• Test plantar and ankle reflexes
Monofilaments. The monofilament is
applied gently until slightly deformed at five
points on each foot. Callus should be
avoided as sensation is reduced. If the
patient feels fewer than 8 out of 1 0
touches, the risk of foot ulceration is
increased 5-10-fold.
722 • DIABETES MELLITUS
Diabetes mellitus is a clinical syndrome characterised by an
increase in plasma blood glucose (hyperglycaemia). It has many
causes (see Box 20.9), most commonly type 1 or type 2 diabetes.
Type 1 diabetes is generally considered to result from autoimmune
destruction of insulin-producing cells ((3 cells) in the pancreas,
leading to marked insulin deficiency, whereas type 2 diabetes
is characterised by reduced sensitivity to the action of insulin
and an inability to produce sufficient insulin to overcome this
‘insulin resistance’. Hyperglycaemia causes both acute and
long-term problems. Acutely, high glucose and lack of insulin
can result in marked symptoms, metabolic decompensation
and hospitalisation. Chronic hyperglycaemia is responsible for
diabetes-specific ‘microvascular’ complications affecting the
eyes (retinopathy), kidneys (nephropathy) and feet (neuropathy).
There is a continuous distribution of blood glucose in the
population, with no clear division between people with normal
values and those with abnormal ones. The diagnostic criteria for
diabetes (a fasting plasma glucose of >7.0 mmol/L (126 mg/
dL) or glucose 2 hours after an oral glucose challenge of
>11.1 mmol/L (200 mg/dL); p. 726) have been selected to
identify a degree of hyperglycaemia that, if untreated, carries a
significant risk of microvascular disease, and in particular diabetic
retinopathy. Less severe hyperglycaemia is called ‘impaired
glucose tolerance’. This is not associated with a substantial risk
of microvascular disease, but is connected with an increased
risk of large-vessel disease (e.g. atheroma leading to myocardial
infarction) and with a greater risk of developing diabetes
in future.
The incidence of diabetes is rising. Globally, it is estimated
that 415 million people had diabetes in 2015 (10% of the
world adult population), and this figure is expected to reach
642 million by 2040. This global pandemic principally involves
type 2 diabetes; prevalence varies considerably around the world
(Fig. 20.1), being associated with differences in genetic factors,
as well as environmental ones such as greater longevity, obesity,
unsatisfactory diet, sedentary lifestyle, increasing urbanisation and
economic development. A pronounced rise in the prevalence of
type 2 diabetes occurs in migrant populations to industrialised
countries, as in Asian and Afro-Caribbean immigrants to the UK
or USA. Type 2 diabetes is now seen in children and adolescents,
particularly in some ethnic groups such as Hispanics, non-Hispanic
blacks and Asian Indians.
The incidence of type 1 diabetes is also increasing: between
1960 and 1996, 3% more children were diagnosed worldwide
each year. It is generally more common in countries closer
to the polar regions. Finland, for instance, has the highest
rate of type 1 diagnosis per year at >60 per 100 000 of the
population, whereas in China, India and Venezuela the incidence
is only 0.1 per 100000. Type 1 diabetes is most common in
Caucasians, and more people are diagnosed in the winter
months.
Diabetes is a major burden on health-care facilities in all
countries. Globally, in 2015, diabetes caused 5 million deaths in
those aged 20-79 years, and health-care expenditure attributed
to diabetes was estimated to be at least 673 billion US dollars,
or 12% of total health-care expenditure.
Fig. 20.1 Prevalence (%) of diabetes in those aged 20-79 years, 2015. Based on estimates from the International Diabetes Federation. IDF Diabetes
Atlas, 7th edn. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org.
Functional anatomy and physiology • 723
Functional anatomy and physiology
Regulation of insulin secretion
Insulin is the primary regulator of glucose metabolism and storage
(Box 20.1), and is secreted from pancreatic p cells into the portal
circulation (Fig. 20.2). The pancreatic p cell is designed to regulate
blood glucose concentrations tightly by coupling glucose and
other nutrient stimulus with insulin secretion (Fig. 20.2). Entry
of glucose into the pancreatic p cell is by facilitated diffusion
20.1 Metabolic actions of insulin
Increase
Decrease
Carbohydrate metabolism
Glucose transport (muscle,
Gluconeogenesis
adipose tissue)
Glucose phosphorylation
Glycogen synthesis
Glycolysis
Pyruvate dehydrogenase activity
Pentose phosphate shunt
Glycogenolysis
Lipid metabolism
Triglyceride synthesis
Lipolysis
Fatty acid synthesis (liver)
Lipoprotein lipase (muscle)
Lipoprotein lipase activity
Ketogenesis
(adipose tissue)
Fatty acid oxidation (liver)
Protein metabolism
Amino acid transport
Protein synthesis
Protein degradation
Fig. 20.2 Pancreatic structure and endocrine function. [A] The normal
adult pancreas contains about 1 million islets, which are scattered
throughout the exocrine parenchyma. Histology is shown in Figure 20.6.
HI The core of each islet consists of p cells that produce insulin, and is
surrounded by a cortex of endocrine cells that produce other hormones,
including glucagon (a cells), somatostatin (5 cells) and pancreatic
polypeptide (PP cells). [C] Schematic representation of the pancreatic p
cell. (1) Glucose enters the cell via a glucose transporter (GLUT1 or
GLUT2). (2) Glucose then enters glycolysis, and subsequent oxidative
phosphorylation in the mitochondria results in a rise in intracellular
adenosine triphosphate (ATP). (3) This ATP acts to close the KATP channel
(which consists of four KIR6.2 subunits and four SUR1 subunits). This
leads to membrane depolarisation. (4) The rise in membrane potential
results in calcium influx due to opening of a voltage-gated calcium
channel. This rise in intracellular calcium causes insulin secretory vesicles
to fuse with the cell membrane, leading to insulin secretion. (5) Other
stimuli, such as glucagon-like peptide-1 (GLP-1) or gastric inhibitory
polypeptide (GIP), act on G-protein-coupled receptors to increase cyclic
adenosine monophosphate (cAMP) and amplify the insulin secretion.
Genetic defects in the p cell result in diabetes. The primary genes are
glucokinase (the initial step in glycolysis) and HNFIa, HNF4a and HNFIp
(nuclear transcription factors). Two groups of drugs act on the p cell to
promote insulin secretion. Sulphonylureas act to close the KATp channel,
causing membrane depolarisation, calcium influx and insulin secretion.
Incretin-acting drugs either increase the concentration of endogenous
GLP-1 and GIP (the dipeptidyl peptidase 4, or DPP-4, inhibitors) or act as
directly on the GLP-1 receptor (GLP-1 receptor agonists). Both of these
drug groups act to augment insulin secretion but only following an initial
stimulus to insulin secretion through closure of p cell KATP channels by
glucose (or sulphonylureas).
down its concentration gradient through cell membrane glucose
transporters (GLUTs). Glucose is then metabolised by glycolysis
and oxidative phosphorylation. The first step of the glycolytic
pathway, the conversion of glucose to glucose-6-phosphate, is
catalysed by the enzyme glucokinase (GK). Glucokinase has a low
affinity for glucose and so its activity under normal physiological
conditions varies markedly, according to the concentration of
glucose. This makes it a very effective glucose sensor in the
P cell. In what is considered a classical direct or triggering
pathway, glucose metabolism results in increased intracellular
adenosine triphosphate (ATP) and reduced adenosine diphosphate
/Duodenum
Accessory ampulla
Ampulla
of Vater
Arteriole
Islet core (p cells)
Other islet cells
r*
Sulphonylureas
KIR6.2
SUR1
724 • DIABETES MELLITUS
mins
Fig. 20.3 Insulin secretion in response to intravenous or oral
glucose. [A] An acute first phase of insulin secretion occurs in response
to an elevated blood glucose, followed by a sustained second phase.
[§] The incretin effect describes the observation that insulin secretion is
greater when glucose is given by mouth than when glucose is administered
intravenously to achieve the same rise in blood glucose concentrations.
The additional stimulus to insulin secretion is mediated by release of
peptides from the gut and these actions are exploited in incretin-based
therapies (p. 747).
(ADP), which causes closure of an ATP-sensitive potassium
channel (KATP). The resulting membrane depolarisation of the p
cell results in insulin secretion due to triggering of calcium release
by voltage-sensitive calcium channels. In addition to this pathway,
the amount of insulin released can be amplified or potentiated
by the background blood glucose, other nutrients and peptides,
and by neuronal control via the sympathetic and parasympathetic
nervous system. A good example of this potentiation of insulin
release is seen with the secretion of two gut peptides following
ingestion of food. Glucagon-like peptide-1 (GLP-1) and gastric
inhibitory polypeptide (GIP) are released from gastrointestinal
L cells and K cells, respectively, following a meal, and act via
receptors on the pancreatic p cells to augment insulin secretion.
Thus, for a given glucose stimulus to the p cell, there is greater
insulin secretion with oral glucose administration (where the
gut peptides are released) compared to intravenous glucose
administration (which does not stimulate gut peptide release).
This enhanced insulin secretion following oral administration of
glucose is termed the ‘incretin’ effect (Fig. 20.3), and GLP-1
and GIP are known as incretin hormones.
Insulin is synthesised as a pro-hormone (pro-insulin) that
consists of an a and a p chain, which are linked by C-peptide
(Fig. 20.4). The C-peptide is cleaved by p-cell peptidases to
create insulin (which now consists of the a and p chains) and
free C-peptide. Insulin secretion in response to a glucose stimulus
Fig. 20.4 Processing of pro-insulin into insulin and C-peptide.
Pro-insulin in the pancreatic p cell is cleaved to release insulin and
equimolar amounts of inert C-peptide (connecting peptide). Measurement
of C-peptide can be used to assess endogenous insulin secretory capacity.
classically occurs in two phases (see Fig. 20.3). The rapid first
phase represents the secretion of pre-formed insulin from granules
within the p cells, while the more prolonged second phase is a
consequence of newly synthesised insulin.
|Regulation of glucagon secretion
Pancreatic islets also contain other endocrine cells such as a
cells that secrete the peptide hormone glucagon, and 5 cells that
produce somatostatin (see Fig. 20.2B). Alpha cells make up about
20% of the human islet cell population. Glucagon has opposite
effects to insulin and acts on the liver (and kidney) to stimulate
glycogenolysis, leading to increased hepatic glucose production.
Regulation of glucagon secretion by the a cell is complex, but
p-cell insulin secretion, co-secreted zinc and y-aminobutyric acid
(GABA), as well as somatostatin from 5 cells, are thought to have
major regulatory roles. This means that insulin and glucagon are
tightly, and reciprocally, regulated, such that the ratio of insulin
to glucagon in the portal vein is a major determinant of hepatic
glucose production. Glucagon is also critically important to the
body’s defence against hypoglycaemia (p. 738).
Blood glucose homeostasis
Blood glucose is tightly regulated and maintained within a narrow
range. This is essential for ensuring a continuous supply of glucose
to the central nervous system. The brain has little capacity to
store energy in the form of glycogen or triglyceride, and the
blood-brain barrier is largely impermeable to fatty acids, so the
brain depends on the liver for a constant supply of glucose for
oxidation and hence generation of ATP. Glucose homeostasis is
achieved through the coordinated actions of multiple organs, but
mainly reflects a balance between the entry of glucose into the
circulation from the liver, supplemented by intestinal absorption
of glucose after meals, and the uptake of glucose by peripheral
tissues, particularly skeletal muscle and brain.
After ingestion of a meal containing carbohydrate, normal
blood glucose levels are maintained by:
• suppression of hepatic glucose production
• stimulation of hepatic glucose uptake
• stimulation of glucose uptake by peripheral tissues
(Fig. 20.5).
The post-prandial rise in portal vein insulin and glucose,
together with a fall in portal glucagon concentrations, suppresses
hepatic glucose production and results in net hepatic glucose
uptake. Depending on the size of the carbohydrate load, around
one-quarter to one-third of ingested glucose is taken up in the
liver. In addition, insulin stimulates glucose uptake in skeletal
muscle and fat, mediated by the glucose transporter GLUT4.
Investigations • 725
Fig. 20.5 Major metabolic pathways of fuel metabolism and the actions of insulin. © indicates stimulation and © indicates suppression by insulin.
In response to a rise in blood glucose, e.g. after a meal, insulin is released, suppressing gluconeogenesis and promoting glycogen synthesis and storage.
Insulin promotes the peripheral uptake of glucose, particularly in skeletal muscle, and encourages storage (as muscle glycogen). It also promotes protein
synthesis and lipogenesis, and suppresses lipolysis. The release of intermediate metabolites, including amino acids (glutamine, alanine), 3-carbon
intermediates in oxidation (lactate, pyruvate) and free fatty acids (FFAs), is controlled by insulin. In the absence of insulin, e.g. during fasting, these
processes are reversed and favour gluconeogenesis in liver from glycogen, glycerol, amino acids and other 3-carbon precursors.
When intestinal glucose absorption declines between meals,
portal vein insulin and glucose concentrations fall while glucagon
levels rise. This leads to increased hepatic glucose output via
gluconeogenesis and glycogen breakdown. The liver now resumes
net glucose production and glucose homeostasis is maintained.
The main substrates for gluconeogenesis are glycerol and amino
acids, as shown in Figure 20.5.
Fat metabolism
Adipocytes (and the liver) synthesise triglyceride from non-
esterified (‘free’) fatty acids (FFAs) and glycerol. Insulin is the major
regulator not only of glucose metabolism but also of fatty acid
metabolism. High insulin levels after meals promote triglyceride
accumulation. In contrast, in the fasting state, low insulin levels
permit lipolysis and the release into the circulation of FFAs (and
glycerol), which can be oxidised by many tissues. Their partial
oxidation in the liver provides energy to drive gluconeogenesis
and also produces ketone bodies (acetoacetate, which can be
reduced to 3 -hydroxy butyrate or decarboxylated to acetone),
which are generated in hepatocyte mitochondria. Ketone bodies
are organic acids that, when formed in small amounts, are
oxidised and utilised as metabolic fuel. However, the rate of
utilisation of ketone bodies by peripheral tissues is limited, and
when the rate of production by the liver exceeds their removal,
hyperketonaemia results. This occurs physiologically during
starvation, when low insulin levels and high catecholamine levels
increase lipolysis and delivery of FFAs to the liver.
Investigations
Urine glucose
Testing the urine for glucose with dipsticks is a common screening
procedure for detecting diabetes. If possible, testing should be
performed on urine passed 1-2 hours after a meal to maximise
sensitivity. Glycosuria always warrants further assessment by
blood testing (see below). The greatest disadvantage of urine
glucose measurement is the individual variation in renal threshold
for glucose. The most frequent cause of glycosuria is a low renal
threshold, which is common during pregnancy and in young
people; the resulting ‘renal glycosuria’ is a benign condition
unrelated to diabetes. Another disadvantage is that some drugs
(such as (3-lactam antibiotics, levodopa and salicylates) may
interfere with urine glucose tests.
726 • DIABETES MELLITUS
Blood glucose
Laboratory glucose testing in blood relies on an enzymatic reaction
(glucose oxidase) and is cheap, usually automated and highly
reliable. However, blood glucose levels depend on whether the
patient has eaten recently, so it is important to consider the
circumstances in which the blood sample was taken.
Blood glucose can also be measured with testing sticks
that are read with a portable electronic meter. These are used
for capillary (fingerprick) testing to monitor diabetes treatment
(p. 742). There is some debate as to whether self-monitoring
in people with type 2 diabetes improves glycaemic control.
Many countries now offer self-monitoring only to people
with type 2 diabetes taking sulphonylurea or insulin therapy
because of the risk of hypoglycaemia. To make the diagnosis of
diabetes, the blood glucose concentration should be estimated
using an accurate laboratory method rather than a portable
technique.
Glucose concentrations are lower in venous than arterial or
capillary (fingerprick) blood. Whole-blood glucose concentrations
are lower than plasma concentrations because red blood cells
contain relatively little glucose. Venous plasma values are
usually the most reliable for diagnostic purposes (Boxes 20.2
and 20.3).
20.2 Diagnosis of diabetes and pre-diabetes
Diabetes is confirmed by:
• either plasma glucose in random sample or 2 hrs after a 75 g
glucose load >11.1 mmol/L (200 mg/dL) or
• fasting plasma glucose >7.0 mmol/L (126 mg/dL) or
• HbA1c >48 mmol/mol
In asymptomatic patients, two diagnostic tests are required to confirm
diabetes; the second test should be the same as the first test to avoid
confusion
‘Pre-diabetes’ is classified as:
• impaired fasting glucose = fasting plasma glucose >6.1 mmol/L
(110 mg/dL) and <7.0 mmol/L (126 mg/dL)
• impaired glucose tolerance = fasting plasma glucose <7.0 mmol/L
(126 mg/dL) and 2-hr glucose after 75 g oral glucose drink
7.8-11.1 mmol/L (140-200 mg/dL)
HbA1c criteria for pre-diabetes vary. The National Institute for Health
and Care Excellence (NICE) guidelines (UK) recommend considering an
HbA1c range of 42-47 mmol/mol to be indicative of pre-diabetes; the
American Diabetes Association (ADA) guidelines suggest a range of
39-47 mmol/mol. The ADA also suggests a lower fasting plasma
glucose limit of > 5.6 mmol/L (100 mg/dL) for impaired fasting
glucose.
20.3 How to perform an oral glucose tolerance
test (OGTT)
Preparation before the test
• Unrestricted carbohydrate diet for 3 days
• Fasted overnight for at least 8 hrs
• Rest for 30 mins
• Remain seated for the duration of the test, with no smoking
Sampling
• Measure plasma glucose before and 2 hrs after a 75 g oral glucose
drink
|jnterstitial glucose
A relatively new approach to measuring glucose levels in diabetes
is through the use of interstitial continuous glucose monitoring
(CGM). CGM systems use a tiny sensor inserted under the skin
to check glucose levels in interstitial fluid. The sensor can stay
in place for up to 2 weeks before being replaced and provides
real-time measurements of glucose levels every 1 or 5 minutes
(see Fig. 20.16, p. 751). These devices are not as accurate as
blood glucose testing, particularly when levels are low or changing
rapidly, so users must still check blood glucose with a glucose
meter before driving or changing therapy. CGM provides useful
information on daily glucose profiles and, in particular, night-time
glucose levels. In addition, alarms can be incorporated into the
CGM device to warn individuals about hypoglycaemia.
Urine and blood ketones
Acetoacetate can be identified in urine by the nitroprusside
reaction, using either tablets or dipsticks. Ketonuria may be
found in normal people who have been fasting or exercising
strenuously for long periods, vomiting repeatedly, or eating a
diet high in fat and low in carbohydrate. Ketonuria is therefore
not pathognomonic of diabetes but, if it is associated with
glycosuria, the diagnosis of diabetes is highly likely. Urine ketone
measurements are semi-quantitative, awkward to perform and
retrospective (i.e. the urine has accumulated over several hours).
Also, they do not measure the major ketone found in blood during
diabetic ketoacidosis (DKA), beta-hydroxybutyrate (p-OHB).
Beta-OHB can be measured in blood in the laboratory and
also in a fingerprick specimen of capillary blood with a test stick
and electronic meter. Whole-blood p-OHB monitoring is useful
in assisting with insulin adjustment during intercurrent illness
or sustained hyperglycaemia to prevent or detect DKA. Blood
p-OHB monitoring is also useful in monitoring resolution of DKA
in hospitalised patients (Box 20.4).
| Glycated haemoglobin
Glycated haemoglobin provides an accurate and objective
measure of glycaemic control over a period of weeks to
months.
In diabetes, the slow non-enzymatic covalent attachment of
glucose to haemoglobin (glycation) increases the amount in the
Hb^ (HbA1c) fraction relative to non-glycated adult haemoglobin
(HbA0). These fractions can be separated by chromatography;
BS 20.4 Interpretation of capillary blood ketone
measurements
Measurement*
Interpretation
<0.6 mmol/L
Normal; no action required
0.6-1 .5 mmol/L
Suggests metabolic control may be deteriorating;
the patient should continue to monitor and seek
medical advice if sustained/progressive
1. 5-3.0 mmol/L
With high blood glucose (> 1 0 mmol/L), there is
a high risk of diabetic ketoacidosis; seek medical
advice
>3.0 mmol/L
Severe ketosis; in the presence of high glucose
(> 1 0 mmol/L) suggests presence of diabetic
ketoacidosis; seek urgent medical help
*To convert to mg/dL, multiply values by 18.
Investigations • 727
KM 20.5 Conversion between DCCT and IFCC units
for HbA1c
DCCT units (%)
IFCC units (mmol/mol)
4
20
5
31
6
42
7
53
8
64
9
75
10
86
IFCC HbA1c (mmol/mol) =
[DCCT HbA1c(%)-2.1 5] x 10.929
(DCCT = Diabetes Control and Complications Trial; IFCC = International
Federation of Clinical Chemistry and Laboratory Medicine)
laboratories may report glycated haemoglobin as total glycated
haemoglobin (GHb), HbAi or HbA1c. In most countries, HbA1c is
the preferred measurement. The rate of formation of HbA1c is
directly proportional to the ambient blood glucose concentration;
a rise of 1 1 mmol/mol in HbA1c corresponds to an approximate
average increase of 2 mmol/L (36 mg/dL) in blood glucose.
Although HbA1c concentration reflects the integrated blood
glucose control over the lifespan of erythrocytes (120 days),
HbA1c is most sensitive to changes in glycaemic control occurring
in the month before measurement.
Various assay methods are used to measure HbA1c, but most
laboratories have been reporting HbA1c values (as %) aligned with
the reference range that was used in the Diabetes Control and
Complications Trial (DCCT). To allow worldwide comparisons of
HbA1c values, the International Federation of Clinical Chemistry and
Laboratory Medicine (IFCC) has developed a standard method;
IFCC-standardised HbA1c values are reported in mmol/mol.
In 201 1 , many countries adopted the IFCC reference method
(Box 20.5) and this is used throughout this textbook.
HbA1c estimates may be erroneously diminished in anaemia or
during pregnancy, and may be difficult to interpret with some assay
methods in patients who have uraemia or a haemoglobinopathy.
It is particularly important to be aware of this in some developing
countries where nutritional deficiency is common, especially
when an absolute cut-off point is used, e.g. in the diagnosis
of diabetes.
|jslet autoantibodies
As type 1 diabetes is a characterised by autoimmune destruction
of the pancreatic p cells, it can be useful in the differential
diagnosis of diabetes (see below) to establish evidence of such
an autoimmune process. If islet autoantibodies are present at high
titre, this can be supportive of a diagnosis of type 1 diabetes. The
antibodies that are measured are directed against components
of the islet and consist of antibodies to insulin, glutamic acid
decarboxylase (GAD), protein tyrosine phosphatase-related
proteins (IA-2) and the zinc transporter ZnT8. These antibodies
can be detected in the general population; the level at which
they are called positive does vary by laboratory but is usually at
concentrations greater than the 95th centile or 97.5th centile of
the general population. This means that pancreatic autoantibodies
can be weakly positive in people who do not have type 1 diabetes.
However, if anti-GAD and anti-IA-2 antibodies are measured
together, they will be ‘positive’ (alone or in combination) in
approximately 85% of newly diagnosed type 1 diabetes. Some
laboratories now include anti-ZnT8 antibodies in their panel of
tests, which increases sensitivity for type 1 diabetes to 92%.
| C-peptide
C-peptide is the connecting peptide that is cleaved in the
production of insulin from pro-insulin (see Fig. 20.4). It can be
readily measured in blood and urine by sensitive immunoassays.
Serum C-peptide is a marker of endogenous insulin secretion (a
synthetic insulin does not contain C-peptide) and is particularly
useful if a patient is on exogenous (injected) insulin treatment,
when insulin assays would simply detect the injected insulin.
Serum C-peptide can help clarify the differential diagnosis of
diabetes, as it is usually very low in long-standing type 1 diabetes
and very high in severe insulin resistance. It is also useful in the
diagnosis of spontaneous hypoglycaemia (p. 676).
Urine protein
Standard urine dipstick testing for albumin detects urinary
albumin at concentrations above 300 mg/L, but smaller amounts
(microalbuminuria; see Box 15.9, p. 394) can only be measured
using specific albumin dipsticks or quantitative biochemical
laboratory tests. Microalbuminuria or proteinuria, in the absence
of urinary tract infection, is an important indicator of diabetic
nephropathy and/or increased risk of macrovascular disease
(p. 757).
Establishing the diagnosis of diabetes
Glycaemia can be classified into three categories: normal, impaired
(pre-diabetes) and diabetes (see Box 20.2). The glycaemia cut-off
that defines diabetes is based on the level above which there
is a significant risk of microvascular complications (retinopathy,
nephropathy and neuropathy). People categorised as having
pre-diabetes have blood glucose levels that carry a negligible
risk of microvascular complications but are at increased risk of
developing diabetes. Also, because there is a continuous risk
of macrovascular disease (atheroma of large conduit blood
vessels) with increasing glycaemia in the population, people with
pre-diabetes have an increased risk of cardiovascular disease
(myocardial infarction, stroke and peripheral vascular disease).
The traditional way to diagnose diabetes or pre-diabetes has
been by using random or fasting plasma glucose and/or an
oral glucose tolerance test (OGTT). In 201 1 , the World Health
Organisation (WHO) advocated the use of glycated haemoglobin
(HbA1c, see above) to diagnose diabetes and this has been
adopted in some regions. When a person has symptoms of
diabetes, the diagnosis can be confirmed with either a fasting
glucose of >7.0 mmol/L (126 mg/dL) or a random glucose
of >11.1 mmol/L (200 mg/dL) (see Box 20.2). Asymptomatic
individuals should have a second confirmatory test. Diabetes
should not be diagnosed on capillary blood glucose results.
Alternatively, an HbA1c of >48 mmol/mol is also diagnostic of
diabetes. As HbA1c reflects the last 2-3 months of glycaemia, it
should not be used to diagnose diabetes where the duration of
onset is short, i.e. in someone with suspected type 1 diabetes
or severe symptomatic hyperglycaemia (p. 734). If there is a high
clinical suspicion of diabetes with an HbA1c of less than 48 mmol/
mol, then a fasting glucose measurement is required to rule out
diabetes. It should be noted that the two populations identified
using blood glucose and using HbA1c will not be identical, some
728 • DIABETES MELLITUS
being diagnosed with diabetes using one criterion but not the
other. When a person is asymptomatic and repeat testing is
required, the same method should be used for the confirmatory
test to avoid diagnostic confusion.
Pre-diabetes can be subclassified as ‘impaired fasting glucose’
(IFG), based on a fasting plasma glucose result, or ‘impaired
glucose tolerance’ (IGT), based on the fasting and 2-hour OGTT
results (see Box 20.3). Patients with pre-diabetes should be
advised of their risk of progression to diabetes, given advice about
lifestyle modification to reduce this risk (as for type 2 diabetes,
p. 743), and have aggressive management of cardiovascular risk
factors such as hypertension and dyslipidaemia. The HbA1c criteria
for pre-diabetes are less clear. The NICE guidelines (UK) suggest
a range of 42-47 mmol/mol, whereas the American Diabetes
Association guidelines recommend a range of 39-47 mmol/mol.
In some people (especially those with pre-existing insulin
resistance or low (3-cell mass/function), an abnormal blood
glucose result is observed during acute severe illness, such as
infection or myocardial infarction. This ‘stress hyperglycaemia’ is a
consequence of hormones, such as cortisol and catecholamines,
antagonising the action of insulin and thereby increasing insulin
resistance. It usually disappears after the acute illness has
resolved, but affected individuals have a significantly increased
risk of type 2 diabetes in subsequent years. A similar mechanism
explains the occurrence of diabetes in some people treated with
glucocorticoids (steroid-induced diabetes).
The diagnostic criteria recommended for diabetes in pregnancy
are more stringent than those for non-pregnant patients (see Box
20.31). Pregnant women with abnormal glucose tolerance should
be referred urgently to a specialist unit for full evaluation. Due
to the increased red cell turnover that occurs in pregnancy, an
HbA1c test should not be used to diagnose diabetes in pregnancy
When a diagnosis of diabetes is confirmed, other investigations
should include plasma urea, creatinine and electrolytes, lipids,
liver and thyroid function tests, blood or urine ketones, and
urine protein.
Aetiology and pathogenesis of diabetes
In both of the common types of diabetes, environmental factors
interact with genetic susceptibility to determine which people
develop the clinical syndrome, and the timing of its onset.
However, the underlying genes, precipitating environmental
factors and pathophysiology differ substantially between type
1 and type 2 diabetes. Type 1 diabetes was previously termed
‘insulin-dependent diabetes mellitus’ (IDDM) and is invariably
associated with insulin deficiency requiring replacement therapy.
Type 2 diabetes was previously termed ‘non-insulin-dependent
diabetes mellitus’ (NIDDM) because patients retain the capacity to
secrete insulin, and measured insulin levels are often higher than
those seen in people without diabetes. In type 2 diabetes, though,
there is an impaired sensitivity to insulin (insulin resistance) and,
initially, affected individuals can usually be treated without insulin
replacement therapy. However, 20% or more of patients with
type 2 diabetes will ultimately develop insulin deficiency requiring
replacement therapy, so IDDM and NIDDM were misnomers.
Type 1 diabetes
Pathology
Type 1 diabetes is generally considered a T-cell-mediated
autoimmune disease (p. 81) involving destruction of the
insulin-secreting p cells in the pancreatic islets. The natural history
of type 1 diabetes is based on the model proposed by Eisenbarth
in 1 986, which proposed that genetically susceptible individuals
with a given p-cell mass who were subsequently exposed to an
environmental trigger then developed p-cell autoimmunity that
led to progressive loss of p cells. This process was seen to
take place over a prolonged period (months to years). Marked
hyperglycaemia, accompanied by the classical symptoms of
diabetes, occurs only when 80-90% of the functional capacity of
p cells has been lost. More recent data have led to modifications
of this model. For example, it is now recognised that pancreatic
p cells can persist in some individuals with very long-standing
diabetes and may never reach zero. On the contrary, some
individuals present with much higher levels of p-cell viability
(40-50%) and that may reflect lower levels of physical activity
or increased body mass. Despite this uncertainty, in the natural
history of type 1 diabetes there is initially a loss of first-phase
insulin secretion, followed by a period of glucose intolerance
and clinically undiagnosed diabetes.
The pathology in the pre-diabetic pancreas is characterised
by an inflammatory lesion within islets, ‘insulitis’ (Fig. 20.6), with
infiltration of the islets by mononuclear cells containing activated
macrophages, helper cytotoxic and suppressor T lymphocytes,
natural killer cells and B lymphocytes. Initially, these lesions are
patchy and, until a very late stage, lobules containing heavily
infiltrated islets are seen adjacent to unaffected lobules. The
destructive process is p-cell-specific. It is unclear why other
hormone-secreting cells in the islets, such as a and 6 cells,
remain intact. In addition, while a number of theories such as
molecular mimicry, oxidative stress and viral infections have been
proposed, the specific mechanisms for inducing autoimmunity
in type 1 diabetes are unknown.
Autoimmunity in type 1 diabetes is identified by the presence of
autoantibodies to islet and/or p-cell antigens. Islet cell antibodies
can be present long before the clinical presentation of type
1 diabetes, and their detection can be useful in confirming a
diagnosis of type 1 diabetes, but they are poorly predictive
of disease progression and disappear over time (Fig. 20.6).
Autoantibodies are typically present in 70-80% of newly diagnosed
type 1 diabetes, but this can vary depending on age, gender and
ethnicity, as well as quality of the assay employed. Autoantibodies
can also be used to predict disease with a 5-year risk of type
1 diabetes of about 20-25% in people with a single positive
autoantibody, 50-60% in those with two positive autoantibodies,
and 70% in those with three autoantibodies. Type 1 diabetes is
associated with other autoimmune disorders (Ch. 4), including
thyroid disease (p. 638), coeliac disease (p. 805), Addison’s
disease (p. 671), pernicious anaemia (p. 944) and vitiligo (p. 1257).
The association between type 1 diabetes and coeliac disease
is particularly strong; it is estimated that around 1 in 20 people
with type 1 diabetes (especially when diagnosed in childhood)
will have biopsy-proven coeliac disease and so many countries
advocate routine screening for this condition.
Genetic predisposition
Although not showing a simple pattern of inheritance, type 1
diabetes is strongly influenced by genetic factors. The relationship
is complex and, as indicated, multifactorial. Monozygotic twins
have a disease concordance rate of 30-50%, while dizygotic
twins have a concordance of 6-10%. In the USA, the risk of
developing type 1 diabetes is 1 : 20 for those with a first-degree
relative, compared with a 1 :300 risk in the general population.
Children of mothers with type 1 diabetes have a 1-4% risk of
Aetiology and pathogenesis of diabetes • 729
(3-cell destruction
Genetic
susceptibility to
immune dysfunction
Inflammatory cell infiltration of islet
Antibody-mediated (3-cell destruction
Autoantibodies present in blood
Loss of first-phase
insulin secretion
Impaired glucose Overt
tolerance diabetes
Time
Fig. 20.6 Pathogenesis of type 1 diabetes. Proposed sequence of events in the development of type 1 diabetes. Environmental triggers are described
in the text. Insets (normal islet, (5-cell destruction) Courtesy of Dr A. Foulis, Dept of Pathology, University of Glasgow.
BS 20.6 Risk of type 1 diabetes among first-degree
relatives of patients with type 1 diabetes
Relative with type 1 diabetes
% overall risk
Identical twin
30-50
Non-identical twin
6-10
HLA-identical sibling
16
Non-HLA-identical sibling
5
Father
10
Mother
1-4
Both parents
Up to 30
developing type 1 diabetes, but children of fathers with type 1
diabetes have a 1 0% risk. Despite this genetic influence, 80-85%
of new cases present in individuals with no known family history
of the disease.
The inheritance of type 1 diabetes is polygenic (Box 20.6),
with over 20 different regions of the human genome showing an
association with type 1 diabetes risk. Most interest has focused
on the human leucocyte antigen (HLA) region within the major
histocompatibility complex on the short arm of chromosome
6. The HLA haplotypes DR3 and/or DR4 are associated with
increased susceptibility to type 1 diabetes in Caucasians and
are in ‘linkage disequilibrium’, i.e. they tend to be transmitted
together, with the neighbouring alleles of the HLA-DQA1 and
DQB1 genes. The latter may be the main determinants of genetic
susceptibility, since these HLA class II genes code for proteins
on the surface of cells that present foreign and self-antigens
to T lymphocytes (p. 82). Candidate gene and genome-wide
association studies have also implicated other genes in type
1 diabetes, e.g. CD25, PTPN22, SH2B3, IL2RA and IL-10.
Interestingly, the majority of these disease risk loci are involved
in immune responsiveness, such as recognition of pancreatic
islet antigens, T-cell development and immune regulation. The
genes associated with type 1 diabetes overlap with those for
other autoimmune disorders, such as coeliac disease and
thyroid disease, consistent with clustering of these conditions
in individuals or families.
Environmental predisposition
The wide geographical and seasonal variations in incidence,
and the rapid acquisition of local disease incidence rates in
migrants from low- to high-incidence countries suggest that
environmental factors have an important role in precipitating
disease.
Although hypotheses abound, the nature of these environmental
factors is unknown. They may trigger type 1 diabetes through
direct toxicity to (3 cells or by stimulating an autoimmune reaction
directed against (3 cells. Potential candidates fall into three
main categories: viruses, specific drugs or chemicals, and
dietary constituents. Viruses implicated in the aetiology of type
1 diabetes include mumps, Coxsackie B4, retroviruses, rubella
(in utero), cytomegalovirus and Epstein-Barr virus. Various dietary
nitrosamines (found in smoked and cured meats) and coffee
have been proposed as potentially diabetogenic toxins. Bovine
serum albumin (BSA), a major constituent of cow’s milk, has
been implicated, since children who are given cow’s milk early
in infancy are more likely to develop type 1 diabetes than those
who are breastfed. BSA may cross the neonatal gut and raise
antibodies that cross-react with a heat-shock protein expressed
by (3 cells. It has also been proposed that reduced exposure to
microorganisms in early childhood limits maturation of the immune
system and increases susceptibility to autoimmune disease (the
‘hygiene hypothesis’). In addition, the high incidence rates in
northern Europe have led to the suggestion that low levels of
vitamin D may be important, but to date no clear cause-effect
relationship has been identified.
Metabolic disturbances in type 1 diabetes
Patients with type 1 diabetes present when progressive (3-cell
destruction has crossed a threshold at which adequate insulin
secretion and normal blood glucose levels can no longer be
sustained. Above a certain level, high glucose levels may be toxic
to the remaining (3 cells, so that profound insulin deficiency rapidly
ensues, causing the metabolic sequelae shown in Figure 20.7.
Hyperglycaemia leads to glycosuria and dehydration, causing
fatigue, polyuria, nocturia, thirst and polydipsia, susceptibility to
urinary and genital tract infections, and later tachycardia and
hypotension. Unrestrained lipolysis and proteolysis result in
730 • DIABETES MELLITUS
Fig. 20.7 Acute metabolic complications of insulin deficiency. (FFA = free fatty acid)
weight loss. Ketoacidosis occurs when generation of ketones
exceeds the capacity for their metabolism. Elevated blood
H+ ions drive K+ out of the intracellular compartment, while
secondary hyperaldosteronism encourages urinary loss of K+.
Thus patients usually present with a short history (typically a few
weeks) of hyperglycaemic symptoms (thirst, polyuria, nocturia
and fatigue), infections and weight loss, and may have developed
ketoacidosis (p. 735).
Type 1 diabetes in adults
While type 1 diabetes is classically thought of as a disease of
children and young adults (most commonly presenting between
5 and 7 years of age and at or near puberty), it can manifest at
any age, with as much as half of cases thought to develop in
adults. It is also possible for patients who have a more insidious
onset of diabetes to have an autoimmune aetiology; these
people are sometimes described as having slow-onset type 1
diabetes or latent autoimmune diabetes of adulthood (LADA).
LADA is defined as the presence of islet autoantibodies in high
titre (usually GAD antibodies), without rapid progression to insulin
therapy (which would usually signify type 1 diabetes). Patients
with LADA can often present and be managed similarly to
those with type 2 diabetes, but they do progress more rapidly
to requiring insulin treatment for glucose control. Not all expert
committees recognise LADA as a diagnostic category, however,
and consider LADA to be just a subset of autoimmune type 1
diabetes developing in adulthood.
|jype 2 diabetes
Pathology
Type 2 diabetes is a diagnosis of exclusion, i.e. it is made when
type 1 diabetes and other types of diabetes (see Box 20.9) are
ruled out; it is highly heterogeneous. The natural history of typical
type 2 diabetes is shown in Ligure 20.8. Initially, insulin resistance
leads to elevated insulin secretion in order to maintain normal
blood glucose levels. However, in susceptible individuals, the
pancreatic p cells are unable to sustain the increased demand
for insulin and a slowly progressive insulin deficiency develops.
Some patients develop diabetes at a young age, usually driven by
insulin resistance due to obesity and ethnicity; others, particularly
older patients, develop diabetes despite being non-obese and
may have more pronounced p-cell failure. The key feature is a
‘relative’ insulin deficiency, such that there is insufficient insulin
production to overcome the resistance to insulin action. This
contrasts with type 1 diabetes, in which there is rapid loss of
insulin production, resulting in ketoacidosis and death if the
insulin is not replaced.
Insulin resistance and the metabolic syndrome
Type 2 diabetes and its pre-diabetes antecedents belong to a
cluster of conditions thought to be caused by resistance to insulin
action. Thus, people with type 2 diabetes often have associated
disorders including hypertension, dyslipidaemia (characterised
by elevated levels of small dense low-density lipoprotein (LDL)
Aetiology and pathogenesis of diabetes • 731
0
Plasma
glucose
Plasma
insulin
Deteriorating (3-cell function
Increasing insulin resistance with age, obesity etc.
Normal
Hyperinsulin¬
aemia
Euglycaemia
Impaired
glucose
tolerance
Type 2 diabetes
Diet- Anti- Insulin
controlled diabetic
drugs
Time
E
Fig. 20.8 Natural history of type 2 diabetes. [A] In the early stage of the disorder, the response to progressive insulin resistance is an increase in
insulin secretion by the pancreatic cells, causing hyperinsulinaemia. Eventually, the (3 cells are unable to compensate adequately and blood glucose rises,
producing hyperglycaemia. With further (3-cell failure, glycaemic control deteriorates and treatment requirements escalate. [S] Progressive pancreatic (3-cell
failure in patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS). Beta-cell function was estimated using the homeostasis
model assessment (HOMA) and was already below 50% at the time of diagnosis. Thereafter, long-term incremental increases in fasting plasma glucose
were accompanied by progressive (3-cell dysfunction. If the slope of this progression is extrapolated, it appears that pancreatic dysfunction may have been
developing for many years before diagnosis of diabetes. B, Adapted from Holman RR. Diabetes Res Clin Bract 1998; 40 (Suppl.):S21-S25.
cholesterol and triglycerides, and a low level of high-density
lipoprotein (HDL) cholesterol), non-alcoholic fatty liver disease
(p. 882) and, in women, polycystic ovarian syndrome. This
cluster has been termed the ‘insulin resistance syndrome’ or
‘metabolic syndrome’, and is much more common in individuals
who are obese.
The primary cause of insulin resistance remains unclear; it is
likely that there are multiple defects in insulin signalling, affecting
several tissues. One theory is centred around the adipocyte;
this is particularly appealing, as obesity is a major cause of
increased insulin resistance. Intra-abdominal ‘central’ adipose
tissue is metabolically active and releases large quantities of
FFAs, which may induce insulin resistance because they compete
with glucose as a fuel supply for oxidation in peripheral tissues
such as muscle. In addition, adipose tissue releases a number
of hormones (including a variety of peptides, called ‘adipokines’
because they are structurally similar to immunological ‘cytokines’)
that act on specific receptors to influence sensitivity to insulin in
other tissues. Because the venous drainage of visceral adipose
tissue is into the portal vein, central obesity may have a particularly
potent influence on insulin sensitivity in the liver, and thereby
adversely affect gluconeogenesis and hepatic lipid metabolism.
Physical activity is another important determinant of insulin
sensitivity. Inactivity is associated with down-regulation of
insulin-sensitive kinases and may promote accumulation of
FFAs within skeletal muscle. Sedentary people are therefore
more insulin-resistant than active people with the same degree of
obesity. Moreover, physical activity allows non-insulin-dependent
glucose uptake into muscle, reducing the ‘demand’ on the
pancreatic (3 cells to produce insulin.
Deposition of fat in the liver is a common association
with central obesity and is exacerbated by insulin resistance
and/or deficiency. Many people with type 2 diabetes have
evidence of fatty infiltration of the liver (non-alcoholic fatty liver
disease, NAFLD). This condition may improve with effective
I 1 20.7 Risk of developing type 2 diabetes for siblings
of individuals with type 2 diabetes
Age at onset of type 2
diabetes in proband (years)
Age-corrected risk of type 2
diabetes for siblings (%)
25-44
53
45-54
37
55-64
38
65-80
31
treatment of the diabetes but, despite this, some patients
progress to non-alcoholic steatohepatitis (NASH, p. 882) and
cirrhosis.
Pancreatic (3-cell failure
In the early stages of type 2 diabetes, reduction in the total mass
of pancreatic islet tissue is modest. At the time of diagnosis,
around 50% of (3-cell function has been lost and this declines
progressively (Fig. 20.8B). Some pathological changes are typical
of type 2 diabetes, the most consistent of which is deposition of
amyloid in the islets. In addition, elevated plasma glucose and
FFAs exert toxic effects on pancreatic (3 cells to impair insulin
secretion. However, while (3-cell numbers are reduced, (3-cell
mass is unchanged and glucagon secretion is increased, which
may contribute to hyperglycaemia.
Genetic predisposition
Genetic factors are important in type 2 diabetes, as shown by
marked differences in susceptibility in different ethnic groups
and by studies in monozygotic twins where concordance rates
for type 2 diabetes approach 100%. However, many genes
are involved and the chance of developing diabetes is also
influenced very powerfully by environmental factors (Box 20.7).
Genome-wide association studies have identified over 70 genes
732 • DIABETES MELLITUS
or gene regions that are associated with type 2 diabetes, each
exerting a small effect. Most of the genes known to contribute
to risk of type 2 diabetes are involved in (3-cell function or in
regulation of cell cycling and turnover, suggesting that altered
regulation of (3-cell mass is a key factor. The largest population
genetic effect described to date is seen with variation in TCF7L2 ;
the 1 0% of the population with two copies of the risk variant for
this gene have a nearly twofold increase in risk of developing
type 2 diabetes. In general, other common variants explain much
lower risk than this, many explaining less than a 10% increase
in risk only; as only about 10% of the genetic variance in type
2 diabetes is explained by these common genetic variants,
this has led some to question the relevance of finding diabetes
genes. However, it should be noted that, within a population, the
distribution of risk variants will vary, with some patients having
inherited a high genetic burden (e.g. more than 40 risk variants)
and others having inherited very few. When studies compare those
in the top 20% of this risk band with the lowest 20%, those at
highest risk are over 2.5 times more likely to develop diabetes.
More recent insights into the genetics of type 2 diabetes have
highlighted how some genetic variants may be rare and therefore
affect only a small proportion of the population, but have large
clinical effects. For example, in a Greenlandic population, 3% of
people carry a homozygous variant in an insulin signalling gene,
TBC1D4, that results in muscle insulin resistance; these individuals
are over 10 times more likely to develop type 2 diabetes.
Environmental and other risk factors
Diet and obesity
Epidemiological studies show that type 2 diabetes is associated
with overeating, especially when combined with obesity and
under-activity. Middle-aged people with diabetes eat significantly
more and are fatter and less active than their non-diabetic siblings.
The risk of developing type 2 diabetes increases 10-fold in people
with a body mass index (BMI) of more than 30 kg/m2 (p. 698).
However, although the majority of individuals with type 2 diabetes
are obese, only a minority of obese people develop diabetes,
as most obese people are able to increase insulin secretion to
compensate for the increased demand resulting from obesity
and insulin resistance. Those who develop diabetes may have
genetically impaired (3-cell function, reduced (3-cell mass, or a
susceptibility of (3 cells to attack by toxic substances such as
FFAs or inflammatory cytokines.
Age
Type 2 diabetes is more common in middle-aged and older
individuals (Box 20.8). In the UK, it affects 10% of the population
over 65, and over 70% of all cases of diabetes occur after the
age of 50 years.
Ethnicity
Ethnic origin is a major risk factor for development of diabetes.
For example, within the USA, the prevalence of diabetes is
lowest in Alaskan Natives at 5.5%, moderate for non-Hispanic
whites at 7.1 %, high for non-Hispanic blacks at 1 3% and highest
in Native Americans at 33%. This considerable variation in
prevalence reflects a number of different factors, including a
higher BMI and lower socioeconomic class in high-risk groups in
the USA; differences in health behaviour, e.g. decreased physical
activity and increased smoking; and differences in genetic risk.
Studies in high-risk ethnic groups largely demonstrate increased
insulin resistance and more central/visceral adiposity than in the
lower-risk groups.
Metabolic disturbances in type 2 diabetes
Patients with type 2 diabetes have a slow onset of ‘relative’
insulin deficiency. Relatively small amounts of insulin are required
to suppress lipolysis, and some glucose uptake is maintained
in muscle so that, in contrast to type 1 diabetes, lipolysis
and proteolysis are not unrestrained and weight loss and
ketoacidosis seldom occur. In type 2 diabetes, hyperglycaemia
tends to develop slowly over months or years; because of this
insidious onset many cases of type 2 diabetes are discovered
coincidentally and a large number are undetected. At diagnosis,
patients are often asymptomatic or give a long history (typically
many months) of fatigue, with or without ‘osmotic symptoms’
(thirst and polyuria). However, there are some people with
type 2 diabetes who present acutely with marked osmotic
symptoms and weight loss. These may be presenting late,
such that they have already developed (3-cell failure, but
more usually this decompensation reflects a vicious spiral
of decline. As hyperglycaemia worsens, patients often crave
sugar and will consume large volumes of sugary drinks to
try to quench their thirst; worsening hyperglycaemia is also
associated with increasing lipolysis, and the high circulating
glucose and FFAs are toxic to the (3 cell, resulting in
‘glucolipotoxicity’ and reduced (3-cell function. In these patients,
ketosis and even DKA can occur; this is classically described
in the African American population, where up to half of patients
who present with DKA have type 2 diabetes and not type 1
diabetes. The presentation of DKA in type 2 diabetes is referred
to as ‘ketosis-prone’ diabetes or ‘Flatbush syndrome’, named
after the Flatbush neighbourhood of New York, which had a
large Caribbean population and where presentation with DKA
was common. Importantly in these patients, insulin treatment
is required initially but, as the glucose and lipids are controlled,
the (3 cells recover, and they can usually transfer off insulin
and on to oral treatments such as metformin after 3 months
of insulin treatment.
Intercurrent illness, e.g. with infections, increases the production
of stress hormones that oppose insulin action, such as cortisol,
growth hormone and catecholamines. This can precipitate an
acute exacerbation of insulin resistance and insulin deficiency,
and result in more severe hyperglycaemia and dehydration
(p. 738).
Other forms of diabetes
Other causes of diabetes are shown in Box 20.9. These can
broadly be broken down into genetic disorders including
monogenic diabetes (diabetes due to a mutation in or deletion
of a single gene) or diabetes as part of a genetic syndrome;
endocrine disorders due to excess in hormones that oppose
• Prevalence: increases with age, affecting -10% of people over
65 years. Half of these are undiagnosed. Impaired (3-cell function
and exaggerated insulin resistance with ageing both contribute.
• Glycosuria: the renal threshold for glucose rises with age, so
glycosuria may not develop until the blood glucose concentration is
markedly raised.
• Pancreatic carcinoma: may present in old age with the
development of diabetes, in association with weight loss and
diminished appetite.
20.8 Diagnosis of diabetes mellitus in old age
Aetiology and pathogenesis of diabetes • 733
i
Type 1 diabetes
• Immune-mediated
• Idiopathic
Type 2 diabetes
Other specific types
• Genetic defects of (3-cell function (see Box 20.10)
• Genetic defects of insulin action (e.g. leprechaunism,
lipodystrophies)
• Pancreatic disease (e.g. pancreatitis, pancreatectomy, neoplastic
disease, cystic fibrosis, haemochromatosis, fibrocalculous
pancreatopathy)
• Excess endogenous production of hormonal antagonists to
insulin, e.g.:
Growth hormone - acromegaly
Glucocorticoids - Cushing’s syndrome
Glucagon - glucagonoma
Catecholamines - phaeochromocytoma
Thyroid hormones - thyrotoxicosis
• Drug-induced (e.g. glucocorticoids, thiazide diuretics, phenytoin)
• Uncommon forms of immune-mediated diabetes (e.g. IPEX
syndrome)
• Associated with genetic syndromes (e.g. Down’s syndrome,
Klinefelter’s syndrome, Turner’s syndrome, DIDMOAD (Wolfram’s
syndrome), Friedreich’s ataxia, myotonic dystrophy)
Gestational diabetes
(DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, nerve deafness;
IPEX = immunodysregulation polyendocrinopathy X)
the effects of insulin (Ch. 18); and more generalised diseases
of the pancreas.
Pancreatic disease
Pancreatic disease is a relatively common but often unrecognised
cause of diabetes, largely related to alcohol excess. Alcohol
excess can cause recurrent bouts of acute pancreatitis, with
progressive destruction of the pancreas and subsequent
diabetes. However, more commonly, chronic alcohol excess
can be linked to chronic pancreatitis, which is then termed
alcoholic chronic pancreatitis. Although this is associated
with recurrent abdominal pain, it is asymptomatic in many
patients, resulting in both pancreatic exocrine failure and
endocrine failure. While diabetes due to pancreatic insufficiency
secondary to alcohol excess can be managed with oral therapy,
the insulin deficiency usually requires insulin replacement
therapy.
In some geographical regions, there is a form of chronic
calcific pancreatitis that is not caused by alcohol excess and
causes diabetes to present in adolescence or early adulthood;
this condition is called fibrocalculous pancreatic diabetes (FCPD).
It is characteristically a disease of the tropics, with variable
prevalence across these regions. The aetiology of FCPD is poorly
understood. While there is thought to be a genetic predisposition,
with mutations in SPINK1 being described, it is usually seen in
malnourished individuals, but it is not clear whether this is a
cause or consequence of the disease. FCPD usually presents
with recurrent severe abdominal pain in childhood, diabetes
developing 10-20 years later; there is a 100-fold increased
risk of pancreatic cancer in later life. Insulin treatment is usually
required at or soon after diagnosis.
20.10 Monogenic diabetes mellitus: maturity-onset
diabetes of the young (M0DY)
Functional defect Main type Gene mutated*
(3-cell glucose sensing M0DY2 GCK
The set point for basal insulin release is altered, causing a high fasting
glucose, but sufficient insulin is released after meals. As a result, the
HbA1c is often normal and microvascular complications are rare.
Treatment is rarely required
(3-cell transcriptional regulation M0DY3 HNFIa
M0DY5 HNFip
M0DY1 HNF4a
Diabetes develops during adolescence/early adulthood and can be
managed with diet and tablets for many years, but ultimately, insulin
treatment is required. The HNFIa and 4a forms respond particularly
well to sulphonylurea drugs. All types are associated with
microvascular complications. HNFip mutations also cause renal cysts
and renal failure
*0ther gene mutations have been found in rare cases. For further information,
see diabetesgenes.org.
Monogenic diabetes
Monogenic diabetes accounts for approximately 4% of diabetes
in those diagnosed under the age of 30 in the UK. While there
are a number of monogenic disorders of insulin action, the most
common monogenic forms of diabetes are caused by defects
in insulin secretion, in part because insulin resistance alone is
not sufficient to cause diabetes. Monogenic disorders of the
(3 cell cause two diabetes subtypes: maturity-onset diabetes
of the young (MODY; Box 20.10) and neonatal diabetes. The
common genes involved in MODY and neonatal diabetes are
shown in Figure 20. 2C.
MODY is defined as non-insulin-requiring diabetes that develops
under the age of 25 years in one family member. MODY is
dominantly inherited (p. 46), which means that the diabetes runs
in families, many having a family history of diabetes spanning three
generations or more. MODY itself is a heterogeneous condition,
with multiple subtypes. One form is caused by mutations in
glucokinase (see Fig. 20. 2B); this is the pancreatic glucose
sensor and patients with glucokinase mutations have an altered
set-point for glucose. This results in a high fasting glucose (usually
>5.5 mmol/L (99 mg/dL)) but a normal post-prandial response.
As a result, patients with glucokinase MODY have stable, mild
hyperglycaemia, with only a slightly elevated HbA1c; they do not
require treatment and do not develop diabetes complications. It is
therefore important to identify these patients, to avoid unnecessary
diabetes treatment and monitoring. The other forms of MODY are
mostly caused by defective transcription factors that play a key
role in pancreatic (3-cell development and function (hepatocyte
nuclear factor (HNF) la, 1(3 and 4a). Patients with transcription
factor MODY develop diabetes in adolescence or early adulthood
and the diabetes is progressive, requiring oral diabetes treatment
before eventually needing insulin. Patients with HNFIa and 4a
MODY are extremely sensitive to sulphonylureas and this is the
treatment of choice for these individuals. HNF1 (3 is a critical
transcription factor not only in pancreatic development but also
in renal and genital tract development in utero. Patients with
HNF1 p mutations usually have renal abnormalities, including renal
cystic disease and genital tract malformation, such as absent or
bicornuate uterus or hypospadias and infertility; about 50% of
individuals with the gene mutation have young-onset diabetes.
20.9 Aetiological classification of diabetes mellitus
734 • DIABETES MELLITUS
Neonatal diabetes is variably defined as diabetes that presents
in the neonatal period, although this is usually extended to the first
6 months of life. The presentation is usually that of profound insulin
deficiency with marked hyperglycaemia and DKA. Approximately
half of patients with neonatal diabetes have a transient form
that remits by about 1 year of age, with diabetes recurring in
adolescence or early adulthood; the remaining patients have
permanent neonatal diabetes. In recent years, the genetics of
neonatal diabetes have been unravelled, having a major positive
impact for people with this condition. Approximately two-thirds
of patients with permanent neonatal diabetes have an activating
mutation in the genes encoding the KIR6.2 and SUR1 subunits
of the Katp channel (see Fig. 20.2C). These mutations cause
the Katp channel to be insensitive to the glucose-mediated rise
in intracellular ATP; as a result, the pancreatic (3 cells do not
secrete insulin and patients require insulin treatment from soon
after birth. It has been shown, however, that these individuals
do respond to sulphonylureas; this finding has transformed
their care, over 90% being managed with oral sulphonylurea
treatment.
Presenting problems in
diabetes mellitus
Hyperglycaemia
The diagnosis of diabetes is simple: it is based on confirmation of
hyperglycaemia using either fasting or random glucose, an OGTT
or HbA1c (p. 727). Diabetes, however, results from a variety of
pathological processes, meaning that within this broad category
are many aetiological subtypes. Following the identification of
hyperglycaemia and subsequent diagnosis of diabetes, the
initial management involves a careful clinical assessment of the
patient to decide whether immediate treatment is required and,
with appropriate investigation, to establish the aetiology of the
diabetes, as this will determine subsequent diabetes treatment
(Fig. 20.9). The main differential diagnosis to consider is that of
type 1 or type 2 diabetes; making a diagnosis of type 1 diabetes
is important, as a failure to initiate insulin treatment can result in
New-onset hyperglycaemia
Confirm diagnosis of diabetes (Box 20.2)
Patient unwell
Patient not unwell
and/or
and
Marked symptoms of hyperglycaemia
Mild or no symptoms of hyperglycaemia
and/or
and
Blood ketones elevated
Blood ketones not elevated
j I T
Refer for immediate assessment
Evaluate for DKA/PIPIS and intercurrent illness
- see emergency management
i
DKA HHS Intercurrent illness; No underlying cause
Box 20.16 Box 20.17 dehydration Patient well
Commence IV insulin
and fluids
Commence
SC insulin
Continue on SC insulin
Possible
type 1 diabetes?
Self-monitoring of
blood glucose and
ketones
Low threshold to
start SC insulin
I
T
Probable
type 2 diabetes?
Diet and lifestyle
modification
Early initiation
of metformin
Evaluate aetiology of diabetes*
*
Manage according to diabetes aetiology
Evaluate aetiology of diabetes*
i —
Likely type 1 diabetes
Continue on insulin
— i
Likely type 2 diabetes
Consider introducing
oral agents and
weaning insulin
(careful monitoring
required)
Evaluation of diabetes aetiology
Typical type 1 diabetes?
Not overweight
No family history of diabetes
GAD/IA-2 antibody-positive
Low C-peptide
Typical type 2 diabetes?
Obese or overweight
Aged over 40
Family history of diabetes
Ethnicity high diabetes risk
GAD/IA-2 antibody-negative
Elevated C-peptide
No other cause
Other types?
Chronic pancreatitis/abdominal pain - consider
alcohol-related or pancreatic malignancy
Features of endocrine disease?
Abnormal liver function - consider haemochromatosis
Three-generation family history - consider monogenic diabetes
Renal and urinary tract abnormalities - consider HNF1(3
Fig. 20.9 New-onset hyperglycaemia. (DKA = diabetic ketoacidosis; GAD = glutamic acid decarboxylase; HHS = hyperosmotic hyperglycaemic state;
IA-2 = islet antigen 2; IV = intravenous; SC = subcutaneous)
Presenting problems in diabetes mellitus • 735
the development of DKA and death. If the aetiological diagnosis
is in doubt, it is important not to delay insulin treatment, which
can be withdrawn subsequently if necessary.
Hyperglycaemia causes a wide variety of symptoms (Box
20.11). The classical clinical features of type 1 and type 2
diabetes are compared in Box 20.12. Symptoms of polydipsia,
polyuria, nocturia and rapid weight loss are prominent in type 1
diabetes but are often absent in patients with type 2 diabetes,
many of whom are asymptomatic or have non-specific complaints
such as chronic fatigue and malaise. Uncontrolled diabetes is
associated with an increased susceptibility to infection and patients
may present with skin sepsis (boils) or genital candidiasis, and
complain of pruritus vulvae or balanitis.
While the distinction between type 1 and type 2 diabetes is
usually obvious, overlap occurs, particularly in age at onset,
duration of symptoms and family history. There are many patients
in whom the type of diabetes is not immediately apparent. For
example, patients with type 2 diabetes may present with marked
and rapid weight loss and even DKA (1 0-1 5% of all cases of DKA),
and type 2 diabetes is increasingly diagnosed in children and
young adults. Type 1 diabetes can occur at any age, not just in
younger people, and may develop more insidiously; the presence
of pancreatic autoantibodies confirms the diagnosis of slow-onset
type 1 diabetes or LADA. Islet autoantibodies are detectable at
high titre in many patients with type 1 diabetes, so a negative
result should prompt consideration of other aetiologies. Other
causes of diabetes (see Box 20.9), such as MODY, should not be
forgotten, particularly in those presenting in childhood or as young
adults. A history of pancreatic disease, particularly in patients with
a history of alcohol excess, makes insulin deficiency more likely.
20.11 Symptoms of hyperglycaemia
• Thirst, dry mouth
• Nausea
• Polyuria
• Headache
• Nocturia
• Hyperphagia; predilection for
• Tiredness, fatigue, lethargy
sweet foods
• Change in weight (usually
• Mood change, irritability,
weight loss)
difficulty in concentrating,
• Blurring of vision
apathy
• Pruritus vulvae, balanitis
(genital candidiasis)
20.12 Classical features of type 1 and type 2 diabetes
Type 1
Type 2
Typical age at onset
<40 years
>50 years
Duration of symptoms
Weeks
Months to years
Body weight
Normal or low
Obese
Ketonuria
Yes
No
Rapid death without
treatment with insulin
Yes
No
Autoantibodies
Positive in 80-90%
Negative
Diabetic complications
at diagnosis
No
25%
Family history of
diabetes
Uncommon
Common
Other autoimmune
disease
Common
Uncommon
Sometimes the definitive classification of the type of diabetes is
only made later, once the natural history or responsiveness to
different therapies becomes apparent.
Physical signs in patients with type 2 diabetes at diagnosis
depend on the mode of presentation. In Western populations,
more than 80% are overweight and the obesity is often central
(truncal or abdominal). Obesity is much less evident in Asians.
Hypertension is present in at least 50% of patients with type 2
diabetes. Although dyslipidaemia is also common, skin lesions
such as xanthelasma and eruptive xanthomas are rare.
Presentation with the complications
of diabetes
Patients with long-standing diabetes are at risk of developing a
variety of complications (see Box 20.35, p. 756) and as many as
25% of people with type 2 diabetes have evidence of diabetic
complications at the time of diagnosis. Thus, diabetes may be first
suspected when a patient visits an optometrist or podiatrist, or
presents with hypertension or a vascular event such as an acute
myocardial infarction or stroke. Blood glucose should therefore
be checked in all patients presenting with such pathology. The
detailed investigation and management of diabetic complications
are described on page 755.
Diabetes emergencies
| Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is a medical emergency and remains
a serious cause of morbidity, principally in people with type 1
diabetes. Mortality is low in the UK (approximately 2%) but remains
high in developing countries and among non-hospitalised patients.
Mortality in DKA is most commonly caused in children and
adolescents by cerebral oedema, and in adults by hypokalaemia,
acute respiratory distress syndrome and comorbid conditions
such as acute myocardial infarction, sepsis or pneumonia.
DKA is characteristic of type 1 diabetes (see Box 20.12) and
is often the presenting problem in newly diagnosed patients.
However, an increasing number of patients presenting with DKA
have underlying type 2 diabetes. This appears to be particularly
prevalent in black and non-Hispanic populations. In established
type 1 diabetes, DKA may be precipitated by an intercurrent
illness because of failure to increase insulin dose appropriately
to compensate for the stress response. Sometimes, there is no
evidence of a precipitating infection and DKA develops because
of errors in self-management. In young patients with recurrent
episodes of DKA, up to 20% may have psychological problems
complicated by eating disorders.
Pathogenesis
A clear understanding of the biochemical basis and pathophysiology
of DKA is essential for its efficient treatment (see Fig. 20.7). The
cardinal biochemical features are:
• hyperketonaemia (>3.0 mmol/L) or ketonuria (more than
2+ on standard urine sticks)
• hyperglycaemia (blood glucose >11 mmol/L (approximately
200 mg/dL))
• metabolic acidosis (venous bicarbonate <15 mmol/L and/
or venous pH <7.3 (H+>50 nmol/L)).
The hyperglycaemia causes a profound osmotic diuresis
leading to dehydration and electrolyte loss, particularly of
736 • DIABETES MELLITUS
sodium and potassium. Potassium loss is exacerbated by
secondary hyperaldosteronism as a result of reduced renal
perfusion. Ketosis stems from insulin deficiency, exacerbated by
elevated catecholamines and other stress hormones, leading to
unrestrained lipolysis and supply of FFAs for hepatic ketogenesis.
When this exceeds the capacity to metabolise acidic ketones,
these accumulate in blood. The resulting metabolic acidosis
forces hydrogen ions into cells, displacing potassium ions.
The average loss of fluid and electrolytes in moderately severe
DKA in an adult is shown in Box 20.13. About half the deficit of
total body water is derived from the intracellular compartment
and occurs comparatively early in the development of acidosis
with relatively few clinical features; the remainder represents loss
of extracellular fluid sustained largely in the later stages, when
marked contraction of extracellular fluid volume occurs, with
haemoconcentration, a decreased blood volume, and finally a fall
in blood pressure with associated renal ischaemia and oliguria.
Every patient in DKA is potassium-depleted but the plasma
concentration of potassium gives very little indication of the total
body deficit. Plasma potassium may even be raised initially due
to disproportionate loss of water, catabolism of protein and
glycogen, and displacement of potassium from the intracellular
compartment by H+ ions. However, soon after treatment is started,
there is likely to be a precipitous fall in the plasma potassium
due to dilution of extracellular potassium by administration of
intravenous fluids, the movement of potassium into cells induced
by insulin, and the continuing renal loss of potassium.
The magnitude of the hyperglycaemia does not correlate with
the severity of the metabolic acidosis; moderate elevation of blood
glucose may be associated with life-threatening ketoacidosis.
Type 1 diabetes in pregnancy is one situation where DKA can
occur with blood glucose levels that are not especially high.
Conversely, in other situations, hyperglycaemia predominates and
acidosis is minimal, with patients presenting in a hyperosmolar
state (p. 738).
Clinical assessment
The clinical features of ketoacidosis are listed in Box 20.14. In
the fulminating case, the striking features are those of salt and
20.13 Average loss of fluid and electrolytes in adult
diabetic ketoacidosis of moderate severity
i
• Water: 6 L
• Sodium: 500 mmol
• Chloride: 400 mmol
• Potassium: 350 mmol
3 L extracellular
- replace with saline
3 L intracellular
- replace with dextrose
20.14 Clinical features of diabetic ketoacidosis
Symptoms
• Polyuria, thirst
• Weight loss
• Weakness
• Nausea, vomiting
Signs
• Dehydration
• Hypotension (postural or
supine)
• Cold extremities/peripheral
cyanosis
• Tachycardia
Leg cramps
Blurred vision
Abdominal pain
Air hunger (Kussmaul
breathing)
Smell of acetone
Hypothermia
Delirium, drowsiness, coma
(10%)
water depletion, with loss of skin turgor, furred tongue and
cracked lips, tachycardia, hypotension and reduced intra-ocular
pressure. Breathing may be deep and sighing (Kussmaul’s sign),
the breath is usually fetid, and the sickly-sweet smell of acetone
may be apparent. Mental apathy, delirium or a reduced conscious
level may be present, although coma is uncommon. Indeed, a
patient with dangerous ketoacidosis requiring urgent treatment
may walk into the consulting room. For this reason, the term
‘diabetic ketoacidosis’ is to be preferred to ‘diabetic coma’,
which implies that there is no urgency until unconsciousness
supervenes. In fact, it is imperative that energetic treatment is
started at the earliest possible stage.
Abdominal pain is sometimes a feature of DKA, particularly
in children, and vomiting is common. Serum amylase may
be elevated but rarely indicates coexisting pancreatitis. In
infected patients, pyrexia may not be present initially because
of vasodilatation secondary to acidosis.
Investigations
The following investigations are important but should not delay
the institution of intravenous fluid and insulin replacement:
• Venous blood: for urea and electrolytes, glucose,
bicarbonate and acid-base status (venous blood can be
used in portable and fixed blood gas analysers, and
differences between venous and arterial pH and
bicarbonate are minor).
• Urine or blood analysis for ketones (p. 726).
• Electrocardiogram (ECG).
• Infection screen: full blood count, blood and urine
culture, C-reactive protein, chest X-ray. Although
leucocytosis invariably occurs in DKA, this represents
a stress response and does not necessarily indicate
infection.
Assessment of severity
The presence of one or more of the features listed in Box 20.1 5
is indicative of severe DKA.
Management
DKA is a medical emergency that should be treated in
hospital, preferably in a high-dependency area. If available, the
diabetes specialist team should be involved. Regular clinical
and biochemical review is essential, particularly during the first
24 hours of treatment. Guidelines for the management of DKA are
shown in Box 20.16. Early specialist involvement is recommended
for high-risk groups such as older people, young adults
(18-25 years), pregnant women, and those with heart or kidney
failure or other serious comorbidities.
20.15 Indicators of severe diabetic ketoacidosis
• Blood ketones >6 mmol/L
• Bicarbonate <5 mmol/L
• Venous/arterial pH <7.0 (H+ >100 nmol/L)
• Hypokalaemia on admission (<3,5 mmol/L)
• Glasgow Coma Scale score <12 (p. 194) or abnormal AVPU scale
score (p. 188)
• 02 saturation <92% on air
• Systolic blood pressure <90 mmHg
• Heart rate >1 00 or <60 beats per minute
• Anion gap >16 mmol/L
Presenting problems in diabetes mellitus • 737
20.16 Emergency management of diabetic ketoacidosis
Adjust potassium chloride infusion:
Time: 0-60 mins
• Establish IV access, assess patient and perform initial
investigations
• Commence 0.9% sodium chloride:
If systolic BP >90 mmHg, give 1 L over 60 mins
If systolic BP <90 mmHg, give 500 ml_ over 10-15 mins, then
re-assess; if BP remains <90 mmHg, repeat and seek senior
review
• Commence insulin treatment:
50 U human soluble insulin in 50 mL 0.9% sodium chloride
infused intravenously at 0.1 U/kg body weight/hr
Continue with SC basal insulin analogue if usually taken by
patient
• Perform further investigations: see text
• Establish monitoring schedule:
Hourly capillary blood glucose and ketone testing
Venous bicarbonate and potassium after 1 and 2 hrs, then every
2 hrs for first 6 hrs
Plasma electrolytes every 4 hrs
Clinical monitoring of 02 saturation, pulse, BP, respiratory rate
and urine output every hour
• Treat any precipitating cause
Time: 60 mins to 6 hrs
• IV infusion of 0.9% sodium chloride with potassium chloride added
as indicated below:
1 L over 2 hrs
1 L over 2 hrs
1 L over 4 hrs
1 L over 4 hrs
1 L over 6 hrs
• Add 10% glucose 125 mL/hr IV when glucose <14 mmol/L
(252 mg/dL)
• Be more cautious with fluid replacement in older or young
people, pregnant patients and those with renal or heart failure;
if plasma sodium is >155 mmol/L, 0.45% sodium chloride
may be used
Plasma potassium Potassium replacement
(mmol/L) (mmol/L of infusion)
>5.5 Nil
3. 5-5. 5 40
<3.5 Senior review - additional
potassium required
Time: 6-12 hrs
• Clinical status, glucose, ketonaemia and acidosis should be improving;
request senior review if not
• Continue IV fluid replacement
• Continue insulin administration
• Assess for complications of treatment (fluid overload, cerebral oedema)
• Avoid hypoglycaemia
Time: 12-24 hrs
• By 24 hrs, ketonaemia and acidosis should have resolved (blood
ketones <0.3 mmol/L, venous bicarbonate >18 mmol/L)
• If patient is not eating and drinking:
Continue IV insulin infusion at lower rate of 2-3 U/hr
Continue IV fluid replacement and biochemical monitoring
• If ketoacidosis has resolved and patient is able to eat and drink:
Re-initiate SC insulin with advice from diabetes team; do not
discontinue IV insulin until 30 mins after SC short-acting insulin
injection
Additional procedures
• Consider urinary catheterisation if anuric after 3 hrs or incontinent
• Insert nasogastric tube if obtunded or there is persistent vomiting
• Insert central venous line if cardiovascular system is compromised, to
allow fluid replacement to be adjusted accurately; also consider in
older patients, pregnant women, renal or cardiac failure, other serious
comorbidities and severe DKA
• Measure arterial blood gases; repeat chest X-ray if 02 saturation <92%
• Institute ECG monitoring in severe cases
• Give thromboprophylaxis with low-molecular-weight heparin
(BP = blood pressure; ECG = electrocardiogram; IV = intravenous; SC = subcutaneous)
Adapted from Joint British Diabetes Societies Inpatient Care Group. The Management of Diabetic Ketoacidosis in Adults, 2nd edn; September 2013; abed. care.
Insulin
A fixed-rate intravenous insulin infusion of 0.1 U/kg body weight/
hr is recommended (Box 20.16). Exceptionally, if intravenous
administration is not feasible, soluble insulin can be given by
intramuscular injection (loading dose of 10-20 U, followed by
5 U hourly), or a fast-acting insulin analogue can be given hourly
by subcutaneous injection (initially 0.3 U/kg body weight, then
0.1 U/kg hourly). The blood glucose concentration should fall by
3-6 mmol/L (approximately 55-110 mg/dL) per hour, or blood
ketone concentrations fall by at least 0.5 mmol/L/hr. A more
rapid decrease in blood glucose should be avoided, as this
might precipitate hypoglycaemia and the serious complication
of cerebral oedema, particularly in children. Failure of blood
glucose to fall within 1 hour of commencing insulin infusion should
lead to a re-assessment of insulin dose. Ketosis, dehydration,
acidaemia, infection and stress combine to produce severe
insulin resistance in some cases, but most will respond to a
low-dose insulin regimen. When the blood glucose has fallen,
1 0% dextrose infusion is introduced and insulin infusion continued
to encourage glucose uptake into cells and restoration of normal
metabolism. In recent years, it has also become increasingly
common to continue with the use of long-acting insulin analogues
administered subcutaneously during the initial management of
DKA; this provides background insulin for when the intravenous
insulin is discontinued, to reduce the risk of in-hospital DKA.
Restoration of the usual insulin regimen, by subcutaneous
injection, should not be instituted until the patient is both
biochemically stable and able to eat and drink normally.
Fluid replacement
In adults, rapid fluid replacement in the first few hours is usually
recommended (Box 20.16). Caution is advised in children and
young adults because of the risk of cerebral oedema. Most
guidelines favour correction of the extracellular fluid deficit with
isotonic saline (0.9% sodium chloride). If the plasma sodium is
greater than 155 mmol/L, 0.45% saline may be used initially.
Introduction of 10% glucose is recommended when the blood
glucose falls below 14 mmol/L (252 mg/dL). The 0.9% saline
infusion should be continued to correct circulating volume so
both glucose and saline infusions are used concurrently.
738 • DIABETES MELLITUS
Potassium
Careful monitoring of potassium is essential to the management
of DKA because both hypo- and hyperkalaemia can occur and
are potentially life-threatening. Potassium replacement is not
usually recommended with the initial litre of fluid because pre-renal
failure may be present secondary to dehydration. Treatment
with 0.9% sodium chloride with potassium chloride 40 mmol/L
is recommended if the serum potassium is below5.5 mmol/L
and the patient is passing urine (Box 20.16). If the potassium
falls below 3.5 mmol/L, the potassium replacement regimen
needs to be reviewed. Aim to maintain potassium between
4.0 and 5.5 mmol/L. Cardiac rhythm should be monitored
in severe DKA because of the risk of electrolyte-induced
cardiac arrhythmia.
Bicarbonate
Adequate fluid and insulin replacement should resolve the acidosis.
The use of intravenous bicarbonate therapy is not recommended.
Acidosis may reflect an adaptive response, improving oxygen
delivery to the tissues, and so excessive bicarbonate may induce
a paradoxical increase in cerebrospinal fluid acidosis and has
been implicated in the pathogenesis of cerebral oedema in
children and young adults.
Phosphate
There is no evidence of benefit with phosphate replacement
unless low levels are detected in the presence of respiratory or
muscle weakness.
Ongoing management
Where possible, refer the patient to the diabetes specialist
team within 24 hours of admission. It is important to review
the precipitating factors that led to DKA, glycaemic control and
insulin injection technique, as well as to discuss prevention of
recurrence and to provide blood ketone meters where available.
There is a significant mortality associated with recurrent DKA
and so early educational assessment and treatment review
are critical.
Hyperglycaemic hyperosmolar state
Hyperglycaemic hyperosmolar state (HHS) is a medical
emergency that is different from DKA and so treatment requires
a different approach. There is no precise definition of HHS but
it is characterised by hypovolaemia, severe hyperglycaemia
(> 30 mmol/L (600 mg/dL)) and hyperosmolality (serum
osmolality >320 mOsmol/kg), without significant ketonaemia
(<3 mmol/L) or acidosis (pH >7.3 (H+ <50 nmol/L), bicarbonate
>15 mmol/L).
As with DKA, there is glycosuria, leading to an osmotic diuresis
with loss of water, sodium, potassium and other electrolytes.
However, in HHS, hyperglycaemia usually develops over a
longer period (a few days to weeks), causing more profound
hyperglycaemia and dehydration (fluid loss may be 10-12 L in a
person weighing 100 kg). The reason that patients with HHS do
not develop significant ketoacidosis is unclear, although it has
been speculated that insulin levels may be too low to stimulate
glucose uptake in insulin-sensitive tissues, but are still sufficient
to prevent lipolysis and subsequent ketogenesis. A mixed picture
of HHS and DKA can occur.
Although typically occurring in older patients, HHS is
increasingly seen in younger adults. Common precipitating
factors include infection, myocardial infarction, cerebrovascular
events or drug therapy (e.g. glucocorticoids). Poor prognostic
signs include hypothermia, hypotension (systolic blood pressure
<90 mmHg), tachy- or bradycardia, severe hypernatraemia
(sodium >160 mmol/L), serum osmolality >360 mOsmol/kg,
and the presence of other serious comorbidities. Mortality rates
are higher than in DKA - up to 20% in the USA - reflecting the
age and frailty of the population and the more frequent presence
of comorbidities.
The principles of therapy are shown in Box 20.17. The aims
are to normalise osmolality, replace fluid and electrolyte losses,
and normalise blood glucose, at the same time as preventing
complications such as arterial or venous thrombosis, cerebral
oedema and central pontine demyelinosis (Ch. 14). Comorbidities
also need to be taken into account; for example, rapid fluid
replacement may precipitate cardiac failure in patients with
coronary artery disease. Historically, management of HHS
has followed DKA guidelines, but increasing recognition of
the differences between HHS and DKA has led to new
approaches in HHS. In particular, rapid shifts in osmolality
should be avoided through more measured fluid replacement
regimens that are guided by serial calculations of serum
osmolality. Key recommendations are that 0.9% sodium
chloride solution alone is used for initial treatment, and that
insulin is introduced only when the rate of fall in blood glucose
has plateaued.
If osmolality cannot be measured frequently, osmolarity can
be calculated as follows and used as a surrogate (based on
plasma values in mmol/L):
Plasma osmolarity = 2[Na+] + [glucose] + [urea]
The normal value is 280-296 mOsmol/L and consciousness is
impaired when it is high (>340 mOsmol/L), as commonly occurs
in HHS. A limitation of this approach is that hyperglycaemia, by
increasing serum osmolality, causes the movement of water out
of cells, therefore reducing measured Na+ levels by dilution. In
hyperglycaemic patients, the corrected [Na+] should be taken
into account. This is calculated by adding 1 .6 mmol/L to the
measured [Na+] for every 5.55 mmol/L (100 mg/dL) increment
of serum glucose above normal.
Hypoglycaemia
Hypoglycaemia is uncommon in people without diabetes but
relatively frequent in people with diabetes, mainly due to insulin
therapy, and less frequently to use of oral insulin secretagogues
such as sulphonylurea drugs, and rarely with other antidiabetic
drugs. In people with diabetes, hypoglycaemia is defined as a blood
glucose of less than 3.9 mmol/L (70 mg/dL). Severe hypoglycaemia
- the need for external assistance to provide glucose, glucagon or
other corrective action actively - is greatly feared by people with
diabetes and has a major impact on their willingness and ability
to achieve target glucose levels. When hypoglycaemia develops
in non-diabetic people, it is called ‘spontaneous’ hypoglycaemia;
its definition, causes and investigation are described
on page 676.
The critical importance of glucose as a fuel source for the brain
means that, in health, a number of mechanisms are in place to
ensure that glucose homeostasis is maintained. If blood glucose
falls, three primary physiological defence mechanisms operate:
• endogenous insulin release from pancreatic p cells is
suppressed
• release of glucagon from pancreatic a cells is increased
• the autonomic nervous system is activated, with release of
catecholamines both systemically and within the tissues.
Presenting problems in diabetes mellitus • 739
*1
20.17 Emergency management of hyperglycaemic hyperosmolar state
Time 0-60 mins
Time 6-12 hrs
• Commence IV 0.9% sodium chloride 1 L over 1 hr
• Commence insulin infusion (0.05 U/kg/hr) only if there is significant
ketonaemia (3 - hyd roxy b uty rate >1.0 mmol/L)
• Perform initial investigations
• Perform clinical assessment to assess degree of dehydration,
mental status and any source of potential sepsis
• Assess foot risk score
• Establish monitoring regimen - generally hourly glucose and
calculated osmolality (2Na+ + glucose + urea) for first 6 hrs then
2-hourly if responding
• Insert urinary catheter to monitor hourly urine output and calculate
fluid balance
• Commence LMWH in a prophylactic dose
• Consider antibiotic therapy if sepsis suspected
Time 60 mins to 6 hrs
• Continue with 0.9% sodium chloride infusion 0. 5-1.0 L/hr,
depending on clinical assessment and response (target positive
balance of 2-3 L by 6 hrs)
• Calculate osmolality hourly and aim for gradual decline
(3-8 mOsmol/kg/hr); if osmolality is increasing and fluid balance
adequate, consider 0.45% sodium chloride
• If blood glucose is falling at less than 5 mmol/IVhr, check fluid
balance and, if adequate, commence low-dose IV insulin (0.05 11/
kg/hr); if insulin is already running, increase rate to 0.1 U/kg/hr
• Maintain potassium in the reference range (3. 6-5.0 mmol/L), as
with DKA (see Box 20.16)
• Avoid hypoglycaemia - aim to keep blood glucose at 10-15 mmol/L
(180-270 mg/dL) in the first 24 hrs. If blood glucose falls
below 14 mmol/L (252 mg/dL), commence 5% or 10% glucose
infusion in addition to 0.9% saline
• Monitor fluid balance
• Ensure clinical and biochemical parameters are improving
• Assess for complications of treatment
• Continue IV fluid replacement to target 3-6 L positive balance by
12 hrs
• Continue treatment of underlying precipitant
• Avoid hypoglycaemia
Time 12-24 hrs
• Ensure clinical and biochemical parameters are improving;
measurement can be reduced to 4-hourly; biochemistry does not
usually normalise by 24 hrs
• Assess for complications of treatment
• Continue IV fluid replacement to target remaining estimated fluid loss
by 24 hrs
• Continue IV insulin with or without 5% or 10% glucose to maintain
blood glucose at 1 0-1 5 mmol/L (1 80-270 mg/dL)
• Continue treatment of underlying precipitant
• Avoid hypoglycaemia
Time 24 hrs to day 3
• Ensure clinical and biochemical parameters are improving or
normalised; continue IV fluids until eating and drinking; variable-rate
insulin and fluids may be required if not
• Convert to appropriate SC insulin regimen when stable
• Assess for signs of fluid overload
• Encourage early mobilisation
• Carry out daily foot checks
• Continue LMWH until discharge
• Ensure review by diabetes team
(DKA = diabetic ketoacidosis; IV = intravenous; LMWH = low-molecular-weight heparin; SC = subcutaneous)
Adapted from Joint British Diabetes Societies Inpatient Care Group. The Management of the Hyperosmolar Hyperglycaemic State (HHS) in Adults with Diabetes; 2012;
abed. care.
In addition, stress hormones, such as cortisol and growth
hormone, are increased in the blood. These actions reduce
whole-body glucose uptake and increase hepatic glucose
production, maintaining a glucose supply to the brain. People
with type 1 diabetes cannot regulate insulin once it is injected
subcutaneously, and so it continues to act, despite the
development of hypoglycaemia. In addition, within 5 years of
diagnosis, most patients will have lost their ability to release
glucagon specifically during hypoglycaemia. The reasons for
this are unknown, but may result from loss of a-cell regulation
by insulin or other products of the (3 cell. These two primary
defects mean that hypoglycaemia occurs much more frequently
in people with type 1 and longer-duration type 2 diabetes.
Clinical assessment
Symptoms of hypoglycaemia (Box 20.18) comprise two main
groups: those related to acute activation of the autonomic
nervous system and those secondary to glucose deprivation of
the brain (neuroglycopenia). Symptoms of hypoglycaemia are
idiosyncratic, differing with age and duration of diabetes, and
also depending on the circumstances in which hypoglycaemia
occurs. Hypoglycaemia also affects mood, inducing a state of
increased tension and low energy. Learning to recognise the early
onset of hypoglycaemia is an important aspect of the education
of people with diabetes treated with insulin.
20.18 Most common symptoms of hypoglycaemia
Autonomic
• Sweating
• Trembling
• Pounding heart
Neuroglycopenic
• Delirium
• Drowsiness
• Speech difficulty
Non-specific
• Nausea
• Tiredness
• Hunger
• Anxiety
• Inability to concentrate
• Incoordination
• Irritability, anger
• Headache
N.B. Symptoms differ with age; children exhibit behavioural changes (such as
naughtiness or irritability), while older people experience more prominent
neurological symptoms (such as visual disturbance and ataxia).
Circumstances of hypoglycaemia
Risk factors and causes of hypoglycaemia in patients taking
insulin or sulphonylurea drugs are listed in Box 20.19. Severe
hypoglycaemia can have serious morbidity (e.g. convulsions,
coma, focal neurological lesions) and has a mortality of up to
740 • DIABETES MELLITUS
20.19 Hypoglycaemia in diabetes: common causes
and risk factors
Medical issues
• Rapid improvement in and/or strict glycaemic control
• Previous severe hypoglycaemia
• Impaired awareness of hypoglycaemia
• Long-duration type 1 diabetes
• Duration of insulin therapy in type 2 diabetes
• Lipohypertrophy at injection sites causing variable insulin absorption
• Severe hepatic dysfunction
• Impaired renal function
• Inadequate treatment of previous hypoglycaemia
• Terminal illness
• Bariatric surgery involving bowel resection
• Unrecognised other endocrine disorder, e.g. Addison’s disease
Reduced carbohydrate intake
• Gastroparesis due to autonomic neuropathy causing variable
carbohydrate absorption
• Malabsorption, e.g. coeliac disease
• Eating disorder
Lifestyle issues
• Exercise
• Irregular lifestyle
• Increasing age
• Alcohol
• Early pregnancy
• Breastfeeding
• No or inadequate glucose
monitoring
• Factitious (deliberately
induced)
4% in insulin-treated patients. Rarely, sudden death during sleep
occurs in otherwise healthy young patients with type 1 diabetes
(‘dead-in-bed syndrome’) and may result from hypoglycaemia-
induced cardiac arrhythmia. Severe hypoglycaemia is very
disruptive and impinges on many aspects of the patient’s life,
including employment, driving (see Box 20.24), travel, sport and
personal relationships.
Nocturnal hypoglycaemia in patients with type 1 diabetes is
common but often undetected, as hypoglycaemia does not usually
waken a person from sleep. Patients may describe poor quality
of sleep, morning headaches and vivid dreams or nightmares, or
a partner may observe profuse sweating, restlessness, twitching
or even seizures. The only reliable way to identify this problem is
to measure blood glucose during the night. High glucose levels
in the morning are not, as commonly perceived, an indicator of
nocturnal hypoglycaemia.
Exercise-induced hypoglycaemia occurs in people with well-
controlled, insulin-treated diabetes because of hyperinsulinaemia.
Suppression of endogenous insulin secretion to allow increased
hepatic glucose production to meet the increased metabolic
demand is key to the normal physiological response to exercise.
In insulin-treated diabetes, insulin levels may actually increase
with exercise because of improved blood flow at the site of
injection, and this increases the risk of hypoglycaemia. This
means that both insulin and muscle contraction will increase
glucose uptake, causing a fall in blood glucose. This occurs most
commonly with prolonged and/or aerobic exercise. In addition, the
‘double hit’ of hypoglycaemia with exercise reflects the additional
increased risk of nocturnal hypoglycaemia that can occur after
exercise, possibly as a result of glycogen depletion. In contrast,
high-intensity exercise because of the marked stimulation to
adrenaline (epinephrine) production may actually cause blood
glucose to rise significantly. Education is key to preventing
exercise-induced hypoglycaemia.
Hypoglycaemia may also occur within the hospital setting.
This may result from errors in insulin dose or type of insulin
prescribed, infusion of IV insulin without glucose, changes in meal
timings or content and failure to provide usual snacks, reduced
carbohydrate intake because of vomiting or reduced appetite, or
factors related to the hospital admission, e.g. concurrent illness
or discontinuation of long-term glucocorticoid therapy.
Awareness of hypoglycaemia
For most individuals, the glucose level (threshold) at which
they first become aware of hypoglycaemia is not constant but
varies according to the circumstances in which hypoglycaemia
arises (e.g. during the night or during exercise). In addition,
with longer duration of disease, and particularly in response
to frequent hypoglycaemia, the threshold for generation of
symptom responses to hypoglycaemia shifts to a lower glucose
concentration. This cerebral adaptation has a similar effect on the
counter-regulatory hormonal response to hypoglycaemia. Taken
together, this means that individuals with type 1 diabetes may
have reduced (impaired) awareness of hypoglycaemia. Symptoms
can be experienced less intensely, or even be absent, despite
blood glucose concentrations below 3.0 mmol/L (55 mg/dL). Such
individuals are at an especially high risk of severe hypoglycaemia.
The prevalence of impaired awareness of hypoglycaemia
increases with time; overall, it affects around 20-25% of people
with type 1 diabetes and under 10% with insulin-treated type
2 diabetes.
Management
Acute treatment of hypoglycaemia
Treatment of hypoglycaemia depends on its severity and on
whether the patient is conscious and able to swallow (Box
20.20). Oral carbohydrate usually suffices if hypoglycaemia
is recognised early. If parenteral therapy is required, then as
soon as the patient is able to swallow, glucose should be given
orally. Full recovery may not occur immediately and reversal of
cognitive impairment may not be complete until 60 minutes after
normoglycaemia is restored. When hypoglycaemia has occurred
in a patient treated with a long- or intermediate-acting insulin or a
long-acting sulphonylurea, such as glibenclamide, the possibility
of recurrence should be anticipated; to prevent this, infusion of
10% dextrose, titrated to the patient’s blood glucose, or provision
of additional carbohydrate may be necessary.
If the patient fails to regain consciousness after blood glucose
is restored to normal, then cerebral oedema and other causes
of impaired consciousness - such as alcohol intoxication, a
post-ictal state or cerebral haemorrhage - should be considered.
Cerebral oedema has a high mortality and morbidity.
Following recovery, it is important to try to identify a cause and
make appropriate adjustments to the patient’s therapy. Unless
the reason for a hypoglycaemic episode is clear, the patient
should reduce the next dose of insulin by 10-20% and seek
medical advice about further adjustments in dose.
The management of self-poisoning with oral antidiabetic agents
is described on page 141.
Prevention of hypoglycaemia
Patient education is fundamental to the prevention of
hypoglycaemia. Risk factors for, and treatment of, hypoglycaemia
should be discussed. The importance of regular blood glucose
monitoring and the need to have glucose (and glucagon) readily
available should be stressed. A review of insulin and carbohydrate
Management of diabetes • 741
20.20 Emergency treatment of hypoglycaemia
Biochemical or symptomatic hypoglycaemia (self-treated)
In the UK, it is recommended that all glucose levels <4.0 mmol/L
(72 mg/dl_) are treated (‘4 is the floor’). People with diabetes who
recognise developing hypoglycaemia are encouraged to treat
immediately. Options available include:
• Oral fast-acting carbohydrate (10-15 g) is taken as glucose drink or
tablets or confectionery, e.g. 5-7 Dextrosol tablets (or 4-5
Glucotabs), 90-120 mL original Lucozade, 150-200 mL pure fruit
juice, 3-4 heaped teaspoons of sugar dissolved in water)
• Repeat capillary glucose measurement 1-15 mins later. If still
<4.0 mmol/L, repeat above treatment
• If blood glucose remains <4.0 mmol/L after three cycles
(30-45 mins), contact a doctor. Consider glucagon 1 mg IM or
150-200 mL 10% glucose over 15 mins IV
• Once blood glucose is >4.0 mmol/L, take additional long-acting
carbohydrate of choice
• Do not omit insulin injection if due but review regimen
Severe (external help required)
This means individuals are either unconscious or unable to treat
hypoglycaemia themselves. Treatment is usually by a relative or by
paramedical or medical staff. Immediate treatment as below is needed.
• If patient is semiconscious or unconscious, parenteral treatment is
required:
IV 75-100 mL 20% dextrose over 15 mins (=15 g; give
0.2 g/kg in children)*
Or
IV 150-200 mL 10% dextrose over 15 mins
Or
IM glucagon (1 mg; 0.5 mg in children) - may be less effective
in patients on sulphonylurea/under the influence of alcohol
• If patient is conscious and able to swallow:
Give oral refined glucose as drink or sweets (= 25 g) or 1 .5-2
tubes of Glucogel/Dextrogel
Or
Apply glucose gel or jam or honey to buccal mucosa
• Repeat blood glucose measurement after 10-15 mins and manage
as per biochemical hypoglycaemia
*Use of 50% dextrose is no longer recommended.
Adapted from Joint British Diabetes Societies. The hospital management of
hypoglycaemia in adults with diabetes mellitus (2013). Available at: abed. care.
management during exercise is particularly useful. Advice for
patients when travelling is summarised in Box 20.21 .
Relatives and friends also need to be familiar with the symptoms
and signs of hypoglycaemia and should be instructed in how to
help (including how to inject glucagon).
It is important to recognise that all current insulin replacement
regimens are suboptimal and do not accurately replicate normal
physiological insulin profiles. Understanding the pharmacokinetics
and pharmacodynamics of the insulin regimen in use by the patient
will help prevent further hypoglycaemia (p. 748). For example, an
individual experiencing regular nocturnal hypoglycaemia between
midnight and 0200 hrs may be found to be taking twice-daily
soluble and intermediate-acting insulins before breakfast and
before the main evening meal between 1700 and 1900 hrs. In this
case, the peak action of the isophane insulin will coincide with the
period of maximum sensitivity to insulin - namely, 2300-0200 hrs
- and increase the risk of nocturnal hypoglycaemia. To address
this, the evening dose of depot intermediate-acting insulin should
20.21 Avoidance and treatment of hypoglycaemia
during travel
• Carry a supply of fast-acting carbohydrate (non-perishable, in
suitable containers):
Screwtop plastic bottles for glucose drinks
Packets of powdered glucose (for use in hot, humid climates)
Confectionery (foil-wrapped in hot climates)
• Ask companions to carry additional oral carbohydrate, and glucagon
• Perform frequent blood glucose testing (carry spare meter and/or
visually read strips)
• Use fast-acting insulin analogues for long-distance air travel
be deferred until bedtime (after 2300 hrs), shifting its peak action
period to 0500-0700 hrs. It is also a sensible precaution for
patients to measure their blood glucose before they retire to
bed and to have a carbohydrate snack if the reading is less
than 6.0 mmol/L (approximately 110 mg/dL).
Management of diabetes
The aims are to improve symptoms of hyperglycaemia and
minimise the risks of long-term microvascular and macrovascular
complications. Treatment methods for diabetes include dietary/
lifestyle modification, oral antidiabetic drugs and injected therapies.
Initial investigation and management is outlined in Figure 20.10.
In patients with suspected type 1 diabetes, urgent treatment with
insulin is required and prompt referral to a specialist is usually
needed. In patients with suspected type 2 diabetes, the first
approach to management involves advice about dietary and
lifestyle modification. Oral antidiabetic drugs are usually added
in those who do not achieve glycaemic targets, or who have
symptomatic hyperglycaemia at diagnosis and a high HbA1c.
However, the guidelines in some countries are to introduce
medication immediately on diagnosis of diabetes without waiting
to assess the impact of diet and lifestyle changes. Patients
with type 2 diabetes who present with marked symptomatic
hyperglycaemia or DKA will require initial management with
insulin treatment.
For most people, types 1 and 2 diabetes are chronic conditions
that will impact on their day-to-day activities and require sustained
changes to lifestyle. Education is key to achieving and maintaining
a healthy lifestyle and to managing diabetes. Early educational
intervention at diagnosis and repeated education are essential
if these goals are to be successfully achieved. Management of
people with diabetes should be individualised where possible,
taking into account personal and cultural beliefs, individual
circumstances, comorbidities and other factors.
Diabetes is a complex disorder that progresses in severity
with time, so people with diabetes should be seen at regular
intervals for the remainder of their lives, either at a specialist
diabetic clinic or in primary care where facilities are available
and staff are trained in diabetes care. A checklist for follow-up
visits is given in Box 20.22. The frequency of visits is variable,
ranging from weekly during pregnancy to annually in the case
of patients with well-controlled type 2 diabetes.
In parallel with treatment of hyperglycaemia, other risk factors
for complications of diabetes need to be addressed, including
treatment of hypertension (p. 510) and dyslipidaemia (p. 373),
and advice on smoking cessation (p. 94).
742 • DIABETES MELLITUS
Monotherapy
Efficacy
Hypoglycaemia risk
Weight
Side-effects
Costs
Dual therapy
Efficacy
Hypoglycaemia risk
Weight
Side-effects
Costs
Triple therapy
Combination
injectable therapy
Healthy eating, weight control, increased physical activity and diabetes education
Metformin
high
low risk
neutral/loss
Gl/lactic acidosis
low
If HbAic target not achieved after ~3 months of monotherapy, proceed to two-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- and disease-specific factors)
Metformin
+
Sulphonylurea
high
moderate risk
gain
hypoglycaemia
low
Metformin
+
Thiazolidine-
dione
high
low risk
gain
oedema, HF, fxs
low
Metformin
+
DPP-4
inhibitor
intermediate
low risk
neutral
rare
high
Metformin
+
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
Metformin
+
GLP-1 receptor
agonist
high
low risk
loss
Gl
high
Metformin
+
Insulin (basal)
highest
high risk
gain
hypoglycaemia
variable
If HbAic target not achieved after ~3 months of dual therapy, proceed to three-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- and disease-specific factors)
Metformin
+
Sulphonylurea
TZD
or DPP-4-i
or SGLT2-S
or GLP-1 -RA
or Insulin
Metformin
+
Thiazolidine-
dione
SU
or DPP-4-i
or SGLT2-i
or GLP-1 -RA
or Insulin
Metformin
+
DPP-4
inhibitor
+
SU
or TZD
or SGLT2-i
or Insulin
Metformin
+
SGLT2
inhibitor
+
SU
or
TZD
or DPP-4-i
or Insulin
Metformin
+
GLP-1 receptor
agonist
+
SU
or TZD
or Insulin
Metformin
+
Insulin (basal)
+
TZD
or DPP-4-i
or SGLT2-S
or GLP-1 -RA
If HbAic target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectabies; (2) on
GLP-1 -RA, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1 -RA or mealtime insulin. In refractory
patients consider adding TDZ or SGLT2-1
Metformin
+
Basal insulin + Mealtime insulin or GLP-1 -RA
Fig. 20.10 The recommended approach for the management of type 2 diabetes. First-line drug treatment should be metformin. Second- and
third-line treatment should be chosen based on the efficacy, hypoglycaemia risk, weight effects and other side-effects, and costs of the therapy in
discussion with the patient. (DPP-4-i = dipeptidyl peptidase 4 inhibitor; fxs = fractures; Gl = gastrointestinal; GLP-1 -RA = glucagon-like peptide 1 receptor
agonist; GU = genitourinary; HF, heart failure; SGLT2-i = sodium and glucose transporter 2 inhibitor; SU, sulphonylurea; TZD = thiazolidinedione) Adapted
from the American Diabetes Association/European Association for the Study of Diabetes joint position statement, 2015. Diabetes Care 2015; 38:140-149.
Self-assessment of glycaemic control
In people with type 2 diabetes, there is not usually a need
for regular self-assessment of blood glucose, unless they are
treated with insulin, or at risk of hypoglycaemia while taking
sulphonylureas. Blood glucose testing can be used for self-
education (i.e. demonstrating how different food and exercise
regimes affect blood glucose) and may be useful in acute illness.
Blood glucose targets vary according to individual circumstances
but, in general, fasting glucose levels of 5-7 mmol/L (90—
126 mg/dL), pre-meal values of 4-7 mmol/L (72-126 mg/dL)
and 2-hour post-meal values of 4-8 mmol/L (72-144 mg/dL)
represent optimal control.
Insulin-treated patients should be taught how to monitor
their own blood glucose using capillary blood glucose meters.
Immediate knowledge of blood glucose levels can be used by
patients to guide their insulin dosing and to manage exercise and
illness. This can be supplemented with blood testing for ketones
when blood glucose is high and/or during intercurrent illness.
More recently, continuous glucose monitoring systems (CGMS)
have been developed that allow for a more detailed examination
of daily glucose profiles. These can be used continuously as
part of day-to-day diabetes management or intermittently as
an educational tool.
Urine testing for glucose is not recommended because
variability in renal threshold means that some patients with
inadequate glycaemic control will not find glucose in their urine.
Therapeutic goals
The target HbA1c depends on the individual patient. Early on in
diabetes (i.e. patients managed by diet or one or two oral agents),
a target of 48 mmol/mol or less may be appropriate. However,
a higher target of 58 mmol/mol may be more appropriate in
older patients with pre-existing cardiovascular disease, or those
treated with insulin and therefore at risk of hypoglycaemia. In
general, the benefits of lower target HbA1c (primarily, a lower
risk of microvascular disease) need to be weighed against
any increased risks (primarily, hypoglycaemia in insulin-treated
patients). Type 2 diabetes is usually a progressive condition
Management of diabetes • 743
20.22
Lifestyle issues
• General health
• Work or school
• Smoking
• Alcohol intake
Body weight and BMI
Blood pressure
• Individualised target of 130-140/70-80 mmHg, depending on risk
factors and presence of nephropathy
Urinalysis
• Analyse fasting specimen for glucose, ketones, albumin (both
macro- and micro-albuminuria)
Biochemistry
• Renal, liver and thyroid function
• Lipid profile and estimated 10-year cardiovascular risk to guide
need for lipid-lowering therapy (p. 487)
Glycaemic control
• Glycated haemoglobin (HbA1c); individualised target between 48 and
58 mmol/mol
• Inspection of home blood glucose monitoring record (if carried out
by patient)
Hypoglycaemic episodes
• Number and cause of severe (requiring assistance for treatment)
events and frequency of mild (self-treated) episodes and
biochemical hypoglycaemia
• Awareness of hypoglycaemia
• Driving advice
Assessment of injection sites if insulin-treated
Eye examination
• Visual acuities (near and distance)
• Ophthalmoscopy (with pupils dilated) or digital photography
Examination of lower limbs and feet
• Assessment of foot risk (p. 721)
to review a patient in the diabetes clinic
• Stress or depression
• Sexual health
• Exercise
(Fig. 20.11) unless there are major diet and lifestyle changes,
so that there is usually a need to increase diabetes medication
over time to achieve the individualised target HbA1c.
In people with type 2 diabetes, treatment of coexisting
hypertension and dyslipidaemia is usually required. This can
be decided by assessing absolute risk of a cardiovascular
disease event (p. 510) and adjusting targets to individual
circumstances. The target for blood pressure is usually below
140/80 mmHg, although some guidelines suggest 130/80 mmHg.
For lipid-lowering, there is a reduction in cardiovascular risk
even with normal cholesterol levels, but statin therapy is usually
recommended when the 1 0-year cardiovascular event risk is at
least 20%. As a rule, anyone with type 2 diabetes who is over the
age of 40 years should receive a statin, irrespective of baseline
cholesterol levels. Some guidelines do not propose a target level
once the patient is started on a statin but others suggest a total
cholesterol of less than 4.0 mmol/L (approximately 150 mg/dL)
and an LDL cholesterol of less than 2.0 mmol/L (approximately
75 mg/dL). Similar targets are appropriate in type 1 diabetes,
although there is a shortage of data from clinical trials.
Patient education, diet and lifestyle
The importance of lifestyle changes, such as undertaking
regular physical activity, observing a healthy diet and reducing
Years from randomisation
Fig. 20.11 Time course of changes in HbA1c during the United
Kingdom Prospective Diabetes Study (UKPDS). In the UKPDS there was
loss of glycaemic control with time in patients receiving monotherapy,
independently of their randomisation to conventional or intensive glycaemic
control, consistent with progressive decline in (3-cell function (see Fig.
20.8). Adapted from UK Prospective Diabetes Study Group. UKPDS 33.
Lancet 1998; 352:837-853.
alcohol consumption, should not be under-estimated in
improving glycaemic control for people with both type 1 and
type 2 diabetes. Many people find this difficult to sustain and
constant reinforcement of the benefits of lifestyle change
will usually be required. Patients should be encouraged to
stop smoking.
Healthy eating
All people with diabetes need to pay special attention to their
diet (Box 20.23; see also p. 694). They should have access
to a dietitian at diagnosis, at review and at times of treatment
change. Nutritional advice should be tailored to individuals
and take account of their age, lifestyle, culture and personal
circumstances. Structured education programmes are
available for both common types of diabetes and, if possible,
a clear referral mechanism for diabetes education should be
in place.
Between 80% and 90% of people with type 2 diabetes are
overweight and so the majority require dietary advice for achieving
weight loss, to include caloric restriction. There is, however,
limited evidence for the ideal macronutrient composition of the
diet in type 2 diabetes. In general, high fat intake (especially
saturated fats) is associated with a raised HbA1c, but it is unclear
how the type and amount of fat influence post-prandial glucose
control. Reduction of caloric intake and weight loss should be
the major goals. Some evidence for the Mediterranean diet,
low-carbohydrate diets and meal replacements is emerging.
Whichever approach is taken, weight loss in overweight and
obese individuals with diabetes markedly improves glycaemic
control and slows diabetes progression.
Carbohydrate
While it is recognised that the total amount of carbohydrate
is the major determinant of post-prandial glucose (p. 694),
there is little evidence to support specific strategies for
carbohydrate intake in type 2 diabetes or to identify the ideal
amount of carbohydrate in their diet. Current UK government
Food Standards Agency recommendations are that the total
carbohydrate intake should be no more than 50% of energy,
and of this non-milk extrinsic sugars (e.g. table sugar, honey,
744 • DIABETES MELLITUS
i
glucose and fructose sugars) should not be more than 1 1 %. Low
glycaemic index (Gl) diets have, in some short-term trials, been
shown to improve HbA1c, but the literature concerning Gl and
glycaemic control is mixed. The Gl of a carbohydrate-containing
food is a measure of the change in blood glucose following its
ingestion relative to the rise in blood glucose observed following
a liquid OGTT. Different foods can be ranked by their effect
on post-prandial glycaemia. Low-GI foods, such as starchy
foods (e.g. basmati rice, spaghetti, porridge, noodles, granary
bread, and beans and lentils), may reduce post-prandial glucose
excursions. However, different methods of food processing and
preparation can influence the Gl of foods, and this may limit
their benefit.
Low-carbohydrate diets may lead to significant reductions
in body weight and improved glycaemic control in the short
term, although high dropout rates and poor adherence have
limited widespread application of this approach. Increased
consumption of whole grains has not been shown to improve
glycaemic control.
Fat
There is limited evidence on the ideal fat content in the diet of
people with diabetes. Current UK government Food Standards
Agency recommendations are that intake of total fat should be
not more than 35% of energy intake, of which not more than 1 1 %
should consist of polyunsaturated fats. The type of fatty acids
consumed may be more important when looking at glycaemic
targets and risk of cardiovascular disease. Mediterranean diets rich
in monounsatu rated fats appear more beneficial (Box 20.23). The
influence of dietary fats on plasma lipid profile and cardiovascular
disease is discussed on page 697.
Salt
People with diabetes should follow the advice given to the general
population: namely, adults should limit their sodium intake to no
more than 6 g daily.
Weight management
In patients with diabetes, weight management is important, as a
high percentage of people with type 2 diabetes are overweight
or obese, and many antidiabetic drugs, including insulin,
encourage weight gain. Obesity, particularly central obesity with
increased waist circumference, also predicts insulin resistance
and cardiovascular risk.
Management of obesity is described on page 700. Weight
loss can be achieved through a reduction in energy intake and
an increase in energy expenditure through physical activity.
Lifestyle interventions or pharmacotherapy for obesity, when
associated with weight reduction, have beneficial effects on
HbA1c, but long-term benefits in terms of glycaemic control
and microvascular disease have not been adequately
assessed. More recently, bariatric surgery (p. 703) has been
shown to induce marked weight loss in obese individuals with
type 2 diabetes and this is often associated with significant
improvements in HbA1c and withdrawal of or reduction in diabetes
medications.
| Exercise
All patients with diabetes should be advised to achieve a significant
level of physical activity and to maintain this in the long term. This
can include activities such as walking, gardening, swimming or
cycling. Supervised and structured exercise programmes may
be of particular benefit in type 2 diabetes. Various guidelines
exist for physical activity in the general population. The American
Diabetes Association recommends that all adults with diabetes
are encouraged to reduce sedentary time, and suggest that
adults over 18 years of age should do either 150 minutes per
week of moderate-intensity exercise or 75 minutes per week of
vigorous-intensity exercise, or a combination thereof. Muscle¬
strengthening (resistance) exercise is recommended on 2 or
more days of the week. Adults over 65 years or those with
disabilities should follow the recommended guidelines if possible
or be as physically active as they are able. Recent evidence
also indicates that extended sedentary time (>90 mins) should
be avoided.
People with type 1 diabetes appear to exercise less frequently
than the general population, perhaps because of perceived
concerns about hypoglycaemia and difficulties in insulin
management around exercise. However, the health benefits of
exercise are equally important in type 1 diabetes, so this should
be addressed in the clinic and specialist advice sought on
insulin and carbohydrate management before, during and after
exercise.
Alcohol
Alcohol is recognised as having both beneficial and harmful
effects on cardiovascular disease and this also appears to apply
in patients with diabetes. Alcohol can therefore be taken in
moderation in diabetes, with the aim of keeping within national
guidelines relating to recommendations for people without
diabetes (e.g. in the UK, the weekly recommended maximum
is 14 units for women and men). However, alcohol can reduce
hypoglycaemia awareness and, by suppressing gluconeogenesis,
increase hypoglycaemia risk. The latter occurs when individuals
are in the fasted state and so people with diabetes who drink
should be advised to eat at the same time. In addition, all
patients with diabetes should be made aware of the high calorie
20.23 Dietary management of diabetes
Aims of dietary management
• Achieve good glycaemic control
• Reduce hyperglycaemia and avoid hypoglycaemia
• Assist with weight management:
Weight maintenance for type 1 diabetes and non-obese type 2
diabetes
Weight loss for overweight and obese type 2 diabetes
• Reduce the risk of micro- and macrovascular complications
• Ensure adequate nutritional intake
• Avoid ‘atherogenic’ diets or those that aggravate complications, e.g.
high protein intake in nephropathy
Dietary constituents and recommended % of energy intake
• Carbohydrate: 50%:
Sucrose: up to 1 0%
• Fat (total): <35%:
n-6 Polyunsaturated: <10%
n-3 Polyunsaturated: eat 1 portion (140 g) oily fish once or twice
weekly
Monounsaturated: 10-20%
Saturated: <10%
• Protein: 10-15% (do not exceed 1 g/kg body weight/day)
• Fruit/vegetables: 5 portions daily
Management of diabetes • 745
content of some alcohols and the implications for body weight
management, which are often overlooked.
|Driving
European legislation on driving has had a major impact on
people with diabetes. Legislation will vary from country to country
and so individuals should contact their nurse or doctor to find
out if their treatment means they need to inform the licensing
authority (Box 20.24). To drive a car or ride a motorcycle in the
UK, people with diabetes who take insulin replacement therapy
must notify the Driver and Vehicle Licensing Agency (DVLA).
They must have adequate awareness of hypoglycaemia, have
had no more than one episode of severe hypoglycaemia in the
preceding 12 months, meet the standards for visual acuity and
visual fields, and not be regarded as a likely risk to the public
while driving. In addition, blood glucose testing is required to be
performed no more than 2 hours before the start of a journey
and every 2 hours while driving. Blood glucose levels should
be over5 mmol/L (90 mg/dL) before driving; if they are below
4.0 mmol/L (72 mg/dL) or there are symptoms of hypoglycaemia,
the person should not drive. Legislative requirements for people
on insulin therapy who drive larger vehicles such as buses or
lorries require, in addition, an annual examination by a diabetes
specialist, along with review of 3 months of glucose meter
readings. Legislation differs between countries and patients
and health-care specialists need to be aware of current
requirements.
20.24 Diabetes and driving
• Licensing regulations vary considerably between countries. In the
UK, diabetes requiring insulin therapy or any complication that could
affect driving should be declared to the Driver and Vehicle Licensing
Agency; ordinary driving licences are ‘period -restricted’ for
insulin-treated drivers; and vocational licences (large goods vehicles
and public service vehicles) may be granted but require very strict
criteria to be met
• The main risk to driving performance is hypoglycaemia. Visual
impairment and other complications may occasionally cause
problems
• Insulin-treated diabetic drivers should:
Check blood glucose before driving and 2-hourly during long
journeys
Keep an accessible supply of fast-acting carbohydrate in the
vehicle
Take regular snacks or meals during long journeys
Stop driving if hypoglycaemia develops
Refrain from driving until at least 45 mins after treatment of
hypoglycaemia (delayed recovery of cognitive function)
Carry identification in case of injury
Ramadan
The Qur’an requires Muslims to fast during the month of
Ramadan from sunrise to sunset. While people with diabetes
are a recognised exception to this and are not required to fast,
many will choose to do so. In this context, patient education,
regular glucose monitoring and adjustment of treatment regimens
are essential and should occur weeks prior to Ramadan.
The highest risk of hypoglycaemia is in patients treated with
20.25 Recommendations for management of
diabetes during Ramadan
• Monitor blood glucose: depending on treatment regimen, glucose
levels should be checked daily or several times a day. Patients
treated with insulin and insulin secretagogues should measure
glucose before, during and after fasting (2-4 times daily)
• Consult diabetes team for medication adjustment at least 1 month
prior to Ramadan. Treatment should be evaluated and modified
according to risk of hypoglycaemia. Avoid or reduce sulphonylureas
and/or insulin daily dosage
• Avoid skipping pre-dawn meals
• Avoid strenuous physical activity during fasting period
• Adjust medication dose and eat a snack in the presence of
hypoglycaemia. Break the fast if there is severe or recurrent
hypoglycaemia
sulphonylureas and insulin (particularly older people or those
with renal failure); such individuals need careful blood glucose
monitoring and, if necessary their treatment regimens may need
to be adjusted (Box 20.25). Diabetes therapies that do not cause
hypoglycaemia may prove safest during Ramadan if glycaemic
control permits. DPP-4 inhibitors or GLP-1 receptor agonists may
be especially useful because their effect on insulin secretion is
glucose-dependent.
Drugs to reduce hyperglycaemia
Patients whose glycaemic control deteriorates after a period of
satisfactory control need their therapy to be adjusted. However,
this is not a homogeneous group; it includes some patients with
late-onset type 1 diabetes who develop an absolute deficiency
of insulin, some with type 2 diabetes whose (3-cell failure is
advanced, and others who are not adhering to the recommended
lifestyle changes or medication. Weight loss suggests worsening
|3-cell function. During continuing follow-up, the majority of
patients will require combinations of antidiabetic drugs, often with
additional insulin replacement, to obtain satisfactory glycaemic
control.
For many years, only a few choices of drug were available for
type 2 diabetes - the biguanide metformin, the sulphonylureas
and insulin. Insulin is the only treatment for type 1 diabetes,
although sometimes metformin is used with insulin in type 1
diabetes. Acarbose is also available but is little used in most
countries. Since the late 1 990s, however, several new classes
of agent have been approved for use in type 2 diabetes, with
more in development. These include thiazolidinediones, dipeptidyl
peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1)
receptor agonists, and sodium and glucose transporter 2 (SGLT2)
inhibitors. The effects of these drugs are compared in Box 20.26.
This makes for an exciting time in diabetes pharmacotherapy
but exactly how, when and in what order these agents should
be used remains uncertain. The older drugs are cheaper and
have established benefits for reducing microvascular disease;
they are therefore usually recommended as first-line therapy.
Use of the newer drugs is not supported by evidence for
reduction in microvascular disease (because the trials have not
yet been done) and they are much more expensive, so are often
reserved for later therapy after failure of metformin and
sulphonylureas. The American Diabetes Association/European
Association for the Study of Diabetes (ADA/EASD) consensus
746 • DIABETES MELLITUS
20.26 Effects of drugs used in the treatment of type 2 diabetes
Insulin
Sulphonylureas
and meglitinides
Metformin
Alpha-
glucosidase
inhibitors
Thiazolidinediones
(glitazones)
DPP-4
inhibitors
(gliptins)
GLP-1
receptor
agonists
SGLT2
inhibitors
Fasting blood
glucose
i
i
i
\
i
i
i
i
Post-prandial
blood glucose
4-
i
4-
4.
4.
4.
4-
4.
Plasma insulin
t
t
1
i
i
t
t
i
Body weight
t
t
— >
— >
t
— »
4-
4.
Cardiovascular
benefit?
No
No
Possible
No
Probable
(pioglitazone)
No
Yes
Yes
Risk of
hypoglycaemia
++
+
-
-
-
-
-
-
Tolerability
Good
Good
Moderate
Moderate
Moderate
Good
Moderate
Limited
experience
(\ = small reduction; DPP-4 =
dipeptidyl peptidase 4; GLP-'
1 = glucagon-like peptide 1 ; SGLT2
= sodium and glucose transporter 2)
guidelines are shown in Figure 20.10. These position metformin
in the first line, and then aim to encourage choice of second-line
treatment to be personalised for each patient. This personalisation
is largely based on the adverse risk profile of the drug - in
particular, risk of hypoglycaemia (avoid where hypoglycaemia
would be a problem, e.g. in drivers of heavy goods vehicles)
and weight gain. There is little evidence to guide the clinician
and patient in choosing the second- or third-line treatment,
and until biomarkers are identified that predict who will respond
best and/or experience the fewest side-effects with one drug
rather than another, this individualisation of treatment needs to
be largely empirical. A trial-and-error approach may be best:
stop a drug that does not work or that causes side-effects
and trial the next drug. At the time of writing, the ADA/EASD
guidelines were already out of date; in 2015/16, the SGLT2
inhibitor empagliflozin and the GLP-1 receptor agonist liraglutide
were shown to reduce adverse cardiovascular outcomes and
mortality. It is likely that the guidelines will change to take these
exciting results into account and we will probably see these
newer, more expensive drugs used earlier in the diabetes
trajectory.
Biguanides
Metformin is the only biguanide available. Its long-term benefits
were shown in the UK Prospective Diabetes Study (UKPDS, p. 756)
and it is now widely used as first-line therapy for type 2 diabetes,
irrespective of body weight. It is also given as an adjunct to insulin
therapy in obese patients with type 1 diabetes. Approximately
25% of patients develop mild gastrointestinal side-effects with
metformin, but only 5% are unable to tolerate it even at low dose.
The main side-effects are diarrhoea, abdominal cramps, bloating
and nausea.
Mechanism of action
The mechanism of action of metformin has not been precisely
defined. While classically considered an ‘insulin sensitised
because it lowers insulin levels, its main effects are on fasting
glucose and are insulin-independent. Metformin reduces hepatic
glucose production, may also increase insulin-mediated glucose
uptake, and has effects on gut glucose uptake and utilisation.
At the molecular level, metformin acts as a weak inhibitor of
mitochondrial respiration, which increases intracellular adenosine
monophosphate (AMP) and reduces adenosine triphosphate
(ATP). This has direct effects on the flux through gluconeogenesis,
and activates the intracellular energy sensor, AMP-activated
protein kinase (AMPK), leading to multiple beneficial metabolic
effects. However, metformin is still effective in mice lacking
AMPK, and a number of AMPK-independent mechanisms have
been proposed.
Clinical use
Metformin is a potent blood glucose-lowering treatment that
is weight-neutral or causes weight loss, does not cause
hypoglycaemia and has established benefits in microvascular
disease. It is employed as first-line therapy in all patients who
tolerate it, and its use is maintained when additional agents are
added as glycaemia deteriorates (see Fig. 20.10). Metformin is
usually introduced at low dose (500 mg twice daily) to minimise
the risk of gastrointestinal side-effects. The usual maintenance
dose is 1 g twice daily. There is a modified-release formulation
of metformin, which may be better tolerated by patients with
gastrointestinal side-effects.
Metformin can increase susceptibility to lactic acidosis, although
this is much less common than was previously thought. As
metformin is cleared by the kidneys, it can accumulate in renal
impairment, so the dose should be halved when estimated
glomerular filtration rate (eGFR) is 30-45 mLVmin/1 .73 m2, and
it should not be used below an eGFR of 30 mL/min/1 .73 m2.
It should be omitted temporarily during any acute illness where
acute kidney injury is possible, as this greatly increases the
risk of lactic acidosis; insulin treatment may be required while
metformin is withheld. Its use is also contraindicated in patients
with significantly impaired hepatic function and in those who
drink alcohol in excess, in whom the risk of lactic acidosis is
significantly increased.
| Sulphonylureas
Sulphonylureas are ‘insulin secretagogues’, i.e. they promote
pancreatic (3-cell insulin secretion. Similar to metformin, the
long-term benefits of sulphonylureas in lowering microvascular
Management of diabetes • 747
complications of diabetes were established in the UKPDS
(p. 756).
Mechanism of action
Sulphonylureas act by closing the pancreatic (3-cell ATP-sensitive
potassium (KATP) channel, decreasing K+ efflux, which ultimately
triggers insulin secretion (see Fig. 20.2C). Meglitinides (e.g.
repaglinide and nateglinide) also work in this way and, although
short-acting, are essentially sulphonylurea-like drugs.
Clinical use
Sulphonylureas are an effective therapy for lowering blood
glucose and are often used as an add-on to metformin, if
glycaemia is inadequately controlled on metformin alone (see
Fig. 20.10). The main adverse effects of sulphonylureas are
weight gain and hypoglycaemia. The weight gain is not ideal
in patients with diabetes who are already overweight or obese,
although sulphonylureas are effective treatments in this group.
Flypoglycaemia occurs because the closure of KATp channels
brings about unregulated insulin secretion, even with normal or
low blood glucose levels.
There are a number of sulphonylureas. In the UK, gliclazide is
the most commonly used; in contrast, in the USA, glibenclamide
(also known as glyburide) is widely used. Glibenclamide, however,
is long-acting and prone to inducing hypoglycaemia, so should
be avoided in older patients. Other sulphonylureas include
glimepiride and glipizide. The dose-response of all sulphonylureas
is steepest at low doses; little additional benefit is obtained when
the dose is increased above half-maximal doses.
Alpha-glucosidase inhibitors
The a-glucosidase inhibitors delay carbohydrate absorption in
the gut by inhibiting disaccharidases. Acarbose and miglitol are
available and are taken with each meal. Both lower post-prandial
blood glucose and modestly improve overall glycaemic control.
They can be combined with a sulphonylurea. The main side-effects
are flatulence, abdominal bloating and diarrhoea. They are used
widely in the Far East but infrequently in the UK.
| Thiazolidinediones
Mechanism of action
These drugs (also called TZDs, ‘glitazones’ or PPARy agonists)
bind and activate peroxisome prol iterator-activated receptor-y,
a nuclear receptor present mainly in adipose tissue, which
regulates the expression of several genes involved in metabolism.
TZDs enhance the actions of endogenous insulin, both directly
(in the adipose cells) and indirectly (by altering release of
‘adipokines’, such as adiponectin, which alter insulin sensitivity
in the liver). Plasma insulin concentrations are not increased
and hypoglycaemia does not occur. TZDs increase pre¬
adipocyte differentiation, resulting in an increase in fat mass and
body weight.
Clinical use
TZDs have been prescribed widely since the late 1990s but a
number of adverse effects have become apparent and their use
has declined. One popular TZD, rosiglitazone, was reported to
increase the risk of myocardial infarction and was withdrawn in
2010. The other TZD in common use, pioglitazone, does not
appear to increase the risk of myocardial infarction but may
exacerbate cardiac failure by causing fluid retention, and recent
data show that it increases the risk of bone fracture and possibly
bladder cancer. These observations have led to a dramatic
reduction in the use of pioglitazone.
Pioglitazone can be very effective at lowering blood glucose
in some patients and appears more effective in insulin-resistant
patients. In addition, it has a beneficial effect in reducing fatty liver
and NASH (p. 882). Pioglitazone is usually added to metformin
with or without sulphonylurea therapy (see Fig. 20.10). It may be
given with insulin therapy, when it can be very effective, but the
combination of insulin and TZDs markedly increases fluid retention
and risk of cardiac failure, so should be used with caution.
I Incretin-based therapies: DPP-4 inhibitors
and GLP-1 receptor agonists
The incretin effect is the augmentation of insulin secretion seen
when a glucose stimulus is given orally rather than intravenously,
and reflects the release of incretin peptides from the gut (see
Fig. 20.3). The incretin hormones are primarily glucagon-like
peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), which
act to potentiate insulin secretion (see Fig. 20.2). These are
rapidly broken down by dipeptidyl peptidase 4 (DPP-4). The
incretin effect is diminished in type 2 diabetes, and this has
stimulated the development of two incretin-based therapeutic
approaches.
The ‘gliptins’, or DPP-4 inhibitors, prevent breakdown and
therefore enhance concentrations of endogenous GLP-1 and GIP.
The first DPP-4 inhibitor to market was sitagliptin; others now
available include vildagliptin, saxagliptin, linagliptin and alogliptin.
These drugs are very well tolerated and are weight-neutral (see
Box 20.26). Recent cardiovascular outcome studies have shown
mixed results with the DPP-4 inhibitors. The Trial to Evaluate
Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS)
study reported no adverse cardiovascular outcomes for sitagliptin,
but the Saxagliptin Assessment of Vascular Outcomes Recorded
in Patients with Diabetes Mellitus - Thrombolysis in Myocardial
Infarction (SAVOR-TIMI) study found an increased risk of heart
failure in patients treated with saxagliptin.
The GLP-1 receptor agonists have a similar structure to
GLP-1 but have been modified to resist breakdown by DPP-4.
These agents are not orally active and have to be given by
subcutaneous injection. However, they have a key advantage
over the DPP-4 inhibitors: because the GLP-1 activity achieved
is supra-physiological, it delays gastric emptying and, at the
level of the hypothalamus, decreases appetite. Thus, injectable
GLP-1 receptor agonists lower blood glucose and result in weight
loss - an appealing therapy, as the majority of patients with
type 2 diabetes are obese. Currently available GLP-1 receptor
agonists include exenatide (twice daily), exenatide modified-release
(once weekly), liraglutide (once daily), lixisenatide (once daily) and
albiglutide (once weekly). Recently, GLP-1 receptor agonists
and long-acting insulin analogue have been combined, enabling
co-administration of insulin and GLP-1 receptor agonists with one
injection. The GLP-1 receptor agonists vary in their side-effect
profile, depending on whether they are administered daily or
weekly, but the main side-effect that often limits use is nausea.
The Liraglutide Effect and Action in Diabetes: Evaluation of
Cardiovascular Outcome Results (LEADER) study has recently
demonstrated that liraglutide, when added to usual therapy,
results in improved cardiovascular outcomes over placebo in
patients at high risk for cardiovascular disease; this contrasts
with the Evaluation of Lixisenatide in Acute Coronary Syndrome
(ELIXA) study, which showed that lixisenatide was neutral with
respect to cardiovascular disease.
748 • DIABETES MELLITUS
All the incretin-acting drugs have been reported to be
associated with an increased risk of pancreatitis, although this
risk is small: between 1 and 10 cases per 1000 patients treated.
Unlike sulphonylureas, both incretin-based therapies promote
insulin secretion only when there is a glucose ‘trigger’ for it. Thus,
when the blood glucose is normal, the insulin secretion is not
augmented and so these agents do not cause hypoglycaemia
when used as monotherapy or with other drugs that do not
cause hypoglycaemia.
SGLT2 inhibitors
The sodium and glucose transporter 2 (SGLT2) inhibitor,
dapagliflozin, was licensed for use in 2012. Subsequently,
canagliflozin and empagliflozin have also been licensed. Glucose is
filtered freely in the renal glomeruli and reabsorbed in the proximal
tubules. SGLT2 is involved in reabsorption of glucose (Fig. 20.12).
Inhibition results in approximately 25% of the filtered glucose
not being reabsorbed, with consequent glycosuria. Although
this helps to lower blood glucose and results in calorie loss and
subsequent weight loss, the glycosuria does also lead to genital
fungal infections. There has been increasing use of these agents
over the last few years; however, the recent announcement of the
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2
Diabetes (EM PA- REG Outcomes) trial has the potential to change
dramatically the way these drugs are now used. Empagliflozin
therapy resulted in a 35% reduction in cardiovascular mortality
and a similar reduction in admissions to hospital with heart
failure. This result was much greater than anticipated and the
mechanism behind it is still being investigated, but this landmark
study was the first to show such striking benefits in mortality
reduction from a glucose-lowering agent; as such, these drugs
should now, at the very least, be used in all patients who fulfil the
inclusion criteria of the trial - prior myocardial infarction, coronary
artery disease, stroke, unstable angina or occlusive peripheral
arterial disease. Euglycaemic diabetic ketoacidosis (i.e. DKA not
associated with marked hyperglycaemia) has been recognised
as a rare complication of this class of drugs.
Insulin therapy
Manufacture and formulation
Insulin was discovered in 1921 and transformed the management
of type 1 diabetes, which was a fatal disorder until then. Up to
the 1980s, insulin was obtained by extraction and purification
from pancreases of cows and pigs (bovine and porcine insulins),
and some patients still prefer to use animal insulins. Recombinant
DNA technology enabled large-scale production of human insulin.
Unmodified (‘soluble’ or ‘regular’) insulin aggregates into hexamers
in subcutaneous tissues; these must dissociate before systemic
absorption can occur and this process helps extend the duration
of action to nearly 8 hours. The amino acid sequence of insulin
can be altered to produce analogues of insulin, which differ in
their rate of absorption from the site of injection. For example,
in insulin lispro, the penultimate lysine and proline residues on
the C-terminal end of the p chain are reversed (Fig. 20.13). This
prevents the insulin molecules from aggregating as hexamers in
subcutaneous tissues after injection and so speeds absorption,
leading to a more rapid onset and shorter duration of action
than soluble insulin (Box 20.27). The onset of action of insulin
analogues may be further hastened by the addition of excipients
to the formulation (e.g. nicotinamide and arginine to insulin
aspart). Conversely, in insulin glargine, a substitution of glycine
for asparagine in the a chain and the addition of two additional
arginine residues to the C-terminal end of the p chain serves to
prolong the duration of action of the insulin to over 24 hours. The
amino acid modifications shift the isoelectric point from a pH of
5.4 to 6.7, making the molecule less soluble at a physiological
pH (see Fig. 20.13). Duration of action can also be extended by
adding chemicals to soluble insulin solution or by adding other
molecules to the insulin structure. Chemical additives include
protamine and zinc at neutral pH (isophane or NPH insulin) or
excess zinc ions (lente insulins). In insulin detemir and degludec,
the duration of action is extended by adding fatty acids to a
slightly truncated C-terminal end of the p chain (Fig. 20.13).
Following subcutaneous injection, these bind to albumin in the
Fig. 20.12 Glucose filtration and reabsorption
by the nephron. Some 90% of filtered glucose is
reabsorbed by sodium and glucose transporter 2
(SGLT2) and 10% by SGLT1. SGLT2 inhibitors
reduce net reabsorbed glucose by 25%. For a
mean plasma glucose of 8 mmol/L (144 mg/dL),
this results in a glucose loss of approximately 80 g
per day in the urine, which in turn reduces plasma
glucose. This equates to 320 kcal per day and
subsequent weight loss.
Management of diabetes
749
Fast-acting analogues
Long-acting analogues
Lispro
As part
Glulisine
Glargine
I Detemir/Degludec
^W^(PrOLys
Fig. 20.13 Amino acid structure of insulin and insulin analogues. The areas in the shaded colours show the modifications made to the normal
structure of insulin. These are important in altering the pharmocokinetic properties of the analogues.
^9 20.27 Duration of action (in hours) of insulin
preparations
Insulin
Onset
Peak
Duration
Rapid-acting
(insulin analogues: lispro,
aspart, glulisine)
<0.5
0.5-2. 5
3-4.5
Short-acting
(soluble (regular))
0.5-1
1-4
4-8
Intermediate-acting
(isophane (NPH), lente)
1-3
3-8
7-14
Long-acting
(bovine ultralente)
2-4
6-12
12-30
Long-acting
(insulin analogues: glargine,
detemir, degludec)
1-2
None
18-26
blood, from which the insulin slowly disassociates. The duration
of action of insulin degludec may also be extended as the fatty
acid moiety promotes the formation of multi-hexamers of insulin
in the subcutaneous tissues (Box 20.27).
Isophane and lente insulins are cloudy preparations and have to
be resuspended prior to injection to ensure adequate mixing of the
components. The more modern, structurally modified, long-acting
insulins (e.g. glargine, detemir and degludec) are clear and do
not require resuspension. Pre-mixed formulations containing
short-acting and isophane insulins in various proportions are
available.
In most countries, the insulin concentration in available
formulations has been standardised at 100 U/mL. Increasing
levels of obesity, which are associated with increased daily
insulin requirements, have stimulated pharmaceutical companies
to develop more concentrated insulin formulations to reduce the
20.28 How to inject insulin subcutaneously
• Needle sited at right angle to the skin
• Subcutaneous (not intramuscular) injection
• Delivery devices: glass syringe (requires resterilisation), plastic
syringe (disposable), pen device (reusable, some disposable),
infusion pump
discomfort of injecting bigger volumes and also to reduce variability
in insulin delivery from the subcutaneous depot. Therefore,
U 200, U 300 and U 500 formulations of insulin are available, which
are, respectively, two, three and five times more concentrated
than standard insulin. Expert advice should be sought before
using concentrated insulin because errors in prescribing can
cause severe hypoglycaemia.
Subcutaneous multiple dose insulin therapy
In most patients, insulin is injected subcutaneously several times
a day into the anterior abdominal wall, upper arms, outer thighs
and buttocks (Box 20.28). Accidental intramuscular injection
often occurs in children and thin adults. The rate of absorption of
insulin may be influenced by many factors other than the insulin
formulation, including the site, depth and volume of injection, skin
temperature (warming), local massage and exercise. Absorption
is delayed from areas of lipohypertrophy at injection sites
(p. 721), which results from the local trophic action of insulin,
so repeated injection at the same site should be avoided. Other
routes of administration (intravenous and intraperitoneal) are
reserved for specific circumstances.
Once absorbed into the blood, insulin has a half-life of just
a few minutes. It is removed mainly by the liver and also the
kidneys, so plasma insulin concentrations are elevated in patients
with liver disease or renal failure. Rarely, the rate of clearance
can be affected by binding to insulin antibodies.
750 • DIABETES MELLITUS
20.29 Side-effects of insulin therapy
• Hypoglycaemia
• Weight gain
• Peripheral oedema (insulin treatment causes salt and water
retention in the short term)
• Insulin antibodies
• Local allergy (rare)
• Lipohypertrophy or lipoatrophy at injection sites
Insulin can be administered using a disposable plastic syringe
with a fine needle (which can be re-used several times), but this
has largely been replaced by pen injectors containing insulin in
cartridges sufficient for multiple dosing. These are also available
as pre-loaded disposable pens.
For the most part, insulin analogues have replaced soluble
and isophane insulins, especially for people with type 1 diabetes,
because they allow greater flexibility and convenience and
reduce risk of hypoglycaemia (see Box 20.26). Unlike soluble
insulin, which should be injected 30-60 minutes before eating,
rapid-acting insulin analogues can be administered immediately
before, during or even after meals, although are better injected
15 minutes before eating. Long-acting insulin analogues are
also better able than isophane insulin to maintain ‘basal’ insulin
levels for up to 24 hours.
Despite these pharmacokinetic benefits, the impact of
insulin analogues on overall glycaemic control is minor, but
studies consistently show a significant reduction in frequency
of hypoglycaemia, particularly overnight.
The complications of insulin therapy are listed in Box 20.29; the
most important of these is hypoglycaemia (p. 738). A common
problem is fasting hyperglycaemia (‘the dawn phenomenon’),
which arises through a combination of the normal circadian
rhythm and release of hormones such as growth hormone and
cortisol during the later part of the night, as well as diminishing
levels of overnight isophane insulin. The dawn phenomenon is
not a consequence of prior nocturnal hypoglycaemia.
Insulin dosing regimens
The choice of regimen depends on the desired degree of
glycaemic control, the severity of underlying insulin deficiency, the
patient’s lifestyle, and his or her ability to adjust the insulin dose.
The time-action profile of different insulin regimens, compared
to the secretory pattern of insulin in the non-diabetic state, is
shown in Figure 20.14. People with type 1 diabetes are best
managed by multiple daily insulin injections or an insulin pump.
In type 2 diabetes, insulin is usually initiated as a once-daily
long-acting insulin, either alone or in combination with oral
antidiabetic agents. However, in time, more frequent insulin
injections are usually required.
Twice-daily administration of a short-acting and intermediate¬
acting insulin (usually soluble and isophane insulins), given in
combination before breakfast and the evening meal, is the
simplest regimen and is still commonly used in many countries.
Initially, two-thirds of the total daily requirement of insulin is given
in the morning in a ratio of short-acting to intermediate-acting of
1 :2, and the remaining third is given in the evening. Pre-mixed
formulations are available that contain different proportions of
soluble and isophane insulins (e.g. 30:70 and 50:50). These
are useful as they avoid the need for directly mixing insulins, but
are inflexible as the individual components cannot be adjusted
independently. They need to be resuspended by shaking the
Soluble before meals, long-acting
insulin late evening
0600 1000 1400 1800 2200 0200 0600
Clock time (hrs)
Key
Injection of insulin
T Soluble or I Isophane i Long -acting 1 |Mea|
▼ fast-acting ▼ ▼analogue
analogue
Fig. 20.14 Profiles of plasma insulin associated with different
insulin regimens. The schematic profiles are compared with the insulin
responses (mean ± 1 standard deviation) observed in non-diabetic adults
shown in the top panel (shaded area). These are theoretical patterns of
plasma insulin and may differ considerably in magnitude and duration of
action between individuals.
vial several times before administration. Fixed-mixture insulins
also have altered pharmacodynamic profiles, such that the peak
insulin action and time to peak effect are significantly reduced
compared with separately injecting the same insulins. This
increases the risk of hypoglycaemia.
Multiple injection regimens (intensive insulin therapy) are popular,
with short-acting insulin being taken before each meal, and
intermediate- or long-acting insulin being injected once or twice
daily (basal-bolus regimen, Box 20.30). This type of regimen is
more physiological and allows greater freedom with regard to
meal timing, as well more variable day-to-day physical activity.
Management of diabetes • 751
20.30 Example of a meal bolus calculation
RL has type 1 diabetes treated with an insulin pump. His pre-breakfast
glucose (G) is 12 mmol/L (216 mg/dL). He is having a breakfast meal
of cereal with milk containing 30 g of carbohydrate (CHO) in total. His
insulin: carbohyd rate ratio (ICR) is 10 (1 U of insulin for every 10 g of
CHO) and his insulin sensitivity factor (ISF) is 2 (1 U of insulin to bring
down blood glucose by 2 mmol/L (36 mg/dL)). He wants to achieve a
glucose target (GT) of 8 mmol/L (144 mg/dL) after eating.
Calculation of estimated bolus dose:
Bolus dose = (CHO - ICR) + ((G - GT ) + ISF)
= (30 + 10) + ((12-8) + 2)
= 5U of insulin
Subcutaneous continuous insulin therapy
Subcutaneous continuous insulin therapy, commonly know
as the insulin pump, is a system of insulin delivery that uses a
battery-operated medical device to deliver insulin continuously
to the individual with type 1 diabetes. Device configurations
vary between manufacturers but will include the pump with
controls, processing module and batteries, a disposable insulin
reservoir, and a disposable insulin set including cannula for
subcutaneous insertion and a tubing system to deliver insulin
from the reservoir to the cannula. Some recent versions are
disposable or semi-disposable and eliminate tubing from the
infusion set (patch pumps).
Insulin pumps allow the individual more flexibility with bolus
insulin injections in both timing and shape (e.g. using an extended
bolus when covering high-fat/protein meals such as steak, or
when diabetes is complicated by gastroparesis), and also in
changing basal insulin infusion rates. This is especially useful
overnight when basal rates can be reduced to prevent low
glucose, but increased pre-dawn to prevent high glucose. In
addition, the temporary basal rates can be used to lessen the
risk of hypoglycaemia with exercise. Determining an individual’s
basal rate on the pump requires help from a specialist, but
in essence is determined by fasting for periods of at least
4 hours while periodically evaluating the blood glucose levels and
adjusting the pump infusion rate to maintain glucose in the normal
range. Basal rates will change and can be influenced by factors
such as increasing duration of disease, puberty, weight gain or
loss, drugs that affect insulin sensitivity (e.g. glucocorticoids),
and a change in fitness levels with exercise on overall
glycaemic control. An example of an insulin pump is shown in
Figure 20.15.
Closed loop insulin therapy
A further iteration in insulin pump therapy in recent years is the
development of a ‘closed loop’ system, also known as the artificial
pancreas (Fig. 20.16). These systems aim to integrate insulin
pumps with continuous glucose monitoring systems (CGMS).
In a closed loop system, the CGMS device communicates with
the insulin pump via a computerised program. This means that
real-time glucose data obtained through the CGMS can be
used to calculate an insulin dosage to be dispensed through the
insulin pump (Fig. 20.17). Features might include a ‘low-glucose
suspend’ function, where detection of hypoglycaemia or a glucose
level falling below a pre-set threshold (e.g. 4.0 mmol/L (72 mg/
dL)) signals the pump to stop dispensing insulin until the wearer
can treat the hypoglycaemia with food or glucose tabs. Current
cartridge of insulin, battery and internal
computer to program insulin delivery
Fig. 20.15 Insulin pump. An insulin pump is an alternative means of
delivering insulin in type 1 diabetes. Different types are available and
include the pump device itself (with controls, processing module and
batteries), a disposable reservoir for insulin (inside the pump) and a
disposable infusion set (with tubing and a cannula for subcutaneous
insertion). Alternative configurations include disposable or semi-disposable
pumps, and pumps without infusion tubing. Insulin pumps deliver
rapid-acting insulin continuously, and can be adjusted by the user, based
on regular glucose monitoring and carbohydrate counting.
Fig. 20.16 Artificial pancreas. The artificial pancreas (AP) can vary in
its set up and the different components employed in its delivery but core
to an AP system are: (1) a continuous glucose monitor (CGM) measuring
interstitial glucose levels every 5-15 minutes; (2) a smartphone (or
personal glucose monitor) with an app that uses the glucose information
from the CGM along with modifications inserted by the user to calculate
how much insulin should be delivered. This is communicated wirelessly to
(3) the insulin pump that delivers insulin subcutaneously as directed.
clinical trials in children and adults in the hospital or free-living
setting aim to determine how effective this approach will be in
optimising management of type 1 diabetes. Widespread use
may, however, be limited by cost.
Alternative routes of insulin delivery have also been investigated.
Clinical trials with intrapulmonary (inhalation), transdermal
and oral insulins are ongoing but as yet none has proven
commercially viable. Inhaled insulin has been approved for use
in the USA as a mealtime insulin, but experience with this is
very limited.
752 • DIABETES MELLITUS
E
a.m. a.m. a.m. a.m. a.m. a.m. p.m. p.m. p.m. p.m. p.m. p.m. a.m.
Time through the day
a.m. a.m. a.m. a.m. a.m. a.m. p.m. p.m. p.m. p.m. p.m. p.m. a.m.
Time through the day
Fig. 20.17 Continuous glucose monitoring (CGM) profiles: sensor data. [A] CGM profile from an individual without diabetes. [§] CGM profile from an
individual with type 1 diabetes. The green box shows the reference range. CGM devices may be worn for 7-14 days and the glucose profile of each day
illustrated by a different colour. Based on this, the person with diabetes and their health-care team can review overall profiles and adjust treatment as
necessary to improve control and avoid hypoglycaemia.
Transplantation
Whole-pancreas transplantation is carried out in a small number
of patients with diabetes each year, but it presents problems
relating to exocrine pancreatic secretions and long-term
immunosuppression is necessary.
There are currently four main types of whole-pancreas
transplantation:
• pancreas transplant alone
• simultaneous pancreas-kidney (SPK) transplant, when
pancreas and kidney are transplanted simultaneously from
the same deceased donor
• pancreas-after- kidney (PAK) transplant, when a cadaveric,
or deceased, donor pancreas transplant is performed after
a previous, and different, living or deceased donor kidney
transplant
• simultaneous deceased donor pancreas and live donor
kidney (SPLK) transplant.
The principal complications occurring immediately after surgery
include thrombosis, pancreatitis, infection, bleeding and rejection.
Prognosis is improving: 1 year after transplantation more than
95% of all patients are still alive and 80-85% of all pancreases
are still functional. After transplantation, patients will need life-long
immunosuppression, which carries with it an increased risk of
infection and cancer.
An alternative form of transplantation is allogenic islet
transplantation, which involves the transplantation of islets from a
donor pancreas into a person with type 1 diabetes. The isolated
pancreatic islets are usually infused into the patient’s liver via the
portal vein. This approach has now been successfully adopted in
a number of centres around the world (Fig. 20.18). At present,
islet transplantation is usually suitable only for patients with
unstable glycaemic control characterised by recurrent severe
hypoglycaemia that cannot be corrected by standard conventional
and intensive insulin therapies. Progress is being made towards
meeting the needs of supply, purification and storage of islets, but
problems remain relating to transplant rejection, and destruction
by the patient’s autoantibodies against p cells. Nevertheless, the
development of methods of inducing tolerance to transplanted
islets and the potential use of stem cells (p. 58) mean that this
may still prove the most promising approach in the long term.
Adoption of newer immunosuppressive protocols has resulted in
far better outcomes and now nearly 50% of transplanted patients
will be insulin-independent at 3 years post transplantation.
Management of diabetes in
special situations
Diabetes in pregnancy
The management of women with pre-existing diabetes who
are pregnant or who have developed diabetes in pregnancy
(gestational diabetes) is discussed in detail on page 1278 and
summarised in Box 20.31 . This is a highly specialised area and
requires careful and attentive management, as elevated maternal
Management of diabetes • 753
Fig. 20.18 Transplanting islet cells. (1) Pancreas obtained from suitable human donor. (2) Pancreatic islets containing insulin-producing p cells are
isolated first in a Ricordi chamber. (3) Islets, once separated and purified, are infused into the hepatic portal vein. (4) Once embedded in the liver,
pancreatic islets secrete insulin in response to changes in portal vein glucose.
Box 20.31 Diabetes in pregnancy
• Control of established diabetes before and during
pregnancy: must be meticulous, to reduce the risk of
complications such as pre-eclampsia, congenital malformations and
stillbirth.
• Gestational diabetes: most commonly an inability to increase
insulin secretion adequately to compensate for pregnancy-induced
insulin resistance.
• Screening for gestational diabetes: all women at high risk
should have an oral glucose tolerance test at 24-28 weeks.
Measurement of HbA1c and/or blood glucose at booking visit is
usually recommended.
• Management of gestational diabetes: reduce intake of refined
carbohydrate, and add metformin, glibenclamide and/or insulin if
necessary to optimise glycaemic control.
• Self-monitoring of glucose: targets are a pre-prandial level of
<5.3 mmol/L (95 mg/dL) and a 1-hour or 2-hour post-prandial
level of <7.8 mmol/L (140 mg/dL) and <6.4 mmol/L (114 mg/dL),
respectively.
blood glucose in pregnancy is associated with significant maternal
and fetal morbidity.
I Children, adolescents and young adults
with diabetes
Most type 1 diabetes is diagnosed in children below 18 years
of age, with peak incidence rates between 5 and 7 years of
age and at puberty. The management of diabetes in children
and adolescents presents particular challenges, which should
be addressed in specialised clinics with multidisciplinary input
(Box 20.32). Some of the unique aspects of childhood type 1
20.32 Diabetes in adolescence
• Type of diabetes: type 1 diabetes is predominant in children and
adolescents, but type 2 diabetes is now presenting in unprecedented
numbers of obese, inactive teenagers. Monogenic diabetes (MODY)
should also be considered (see Box 20.10, p. 733).
• Physiological changes: hormonal, physical and lifestyle changes in
puberty affect dietary intake, exercise patterns and sensitivity to
insulin, necessitating alterations in insulin regimen.
• Emotional changes: adolescence is a phase of transition into
independence (principally from parental care). Periods of rebellion
against parental control, experimentation (e.g. with alcohol) and a
more chaotic lifestyle are common, and often impact adversely on
control of diabetes.
• Glycaemic control: a temporary deterioration in control is common,
although not universal. It is sometimes more important to maintain
contact and engagement with a young person than to insist on tight
glycaemic control.
• Diabetic ketoacidosis: a few adolescents and young adults present
with frequent episodes of DKA, often because of non-adherence to
insulin therapy. This is more common in females. Motivating factors
may include weight loss, rebellion, and manipulation of family or
schooling circumstances.
• Adolescent diabetes clinics: these challenges are best tackled
with support from a specialised multidisciplinary team, including
paediatricians, physicians, nurses and psychologists. Support is
required for the patient and parents.
diabetes management include changing insulin sensitivity related
to sexual maturity and physical growth, unique vulnerability to
hypoglycaemia (especially in children below 6 years of age) and
possibly hyperglycaemia, as well as DKA. In addition, family
dynamics, child care and schooling, developmental stages and
754 • DIABETES MELLITUS
20.34 How to carry out pre-operative assessment of
patients with diabetes
• Assess glycaemic control:
Consider delaying surgery and refer to the diabetes team if HbA1c
>75 mmol/mol; this should be weighed against the need for
surgery
• Assess cardiovascular status
Optimise blood pressure
Perform an ECG for evidence of (possibly silent) ischaemic heart
disease and to assess QTc (p. 448)
• Assess foot risk (p. 761)
Patients with high-risk feet should have suitable pressure relief
provided during post-operative nursing
• For minor/moderate operations where only one meal will be omitted,
plan for the patient to be first on the list
20.33 Recommended therapeutic targets in
childhood and adolescence
Plasma glucose levels
• Before meals 4. 0-7.0 mmol/L (72-126 mg/dL)
• After meals 5. 0-9.0 mmol/L (90-160 mg/dL)
HbA1c
• <53 mmol/mol (7.0%) with a target of 48 mmol/L
Recommended screening
• HbA1c up to four times per year
• Thyroid disease at diagnosis and annually thereafter
• Diabetic retinopathy annually from 12 years
• Albuminuria (albumimcreatinine ratio (ACR) 3-30 mg/mmol;
‘microalbuminuria’) to detect diabetic kidney disease, annually from
1 2 years
• Hypertension annually from 1 2 years
Adapted from National Institute for Health and Care Excellence NG1 8- Diabetes
(type 1 and type 2) in children and young people: diagnosis and management;
2015.
ability to self-care all have to be considered in the management
plan, as well as, in older children and adolescents, issues of
body image, eating disorders and recreational drug and alcohol
use. It is also notable that there is very limited clinical research
in children with diabetes and so most recommendations are
based on expert opinion. The prevalence of type 2 diabetes in
those below 20 years has been increasing and is estimated to
increase fourfold in the next 40 years. Management of these
children and young adults is difficult.
Coeliac disease and thyroid disease are much more common
in children with type 1 diabetes than in the general population
and so it is currently recommended that these conditions are
screened for. Current recommendations for screening in type 1
diabetes are shown in Box 20.33.
Hyperglycaemia in acute medical illness
Hyperglycaemia is often found in patients who are admitted to
hospital as an emergency. In most people this occurs in the
context of a known diagnosis of diabetes; in some individuals,
however, it is a consequence of stress hyperglycaemia (p. 728),
while in others it is due to undiagnosed diabetes. Hyperglycaemia
on admission to hospital is associated with increased length of
stay and increased mortality in a wide variety of acute medical
emergencies, including acute coronary syndrome and acute
stroke. Intuitively, intensive glycaemic control with intravenous
insulin should improve outcomes during acute illness. However,
recent studies have shown that strategies aiming for near-normal
blood glucose levels in acutely ill patients are associated with
either increased mortality or no overall benefit. The reasons
for the adverse outcomes are not established, but intensive
glycaemic control is inevitably associated with an increased risk
of hypoglycaemia because of the inherent limitations of modern
insulins, the restricted frequency of glucose monitoring in a ward
environment and the relative imprecision of near-patient blood
glucose meters. The activation of the sympathetic nervous
system and release of counter-regulatory hormones during
acute hypoglycaemia could have deleterious consequences for
the acutely ill patient.
There is no consensus on the optimum glucose targets in
acutely ill patients but extremes of blood glucose should be
avoided, and so a target of between 6 and 12 mmol/L (105
and 180 mg/dL) seems appropriate. Achieving such a target
may require the use of intravenous insulin and dextrose in some
individuals.
| Surgery and diabetes
Patients with diabetes are reported to have up to 50% higher
perioperative mortality than patients without diabetes. Surgery
causes catabolic stress and secretion of counter-regulatory
hormones (including catecholamines and cortisol) in both normal
and diabetic individuals. This results in increased glycogenolysis,
gluconeogenesis, lipolysis, proteolysis and insulin resistance.
Starvation exacerbates this process by increasing lipolysis.
In the non-diabetic person, these metabolic effects lead to a
secondary increase in the secretion of insulin, which exerts a
controlling influence. In diabetic patients, either there is absolute
deficiency of insulin (type 1 diabetes) or insulin secretion is
delayed and impaired (type 2 diabetes), so that in untreated or
poorly controlled diabetes, the uptake of metabolic substrate
into tissues is significantly reduced, catabolism is increased and,
ultimately, metabolic decompensation in the form of DKA may
develop in both types of diabetes. In addition, hyperglycaemia
impairs wound healing and innate immunity, leading to increased
risk of infection. Patients with diabetes are also more likely to
have underlying pre-operative morbidity, especially cardiovascular
disease. Finally, management errors in diabetes may cause
dangerous hyperglycaemia or hypoglycaemia. Careful pre¬
operative assessment and perioperative management are therefore
essential, ideally with support from the diabetes specialist team.
Pre-operative assessment
Unless a surgical intervention is an emergency, patients with
diabetes should be assessed well in advance of surgery so that
poor glycaemic control and other risk factors can be addressed
(Box 20.34). There is good evidence that a higher HbA1c is
associated with adverse perioperative outcome. In general, an
upper limit for an acceptable HbA1c should be between 64 and
75 mmol/mol (8% and 9%). However, since optimisation of
care may take weeks or months to achieve, the benefits need
to be weighed against the need for early surgical intervention.
Perioperative management
Figure 20.19 outlines a general approach to perioperative
management of diabetes, although this may need to be adapted
according to the patient, the surgical procedure and local
guidelines. Patients with diabetes who are considered low-risk
can attend as day cases or be admitted on the day of surgery.
Complications of diabetes • 755
Check U&Es at least daily while on IV
insulin and fluids; ensure adequate
potassium replacement and avoid
hyponatraemia from dextrose infusion
i
Fig. 20.19 Management of diabetic patients undergoing surgery and general anaesthesia. (eGFR = estimated glomerular filtration rate; GLP-1 =
glucagon-like peptide 1; IV = intravenous; U&Es = urea and electrolytes)
Occasionally, patients may be admitted the night before to
ensure optimal management.
Post-operative management
Patients who need to continue fasting after surgery should be
maintained on intravenous insulin and fluids until they are able
to eat and drink (Fig. 20.19). During this time, care must be
taken with fluid balance and electrolyte levels. Insulin infusion
necessitates dextrose infusion to maintain a supply of glucose
but this combination drives down plasma potassium (p. 360) and
can result in hyponatraemia. Intravenous fluids during prolonged
insulin infusion should therefore include saline and potassium
supplementation. UK guidelines recommend the use of dextrose/
saline (0.45% saline with 5% dextrose and 0.15% potassium
chloride).
Once a patient’s usual treatment has been reinstated, care
must be taken to continue to control the blood glucose, ideally
between 6 and 10 mmol/L (105-180 mg/dL), in order to optimise
wound healing and recovery. Patients normally controlled on
tablets may require temporary subcutaneous insulin treatment
until the increased ‘stress’ of surgery, wound healing or infection
has resolved.
Complications of diabetes
Despite all the treatments now available, the outcome for patients
with diabetes remains disappointing. Long-term complications
of diabetes still cause significant morbidity and mortality
(Boxes 20.35 and 20.36).
Excess mortality in diabetes is caused mainly by large blood
vessel disease, particularly myocardial infarction and stroke.
Macrovascular disease also causes substantial morbidity
from myocardial infarction, stroke, angina, cardiac failure
and intermittent claudication. The pathological changes of
atherosclerosis in diabetic patients are similar to those in the
non-diabetic population but occur earlier in life and are more
extensive and severe. Diabetes amplifies the effects of the
other major cardiovascular risk factors: smoking, hypertension
and dyslipidaemia (Fig. 20.20). Moreover, patients with type
2 diabetes are more likely to have additional cardiovascular
risk factors, which co-segregate with insulin resistance in the
metabolic syndrome (p. 730). Mortality statistics from the USA
indicate that cardiovascular death rates are 1 .7 times higher in
adults with diabetes aged 20 years or older compared to adults
in the same age group who do not have diabetes, while similar
figures for myocardial infarction show a 1 .8 times greater rate.
Hospitalisation rates for stroke were 1 .5 times higher in adults
with diabetes than in those without diabetes. In addition, 60% of
non-traumatic amputations among people aged 20 years or older
were reported to be in people with diabetes. Type 1 diabetes is
also associated with increased cardiovascular risk. Recent data
from Scotland show that the age-adjusted incidence rate ratio
for first cardiovascular event was 3 times higher in women and
2.3 times higher in men with type 1 diabetes compared to those
without diabetes.
Resume usual medication with first meal;
if it is lunch for patient using mixed
insulin, give half of usual morning dose
Once patient is eating, prescribe usual oral
or injectable treatment with a meal and
discontinue insulin infusion 1 hr later
Withhold metformin if eGFR < 30 mUmin/l .73 m2
No need for IV insulin unless unable
to eat post-operatively,
blood glucose > 14 mmol/L (250 mg/dL),
or ketones present in urine or blood
756 • DIABETES MELLITUS
20.35 Complications of diabetes
Microvascular/neuropathic
Retinopathy, cataract
• Impaired vision
Nephropathy
• Renal failure
Peripheral neuropathy
• Sensory loss
• Motor weakness
• Pain
Autonomic neuropathy
• Gastrointestinal problems
• Postural hypotension
(gastroparesis; altered bowel
habit)
Foot disease
• Ulceration
• Arthropathy
Macrovascular
Coronary circulation
• Myocardial ischaemia/infarction
Cerebral circulation
• Transient ischaemic attack
• Stroke
Peripheral circulation
• Claudication
• Ischaemia
20.36 Mortality in diabetes
Risk versus non-diabetic controls (mortality ratio)
• Overall
2.6
• Coronary heart disease i
Cerebrovascular disease
2.8
Peripheral vascular disease J
• All other causes, including
2.7
renal failure
Causes of death in diabetes (approximate proportion)
• Cardiovascular disease
70%
• Renal failure
10%
• Cancer
10%
• Infections
6%
• Diabetic ketoacidosis
1%
• Other
3%
Risk factors for increased morbidity and mortality in diabetes
• Duration of diabetes
• Raised blood pressure
• Early age at onset of disease
• Proteinuria; microalbuminuria
• High glycated haemoglobin
• Dyslipidaemla
(HbA1c)
• Obesity
Disease of small blood vessels is a specific complication of
diabetes and is termed diabetic microangiopathy. It contributes
to mortality through renal failure caused by diabetic nephropathy,
and is responsible for substantial morbidity and disability: for
example, blindness from diabetic retinopathy, difficulty in walking,
chronic ulceration of the feet from peripheral neuropathy, and
bowel and bladder dysfunction from autonomic neuropathy.
The risk of microvascular disease is positively correlated with
the duration and degree of sustained hyperglycaemia, however
it is caused and at whatever age it develops.
Pathophysiology
The histopathological hallmark of diabetic microangiopathy is
thickening of the capillary basement membrane, with associated
increased vascular permeability, which occurs throughout the
HbA1c(%)
Fig. 20.20 Association between HbA1c and risk of microvascular and
macrovascular diabetes complications. These data were obtained
amongst participants in the UK Prospective Diabetes Study and were
adjusted for effects of age, sex and ethnicity; the incidences show what
could be expected amongst white men aged 50-54 years at diagnosis of
type 2 diabetes, followed up for 1 0 years. Microvascular disease included
retinopathy requiring photocoagulation, vitreous haemorrhage and renal
failure. Macrovascular disease included fatal and non-fatal myocardial
infarction and sudden death. A 1% change in HbA1c is equivalent to a
reduction of 11 mmol/mol.
body. The development of the characteristic clinical syndromes
of diabetic retinopathy, nephropathy, neuropathy and accelerated
atherosclerosis is thought to result from the local response to
generalised vascular injury. For example, in the wall of large
vessels, increased permeability of arterial endothelium, particularly
when combined with hyperinsulinaemia and hypertension,
may increase the deposition of atherogenic lipoproteins. The
mechanisms linking hyperglycaemia to these pathological changes
are, however, poorly characterised.
Preventing diabetes compiications
Glycaemic control
The evidence that improved glycaemic control decreases the
risk of developing microvascular complications of diabetes was
established by the DCCT in type 1 diabetes and the UKPDS
in type 2 diabetes. The DCCT was a large study that lasted
9 years; it randomised patients with type 1 diabetes to intensive
treatment (mean HbA1c 53 mmol/mol) and conventional treatment
(mean HbA1c 75 mmol/mol). There was a 60% overall reduction
in the risk of developing diabetic complications in patients with
type 1 diabetes on intensive therapy with strict glycaemic control,
compared with those on conventional therapy. No single factor
other than glycaemic control had a significant effect on outcome.
However, the group that was intensively treated to lower blood
glucose had three times the rate of severe hypoglycaemia.
The UKPDS randomised patients to intensive treatment (mean
HbA1c 53 mmol/mol) versus conventional treatment (mean HbA1c
64 mmol/mol). This study showed that, in type 2 diabetes, the
frequency of diabetic complications is lower and progression is
slower with good glycaemic control and effective treatment of
hypertension, irrespective of the type of therapy used. Extrapola¬
tion from the UKPDS suggests that, for every 11 mmol/mol
Complications of diabetes • 757
t
• Glycaemic control: the optimal target for glycaemic control in older
people has yet to be determined. Strict glycaemic control should be
avoided in frail patients with comorbidities and in older patients with
long duration of diabetes.
• Cognitive function and affect: may benefit from improved
glycaemic control but it is important to avoid hypoglycaemia.
• Hypoglycaemia: older people have reduced symptomatic
awareness of hypoglycaemia and limited knowledge of symptoms,
and are at greater risk of, and from, hypoglycaemia.
• Mortality: the mortality rate of older people with diabetes is more
than double that of age-matched non-diabetic people, largely
because of increased deaths from cardiovascular disease.
reduction in HbA1c, there is a 21% reduction in death related to
diabetes, a 1 4% reduction in myocardial infarction and 30-40%
reduction in risk of microvascular complications (Fig. 20.20).
These landmark trials demonstrated that diabetic complications
are preventable and that the aim of treatment should be ‘near¬
normal’ glycaemia. More recent studies, however, such as the
Action to Control Cardiovascular Risk in Diabetes (ACCORD),
showed increased mortality in a subgroup of patients who were
aggressively treated to lower HbA1c to a target of less than
48 mmol/mol. The patients in this study had poor glycaemic
control at baseline, a long duration of diabetes and a high
prevalence of cardiovascular disease. It appears that, while a
low target HbA1c is appropriate in younger patients with earlier
diabetes who do not have underlying cardiovascular disease,
aggressive glucose-lowering is not beneficial in older patients with
long duration of diabetes and multiple comorbidities (Box 20.37).
Control of other risk factors
Randomised controlled trials have shown that aggressive
management of blood pressure minimises the microvascular and
macrovascular complications of diabetes. Angiotensin-converting
enzyme (ACE) inhibitors are valuable in improving outcome in heart
disease and in treating diabetic nephropathy (see below). The
management of dyslipidaemia with a statin limits macrovascular
disease in people with diabetes (p. 375). This often results in the
necessary use of multiple medications, which exacerbates the
problem of adherence to therapy by patients; it is not unusual
for a patient to be taking two or more diabetes therapies, two
or more blood pressure drugs and a statin.
Diabetic retinopathy
Diabetic retinopathy (DR) is one of the most common causes of
blindness in adults between 30 and 65 years of age in developed
countries. The prevalence of DR increases with duration of
diabetes, and almost all individuals with type 1 diabetes and the
majority of those with type 2 diabetes will have some degree
of DR after 20 years. The pathogenesis, clinical features and
management of diabetic retinopathy, as well as screening and
prevention, are described on page 1 1 74. Other causes of visual
loss in type 2 diabetes are also covered in Chapter 27.
Diabetic nephropathy
Diabetic nephropathy is an important cause of morbidity and
mortality in both type 1 and type 2 diabetes. It is now the most
common cause of end-stage renal failure in developed countries
i
• Poor glycaemic control
• Long duration of diabetes
• Presence of other microvascular complications
• Ethnicity (e.g. Asians, Pima Indians)
• Pre-existing hypertension
• Family history of diabetic nephropathy
• Family history of hypertension
and accounts for between 20% and 50% of patients starting
renal replacement therapy.
About 30% of patients with type 1 diabetes have developed
diabetic nephropathy 20 years after diagnosis, but the risk after
this time falls to less than 1 % per year, and from the outset the
risk is not equal in all patients (Box 20.38). The risk of nephropathy
in Caucasian populations with type 2 diabetes is similar to
those with type 1 diabetes but the rate of progression may be
exacerbated by concomitant obesity and other risk factors. The
risk of nephropathy is much greater in some ethnic groups, with
epigenetic and genetic factors thought to influence this increased
risk. Some patients do not develop nephropathy, however, despite
having long-standing, poorly controlled diabetes, suggesting
that they do not have a genetic predisposition. While variants
in a few genes have been implicated in diabetic nephropathy,
the major differences in individual risk remain unexplained. With
improved standards of care focusing on glycaemic control and
blood pressure lowering, the proportion of patients with overt
nephropathy is reducing; however, due to the global rise in the
incidence of type 2 diabetes, the prevalent number of people
with diabetes and end-stage renal failure continues to rise.
The pathophysiology is not fully understood and there are
several postulated mechanisms by which hyperglycaemia causes
the pathological changes seen in diabetic nephropathy. The
central features are activation of the renin-angiotensin system,
leading to both intrarenal and systemic effects, as well as
direct toxic effects of prolonged hyperglycaemia, leading to
renal inflammation and fibrosis. The pattern of progression of
renal abnormalities in diabetes is shown schematically in Figure
20.21 . Pathologically, the first changes coincide with the onset
of microalbuminuria and include thickening of the glomerular
basement membrane and accumulation of matrix material in
the mesangium. Subsequently, nodular deposits (Fig. 20.22)
are characteristic, and glomerulosclerosis worsens as heavy
proteinuria develops, until glomeruli are progressively lost and
renal function deteriorates.
Diagnosis and screening
Microalbuminuria (Box 20.39) is the presence in the urine
of small amounts of albumin, at a concentration below that
detectable using a standard urine dipstick. Overt nephropathy
is defined as the presence of macroalbuminuria (urinary albumin
>300 mg/24 hrs, detectable on urine dipstick). Microalbuminuria
is a good predictor of progression to nephropathy in type 1
diabetes. It is a less reliable predictor of nephropathy in older
patients with type 2 diabetes, in whom it may be accounted
for by other diseases (p. 394), although it is a potentially useful
marker of an increased risk of macrovascular disease.
Management
The presence of established microalbuminuria or overt
nephropathy should prompt vigorous efforts to reduce the
20.37 Diabetes management in old age
20.38 Risk factors for diabetic nephropathy
758 • DIABETES MELLITUS
t
Microalbuminuria
t
Nephrotic range proteinuria
Sustained proteinuria
Fig. 20.21 Natural history of diabetic nephropathy. In the first few
years of type 1 diabetes mellitus, there is hyperfiltration, which declines
fairly steadily to return to a normal value at approximately 10 years (blue
line). In susceptible patients (about 30%), after about 10 years, there is
sustained proteinuria, and by approximately 14 years it has reached the
nephrotic range (red line). Renal function continues to decline, with the end
stage being reached at approximately 16 years.
Fig. 20.22 Nodular diabetic glomerulosclerosis. There is thickening of
basement membranes, mesangial expansion and a Kimmelstiel— Wilson
nodule (arrow), which is pathognomonic of diabetic kidney disease.
20.39 Screening for microalbuminuria
• Screening identifies incipient nephropathy in type 1 and type 2
diabetes; is an independent predictor of macrovascular disease in
type 2 diabetes
• Risk factors include high blood pressure, poor glycaemic control
and smoking
• Early morning urine is measured for the albumimcreatinine ratio
(ACR). Microalbuminuria is present if:
Male ACR 2.5-30 mg/mmol creatinine
Female ACR 3.5-30 mg/mmol creatinine
• An elevated ACR should be followed by a repeat test:
There is established microalbuminuria if 2 out of 3 tests are
positive
An ACR >30 mg/mmol creatinine is consistent with overt
nephropathy
risk of progression of nephropathy and of cardiovascular
disease by:
• aggressive reduction of blood pressure
• aggressive reduction of cardiovascular risk factors
• optimisation of glycaemic control
Blockade of the renin-angiotensin system using either ACE
inhibitors or angiotensin 2 receptor blockers (ARBs) has been
shown to have an additional benefit over similar levels of blood
pressure control achieved with other anti hypertensive agents and
is recommended as first-line therapy. The addition of a diuretic
and/or salt restriction increase both the anti-proteinuric and
antihypertensive effect of angiotensin blockade and therefore
constitute an ideal second-line treatment. The benefit from
blockade of the renin-angiotensin system arises from a reduction in
the angiotensin ll-mediated vasoconstriction of efferent arterioles in
glomeruli (see Fig. 15.1 D, p. 385). The resulting dilatation of these
vessels decreases glomerular filtration pressure and, therefore,
the hyperfiltration and protein leak. Both ACE inhibitors and ARBs
increase risk of hyperkalaemia (p. 362) and, in the presence of
renal artery stenosis (p. 406), may induce marked deterioration in
renal function. Therefore, electrolytes and renal function should be
checked after initiation or each dose increase. If blockade of the
renin-angiotensin system is not possible, blood pressure should
managed with standard treatment, such as calcium channel
blockers and diuretics. There may be a role for spironolactone
(an aldosterone antagonist) but this is limited by hyperkalaemia.
Halving the amount of albuminuria with an ACE inhibitor
or ARB results in a nearly 50% reduction in long-term risk
of progression to end-stage renal disease. Some patients
do progress, however, with worsening renal function. Renal
replacement therapy (p. 420) is often required at a higher eGFR
than in other causes of renal failure, due to fluid overload or
symptomatic uraemia.
Renal transplantation dramatically improves the life of many, and
any recurrence of diabetic nephropathy in the allograft is usually
too slow to be a serious problem; associated macrovascular and
microvascular disease elsewhere may still progress, however.
Pancreatic transplantation (generally carried out at the same
time as renal transplantation) can produce insulin independence
and delay or reverse microvascular disease, but the supply of
organs is limited and this option is available to few. For further
information on management, see Chapter 15.
Diabetic neuropathy
Diabetic neuropathy causes substantial morbidity and increases
mortality. It is diagnosed on the basis of symptoms and signs,
after the exclusion of other causes of neuropathy (p. 1138).
Depending on the criteria used for diagnosis, it affects between
50% and 90% of patients with diabetes, and of these, 1 5-30%
will have painful diabetic neuropathy (PDN). Like retinopathy,
neuropathy occurs secondary to metabolic disturbance, and
prevalence is related to the duration of diabetes and the degree of
metabolic control.
Pathological features can occur in any peripheral nerves. They
include axonal degeneration of both myelinated and unmyelinated
fibres, with thickening of the Schwann cell basal lamina, patchy
segmental demyelination and abnormal intraneural capillaries
(with basement membrane thickening and microthrombi).
Various classifications of diabetic neuropathy have been
proposed. One is shown in Box 20.40 but motor, sensory and
autonomic nerves may be involved in varying combinations, so
that clinically mixed syndromes usually occur.
Clinical features
Symmetrical sensory polyneuropathy
This is frequently asymptomatic. The most common clinical signs
are diminished perception of vibration sensation distally, ‘glove
Complications of diabetes • 759
Peripheral neuropathy
Peripheral vascular disease
^ Clawing of toes
^ Proximal arterial
occlusion
Fig. 20.23 Diabetic foot disease. Patients with diabetes can have neuropathy, peripheral vascular disease or both. Clawing of the toes is thought to be
caused by intrinsic muscle atrophy and subsequent imbalance of muscle function, and causes greater pressure on the metatarsal heads and pressure on
flexed toes, leading to increased callus and risk of ulceration. A Charcot foot occurs only in the presence of neuropathy, and results in bony destruction
and ultimately deformity (this X-ray shows a resulting ‘rocker bottom foot’). The angiogram reveals disease of the superficial femoral arteries (occlusion of
the left and stenosis of the right). Insets (Proximal arterial occlusion) From http://emedicine.meclscape.com/article/4601 78-overview#a01 04; (Toe clawing)
BowkerJH, Pfeifer MA. Levin and O’Neal’s The diabetic foot, 7th edn. Philadelphia: Mosby, Elsevier Inc.; 2008; (Neuropathic foot ulcer) Levy MJ, Valabhji
J. Vascular II: The diabetic foot. Surgery 2008; 26:25-28; (Digital gangrene) Swartz MH. Textbook of physical diagnosis, 5th edn. Philadelphia: I /IB
Saunders, Elsevier Inc.; 2006.
i
and stocking’ impairment of all other modalities of sensation
(Fig. 20.23), and loss of tendon reflexes in the lower limbs. In
symptomatic patients, sensory abnormalities are predominant.
Symptoms include paraesthesiae in the feet (and, rarely, in the
hands), pain in the lower limbs (dull, aching and/or lancinating,
worse at night, and felt mainly on the anterior aspect of the
legs), burning sensations in the soles of the feet, cutaneous
hyperaesthesia and, when severe, an abnormal gait (commonly
wide-based), often associated with a sense of numbness in the
feet. Weakness and atrophy, in particular of the interosseous
muscles, develops, leading to structural changes in the foot
with loss of lateral and transverse arches, clawing of the toes
and exposure of the metatarsal heads. This results in increased
pressure on the plantar aspects of the metatarsal heads, with the
development of callus skin at these and other pressure points.
Electrophysiological tests (p. 1074) demonstrate slowing of both
motor and sensory conduction, and tests of vibration sensitivity
and thermal thresholds are abnormal.
A diffuse small-fibre neuropathy causes altered perception
of pain and temperature, and is associated with symptomatic
autonomic neuropathy; characteristic features include foot ulcers
and Charcot neuroarthropathy.
Asymmetrical motor diabetic neuropathy
Sometimes called diabetic amyotrophy, this presents as severe
and progressive weakness and wasting of the proximal muscles
of the lower (and occasionally the upper) limbs. It is commonly
accompanied by severe pain, felt mainly on the anterior aspect
of the leg, and hyperaesthesia and paraesthesiae. Sometimes
there may also be marked loss of weight (‘neuropathic
cachexia’). The patient may look extremely ill and be unable to
get out of bed. Tendon reflexes may be absent on the affected
side(s). Sometimes there are extensor plantar responses and
the cerebrospinal fluid protein is often raised. This condition
is thought to involve acute infarction of the lower motor
neurons of the lumbosacral plexus. Other lesions involving
this plexus, such as neoplasms and lumbar disc disease,
must be excluded. Although recovery usually occurs within
1 2 months, some deficits are permanent. Management is mainly
supportive.
20.40 Classification of diabetic neuropathy
Somatic
• Polyneuropathy:
Symmetrical, mainly sensory and distal
Asymmetrical, mainly motor and proximal (including amyotrophy)
• Mononeuropathy (including mononeuritis multiplex)
Visceral (autonomic)
• Cardiovascular
• Sudomotor
• Gastrointestinal
• Vasomotor
• Genitourinary
• Pupillary
760 • DIABETES MELLITUS
i
Mononeuropathy
Either motor or sensory function can be affected within a single
peripheral or cranial nerve. Unlike the gradual progression of distal
symmetrical and autonomic neuropathies, mononeuropathies
are severe and of rapid onset, but they eventually recover. The
nerves most commonly affected are the 3rd and 6th cranial
nerves (resulting in diplopia), and the femoral and sciatic nerves.
Rarely, involvement of other single nerves results in paresis and
paraesthesiae in the thorax and trunk (truncal radiculopathies).
Nerve compression palsies are more common in diabetes,
frequently affecting the median nerve and giving the clinical
picture of carpal tunnel syndrome, and less commonly the
ulnar nerve. Lateral popliteal nerve compression occasionally
causes foot drop. Compression palsies may be more common
because of glycosylation and thickening of connective tissue
and/or because of increased susceptibility of nerves affected by
diabetic microangiopathy.
Autonomic neuropathy
This is not necessarily associated with peripheral somatic
neuropathy. Parasympathetic or sympathetic nerves may be
predominantly affected in one or more visceral systems. The
resulting symptoms and signs are listed in Box 20.41 and
tests of autonomic function in Box 20.42. The development of
autonomic neuropathy is related to poor metabolic control less
clearly than to somatic neuropathy, and improved control rarely
results in improved symptoms. Within 10 years of developing
overt symptoms of autonomic neuropathy, 30-50% of patients
are dead, many from sudden cardiorespiratory arrest. Patients
with postural hypotension (a drop in systolic pressure of
30 mmHg or more on standing from the supine position) have
the highest subsequent mortality.
20.42 How to test cardiovascular autonomic function
Simple reflex tests
Normal
Borderline
Abnormal
Heart rate responses
To Valsalva manoeuvre
(15 secs)1: ratio of longest to
shortest R-R interval
>1.21
<1.20
To deep breathing (6 breaths
over 1 min): maximum-
minimum heart rate
>15
11-14
<10
To standing after lying: ratio
of R-R interval of 30th to
1 5th beats
>1.04
1.01-1.03
<1.00
Blood pressure response2
To standing: systolic blood
pressure fall (mmHg)
<10
11-29
>30
Specialised tests
• Heart rate and blood pressure responses to sustained handgrip
• Heart rate variability using power spectral analysis of ECG
monitoring
• Heart rate and blood pressure variability using time-domain analysis
of ambulatory monitoring
• MIBG (meta-iodobenzylguanidine) scan of the heart
10mit in patients with previous laser therapy for proliferative retinopathy. 2Avoid
arm with arteriovenous fistula in dialysed patients.
Gastroparesis
Gastroparesis is diagnosed when there is an objectively measured
delay in gastric emptying in the absence of mechanical obstruction.
It is most commonly a manifestation of autonomic neuropathy in
diabetes, but can occur with eating disorders such as anorexia
nervosa or bulimia that are also associated with diabetes.
Prevalence rates are estimated to be approximately 5% in type
1 diabetes and 1 % in type 2 diabetes. The main symptoms
are chronic nausea, vomiting (especially of undigested food),
abdominal pain and a feeling of fullness/early satiety. Diagnosis is
most commonly made by 99m-technetiurn scintigraphy following a
solid-phase meal with standard imaging over 4 hours. In this test it
is important to recognise that high glucose levels can delay gastric
emptying and so every attempt should be made to conduct the
test when glucose levels are below 15 mmol/L (270 mg/dL). Other
tests include upper gastrointestinal endoscopy, wireless motility
capsules and breath testing (pp. 774, 776 and 777). Management
is difficult, with glucose levels directly impacting on gastric motility
and, conversely, gastroparesis affecting absorption of ingested
carbohydrate. Insulin pump therapy may be especially useful
in this context; patients on conventional injection therapy may
benefit from injecting rapid-acting insulin after a meal rather than
before. Recommended dietary changes include following low-fibre
and low-residue diets, as well as eating smaller amounts more
frequently. Enteral nutrition is rarely required unless gastroparesis
is very severe. Recommended pharmacological and interventional
therapy is shown in Box 20.43.
Erectile dysfunction
Erectile failure (impotence) affects 30% of diabetic males and is
often multifactorial. Although neuropathy and vascular causes
are common, psychological factors, including depression,
anxiety and reduced libido, may be partly responsible. Alcohol
and antihypertensive drugs, such as thiazide diuretics and
p-adrenoceptor antagonists (p-blockers), may cause sexual
dysfunction and in some patients there may be an endocrine
20.41 Clinical features of autonomic neuropathy
Cardiovascular
• Postural hypotension • Fixed heart rate
• Resting tachycardia
Gastrointestinal
• Dysphagia, due to oesophageal atony
• Abdominal fullness, nausea and vomiting, unstable glycaemia, due
to delayed gastric emptying (‘gastroparesis’)
• Nocturnal diarrhoea ± faecal incontinence
• Constipation, due to colonic atony
Genitourinary
• Difficulty in micturition, urinary incontinence, recurrent infection, due
to atonic bladder
• Erectile dysfunction and retrograde ejaculation
Sudomotor
• Nocturnal sweats without • Gustatory sweating
hypoglycaemia • Anhidrosis; fissures in the feet
Vasomotor
• Feet feel cold, due to loss of skin vasomotor responses
• Dependent oedema, due to loss of vasomotor tone and increased
vascular permeability
• Bulla formation
Pupillary
• Decreased pupil size • Delayed or absent reflexes to
• Resistance to mydriatics light
Complications of diabetes • 761
20.43 Management options for peripheral
sensorimotor and autonomic neuropathies
Pain and paraesthesiae from peripheral somatic neuropathies
• Intensive insulin therapy (strict glycaemic control)
• Anticonvulsants (gabapentin, pregabalin, carbamazepine, phenytoin)
• Tricyclic antidepressants (amitriptyline, imipramine)
• Other antidepressants (duloxetine)
• Substance P depleter (capsaicin - topical)
• Opiates (tramadol, oxycodone)
• Membrane stabilisers (mexiletine, IV lidocaine)
• Antioxidant (oc-lipoic acid)
Postural hypotension
• Support stockings
• Fludrocortisone
• NSAIDs
Gastroparesis
• Dopamine antagonists
(metoclopramide, domperidone)
• Erythromycin
• Botulinum toxin
Diarrhoea (p. 783)
• Loperamide • Clonidine
• Broad-spectrum antibiotics • Octreotide
Constipation
• Stimulant laxatives (senna)
Atonic bladder
• Intermittent self-catheterisation (p. 1 093)
Excessive sweating
• Anticholinergic drugs (propantheline, poldine, oxybutinin)
• Clonidine
• Topical antimuscarinic agent (glycopyrrolate cream)
Erectile dysfunction (p. 440)
• Phosphodiesterase type 5 inhibitors (sildenafil, vardenafil, tadalafil)
- oral
• Dopamine agonist (apomorphine) - sublingual
• Prostaglandin E A (alprostadil) - injected into corpus cavernosum or
intra-urethral administration of pellets
• Vacuum tumescence devices
• Implanted penile prosthesis
• Psychological counselling; psychosexual therapy
(NSAIDs = non-steroidal anti-inflammatory drugs)
cause, such as testosterone deficiency or hyperprolactinaemia.
For further information, see page 440.
Management
Management of neuropathies is outlined in Box 20.43.
The diabetic foot
The foot is a frequent site of complications in patients with
diabetes and for this reason foot care is particularly important.
Tissue necrosis in the feet is a common reason for hospital
admission in diabetic patients. Treatment of the foot complications
of diabetes accounts for more inpatient days than any other
diabetes-related complication.
Aetiology
Foot ulceration occurs as a result of trauma (often trivial) in
the presence of neuropathy and/or peripheral vascular disease
20.44 Clinical features of the diabetic foot
Neuropathy
Ischaemia
Symptoms
None
None
Paraesthesiae
Claudication
Pain
Numbness
Rest pain
Structural damage
Ulcer
Ulcer
Sepsis
Sepsis
Abscess
Osteomyelitis
Digital gangrene
Charcot joint
Gangrene
(p. 502 and Fig. 20.23); with infection is a secondary phenomenon
following disruption of the protective epidermis. Most ulcers
develop at the site of a plaque of callus skin, beneath which
tissue necrosis occurs and eventually breaks through to the
surface. In many cases, multiple components are involved but
sometimes neuropathy or ischaemia predominates (Box 20.44).
Ischaemia alone accounts for a minority of foot ulcers in diabetic
patients, with most being either neuropathic or neuro-ischaemic.
Charcot neuroarthropathy is a progressive condition
affecting the bones and joints of the foot; it is characterised
by early inflammation and then joint dislocation, subluxation
and pathological fractures of the foot of neuropathic patients,
often resulting in debilitating deformity (Fig. 20.23 and p. 720).
Charcot neuroarthropathy can arise in any condition that causes
neuropathy (including syphilis, spinal cord injury, syringomyelia etc.)
but diabetes is the most common cause. The pathophysiological
mechanisms remain poorly understood but may involve
unperceived trauma, leading to progressive destruction (the
‘neurotraumatic’ theory) and/or increased blood flow that results in
a mismatch of bone destruction and synthesis (the ‘neurovascular’
theory). More recent evidence points to disordered inflammation
mediated via the nuclear factor kappa B (NFKB)/receptor activator
of NFkB ligand (RANKL) pathway, opening the way for trials of
the RANKL inhibitor denosumab (p. 1048).
Management
Management can be divided into primary prevention and
treatment of an active problem. All patients should be educated
in preventative measures (Box 20.45). The feet of people with
diabetes should be screened annually, following the steps listed
on page 721 . Two simple tests are required to grade risk: a
10 g monofilament should be used to assess sensation at
five points on each foot, and foot pulses should be palpated
(dorsalis pedis and/or posterior tibial). Combined with the clinical
scenario, these tests guide appropriate referral and monitoring
(Fig. 20.24). Removal of callus skin with a scalpel is best done
by a podiatrist who has specialist training and experience in
diabetic foot problems.
Foot ulcer
Once a foot ulcer develops, patients should ideally be referred
to a multidisciplinary foot team, involving a diabetes specialist,
a podiatrist, a vascular surgeon and an orthotist. Treatment
involves: debridement of dead tissue; prompt, often prolonged,
treatment with antibiotics if required, as infection can accelerate
tissue necrosis and lead to gangrene; and pressure relief using
customised insoles, specialised orthotic footwear and sometimes
total contact plaster cast or an irremovable aircast boot. If an ulcer
a-adrenoceptor agonist
(midodrine)
Gastric pacemaker;
percutaneous enteral (jejunal)
feeding (see Fig. 19.10,
p. 708)
762 • DIABETES MELLITUS
Current foot ulcer, infection,
critical ischaemia, gangrene or
unexplained hot, red swollen foot
Previous foot ulcer or amputation
Sensation impaired
and
foot pulses absent
Sensation impaired
or
foot pulses absent
Skin callus or
foot deformity?
Inability to self-
care for feet
Sensation
unimpaired and
foot pulses present
Screening
Urgent referral to
specialist team
►
Annual assessment
by specialist podiatrist
Annual assessment
by podiatrist
Annual screening by
health-care professional
Management
Fig. 20.24 Risk assessment and management of foot problems in diabetes. Adapted from Scottish Intercollegiate Guidelines Network (SIGN)
guideline number 1 16.
20.45 Care of the feet in patients with diabetes
Preventative advice
All diabetic patients
• Inspect feet every day «
• Wash feet every day *
• Moisturise skin if dry «
• Cut or file toenails regularly
• Change socks or stockings «
every day «
• Avoid walking barefoot
Moderate- and high-risk patients
As above plus:
• Do not attempt corn removal
• Avoid high and low temperatures
Podiatric care
Check footwear for foreign bodies
Wear suitable, well-fitting shoes
Cover minor cuts with sterile
dressings
Do not burst blisters
Avoid over-the-counter corn/
callus remedies
• A podiatrist is an integral part of the diabetes team to ensure regular
and effective podiatry and to educate patients in care of the feet
Orthotic footwear
• Specially manufactured and fitted orthotic footwear is required to
prevent recurrence of ulceration and to protect the feet of patients
with Charcot neuroarthropathy
is neuro-ischaemic, a vascular assessment is often carried out,
by ultrasound or angiography, as revascularisation by angioplasty
or surgery may be required to allow the ulcer to heal. In cases
of severe secondary infection or gangrene, an amputation may
be required. This can be limited to the affected toe or involve
more extensive limb amputation.
Charcot neuroarthropathy
Acute Charcot neuroarthropathy almost always presents with
signs of inflammation - a hot, red, swollen foot. The initial X-ray
may show bony destruction but is often normal. As about 40%
of patients with a Charcot joint also have a foot ulcer, it can be
difficult to differentiate from osteomyelitis. Magnetic resonance
imaging (MRI) of the foot is often helpful. The mainstay of treatment
for an active Charcot foot is immobilisation and, ideally, avoidance
of weight-bearing on the affected foot. The rationale is that if
no pressure is applied through the foot, the destructive process
involving the bones will not result in significant deformity when
the acute inflammatory process subsides. Immobilisation is often
achieved by a total contact plaster cast or ‘aircast’ boot. The
acute phase frequently lasts 3-6 months and sometimes longer.
In the post-acute phase, there is consolidation and remodelling
of fracture fragments, eventually resulting in a stable foot.
Further information
Books and journal articles
Diabetes Control and Complications Trial Research Group. The effect
of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent
diabetes mellitus. N Engl J Med 1993; 329:977-986.
Nathan DM, Cleary PA, Backlud JY, et al. Diabetes Control and
Complications Trial/Epidemiology of Diabetes Interventions and
Complications (DCCT/EDIC) Study Research Group. Intensive
diabetes treatment and cardiovascular disease in patients with type
1 diabetes. N Engl J Med 2005; 353:2643-2653.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with
type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-853, 854-865.
Websites
cdc.gov/diabetes/ Diabetes Public Health Resource. Useful American
site with resources for patients and health-care professionals.
diabetes.org American Diabetes Association. Includes information on
research and advocacy issues.
diabetes.org.uk Diabetes UK. Includes information for patients and
leaflets.
idf.org International Diabetes Federation. Useful information on
international aspects of care and education.
joslin.org Joslin Diabetes Center. Well-written resource for patients and
health-care professionals, and information on diabetes research.
mydiabetesmyway.scot.nhs.uk An interactive diabetes website for
patients with diabetes and their carers.
ndei.org National Diabetes Education Initiative. Web-based education
for health-care professionals, including case studies and slides.
Gastroenterology
Clinical examination of the gastrointestinal tract 764
Functional anatomy and physiology 766
Oesophagus, stomach and duodenum 766
Small intestine 767
Pancreas 770
Colon 770
Intestinal microbiota 771
Control of gastrointestinal function 771
Gut hormones 772
Diseases of the stomach and duodenum 797
Gastritis 797
Peptic ulcer disease 798
Functional disorders 802
Tumours of the stomach 803
Diseases of the small intestine 805
Disorders causing malabsorption 805
Motility disorders 810
Miscellaneous disorders of the small intestine 81 1
Investigation of gastrointestinal disease 772
Imaging 772
Tests of infection 111
Tests of function 111
Radioisotope tests 778
Gut hormone testing 778
Presenting problems in gastrointestinal disease 778
Dysphagia 778
Dyspepsia 779
Heartburn and regurgitation 779
Vomiting 780
Gastrointestinal bleeding 780
Diarrhoea 783
Malabsorption 783
Weight loss 785
Constipation 786
Abdominal pain 787
Diseases of the mouth and salivary glands 790
Diseases of the oesophagus 791
Gastro-oesophageal reflux disease 791
Motility disorders 794
Tumours of the oesophagus 796
Perforation of the oesophagus 797
Adverse food reactions 81 2
Infections of the small intestine 81 2
Tumours of the small intestine 813
Inflammatory bowel disease 813
Irritable bowel syndrome 824
HIV/AIDS and the gastrointestinal tract 826
Ischaemic gut injury 827
Disorders of the colon and rectum 827
Tumours of the colon and rectum 827
Diverticulosis 833
Constipation and disorders of defecation 834
Anorectal disorders 835
Diseases of the peritoneal cavity 836
Other disorders 837
Diseases of the pancreas 837
Acute pancreatitis 837
Chronic pancreatitis 839
Congenital abnormalities affecting the pancreas 842
Tumours of the pancreas 842
764 • GASTROENTEROLOGY
Clinical examination of the gastrointestinal tract
3 Head and neck
Pallor
Jaundice
Angular stomatitis
Glossitis
Parotid enlargement
Mouth ulcers
Dentition
Lymphadenopathy
A Virchow’s gland in
gastric cancer
A Atrophic glossitis and
angular stomatitis in
vitamin B12 deficiency
2 Hands
Clubbing
Koilonychia
Signs of liver disease
(Ch. 22)
A Clubbing in patient with
malabsorption
1 Skin and nutritional
status
Muscle bulk
Signs of weight loss
A Pyoderma gangrenosum
in ulcerative colitis
Observation
• Distressed/in pain?
• Fever?
• Dehydrated?
• Habitus
• Skin
4 Abdominal examination
(see opposite)
Observe
Distension
Respiratory movements
Scars
Colour
A Multiple surgical scars,
a prolapsing ileostomy
and enterocutaneous
fistulae in a patient
with Crohn’s disease
Palpate
Tender/guarding
Masses
Viscera
Liver (Ch. 22)
Kidneys (Ch. 15)
Spleen
Percuss
Ascites
Viscera
Auscultate
Bowel sounds
Bruits
5 Groin
Herniae
Lymph nodes
6 Perineum/rectal
(see opposite)
Fistulae
Skin tags
Haemorrhoids
Masses
Clinical examination of the gastrointestinal tract • 765
4 Abdominal examination: possible findings
Epigastric mass
Hepatomegaly
Palpable gallbladder
(Ch. 22)
Gastric cancer
Pancreatic cancer
Aortic aneurysm
% 0-
Left upper quadrant mass
P ?Sp!een
?Kidney
J Edge
Rounded
Can’t get above it
Can get above it
Moves towards right
Moves down
iliac fossa
Dull percussion note
Resonant to percussion
Notch
Ballotable
Tender to palpation
?Peritonitis
?Obstruction
Guarding and rebound
1 Distended
Absent bowel sounds
Tinkling bowel sounds
Rigidity
Visible peristalsis
Left iliac fossa mass
Sigmoid colon cancer
Constipation
Diverticular mass
Generalised distension
^ Right iliac fossa mass
' Suprapubic mass
Fat (obesity)
Caecal carcinoma
Bladder
Fluid (ascites)
Crohn’s disease
Pregnancy
Flatus (obstruction/ileus)
Appendix abscess
Fibroids/carcinoma
Faeces (constipation)
Fetus (pregnancy)
6 Rectal examination: common findings
21
766 • GASTROENTEROLOGY
Diseases of the gastrointestinal tract are a major cause of
morbidity and mortality. Approximately 1 0% of all GP consultations
in the UK are for indigestion and 1 in 14 is for diarrhoea. Infective
diarrhoea and malabsorption are responsible for much ill health
and many deaths in the developing world. The gastrointestinal
tract is the most common site for cancer development. Colorectal
cancer is the third most common cancer in men and women
and population-based screening programmes exist in many
countries. Functional bowel disorders affect up to 1 0-1 5% of
the population and consume considerable health-care resources.
The inflammatory bowel diseases, Crohn’s disease and ulcerative
colitis, together affect 1 in 250 people in the Western world, with
substantial associated morbidity.
Functional anatomy and physiology
Oesophagus, stomach and duodenum
The oesophagus is a muscular tube that extends 25 cm from
the cricoid cartilage to the cardiac orifice of the stomach. It has
an upper and a lower sphincter. A peristaltic swallowing wave
propels the food bolus into the stomach (Fig. 21 .1).
The stomach acts as a ‘hopper’, retaining and grinding
food, and then actively propelling it into the upper small bowel
(Fig. 21.2).
Swallowing begins as a
voluntary process. The
food bolus is forcibly
propelled by the tongue
into the pharynx
The upper oesophageal
sphincter relaxes
Peristaltic activity,
controlled by a brainstem
centre, is mediated
by autonomic nerves
The lower oesophageal
sphincter relaxes. The
food enters the stomach
Fig. 21.1 The oesophagus: anatomy and function. The swallowing wave.
Vagus nerves
Diaphragm
Fundus
Body
Endoscopic view
Fig. 21.2 Normal gastric and duodenal anatomy.
Functional anatomy and physiology • 767
Gastric secretion
Gastrin, histamine and acetylcholine are the key stimulants
of acid secretion. Hydrogen and chloride ions are secreted
from the apical membrane of gastric parietal cells into the
lumen of the stomach by a hydrogen-potassium adenosine
triphosphatase (ATPase) (‘proton pump’) (Fig. 21.3). The
hydrochloric acid sterilises the upper gastrointestinal tract and
converts pepsinogen, which is secreted by chief cells, to pepsin.
The glycoprotein intrinsic factor, secreted in parallel with acid,
is necessary for vitamin B12 absorption.
Gastrin, somatostatin and ghrelin
The hormone gastrin is produced by G cells in the antrum,
whereas somatostatin is secreted from D cells throughout the
stomach. Gastrin stimulates acid secretion and mucosal growth
while somatostatin suppresses it. Ghrelin, secreted from oxyntic
glands, stimulates acid secretion but also appetite and gastric
emptying.
Protective factors
Bicarbonate ions, stimulated by prostaglandins, mucins and
trefoil factor family (TFF) peptides, together protect the gastro-
Enterochromaff in-like
cell
K+ H+ Cl" H+/K+ ATPase
Fig. 21.3 Control of acid secretion. Gastrin released from antral G cells
in response to food (protein) binds to cholecystokinin receptors (CCK-2R)
on the surface of enterochromaffin-like (ECL) cells, which in turn release
histamine. The histamine binds to H2 receptors on parietal cells and this
leads to secretion of hydrogen ions in exchange for potassium ions at the
apical membrane. Parietal cells also express CCK-2R and it is thought that
activation of these receptors by gastrin is involved in regulatory proliferation
of parietal cells. Cholinergic (vagal) activity and gastric distension also
stimulate acid secretion; somatostatin, vasoactive intestinal polypeptide
(V IP) and gastric inhibitory polypeptide (GIP) may inhibit it. (ACh-R =
acetylcholine receptor; ATPase = adenosine triphosphatase)
duodenal mucosa from the ulcerative properties of acid and
pepsin.
Small intestine
The small bowel extends from the ligament of Treitz to the
ileocaecal valve (Fig. 21 .4). During fasting, a wave of peristaltic
activity passes down the small bowel every 1-2 hours. Entry
of food into the gastrointestinal tract stimulates small bowel
peristaltic activity. Functions of the small intestine are:
• digestion (mechanical, enzymatic and peristaltic)
• absorption - the products of digestion, water, electrolytes
and vitamins
• protection against ingested toxins
• immune regulation.
Fig. 21.4 Small intestine: anatomy. Epithelial cells are formed in crypts
and differentiate as they migrate to the tip of the villi to form enterocytes
(absorptive cells) and goblet cells.
768 • GASTROENTEROLOGY
| Digestion and absorption
Fat
Dietary lipids comprise long-chain triglycerides, cholesterol
esters and lecithin. Lipids are insoluble in water and undergo
lipolysis and incorporation into mixed micelles before they can
be absorbed into enterocytes along with the fat-soluble vitamins
A, D, E and K. The lipids are processed within enterocytes and
pass via lymphatics into the systemic circulation. Fat absorption
and digestion can be considered as a stepwise process, as
outlined in Figure 21 .5.
Carbohydrates
Starch is hydrolysed by salivary and pancreatic amylases to:
• oc-limit dextrins containing 4-8 glucose molecules
• the disaccharide maltose
• the trisaccharide maltotriose.
Disaccharides are digested by enzymes fixed to the microvillous
membrane to form the monosaccharides glucose, galactose
and fructose. Glucose and galactose enter the cell by an
energy-requiring process involving a carrier protein, and fructose
enters by simple diffusion.
Protein
The steps involved in protein digestion are shown in Figure 21 .6.
Intragastric digestion by pepsin is quantitatively modest but
important because the resulting polypeptides and amino acids
stimulate cholecystokinin (CCK) release from the mucosa of the
proximal jejunum, which in turn stimulates release of pancreatic
proteases, including trypsinogen, chymotrypsi nogen, pro-elastases
and procarboxypeptidases, from the pancreas. On exposure
to brush border enterokinase, inert trypsinogen is converted to
the active proteolytic enzyme trypsin, which activates the other
pancreatic pro-enzymes. Trypsin digests proteins to produce
oligopeptides, peptides and amino acids. Oligopeptides are
further hydrolysed by brush border enzymes to yield dipeptides,
tripeptides and amino acids. These small peptides and the
amino acids are actively transported into the enterocytes, where
intracellular peptidases further digest peptides to amino acids.
Amino acids are then actively transported across the basal cell
membrane of the enterocyte into the portal circulation and the liver.
Fig. 21.5 Fat digestion. Step 1: Luminal phase. Fatty acids stimulate cholecystokinin (CCK) release from the duodenum and upper jejunum. The CCK
stimulates release of amylase, lipase, colipase and proteases from the pancreas, causes gallbladder contraction and relaxes the sphincter of Oddi, allowing
bile to flow into the intestine. Step 2: Fat solubilisation. Bile acids and salts combine with dietary fat to form mixed micelles, which also contain cholesterol
and fat-soluble vitamins. Step 3: Digestion. Pancreatic lipase, in the presence of its co-factor, colipase, cleaves long-chain triglycerides, yielding fatty acids
and monoglycerides. Step 4: Absorption. Mixed micelles diffuse to the brush border of the enterocytes. Within the brush border, long-chain fatty acids bind
to proteins, which transport the fatty acids into the cell, whereas cholesterol, short-chain fatty acids, phospholipids and fat-soluble vitamins enter the cell
directly. The bile salts remain in the small intestinal lumen and are actively transported from the terminal ileum into the portal circulation and returned to
the liver (the enterohepatic circulation). Step 5: Re-esterification. Within the enterocyte, fatty acids are re-esterified to form triglycerides. Triglycerides
combine with cholesterol ester, fat-soluble vitamins, phospholipids and apoproteins to form chylomicrons. Step 6: Transport. Chylomicrons leave the
enterocytes by exocytosis, enter mesenteric lymphatics, pass into the thoracic duct and eventually reach the systemic circulation.
Functional anatomy and physiology • 769
Water and electrolytes
Absorption and secretion of electrolytes and water occur
throughout the intestine. Electrolytes and water are transported
by two pathways:
• the paracellular route, in which passive flow through tight
junctions between cells is a consequence of osmotic,
electrical or hydrostatic gradients
• the transcellular route across apical and basolateral
membranes by energy-requiring specific active transport
carriers (pumps).
In healthy individuals, fluid balance is tightly controlled, such
that only 1 00 ml_ of the 8 litres of fluid entering the gastrointestinal
tract daily is excreted in stools (Fig. 21 .7).
Vitamins and trace elements
Water-soluble vitamins are absorbed throughout the intestine.
The absorption of folic acid, vitamin B12, calcium and iron is
described on page 943.
Protective function of the small intestine
Physical defence mechanisms
There are several levels of defence in the small bowel (Fig.
21 .8). Firstly, the gut lumen contains host bacteria (see below),
mucins and secreted antibacterial products, including defensins
and immunoglobulins that help combat pathogenic infections.
Secondly, epithelial cells have relatively impermeable brush
border membranes and passage between cells is prevented
by tight and adherens junctions. These cells can react to
foreign peptides (‘innate immunity’) using pattern recognition
receptors found on cell surfaces (Toll receptors) or intracellularly.
Lastly, in the subepithelial layer, immune responses occur under
control of the adaptive immune system in response to pathogenic
compounds.
Immunological defence mechanisms
Gastrointestinal mucosa-associated lymphoid tissue (MALT)
constitutes 25% of the total lymphatic tissue of the body and
is at the heart of adaptive immunity. Within Peyer’s patches,
770 • GASTROENTEROLOGY
Fig. 21.8 Intestinal defence mechanisms. See text for details.
B lymphocytes differentiate to plasma cells following exposure to
antigens and these migrate to mesenteric lymph nodes to enter
the blood stream via the thoracic duct. The plasma cells return to
the lamina propria of the gut through the circulation and release
immunoglobulin A (IgA), which is transported into the lumen of
the intestine. Intestinal T lymphocytes help localise plasma cells
to the site of antigen exposure, as well as producing inflammatory
mediators. Macrophages in the gut phagocytose foreign materials
and secrete a range of cytokines, which mediate inflammation.
Similarly, activation of mast-cell surface IgE receptors leads
to degranulation and release of other molecules involved in
inflammation.
Pancreas
The exocrine pancreas (Box 21 .1) is necessary for the digestion
of fat, protein and carbohydrate. Pro-enzymes are secreted from
pancreatic acinar cells in response to circulating gastrointestinal
21.1 Pancreatic enzymes
Enzyme
Substrate
Product
Amylase
Starch and
Limit dextrans
glycogen
Maltose
Maltriose
Lipase
Triglycerides
Monoglycerides and
Colipase
free fatty acids
Proteolytic enzymes
Proteins and
Short polypeptides
Trypsinogen
Chymotrypsi nogen
Pro-elastase
Pro-carboxypeptidases
polypeptides
hormones (Fig. 21 .9) and are activated by trypsin. Bicarbonate-rich
fluid is secreted from ductular cells to produce an optimum alkaline
pH for enzyme activity. The endocrine pancreas is discussed in
Chapters 1 8 and 20.
Colon
The colon (Fig. 21.10) absorbs water and electrolytes. It also
acts as a storage organ and has contractile activity. Two types
of contraction occur. The first of these is segmentation (ring
contraction), which leads to mixing but not propulsion; this
promotes absorption of water and electrolytes. Propulsive
(peristaltic contraction) waves occur several times a day and
propel faeces to the rectum. All activity is stimulated after meals
through the gastrocolic reflex in response to release of hormones
such as 5-hydroxytryptamine (5-HT, serotonin), motilin and CCK.
Faecal continence depends on maintenance of the anorectal
angle and tonic contraction of the external anal sphincters.
On defecation, there is relaxation of the anorectal muscles,
increased intra-abdominal pressure from the Valsalva manoeuvre
and contraction of abdominal muscles, and relaxation of the
anal sphincters.
Accessory ampulla
MRCP-normal pancreas
5 cm
Secretin
CCK
Secretin
VIP
Acetylcholine
Bombesin
Substance P
enzyme ^■►HCOo + water
Ductule
Duodenum
Ampulla of Vater
Fig. 21.9 Pancreatic structure and function. Ductular cells secrete alkaline fluid in response to secretin. Acinar cells secrete digestive enzymes from
zymogen granules in response to a range of secretagogues. The photograph shows a normal pancreatic duct (PD) and side branches, as defined at
magnetic resonance cholangiopancreatography (MRCP). Note the incidental calculi in the gallbladder and common bile duct (arrow). (CCK = cholecystokinin;
VIP = vasoactive intestinal polypeptide)
Functional anatomy and physiology • 771
Caecum
Fig. 21.10 The normal colon, rectum and anal canal.
Intestinal microbiota
The human microbiota comprises 1014 microbial residents in
the human body, vastly outnumbering host cells. Indeed, the
number of bacterial genes in the microbiota genome exceeds
that of the host by 1 00-fold or more. This represents a vast
ecosystem that is central to health and homeostasis, and is
disordered in disease. In terms of nomenclature, ‘microbiota’
refers to the microorganisms that live in a particular niche,
while ‘microbiome’ refers to the collective genomes of these
microbiota. The metabolic capacity of the gut microbiota is
equivalent to that of the liver. The Human Microbiome Project
revealed that there are unique communities at different body sites
and in the gut particular phyla predominate: namely, Firmicutes,
Bacteriodetes, Proteobacteria and Actinobacteria. There is a
degree of heritability of this microbiota, as shown in twin studies,
but it is clear that there are many environmental factors that can
impact, including diet, drugs, physical activity, smoking, stress
and natural ageing. Generally, we acquire our adult intestinal
microbiota by the age of 2 years. A dysbiosis or imbalance
between the different components of the intestinal microbiota
has been associated with diseases of the gastrointestinal tract,
such as inflammatory bowel disease and colorectal cancer; liver
disease, including hepatocellular carcinoma; and pathologies
outside the gastrointestinal tract, such as diabetes, obesity,
cardiovascular disorders, cerebrovascular disorders, asthma
and psychiatric disorders, such as depression. Many challenges
remain in understanding the intestinal microbiota and how it
impacts on health and disease. It is not clear what constitutes
a ‘healthy’ phenotype; there are questions over best sampling
practice from either the faecal stream or the mucosa; and
there are technical considerations to ensure consistency in
methodologies and data analysis.
Control of gastrointestinal function
Secretion, absorption, motor activity, growth and differentiation
of the gut are all modulated by a combination of neuronal and
hormonal factors.
I The nervous system and
gastrointestinal function
The central nervous system (CNS), the autonomic system (ANS)
and the enteric nervous system (ENS) interact to regulate gut
function. The ANS comprises:
• parasympathetic pathways (vagal and sacral efferent),
which are cholinergic, and increase smooth muscle tone
and promote sphincter relaxation
• sympathetic pathways, which release noradrenaline
(norepinephrine), reduce smooth muscle tone and
stimulate sphincter contraction.
The enteric nervous system
In conjunction with the ANS, the ENS senses gut contents and
conditions, and regulates motility, fluid exchange, secretion, blood
flow and other key gut functions. It comprises two major networks
intrinsic to the gut wall. The myenteric (Auerbach’s) plexus in the
smooth muscle layer regulates motor control; and the submucosal
(Meissner’s) plexus exerts secretory control over the epithelium,
entero-endocrine cells and submucosal vessels. Together, these
plexuses form a two-layered neuronal mesh along the length of
772 • GASTROENTEROLOGY
21.2 Gut hormones and peptides
Hormone
Origin
Stimulus
Action
Gastrin
Stomach (G cell)
Products of protein digestion
Suppressed by acid and somatostatin
Stimulates gastric acid secretion
Stimulates growth of gastrointestinal mucosa
Somatostatin
Throughout gastrointestinal
tract (D cell)
Fat ingestion
inhibits gastrin and insulin secretion
Decreases acid secretion
Decreases absorption
Inhibits pancreatic secretion
Cholecystokinin
(CCK)
Duodenum and jejunum
(1 cells); also ileal and
colonic nerve endings
Products of protein digestion
Fat and fatty acids
Suppressed by trypsin
Stimulates pancreatic enzyme secretion
Stimulates gallbladder contraction
Relaxes sphincter of Oddi
Modulates satiety
Decreases gastric acid secretion
Reduces gastric emptying
Regulates pancreatic growth
Secretin
Duodenum and jejunum
(S cells)
Duodenal acid
Fatty acids
Stimulates pancreatic fluid and bicarbonate secretion
Decreases acid secretion
Reduces gastric emptying
Motilin
Duodenum, small intestine
and colon (Mo cells)
Fasting
Dietary fat
Regulates peristaltic activity, including migrating
motor complexes (MMCs)
Gastric inhibitory
polypeptide (GIP)
Duodenum (K cells) and
jejunum
Glucose and fat
Stimulates insulin release (also known as
glucose-dependent insulinotrophic polypeptide)
Inhibits acid secretion
Enhances satiety
Glucagon-like
peptide-1 (GLP-1)
Ileum and colon (L cells)
Carbohydrates, protein and fat
Stimulates insulin release
Inhibits acid secretion and gastric emptying
Enhances satiety
Vasoactive intestinal
peptide (VIP)
Nerve fibres throughout
gastrointestinal tract
Unknown
Has vasodilator action
Relaxes smooth muscle
Stimulates water and electrolyte secretion
Ghrelin
Stomach
Fasting
Inhibited by eating
Stimulates appetite, acid secretion and gastric
emptying
Peptide YY
Ileum and colon
Feeding
Modulates satiety
the gut. Although connected centrally via the ANS, the ENS can
function autonomously using a variety of transmitters, including
acetylcholine, noradrenaline (norepinephrine), 5-HT, nitric oxide,
substance P and calcitonin gene-related peptide (CGRP). There
are local reflex loops within the ENS but also loops involving the
coeliac and mesenteric ganglia and the paravertebral ganglia.
The parasympathetic system generally stimulates motility and
secretion, while the sympathetic system generally acts in an
inhibitory manner.
Peristalsis
Peristalsis is a reflex triggered by gut wall distension, which
consists of a wave of circular muscle contraction to propel
contents from the oesophagus to the rectum. It can be influenced
by innervation but functions independently. It results from a basic
electrical rhythm originating from the interstitial cells of Cajal in
the circular layer of intestinal smooth muscle. These are stellate
cells of mesenchymal origin with smooth muscle features, which
act as the ‘pacemaker’ of the gut.
Migrating motor complexes
Migrating motor complexes (MMCs) are waves of contraction
spreading from the stomach to the ileum, occurring at a frequency
of about 5 per minute every 90 minutes or so, between meals
and during fasting. They may serve to sweep intestinal contents
distally in preparation for the next meal and are inhibited by eating.
Gut hormones
The origin, action and control of the major gut hormones, peptides
and non-peptide signalling transmitters are summarised in
Box 21 .2.
Investigation of
gastrointestinal disease
A wide range of tests is available for the investigation of patients
with gastrointestinal symptoms. These can be classified broadly
into tests of structure, tests for infection and tests of function.
Imaging
| Plain X-rays
Plain X-rays of the abdomen are useful in the diagnosis of
intestinal obstruction or paralytic ileus, where dilated loops
of bowel and (in the erect position) fluid levels may be seen
(Fig. 21 .1 1). Calcified lymph nodes, gallstones and renal stones
can also be detected. Chest X-ray (performed with the patient in
erect position) is useful in the diagnosis of suspected perforation,
as it shows subdiaphragmatic free air (Fig. 21 .1 1).
Investigation of gastrointestinal disease • 773
Fig. 21.11 Examples of plain X-rays. [A] Abdominal X-ray showing dilatation of loops of small bowel (arrows), which are indicative of obstruction (in this
case due to adhesions from previous surgery). \W\ Chest X-ray showing free air under both hemi-diaphragms (arrows), which is indicative of acute
perforation of an abdominal viscus.
21.3 Contrast radiology in the investigation of gastrointestinal disease
Barium swallow/meal Barium follow-through Barium enema
Indications and Motility disorders (achalasia and
major uses gastroparesis)
Perforation or fistula (non-ionic contrast)
Diarrhoea and abdominal pain of small
bowel origin
Possible obstruction by strictures
Suspected malabsorption
Assessment of Crohn’s disease
Altered bowel habit
Evaluation of strictures or diverticular
disease
Megacolon
Chronic constipation
Limitations Risk of aspiration
Poor mucosal detail
Low sensitivity for early cancer
Inability to biopsy
Time-consuming nature
Radiation exposure
Relative insensitivity
Difficulty in frail or incontinent patients
Sigmoidoscopy needed to see rectum
Low sensitivity for lesions <1 cm
Fig. 21.12 Examples of contrast radiology. [A] Barium swallow showing a large pharyngeal pouch (P) with retained contrast creating an air-fluid
level. [§] Barium follow-through. There are multiple diverticula (arrows) in this patient with jejunal diverticulosis. [C] Barium enema showing severe
diverticular disease. There is tortuosity and narrowing of the sigmoid colon with multiple diverticula (arrows).
Contrast studies
X-rays with contrast medium are usually performed to assess not
only anatomical abnormalities but also motility. Barium sulphate
provides good mucosal coating and excellent opacification but
can precipitate impaction proximal to an obstructive lesion.
Water-soluble contrast is used to opacify bowel prior to abdominal
computed tomography and in cases of suspected perforation.
The double contrast technique improves mucosal visualisation
by using gas to distend the barium-coated intestinal surface.
Contrast studies are useful for detecting filling defects, such as
tumours, strictures, ulcers and motility disorders, but are inferior
to endoscopic procedures and more sophisticated cross-sectional
imaging techniques, such as computed tomography and magnetic
resonance imaging. The major uses and limitations of various
contrast studies are shown in Box 21 .3 and Figure 21 .12.
774 • GASTROENTEROLOGY
I Ultrasound, computed tomography and
magnetic resonance imaging
Ultrasound, computed tomography (Cl) and magnetic resonance
imaging (MRI) are key tests in the evaluation of intra-abdominal
disease. They are non-invasive and offer detailed images
of the abdominal contents. Fluorodeoxyglucose-positron
emission tomography (FDG-PET) is increasingly used in the
staging of malignancies and images may be fused with CT to
enhance localisation. Their main applications are summarised in
Box 21.4 and Figure 21.13.
Endoscopy
Videoendoscopes provide high-definition imaging and accessories
can be passed down the endoscope to allow both diagnostic
and therapeutic procedures, some of which are illustrated in
Figure 21 .14. Endoscopes with magnifying lenses allow almost
microscopic detail to be observed, and imaging modalities, such
as confocal endomicroscopy, autofluorescence and ‘narrow-band
imaging’, are increasingly used to detect subtle abnormalities
not visible by standard ‘white light’ endoscopy.
Upper gastrointestinal endoscopy
This is performed under light intravenous benzodiazepine
sedation, or using only local anaesthetic throat spray after
the patient has fasted for at least 4 hours. With the patient
in the left lateral position, the entire oesophagus (excluding
pharynx), stomach and first two parts of duodenum can be seen.
Indications, contraindications and complications are given in
Box 21 .5.
Endoscopic ultrasound
Endoscopic ultrasound (EUS) combines endoscopy with
intraluminal ultrasonography using a high-frequency transducer
to produce high-resolution ultrasound images. This allows
visualisation through the wall of the gastrointestinal tract and
into surrounding tissues, e.g. the pancreas or lymph nodes.
It can therefore be used to perform fine needle aspiration or
biopsy of mass lesions. EUS is helpful in the diagnosis of
pancreatic tumours, chronic pancreatitis, pancreatic cysts,
cholangiocarcinoma, common bile duct stones, ampullary
lesions and submucosal tumours. It also plays an important
role in the staging of certain cancers, e.g. those of oesophagus
and pancreas. EUS can also be therapeutic, as in drainage of
pancreatic fluid collections and coeliac plexus block for pain
management. Possible complications of EUS include bleeding,
infection, cardiopulmonary events and perforation.
Capsule endoscopy
Capsule endoscopy (Fig. 21.15) uses a capsule containing
an imaging device, battery, transmitter and antenna; as it
traverses the small intestine, it transmits images to a battery-
powered recorder worn on a belt round the patient’s waist. After
approximately 8 hours, the capsule is excreted. Images from
the capsule are analysed as a video sequence and it is usually
possible to localise the segment of small bowel in which lesions
are seen. Abnormalities detected usually require enteroscopy
Investigation of gastrointestinal disease • 775
Control of
bleeding
s
N
V~~
===Z^J
Injection sclerotherapy Diathermy
Variceal ligation Laser therapy Endoscopic clipping
Treatment of
tumours
Jf
itHf
Laser therapy
L _ i
Polypectomy
V _ /
Photodynamic Endoscopic mucosal Endoscopic
therapy/radiofrequency resection submucosal
ablation dissection (ESD)
s
Treatment of
11
strictures
V _
•
f
\
V _
r
J
Management
of biliary and
pancreatic
disease
Sphincterotomy Basket retrieval
Fig. 21.14 Examples of therapeutic techniques in endoscopy.
Stent insertion Pseudocyst drainage
21.5 Upper gastrointestinal endoscopy
Indications
• Dyspepsia in patients >55 years of age or with alarm symptoms
• Atypical chest pain
• Dysphagia
• Vomiting
• Weight loss
• Acute or chronic gastrointestinal bleeding
• Screening for oesophageal varices in chronic liver disease
• Abnormal CT scan or barium meal
• Duodenal biopsies in the investigation of malabsorption and
confirmation of a diagnosis of coeliac disease prior to commencement
of gluten-free diet
• Therapy, including treatment of bleeding lesions, banding/injection of
varices, dilatation of strictures, insertion of stents, placement of
percutaneous gastrostomies, ablation of Barrett’s oesophagus and
resection of high-grade dysplastic lesions and early neoplasia in the
upper gastrointestinal tract
Contraindications
• Severe shock
• Recent myocardial infarction, unstable angina, cardiac arrhythmia*
• Severe respiratory disease*
• Atlantoaxial subluxation*
• Possible visceral perforation
Complications
• Cardiorespiratory depression due to sedation
• Aspiration pneumonia
• Perforation
*These are ‘relative’ contraindications; in experienced hands, endoscopy can be safely performed.
776 • GASTROENTEROLOGY
21.6 Wireless capsule endoscopy
Indications
• Obscure gastrointestinal bleeding
• Small bowel Crohn’s disease
• Assessment of coeliac disease and its complications
• Screening and surveillance in familial polyposis syndromes
Contraindications
• Known or suspected small bowel stricture (risk of capsule retention)
• Caution in people with pacemakers or implantable defibrillators
Complications
• Capsule retention (< 1 %)
21.7 Double balloon enteroscopy
Indications
Diagnostic
• Obscure gastrointestinal bleeding
• Malabsorption or unexplained diarrhoea
• Suspicious radiological findings
• Suspected small bowel tumour
• Surveillance of polyposis syndromes
Therapeutic
• Coagulation/diathermy of bleeding lesions
• Jejunostomy placement
Contraindications
• As for upper gastrointestinal endoscopy
Complications
• As for upper gastrointestinal endoscopy
• Post-procedure abdominal pain (< 20%)
• Pancreatitis (1-3%)
• Perforation (especially after resection of large polyps)
for confirmation and therapy. Indications, contraindications and
complications are listed in Box 21 .6.
Double balloon enteroscopy
While endoscopy can reach the proximal small intestine in
most patients, a technique called double balloon enteroscopy
is also available, which uses a long endoscope with a flexible
overtube. Sequential and repeated inflation and deflation of
balloons on the tip of the overtube and enteroscope allow the
operator to push and pull along the entire length of the small
intestine to the terminal ileum, in order to diagnose or treat small
bowel lesions detected by capsule endoscopy or other imaging
modalities. Indications, contraindications and complications are
listed in Box 21 .7.
Sigmoidoscopy and colonoscopy
Sigmoidoscopy can be carried out either in the outpatient clinic
using a 20 cm rigid plastic sigmoidoscope or in the endoscopy
suite using a 60 cm flexible colonoscope following bowel
preparation. When sigmoidoscopy is combined with proctoscopy,
accurate detection of haemorrhoids, ulcerative colitis and distal
colorectal neoplasia is possible. After full bowel cleansing, it is
possible to examine the entire colon and the terminal ileum
using a longer colonoscope. Indications, contraindications and
complications of colonoscopy are listed in Box 21 .8.
21.8 Colonoscopy
Indications*
• Suspected inflammatory bowel disease
• Chronic diarrhoea
• Altered bowel habit
• Rectal bleeding or iron deficiency anaemia
• Assessment of abnormal CT colonogram or barium enema
• Colorectal cancer screening
• Colorectal adenoma and carcinoma follow-up
• Therapeutic procedures, including endoscopic resection,
dilatation of strictures, laser, stent insertion and argon plasma
coagulation
Contraindications
• Acute severe ulcerative colitis (unprepared flexible sigmoidoscopy is
preferred)
• As for upper gastrointestinal endoscopy
Complications
• Cardiorespiratory depression due to sedation
• Perforation
• Bleeding following polypectomy
*Colonoscopy is not useful in the investigation of constipation.
21.9 Endoscopy in old age
• Tolerance: endoscopic procedures are generally well tolerated,
even in very old people.
• Side-effects from sedation: older people are more sensitive, and
respiratory depression, hypotension and prolonged recovery times
are more common.
• Bowel preparation for colonoscopy: can be difficult in frail,
immobile people. Sodium phosphate-based preparations can cause
dehydration or hypotension and should be avoided in those with
underlying cardiac or renal failure. Minimal-preparation CT
colonograms provide an excellent alternative in these individuals.
• Antiperistaltic agents: hyoscine should be avoided in those with
glaucoma and can also cause tachyarrhythmias. Glucagon is
preferred if an antiperistaltic agent is needed.
Magnetic resonance cholangiopancreatography
Magnetic resonance cholangiopancreatography (MRCP) has
largely replaced endoscopic retrograde cholangiopancreatography
(ERCP) in the evaluation of obstructive jaundice since it produces
comparable images of the biliary tree and pancreas, providing
information that complements that obtained from CT and
endoscopic ultrasound examination (EUS).
Endoscopic retrograde cholangiopancreatography
Using a side-viewing duodenoscope, it is possible to cannulate
the main pancreatic duct and common bile duct. Nowadays,
ERCP is used mainly in the treatment of a range of biliary and
pancreatic diseases that have been identified by other imaging
techniques such as MRCP, EUS and CT. Indications for and
risks of ERCP are listed in Box 21 .10.
Histology
Biopsy material obtained endoscopically or percutaneously can
provide useful information (Box 21 .1 1).
Investigation of gastrointestinal disease • 111
21.10 Endoscopic retrograde
cholangiopancreatography
Indications
Diagnostic
• Biliary or pancreatic disease where other imaging is equivocal or
contraindicated
• Ampullary biopsy or biliary cytology
Therapeutic
• Biliary disease:
Removal of common bile duct calculi*
Palliation of malignant biliary obstruction
Management of biliary leaks/damage complicating surgery
Dilatation of benign strictures
Primary sclerosing cholangitis
• Pancreatic disease:
Drainage of pancreatic pseudocysts and fistulae
Removal of pancreatic calculi (selected cases)
Contraindications
• Severe cardiopulmonary comorbidity
• Coagulopathy
Complications
• Occur in 5-10% with a 30-day mortality of 0.5-1%
General
• As for upper endoscopy
Specific
• Biliary disease:
Bleeding following sphincterotomy
Cholangitis (if biliary obstruction is not relieved by ERCP)
Gallstone impaction
• Pancreatic disease:
Acute pancreatitis
Infection of pseudocyst
*Laparoscopic surgery is preferred in fit individuals who also require
cholecystectomy.
21 .1 1 Reasons for biopsy or cytological examination
• Suspected malignant lesions
• Assessment of mucosal abnormalities
• Diagnosis of infection ( Candida , Helicobacter pylori, Giardia lamblia)
• Analysis of genetic mutations
Tests of infection
Bacterial cultures
Stool cultures are essential in the investigation of diarrhoea,
especially when it is acute or bloody, in order to identify pathogenic
organisms (Ch. 11).
Serology
Detection of antibodies plays a limited role in the diagnosis
of gastrointestinal infection caused by organisms such as
Helicobacter pylori, Salmonella species and Entamoeba histolytica.
Breath tests
Non-invasive breath tests for H. pylori infection are discussed
on page 800 and breath tests for suspected small intestinal
bacterial overgrowth on page 808.
Tests of function
A number of dynamic tests can be used to investigate aspects
of gut function, including digestion, absorption, inflammation and
epithelial permeability. Some of the more common ones are listed
in Box 21.12. In the assessment of suspected malabsorption,
blood tests (full blood count, erythrocyte sedimentation rate (ESR),
and measurement of C-reactive protein (CRP), folate, vitamin B12,
21.12 Tests of gastrointestinal function
Process
Test
Principle
Comments
Absorption
Lactose
Lactose H2 breath test
Measurement of breath H2 content after 50 g
oral lactose. Undigested sugar is metabolised by
colonic bacteria in hypolactasia and expired
hydrogen is measured
Non-invasive and accurate. May provoke pain
and diarrhoea in sufferers
Bile acids
75SeHCAT test
Serum
7a-hydroxycholestenone
Isotopic quantification of 7-day whole-body
retention of oral dose 75Se-labelled
homocholyltaurine (>15% = normal, 5-15%
borderline, <5% = abnormal)
Intermediate metabolite of the bile acid synthetic
pathway. Serum levels indicate activity of the
pathway and are elevated in bile acid diarrhoea
Accurate and specific but requires two visits and
involves radiation. Results can be equivocal.
Serum 7a-hydroxycholestenone is almost as
sensitive and specific
Simple test to perform and only marginally less
sensitive and specific than 75SeHCAT test
Pancreatic
exocrine
function
Pancreolauryl test
Faecal elastase
Pancreatic esterases cleave fluorescein dilaurate
after oral ingestion. Fluorescein is absorbed and
quantified in urine
Immunoassay of pancreatic enzymes on stool
sample
Accurate and avoids duodenal intubation Takes
2 days. Accurate urine collection essential.
Rarely performed
Simple, quick and avoids urine collection. Does
not detect mild disease
Mucosal
inflammation/
permeability
Faecal calprotectin
A protein secreted non-specifically by
neutrophils into the colon in response to
inflammation or neoplasia
Useful screening test for gastrointestinal
inflammation and for monitoring patients with
Crohn’s disease and ulcerative colitis. Poor
sensitivity for cancer
(75SeHCAT = 75Se-homocholic acid taurine)
778 • GASTROENTEROLOGY
iron status, albumin, calcium and phosphate) are essential, and
endoscopy is undertaken to obtain mucosal biopsies. Faecal
calprotectin is very sensitive at detecting mucosal inflammation.
Oesophageal motility
A barium swallow can give useful information about oesophageal
motility. Videofluoroscopy, with joint assessment by a speech
and language therapist and a radiologist, may be necessary in
difficult cases. Oesophageal manometry (see Fig. 21.1), often
in conjunction with 24-hour pH measurements, is of value
in diagnosing cases of refractory gastro-oesophageal reflux,
achalasia and non-cardiac chest pain. Oesophageal impedance
testing is useful for detecting non-acid or gas reflux events,
especially in patients with atypical symptoms or those who
respond poorly to acid suppression.
Gastric emptying
This involves administering a test meal containing solids and
liquids labelled with different radioisotopes and measuring the
amount retained in the stomach afterwards (Box 21.13). It is
useful in the investigation of suspected delayed gastric emptying
(gastroparesis) when other studies are normal.
| Colonic and anorectal motility
A plain abdominal X-ray taken on day 5 after ingestion of different¬
shaped inert plastic pellets on days 1-3 gives an estimate of
whole-gut transit time. The test is useful in the evaluation of
chronic constipation, when the position of any retained pellets can
be observed, and helps to differentiate cases of slow transit from
those due to obstructed defecation. The mechanism of defecation
and anorectal function can be assessed by anorectal manometry,
electrophysiological tests and defecating proctography.
Radioisotope tests
Many different radioisotope tests are used (Box 21 .13). In some,
structural information is obtained, such as the localisation of a
Meckel’s diverticulum. Others provide functional information,
such as the rate of gastric emptying or ability to reabsorb bile
acids. Yet others are tests of infection and rely on the presence
of bacteria to hydrolyse a radio-labelled test substance followed
by detection of the radioisotope in expired air, such as the urea
breath test for H. pylori.
Gut hormone testing
Excess gut hormone secretion by some gastrointestinal and
pancreatic neuro-endocrine tumours can be assessed by
measuring levels in blood. Commonly measured hormones
include gastrin, somatostatin, vasoactive intestinal polypeptide
(VIP) and pancreatic polypeptide.
Presenting problems in
gastrointestinal disease
Dysphagia
Dysphagia is defined as difficulty in swallowing. It may coexist
with heartburn or vomiting but should be distinguished from
both globus sensation (in which anxious people feel a lump in
the throat without organic cause) and odynophagia (pain during
swallowing, usually from gastro-oesophageal reflux or candidiasis).
Dysphagia can occur due to problems in the oropharynx or
oesophagus (Fig. 21.16). Oropharyngeal disorders affect the
initiation of swallowing at the pharynx and upper oesophageal
sphincter. The patient has difficulty initiating swallowing and
complains of choking, nasal regurgitation or tracheal aspiration.
Drooling, dysarthria, hoarseness and cranial nerve or other
neurological signs may be present. Oesophageal disorders cause
dysphagia by obstructing the lumen or by affecting motility.
Patients with oesophageal disease complain of food ‘sticking’
after swallowing, although the level at which this is felt correlates
poorly with the true site of obstruction. Swallowing of liquids is
normal until strictures become extreme.
Investigations
Dysphagia should always be investigated urgently. Endoscopy is
the investigation of choice because it allows biopsy and dilatation
of strictures. Even if the appearances are normal, biopsies should
be taken to look for eosinophilic oesophagitis. If no abnormality
is found, then barium swallow with videofluoroscopic swallowing
assessment is indicated to detect major motility disorders. In
some cases, oesophageal manometry is required. High-resolution
manometry allows accurate classification of abnormalities. Figure
21 .16 summarises a diagnostic approach to dysphagia and lists
the major causes.
21.13 Commonly used radioisotope tests in gastroenterology
Test
Isotope
Major uses and principle of test
Gastric emptying study
99mTc-sulphur
'"In-DTPA
Assessment of gastric emptying, particularly for possible gastroparesis
Urea breath test
13C-urea
Non-invasive diagnosis of Helicobacter pylori. Bacterial urease enzyme
splits urea to ammonia and C02l which is detected in expired air
Meckel’s scan
99mTc-pertechnate
Diagnosis of Meckel’s diverticulum in cases of obscure gastrointestinal
bleeding. Isotope is injected intravenously and localises in ectopic parietal
mucosa within diverticulum
Somatostatin receptor
scintigraphy (SRS)
1 1 1 1 n - DTPA-octreoti de
Labelled somatostatin analogue binds to cell surface somatostatin
receptors on pancreatic neuro-endocrine tumours
Positron emission
1 8F-f 1 uorodeoxygl ucose (FDG)
Staging high-grade cancers
tomography (PET)
68Gallium-labelled somatostatin analogue
More sensitive and specific than SRS for staging neuro-endocrine tumours
Presenting problems in gastrointestinal disease • 779
Fig. 21.16 Investigation of dysphagia.
Dyspepsia
Dyspepsia describes symptoms such as discomfort, bloating
and nausea, which are thought to originate from the upper
gastrointestinal tract. There are many causes (Box 21.14),
including some arising outside the digestive system. Heartburn and
other ‘reflux’ symptoms are separate entities and are considered
elsewhere. Although symptoms often correlate poorly with the
underlying diagnosis, a careful history is important to detect
i
Upper gastrointestinal disorders
• Peptic ulcer disease
• Acute gastritis
• Gallstones
• Oesophageal spasm
• Non-ulcer dyspepsia
• Irritable bowel syndrome
Other gastrointestinal disorders
• Pancreatic disease (cancer,
• Hepatic disease (hepatitis,
chronic pancreatitis)
metastases)
• Colonic carcinoma
Systemic disease
• Renal failure
• Hypercalcaemia
Drugs
• Non-steroidal anti¬
• Iron and potassium
inflammatory drugs (NSAIDs)
supplements
• Glucocorticoids
• Digoxin
Others
• Psychological (anxiety,
• Alcohol
depression)
i
• Weight loss • Haematemesis and/or melaena
• Anaemia • Dysphagia
• Vomiting • Palpable abdominal mass
‘alarm’ features requiring urgent investigation (Box 21.15) and
to detect atypical symptoms that might be due to problems
outside the gastrointestinal tract.
Dyspepsia affects up to 80% of the population at some time
in life and most patients have no serious underlying disease.
People who present with new dyspepsia at an age of more
than 55 years and younger patients unresponsive to empirical
treatment require investigation to exclude serious disease.
An algorithm for the investigation of dyspepsia is outlined in
Figure 21.17.
Heartburn and regurgitation
Heartburn describes retrosternal, burning discomfort, often rising
up into the chest and sometimes accompanied by regurgitation
of acidic or bitter fluid into the throat. These symptoms often
occur after meals, on lying down or with bending, straining or
heavy lifting. They are classical symptoms of gastro-oesophageal
reflux but up to 50% of patients present with other symptoms,
such as chest pain, belching, halitosis, chronic cough or sore
throats. In young patients with typical symptoms and a good
response to dietary changes, antacids or acid suppression
investigation is not required, but in patients over 55 years of
age and those with alarm symptoms or atypical features urgent
endoscopy is necessary.
21.14 Causes of dyspepsia
21.15 Alarm features in dyspepsia
780 • GASTROENTEROLOGY
Positive Negative
\ i
Helicobacter pylori Treat
eradication symptomatically
or
consider other
diagnoses
Symptoms Symptoms
resolve persist
follow-up Endoscopy
Fig. 21.17 Investigation of dyspepsia.
Vomiting
Vomiting is a complex reflex involving both autonomic and somatic
neural pathways. Synchronous contraction of the diaphragm,
intercostal muscles and abdominal muscles raises intra-abdominal
pressure and, combined with relaxation of the lower oesophageal
sphincter, results in forcible ejection of gastric contents. It is
important to distinguish true vomiting from regurgitation and
to elicit whether the vomiting is acute or chronic (recurrent), as
the underlying causes may differ. The major causes are shown
in Figure 21 .18.
Gastrointestinal bleeding
Acute upper gastrointestinal haemorrhage
This is the most common gastrointestinal emergency, accounting
for 50-1 70 admissions to hospital per 1 00 000 of the population
each year in the UK. The mortality of patients admitted to hospital
is about 1 0% but there is some evidence that outcome is better
when individuals are treated in specialised units. Risk scoring
systems have been developed to stratify the risk of needing
endoscopic therapy or of having a poor outcome (Box 21 .16).
The advantage of the Blatchford score is that it may be used
before endoscopy to predict the need for intervention to treat
bleeding. Low scores (2 or less) are associated with a very low
risk of adverse outcome. The common causes are shown in
Figure 21 .19.
Clinical assessment
Haematemesis is red with clots when bleeding is rapid and
profuse, or black (‘coffee grounds’) when less severe. Syncope
may occur and is caused by hypotension from intravascular
volume depletion. Symptoms of anaemia suggest chronic
bleeding. Melaena is the passage of black, tarry stools
containing altered blood; it is usually caused by bleeding from
the upper gastrointestinal tract, although haemorrhage from
the right side of the colon is occasionally responsible. The
characteristic colour and smell are the result of the action of
digestive enzymes and of bacteria on haemoglobin. Severe acute
upper gastrointestinal bleeding can sometimes cause maroon or
bright red stool.
Drugs
• NSAIDs
• Opiates
• Digoxin
• Antibiotics
• Cytotoxins
Infections
• Hepatitis
• Gastroenteritis
• Urinary tract infection
Metabolic
• Diabetic ketoacidosis
• Addison’s disease
Psychogenic
Central nervous system disorders
• Vestibular neuronitis
• Migraine
• Raised intracranial pressure
• Meningitis
Gastroduodenal
• Peptic ulcer disease
• Gastric cancer
• Gastroparesis
Uraemia
The acute abdomen
• Appendicitis
• Cholecystitis
• Pancreatitis
• Intestinal obstruction
Fig. 21.18 Causes of vomiting. (NSAIDs = non-steroidal anti-inflammatory drugs)
Presenting problems in gastrointestinal disease • 781
Management
The principles of emergency management of non-variceal bleeding
are discussed in detail below. Management of variceal bleeding
is discussed on page 869.
21.16 Modified Blatchford score: risk stratification in
acute upper gastrointestinal bleeding
Score component
Admission risk marker value
Blood urea
>25 mmol/L (70 mg/dL)
10-25 mmol/L (28-70 mg/dL)
8-10 mmol/L (21.4-28 mg/dL)
6.5-8 mmol/L (18.2-22.4 mg/dL)
<6.5 mmol/L (18.2 mg/dL)
Haemoglobin for men
<100 g/L (lOg/dL)
100-11 9 g/L (10-11.9 g/dL)
120-129 g/L (12-12.9 g/dL)
>130 g/L (13 g/dL)
Haemoglobin for women
<100 g/L (10 g/dL)
100-1 19 g/L (10-11.9 g/dL)
>120 g/L (12 g/dL)
Systolic blood pressure
<90 mmHg
90-99 mmHg
100-109 mmHg
>109 mmHg
Other markers
Presentation with syncope
Hepatic disease
Cardiac failure
Pulse >100 beats/min
Presentation with melaena
None of the above
1 . Intravenous access
The first step is to gain intravenous access using at least one
large-bore cannula.
2. Initial clinical assessment
• Define circulatory status. Severe bleeding causes
tachycardia, hypotension and oliguria. The patient is cold
and sweating, and may be agitated.
• Seek evidence of liver disease (p. 846). Jaundice,
cutaneous stigmata, hepatosplenomegaly and ascites may
be present in decompensated cirrhosis.
• Identify comorbidity. The presence of cardiorespiratory,
cerebrovascular or renal disease is important, both because
these may be worsened by acute bleeding and because they
increase the hazards of endoscopy and surgical operations.
These factors can be combined using the Blatchford score
(Box 21 .16), which can be calculated at the bedside. A score of
2 or less is associated with a good prognosis, while progressively
higher scores are associated with poorer outcomes.
3. Basic investigations
• Full blood count. Chronic or subacute bleeding leads to
anaemia but the haemoglobin concentration may be
normal after sudden, major bleeding until haemodilution
occurs. Thrombocytopenia may be a clue to the presence
of hypersplenism in chronic liver disease.
• Urea and electrolytes. This test may show evidence of
renal failure. The blood urea rises as the absorbed
products of luminal blood are metabolised by the liver; an
elevated blood urea with normal creatinine concentration
implies severe bleeding.
• Liver function tests. These may show evidence of chronic
liver disease.
• Prothrombin time. Check when there is a clinical
suggestion of liver disease or patients are anticoagulated.
• Cross-matching. At least 2 units of blood should be
cross-matched if a significant bleed is suspected.
Fig. 21.19 Causes of acute upper gastrointestinal haemorrhage. Frequency is given in parentheses. (NSAIDs = non-steroidal anti-inflammatory drugs)
782 • GASTROENTEROLOGY
4. Resuscitation
Intravenous crystalloid fluids should be given to raise the blood
pressure, and blood should be transfused when the patient
is actively bleeding with low blood pressure and tachycardia.
Comorbidities should be managed as appropriate. Patients with
suspected chronic liver disease should receive broad-spectrum
antibiotics.
5. Oxygen
This should be given to all patients in shock.
6. Endoscopy
This should be carried out after adequate resuscitation, ideally
within 24 hours, and will yield a diagnosis in 80% of cases.
Patients who are found to have major endoscopic stigmata of
recent haemorrhage (Fig. 21 .20) can be treated endoscopically
using a thermal or mechanical modality, such as a ‘heater probe’
or endoscopic clips, combined with injection of dilute adrenaline
(epinephrine) into the bleeding point (‘dual therapy’). A biologically
inert haemostatic mineral powder (TC325, ‘haemospray’) can be
used as rescue therapy when standard therapy fails. This may
stop active bleeding and, combined with intravenous proton
pump inhibitor (PPI) therapy, may prevent rebleeding, thus
avoiding the need for surgery. Patients found to have bled from
varices should be treated by band ligation (p. 870); if this fails,
balloon tamponade is another option, while arrangements are
made for a transjugular intrahepatic portosystemic shunt (TIPSS).
7. Monitoring
Patients should be closely observed, with hourly measurements
of pulse, blood pressure and urine output.
8. Surgery
Surgery is indicated when endoscopic haemostasis fails to
stop active bleeding and if rebleeding occurs on one occasion
in an elderly or frail patient, or twice in a younger, fitter patient.
If available, angiographic embolisation is an effective alternative
to surgery in frail patients.
The choice of operation depends on the site and diagnosis of
the bleeding lesion. Duodenal ulcers are treated by under-running,
with or without pyloroplasty. Under-running for gastric ulcers
can also be carried out (a biopsy must be taken to exclude
carcinoma). Local excision may be performed, but when neither
is possible, partial gastrectomy is required.
9. Eradication
Following treatment for ulcer bleeding, all patients should avoid
non-steroidal anti-inflammatory drugs (NSAIDs) and those who
test positive for H. pylori infection should receive eradication
therapy (p. 800). Successful eradication should be confirmed
by urea breath or faecal antigen testing.
|Lower gastrointestinal bleeding
This may be caused by haemorrhage from the colon, anal canal
or small bowel. It is useful to distinguish those patients who
present with profuse, acute bleeding from those who present
with chronic or subacute bleeding of lesser severity (Box 21.17).
Severe acute lower gastrointestinal bleeding
This presents with profuse red or maroon diarrhoea and with
shock. Diverticular disease is the most common cause and is often
due to erosion of an artery within the mouth of a diverticulum.
Bleeding almost always stops spontaneously, but if it does not, the
diseased segment of colon should be resected after confirmation
of the site by angiography or colonoscopy. Angiodysplasia is a
disease of the elderly, in which vascular malformations develop in
the proximal colon. Bleeding can be acute and profuse; it usually
21.17 Causes of lower gastrointestinal bleeding
Severe acute
• Diverticular disease
• Meckel’s diverticulum
• Angiodysplasia
• Inflammatory bowel disease
• Ischaemia
(rarely)
Moderate, chronic/subacute
• Fissure
• Large polyps
• Haemorrhoids
• Angiodysplasia
• Inflammatory bowel disease
• Radiation enteritis
• Carcinoma
• Solitary rectal ulcer
Fig. 21.20 Major stigmata of recent haemorrhage and endoscopic treatment. [A] Active bleeding from a duodenal ulcer. [§] Haemostasis is
achieved after endoscopic injection of adrenaline (epinephrine) and application of a heater probe.
Presenting problems in gastrointestinal disease • 783
stops spontaneously but commonly recurs. Diagnosis is often
difficult. Colonoscopy may reveal characteristic vascular spots and,
in the acute phase, visceral angiography can show bleeding into
the intestinal lumen and an abnormal large, draining vein. In some
patients, diagnosis is achieved only by laparotomy with on-table
colonoscopy. The treatment of choice is endoscopic thermal
ablation but resection of the affected bowel may be required if
bleeding continues. Bowel ischaemia due to occlusion of the
inferior mesenteric artery can present with abdominal colic and
rectal bleeding. It should be considered in patients (particularly
the elderly) who have evidence of generalised atherosclerosis.
The diagnosis is made at colonoscopy. Resection is required only
in the presence of peritonitis. Meckel’s diverticulum with ectopic
gastric epithelium may ulcerate and erode into a major artery. The
diagnosis should be considered in children or adolescents who
present with profuse or recurrent lower gastrointestinal bleeding.
A Meckel’s 99mTc-pertechnetate scan is sometimes positive but
the diagnosis is commonly made only by laparotomy, at which
time the diverticulum is excised.
Subacute or chronic lower gastrointestinal bleeding
This can occur at all ages and is usually due to haemorrhoids
or anal fissure. Haemorrhoidal bleeding is bright red and occurs
during or after defecation. Proctoscopy can be used to make
the diagnosis, but subjects who have altered bowel habit and
those who present over the age of 40 years should undergo
colonoscopy to exclude coexisting colorectal cancer. Anal fissure
should be suspected when fresh rectal bleeding and anal pain
occur during defecation.
I Major gastrointestinal bleeding of
unknown cause
In some patients who present with major gastrointestinal bleeding,
upper endoscopy and colonoscopy fail to reveal a diagnosis. When
severe life-threatening bleeding continues, urgent CT mesenteric
angiography is indicated. This will usually identify the site if the
bleeding rate exceeds 1 mLTmin and then formal angiographic
embolisation can often stop the bleeding. If angiography is
negative or bleeding is less severe, push or double balloon
enteroscopy can visualise the small intestine (Fig. 21.21) and
treat the bleeding source. Wireless capsule endoscopy is often
Fig. 21.21 Jejunal angiodysplastic lesion seen at enteroscopy in a
patient with recurrent obscure bleeding.
used to define a source of bleeding prior to enteroscopy. When
all else fails, laparotomy with on-table endoscopy is indicated.
Chronic occult gastrointestinal bleeding
In this context, occult means that blood or its breakdown products
are present in the stool but cannot be seen by the naked eye.
Occult bleeding may reach 200 ml_ per day and cause iron
deficiency anaemia. Any cause of gastrointestinal bleeding may be
responsible but the most important is colorectal cancer, particularly
carcinoma of the caecum, which may produce no gastrointestinal
symptoms. In clinical practice, investigation of the upper and
lower gastrointestinal tract should be considered whenever
a patient presents with unexplained iron deficiency anaemia.
Testing the stool for the presence of blood is unnecessary and
should not influence whether or not the gastrointestinal tract
is imaged because bleeding from tumours is often intermittent
and a negative faecal occult blood (FOB) test does not exclude
the diagnosis. The only value of FOB testing is as a means of
population screening for colonic neoplasia in asymptomatic
individuals (p. 832).
Diarrhoea
Diarrhoea is defined as the passage of more than 200 g of stool
daily and measurement of stool volume is helpful in confirming
this. The most severe symptom in many patients is urgency of
defecation, and faecal incontinence is a common event in acute
and chronic diarrhoeal illnesses.
Acute diarrhoea
This is extremely common and is usually caused by faecal-oral
transmission of bacteria or their toxins, viruses or parasites
(Ch. 11). Infective diarrhoea is usually short-lived and patients who
present with a history of diarrhoea lasting more than 1 0 days rarely
have an infective cause. A variety of drugs, including antibiotics,
cytotoxic drugs, PPIs and NSAIDs, may be responsible.
| Chronic or relapsing diarrhoea
The most common cause is irritable bowel syndrome (p. 824),
which can present with increased frequency of defecation and
loose, watery or pellety stools. Diarrhoea rarely occurs at night
and is most severe before and after breakfast. At other times,
the patient is constipated and there are other characteristic
symptoms of irritable bowel syndrome. The stool often contains
mucus but never blood, and 24-hour stool volume is less than
200 g. Chronic diarrhoea can be categorised as being caused
by disease of the colon or small bowel, or to malabsorption (Box
21.18). Clinical presentation, examination of the stool, routine
blood tests and imaging reveal a diagnosis in many cases. A
series of negative investigations usually implies irritable bowel
syndrome but some patients clearly have organic disease and
need more extensive investigations.
Malabsorption
Diarrhoea and weight loss in patients with a normal diet are likely
to be caused by malabsorption. The symptoms are diverse in
nature and variable in severity. A few patients have apparently
normal bowel habit but diarrhoea is usual and may be watery
and voluminous. Bulky, pale and offensive stools that float in
the toilet (steatorrhoea) signify fat malabsorption. Abdominal
784 • GASTROENTEROLOGY
mm
21 .18 Chronic or relapsing diarrhoea
Colonic
Malabsorption
Small bowel
Clinical features
Blood and mucus in stool
Cramping lower abdominal pain
Steatorrhoea
Undigested food in the stool
Weight loss and nutritional disturbances
Large-volume, watery stool
Abdominal bloating
Cramping mid-abdominal pain
Some causes
Inflammatory bowel disease
Microscopic colitis
Neoplasia
Ischaemia
Irritable bowel syndrome
Pancreatic:
Chronic pancreatitis
Cancer of pancreas
Cystic fibrosis
Enteropathy:
Coeliac disease
Tropical sprue
Lymphoma
Lymphangiectasia
Crohn’s disease
VIPoma
Drug-induced:
NSAIDs
Aminosalicylates
SSRIs
Investigations
Faecal calprotectin
lleocolonoscopy with biopsies
Faecal elastase
Ultrasound, CT and MRCP
Small-bowel biopsy
Barium follow-through or small-bowel MRI
Faecal calprotectin
Stool volume
Gut hormone profile
Barium follow-through or small-bowel MRI
(CT = computed tomography; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging; NSAIDs = non-steroidal anti-inflammatory drugs;
SSRIs = selective serotonin re-uptake inhibitors; VIP = vasoactive intestinal polypeptide)
Night blindness
(vitamin A)
Anaemia
(iron, folate, B12)
Angular stomatitis, glossitis
(iron, folate, B12)
Bleeding gums
(vitamin C)
Follicular
hyperkeratosis
(vitamin A)
Acrodermatitis enteropathica
(zinc)
Koilonychia
(iron)
Paraesthesia, tetany
(calcium, magnesium)
Clubbing
Osteomalacia, rickets
(calcium, vitamin D)
Muscle wasting (protein)
Proximal myopathy
(vitamin D)
Peripheral neuropathy
(Bid
Peripheral oedema
(hypoalbuminaemia)
Fig. 21.22 Possible physical consequences of malabsorption.
distension, borborygmi, cramps, weight loss and undigested
food in the stool may be present. Some patients complain
only of malaise and lethargy. In others, symptoms related to
deficiencies of specific vitamins, trace elements and minerals
may occur (Fig. 21 .22).
Pathophysiology
Malabsorption results from abnormalities of the three processes
that are essential to normal digestion:
• Intraluminal maldigestion occurs when deficiency of bile or
pancreatic enzymes results in inadequate solubilisation
Presenting problems in gastrointestinal disease • 785
and hydrolysis of nutrients. Fat and protein malabsorption
results. This may also occur with small bowel bacterial
overgrowth.
• Mucosal malabsorption results from small bowel resection
or conditions that damage the small intestinal epithelium,
thereby diminishing the surface area for absorption and
depleting brush border enzyme activity.
• ‘Post-mucosal’ lymphatic obstruction prevents the uptake
and transport of absorbed lipids into lymphatic vessels.
Increased pressure in these vessels results in leakage into
the intestinal lumen, leading to protein-losing enteropathy.
Investigations
Investigations should be performed both to confirm the
presence of malabsorption and to determine the underlying
21.19 Routine blood test abnormalities
in malabsorption
Haematology
• Microcytic anaemia (iron deficiency)
• Macrocytic anaemia (folate or B12 deficiency)
• Increased prothrombin time (vitamin K deficiency)
Biochemistry
• Hypoalbuminaemia
• Hypocalcaemia
• Hypomagnesaemia
• Hypophosphataemia
• Low serum zinc
Fig. 21.23 Investigation for suspected malabsorption. (CT = computed
tomography; MRCP = magnetic resonance cholangiopancreatography; MRI
= magnetic resonance imaging; 75SeHCAT = 75Se-homocholic acid taurine)
cause. Routine blood tests may show one or more of the
abnormalities listed in Box 21 .19. Tests to confirm fat and protein
malabsorption should be performed, as described on page 777.
An approach to the investigation of malabsorption is shown
in Figure 21.23.
Weight loss
Weight loss may be physiological, due to dieting, exercise,
starvation, or the decreased nutritional intake that accompanies
old age. Weight loss of more than 3 kg over 6 months is
significant and often indicates the presence of an underlying
disease. Hospital and general practice weight records may be
valuable in confirming that weight loss has occurred, as may
reweighing patients at intervals; sometimes weight is regained
or stabilises in those with no obvious cause. Pathological
weight loss can be due to psychiatric illness, systemic disease,
gastrointestinal causes or advanced disease of many organ
systems (Fig. 21 .24).
Physiological causes
Weight loss can occur in the absence of serious disease in
healthy individuals who have changes in physical activity or social
circumstances. It may be difficult to be sure of this diagnosis in
older patients, when the dietary history may be unreliable, and
professional help from a dietitian is often valuable under these
circumstances.
Psychiatric illness
Features of anorexia nervosa (p. 1203), bulimia (p. 1204) and
affective disorders (p. 1 1 98) may be apparent only after formal
psychiatric input. Alcoholic patients lose weight as a consequence
of self-neglect and poor dietary intake. Depression may cause
weight loss.
Systemic disease
Chronic infections, including tuberculosis (p. 588), recurrent
urinary or chest infections, and a range of parasitic and protozoan
infections (Ch. 11), should be considered. A history of foreign
travel, high-risk activities and specific features, such as fever,
night sweats, rigors, productive cough and dysuria, must be
sought. Promiscuous sexual activity and drug misuse suggest
HIV-related illness (Ch. 12). Weight loss is a late feature of
disseminated malignancy, but by the time the patient presents,
other features of cancer are often present. Chronic inflammatory
diseases, such as rheumatoid arthritis (p. 1021) and polymyalgia
rheumatica (p. 1042), are often associated with weight loss.
Gastrointestinal disease
Almost any disease of the gastrointestinal tract can cause weight
loss. Dysphagia and gastric outflow obstruction (pp. 778 and
801) cause weight loss by reducing food intake. Malignancy
at any site may cause weight loss by mechanical obstruction,
anorexia or cytokine-mediated systemic effects. Malabsorption
from pancreatic diseases (p. 837) or small bowel causes may
lead to profound weight loss with specific nutritional deficiencies
(p. 704). Inflammatory diseases, such as Crohn’s disease or
ulcerative colitis (p. 813), cause anorexia, fear of eating and loss
of protein, blood and nutrients from the gut.
Metabolic disorders and miscellaneous causes
Weight loss may occur in association with metabolic disorders,
as well as end-stage respiratory and cardiac disease.
786 • GASTROENTEROLOGY
Psychosocial
Deprivation, starvation
Eating disorders
Depression, bipolar illness
Bereavement
Chronic pain/sleep
deprivation
Alcoholism
Respiratory
Chronic obstructive pulmonary disease
Pulmonary tuberculosis
Occult malignancy (especially
small-cell carcinoma)
Empyema
Gastrointestinal
Poor dentition
Any cause of oral pain,
dysphagia
Malabsorption
Malignancy at any site
Inflammatory bowel disease
Chronic infection
Cirrhosis
Chronic infection
HIV/AIDS
Tuberculosis
Brucellosis
Gut infestations
Neurodegenerative
Parkinsonism
Dementia
Motor neuron disease
Endocrine
Type 1 diabetes
Thyrotoxicosis
Addison’s disease
Cardiac
Congestive cardiac failure
Infective endocarditis
Renal
Occult malignancy
Chronic renal failure
Salt-losing
nephropathy
Rheumatological
Rheumatoid arthritis
Mixed connective tissue disease
Systemic sclerosis
Systemic lupus erythematosus
Fig. 21.24 Some important causes of weight loss.
Investigations
In cases where the cause of weight loss is not obvious after
thorough history taking and physical examination, or where an
existing condition is considered unlikely, the following investigations
are indicated: urinalysis for glucose, protein and blood; blood tests,
including liver function tests, random blood glucose and thyroid
function tests; CRP and ESR (may be raised in unsuspected
infections, such as tuberculosis, connective tissue disorders
and malignancy); and faecal calprotectin. Sometimes invasive
tests, such as bone marrow aspiration or liver biopsy, may be
necessary to identify conditions like cryptic miliary tuberculosis
(p. 588). Rarely, abdominal and pelvic imaging by CT may
be required, but before embarking on invasive or very costly
investigations it is always worth revisiting the patient’s history
and reweighing at intervals.
Constipation
Constipation is defined as infrequent passage of hard stools.
Patients may also complain of straining, a sensation of incomplete
evacuation and either perianal or abdominal discomfort.
Constipation may occur in many gastrointestinal and other
medical disorders (Box 21 .20).
Clinical assessment and management
The onset, duration and characteristics are important; for example,
a neonatal onset suggests Hirschsprung’s disease, while a recent
change in bowel activity in middle age should raise the suspicion of
an organic disorder, such as colonic carcinoma. The presence of
rectal bleeding, pain and weight loss is important, as are excessive
21.20 Causes of constipation
Gastrointestinal causes
Dietary
• Lack of fibre and/or fluid intake
Motility
• Slow-transit constipation
• Chronic intestinal
• Irritable bowel syndrome
pseudo-obstruction
• Drugs (see below)
Structural
• Colonic carcinoma
• Hirschsprung’s disease
• Diverticular disease
Defecation
• Anorectal disease (Crohn’s,
• Obstructed defecation
fissures, haemorrhoids)
Non-gastrointestinal causes
Drugs
• Opiates
• Iron supplements
• Anticholinergics
• Aluminium-containing antacids
• Calcium antagonists
Neurological
• Multiple sclerosis
• Cerebrovascular accidents
• Spinal cord lesions
• Parkinsonism
Metabolic/endocrine
• Diabetes mellitus
• Hypothyroidism
• Hypercalcaemia
• Pregnancy
Others
• Any serious illness with
• Depression
immobility, especially in the
elderly
Presenting problems in gastrointestinal disease • 787
straining, symptoms suggestive of irritable bowel syndrome, a
history of childhood constipation and emotional distress.
Careful examination contributes more to the diagnosis than
extensive investigation. A search should be made for general
medical disorders, as well as signs of intestinal obstruction.
Neurological disorders, especially spinal cord lesions, should be
sought. Perineal inspection and rectal examination are essential
and may reveal abnormalities of the pelvic floor (abnormal
descent, impaired sensation), anal canal or rectum (masses,
faecal impaction, prolapse).
It is neither possible nor appropriate to investigate every
person with constipation. Most respond to increased fluid intake,
dietary fibre supplementation, exercise and the judicious use of
laxatives. Middle-aged or elderly patients with a short history or
worrying symptoms (rectal bleeding, pain or weight loss) must be
investigated promptly, by either barium enema or colonoscopy.
For those with simple constipation, investigation will usually
proceed along the lines described below.
Initial visit
Digital rectal examination, proctoscopy and sigmoidoscopy (to
detect anorectal disease), routine biochemistry, including serum
calcium and thyroid function tests, and a full blood count should
be carried out. If these are normal, a 1 -month trial of dietary
fibre and/or laxatives is justified.
Next visit
If symptoms persist, then examination of the colon by barium enema
or CT colonography is indicated to look for structural disease.
Further investigation
If no cause is found and disabling symptoms are present, then
specialist referral for investigation of possible dysmotility may
be necessary. The problem may be one of infrequent desire to
defecate (‘slow transit’) or else may result from neuromuscular
incoordination and excessive straining (‘functional obstructive
defecation’, p. 803). Intestinal marker studies, anorectal
manometry, electrophysiological studies and magnetic resonance
proctography can all be used to define the problem.
Abdominal pain
There are four types of abdominal pain:
• Visceral. Gut organs are insensitive to stimuli such as
burning and cutting but are sensitive to distension,
contraction, twisting and stretching. Pain from unpaired
structures is usually, but not always, felt in the midline.
• Parietal. The parietal peritoneum is innervated by somatic
nerves and its involvement by inflammation, infection or
neoplasia causes sharp, well-localised and lateralised pain.
• Referred pain. Gallbladder pain, for example, may be
referred to the back or shoulder tip.
• Psychogenic. Cultural, emotional and psychosocial factors
influence everyone’s experience of pain. In some patients,
no organic cause can be found despite investigation, and
psychogenic causes (depression or somatisation disorder)
may be responsible (pp. 1198 and 1202).
| The acute abdomen
This accounts for approximately 50% of all urgent admissions
to general surgical units. The acute abdomen is a consequence
of one or more pathological processes (Box 21 .21):
• Inflammation. Pain develops gradually, usually over several
hours. It is initially rather diffuse until the parietal
21 .21 Causes of acute abdominal pain
Inflammation
• Appendicitis • Pancreatitis
• Diverticulitis • Pyelonephritis
• Cholecystitis • Intra-abdominal abscess
• Pelvic inflammatory disease
Perforation/rupture
• Peptic ulcer
• Ovarian cyst
• Diverticular disease
• Aortic aneurysm
Obstruction
• Intestinal obstruction
• Biliary colic
• Ureteric colic
Other (rare)
• See Box 21 .23
peritoneum is involved, when it becomes localised.
Movement exacerbates the pain; abdominal rigidity and
guarding occur.
• Perforation. When a viscus perforates, pain starts abruptly;
it is severe and leads to generalised peritonitis.
• Obstruction. Pain is colicky, with spasms that cause the
patient to writhe around and double up. Colicky pain
that does not disappear between spasms suggests
complicating inflammation.
Initial clinical assessment
If there are signs of peritonitis (guarding and rebound tenderness
with rigidity), the patient should be resuscitated with oxygen,
intravenous fluids and antibiotics. In other circumstances, further
investigations are required (Fig. 21.25).
Investigations
Patients should have a full blood count, urea and electrolytes,
glucose and amylase taken to look for evidence of dehydration,
leucocytosis and pancreatitis. Urinalysis is useful in suspected
renal colic and pyelonephritis. An erect chest X-ray may show
air under the diaphragm, suggestive of perforation, and a plain
abdominal film may show evidence of obstruction or ileus (see
Fig. 21.11). An abdominal ultrasound may help if gallstones
or renal stones are suspected. Ultrasonography is also useful
in the detection of free fluid and any possible intra-abdominal
abscess. Contrast studies, by either mouth or anus, are useful
in the further evaluation of intestinal obstruction, and essential
in the differentiation of pseudo-obstruction from mechanical
large-bowel obstruction. Other investigations commonly used
include CT (seeking evidence of pancreatitis, retroperitoneal
collections or masses, including an aortic aneurysm or renal
calculi) and angiography (mesenteric ischaemia).
Diagnostic laparotomy should be considered when the
diagnosis has not been revealed by other investigations. All
patients must be carefully and regularly re-assessed (every
2-4 hours) so that any change in condition that might alter both
the suspected diagnosis and clinical decision can be observed
and acted on early.
Management
The general approach is to close perforations, treat inflammatory
conditions with antibiotics or resection, and relieve obstructions.
The speed of intervention and the necessity for surgery depend
on the organ that is involved and on a number of other factors,
788 • GASTROENTEROLOGY
I
Symptoms and signs
of peritonitis
Pain
i
No clear evidence
of peritonitis
Blood tests
T Amylase/lipase
No diagnosis
Erect
chest X-ray
No free air
J
Free air
Ultrasound
No abnormality
r
and thickened
gallbladder wall
Contrast
radiology
No abnormality
CT scan
Abnormality
detected
No abnormality
I
Abnormality
detected
Symptoms
Laparotomy
Inconclusive
investigations
settle
Observe
Symptoms persist
Laparoscopy
Fig. 21.25 Management of acute abdominal pain: an algorithm.
Acute
pancreatitis
Perforation
Resuscitation
Abdominal
X-ray
Dilated loops
of bowel
Intestinal
obstruction/ileus
No abnormality
Gallstones
Cholecystitis
Perforation
Pseudo-obstruction
Pancreatitis
Abscess
Aortic aneurysm
Malignancy
• Presentation: severity and localisation may blunt with age.
Presentation may be atypical, e.g. with delirium, collapse and/or
immobility.
• Cancer: a more common cause of acute pain in those over
70 years of age than in those under 50 years. Older people with
vague abdominal symptoms should therefore be carefully assessed.
• Non-specific symptoms: intra-abdominal inflammatory conditions,
such as diverticulitis, may present with non-specific symptoms,
such as delirium or anorexia and relatively little abdominal
tenderness. The reasons for this are not clear but may stem from
altered sensory perception.
• Outcome of abdominal surgery: determined by how frail the
patient is and whether surgery is elective or emergency, rather than
by chronological age.
of which the presence or absence of peritonitis is the most
important. A treatment summary of some of the more common
surgical conditions follows.
Acute appendicitis
This should be treated by early surgery, since there is a
risk of perforation and recurrent attacks with non-operative
treatment. The appendix can be removed through a conven¬
tional right iliac fossa skin crease incision or by laparoscopic
techniques.
Acute cholecystitis
This can be successfully treated non-operatively but the high
risk of recurrent attacks and the low morbidity of surgery have
made early laparoscopic cholecystectomy the treatment of
choice.
Acute diverticulitis
Conservative therapy is standard but if perforation has occurred,
resection is advisable. Depending on peritoneal contamination
and the state of the patient, primary anastomosis is preferable
to a Hartmann’s procedure (oversew of rectal stump and
end-colostomy).
Small bowel obstruction
If the cause is obvious and surgery inevitable (such as with a
strangulated hernia), an early operation is appropriate. If the
suspected cause is adhesions from previous surgery, only
those patients who do not resolve within the first 48 hours
or who develop signs of strangulation (colicky pain becoming
constant, peritonitis, tachycardia, fever, leucocytosis) should have
surgery.
21.22 Acute abdominal pain in old age
Presenting problems in gastrointestinal disease • 789
Large bowel obstruction
Pseudo-obstruction should be treated non-operatively. Some
patients benefit from colonoscopic decompression but mechanical
obstruction merits resection, usually with a primary anastomosis.
Differentiation between the two is made by water-soluble contrast
enema.
Perforated peptic ulcer
Surgical closure of the perforation is standard practice but
some patients without generalised peritonitis can be treated
non-operatively once a water-soluble contrast meal has confirmed
spontaneous sealing of the perforation. Adequate and aggressive
resuscitation with intravenous fluids, antibiotics and analgesia is
mandatory before surgery.
For a more detailed discussion of acute abdominal pain, the
reader is referred to the sister volume of this text, Principles and
Practice of Surgery.
Note should be made of the patient’s general demeanour,
mood and emotional state, signs of weight loss, fever, jaundice
or anaemia. If a thorough abdominal and rectal examination is
normal, a careful search should be made for evidence of disease
affecting other structures, particularly the vertebral column, spinal
cord, lungs and cardiovascular system.
Investigations will depend on the clinical features elicited during
the history and examination:
• Endoscopy and ultrasound are indicated for epigastric
pain, and for dyspepsia and symptoms suggestive of
gallbladder disease.
• Colonoscopy is indicated for patients with altered bowel
habit, rectal bleeding or features of obstruction suggesting
colonic disease.
• CT or MR angiography should be considered when pain
is provoked by food in a patient with widespread
atherosclerosis, since this may indicate mesenteric
ischaemia.
• Persistent symptoms require exclusion of colonic or
small bowel disease. However, young patients with pain
relieved by defecation, bloating and alternating bowel
habit are likely to have irritable bowel syndrome (p. 824).
Simple investigations (blood tests, faecal calprotectin
and sigmoidoscopy) are sufficient in the absence of
rectal bleeding, weight loss and abnormal physical
findings.
• Ultrasound, CT and faecal elastase are required for
patients with upper abdominal pain radiating to the
back. A history of alcohol misuse, weight loss and
diarrhoea suggests chronic pancreatitis or pancreatic
cancer.
• Recurrent attacks of pain in the loins radiating to the flanks
with urinary symptoms should prompt investigation for
renal or ureteric stones by abdominal X-ray, ultrasound
and computed tomography of the kidneys, ureters and
bladder (CT KUB).
• A past history of psychiatric disturbance, repeated
negative investigations or vague symptoms that do not fit
any disease or organ pattern suggest a psychological
origin for the pain. Careful review of case notes and
previous investigations, along with open and honest
discussion with the patient, reduces the need for further
cycles of unnecessary and invasive tests. Care must
always be taken, however, not to miss rare pathology,
such as acute intermittent porphyria (p. 378), or atypical
presentations of common diseases.
Ijtonstant abdominal pain
Patients with chronic pain that is constant or nearly always
present usually have features to suggest the underlying
diagnosis. No cause will be found in a minority, despite
thorough investigation, leading to the diagnosis of ‘chronic
functional abdominal pain’. In these patients, there appears
to be abnormal CNS processing of normal visceral afferent
sensory input and psychosocial factors are often operative
(p. 1186); the most important tasks are to provide symptom
control, if not relief, and to minimise the effects of the pain on
social, personal and occupational life. Patients are best managed in
specialised pain clinics where, in addition to psychological support,
appropriate use of drugs, including tricyclic antidepressants,
gabapentin or pregabalin, ketamine and opioids, may be
necessary.
Chronic or recurrent abdominal pain
It is essential to take a detailed history, paying particular attention
to features of the pain and any associated symptoms (Boxes
21.23 and 21.24).
Bl 21 .23 Extra-intestinal causes of chronic or recurrent
abdominal pain
Retroperitoneal
• Aortic aneurysm
• Lymphadenopathy
• Malignancy
• Abscess
Psychogenic
• Depression
• Hypochondriasis
• Anxiety
• Somatisation
Locomotor
• Vertebral compression/fracture
• Abdominal muscle strain
Metabolic/endocrine
• Diabetes mellitus
• Hypercalcaemia
• Acute intermittent porphyria
Drugs/toxins
• Glucocorticoids
• Lead
• Azathioprine
• Alcohol
Haematological
• Sickle-cell disease
• Haemolytic disorders
Neurological
• Spinal cord lesions
• Radiculopathy
• Tabes dorsalis
21 .24 How to assess abdominal pain
• Duration
• Site and radiation
• Severity
• Precipitating and relieving factors (food, drugs, alcohol, posture,
movement, defecation)
• Nature (colicky, constant, sharp or dull, wakes patient at night)
• Pattern (intermittent or continuous)
• Associated features (vomiting, dyspepsia, altered bowel habit)
790 • GASTROENTEROLOGY
Diseases of the mouth and
salivary glands
Aphthous ulceration
Aphthous ulcers are superficial and painful; they occur in any part
of the mouth. Recurrent ulcers afflict up to 30% of the population
and are particularly common in women prior to menstruation.
The cause is unknown, but in severe cases other causes of oral
ulceration must be considered (Box 21 .25). Biopsy is occasionally
necessary for diagnosis.
Management is with topical glucocorticoids (such as
0.1% triamcinolone in Orabase) or choline salicylate (8.7%)
gel. Symptomatic relief is achieved using local anaesthetic
mouthwashes. Rarely, patients with very severe, recurrent
aphthous ulcers may need oral glucocorticoids.
21.25 Causes of oral ulceration
Aphthous
• Idiopathic
• Premenstrual
Infection
• Fungal (candidiasis)
• Bacterial, including syphilis,
• Viral (herpes simplex, HI V)
tuberculosis
Gastrointestinal diseases
• Crohn’s disease
• Coeliac disease
Dermatological conditions
• Lichen planus
• Dermatitis herpetiformis
• Immunobullous disorders
• Erythema multiforme
(p. 1255)
Drugs
• Nicorandil, NSAIDs,
• Stevens-Johnson syndrome
methotrexate, penicillamine,
(pp. 1254 and 1264)
losartan, ACE inhibitors
• Cytotoxic drugs
Systemic diseases
• Systemic lupus erythematosus
• Behget’s disease (p. 1 043)
(p. 1034)
Neoplasia
• Carcinoma
• Kaposi’s sarcoma
• Leukaemia
(ACE = angiotensin-converting enzyme; NSAIDs = non-steroidal anti-inflammatory
drugs)
Oral cancer
Squamous carcinoma of the oral cavity is common worldwide
and the incidence has increased by 25% in the last decade in
the UK. The mortality rate is around 50%, largely as a result of
late diagnosis. Poor diet, alcohol excess and smoking or tobacco
chewing are the traditional risk factors but high-risk, oncogenic
strains of human papillomavirus (HPV-16 and HPV-18) have been
identified as being responsible for much of the recent increase
in incidence, especially in cases affecting the base of tongue,
soft palate and tonsils. In parts of Asia, the disease is common
among people who chew areca nuts wrapped in leaves of the
betel plant (‘betel nuts’).
i
• Solitary ulcer without precipitant, e.g. local trauma
• Solitary white patch (‘leukoplakia’) that fails to wipe off
• Solitary red patch
• Fixed lump
• Lip numbness in absence of trauma or infection
• Trismus (pain/difficulty in opening the mouth)
• Cervical lymphadenopathy
Oral cancer may present in many ways (Box 21 .26) and a
high index of suspicion is required. All possible sources of local
trauma or infection should be treated in patients with suspicious
lesions and they should be reviewed after 2 weeks, with biopsy if
the lesion persists. Small cancers can be resected but extensive
surgery, with neck dissection to remove involved lymph nodes,
may be necessary. Some patients can be treated with radical
radiotherapy alone, and sometimes radiotherapy is also given
after surgery to treat microscopic residual disease. Some tumours
may be amenable to photodynamic therapy (PDT), avoiding the
need for surgery.
Candidiasis
The yeast Candida albicans is a normal mouth commensal but it
may proliferate to cause thrush. This occurs in babies, debilitated
patients, people receiving glucocorticoid or antibiotic therapy,
individuals with diabetes and immunosuppressed patients,
especially those receiving cytotoxic therapy and those with HIV
infection. White patches are seen on the tongue and buccal
mucosa. Odynophagia or dysphagia suggests pharyngeal
and oesophageal candidiasis. A clinical diagnosis is sufficient
to instigate therapy, although brushings or biopsies can be
obtained for mycological examination. Oral thrush is treated
using nystatin or amphotericin suspensions or lozenges.
Resistant cases or immunosuppressed patients may require oral
fluconazole.
| Parotitis
Parotitis is caused by viral or bacterial infection. Mumps causes
a self-limiting acute parotitis (p. 240). Bacterial parotitis usually
occurs as a complication of major surgery. It is a consequence
of dehydration and poor oral hygiene, and can be avoided by
good post-operative care. Patients present with painful parotid
swelling and this can be complicated by abscess formation.
Broad-spectrum antibiotics are required, while surgical drainage
is necessary for abscesses. Other causes of salivary gland
enlargement are listed in Box 21 .27.
21.27 Causes of salivary gland swelling
• Infection:
• Tumours:
Mumps
Benign: pleomorphic
Bacterial (post-operative)
adenoma (95% of cases)
• Calculi
Intermediate:
• Sjogren’s syndrome (p. 1038)
mucoepidermoid tumour
• Sarcoidosis
Malignant: carcinoma
21.26 Symptoms and signs of oral cancer
Diseases of the oesophagus • 791
• Dry mouth: affects around 40% of healthy older people.
• Gustatory and olfactory sensation: declines and chewing power
is diminished.
• Salivation: baseline salivary flow falls but stimulated salivation is
unchanged.
• Root caries and periodontal disease: common partly because
oral hygiene deteriorates with increasing frailty.
• Bacteraemia and sepsis: may complicate Gram-negative
anaerobic infection in the periodontal pockets of the
very frail.
21.28 Oral health in old age
Diseases of the oesophagus
Gastro-oesophageal reflux disease
Gastro-oesophageal reflux resulting in heartburn affects
approximately 30% of the general population.
Pathophysiology
Occasional episodes of gastro-oesophageal reflux are common
in healthy individuals. Reflux is normally followed by oesophageal
peristaltic waves that efficiently clear the gullet, alkaline saliva
neutralises residual acid and symptoms do not occur. Gastro-
oesophageal reflux disease develops when the oesophageal
mucosa is exposed to gastroduodenal contents for prolonged
periods of time, resulting in symptoms and, in a proportion of
cases, oesophagitis. Several factors are known to be involved
in the development of gastro-oesophageal reflux disease and
these are shown in Figure 21 .26.
Abnormalities of the lower oesophageal sphincter
The lower oesophageal sphincter is tonically contracted under
normal circumstances, relaxing only during swallowing (p. 766).
Some patients with gastro-oesophageal reflux disease have
reduced lower oesophageal sphincter tone, permitting reflux when
intra-abdominal pressure rises. In others, basal sphincter tone
is normal but reflux occurs in response to frequent episodes of
inappropriate sphincter relaxation.
Hiatus hernia
Hiatus hernia (Box 21 .29 and Fig. 21 .27) causes reflux because
the pressure gradient is lost between the abdominal and thoracic
cavities, which normally pinches the hiatus. In addition, the oblique
angle between the cardia and oesophagus disappears. Many
patients who have large hiatus hernias develop reflux symptoms
but the relationship between the presence of a hernia and
symptoms is poor. Hiatus hernia is very common in individuals
who have no symptoms, and some symptomatic patients have
only a very small or no hernia. Nevertheless, almost all patients
who develop oesophagitis, Barrett’s oesophagus or peptic
strictures have a hiatus hernia.
Delayed oesophageal clearance
Defective oesophageal peristaltic activity is commonly found in
patients who have oesophagitis. It is a primary abnormality, since
it persists after oesophagitis has been healed by acid-suppressing
drug therapy. Poor oesophageal clearance leads to increased
acid exposure time.
Defective
oesophageal
clearance
Abnormal lower
oesophageal
sphincter
• Reduced tone
• Inappropriate
relaxation
Delayed
gastric
emptying
Increased
It intra-abdominal
pressure
Fig. 21 .26 Factors associated with the development of gastro-
oesophageal reflux disease.
21 .29 Important features of hiatus hernia
• Herniation of the stomach through the diaphragm into the chest
• Occurs in 30% of the population over the age of 50 years
• Often asymptomatic
• Heartburn and regurgitation can occur
• Gastric volvulus may complicate large hernias
Gastric contents
Gastric acid is the most important oesophageal irritant and
there is a close relationship between acid exposure time and
symptoms. Pepsin and bile also contribute to mucosal injury.
Defective gastric emptying
Gastric emptying is delayed in patients with gastro-oesophageal
reflux disease. The reason is unknown.
Increased intra-abdominal pressure
Pregnancy and obesity are established predisposing causes.
Weight loss may improve symptoms.
Dietary and environmental factors
Dietary fat, chocolate, alcohol, tea and coffee relax the lower
oesophageal sphincter and may provoke symptoms. The foods
that trigger symptoms vary widely between affected individuals.
Patient factors
Visceral sensitivity and patient vigilance play a role in determining
symptom severity and consulting behaviour in individual patients.
Clinical features
The major symptoms are heartburn and regurgitation, often
provoked by bending, straining or lying down. ‘Waterbrash’,
which is salivation due to reflex salivary gland stimulation as acid
enters the gullet, is often present. The patient is often overweight.
Some patients are woken at night by choking as refluxed fluid
792 • GASTROENTEROLOGY
Fig. 21.27 Types of hiatus hernia. {K\ Rolling or para-oesophageal. Inset: Barium meal showing a large para-oesophageal hernia with intrathoracic
stomach. [J] Sliding. Inset: Barium meal showing a gastric volvulus (small arrows) complicating a sliding hiatus hernia (large arrow).
irritates the larynx. Others develop odynophagia or dysphagia. A
variety of other features have been described, such as atypical
chest pain that may be severe and can mimic angina; it may
be due to reflux- induced oesophageal spasm. Others include
hoarseness (‘acid laryngitis’), recurrent chest infections, chronic
cough and asthma. The true relationship of these features to
gastro-oesophageal reflux disease remains unclear.
Complications
Oesophagitis
A range of endoscopic findings is recognised, from mild redness
to severe bleeding ulceration with stricture formation, although
appearances may be completely normal (Fig. 21 .28). There is
a poor correlation between symptoms and histological and
endoscopic findings.
Barrett’s oesophagus
Barrett’s oesophagus is a pre-malignant condition, in which the
normal squamous lining of the lower oesophagus is replaced
by columnar mucosa (columnar lined oesophagus; CLO) that
may contain areas of intestinal metaplasia (Fig. 21 .29). It is an
adaptive response to chronic gastro-oesophageal reflux and
is found in 10% of patients undergoing gastroscopy for reflux
symptoms. Community-based epidemiological studies suggest
that the true prevalence may be up to 1 .5-5% of the population,
as the condition is often asymptomatic until discovered when
the patient presents with oesophageal cancer. The relative
risk of oesophageal cancer is increased 40-120-fold but the
absolute risk is low (0.1 -0.5% per year). The epidemiology
and aetiology of Barrett’s oesophagus are poorly understood.
The prevalence is increasing, and it is more common in men
(especially white), the obese and those over 50 years of age. It is
weakly associated with smoking but not alcohol intake. The risk
of cancer seems to relate to the severity and duration of reflux
rather than the presence of Barrett’s oesophagus per se, and
it has been suggested that duodenogastro-oesophageal reflux
of bile, pancreatic enzymes and pepsin, as well as gastric acid,
Fig. 21.28 Severe reflux oesophagitis. There is near-circumferential
superficial ulceration and inflammation extending up the gullet.
may be important in the pathogenesis. The molecular events
underlying progression of Barrett’s oesophagus to dysplasia
and cancer are incompletely understood but inactivation of the
tumour suppression protein pi 6 by loss of heterozygosity or
promoter hypermethylation is a key event, followed by somatic
inactivation of TP53, which promotes aneuploidy and tumour
progression. Studies are in progress to develop biomarkers that
will allow detection of those at higher cancer risk.
Diagnosis This requires multiple systematic biopsies to maximise
the chance of detecting intestinal metaplasia and/or dysplasia.
Management Neither potent acid suppression nor anti-reflux
surgery stops progression or induces regression of Barrett’s
Diseases of the oesophagus • 793
Fig. 21.29 Barrett’s oesophagus. Tongues of pink columnar mucosa
are seen extending upwards above the oesophago-gastric junction.
oesophagus, and treatment is indicated only for symptoms of
reflux or complications, such as stricture. Endoscopic therapies,
such as radiofrequency ablation or photodynamic therapy, can
induce regression but at present are used only for those with
dysplasia or intramucosal cancer. Regular endoscopic surveillance
can detect dysplasia at an early stage and may improve survival
but, because most Barrett’s oesophagus is undetected until
cancer develops, surveillance strategies are unlikely to influence
the overall mortality rate of oesophageal cancer. Surveillance is
expensive and cost-effectiveness studies have been conflicting. It
is currently recommended that patients with Barrett’s oesophagus
with intestinal metaplasia, but without dysplasia, should undergo
endoscopy at 3-5-yearly intervals if the length of the Barrettic
segment is less than 3 cm and at 2-3-yearly intervals if the
length is greater than 3 cm. Those with low-grade dysplasia
should be endoscoped at 6-monthly intervals.
For those with high-grade dysplasia or intramucosal carcinoma,
the treatment options are either oesophagectomy or endoscopic
therapy, with a combination of endoscopic resection of any visibly
abnormal areas and radiofrequency ablation of the remaining
Barrett’s mucosa, as an ‘organ -preserving’ alternative to surgery.
These cases should be discussed in a multidisciplinary team
meeting and managed in specialist centres.
Anaemia
Iron deficiency anaemia can occur as a consequence of occult
blood loss from long-standing oesophagitis. Most patients have
a large hiatus hernia and bleeding can stem from subtle erosions
in the neck of the sac (‘Cameron lesions’). Nevertheless, hiatus
hernia is very common and other causes of blood loss, particularly
colorectal cancer, must be considered in anaemic patients, even
when endoscopy reveals oesophagitis.
Benign oesophageal stricture
Fibrous strictures can develop as a consequence of long¬
standing oesophagitis, especially in the elderly and those with
poor oesophageal peristaltic activity. The typical presentation
is with dysphagia that is worse for solids than for liquids. Bolus
obstruction following ingestion of meat causes absolute dysphagia.
A history of heartburn is common but not invariable; many elderly
patients presenting with strictures have no preceding heartburn.
Diagnosis is by endoscopy, when biopsies of the stricture can
be taken to exclude malignancy. Endoscopic balloon dilatation
or bouginage is helpful. Subsequently, long-term therapy with
a PPI drug at full dose should be started to reduce the risk
of recurrent oesophagitis and stricture formation. The patient
should be advised to chew food thoroughly and it is important
to ensure adequate dentition.
Gastric volvulus
Occasionally, a massive intrathoracic hiatus hernia may twist on
itself, leading to a gastric volvulus. This gives rise to complete
oesophageal or gastric obstruction and the patient presents
with severe chest pain, vomiting and dysphagia. The diagnosis
is made by chest X-ray (air bubble in the chest) and barium
swallow (see Fig. 21 .27B). Most cases spontaneously resolve but
recurrence is common, and surgery is usually advised after the
acute episode has been treated by nasogastric decompression.
Investigations
Young patients who present with typical symptoms of gastro-
oesophageal reflux, without worrying features such as dysphagia,
weight loss or anaemia, can be treated empirically without
investigation. Investigation is advisable if patients present over the
age of 50-55 years, if symptoms are atypical or if a complication
is suspected. Endoscopy is the investigation of choice. This is
performed to exclude other upper gastrointestinal diseases that
can mimic gastro-oesophageal reflux and to identify complications.
A normal endoscopy in a patient with compatible symptoms
should not preclude treatment for gastro-oesophageal reflux
disease.
Twenty-four-hour pH monitoring is indicated if the diagnosis
is unclear or surgical intervention is under consideration. This
involves tethering a slim catheter with a terminal radiotelemetry
pH-sensitive probe above the gastro-oesophageal junction. The
intraluminal pH is recorded while the patient undergoes normal
activities, and episodes of symptoms are noted and related to
pH. A pH of less than 4 for more than 6-7% of the study time
is diagnostic of reflux disease. In a few patients with difficult
reflux, impedance testing can detect weakly acidic or alkaline
reflux that is not revealed by standard pH testing.
Management
A treatment algorithm for gastro-oesophageal reflux is outlined in
Figure 21 .30. Lifestyle advice should be given, including weight
loss, avoidance of dietary items that the patient finds worsen
symptoms, elevation of the bed head in those who experience
nocturnal symptoms, avoidance of late meals and cessation of
smoking. Patients who fail to respond to these measures should
be offered PPIs, which are usually effective in resolving symptoms
and healing oesophagitis. Recurrence of symptoms is common
when therapy is stopped and some patients require life-long
treatment at the lowest acceptable dose. When dysmotility
features are prominent, domperidone can be helpful. There is
no evidence that H. pylori eradication has any therapeutic value.
Proprietary antacids and alginates can also provide symptomatic
benefit. H2-receptor antagonist drugs relieve symptoms without
healing oesophagitis.
Long-term PPI therapy is associated with reduced absorption
of iron, B12 and magnesium, and a small but increased risk of
osteoporosis and fractures (odds ratio 1 .2-1 .5). The drugs also
predispose to enteric infections with Salmonella, Campylobacter
and possibly Clostridium difficile, and have recently been shown
to have an undesirable impact on the composition of the gut
794 • GASTROENTEROLOGY
Symptoms
Antacids/alginates
Proton pump inhibitor at full dose
Good response Poor response
Fig. 21.30 Treatment of gastro-oesophageal reflux disease: a
‘step-down’ approach.
• Prevalence: higher.
• Severity of symptoms: does not correlate with the degree of
mucosal inflammation.
• Complications: late complications, such as peptic strictures or
bleeding from oesophagitis, are more common.
• Recurrent pneumonia: consider aspiration from occult gastro-
oesophageal reflux disease.
21.30 Gastro-oesophageal reflux disease in old age
microbiota. Long-term therapy increases the risk of Helicobacter-
associated progression of gastric mucosal atrophy (see below)
and H. pylori eradication is advised in patients requiring PPIs
for more than 1 year.
Patients who fail to respond to medical therapy, those who
are unwilling to take long-term PPIs and those whose major
symptom is severe regurgitation should be considered for
laparoscopic anti -reflux surgery (see Principles and Practice of
Surgery). Although heartburn and regurgitation are alleviated in
most patients, a small minority develop complications, such as
inability to vomit and abdominal bloating (‘gas-bloat’ syndrome’).
Other causes of oesophagitis
Infection
Oesophageal candidiasis occurs in debilitated patients and
those taking broad-spectrum antibiotics or cytotoxic drugs. It
is a particular problem in patients with HIV/AIDS, who are also
susceptible to a spectrum of other oesophageal infections (p. 31 6).
Corrosives
Suicide attempt by ingestion of strong household bleach or
battery acid is followed by painful burns of the mouth and pharynx
and by extensive erosive oesophagitis (p. 147). This may be
complicated by oesophageal perforation with mediastinitis and
by stricture formation. At the time of presentation, treatment
is conservative, based on analgesia and nutritional support;
vomiting and endoscopy should be avoided because of the
high risk of oesophageal perforation. After the acute phase, a
barium swallow should be performed to demonstrate the extent
of stricture formation. Endoscopic dilatation is usually necessary
but it is difficult and hazardous because strictures are often long,
tortuous and easily perforated.
Drugs
Potassium supplements and NSAIDs may cause oesophageal
ulcers when the tablets are trapped above an oesophageal
stricture. Liquid preparations of these drugs should be used in
such patients. Bisphosphonates cause oesophageal ulceration and
should be used with caution in patients with known oesophageal
disorders.
Eosinophilic oesophagitis
This is more common in children but increasingly recognised
in young adults. It occurs more often in atopic individuals and
is characterised by eosinophilic infiltration of the oesophageal
mucosa. Patients present with dysphagia or food bolus obstruction
more often than heartburn, and other symptoms, such as chest
pain and vomiting, may be present. Endoscopy is usually normal
but mucosal rings (that sometimes need endoscopic dilatation),
strictures or a narrow-calibre oesophagus can occur. Children
may respond to elimination diets but these are less successful in
adults, who should first be treated with PPIs. The condition can be
treated with 8-12 weeks of therapy with topical glucocorticoids,
such as fluticasone or betamethasone. The usual approach is
to prescribe a metered-dose inhaler but to tell the patient to
spray this into the mouth and swallow it rather than inhale it.
Refractory symptoms sometimes respond to montelukast, a
leukotriene inhibitor.
Motility disorders
| Pharyngeal pouch
This occurs because of incoordination of swallowing within the
pharynx, which leads to herniation through the cricopharyngeus
muscle and formation of a pouch. It is rare, affecting 1 in 100000
people; it usually develops in middle life but can arise at any age.
Many patients have no symptoms but regurgitation, halitosis and
dysphagia can be present. Some notice gurgling in the throat
after swallowing. The investigation of choice is a barium swallow
(see Fig. 21.1 2 A) , which demonstrates the pouch and reveals
incoordination of swallowing, often with pulmonary aspiration.
Endoscopy may be hazardous, since the instrument may enter
and perforate the pouch. Surgical myotomy (‘diverticulotomy’),
with or without resection of the pouch, is indicated in symptomatic
patients.
Achalasia of the oesophagus
Pathophysiology
Achalasia is characterised by:
• a hypertonic lower oesophageal sphincter, which fails to
relax in response to the swallowing wave
• failure of propagated oesophageal contraction, leading to
progressive dilatation of the gullet.
The cause is unknown. Defective release of nitric oxide by
inhibitory neurons in the lower oesophageal sphincter has been
reported, and there is degeneration of ganglion cells within the
Diseases of the oesophagus • 795
sphincter and the body of the oesophagus. Loss of the dorsal
vagal nuclei within the brainstem can be demonstrated in later
stages. Infection with Trypanosoma cruzi in Chagas’ disease
(p. 279) causes a syndrome that is clinically indistinguishable
from achalasia.
Clinical features
The presentation is with dysphagia. This develops slowly, is initially
intermittent, and is worse for solids and eased by drinking liquids
and by standing and moving around after eating. Heartburn
does not occur because the closed oesophageal sphincter
prevents gastro-oesophageal reflux. Some patients experience
episodes of chest pain due to oesophageal spasm. As the
disease progresses, dysphagia worsens, the oesophagus empties
poorly and nocturnal pulmonary aspiration develops. Achalasia
predisposes to squamous carcinoma of the oesophagus.
Investigations
Endoscopy should always be carried out because carcinoma
of the cardia can mimic the presentation and radiological and
manometric features of achalasia (‘pseudo-achalasia’). A barium
swallow shows tapered narrowing of the lower oesophagus and,
in late disease, the oesophageal body is dilated, aperistaltic and
food-filled (Fig. 21 .31 A). Manometry confirms the high-pressure,
non-relaxing lower oesophageal sphincter with poor contractility
of the oesophageal body (Fig. 21 .31 B).
Management
Endoscopic
Forceful pneumatic dilatation using a 30-35-mm-diameter,
fluoroscopically positioned balloon disrupts the oesophageal
sphincter and improves symptoms in 80% of patients. Some
patients require more than one dilatation but those needing
frequent dilatation are best treated surgically. Endoscopically
directed injection of botulinum toxin into the lower oesophageal
sphincter induces clinical remission but relapse is common.
Recently, a complex endoscopic technique has been developed
in specialist centres (peroral endoscopic myotomy, POEM).
Surgical
Surgical myotomy (Heller’s operation), performed either
laparoscopically or as an open operation, is effective but is more
invasive than endoscopic dilatation. Both pneumatic dilatation
and myotomy may be complicated by gastro-oesophageal reflux,
and this can lead to severe oesophagitis because oesophageal
clearance is so poor. For this reason, Heller’s myotomy is
accompanied by a partial fundoplication anti-reflux procedure.
PPI therapy is often necessary after surgery.
Other oesophageal motility disorders
Diffuse oesophageal spasm presents in late middle age with
episodic chest pain that may mimic angina but is sometimes
accompanied by transient dysphagia. Some cases occur in
response to gastro-oesophageal reflux. Treatment is based on
the use of PPI drugs when gastro-oesophageal reflux is present.
Oral or sublingual nitrates or nifedipine may relieve attacks of
pain. The results of drug therapy are often disappointing, as
are the alternatives: pneumatic dilatation and surgical myotomy.
‘Nutcracker’ oesophagus is a condition in which extremely forceful
peristaltic activity leads to episodic chest pain and dysphagia.
Treatment is with nitrates or nifedipine. Some patients present
with oesophageal motility disorders that do not fit into a specific
disease entity. The patients are usually elderly and present with
dysphagia and chest pain. Manometric abnormalities, ranging
from poor peristalsis to spasm, occur. Treatment is with dilatation
and/or vasodilators for chest pain.
| Secondary causes of oesophageal dysmotility
In systemic sclerosis or CREST syndrome (p. 1 037), the muscle of
the oesophagus is replaced by fibrous tissue, which causes failure
of peristalsis leading to heartburn and dysphagia. Oesophagitis
is often severe and benign fibrous strictures occur. These
patients require long-term therapy with PPIs. Dermatomyositis,
rheumatoid arthritis and myasthenia gravis may also cause
dysphagia.
Benign oesophageal stricture
Benign oesophageal stricture is usually a consequence of
gastro-oesophageal reflux disease (Box 21.31) and occurs
most often in elderly patients who have poor oesophageal
clearance. Rings, caused by submucosal fibrosis, are found at the
oesophago-gastric junction (‘Schatzki ring’) and cause intermittent
Fig. 21.31 Achalasia. [A] X-ray showing a dilated, barium-filled oesophagus (0) with fluid level and distal tapering, and a closed lower oesophageal
sphincter (LOS). (D = diaphragm) [§] High-resolution manometry in achalasia showing absence of peristaltic swallowing wave in oesophageal body (black
arrows) and raised LOS pressure with failure of relaxation on swallowing (white arrow). Compare with normal appearances in Figure 21 .1 (p. 766).
796 • GASTROENTEROLOGY
21 .31 Causes of oesophageal stricture
• Gastro-oesophageal reflux disease
• Webs and rings
• Carcinoma of the oesophagus or cardia
• Eosinophilic oesophagitis
• Extrinsic compression from bronchial carcinoma
• Corrosive ingestion
• Post-operative scarring following oesophageal resection
• Post-radiotherapy
• Following long-term nasogastric intubation
• Bisphosphonates
dysphagia, often starting in middle age. A post-cricoid web is
a rare complication of iron deficiency anaemia (Paterson-Kelly
or Plummer-Vinson syndrome), and may be complicated by
the development of squamous carcinoma. Benign strictures
can be treated by endoscopic dilatation, in which wire-guided
bougies or balloons are used to disrupt the fibrous tissue of
the stricture.
Tumours of the oesophagus
Benign tumours
The most common is a leiomyoma. This is usually asymptomatic
but may cause bleeding or dysphagia.
Carcinoma of the oesophagus
Squamous oesophageal cancer (Box 21 .32) is relatively rare in
Caucasians (4:100000) but is more common in Iran, parts of
Africa and China (200:100000). Squamous cancer can occur
in any part of the oesophagus and almost all tumours in the
upper oesophagus are squamous cancers. Adenocarcinomas
typically arise in the lower third of the oesophagus from Barrett’s
oesophagus or from the cardia of the stomach. The incidence is
increasing and is now approximately 5: 100000 in the UK; this is
possibly because of the high prevalence of gastro-oesophageal
reflux and Barrett’s oesophagus in Western populations. Despite
modern treatment, the overall 5-year survival of patients presenting
with oesophageal cancer is only 13%.
Clinical features
Most patients have a history of progressive, painless dysphagia
for solid foods. Others present acutely because of food bolus
obstruction. In the late stages, weight loss is often extreme; chest
pain or hoarseness suggests mediastinal invasion. Fistulation
between the oesophagus and the trachea or bronchial tree leads
to coughing after swallowing, pneumonia and pleural effusion.
Physical signs may be absent but, even at initial presentation,
cachexia, cervical lymphadenopathy or other evidence of
metastatic spread is common.
Investigations
The investigation of choice is upper gastrointestinal endoscopy
(Fig. 21.32) with biopsy. A barium swallow demonstrates the
site and length of the stricture but adds little useful information.
Once a diagnosis has been made, investigations should be
performed to stage the tumour and define operability. Thoracic
and abdominal CT, often combined with positron emission
tomography (PET-CT), should be carried out to identify metastatic
| 21.32 Squamous carcinoma: aetiological factors
• Smoking
• Coeliac disease
• Alcohol excess
• Post-cricoid web
• Chewing betel nuts or
• Post-caustic stricture
tobacco
• Tylosis (familial hyperkeratosis
• Achalasia of the oesophagus
of palms and soles)
Fig. 21.32 Adenocarcinoma of the lower oesophagus. A polypoidal
adenocarcinoma in association with Barrett’s oesophagus.
Fig. 21.33 Positron emission tomography-computed tomography
(PET-CT) staging of oesophageal carcinoma. Whole-body PET scan
showing avid uptake in the primary tumour (thick arrow) but also in distant
paratracheal (superior thin arrow) and gastro-oesophageal (inferior thin
arrow) lymph nodes.
spread and local invasion (Fig. 21.33). Invasion of the aorta,
major airways or coeliac axis usually precludes surgery, but
patients with resectable disease on imaging should undergo
EUS to determine the depth of penetration of the tumour into
the oesophageal wall and to detect locoregional lymph node
Diseases of the stomach and duodenum • 797
■
| 1
T
/ \
Fig. 21.34 Endoscopic ultrasound staging of oesophageal
carcinoma. There is a superficial adenocarcinoma of the oesophagus (T).
The submucosa (white band, white arrows) is not involved but there is a
small involved local lymph node (white arrow, inset). The tumour is
therefore staged Tla, N1 .
involvement (Fig. 21.34). These investigations will define the
TNM stage of the disease (p. 1322).
Management
The treatment of choice is surgery if the patient presents at a point
at which resection is possible. For very early superficial tumours,
endoscopic submucosal dissection may offer an alternative to
surgery but is not widely used outside of Japan and Korea.
Patients with tumours that have extended beyond the wall of the
oesophagus (T3) or that have lymph node involvement (N1) carry
a 5-year survival of around 1 0%. This figure improves significantly,
however, if the tumour is confined to the oesophageal wall and
there is no spread to lymph nodes. Overall survival following
‘potentially curative’ surgery (all macroscopic tumour removed)
is about 30% at 5 years but recent studies have suggested that
this can be improved by neoadjuvant chemotherapy. Although
squamous carcinomas are radiosensitive, radiotherapy alone
is associated with a 5-year survival of only 5% but combined
chemoradiotherapy for these tumours can achieve 5-year survival
rates of 25-30%.
Approximately 70% of patients have extensive disease at
presentation; in these, treatment is palliative and should focus
on relief of dysphagia and pain. Endoscopic laser therapy or
self-expanding metallic stents can be used to improve swallowing.
Palliative radiotherapy may induce shrinkage of both squamous
cancers and adenocarcinomas but symptomatic response may
be slow. Quality of life can be improved by nutritional support
and appropriate analgesia.
Perforation of the oesophagus
The most common cause is endoscopic perforation complicating
dilatation or intubation. Malignant, corrosive or post-radiotherapy
strictures are more likely to be perforated than peptic strictures.
A perforated peptic stricture is managed conservatively using
broad-spectrum antibiotics and parenteral nutrition; most cases
heal within days. Malignant, caustic and radiotherapy stricture
perforations require resection or stenting.
Spontaneous oesophageal perforation (‘Boerhaave’s syndrome’)
results from forceful vomiting and retching. Severe chest pain
and shock occur as oesophago-gastric contents enter the
mediastinum and thoracic cavity. Subcutaneous emphysema,
pleural effusions and pneumothorax develop. The diagnosis can
be made using a water-soluble contrast swallow but, in difficult
cases, both CT and careful endoscopy (usually in an intubated
patient) may be required. Treatment is surgical. Delay in diagnosis
is a key factor in the high mortality associated with this condition.
Diseases of the stomach
and duodenum
Gastritis
Gastritis is a histological diagnosis, although it can also be
recognised at endoscopy.
Acute gastritis
Acute gastritis is often erosive and haemorrhagic. Neutrophils are
the predominant inflammatory cell in the superficial epithelium.
Many cases result from alcohol, aspirin or NSAID ingestion
(Box 21.33). Acute gastritis often produces no symptoms
but may cause dyspepsia, anorexia, nausea or vomiting, and
haematemesis or melaena. Many cases resolve quickly and do
not merit investigation; in others, endoscopy and biopsy may be
necessary to exclude peptic ulcer or cancer. Treatment should be
directed at the underlying cause. Short-term symptomatic therapy
with antacids, and acid suppression using PPIs, prokinetics
(domperidone) or antiemetics (metoclopramide) may be necessary.
I Chronic gastritis due to Helicobacter
pylori infection
This is the most common cause of chronic gastritis (Box 21 .33).
The predominant inflammatory cells are lymphocytes and
plasma cells. Correlation between symptoms and endoscopic
or pathological findings is poor. Most patients are asymptomatic
and do not require treatment but patients with dyspepsia may
benefit from H. pylori eradication.
| Autoimmune chronic gastritis
This involves the body of the stomach but spares the antrum; it
results from autoimmune damage to parietal cells. The histological
features are diffuse chronic inflammation, atrophy and loss of
fundic glands, intestinal metaplasia and sometimes hyperplasia of
enterochromaffin-like (ECL) cells. Circulating antibodies to parietal
cell and intrinsic factor may be present. In some patients, the
degree of gastric atrophy is severe and loss of intrinsic factor
secretion leads to pernicious anaemia (p. 944). The gastritis
itself is usually asymptomatic. Some patients have evidence of
other organ-specific autoimmunity, particularly thyroid disease.
In the long term, there is a two- to threefold increase in the risk
of gastric cancer (see also p. 803).
|Menetrier’s disease
In this rare condition, the gastric pits are elongated and tortuous,
with replacement of the parietal and chief cells by mucus-secreting
cells. The cause is unknown but there is excessive production
of transforming growth factor alpha (TGF-a). As a result, the
798 • GASTROENTEROLOGY
21.33 Common causes of gastritis
Acute gastritis (often erosive and haemorrhagic)
• Aspirin, NSAIDs
• Helicobacter pylori (initial infection)
• Alcohol
• Other drugs, e.g. iron preparations
• Severe physiological stress, e.g. burns, multi-organ failure, central
nervous system trauma
• Bile reflux, e.g. following gastric surgery
• Viral infections, e.g. CMV, herpes simplex virus in HIV/AIDS (p. 316)
Chronic non-specific gastritis
• H. pylori infection
• Autoimmune (pernicious anaemia)
• Post-gastrectomy
Chronic ‘specific’ forms (rare)
• Infections, e.g. CMV, tuberculosis
• Gastrointestinal diseases, e.g. Crohn’s disease
• Systemic diseases, e.g. sarcoidosis, graft-versus-host disease
• Idiopathic, e.g. granulomatous gastritis
(CMV = cytomegalovirus; NSAIDs = non-steroidal anti-inflammatory drugs)
mucosal folds of the body and fundus are greatly enlarged. Most
patients are hypochlorhydric. While some patients have upper
gastrointestinal symptoms, the majority present in middle or old
age with protein-losing enteropathy (p. 811) due to exudation
from the gastric mucosa. Endoscopy shows enlarged, nodular
and coarse folds, although biopsies may not be deep enough to
show all the histological features. Treatment with antisecretory
drugs, such as PPIs with or without octreotide, may reduce
protein loss and H. pylori eradication may be effective, but
unresponsive patients require partial gastrectomy.
Peptic ulcer disease
The term ‘peptic ulcer’ refers to an ulcer in the lower oesophagus,
stomach or duodenum, in the jejunum after surgical anastomosis
to the stomach or, rarely, in the ileum adjacent to a Meckel’s
diverticulum. Ulcers in the stomach or duodenum may be acute
or chronic; both penetrate the muscularis mucosae but the acute
ulcer shows no evidence of fibrosis. Erosions do not penetrate
the muscularis mucosae.
Gastric and duodenal ulcer
The prevalence of peptic ulcer (0.1 -0.2%) is decreasing in
many Western communities as a result of widespread use of
Helicobacter pylori eradication therapy but it remains high in
developing countries. The male-to-female ratio for duodenal
ulcer varies from 5:1 to 2 : 1 , while that for gastric ulcer is 2 : 1
or less. Chronic gastric ulcer is usually single; 90% are situated
on the lesser curve within the antrum or at the junction between
body and antral mucosa. Chronic duodenal ulcer usually occurs
in the first part of the duodenum and 50% are on the anterior
wall. Gastric and duodenal ulcers coexist in 10% of patients
and more than one peptic ulcer is found in 10-15% of patients.
Pathophysiology
H. pylori
Peptic ulceration is strongly associated with H. pylori infection. The
prevalence of the infection in developed nations rises with age and
Other factors
• Vacuolating cytotoxin (vacA)
• Cytotoxin-associated gene (cagA)
• Adhesins (babA)
• Outer inflammatory protein A (oipA)
Fig. 21.35 Factors that influence the virulence of Helicobacter
pylori.
in the UK approximately 50% of people over the age of 50 years
are infected. In the developing world infection is more common,
affecting up to 90% of adults. These infections are probably
acquired in childhood by person-to-person contact. The vast
majority of colonised people remain healthy and asymptomatic,
and only a minority develop clinical disease. Around 90% of
duodenal ulcer patients and 70% of gastric ulcer patients are
infected with H. pylori. The remaining 30% of gastric ulcers are
caused by NSAIDs and this proportion is increasing in Western
countries as a result of H. pylori eradication strategies.
H. pylori is Gram-negative and spiral, and has multiple flagella
at one end, which make it motile, allowing it to burrow and live
beneath the mucus layer adherent to the epithelial surface.
It uses an adhesin molecule (BabA) to bind to the Lewis b
antigen on epithelial cells. Here the surface pH is close to neutral
and any acidity is buffered by the organism’s production of
the enzyme urease. This produces ammonia from urea and
raises the pH around the bacterium and between its two cell
membrane layers. H. pylori exclusively colonises gastric-type
epithelium and is found in the duodenum only in association
with patches of gastric metaplasia. It causes chronic gastritis
by provoking a local inflammatory response in the underlying
epithelium (Fig. 21.35). This depends on numerous factors,
notably expression of bacterial cagA and vacA genes. The CagA
gene product is injected into epithelial cells, interacting with
numerous cell-signalling pathways involved in cell replication and
apoptosis. H. pylori strains expressing CagA (CagA+) are more
often associated with disease than CagA- strains. Most strains
also secrete a large pore-forming protein called VacA, which
causes increased cell permeability, efflux of micronutrients from
the epithelium, induction of apoptosis and suppression of local
immune cell activity. Several forms of VacA exist and pathology
is most strongly associated with the si /ml form of the toxin.
The distribution and severity of H. py/or/'-induced gastritis
determine the clinical outcome. In most people, H. pylori causes
a mild pangastritis with little effect on acid secretion and the
majority develop no significant clinical outcomes. In a minority (up
Diseases of the stomach and duodenum • 799
to 10% in the West), the infection causes an antral-predominant
pattern of gastritis characterised by hypergastrinaemia and a very
exaggerated acid production by parietal cells, which could lead
to duodenal ulceration (Fig. 21 .36). In a much smaller number of
infected people, H. pylori causes a corpus-predominant pattern
of gastritis leading to gastric atrophy and hypochlorhydria.
This phenotype is much more common in Asian countries,
particularly Japan, China and Korea. The hypochlorhydria allows
other bacteria to proliferate within the stomach; these other
bacteria continue to drive the chronic inflammation and produce
mutagenic nitrites from dietary nitrates, predisposing to the
development of gastric cancer (Fig. 21.37). The effects of H.
pylori are more complex in gastric ulcer patients compared to
those with duodenal ulcers. The ulcer probably arises because
of impaired mucosal defence resulting from a combination of H.
pylori infection, NSAIDs and smoking, rather than excess acid.
ulceration
Fig. 21.36 Sequence of events in the pathophysiology of duodenal
ulceration.
ulcer ulcer cancer
Fig. 21.37 Consequences of Helicobacter pylori infection. (CagA =
cytotoxin-associated gene; IL-1 p = interleukin-1 beta; NSAIDs =
non-steroidal anti-inflammatory drugs; TNF-a = tumour necrosis factor
alpha; VacA = vacuolating cytotoxin)
NSAIDs
Treatment with NSAIDs is associated with peptic ulcers due to
impairment of mucosal defences, as discussed on page 1002.
Smoking
Smoking confers an increased risk of gastric ulcer and, to a
lesser extent, duodenal ulcer. Once the ulcer has formed, it is
more likely to cause complications and less likely to heal if the
patient continues to smoke.
Clinical features
Peptic ulcer disease is a chronic condition with spontaneous
relapses and remissions lasting for decades, if not for life. The
most common presentation is with recurrent abdominal pain that
has three notable characteristics: localisation to the epigastrium,
relationship to food and episodic occurrence. Occasional vomiting
occurs in about 40% of ulcer subjects; persistent daily vomiting
suggests gastric outlet obstruction. In one-third, the history is
less characteristic, especially in elderly people or those taking
NSAIDs. In this situation, pain may be absent or so slight that
it is experienced only as a vague sense of epigastric unease.
Occasionally, the only symptoms are anorexia and nausea, or
early satiety after meals. In some patients, the ulcer is completely
‘silent’, presenting for the first time with anaemia from chronic
undetected blood loss, as abrupt haematemesis or as acute
perforation; in others, there is recurrent acute bleeding without
ulcer pain. The diagnostic value of individual symptoms for peptic
ulcer disease is poor; the history is therefore a poor predictor
of the presence of an ulcer.
Investigations
Endoscopy is the preferred investigation (Fig. 21.38). Gastric
ulcers may occasionally be malignant and therefore must always
be biopsied and followed up to ensure healing. Patients should
be tested for H. pylori infection. The current options available are
listed in Box 21 .34. Some are invasive and require endoscopy;
others are non-invasive. They vary in sensitivity and specificity.
Breath tests or faecal antigen tests are best because of accuracy,
simplicity and non-invasiveness.
Fig. 21.38 Endoscopic identification of a duodenal ulcer. The ulcer
has a clean base and there are no stigmata of recent haemorrhage.
800 • GASTROENTEROLOGY
21 .34 Methods for the diagnosis of Helicobacter
pylori infection
Test
Advantages
Disadvantages
Non-invasive
Serology
Rapid office kits
Lacks specificity
available
Cannot differentiate
Good for population
current from past
studies
infection
13C-urea breath test
High sensitivity and
Requires expensive
specificity
mass spectrometer
Faecal antigen test
Cheap, specific (>95%)
Acceptability
Invasive (antral biopsy)
Histology
Specificity
False negatives
Takes several days
to process
Rapid urease test
Cheap, quick, specific
(>95%)
Sensitivity 85%
Microbiological
‘Gold standard’
Slow and laborious
culture
Defines antibiotic
sensitivity
Lacks sensitivity
21.35 Common side-effects of Helicobacter pylori
eradication therapy
• Diarrhoea: 30-50% of patients; usually mild but Clostridium
difficile- associated diarrhoea can occur
• Flushing and vomiting when taken with alcohol (metronidazole)
• Nausea, vomiting
• Abdominal cramps
• Headache
• Rash
Management
The aims of management are to relieve symptoms, induce
healing and prevent recurrence. H. pylori eradication is the
cornerstone of therapy for peptic ulcers, as this will successfully
prevent relapse and eliminate the need for long-term therapy in
the majority of patients.
H. pylori eradication
All patients with proven ulcers who are H. pylori- positive should
be offered eradication as primary therapy. Treatment is based on
a PPI taken simultaneously with two antibiotics (from amoxicillin,
clarithromycin and metronidazole) for at least 7 days. High-dose,
twice-daily PPI therapy increases efficacy of treatment, as does
extending treatment to 10-14 days. Success is achieved in
80-90% of patients, although adherence, side-effects (Box
21.35) and antibiotic resistance influence this. Resistance to
amoxicillin is rare but rates of metronidazole resistance reach
more than 50% in some countries and rates of clarithromycin
resistance of 20-40% have recently become common. Where
the latter exceed 15%, a quadruple therapy regimen, consisting
of omeprazole (or another PPI), bismuth subcitrate, metronidazole
and tetracycline (OBMT) for 10-14 days, is recommended. In
areas of low clarithromycin resistance, this regimen should also
be offered as second-line therapy to those who remain infected
after initial therapy, once adherence has been checked. For
those who are still colonised after two treatments, the choice
lies between a third attempt guided by antimicrobial sensitivity
testing, rescue therapy (levofloxacin, PPI and clarithromycin) or
long-term acid suppression.
H. pylori and NSAIDs are independent risk factors for ulcer
disease and patients requiring long-term NSAID therapy should
21.36 Indications for Helicobacter pylori eradication
Definite
• Peptic ulcer
• Extranodal marginal-zone lymphomas of MALT type
• Family history of gastric cancer
• Previous resection for gastric cancer
• H. py/or/'- positive dyspepsia
• Long-term NSAID or low-dose aspirin users
• Chronic (>1 year) PPI users
• Extragastric disorders:
Unexplained vitamin B12 deficiency*
Idiopathic thrombocytopenic purpura*
Iron deficiency anaemia* (see text)
Not indicated
• Gastro-oesophageal reflux disease
• Asymptomatic people without gastric cancer risk factors
If H. pylori- positive on testing.
(MALT = mucosa-associated lymphoid tissue; NSAID = non-steroidal
anti-inflammatory drug; PPI = proton pump inhibitor)
21.37 Indications for surgery in peptic ulcer
Emergency
• Perforation
• Flaemorrhage
Elective
• Gastric outflow obstruction
• Persistent ulceration despite adequate medical therapy
• Recurrent ulcer following gastric surgery
first undergo eradication therapy to reduce ulcer risk. Subsequent
co-prescription of a PPI along with the NSAID is advised but is
not always necessary for patients being given low-dose aspirin,
in whom the risk of ulcer complications is lower.
Other indications for H. pylori eradication are shown in Box
21 .36. Eradication of the infection has proven benefits in several
extragastric disorders, including unexplained B12 deficiency and
iron deficiency anaemia, once sources of gastrointestinal bleeding
have been looked for and excluded. Platelet counts improve
and may normalise after eradication therapy in patients with
idiopathic thrombocytopenic purpura (p. 979); the mechanism
for this is unclear.
General measures
Cigarette smoking, aspirin and NSAIDs should be avoided.
Alcohol in moderation is not harmful and no special dietary
advice is required.
Maintenance treatment
Continuous maintenance treatment should not be necessary after
successful H. pylori eradication. For the minority who do require
it, the lowest effective dose of PPI should be used.
Surgical treatment
Surgery is now rarely required for peptic ulcer disease but it is
needed in some cases (Box 21 .37).
The operation of choice for a chronic non-healing gastric ulcer
is partial gastrectomy, preferably with a Billroth I anastomosis, in
which the ulcer itself and the ulcer-bearing area of the stomach
are resected. The reason for this is to exclude an underlying
Diseases of the stomach and duodenum • 801
cancer. In an emergency, ‘under-running’ the ulcer for bleeding
or ‘oversewing’ (patch repair) for perforation is all that is required,
in addition to taking a biopsy. For giant duodenal ulcers, partial
gastrectomy using a ‘Polya’ or Billroth II reconstruction may
be required.
Complications of gastric resection or vagotomy
Up to 50% of patients who undergo gastric surgery for peptic
ulcer surgery experience long-term adverse effects. In most cases
these are minor but in 1 0% they significantly impair quality of life.
Dumping Rapid gastric emptying leads to distension of the
proximal small intestine as the hypertonic contents draw fluid
into the lumen. This leads to abdominal discomfort and diarrhoea
after eating. Autonomic reflexes release a range of gastrointestinal
hormones that provoke vasomotor features, such as flushing,
palpitations, sweating, tachycardia and hypotension. Patients
should therefore avoid large meals with high carbohydrate content.
Chemical (bile reflux) gastropathy Duodenogastric bile reflux leads
to chronic gastropathy. Treatment with aluminium-containing
antacids or sucralfate may be effective. A few patients require
revisional surgery with creation of a Roux en Y loop to prevent
bile reflux.
Diarrhoea and maldigestion Diarrhoea may develop after any peptic
ulcer operation and usually occurs 1-2 hours after eating. Poor
mixing of food in the stomach, with rapid emptying, inadequate
mixing with pancreaticobiliary secretions, rapid transit and bacterial
overgrowth, may lead to malabsorption. Diarrhoea often responds
to small, dry meals with a reduced intake of refined carbohydrates.
Antidiarrhoeal drugs, such as codeine phosphate (15-30 mg
4-6 times daily) or loperamide (2 mg after each loose stool),
are helpful.
Weight loss Most patients lose weight shortly after surgery and
30-40% are unable to regain all the weight that is lost. The usual
cause is reduced intake because of a small gastric remnant but
diarrhoea and mild steatorrhoea also contribute.
Anaemia Anaemia is common many years after subtotal
gastrectomy. Iron deficiency is the most common cause; folic
acid and B12 deficiency are much less frequent. Inadequate
dietary intake of iron and folate, lack of acid and intrinsic factor
secretion, mild chronic low-grade blood loss from the gastric
remnant and recurrent ulceration are responsible.
Metabolic bone disease Both osteoporosis and osteomalacia can
occur as a consequence of calcium and vitamin D malabsorption.
Gastric cancer An increased risk of gastric cancer has been
reported from several epidemiological studies. Surgery itself is an
(fx
independent risk factor for late development of malignancy in the
gastric remnant but the risk is higher in those with hypochlorhydria,
duodenogastric reflux of bile, smoking and H. pylori infection.
Although the relative risk is increased, the absolute risk of cancer
remains low and endoscopic surveillance is not indicated following
gastric surgery.
Complications of peptic ulcer disease
Perforation
When perforation occurs, the contents of the stomach escape into
the peritoneal cavity, leading to peritonitis. This is more common
in duodenal than in gastric ulcers and is usually found with ulcers
on the anterior wall. About one-quarter of all perforations occur
in acute ulcers and NSAIDs are often incriminated. Perforation
can be the first sign of ulcer and a history of recurrent epigastric
pain is uncommon. The most striking symptom is sudden, severe
pain; its distribution follows the spread of the gastric contents
over the peritoneum. The pain initially develops in the upper
abdomen and rapidly becomes generalised; shoulder tip pain is
caused by irritation of the diaphragm. The pain is accompanied by
shallow respiration, due to limitation of diaphragmatic movements,
and by shock. The abdomen is held immobile and there is
generalised ‘board-like’ rigidity. Bowel sounds are absent and
liver dullness to percussion decreases due to the presence of
gas under the diaphragm. After some hours, symptoms may
improve, although abdominal rigidity remains. Later, the patient’s
condition deteriorates as general peritonitis develops. In at least
50% of cases, an erect chest X-ray shows free air beneath the
diaphragm (see Fig. 21 .1 1 B, p. 773). If not, a water-soluble contrast
swallow will confirm leakage of gastroduodenal contents. After
resuscitation, the acute perforation should be treated surgically,
either by simple closure or by conversion of the perforation into
a pyloroplasty if it is large. On rare occasions, a ‘Polya’ partial
gastrectomy is required. Following surgery, H. pylori should be
treated (if present) and NSAIDs avoided. Perforation carries a
mortality of 25%, reflecting the advanced age and significant
comorbidity of the population that are affected.
Gastric outlet obstruction
The causes are shown in Box 21 .39. The most common is an
ulcer in the region of the pylorus. The presentation is with nausea,
vomiting and abdominal distension. Large quantities of gastric
content are often vomited and food eaten 24 hours or more
previously may be recognised. Physical examination may show
evidence of wasting and dehydration. A succussion splash may
be elicited 4 hours or more after the last meal or drink. Visible
gastric peristalsis is diagnostic of gastric outlet obstruction. Loss
of acidic gastric contents leads to alkalosis and dehydration with
low serum chloride and potassium and raised serum bicarbonate
and urea concentrations (hypochloraemic metabolic alkalosis).
i
21.39 Differential diagnosis and management of
gastric outlet obstruction
Cause
Management
Fibrotic stricture from duodenal ulcer
(pyloric stenosis)
Balloon dilatation or surgery
Oedema from pyloric channel or
duodenal ulcer
Proton pump inhibitor therapy
Carcinoma of antrum
Surgery
Adult hypertrophic pyloric stenosis Surgery
• Gastroduodenal ulcers: have a greater incidence, admission rate
and mortality.
• Causes: high prevalence of H. pylori, use of non-steroidal
anti-inflammatory drugs and impaired defence mechanisms.
• Atypical presentations: pain and dyspepsia are frequently absent
or atypical. Older people often develop complications, such as
bleeding or perforation, without a dyspeptic history.
• Bleeding: older patients require more intensive management
because they have more limited reserve to withstand hypovolaemia.
21.38 Peptic ulcer disease in old age
802 • GASTROENTEROLOGY
Paradoxical aciduria occurs because of enhanced renal absorption
of Na+ in exchange for H+. Endoscopy should be performed after
the stomach has been emptied using a wide-bore nasogastric
tube. Intravenous correction of dehydration is undertaken and,
in severe cases, at least 4 L of isotonic saline and 80 mmol of
potassium may be necessary during the first 24 hours. In some
patients, PPI drugs heal ulcers, relieve pyloric oedema and
overcome the need for surgery. Endoscopic balloon dilatation of
benign stenoses may be possible in some patients but in others
partial gastrectomy is necessary; this is best done after a 7-day
period of nasogastric aspiration, which enables the stomach
to return to normal size. A gastroenterostomy is an alternative
operation but, unless this is accompanied by vagotomy, patients
will require long-term PPI therapy to prevent stomal ulceration.
Bleeding
See page 780.
Zollinger— Ellison syndrome
This is a rare disorder characterised by the triad of severe peptic
ulceration, gastric acid hypersecretion and a neuro-endocrine
tumour (p. 678) of the pancreas or duodenum (‘gastrinoma’).
It probably accounts for about 0.1% of all cases of duodenal
ulceration. The syndrome occurs in either sex at any age, although
it is most common between 30 and 50 years of age.
Pathophysiology
The tumour secretes gastrin, which stimulates acid secretion
to its maximal capacity and increases the parietal cell mass
three- to sixfold. The acid output may be so great that it reaches
the upper small intestine, reducing the luminal pH to 2 or less.
Pancreatic lipase is inactivated and bile acids are precipitated.
Diarrhoea and steatorrhoea result. Around 90% of tumours occur
in the pancreatic head or proximal duodenal wall. At least half
are multiple and tumour size can vary from 1 mm to 20 cm.
Approximately one-half to two-thirds are malignant but are often
slow-growing. Between 20% and 60% of patients have multiple
endocrine neoplasia (MEN) type 1 (p. 688).
Clinical features
The presentation is with severe and often multiple peptic ulcers
in unusual sites, such as the post-bulbar duodenum, jejunum or
oesophagus. There is a poor response to standard ulcer therapy.
The history is usually short, and bleeding and perforations are
common. Diarrhoea is seen in one-third or more of patients and
can be the presenting feature.
Investigations
Hypersecretion of acid under basal conditions, with little increase
following pentagastrin, may be confirmed by gastric aspiration.
Serum gastrin levels are grossly elevated (10- to 1000-fold).
Injection of the hormone secretin normally causes no change
or a slight decrease in circulating gastrin concentrations,
but in Zollinger— Ellison syndrome it produces a paradoxical
and dramatic increase in gastrin. Tumour localisation (and
staging) is best achieved by a combination of CT and EUS;
radio-labelled somatostatin receptor scintigraphy and 68gallium
DOTATATE PET scanning may also be used for tumour detection
and staging.
Management
Some 30% of small and single tumours can be localised and
resected but many tumours are multifocal (especially in the context
of MEN 1). Some patients present with metastatic disease and,
in these circumstances, surgery is inappropriate. In the majority
of these individuals, continuous therapy with omeprazole or other
PPIs can be successful in healing ulcers and alleviating diarrhoea,
although double the normal dose is required. The synthetic
somatostatin analogue, octreotide, given by subcutaneous
injection, reduces gastrin secretion and may be of value. Other
treatment options for pancreatic neuro-endocrine tumours are
discussed on page 678. Overall 5-year survival is 60-75% and
all patients should undergo genetic screening for MEN 1 .
Functional disorders
| Functional dyspepsia
This is defined as chronic dyspepsia in the absence of organic
disease. Other commonly reported symptoms include early satiety,
fullness, bloating and nausea. ‘Ulcer-like’ and ‘dysmotility-type’
subgroups are often reported but there is overlap between these
and with irritable bowel syndrome.
Pathophysiology
The cause is poorly understood but probably covers a spectrum
of mucosal, motility and psychiatric disorders.
Clinical features
Patients are usually young (< 40 years) and women are affected
twice as commonly as men. Abdominal discomfort is associated
with a combination of other ‘dyspeptic’ symptoms, the most
common being nausea, satiety and bloating after meals. Morning
symptoms are characteristic and pain or nausea may occur on
waking. Direct enquiry may elicit symptoms suggestive of irritable
bowel syndrome. Peptic ulcer disease must be considered,
while in older people intra-abdominal malignancy is a prime
concern. There are no diagnostic signs, apart from inappropriate
tenderness on abdominal palpation, perhaps. Symptoms may
appear disproportionate to clinical well-being and there is no
weight loss. Patients often appear anxious. A drug history should
be taken and the possibility of a depressive illness should be
considered. Pregnancy should be ruled out in young women
before radiological studies are undertaken. Alcohol misuse
should be suspected when early-morning nausea and retching
are prominent.
Investigations
The history will often suggest the diagnosis. All patients should
be checked for H. pylori infection and patients over the age of
55 years should undergo endoscopy to exclude mucosal disease.
While an ultrasound scan may detect gallstones, these are rarely
responsible for dyspeptic symptoms.
Management
The most important elements are explanation and reassurance.
Possible psychological factors should be explored and the
concept of psychological influences on gut function should be
explained. Idiosyncratic and restrictive diets are of little benefit
but smaller portions and fat restriction may help.
Up to 1 0% of patients benefit from H. pylori eradication therapy
and this should be offered to infected individuals. Eradication also
removes a major risk factor for peptic ulcers and gastric cancer
but at the cost of a small risk of side-effects and worsening
symptoms of underlying gastro-oesophageal reflux disease. Drug
treatment is not especially successful but merits trial. Antacids,
Diseases of the stomach and duodenum • 803
such as hydrotalcite, are sometimes helpful. Prokinetic drugs,
such as metoclopramide (10 mg 3 times daily) or domperidone
(10-20 mg 3 times daily), may be given before meals if nausea,
vomiting or bloating is prominent. Metoclopramide may induce
extrapyramidal side-effects, including tardive dyskinesia in young
patients. H2-receptor antagonist drugs may be tried if night pain
or heartburn is troublesome. Low-dose tricyclic agents, such as
amitriptyline, are of value in up to two-thirds.
Symptoms that can be associated with an identifiable cause
of stress resolve with appropriate counselling. Some patients
have major psychological disorders that result in persistent
or recurrent symptoms and need behavioural or other formal
psychotherapy (p. 1190).
Functional causes of vomiting
Psychogenic retching or vomiting may arise in anxiety. It typically
occurs on wakening or immediately after breakfast, and only
rarely later in the day. The disorder is probably a reaction to
facing up to the worries of everyday life; in the young, it can
be due to school phobia. Early morning vomiting also occurs in
pregnancy, alcohol misuse and depression. Although functional
vomiting may occur regularly over long periods, there is little
or no weight loss. Children, and less often adults, sometimes
suffer from acute and recurrent disabling bouts of vomiting for
days at a time. The cause of this cyclical vomiting syndrome is
unknown but in some adults it is associated with cannabis use.
In all patients it is essential to exclude other common causes
(p. 780). Tranquillisers and antiemetic drugs (metoclopramide
10 mg 3 times daily, domperidone 10 mg 3 times daily, prochlor¬
perazine 5-10 mg 3 times daily) have only a secondary place
in management. Antidepressants in full dose may be effective
(p. 1199).
Gastroparesis
Defective gastric emptying without mechanical obstruction of
the stomach or duodenum can occur as a primary event, due
to inherited or acquired disorders of the gastric pacemaker, or
can be secondary to disorders of autonomic nerves (particularly
diabetic neuropathy) or the gastroduodenal musculature
(systemic sclerosis, myotonic dystrophies and amyloidosis).
Drugs such as opiates, calcium channel antagonists and those
with anticholinergic activity (tricyclics, phenothiazines) can also
cause gastroparesis. Early satiety and recurrent vomiting are
the major symptoms; abdominal fullness and a succussion
splash may be present on examination. Treatment is based on
small, frequent, low-fat meals and the use of metoclopramide
and domperidone. In severe cases, nutritional failure can occur
and long-term jejunostomy feeding or total parenteral nutrition
is required. Surgical insertion of a gastric neurostimulator has
been successful in some cases, especially those complicating
diabetic autonomic neuropathy.
Tumours of the stomach
Gastric carcinoma
Gastric carcinoma is the third leading cause of cancer death
worldwide but there is marked geographical variation in incidence.
It is most common in China, Japan, Korea (incidence 40/100000
males), Eastern Europe and parts of South America (20/100000).
Rates in the UK are 12/100000 for men. In most countries, the
incidence is 50% lower in women. In both sexes, it rises sharply
after 50 years of age. Studies of Japanese migrants to the USA
have revealed a much lower incidence in the second generation,
confirming the importance of environmental factors. The overall
prognosis is poor, with less than 30% surviving 5 years, and the
best hope for improved survival lies in more efficient detection
of tumours at an earlier stage.
Pathophysiology
Infection with H. pylori plays a key pathogenic role and the
infection has been classified by the International Agency for
Research on Cancer (IARC) as a definite human carcinogen.
It is associated with chronic atrophic gastritis, gastric mucosal
atrophy and gastric cancer (Fig. 21.39). It has been estimated
that H. pylori infection may contribute to the occurrence of
gastric cancer in 70% of cases. Although the majority of H.
pylori- infected individuals have normal or increased acid secretion,
a few become hypo- or achlorhydric and these people are thought
to be at greatest risk. H. py/or/'-induced chronic inflammation
with generation of reactive oxygen species and depletion of the
normally abundant antioxidant ascorbic acid are also important.
There is strong evidence that H. pylori eradication, especially
if achieved before irreversible pre-neoplastic changes (atrophy
and intestinal metaplasia) have developed, reduces the risk of
cancer development in high-risk populations and is cost-effective.
Diets rich in salted, smoked or pickled foods and the
consumption of nitrites and nitrates may increase cancer risk.
Carcinogenic /V-nitroso-compounds are formed from nitrates by
the action of nitrite-reducing bacteria that colonise the achlorhydric
stomach. Diets lacking in fresh fruit and vegetables, as well as
vitamins C and A, may also contribute. Other risk factors are
listed in Box 21.40. No predominant genetic abnormality has
been identified, although cancer risk is increased two- to threefold
in first-degree relatives of patients, and links with blood group
A have been reported. Some host genetic factors related to
inflammatory genes and prostate stem cell antigen have recently
been associated with increased risk of gastric caner. Rarely,
gastric cancer may be inherited in an autosomal dominant manner
in association with mutations of the E-cadherin (CDH1) gene.
Normal gastric
epithelium
Carcinoma
Fig. 21.39 Gastric carcinogenesis: a possible mechanism.
(CagA = cytotoxin-associated gene)
804 • GASTROENTEROLOGY
21 .40 Risk factors for gastric cancer
• Helicobacter pylori
• Smoking
• Alcohol
• Dietary associations (see text)
• Autoimmune gastritis (pernicious anaemia)
• Adenomatous gastric polyps
• Previous partial gastrectomy (>20 years)
• Menetrier’s disease
• Hereditary diffuse gastric cancer families ( CDH1 mutations)
• Familial adenomatous polyposis (p. 828)
Virtually all tumours are adenocarcinomas arising from mucus-
secreting cells in the base of the gastric crypts. Most develop on a
background of chronic atrophic gastritis with intestinal metaplasia
and dysplasia. Cancers are either ‘intestinal’, arising from areas
of intestinal metaplasia with histological features reminiscent
of intestinal epithelium, or ‘diffuse’, arising from normal gastric
mucosa. Intestinal carcinomas are more common and arise
against a background of chronic mucosal injury. Diffuse cancers
tend to be poorly differentiated and occur in younger patients.
In the developing world, 50% of gastric cancers develop in the
antrum; 20-30% occur in the gastric body, often on the greater
curve; and 20% are found in the cardia. In Western populations,
however, proximal gastric tumours are becoming more common
than those arising in the body and distal stomach. This change
in disease pattern may be a reflection of changes in lifestyle
or the decreasing prevalence of H. pylori in the West. Diffuse
submucosal infiltration by a scirrhous cancer (linitis plastica) is
uncommon. Early gastric cancer is defined as cancer confined
to the mucosa or submucosa. It is more often recognised in
Japan, where widespread screening is practised. Some cases
can be cured by endoscopic mucosal or submucosal resection.
The majority of patients (>80%) in the West, however, present
with advanced gastric cancer.
Clinical features
Early gastric cancer is usually asymptomatic but may be discovered
during endoscopy for investigation of dyspepsia. Two-thirds of
patients with advanced cancers have weight loss and 50% have
ulcer-like pain. Anorexia and nausea occur in one-third, while early
satiety, haematemesis, melaena and dyspepsia alone are less
common. Dysphagia occurs in tumours of the gastric cardia that
obstruct the gastro-oesophageal junction. Anaemia from occult
bleeding is also common. Examination may reveal no abnormalities
but signs of weight loss, anaemia and a palpable epigastric mass
are not infrequent. Jaundice or ascites signifies metastatic spread.
Occasionally, tumour spread occurs to the supraclavicular lymph
nodes (Troisier’s sign), umbilicus (Sister Joseph’s nodule) or
ovaries (Krukenberg tumour). Paraneoplastic phenomena, such
as acanthosis nigricans, thrombophlebitis (Trousseau’s sign) and
dermatomyositis, occur rarely. Metastases arise most commonly
in the liver, lungs, peritoneum and bone marrow.
Investigations
Upper gastrointestinal endoscopy is the investigation of choice
(Fig. 21 .40) and should be performed promptly in any dyspeptic
patient with ‘alarm features’ (see Box 21.15, p. 779). Multiple
biopsies from the edge and base of a gastric ulcer are required.
Barium meal is a poor alternative, since any abnormalities must
be followed by endoscopy and biopsy. Once the diagnosis is
jjB
■Lf V * . ,4 I
p ■
. Vv
Fig. 21.40 Gastric carcinoma. Endoscopic finding of a large polypoidal
mass arising from the wall of the stomach.
made, further imaging is necessary for staging and assessment of
resectability. CT will provide evidence of intra-abdominal spread
or liver metastases. Even with these techniques, laparoscopy
with peritoneal washings is required to determine whether the
tumour is resectable, as it is the only modality that will reliably
detect peritoneal spread.
Management
Surgery
Resection offers the only hope of cure and this can be achieved in
about 90% of patients with early gastric cancer. For the majority
of patients with locally advanced disease, total gastrectomy with
lymphadenectomy is the operation of choice, preserving the
spleen if possible. Proximal tumours involving the oesophago-
gastric junction also require a distal oesophagectomy. Small,
distally sited tumours can be managed by a partial gastrectomy
with lymphadenectomy and either a Billroth I or a Roux en Y
reconstruction. More extensive lymph node resection may increase
survival rates but carries greater morbidity. Even for those who
cannot be cured, palliative resection may be necessary when
patients present with bleeding or gastric outflow obstruction.
Following surgery, recurrence is much more likely if serosal
penetration has occurred, although complete removal of all
macroscopic tumour combined with lymphadenectomy will achieve
a 50-60% 5-year survival. Perioperative chemotherapy with
epirubicin, cisplatin and fluorouracil (ECF) improves survival rates.
Palliative treatment
In patients with inoperable tumours, survival can be improved
and palliation of symptoms achieved with chemotherapy using
5-fluorouracil and cisplatin, ECF or other platinum- and taxane-
based regimens. The biological agent trastuzumab may benefit
some patients whose tumours over-express HER2 (p. 1322).
Endoscopic laser ablation for control of dysphagia or recurrent
bleeding benefits some patients. Carcinomas at the cardia
or pylorus may require endoscopic dilatation or insertion of
expandable metallic stents for relief of dysphagia or vomiting.
A nasogastric tube may offer temporary relief of vomiting due
to gastric outlet obstruction (Box 21 .41).
Diseases of the small intestine • 805
21 .41 How to insert a nasogastric tube
Equipment
• 8-9F ‘fine-bore’ tube for feeding or 16-18F ‘wide-bore’ tube for
drainage
• Lubricant jelly
• Cup of water and straw for sipping
• Adhesive tape
• pH (not litmus) paper
• Sickness bowl and tissues
• Catheter drainage bag and clamp (for drainage)
Technique
• A clear explanation and a calm patient are essential
• Establish a ‘stop signal’ for the patient to use, if needed
• Ask the patient to sit semi-upright
• Examine the nose for deformity or blockage to determine which side
to use
• Measure the distance from ear to xiphoid process via the nose and
mark the position on the tube
• Advance the lubricated tube tip slowly along the floor of the nasal
passage to the oropharynx
• Ask the patient to sip water and advance the tube 2-3 cm with
each swallow
• Stop, withdraw and retry if the patient is distressed or coughing, as
the tube may have entered the larynx
• Advance until the mark on the tube reaches the tip of the nose and
secure with tape
• Aspirate the contents and check pH (gastric acid confirmed if pH
<5). If in doubt, perform a chest X-ray to confirm tube position
(usually necessary with feeding tubes)
• Attach the catheter drainage bag, if necessary, and clamp
Aftercare
• Flush the tube daily after feeding or drug dosing
• Check position regularly and look for signs of displacement
• Check with the pharmacist what drugs, if any, can be safely given
via the tube
Gastric lymphoma
This is a rare tumour, accounting for less than 5% of all gastric
malignancies. The stomach is, however, the most common site
for extranodal non-Hodgkin lymphoma and 60% of all primary
gastrointestinal lymphomas occur at this site. Lymphoid tissue
is not found in the normal stomach but lymphoid aggregates
develop in the presence of H. pylori infection. Indeed, H. pylori
infection is closely associated with the development of a low-grade
lymphoma (classified as extranodal marginal-zone lymphomas of
MALT type). EUS plays an important role in staging these lesions
by accurately defining the depth of invasion into the gastric wall.
The clinical presentation is similar to that of gastric cancer and
endoscopically the tumour appears as a polypoid or ulcerating
mass. While initial treatment of low-grade lesions confined to
the superficial layers of the gastric wall consists of H. pylori
eradication and close observation, 25% contain t(11:18)
chromosomal translocations. In these cases, additional
radiotherapy or chemotherapy is usually necessary. High-grade
B-cell lymphomas should be treated by a combination of rituximab,
chemotherapy (p. 962), surgery and radiotherapy. The choice
depends on the site and extent of tumour, the presence of
comorbid illnesses, and other factors, such as symptoms of
bleeding and gastric outflow obstruction. The prognosis depends
on the stage at diagnosis. Features predicting a favourable
prognosis are stage I or II disease, small resectable tumours,
tumours with low-grade histology, and age below 60 years.
Other tumours of the stomach
Gastrointestinal stromal cell tumours (GISTs), arising from
the interstitial cells of Cajal, are occasionally found at upper
gastrointestinal endoscopy. They are differentiated from other
mesenchymal tumours by expression of the c-kit proto-oncogene,
which encodes a tyrosine kinase receptor. These tumours,
particularly the smaller lesions of less than 2 cm, are usually
benign and asymptomatic, but the larger ones may have malignant
potential and may occasionally be responsible for dyspepsia,
ulceration and gastrointestinal bleeding. Small lesions (<2 cm) are
usually followed by endoscopy, while larger ones require surgical
resection. Very large lesions should be treated pre-operatively
with imatinib (a tyrosine kinase inhibitor) to reduce their size
and make surgery easier. Imatinib can also provide prolonged
control of metastatic GISTs.
A variety of polyps occur. Hyperplastic polyps and fundic cystic
gland polyps are common and of no consequence. Adenomatous
polyps are rare but have malignant potential and should be
removed endoscopically.
Occasionally, gastric carcinoid tumours are seen in the fundus
and body in patients with long-standing pernicious anaemia. These
benign tumours arise from ECL or other endocrine cells, and
are often multiple but rarely invasive. Unlike carcinoid tumours
arising elsewhere in the gastrointestinal tract, they usually run a
benign and favourable course. Large (>2 cm) carcinoids may,
however, metastasise and should be removed. Rarely, small
nodules of ectopic pancreatic exocrine tissue are found. These
‘pancreatic rests’ may be mistaken for gastric neoplasms and
usually cause no symptoms. EUS is the most useful investigation.
Diseases of the small intestine
Disorders causing malabsorption
Coeliac disease
Coeliac disease is an inflammatory disorder of the small bowel
occurring in genetically susceptible individuals, which results from
intolerance to wheat gluten and similar proteins found in rye, barley
and, to a lesser extent, oats. It can result in malabsorption and
responds to a gluten-free diet. The condition occurs worldwide
but is more common in northern Europe. The prevalence in
the UK is approximately 1%, although 50% of these people
are asymptomatic. These include both undiagnosed ‘silent’
cases of the disease and cases of ‘latent’ coeliac disease -
genetically susceptible people who may later develop clinical
coeliac disease.
Pathophysiology
The precise mechanism of mucosal damage is unclear but
immunological responses to gluten play a key role (Fig. 21 .41).
There is a strong genetic component, with around 10% of
first-degree relatives of an index case affected, and there is
strong (approximately 75%) concordance in monozygotic twins.
There is a strong association with human leukocyte antigen
(HLA)-DQ2/DQ8. Dysbiosis of the intestinal microbiota has been
identified but it is unclear if this is pathological or a response to
the underlying mucosal changes.
806 • GASTROENTEROLOGY
Q O
Gluten peptides
presenting
cell
Fig. 21.41 Pathophysiology of coeliac disease. After being taken up by epithelial cells, gluten peptides are deamidated by the enzyme tissue
transglutaminase in the subepithelial layer. They are then able to fit the antigen-binding motif on human leucocyte antigen (HLA)-DQ2-positive antigen-
presenting cells. Recognition by CD4+ T cells triggers a Th-i immune response with generation of pro-inflammatory cytokines: interleukin-1 (IL-1), interferon
gamma (IFN-7) and tumour necrosis factor alpha (TNF-a). Lymphocytes infiltrate the lamina propria and an increase in intra-epithelial lymphocytes (lELs),
crypt hyperplasia and villous atrophy ensue.
Clinical features
Coeliac disease can present at any age. In infancy, it occurs
after weaning on to cereals and typically presents with diarrhoea,
malabsorption and failure to thrive. In older children, it may present
with non-specific features, such as delayed growth. Features
of malnutrition are found on examination and mild abdominal
distension may be present. Affected children have growth and
pubertal delay, leading to short stature in adulthood.
In adults, the disease usually presents during the third or
fourth decade and females are affected twice as often as
males. The presentation is highly variable, depending on the
severity and extent of small bowel involvement. Some have florid
malabsorption, while others develop non-specific symptoms,
such as tiredness, weight loss, folate deficiency or iron deficiency
anaemia. Other presentations include oral ulceration, dyspepsia
and bloating. Unrecognised coeliac disease is associated with
mild under-nutrition and osteoporosis.
Coeliac disease is associated with other HLA-linked autoimmune
disorders and with certain other diseases (Box 21 .42). In some
centres, people at higher risk of developing coeliac disease, such
as those with type 1 diabetes, may undergo periodic antibody
screening. Such screening may identify people with asymptomatic
or minimally symptomatic disease; there is controversy about the
optimum management strategy for such individuals.
Investigations
These are performed to confirm the diagnosis and to look for
consequences of malabsorption.
Duodenal biopsy
Endoscopic small bowel biopsy is the gold standard. Endoscopic
appearances should not preclude biopsy, as the mucosa usually
looks normal. As the histological changes can be patchy, an
adequate number of biopsies - currently, more than four biopsies
from the second part of the duodenum plus one from the
duodenal bulb - should be retrieved. The histological features are
21.42 Disease associations of coeliac disease
• Type 1 diabetes mellitus
•
Myasthenia gravis
(2-8%)
•
Dermatitis herpetiformis
• Thyroid disease (5%)
•
Down’s syndrome
• Primary biliary cirrhosis (3%)
•
Enteropathy-associated T-cell
• Sjogren’s syndrome (3%)
lymphoma
• Immunoglobulin A deficiency
•
Small bowel carcinoma
(2%)
•
Squamous carcinoma of
• Pernicious anaemia
oesophagus
• Sarcoidosis
•
Ulcerative jejunitis
• Neurological complications:
•
Pancreatic insufficiency
Encephalopathy
•
Microscopic colitis
Cerebellar atrophy
•
Splenic atrophy
Peripheral neuropathy
Epilepsy
21.43 Important causes of subtotal villous atrophy
• Coeliac disease
• Giardiasis
• Tropical sprue
• Hypogammaglobulinaemia
• Dermatitis herpetiformis
• Radiation
• Lymphoma
• Whipple’s disease
• HIV-related enteropathy
• Zollinger— Ellison syndrome
usually characteristic but other causes of villous atrophy should
be considered (Box 21.43 and Fig. 21.42). Sometimes the villi
appear normal but there are excess numbers of intra-epithelial
lymphocytes (lymphocytic duodenosis).
Antibodies
Antibody tests constitute a valuable screening tool in patients
with diarrhoea or other suggestive symptoms but are not a
diagnostic substitute for small bowel biopsy at present. Tissue
transglutaminase (tTG) is now recognised as the autoantigen for
Diseases of the small intestine • 807
Fig. 21.42 Jejunal mucosa. [A] Normal Jp Subtotal villous atrophy in coeliac disease. There is blunting of villi (B), crypt hyperplasia (H) and inflammatory
infiltration of the lamina propria (I).
anti-endomysial antibodies. If the antibody screen is positive,
adult patients should remain on a gluten-containing diet until
duodenal biopsies are taken. High-titre serology in children
can be diagnostic without the need for endoscopy and biopsy.
Antibody titres usually become negative with successful treatment.
Anti-endomysial antibodies of the IgA class are detectable by
immunofluorescence in most untreated cases. They are sensitive
(85-95%) and specific (approximately 99%) for the diagnosis,
except in very young infants. IgG antibodies, however, must be
analysed in patients with coexisting IgA deficiency. The tTG assay
has become the serological test of choice in many countries,
as it is easier to perform, is semi-quantitative, has more than
95% sensitivity and specificity, and is more accurate in patients
with IgA deficiency.
Haematology and biochemistry
A full blood count may show microcytic or macrocytic anaemia
from iron or folate deficiency and features of hyposplenism (target
cells, spherocytes and Howell-Jolly bodies). Biochemical tests
may reveal reduced concentrations of calcium, magnesium,
total protein, albumin or vitamin D. Serum IgA measurement is
required to ensure an appropriate IgA response and to allow
analysis of serological testing.
Other investigations
Measurement of bone density should be considered to look
for evidence of osteoporosis, especially in older patients and
post-menopausal women.
Management
The aims are to correct existing deficiencies of micronutrients,
such as iron, folate, calcium and/or vitamin D, and to achieve
mucosal healing through a life-long gluten-free diet. This requires
the exclusion of wheat, rye, barley and initially oats, although oats
may be re-introduced safely in most patients after 6-1 2 months.
Initially, frequent dietary counselling is required to make sure the
diet is being observed, as the most common reason for failure
to improve with dietary treatment is accidental or unrecognised
gluten ingestion. Mineral and vitamin supplements are also given
when indicated but are seldom necessary when a strict gluten-free
diet is adhered to. Booklets produced by coeliac societies in
many countries, containing diet sheets and recipes for the use
of gluten-free flour, are of great value. Dietetic follow-up is key
to management. Patients should be followed up after initiation
of a gluten-free diet, with assessment of symptoms, weight and
nutritional status, and blood should be taken for measurement
of tTG or anti-endomysial antibodies. There are currently no
additional non-invasive tests to assess small bowel mucosal
healing. Repeat small bowel biopsies are not required routinely
but should be considered in patients whose symptoms fail to
improve and those in whom antibody levels remain high. In these
circumstances, if the diet is satisfactory, then other conditions,
such as pancreatic insufficiency or microscopic colitis, should
be sought, as should complications of coeliac disease, such as
ulcerative jejunitis or enteropathy-associated T-cell lymphoma.
There remain a small number of patients who fail to respond
adequately to a gluten-free diet and they require therapy with
glucocorticoids or immunosuppressive drugs.
Complications
A twofold-increased risk of malignancy, particularly of enteropathy-
associated T-cell lymphoma, small bowel carcinoma and
squamous carcinoma of the oesophagus, has been reported.
A few patients develop ulcerative jejuno-ileitis. This may present
with fever, pain, obstruction or perforation. This diagnosis can
be made by barium studies or enteroscopy but laparotomy and
full-thickness biopsy may be required. Treatment is difficult.
Glucocorticoids are used with mixed success and some patients
require surgical resection and parenteral nutrition. The course
is often progressive.
Osteoporosis and osteomalacia may occur in patients with long¬
standing, poorly controlled coeliac disease. These complications
are less common in those who adhere strictly to a gluten -free diet.
Dermatitis herpetiformis
This is characterised by crops of intensely itchy blisters over the
elbows, knees, back and buttocks (p. 1256). Immunofluorescence
shows granular or linear IgA deposition at the dermo-epidermal
junction. Almost all patients have partial villous atrophy on
duodenal biopsy, identical to that seen in coeliac disease,
even though they usually have no gastrointestinal symptoms.
In contrast, fewer than 1 0% of coeliac patients have evidence of
dermatitis herpetiformis, although both disorders are associated
with the same histocompatibility antigen groups. The rash usually
responds to a gluten-free diet but some patients require additional
treatment with dapsone (100-150 mg daily).
| Tropical sprue
Tropical sprue is defined as chronic, progressive malabsorption in
a patient in or from the tropics, associated with abnormalities of
small intestinal structure and function. The disease occurs mainly
in the West Indies and in southern India, Malaysia and Indonesia.
Pathophysiology
The epidemiological pattern and occasional epidemics suggest
that an infective agent may be involved. Although no single
bacterium has been isolated, the condition often begins after
an acute diarrhoeal illness. Small bowel bacterial overgrowth
with Escherichia coli, Enterobacter and Klebsiella is frequently
seen. The changes closely resemble those of coeliac disease.
808 • GASTROENTEROLOGY
Clinical features
There is diarrhoea, abdominal distension, anorexia, fatigue
and weight loss. In visitors to the tropics, the onset of severe
diarrhoea may be sudden and accompanied by fever. When the
disorder becomes chronic, the features of megaloblastic anaemia
(vitamin B12 and folic acid malabsorption) and other deficiencies,
including ankle oedema, glossitis and stomatitis, are common.
Remissions and relapses may occur. The differential diagnosis
in the indigenous tropical population is an infective cause of
diarrhoea. The important differential diagnosis in visitors to the
tropics is giardiasis (p. 287).
Management
Tetracycline (250 mg 4 times daily for 28 days) is the treatment
of choice and brings about long-term remission or cure. In most
patients, pharmacological doses of folic acid (5 mg daily) improve
symptoms and jejunal morphology. In some cases, treatment
must be prolonged before improvement occurs and occasionally
patients must leave the tropics.
I Small bowel bacterial overgrowth
(‘blind loop syndrome’)
The normal duodenum and jejunum contain fewer than 104/mL
organisms, which are usually derived from saliva. The count
of coliform organisms never exceeds 103/ml_. In bacterial
overgrowth, there may be 1 08-1 010/ml_ organisms, most of which
are normally found only in the colon. Disorders that impair the
normal physiological mechanisms controlling bacterial proliferation
in the intestine predispose to bacterial overgrowth (Box 21 .44).
The most important are loss of gastric acidity, impaired intestinal
motility and structural abnormalities that allow colonic bacteria to
gain access to the small intestine or provide a secluded haven
from the peristaltic stream.
Pathophysiology
Bacterial overgrowth can occur in patients with small bowel
diverticuli. Another cause is diabetic autonomic neuropathy
(p. 760), which reduces small bowel motility and affects enterocyte
secretion. In systemic sclerosis, bacterial overgrowth arises
because the circular and longitudinal layers of the intestinal
muscle are fibrosed and motility is abnormal. In idiopathic
21.44 Causes of small bowel bacterial overgrowth
Mechanism
Examples
Hypo- or achlorhydria
Pernicious anaemia
Partial gastrectomy
Long-term proton pump inhibitor
therapy
Impaired intestinal motility
Systemic sclerosis
Diabetic autonomic neuropathy
Chronic intestinal pseudo-obstruction
Structural abnormalities
Gastric surgery (blind loop after
Billroth II operation)
Jejunal diverticulosis
Enterocolic fistulae*
Extensive small bowel resection
Strictures*
Impaired immune function
Hypogammaglobulinaemia
*Most commonly caused by Crohn’s disease.
hypogammaglobulinaemia (p. 78), bacterial overgrowth occurs
because the IgA and IgM levels in serum and jejunal secretions
are reduced. Chronic diarrhoea and malabsorption occur because
of bacterial overgrowth and recurrent gastrointestinal infections
(particularly giardiasis, p. 287).
Clinical features
The patient presents with watery diarrhoea and/or steatorrhoea,
and with anaemia due to B12 deficiency. These arise because of
deconjugation of bile acids, which impairs micelle formation, and
because of bacterial utilisation of vitamin B12. There may also
be symptoms from the underlying intestinal cause.
Investigations
The diagnosis of blind loops or fistulae can often be made by
barium small bowel meal and follow-through or small bowel
MRI enterography. Endoscopic duodenal biopsies are useful in
excluding coeliac disease. Jejunal contents for bacteriological
examination can also be aspirated at endoscopy but laboratory
analysis requires anaerobic and aerobic culture techniques.
Bacterial overgrowth can also be diagnosed non-invasively using
hydrogen breath tests, although they lack sensitivity. These
simple, non-radioactive tests involve serial measurement of breath
samples for hydrogen after oral ingestion of 50 g of glucose or
lactulose. If bacteria are present within the small bowel, they
rapidly metabolise the glucose, causing an early rise in exhaled
hydrogen, in advance of that normally resulting from metabolism
by colonic flora. Biochemical analysis may reveal low serum levels
of vitamin B12, with normal or elevated folate levels because the
bacteria produce folic acid. Hypogammaglobulinaemia can be
diagnosed by measurement of serum immunoglobulins and by
intestinal biopsy, which shows reduced or absent plasma cells
and nodular lymphoid hyperplasia.
Management
The underlying cause of small bowel bacterial overgrowth should be
addressed, where possible. A course of broad-spectrum antibiotic
for 2 weeks is the first-line treatment, although there is no consensus
on agent or dose. Examples include tetracycline (250 mg 4 times
daily), metronidazole (400 mg 3 times daily), amoxicillin (250 mg
3 times daily) or ciprofloxacin (250 mg twice daily). If breath testing
reveals high methane production, addition of neomycin (500 mg
twice daily) may be beneficial. Up to 50% of patients do not respond
adequately and relapse rates are high. Some patients require up to
4 weeks of treatment and, in a few, continuous rotating courses
of antibiotics are necessary. Consideration should be given to the
risk of emerging antimicrobial resistance. Intramuscular vitamin
B12 supplementation may be needed in chronic cases, as the
bacteria utilise vitamin B12. Patients with motility disorders, such
as diabetes and systemic sclerosis, can sometimes benefit from
antidiarrhoeal drugs (diphenoxylate (5 mg 3 times daily orally)
or loperamide (2 mg 4-6 times daily) orally). Giardiasis should
if
• Coeliac disease: symptoms such as dyspepsia tend to be vague;
only 25% present classically with diarrhoea and weight loss.
Metabolic bone disease, folate or iron deficiency, coagulopathy and
small bowel lymphoma are more common.
• Small bowel bacterial overgrowth: more common due to atrophic
gastritis, resulting in hypo- or achlorhydria, increased prevalence of
jejunal diverticulosis and long-term adverse effects of gastric
surgery for ulcer disease.
21.45 Malabsorption in old age
Diseases of the small intestine • 809
be controlled in patients with hypogammaglobulinaemia using
metronidazole or tinidazole, but if symptoms fail to respond
adequately, immunoglobulin infusions may be required.
Whipple’s disease
This rare condition is characterised by infiltration of small intestinal
mucosa by ‘foamy’ macrophages, which stain positive with
periodic acid-Schiff (PAS) reagent. The disease is a multisystem
one and almost any organ can be affected, sometimes long before
gastrointestinal involvement becomes apparent (Box 21 .46).
Pathophysiology
Whipple’s disease is caused by infection with the Gram-positive
bacillus Tropheryma whipplei, which becomes resident within
macrophages in the bowel mucosa. Villi are widened and flattened,
containing densely packed macrophages in the lamina propria,
which obstruct lymphatic drainage and cause fat malabsorption.
Clinical features
Middle-aged Caucasian men are most frequently affected and
presentation depends on the pattern of organ involvement.
Low-grade fever is common and most patients have joint
symptoms to some degree, often as the first manifestation.
Occasionally, neurological manifestations may predominate and
CNS involvement is the most serious consequence.
Investigations
Diagnosis is made by the characteristic features on small bowel
biopsy, with characterisation of the bacillus by polymerase chain
reaction (PCR).
Management
Whipple’s disease is often fatal if untreated but responds well, at
least initially, to intravenous ceftriaxone (2 g daily for 2 weeks),
followed by oral co-trimoxazole for at least 1 year. Symptoms
21.46 Clinical features of Whipple’s disease
Gastrointestinal (>70%)
• Diarrhoea (75%)
• Steatorrhoea
• Weight loss (90%)
Musculoskeletal (65%)
• Protein-losing enteropathy
• Ascites
• Hepatosplenomegaly (<5%)
• Seronegative large joint
• Sacroiliitis
arthropathy
Cardiac (10%)
• Pericarditis
• Endocarditis
• Myocarditis
• Coronary arteritis
Neurological (10-40%)
• Apathy
• Myoclonus
• Fits
• Meningitis
• Dementia
• Cranial nerve lesions
Pulmonary (10-20%)
• Chronic cough
• Pulmonary infiltrates
• Pleurisy
Haematological (60%)
• Anaemia
• Lymphadenopathy
Other (40%)
• Fever
• Pigmentation
usually resolve quickly and biopsy changes revert to normal in a
few weeks. Long-term follow-up is essential, as clinical relapse
occurs in up to one-third of patients, often within the CNS; in
this case, the same therapy is repeated or else treatment with
doxycycline and hydroxychloroquine is necessary.
Bile acid diarrhoea
Bile acid diarrhoea can occur idiopathically (type 1), as a
complication of small bowel resection, post cholecystectomy
(type 2) or in association with other conditions such as microscopic
colitis, chronic pancreatitis, coeliac disease, small intestinal bacterial
overgrowth or diabetes mellitus. The population prevalence is
estimated at around 1 % and the disease is often under-diagnosed.
It is now appreciated that many patients diagnosed with diarrhoea-
predominant irritable bowel syndrome have evidence of bile acid
diarrhoea. The most common scenario is in patients with Crohn’s
disease who have undergone ileal resection, which can also lead
to other malabsorptive manifestations (Fig. 21 .43). Unabsorbed
bile salts pass into the colon, stimulating water and electrolyte
secretion and causing diarrhoea. If hepatic synthesis of new bile
acids cannot keep pace with faecal losses, fat malabsorption
occurs. Another consequence is the formation of lithogenic
bile, leading to gallstones. Renal calculi, rich in oxalate, develop.
Normally, oxalate in the colon is bound to and precipitated by
calcium. Unabsorbed bile salts preferentially bind calcium, leaving
oxalate to be absorbed, with development of urinary oxalate calculi.
Patients have urgent watery diarrhoea or mild steatorrhoea.
Contrast studies and tests of B12 and bile acid absorption, such
as the 75Se-homocholic acid taurine (SeHCAT) test (p. 777), are
useful investigations but are not available throughout the world
due to use of synthetic radio-labelled compound. An elevated
serum 7a-hydroxycholestenone is a useful non-invasive marker
of bile acid diarrhoea. Diarrhoea usually responds well to bile
acid sequestrants, such as colestyramine or colesevelam, which
bind bile salts in the intestinal lumen. Aluminium hydroxide can
be used as an alternative.
Short bowel syndrome
This is discussed in detail on page 708.
Radiation enteritis and proctocolitis
Intestinal damage occurs in 10-15% of patients undergoing
radiotherapy for abdominal or pelvic malignancy. The risk varies
with total dose, dosing schedule and the use of concomitant
chemotherapy.
Pathophysiology
The rectum, sigmoid colon and terminal ileum are most frequently
involved. Radiation causes acute inflammation, shortening
of villi, oedema and crypt abscess formation. These usually
resolve completely but some patients develop an obliterative
endarteritis affecting the endothelium of submucosal arterioles
over 2-12 months. In the longer term, this can provoke a fibrotic
reaction, leading to adhesions, ulceration, strictures, obstruction
or fistula to adjacent organs.
Clinical features
In the acute phase, there is nausea, vomiting, cramping abdominal
pain and diarrhoea. When the rectum and colon are involved,
rectal mucus, bleeding and tenesmus occur. The chronic phase
develops after 5-1 0 years in some patients and produces one
or more of the problems listed in Box 21 .47.
810 • GASTROENTEROLOGY
Decreased bile salt
pool, lithogenic bile
leading to gallstones
Impaired micelle
formation and fat
malabsorption
Impaired bile salt
absorption leading
to watery diarrhoea
B-12 malabsorption
Fig. 21.43 Consequences of ileal resection.
i
• Proctocolitis
• Bleeding from telangiectasia
• Small bowel strictures
• Fistulae: rectovaginal, colovesical, enterocolic
• Adhesions
• Malabsorption: bacterial overgrowth, bile acid diarrhoea (ileal
damage)
Investigations
In the acute phase, the rectal changes at sigmoidoscopy resemble
ulcerative proctitis (see Fig. 21 .53, p. 81 9). An endoscopic biopsy
from the rectal wall is associated with a 2% risk of fistula formation.
The extent of the lesion can be assessed by colonoscopy. Barium
follow-through or MRI enterography can be of diagnostic value in
showing small bowel strictures, ulcers and fistulae.
Management
Diarrhoea in the acute phase should be treated with codeine
phosphate, diphenoxylate or loperamide. Antibiotics may be
required for bacterial overgrowth. Nutritional supplements are
necessary when malabsorption is present. Colestyramine or
colesevelam is useful for bile acid diarrhoea. Surgery should be
avoided, if possible, because the injured intestine is difficult to
resect and anastomose, but may be necessary for obstruction,
perforation or fistula.
In radiation proctitis, the underlying pathophysiology is tissue
ischaemia rather than inflammation; glucocorticoid enemas are
therefore not effective. Traditionally, endoscopic argon plasma
coagulation therapy was used but this is of limited benefit and
can induce fistula, stricture or perforation. Effective treatments
include sucralfate enema and hyperbaric oxygen.
Abetalipoproteinaemia
This rare autosomal recessive disorder is caused by deficiency of
apolipoprotein B, which results in failure of chylomicron formation.
It leads to fat malabsorption and deficiency of fat-soluble vitamins.
Jejunal biopsy reveals enterocytes distended with resynthesised
triglyceride and normal villous morphology. Serum cholesterol and
triglyceride levels are low. A number of other abnormalities occur
in this syndrome, including acanthocytosis, retinitis pigmentosa
and a progressive neurological disorder with cerebellar and
dorsal column signs. Symptoms may be improved by a low-fat
diet supplemented with medium-chain triglycerides and vitamins
A, D, E and K.
Motility disorders
Chronic intestinal pseudo-obstruction
Small intestinal motility is disordered in conditions that affect
the smooth muscle or nerves of the intestine. Many cases are
‘primary’ (idiopathic), while others are ‘secondary’ to a variety
of disorders or drugs (Box 21 .48).
Clinical features
There are recurrent episodes of nausea, vomiting, abdominal
discomfort and distension, often worse after food. Alternating
constipation and diarrhoea occur and weight loss results from
malabsorption (due to bacterial overgrowth) and fear of eating.
There may also be symptoms of dysmotility affecting other parts
of the gastrointestinal tract, such as dysphagia, and features of
bladder dysfunction in primary cases. Some patients develop
severe abdominal pain for reasons that are poorly understood
and this can be difficult to manage.
Investigations
The diagnosis is often delayed and a high index of suspicion is
needed. Plain X-rays show distended loops of bowel and air-fluid
levels but barium studies demonstrate no mechanical obstruction.
Laparotomy is sometimes required to exclude obstruction and
to obtain full-thickness biopsies of the intestine. Examination of
biopsy material using specialised techniques, such as electron
microscopy, and immunohistochemistry can diagnose the many
21.47 Chronic complications of intestinal irradiation
Diseases of the small intestine • 811
21.48 Causes of chronic intestinal
pseudo-obstruction
Primary or idiopathic
• Rare familial visceral myopathies or neuropathies
• Congenital aganglionosis
Secondary
• Drugs (opiates, tricyclic antidepressants, phenothiazines)
• Smooth muscle disorders (systemic sclerosis, amyloidosis,
mitochondrial myopathies)
• Myenteric plexus disorders, e.g. paraneoplastic syndrome in
small-cell lung cancer
• Central nervous system disorders (Parkinson’s disease, autonomic
neuropathy)
• Endocrine and metabolic disorders (hypothyroidism,
phaeochromocytoma, acute intermittent porphyria)
rare diseases of enteric smooth muscle and nerves that can
cause this syndrome.
Management
This is often difficult. Underlying causes should be addressed
and further surgery avoided. Metoclopramide or domperidone
may enhance motility and antibiotics are given for bacterial
overgrowth. Nutritional and psychological support is also
necessary.
Miscellaneous disorders of the
small intestine
Protein-losing enteropathy
This term is used when there is excessive loss of protein into the
gut lumen, sufficient to cause hypoproteinaemia. Protein-losing
enteropathy occurs in many gut disorders but is most common in
those in which ulceration occurs (Box 21 .49). In other disorders,
protein loss can result from increased mucosal permeability
or obstruction of intestinal lymphatic vessels. Patients present
with peripheral oedema and hypoproteinaemia in the presence
of normal liver function, low albumin and globulin, and without
proteinuria. The diagnosis can be confirmed by measurement of
faecal clearance of a1 -antitrypsin or 51Cr-labelled albumin after
intravenous injection. Other investigations should be performed
to determine the underlying cause. Treatment is that of the
underlying disorder, with nutritional support and measures to
control peripheral oedema.
1 21.49 Causes of protein-losing enteropathy
With mucosal erosions or ulceration
• Crohn’s disease
• Oesophageal, gastric or
• Ulcerative colitis
colonic cancer
• Radiation damage
• Lymphoma
Without mucosal erosions or ulceration
• Menetrier’s disease
• Tropical sprue
• Bacterial overgrowth
• Eosinophilic gastroenteritis
• Coeliac disease
• Systemic lupus erythematosus
With lymphatic obstruction
• Intestinal lymphangiectasia
• Lymphoma
• Constrictive pericarditis
• Whipple’s disease
| Intestinal lymphangiectasia
This may be primary, resulting from congenital malunion
of lymphatics, or secondary to lymphatic obstruction due
to lymphoma, filariasis or constrictive pericarditis. Impaired
drainage of intestinal lymphatic vessels leads to discharge
of protein and fat-rich lymph into the gastrointestinal lumen.
The condition presents with peripheral lymphoedema, pleural
effusions or chylous ascites, and steatorrhoea. Investigations
reveal hypoalbuminaemia, lymphopenia and reduced serum
immunoglobulin concentrations. The diagnosis can be made
by CT scanning and by enteroscopy with jejunal biopsy, which
shows greatly dilated lacteals. Treatment consists of a low-fat
diet with medium-chain triglyceride supplements.
Ulceration of the small intestine
Small bowel ulcers are uncommon and are either idiopathic or
secondary to underlying intestinal disorders (Box 21 .50). Ulcers
are more common in the ileum and cause bleeding, perforation,
stricture formation or obstruction. Barium studies and enteroscopy
confirm the diagnosis.
21.50 Causes of small intestinal ulcers
• Idiopathic
• Lymphoma and carcinoma
• Inflammatory bowel disease
• Infections (tuberculosis,
• Non-steroidal anti¬
typhoid, Yersinia
inflammatory drugs
enterocolitica)
• Ulcerative jejuno-ileitis
• Others (radiation, vasculitis)
NSAID-associated small intestinal toxicity
These drugs cause a spectrum of small intestinal lesions ranging
from erosions and ulcers to mucosal webs, strictures and, rarely,
a condition known as ‘diaphragm disease’, in which intense
submucosal fibrosis results in circumferential stricturing. The
condition can present with pain, obstruction, bleeding or anaemia,
and may mimic Crohn’s disease, carcinoma or lymphoma.
Enteroscopy or capsule endoscopy can reveal the diagnosis but
sometimes this is discovered only at laparotomy.
Eosinophilic gastroenteritis
This disorder of unknown aetiology can affect any part of the
gastrointestinal tract; it is characterised by eosinophil infiltration
involving the gut wall, in the absence of parasitic infection or
eosinophilia of other tissues. It may be mucosal, muscular or
subserosal. Peripheral blood eosinophilia is present in 80% of
cases.
Clinical features
There are features of obstruction and inflammation, such as
colicky pain, nausea and vomiting, diarrhoea and weight loss.
Protein-losing enteropathy occurs and up to 50% of patients
have a history of other allergic disorders. Serosal involvement
may produce eosinophilic ascites.
Investigations and management
The diagnosis is made by histological assessment of multiple
endoscopic biopsies, although full-thickness biopsies are
occasionally required. Other investigations should be performed
812 • GASTROENTEROLOGY
to exclude parasitic infection and other causes of eosinophilia.
The serum IgE concentration is often raised. Dietary manipulations
are rarely effective, although elimination diets, especially of milk,
may benefit a few patients. Severe symptoms are treated with
prednisolone (20-40 mg daily) and/or sodium cromoglicate,
which stabilises mast cell membranes. The prognosis is good
in the majority of patients.
|J/leckel’s diverticulum
This is the most common congenital anomaly of the gastrointestinal
tract and occurs in 0.3-3% of people, but the vast majority
of affected individuals are asymptomatic throughout life. The
diverticulum results from failure of closure of the vitelline duct,
with persistence of a blind-ending sac arising from the anti-
mesenteric border of the ileum; it usually occurs within 100 cm
of the ileocaecal valve and is up to 5 cm long. Approximately
50% contain ectopic gastric mucosa; rarely, colonic, pancreatic
or endometrial tissue is present. Complications most commonly
occur in the first 2 years of life but are occasionally seen in young
adults. Bleeding can result from ulceration of ileal mucosa adjacent
to the ectopic parietal cells and presents as recurrent melaena or
altered blood per rectum. The diagnosis can be made by scanning
the abdomen using a gamma counter following an intravenous
injection of 99mTc-pertechnetate, which is concentrated by ectopic
parietal cells. Other complications include intestinal obstruction,
diverticulitis, intussusception and perforation. Intervention is
unnecessary unless complications occur.
Adverse food reactions
Adverse food reactions are common and are subdivided into
food intolerance and food allergy, the former being much more
common. In food intolerance, there is an adverse reaction to food
that is not immune-mediated and results from pharmacological
(histamine, tyramine or monosodium glutamate), metabolic
(lactase deficiency) or other mechanisms (toxins or chemical
contaminants in food).
Lactose intolerance
Human milk contains around 200 mmol/L (68 g/L) of lactose,
which is normally digested to glucose and galactose by the brush
border enzyme lactase prior to absorption. In most populations,
enterocyte lactase activity declines throughout childhood. The
enzyme is deficient in up to 90% of adult Africans, Asians and
South Americans but only 5% of northern Europeans.
In cases of genetically determined (primary) lactase deficiency,
jejunal morphology is normal. ‘Secondary’ lactase deficiency occurs
as a consequence of disorders that damage the jejunal mucosa,
such as coeliac disease and viral gastroenteritis. Unhydrolysed
lactose enters the colon, where bacterial fermentation produces
volatile short-chain fatty acids, hydrogen and carbon dioxide.
Clinical features
In most people, lactase deficiency is completely asymptomatic.
However, some complain of colicky pain, abdominal distension,
increased flatus, borborygmi and diarrhoea after ingesting milk
or milk products. Irritable bowel syndrome may be suspected
but the correct diagnosis is suggested by clinical improvement
on lactose withdrawal. The lactose hydrogen breath test is a
useful non-invasive investigation.
Dietary exclusion of lactose is recommended, although most
sufferers are able to tolerate small amounts of milk without
symptoms. Addition of commercial lactase preparations to milk
has been effective in some studies but is costly.
| Intolerance of other sugars
‘Osmotic’ diarrhoea can be caused by sorbitol, an unabsorbable
carbohydrate that is used as an artificial sweetener. Fructose
contained within fruit juices may also cause diarrhoea if it is
consumed in greater quantities than can be absorbed.
Food allergy
Food allergies are immune-mediated disorders, most commonly
due to type I hypersensitivity reactions with production of IgE
antibodies, although type IV delayed hypersensitivity reactions
are also seen (p. 83). Up to 20% of the population perceive
themselves as suffering from food allergy but only 1-2% of adults
and 5-7% of children have genuine food allergies. The most
common culprits are peanuts, milk, eggs, soya and shellfish.
Clinical manifestations occur immediately on exposure and
range from trivial to life-threatening or even fatal anaphylaxis.
The common oral allergy syndrome results from contact with
benzoic acid in certain fresh fruit juices, leading to urticaria and
angioedema of the lips and oropharynx. This is not, however,
an immune-mediated reaction. ‘Allergic gastroenteropathy’ has
features similar to eosinophilic gastroenteritis, while ‘gastro¬
intestinal anaphylaxis’ consists of nausea, vomiting, diarrhoea
and sometimes cardiovascular and respiratory collapse. Fatal
reactions to trace amounts of peanuts are well documented.
The diagnosis of food allergy is difficult to prove or refute.
Skin-prick tests and measurements of antigen-specific IgE
antibodies in serum have limited predictive value. Double-blind
placebo-controlled food challenges are the gold standard but
are laborious and are not readily available. In many cases, clinical
suspicion and trials of elimination diets are used.
Treatment of proven food allergy consists of detailed patient
education and awareness, strict elimination of the offending
antigen, and, in some cases, antihistamines or sodium
cromoglicate. Anaphylaxis should be treated as a medical
emergency with resuscitation, airway support and intravenous
adrenaline (epinephrine). Teachers and other carers of affected
children should be trained to deal with this. Patients should
wear an information bracelet and be taught to carry and use a
preloaded adrenaline syringe.
Infections of the small intestine
i Travellers’ diarrhoea, giardiasis
and amoebiasis
See pages 232, 287 and 286.
Abdominal tuberculosis
Mycobacterium tuberculosis is a rare cause of abdominal disease
in Caucasians but must be considered in people in and from
the developing world and in AIDS patients. Gut infection usually
results from human M. tuberculosis, which is swallowed after
coughing. Many patients have no pulmonary symptoms and a
normal chest X-ray.
The area most commonly affected is the ileocaecal region. The
presentation and radiological findings may be very similar to those
of Crohn’s disease. Abdominal pain can be acute or of several
months’ duration but diarrhoea is less common in tuberculosis
Inflammatory bowel disease • 813
than in Crohn’s disease. Low-grade fever is common but not
invariable. Like Crohn’s disease, tuberculosis can affect any part
of the gastrointestinal tract and perianal disease with fistula is
recognised. Peritoneal tuberculosis may result in peritonitis with
exudative ascites, associated with abdominal pain and fever.
Granulomatous hepatitis occurs.
Investigations
Abdominal tuberculosis causes an elevated ESR; a raised
serum alkaline phosphatase concentration suggests hepatic
involvement. Histological confirmation should be sought by
endoscopy, laparoscopy or liver biopsy. Caseation of granulomas
is not always seen and acid- and alcohol-fast bacteria are often
scanty. Culture may be helpful but identification of the organism
may take 6 weeks and diagnosis is now possible on biopsy
specimens using PCR-based techniques.
Management
When the presentation is very suggestive of abdominal
tuberculosis, chemotherapy with multiple anti-tuberculous drugs
should be commenced, even if bacteriological or histological
proof is lacking. Isoniazid, pyrazinamide and ethambutol is a
common standard regime (p. 590), though the precise choice
will be dependent on local drug resistance patterns.
|j)ryptosporidiosis
Cryptosporidiosis and other protozoal infections, including
cystoisosporiasis (Cystoisospora belli) and microsporidiosis,
are dealt with on pages 287 and 317.
Tumours of the small intestine
The small intestine is rarely affected by neoplasia and fewer than
5% of all gastrointestinal tumours occur at this site.
Benign tumours
The most common are adenomas, GISTs, lipomas and
hamartomas. Adenomas are most often found in the periampullary
region and are usually asymptomatic, although occult bleeding
or obstruction due to intussusception may occur. Transformation
to adenocarcinoma is rare. Multiple adenomas are common in
the duodenum of patients with familial adenomatous polyposis
(FAP), who merit regular endoscopic surveillance. Hamartomatous
polyps with almost no malignant potential occur in Peutz-Jeghers
syndrome (p. 829).
| Malignant tumours
These are rare and include, in decreasing order of frequency,
adenocarcinoma, neuro-endocrine tumours, malignant GIST and
lymphoma. The majority occur in middle age or later. Kaposi’s
sarcoma of the small bowel may arise in patients with AIDS.
Adenocarcinomas
Adenocarcinomas occur with increased frequency in patients
with FAP, coeliac disease, small bowel Crohn’s disease and
Peutz-Jeghers syndrome. This is a rare cancer, accounting for
less than 5% of all gastrointestinal malignancies. The non-specific
presentation and rarity of these lesions often lead to a delay
in diagnosis. Despite advances in imaging and endoscopic
techniques, early diagnosis is difficult. Barium follow-through
examination or small bowel enterography studies demonstrate
most lesions of this type. Enteroscopy, capsule endoscopy,
mesenteric angiography and CT also play a role in investigation.
Treatment is by surgical resection.
Neuro-endocrine tumours
These are discussed in detail on page 678.
Lymphoma
Non-Hodgkin lymphoma (p. 964) may involve the gastrointestinal
tract as part of more generalised disease or may rarely arise
in the gut, the small intestine being most commonly affected.
Lymphomas occur with increased frequency in patients with
coeliac disease, HIV/AIDS and other immunodeficiency states.
Most are of B-cell origin, although lymphoma associated with
coeliac disease is derived from T cells (enteropathy-associated
T-cell lymphoma).
Colicky abdominal pain, obstruction and weight loss are the
presenting features and perforation is also seen occasionally.
Malabsorption is a feature of diffuse bowel involvement and
hepatosplenomegaly is rare.
The diagnosis is made by small bowel biopsy, radiological
contrast studies and CT. Staging investigations should be
performed as for lymphomas occurring elsewhere (p. 962).
Surgical resection, where possible, is the treatment of choice,
with radiotherapy and combination chemotherapy reserved for
those with advanced disease. The prognosis depends largely on
the stage at diagnosis, cell type, patient age and the presence
of ‘B’ symptoms (fever, weight loss, night sweats).
Immunoproliferative small intestinal disease
Immunoproliferative small intestinal disease (IPSID), also known
as alpha heavy chain disease, is a rare condition occurring mainly
in Mediterranean countries, the Middle East, India, Pakistan
and North America. It is a variant of B-cell lymphoma of MALT
type and often associated with Campylobacter jejuni infection.
The condition varies in severity from relatively benign to frankly
malignant.
The small intestinal mucosa is diffusely affected, especially
proximally, by a dense lymphoplasmacytic infiltrate. Enlarged
mesenteric lymph nodes are also common. Most patients are
young adults who present with malabsorption, anorexia and fever.
Serum electrophoresis confirms the presence of alpha heavy
chains (from the Fc portion of IgA). Prolonged remissions can be
obtained with long-term antibiotic therapy but chemotherapy is
required for those who fail to respond or who have aggressive
disease.
Inflammatory bowel disease
Ulcerative colitis and Crohn’s disease are chronic inflammatory
bowel diseases that pursue a protracted relapsing and remitting
course, usually extending over years. The diseases have many
similarities and it is sometimes impossible to differentiate between
them. One crucial distinction is that ulcerative colitis involves
only the colon, while Crohn’s disease can involve any part of
the gastrointestinal tract from mouth to anus. A summary of
the main features of ulcerative colitis and Crohn’s disease is
provided in Box 21 .51 .
The incidence of inflammatory bowel disease (IBD) varies
widely between populations. There was a dramatic increase in
the incidence of both ulcerative colitis and Crohn’s disease in the
Western world, starting in the second half of the last century and
814 • GASTROENTEROLOGY
21 .51 Comparison of ulcerative colitis and Crohn’s disease
Ulcerative colitis
Crohn’s disease
Age group
Any
Any
Gender
M = F
Slight female preponderance
Incidence
Stable
Increasing
Ethnic group
Any
Any; more common in Ashkenazi Jews
Genetic factors
HLA-DR*103] colonic epithelial barrier function
(HNF4oc, IAMBI, CDH1)
Defective innate immunity and autophagy ( N0D2 , ATG16L1,
IRGM)
Risk factors
More common in non-/ex-smokers
Appendicectomy protects
More common in smokers
Anatomical distribution
Colon only; begins at anorectal margin with
variable proximal extension
Any part of gastrointestinal tract; perianal disease common;
patchy distribution, skip lesions
Extra-intestinal manifestations
Common
Common
Presentation
Bloody diarrhoea
Variable; pain, diarrhoea, weight loss all common
Histology
Inflammation limited to mucosa; crypt distortion,
cryptitis, crypt abscesses, loss of goblet cells
Submucosal or transmural inflammation common; deep
fissuring ulcers, fistulae; patchy changes; granulomas
Management
5-ASA; glucocorticoids; azathioprine; biological
therapy (anti-TNF, anti-oc4(37 integrin);
colectomy is curative
Glucocorticoids; azathioprine; methotrexate; biological therapy
(anti-TNF, anti-oc4(37 integrin); nutritional therapy; smoking
cessation; surgery for complications is not curative; 5-ASA is
not effective
(5-ASA = 5-aminosalicylic acid; TNF =
tumour necrosis factor)
coinciding with the introduction of a more ‘hygienic’ environment
with the advent of domestic refrigeration and the widespread use
of antibiotics. The developing world has seen similar patterns,
as these countries adopt an increasingly Westernised lifestyle.
In the West, the incidence of ulcerative colitis is stable at
1 0-20 per 1 00 000, with a prevalence of 1 00-200 per 1 00 000,
while the incidence of Crohn’s disease is increasing and is now
5-10 per 100000, with a prevalence of 50-100 per 100000.
Both diseases most commonly start in the second and third
decades of life, with a second smaller incidence peak in the
seventh decade. Approximately 240 000 people are affected by
IBD in the UK (approximately 1 .4 million in the USA), equating
to a prevalence of about 1 in 250. Life expectancy in patients
with IBD is similar to that of the general population. Although
many patients require surgery and admission to hospital for other
reasons, with substantial associated morbidity, the majority have
an excellent work record and pursue a normal life.
Pathophysiology
IBD has both environmental and genetic components, and
evidence from genome-wide association studies suggests that
genetic variants that predispose to Crohn’s disease may have
undergone positive selection by protecting against infectious
diseases, including tuberculosis (Box 21 .52). It is thought that
IBD develops because these genetically susceptible individuals
mount an abnormal inflammatory response to environmental
triggers, such as intestinal bacteria. This leads to inflammation
of the intestine with involvement of a wide array of innate and
adaptive immune cell responses, with release of inflammatory
mediators, including TNF-a, IL-12 and IL-23, which cause
tissue damage (Fig. 21.44). There is an association between
microbial dysbiosis and IBD. For example, there is a reduced
diversity, primarily of Firmicutes and in particular, Faecalibacterium
prausnitzii. Functional changes in the bacteria are important and
include a reduction of anti-inflammatory metabolites, such as
21.52 Factors associated with the development of
inflammatory bowel disease
Genetic
• Both CD and UC are common in Ashkenazi Jews
• 10% have first-degree relative/1 or more close relative with IBD
• High concordance in identical twins (40-50% CD; 20-25% UC)
• 163 susceptibility loci identified at genome-wide levels of
significance; most confer susceptibility to both CD and UC; many
are also susceptibility loci for other inflammatory conditions
(especially ankylosing spondylosis and psoriasis)
• UC and CD are both associated with genetic variants at HLA locus,
and with multiple genes involved with immune signalling (especially
IL-23 and IL-10 pathways)
• CD is associated with genetic defects in innate immunity and
autophagy ( N0D2 , ATG16L1 and IRGM genes)
• UC is associated with genetic defects in barrier function
• N0D2 is associated with ileal and stricturing disease, and hence a
need for resectional surgery
• HLA-DR*103 is associated with severe UC
Environmental
• UC is more common in non-smokers and ex-smokers
• CD is more common in smokers (relative risk = 3)
• CD is associated with a low-residue, high-refined-sugar diet
• Commensal gut microbiota are altered (dysbiosis) in CD and UC
• Appendicectomy protects against UC
(CD = Crohn’s disease; HLA = human leucocyte antigen; IBD = inflammatory
bowel disease; IL = interleukin; UC = ulcerative colitis)
butyrate and other short-chain fatty acids. There is emerging
evidence that the virome and mycobiome (fungal species) may
be important in the development of IBD. In both diseases, the
intestinal wall is infiltrated with acute and chronic inflammatory
cells, but there are important differences between the conditions in
the distribution of lesions and in histological features (Fig. 21 .45).
Inflammatory bowel disease • 815
©
©
Fig. 21.44 Pathogenesis of inflammatory bowel disease. (1) Bacterial
antigens are taken up by specialised M cells, pass between leaky epithelial
cells or enter the lamina propria through ulcerated mucosa. (2) After
processing, they are presented to type 1 T-helper cells by antigen-
presenting cells (APCs) in the lamina propria. (3) T-cell activation and
differentiation results in a Th-i T cell-mediated cytokine response (4) with
secretion of cytokines, including interferon gamma (IFN-7). Further
amplification of T cells perpetuates the inflammatory process with
activation of non-immune cells and release of other important cytokines,
including interleukin 12 (IL-12), IL-23, IL-1, IL-6 and tumour necrosis
factor alpha (TNF-a). These pathways occur in all normal individuals
exposed to an inflammatory insult and this is self-limiting in healthy
subjects. In genetically predisposed persons, dysregulation of innate
immunity may trigger inflammatory bowel disease.
Ulcerative colitis
Inflammation invariably involves the rectum (proctitis) and spreads
proximally in a continuous manner to involve the entire colon in
some cases (pancolitis). In long-standing pancolitis, the bowel
can become shortened and post- inflammatory ‘pseudopolyps’
develop; these are normal or hypertrophied residual mucosa within
areas of atrophy (Fig. 21 .46). The inflammatory process is limited
to the mucosa and spares the deeper layers of the bowel wall
(Fig. 21 .47). Both acute and chronic inflammatory cells infiltrate
the lamina propria and the crypts (‘cryptitis’). Crypt abscesses
are typical. Goblet cells lose their mucus and, in long-standing
Ulcerative
colitis
Proctitis Left-sided colitis
40-50% 30-40%
Extensive colitis
(up to pancolitis)
20%
Crohn's
disease
Ileal or ileocolonic
40%
Small intestinal
30-40%
Crohn's colitis
c. 20%
Perianal disease alone
<10%
Fig. 21.45 Common patterns of disease distribution in inflammatory bowel disease.
816 • GASTROENTEROLOGY
Fig. 21.47 Histology of ulcerative colitis. There is surface ulceration
and inflammation is confined to the mucosa with excess inflammatory cells
in the lamina propria, loss of goblet cells, and crypt abscesses (arrows).
(SM = submucosa)
cases, glands become distorted. Dysplasia, characterised by
heaping of cells within crypts, nuclear atypia and increased mitotic
rate, may herald the development of colon cancer.
Crohn’s disease
The sites most commonly involved are, in order of frequency,
the terminal ileum and right side of colon, colon alone, terminal
ileum alone, ileum and jejunum. The entire wall of the bowel
is oedematous and thickened, and there are deep ulcers that
often appear as linear fissures; thus the mucosa between them
is described as ‘cobblestone’. These may penetrate through
the bowel wall to initiate abscesses or fistulae involving the
bowel, bladder, uterus, vagina and skin of the perineum. The
mesenteric lymph nodes are enlarged and the mesentery is
thickened. Crohn’s disease has a patchy distribution and the
inflammatory process is interrupted by islands of normal mucosa.
On histological examination, the bowel wall is thickened with a
chronic inflammatory infiltrate throughout all layers (Fig. 21 .48).
Clinical features
Ulcerative colitis
The cardinal symptoms are rectal bleeding with passage of mucus
and bloody diarrhoea. The presentation varies, depending on
the site and severity of the disease (see Fig. 21 .45), as well as
the presence of extra-intestinal manifestations. The first attack
is usually the most severe and is followed by relapses and
remissions. Emotional stress, intercurrent infection, gastroenteritis,
antibiotics or NSAID therapy may all provoke a relapse. Proctitis
causes rectal bleeding and mucus discharge, accompanied
by tenesmus. Some patients pass frequent, small-volume fluid
stools, while others pass pellety stools due to constipation
upstream of the inflamed rectum. Constitutional symptoms
do not occur. Left-sided and extensive colitis causes bloody
diarrhoea with mucus, often with abdominal cramps. In severe
cases, anorexia, malaise, weight loss and abdominal pain occur
and the patient is toxic, with fever, tachycardia and signs of
peritoneal inflammation (Box 21 .53).
Crohn’s disease
The major symptoms are abdominal pain, diarrhoea and weight
loss. Ileal Crohn’s disease (Figs 21 .49 and 21 .50) may cause
Fig. 21.48 Histology of Crohn’s disease. [A] Inflammation is
‘transmural’; there is fissuring ulceration (arrow), with inflammation
extending into the submucosa (SM). \B} At higher power, a characteristic
non-caseating granuloma is seen.
Fig. 21.49 Ileal Crohn’s disease. Small bowel magnetic resonance
image showing a terminal ileum that is thickened, narrowed and enhancing
(arrow), with dilatation immediately proximal to this.
subacute or even acute intestinal obstruction. The pain is often
associated with diarrhoea, which is usually watery and does not
contain blood or mucus. Almost all patients lose weight because
they avoid food, since eating provokes pain. Weight loss may
also be due to malabsorption and some patients present with
features of fat, protein or vitamin deficiencies. Crohn’s colitis
presents in an identical manner to ulcerative colitis but rectal
Inflammatory bowel disease • 817
21 .53 Assessment of disease severity in ulcerative colitis
Mild
Moderate
Severe
Daily bowel frequency
<4
4-6
>6*
Blood in stools
+/-
+/++
+++
Stool volume
<200 g/24 hrs
200-400 g/24 hrs
>400 g/24 hrs
Pulse
<90 beats/mi n
<90 beats/m in
>90 beats/m in*
Temperature
Normal
Normal
> 37.8°C*
Haemoglobin
Normal
Normal
<100 g/L (< 10 g/dL)*
Erythrocyte sedimentation rate
Normal
Normal
>30 mm/hr* (or equivalent C-reactive protein)
Serum albumin
>35 g/L (>3.5 g/dL)
<30 g/L (<3 g/dL)
Abdominal X-ray
Normal
Normal
Dilated bowel, mucosal islands, thumb-printing
of mucosa, or absence of features
Sigmoidoscopy
Normal or erythema/granular mucosa
Severe mucosal inflammatory changes;
ulceration; blood in lumen
*The Truelove— Witts criteria for acute severe ulcerative colitis are >6 bloody stools/24 hrs plus one or more of: anaemia, fever, tachycardia and high inflammatory markers.
Fig. 21.50 Barium follow-through showing terminal ileal Crohn’s
disease. A long stricture is present (arrow A), and more proximally there is
ulceration with characteristic ‘rose thorn’ ulcers (arrow B).
sparing and the presence of perianal disease are features that
favour a diagnosis of Crohn’s disease. Many patients present
with symptoms of both small bowel and colonic disease. A few
patients present with isolated perianal disease, vomiting from
jejunal strictures or severe oral ulceration.
Physical examination often reveals evidence of weight loss,
anaemia with glossitis and angular stomatitis. There is abdominal
tenderness, most marked over the inflamed area. An abdominal
mass may be palpable and is due to matted loops of thickened
bowel or an intra-abdominal abscess. Perianal skin tags, fissures
or fistulae are found in at least 50% of patients.
Differential diagnosis
The differential diagnosis is summarised in Box 21 .54. The
most important issue is to distinguish the first attack of acute
colitis from infection. In general, diarrhoea lasting longer than
10 days in Western countries is unlikely to be the result of
infection, whereas a history of foreign travel, antibiotic exposure
^9 21 .54 Conditions that can mimic ulcerative or
Crohn’s colitis
Infective
Bacterial
• Salmonella
•
Gonococcal proctitis
• Shigella
•
Pseudomembranous colitis
• Campylobacter jejuni
• Escherichia coli 01 57
•
Chlamydia proctitis
Viral
• Herpes simplex proctitis
Protozoal
• Amoebiasis
•
Cytomegalovirus
Non-infective
• Ischaemic colitis
•
Diverticulitis
• Collagenous colitis
•
Radiation proctitis
• Non-steroidal anti¬
•
Behget’s disease
inflammatory drugs
•
Colonic carcinoma
21.55 Differential diagnosis of small bowel
Crohn’s disease
• Other causes of right iliac fossa mass:
Caecal carcinoma*
Appendix abscess*
• Infection (tuberculosis, Yersinia , actinomycosis)
• Mesenteric adenitis
• Pelvic inflammatory disease
• Lymphoma
*Common; other causes are rare.
(< Clostridium difficile/ pseudomembranous colitis) or homosexual
contact increases the possibility of infection, which should be
excluded by the appropriate investigations (see below). The
diagnosis of Crohn’s disease is usually more straightforward
and is made on the basis of imaging and clinical presentation,
but in atypical cases biopsy or surgical resection is necessary
to exclude other diseases (Box 21 .55).
818 • GASTROENTEROLOGY
Complications
Life-threatening colonic inflammation
This can occur in both ulcerative colitis and Crohn’s colitis. In
the most extreme cases, the colon dilates (toxic megacolon)
and bacterial toxins pass freely across the diseased mucosa
into the portal and then systemic circulation. This complication
arises most commonly during the first attack of colitis and is
recognised by the features described in Box 21 .53. An abdominal
X-ray should be taken daily because, when the transverse colon
is dilated to more than 6 cm (Fig. 21 .51), there is a high risk of
colonic perforation, although this complication can also occur
in the absence of toxic megacolon. Severe colonic inflammation
with toxic dilatation is a surgical emergency and most often
requires colectomy.
Haemorrhage
Haemorrhage due to erosion of a major artery is rare but can
occur in both conditions.
Fistulae
These are specific to Crohn’s disease. Enteroenteric fistulae can
cause diarrhoea and malabsorption due to blind loop syndrome.
Enterovesical fistulation causes recurrent urinary infections and
pneumaturia. An enterovaginal fistula causes a faeculent vaginal
discharge. Fistulation from the bowel may also cause perianal
or ischiorectal abscesses, fissures and fistulae.
Cancer
The risk of dysplasia and cancer increases with the duration and
extent of uncontrolled colonic inflammation. Thus patients who
have long-standing, extensive colitis are at highest risk. Oral
mesalazine therapy reduces the risk of dysplasia and neoplasia
in ulcerative colitis. Azathioprine also seems to reduce the risk
of colorectal cancer in ulcerative colitis and Crohn’s colitis. This
protective effect probably extends to any medical treatment
that results in sustained healing of the colonic mucosa. The
Fig. 21.51 Plain abdominal X-ray showing a grossly dilated colon
due to severe ulcerative colitis. There is also marked mucosal oedema
and ‘thumb-printing’ (arrows).
cumulative risk for dysplasia in ulcerative colitis may be as high
as 20% after 30 years but is probably lower for Crohn’s colitis.
The risk is particularly high in patients who have concomitant
primary sclerosing cholangitis for unknown reasons. Tumours
develop in areas of dysplasia and may be multiple. Patients
with long-standing colitis are therefore entered into surveillance
programmes beginning 10 years after diagnosis. Targeted biopsies
of areas that show abnormalities on staining with indigo carmine
or methylene blue increase the chance of detecting dysplasia
and this technique (termed pancolonic chromo-endoscopy) has
replaced colonoscopy with random biopsies taken every 1 0 cm
in screening for malignancy. The procedure allows patients to
be stratified into high-, medium- or low-risk groups to determine
the interval between surveillance procedures. Family history of
colon cancer is also an important factor to consider. If high-grade
dysplasia is found, panproctocolectomy is usually recommended
because of the high risk of colon cancer.
Extra-intestinal complications
Extra-intestinal complications are common in IBD and may
dominate the clinical picture. Some of these occur during relapse
of intestinal disease; others appear to be unrelated to intestinal
disease activity (Fig. 21 .52).
Investigations
Investigations are necessary to confirm the diagnosis, define
disease distribution and activity, and identify complications.
Full blood count may show anaemia resulting from bleeding or
malabsorption of iron, folic acid or vitamin B12. Platelet count
can also be high as a marker of chronic inflammation. Serum
albumin concentration falls as a consequence of protein-losing
enteropathy, inflammatory disease or poor nutrition. ESR and
CRP are elevated in exacerbations and in response to abscess
formation. Faecal calprotectin has a high sensitivity for detecting
gastrointestinal inflammation and may be elevated, even when
the CRP is normal. It is particularly useful for distinguishing
inflammatory bowel disease from irritable bowel syndrome at
diagnosis, and for subsequent monitoring of disease activity.
Bacteriology
At initial presentation, stool microscopy, culture and examination
for Clostridium difficile toxin or for ova and cysts, blood
cultures and serological tests should be performed. These
investigations should be repeated in established disease to
exclude superimposed enteric infection in patients who present
with exacerbations of IBD. During acute flares necessitating
hospital admission, three separate stool samples should be sent
for bacteriology to maximise sensitivity.
Endoscopy
Patients who present with diarrhoea plus raised inflammatory
markers or alarm features, such as weight loss, rectal bleeding and
anaemia, should undergo ileocolonoscopy. Flexible sigmoidoscopy
is occasionally performed to make a diagnosis, especially during
acute severe presentations when ileocolonoscopy may confer
an unacceptable risk; ileocolonoscopy should still be performed
at a later date, however, in order to evaluate disease extent. In
ulcerative colitis, there is loss of vascular pattern, granularity,
friability and contact bleeding, with or without ulceration (Fig.
21 .53). In Crohn’s disease, patchy inflammation, with discrete,
deep ulcers, strictures and perianal disease (fissures, fistulae
and skin tags), is typically observed, often with rectal sparing. In
established disease, colonoscopy may show active inflammation
Inflammatory bowel disease • 819
Fig. 21 .53 Sigmoidoscopic view of moderately active ulcerative
colitis. Mucosa is erythematous and friable with contact bleeding.
Submucosal blood vessels are no longer visible.
with pseudopolyps or a complicating carcinoma. Biopsies should
be taken from each anatomical segment (terminal ileum, right
colon, transverse colon, left colon and rectum) to confirm the
diagnosis and define disease extent, and also to seek dysplasia in
patients with long-standing colitis guided by pancolonic chromo¬
endoscopy. In Crohn’s disease, wireless capsule endoscopy is
useful in the identification of small bowel inflammation but should
be avoided in the presence of strictures. Enteroscopy may be
required to make a histological diagnosis of small bowel Crohn’s
disease, when the inflamed segment is out of reach of standard
endoscopes. All children and most adults with Crohn’s disease
should have upper gastrointestinal endoscopy and biopsy to
complete their staging. Not only is upper gastrointestinal Crohn’s
disease relatively common in this group, but also it may help to
make a definitive diagnosis in patients who otherwise appear to
have non-specific colonic inflammation.
Radiology
Barium enema is a less sensitive investigation than colonoscopy
in patients with colitis and, where colonoscopy is incomplete,
a CT colonogram is preferred. Small bowel imaging is essential
to complete staging of Crohn’s disease. Traditional contrast
imaging by barium follow-through demonstrates affected areas
of the bowel as narrowed and ulcerated, often with multiple
strictures (see Fig. 21 .50). This has largely been replaced now by
MRI enterography, which does not involve exposure to radiation
and is a sensitive way of detecting extra- intestinal manifestations
and of assessing pelvic and perineal involvement. These studies
use an orally administered small bowel-distending agent and
intravenous contrast to provide transmural imaging that can
usefully distinguish between predominantly inflammatory strictures
(that should respond to anti-inflammatory medical strategies)
820 • GASTROENTEROLOGY
and fibrotic strictures (that require a mechanical solution, such
as surgical resection, stricturoplasty or endoscopic balloon
dilatation). A plain abdominal X-ray is essential in the management
of patients who present with severe active disease. Dilatation
of the colon (see Fig. 21 .51), mucosal oedema (thumb-printing)
or evidence of perforation may be found. Patients with proctitis
may have features of proximal faecal loading. In small bowel
Crohn’s disease, there may be evidence of intestinal obstruction
or displacement of bowel loops by a mass. Ultrasound is a very
powerful tool to detect small bowel inflammation and stricture
formation but it is operator-dependent. The role of CT is limited
to screening for complications, such as perforation or abscess
formation, in the acutely unwell.
Management
Drugs that are used in the treatment of IBD are listed in Box
21 .56. Although medical therapy plays an important role, optimal
management depends on establishing a multidisciplinary team-
based approach involving physicians, surgeons, radiologists,
nurse specialists and dietitians. Both ulcerative colitis and Crohn’s
disease are life-long conditions and have important psychosocial
implications; specialist nurses, counsellors and patient support
groups have key roles in education, reassurance and coping.
The key aims of medical therapy are to:
• treat acute attacks (induce remission)
• prevent relapses (maintain remission)
• prevent bowel damage
• detect dysplasia and prevent carcinoma
• select appropriate patients for surgery.
Ulcerative colitis
Active proctitis Most patients with ulcerative proctitis respond to
a 1 g mesalazine suppository but some will additionally require
oral 5-aminosalicylate (5-ASA) therapy. Topical glucocorticoids
are less effective and are reserved for patients who are intoler¬
ant of topical mesalazine. Patients with resistant disease may
require treatment with systemic glucocorticoids and immuno¬
suppressants. A stool softener may be required to treat proximal
constipation.
Active left-sided or extensive ulcerative colitis In mild to moderately
active cases, the combination of a once-daily oral and a topical
5-ASA preparation (‘top and tail approach’) is usually effective.
The topical preparation (1 g foam or liquid enema) is typically
withdrawn after 1 month. The oral 5-ASA is continued long-term
to prevent relapse and minimise the risk of dysplasia. In patients
who do not respond to this approach within 2-4 weeks, oral
prednisolone (40 mg daily, tapered by 5 mg/week over an 8-week
total course) is indicated. Glucocorticoids should never be used
for maintenance therapy. At the first signs of glucocorticoid
resistance (lack of efficacy) or in patients who require recurrent
glucocorticoid doses to maintain control, immunosuppressive
therapy with a thiopurine should be introduced. Simultaneous
calcium and vitamin D supplementation should be given along
with glucocorticoids for bone protection.
Severe ulcerative colitis Patients who fail to respond to maximal
oral therapy and those who present with acute severe colitis
(meeting the Truelove-Witts criteria; see Box 21.53) are best
managed in hospital and should be monitored jointly by a physician
and surgeon:
• clinically : for the presence of abdominal pain, temperature,
pulse rate, stool blood and frequency
• by laboratory testing : haemoglobin, white cell count,
albumin, electrolytes, ESR and CRP, stool culture
• radiologically : for colonic dilatation on plain abdominal
X-rays.
All patients should be given supportive treatment with
intravenous fluids to correct dehydration and enteral nutritional
support should be provided for malnourished patients (Box
21 .57). Intravenous glucocorticoids (methylprednisolone 60 mg
or hydrocortisone 400 mg/day) should be given by intravenous
infusion or bolus injection. Topical and oral aminosalicylates have
no role to play in the acute severe attack. Response to therapy
is judged over the first 3 days. Patients who do not respond
promptly to glucocorticoids should be considered for medical
rescue therapy with ciclosporin (intravenous infusion or oral)
or infliximab (5 mg/kg), which can avoid the need for urgent
colectomy in approximately 60% of cases.
Patients who develop colonic dilatation (>6 cm), those whose
clinical and laboratory measurements deteriorate and those who
do not respond after 7-10 days’ maximal medical treatment
usually require urgent colectomy. Subtotal colectomy can also
be performed laparoscopically, given sufficient local expertise.
The surgical and medical teams should liaise early in the disease
course and, if possible, the patient should have the opportunity
to speak with the stoma nurse prior to colectomy.
Maintenance of remission Life-long maintenance therapy is
recommended for all patients with left-sided or extensive disease
but is not necessary in those with proctitis (although 20% of
these patients will develop proximal ‘extension’ over the lifetime
of their disease). Once-daily oral 5-aminosalicylates are the
preferred first-line agents. Sulfasalazine has a higher incidence
of side-effects but is equally effective and can be considered
in patients with coexistent arthropathy. Patients who frequently
relapse despite aminosalicylate drugs should be treated with
thiopurines (azathioprine or 6-mercaptopurine). Biologic therapy
with anti-TNF antibodies (infliximab or adalimumab) or anti-a4 (37
integrin antibodies (vedolizumab) can also be considered for
maintenance treatment in patients with moderate to severe
ulcerative colitis who are intolerant of or non-responsive to
thiopurine immunosuppression.
Crohn’s disease
Principles of treatment Crohn’s disease is a progressive condition
that may result in stricture or fistula formation if suboptimally
treated. It is therefore important to agree long-term treatment
goals with the patient; these are to induce remission and then
maintain glucocorticoid-free remission with a normal quality of
life. Treatment should focus on monitoring the patient carefully
for evidence of disease activity and complications (Box 21 .58),
and ensuring that mucosal healing is achieved.
Induction of remission Glucocorticoids remain the mainstay of
treatment for active Crohn’s disease. The drug of first choice
in patents with ileal disease is budesonide, since it undergoes
90% first-pass metabolism in the liver and has very little systemic
toxicity. A typical regimen is 9 mg once daily for 6 weeks, with
a gradual reduction in dose over the subsequent 2 weeks when
therapy is stopped. If there is no response to budesonide within
2 weeks, the patient should be switched to prednisolone, which
has greater potency. This is typically given in a dose of 40 mg
daily, reducing by 5 mg/week over 8 weeks, at which point
treatment is stopped. Oral prednisolone in the dose regimen
described above is the treatment of choice for inducing remission
Inflammatory bowel disease • 821
1 21 .56 Drugs used in the treatment of inflammatory bowel disease
Class
Mechanism of action
Notes
Aminosalicylates
(mesalazine (Asacol,
Salofalk, Pentasa,
Mezavant), olsalazine,
sulfasalazine, balsalazide)
Modulate cytokine release from mucosa
Different means of delivery to colon:
pH-dependent (Asacol, Salofalk)
time-dependent (Pentasa)
bacterial breakdown by colonic bacteria
from a carrier molecule (sulfasalazine,
balsalazide)
No proven value in CD
Available as oral or topical (enema/suppository)
Sulfasalazine causes side-effects in 10-45%: headache, nausea,
diarrhoea, blood dyscrasias
Other aminosalicylates better tolerated; diarrhoea, headache in
2-5%
Rarely, renal impairment (check urea and electrolytes 6-monthly)
Glucocorticoids
(prednisolone,
hydrocortisone, budesonide)
Anti-inflammatory
Budesonide is a potent glucocorticoid
efficiently cleared from circulation by liver,
thereby minimising adrenocortical suppression
and steroid side-effects
Topical, oral or IV, according to disease severity
Budesonide considered for active ileitis and ileocolitis
High vigilance for complications
Never used for maintenance therapy
Calcium/vitamin D supplements
Thiopurines (azathioprine,
mercaptopurine)
Immunomodulation by inducing T-cell
apoptosis
Azathioprine is metabolised in liver to
mercaptopurine, then by TPMT to thioguanine
nucleotides
Effective 12 weeks after starting therapy
Complications leading to drug withdrawal in approximately 20%:
influenza-like syndrome with myalgia, nausea and vomiting;
leucopenia in 3%, particularly in inherited TPMT deficiency;
hepatotoxicity; pancreatitis
60% of those intolerant of azathioprine will tolerate mercaptopurine
Increase in lymphoma (approximately 2-3-fold) and non-melanoma
skin cancer (life-long sun protection advised)
Check TPMT levels prior to starting treatment and avoid if deficient/
very low due to risk of toxicity
Metabolite levels can be measured to tailor therapy
Use with caution for patients presenting over the age of 60 years
due to risk of malignancy
Methotrexate
Anti-inflammatory
Intolerance in 10-18%
Maximal efficacy when given by SC injection once weekly
Nausea, stomatitis, diarrhoea, hepatotoxicity and pneumonitis
Co-prescription of folic acid and antiemetics.
Teratogenic; robust contraception required for males and females
Ciclosporin
Inhibits T-cell activation
Rescue therapy to prevent surgery in UC responding poorly to
glucocorticoids. No value in CD
Major side-effects in 0-17%: nephrotoxicity, infections, neurotoxicity
(including fits)
Minor complications in up to 50%: tremor, paraesthesiae, abnormal
liver function tests, hirsutism
Anti-TNF antibodies
(infliximab and adalimumab)
Suppress inflammation and induce apoptosis
of inflammatory cells
Moderate to severe CD, including fistulating disease
Moderate to severe UC and acute severe UC as rescue therapy
Acute (anaphylactic) and delayed (serum sickness) infusion reactions
after multiple infusions; anti-drug antibody titres and drug levels can
be measured
Contraindicated in infection; reactivation of latent tuberculosis and
moderate to severe cardiac failure
Increased risk of infections and possibly of malignancy
Rarely, neurological adverse events
Requires assessment for latent tuberculosis and hepatitis B and C
prior to commencement
Continue until treatment failure or 12 months and reassess
Anti-a4p7 integrin
(vedolizumab)
Blocks integrin expressed on leukocytes and
inhibits interaction with gut-specific receptor
on endothelium, reducing leukocyte migration
to gut mucosa
Moderate to severe CD or moderate to severe UC where treatment
with anti-TNF has failed or is not tolerated
Side-effects include nasopharyngitis, arthralgia, headache
Progressive multifocal leukoencephalopathy risk is reduced due to
gut specificity
Induction with 300 mg infusion at weeks 0, 2 and 6; maintenance
8-weekly infusions thereafter
Discontinue if no improvement after 14 weeks
Continue until treatment failure or 12 months and reassess
Antibiotics
Antibacterial
Useful in perianal CD and pouchitis
Major concern is peripheral neuropathy with long-term metronidazole
Antidiarrhoeal agents
(loperamide, co-phenoxylate)
Reduce gut motility and small bowel secretion
Loperamide improves anal function
Avoided in acute flare-ups of disease
May precipitate colonic dilatation
(CD = Crohn’s disease; IV = intravenous; SC = subcutaneous; TNF = tumour necrosis factor; TPMT = thiopurine methyltransferase; UC = ulcerative colitis)
822 • GASTROENTEROLOGY
21.57 Medical management of fulminant
ulcerative colitis
• Admit to hospital for intensive therapy and monitoring
• Give IV fluids and correct electrolyte imbalance
• Consider transfusion if haemoglobin is <100 g/L (<10 g/dL)
• Give IV methylprednisolone (60 mg daily) or hydrocortisone
(400 mg daily)
• Give antibiotics until enteric infection is excluded
• Arrange nutritional support
• Give subcutaneous low-molecular-weight heparin for prophylaxis of
venous thromboembolism
• Avoid opiates and antidiarrhoeal agents
• Consider infliximab (5 mg/kg) or ciclosporin (2 mg/kg) in stable
patients not responding to 3-5 days of glucocorticoids
21.58 Monitoring of inflammatory bowel
disease (IBD)
• Assess symptoms, including extra- intestinal manifestations
• Examine for abdominal mass or perianal disease
• Perform full blood count, urea and electrolytes, liver function tests,
albumin, C-reactive protein (CRP)
• Check haematinics (vitamin B12, folate, iron studies) at least annually
• Check faecal calprotectin (to monitor each disease flare/change in
therapy and assess response)
• Perform stool cultures (at each flare to exclude infection)
• Assess mucosal healing: surrogate markers (CRP/calprotectin),
ileocolonoscopy and/or small bowel magnetic resonance imaging
• Enrol patient in a dedicated IBD clinic (monitoring of stable,
uncomplicated patients may be carried out by a nurse or phone
clinic)
• Arrange IBD multidisciplinary meeting for acutely ill or complex
patients
• Check vaccinations are up to date; ensure surveillance colonoscopy
is scheduled where appropriate
in colonic Crohn’s disease. Calcium and vitamin D supplements
should be co-prescribed in patients who are on glucocorticoids,
to try to compensate for their inhibitory effect on intestinal
calcium absorption.
As an alternative to glucocorticoid therapy, enteral nutrition
with either an elemental (constituent amino acids) or polymeric
(liquid protein) diet may induce remission. Both types of diet are
equally effective but the polymeric one is more palatable when
taken by mouth. It is particularly effective in children, in whom
equal efficacy to glucocorticoids has been demonstrated, and
in extensive ileal disease in adults. As well as resting the gut
and providing excellent nutritional support, it also has a direct
anti-inflammatory effect. It is an effective bridge to urgent staging
investigations at first presentation and can be given by mouth or
by nasogastric tube. With sufficient explanation, encouragement
and motivation, most patients will tolerate it well.
Some individuals with severe colonic disease require admission
to hospital for intravenous glucocorticoids. In severe ileal or
panenteric disease, induction therapy with an anti-TNF agent is
appropriate, provided that acute perforating complications, such
as abscess, have not arisen. Both infliximab and adalimumab are
licensed for use in the UK. Randomised trials have demonstrated
that combination therapy with an anti-TNF antibody and a
thiopurine is the most effective strategy for inducing and
maintaining remission in luminal Crohn’s patients. This strategy
is more effective than anti-TNF monotherapy, which, in turn, is
more effective than thiopurine monotherapy. Following induction
21.59 How to give anti-tumour necrosis factor (TNF)
therapy in inflammatory bowel disease
• Infliximab (5 mg/kg IV infusion) is given as three loading doses (at
0, 2 and 6 weeks), with 8-weekly maintenance thereafter
• Adalimumab is given as SC injections, which patients can be trained
to give themselves. Loading dose is 160 mg, followed by 80 mg
2 weeks later and 40 mg every second week thereafter; some
patients require dose escalation to 40 mg once weekly
• Concomitant immunosuppression with a thiopurine or methotrexate
may be more efficacious than monotherapy but has more
side-effects
• Anti-TNF therapy is contraindicated in the presence of active
infection and latent tuberculosis without appropriate prophylaxis; it
carries an increased risk of opportunistic infections and a possible
increased risk of malignancy; rarely, multiple sclerosis may be
unmasked in susceptible individuals. Counselling about the balance
of risk and benefit for each patient is important
• Prior to therapy, latent tuberculosis must be excluded
• Live vaccines should not be given
• Certolizumab is effective for luminal Crohn’s disease but is not
licensed in Europe
• Etanercept is not effective in Crohn’s disease
of remission, a substantial proportion of patients (20-30%)
remain well without the requirement for maintenance therapy.
Patients with evidence of persistently active disease require
further treatment (see below).
Maintenance therapy Immunosuppressive treatment with
thiopurines (azathioprine and mercaptopurine) forms the core
of maintenance therapy but methotrexate is also effective and can
be given once weekly, either orally or by subcutaneous injection.
Women and men of child-bearing potential who are prescribed
methotrexate must use a robust contraceptive method, and should
be counselled to plan pregnancy with a 3-month methotrexate-free
period prior to conception since it is teratogenic. Combination
therapy with an immunosuppressant and an anti-TNF antibody
is the most effective strategy but costs are high and there is an
increased risk of serious adverse effects. In the UK, the use of
anti-TNF therapy is limited to specific patient subgroups with
severe disease (Box 21 .59). Vedolizumab is a possible option
in patients who have not responded to anti-TNF therapy. It is
a humanised monoclonal antibody against anti-a4p7 integrin.
The a4p7 is expressed on a specific subset of CD4+ leucocytes;
vedolizumab binds to this integrin and blocks interaction with
MAdCAM-1 , expressed on gut endothelial cells, resulting in a
reduced influx of immune cells to the inflamed gut mucosa.
Serious systemic adverse effects, including progressive multifocal
leukoencephalopathy, have been seen with other anti-integrin
drugs (such as natalizumab) but this has not emerged with
vedolizumab due to its gut specificity. Emerging novel medical
therapies for Crohn’s disease are currently in phase III clinical
trials and are likely to be available for clinical use in the near
future. These include ustekinumab (anti-p40, inhibiting both IL-12
and IL-23) and tofacitinib (a Janus kinase inhibitor that blocks
pro-inflammatory cytokine signalling).
Cigarette smokers with Crohn’s disease should be strongly
counselled to stop smoking at every possible opportunity. Those
that do not manage to stop smoking fare much worse, with
increased rates of relapse and surgical intervention. Careful
monitoring of disease activity (see Box 21.58) is the key to
maintaining sustained remission and preventing the accumulation
of bowel damage in Crohn’s disease.
Inflammatory bowel disease • 823
Fistulae and perianal disease Fistulae may develop in relation to
active Crohn’s disease and are often associated with sepsis. The
first step is to define the site by imaging (usually MRI of the pelvis).
Surgical exploration by an examination under anaesthetic is usually
then required, to delineate the anatomy and drain abscesses.
Seton sutures can be inserted through fistula tracts to ensure
adequate drainage and to prevent future sepsis. Glucocorticoids
are ineffective. Use of antibiotics, such as metronidazole and/
or ciprofloxacin, can aid healing as an adjunctive treatment.
Thiopurines can be used in chronic disease but do not usually
result in fistula healing. Infliximab and adalimumab can heal
fistulae and perianal disease in many patients and are indicated
when the measures described above have been ineffective.
Other options for refractory perianal disease are proctectomy
or diverting colostomy.
Surgical treatment
Ulcerative colitis
Up to 60% of patients with extensive ulcerative colitis eventually
require surgery. The indications are listed in Box 21 .60. Impaired
quality of life, with its impact on occupation and social and family
life, is the most important of these. Surgery involves removal of the
entire colon and rectum, and cures the patient. One-third of those
with pancolitis undergo colectomy within 5 years of diagnosis.
Before surgery, patients must be counselled by doctors, stoma
nurses and patients who have undergone similar surgery. The
choice of procedure is either panproctocolectomy with ileostomy,
or proctocolectomy with ileal-anal pouch anastomosis. The sister
text to this book, Principles and Practice of Surgery, should be
consulted for further details.
Crohn’s disease
The indications for surgery are similar to those for ulcerative
colitis. Operations are often necessary to deal with fistulae,
abscesses and perianal disease, and may also be required to
relieve small or large bowel obstruction. In contrast to ulcerative
colitis, surgery is not curative and disease recurrence is the rule.
The only method that has consistently been shown to reduce
post-operative recurrence is smoking cessation. Antibiotics are
effective in the short term only. Use of thiopurines post-surgery is
suggested if there are indicators of a high chance of recurrence,
i.e. more than one resection or evidence of penetrating disease,
such as fistulae or abscess. Otherwise, it is common to undertake
colonoscopy 6 months after surgery to inspect and biopsy the
anastomosis and neo-terminal ileum. Patients with endoscopic
recurrence are then prescribed thiopurines.
i
Impaired quality of life
• Loss of occupation or education
• Disruption of family life
Failure of medical therapy
• Dependence on oral glucocorticoids
• Complications of drug therapy
Fulminant colitis
Disease complications unresponsive to medical therapy
• Arthritis
• Pyoderma gangrenosum
Colon cancer or severe dysplasia
Surgery should be as conservative as possible in order to
minimise the loss of viable intestine and to avoid the creation of
a short bowel syndrome (p. 708). Obstructing or fistulating small
bowel disease may require resection of affected tissue. Patients
who have localised segments of Crohn’s colitis may be managed
by segmental resection and/or multiple stricturoplasties, in which
the stricture is not resected but instead incised in its longitudinal
axis and sutured transversely. Others who have extensive colitis
require total colectomy but ileal-anal pouch formation should be
avoided because of the high risk of recurrence within the pouch
and subsequent fistulae, abscess formation and pouch failure.
Historical datasets show that around 80% of Crohn’s patients
undergo surgery at some stage and 70% of these require more
than one operation during their lifetime. Clinical recurrence
following resectional surgery is present in 50% of all cases at
1 0 years. Emerging data demonstrate that aggressive medical
therapy, coupled with intense monitoring, probably reduces the
requirement for surgery substantially.
|JBD in special circumstances
Childhood
Chronic ill health in childhood or adolescent IBD may result in
growth failure, metabolic bone disease and delayed puberty.
Loss of schooling and social contact, as well as frequent
hospitalisation, can have important psychosocial consequences.
Treatment is similar to that described for adults and may require
glucocorticoids, immunosuppressive drugs, biological agents and
surgery. Monitoring of height, weight and sexual development
is crucial. Children with IBD should be managed by specialised
paediatric gastroenterologists and transitioned to adult care in
dedicated clinics (Box 21 .61).
Pregnancy
A women’s ability to become pregnant is adversely affected by
active IBD. Pre-conceptual counselling should focus on optimising
disease control. During pregnancy, the rule of thirds applies:
roughly one-third of women improve, one-third get worse and
one-third remain stable with active disease. In the post-partum
period, these changes sometimes reverse spontaneously.
Drug therapy, including aminosalicylates, glucocorticoids and
« Delayed growth and pubertal development: chronic active
inflammation, malabsorption, malnutrition and long-term
glucocorticoids contribute to short stature and delayed development,
with physical and psychological consequences.
< Metabolic bone disease: more common with chronic disease
beginning in childhood, resulting from chronic inflammation, dietary
deficiency and malabsorption of calcium and vitamin D.
• Drug side-effects and adherence issues: young people are more
likely to require azathioprine or biological therapy than adults. Poor
adherence to therapy is more common than with adults, as younger
patients may feel well, lack self-motivation to adhere and believe
that drugs are ineffective or cause side-effects.
< Loss of time from education: physical illness, surgery, fatigue in
chronic inflammatory bowel disease, privacy and dignity issues, and
social isolation may all contribute.
< Emotional difficulties: may result from challenges in coping with
illness, problems with forming interpersonal relationships, and
issues relating to body image or sexual function.
21 .60 Indications for surgery in ulcerative colitis
21.61 Inflammatory bowel disease in adolescence
824 • GASTROENTEROLOGY
21.62 Pregnancy and inflammatory bowel
disease (IBD)
Pre-conception
• Outcomes are best when pregnancy is carefully planned and
disease is in remission
• Methotrexate must be stopped 3 months prior to conception; other
IBD drugs should be continued until discussed with a specialist
• Aminosalicylates and azathioprine are safe in pregnancy
• Glucocorticoids are probably safe
• Anti-tumour necrosis factor biological therapy in pregnancy can
continue if established pre-pregnancy but should be withheld in the
third trimester due to placental transfer of antibody
• No data are available for the use of vedolizumab in pregnancy
• Daily high-dose (>2 mg) folic acid supplements are recommended
Pregnancy
• Two-thirds of patients in remission will remain so in pregnancy
• Active disease is likely to remain active
• Severe active disease carries an increased risk of premature
delivery and low birth weight
• Gentle flexible sigmoidoscopy is safe after the first trimester
• X-rays can be performed if clinically indicated but discuss with the
radiologist first
• Colonoscopy can be performed safely if the potential benefits
outweigh the risks
Labour
• This needs careful discussion between patient, gastroenterologist
and obstetrician
• Normal labour and vaginal delivery are possible for most
• Caesarean section may be preferred for patients with perianal
Crohn’s or an ileo-anal pouch to reduce risks of pelvic floor
damage, fistulation and late incontinence
Breastfeeding
• This is safe and does not exacerbate IBD
• Data on the risk to babies from drugs excreted in breast milk are
limited; most of these drugs are probably safe
• Patients should discuss breastfeeding and drug therapy with their
doctor
azathioprine, can be safely continued throughout pregnancy but
methotrexate must be avoided, both during pregnancy and if
the patient is trying to conceive (Box 21.62). Anti-TNF agents
are transmitted through the placenta (but not breast milk) and
are omitted during the last trimester.
Metabolic bone disease
Patients with IBD are prone to developing osteoporosis due to
the effects of chronic inflammation, glucocorticoids, weight loss,
malnutrition and malabsorption. Osteomalacia can also occur in
Crohn’s disease that is complicated by malabsorption, but is less
common than osteoporosis. The risk of osteoporosis increases
with age and with the dose and duration of glucocorticoid therapy.
Refractory Crohn’s disease
Crohn’s disease can be progressive despite maximal medical
therapy and extensive surgery. There are several other
immunomodulatory drugs in the clinical trial pipeline (see above).
Microscopic colitis
Microscopic colitis, which comprises two related conditions called
lymphocytic colitis and collagenous colitis, has no known cause.
The presentation is with watery diarrhoea. The colonoscopic
appearances are normal but histological examination of biopsies
shows a range of abnormalities. It is therefore recommended
that biopsies of the right and left colon plus the terminal ileum
should be undertaken in all patients undergoing colonoscopy for
diarrhoea. Collagenous colitis is characterised by the presence of
a submucosal band of collagen, often with a chronic inflammatory
infiltrate. The disease is more common in women and may be
associated with rheumatoid arthritis, diabetes, coeliac disease
and some drug therapies, such as NSAIDs or PPIs. Treatment
with budesonide or 5-aminosalicylates is usually effective but
the condition will recur in some patients on discontinuation
of therapy.
Irritable bowel syndrome
Irritable bowel syndrome (IBS) is characterised by recurrent
abdominal pain in association with abnormal defecation in the
absence of a structural abnormality of the gut. About 1 0-1 5%
of the population are affected at some time but only 10% of
these consult their doctors because of symptoms. Nevertheless,
IBS is the most common cause of gastrointestinal referral and
accounts for frequent absenteeism from work and impaired
quality of life. Young women are affected 2-3 times more often
than men. Coexisting conditions, such as non-ulcer dyspepsia,
chronic fatigue syndrome, dysmenorrhoea and fibromyalgia, are
common. IBS is sometimes associated with a history of physical
or sexual abuse and this is an important aspect of the history
as these patients benefit from psychologically based therapy.
Pathophysiology
The cause of IBS is incompletely understood but biopsychosocial
factors are thought to play an important role, along with luminal
factors, such as diet and the gut microbiota, as discussed below.
Behavioural and psychosocial factors
Most patients seen in general practice do not have psychological
problems but about 50% of patients referred to hospital have a
psychiatric illness, such as anxiety, depression, somatisation and
neurosis. Panic attacks are also common. Acute psychological
stress and overt psychiatric disease are known to alter visceral
perception and gastrointestinal motility. There is an increased
prevalence of abnormal illness behaviour, with frequent
consultations for minor symptoms and reduced coping ability
(p. 1202). These factors contribute to but do not cause IBS.
Physiological factors
There is some evidence that IBS may be a serotoninergic (5-HT)
disorder, as evidenced by relatively excessive release of 5-HT
in diarrhoea-predominant IBS (D-IBS) and relative deficiency
with constipation-predominant IBS (C-IBS). Accordingly, 5-HT3
receptor antagonists are effective in D-IBS, while 5-HT4 agonists
improve bowel function in C-IBS. There is some evidence that
IBS may represent a state of low-grade gut inflammation or
immune activation, not detectable by tests, with raised numbers
of mucosal mast cells that sensitise enteric neurons by releasing
histamine and tryptase. Some patients respond positively to mast
cell stabilisers, such as ketotifen, which supports a pathogenic
role of mast cells in at least some patients. Immune activation
may be associated with altered CNS processing of visceral pain
signals. This is more common in women and in D-IBS, and may
be triggered by a prior episode of gastroenteritis with Salmonella
or Campylobacter species.
Irritable bowel syndrome • 825
Luminal factors
Both quantitative and qualitative alterations in intestinal bacterial
microbiota have been reported. Small intestinal bacterial
overgrowth (SIBO) may be present in some patients and lead
to symptoms. This ‘gut dysbiosis’ may explain the response to
probiotics or the non-absorbable antibiotic rifaximin.
Dietary factors are also important. Some patients have chemical
food intolerances (not allergy) to poorly absorbed, short-chain
carbohydrates (lactose, fructose and sorbitol, among others),
collectively known as FODMAPs (fermentable oligo-, di- and
monosaccharides, and polyols). Their fermentation in the colon
leads to bloating, pain, wind and altered bowel habit. Non-coeliac
gluten sensitivity (negative coeliac serology and normal duodenal
biopsies) seems to be present in some IBS patients, while others
may be intolerant of chemicals such as salicylates or benzoates,
found in certain foods.
Clinical features
The most common presentation is that of recurrent abdominal
discomfort (Box 21 .63). This is usually colicky or cramping in
nature, felt in the lower abdomen and relieved by defecation.
Abdominal bloating worsens throughout the day; the cause is
unknown but it is not due to excessive intestinal gas. The bowel
habit is variable. Most patients alternate between episodes of
diarrhoea and constipation but it is useful to classify them as
having predominantly constipation or predominantly diarrhoea.
Those with constipation tend to pass infrequent pellety stools,
usually in association with abdominal pain or proctalgia. Those
with diarrhoea have frequent defecation but produce low-volume
stools and rarely have nocturnal symptoms. Passage of mucus
is common but rectal bleeding does not occur. Patients do not
lose weight and are constitutionally well. Physical examination is
generally unremarkable, with the exception of variable tenderness
to palpation.
Investigations
The diagnosis is clinical in nature and can be made confidently
in most patients using the Rome criteria combined with the
absence of alarm symptoms, without resorting to complicated
tests (Box 21 .64). Full blood count and faecal calprotectin, with
21 .63 Rome III criteria for diagnosis of irritable
bowel syndrome
Recurrent abdominal pain or discomfort on at least 3 days per month
in the last 3 months, associated with two or more of the following:
• Improvement with defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form (appearance) of stool
Bl 21 .64 Supporting diagnostic features and alarm
features in irritable bowel syndrome
Features supporting a diagnosis of IBS
• Presence of symptoms for
• Previous medically
more than 6 months
unexplained symptoms
• Frequent consultations for
• Worsening of symptoms by
non-gastrointestinal problems
stress
Alarm features
• Age >50 years; male gender
• Family history of colon cancer
• Weight loss
• Anaemia
• Nocturnal symptoms
• Rectal bleeding
or without sigmoidoscopy, are usually done and are normal in
IBS. Colonoscopy should be undertaken in older patients (over
40 years of age) to exclude colorectal cancer. Endoscopic
examination is also required in patients who report rectal bleeding
to exclude colon cancer and IBD. Those who present atypically
require investigations to exclude other gastrointestinal diseases.
Diarrhoea-predominant patients justify investigations to exclude
coeliac disease (p. 805), microscopic colitis (p. 824), lactose
intolerance (p. 812), bile acid diarrhoea (p. 809), thyrotoxicosis
(p. 635) and, in developing countries, parasitic infection.
Management
The most important steps are to make a positive diagnosis and
reassure the patient. Many people are concerned that they have
developed cancer. A cycle of anxiety leading to colonic symptoms,
which further heighten anxiety, can be broken by explaining that
symptoms are not due to a serious underlying disease but instead
are the result of behavioural, psychosocial, physiological and
luminal factors. In individuals who fail to respond to reassurance,
treatment is traditionally tailored to the predominant symptoms
(Fig. 21 .54). Dietary management is effective for many patients
(Box 21.65).
Up to 20% may benefit from a wheat-free diet, some may
respond to lactose exclusion, and excess intake of caffeine or
artificial sweeteners, such as sorbitol, should be addressed. A
more restrictive, ‘low-FODMAP’ diet, supervised by a dietitian,
with gradual re-introduction of different food groups, may help
some patients, as may a trial of a gluten-free diet. Probiotics,
in capsule form, can be effective if taken for several months,
although the optimum combination of bacterial strains and dose
have yet to be clarified.
Patients with intractable symptoms sometimes benefit from
several months of therapy with a tricyclic antidepressant,
such as amitriptyline or imipramine (10-25 mg orally at night).
Side-effects include dry mouth and drowsiness but these are
usually mild and the drug is generally well tolerated, although
patients with features of somatisation tolerate the drug poorly
and lower doses should be used. It may act by reducing visceral
sensation and by altering gastrointestinal motility. Anxiety and
affective disorders may also require specific treatment (pp.
1200 and 1198). The 5-HT4 agonist prucalopride, the guanylate
cyclase-C receptor agonist linaclotide, and chloride channel
activators, such as lubiprostone, can be effective in constipation-
predominant IBS.
Trials of anti-inflammatory agents, such as ketotifen or
mesalazine, and the antibiotic rifaximin may be considered in
21.65 Dietary management of irritable
bowel syndrome
• Eat regularly and avoid missing meals
• Take time to eat
• Ensure adequate hydration and avoid carbonated and caffeinated
drinks
• Reduce alcohol intake
• Reduce intake of ‘resistant’ starch and insoluble fibre
• Avoid foods with artificial sweeteners
• Consider a wheat-free diet
• Consider a lactose exclusion diet
• Consider a diet low in FODMAPs
(FODMAPs = fermentable oligo-, di- and monosaccharides, and polyols)
826 • GASTROENTEROLOGY
Symptoms persist
_ i
• Duloxetine 30-60 mg at night
• Relaxation therapy
• Biofeedback
• Hypnotherapy
Fig. 21.54 Management of irritable bowel syndrome. (FODMAP = fermentable oligo-, di- and monosaccharides, and polyols)
21 .66 Complementary and alternative therapies for
irritable bowel syndrome
Manipulative and body-based
• Massage, chiropractic
Mind-body interventions
• Meditation, hypnosis*, cognitive therapy
Biologically based
• Herbal products*, dietary additives, probiotics*
Energy healing
• Biofield therapies (reiki), bio-electromagnetic field therapies
Alternative medical systems
• Ayurveda, homeopathy, traditional Chinese medicine
*Some evidence for benefit exists.
From Hussain Z, Quigley EMM. Systematic review: complementary and alternative
medicine in the irritable bowel syndrome. Aliment Pharmacol Ther 2006;
23:465-471.
some patients with difficult symptoms but are best prescribed
only after specialist referral.
Psychological interventions, such as cognitive behavioural
therapy, relaxation and gut-directed hypnotherapy, should be
reserved for the most difficult cases. A range of complementary
and alternative therapies exist; most lack a good evidence base
but are popular and help some patients (Box 21 .66).
Most patients have a relapsing and remitting course. Exac¬
erbations often follow stressful life events, occupational
dissatisfaction and difficulties with interpersonal relationships.
HIV/AIDS and the gastrointestinal tract
Patients with HIV/AIDS may develop several symptoms referable
to the gastrointestinal tract, as discussed in detail on page 31 6.
HIV testing should be considered in all patients with atypical or
unexplained gastrointestinal symptoms and in those resident in
areas of high prevalence.
Disorders of the colon and rectum • 827
Ischaemic gut injury
Ischaemic gut injury is usually the result of arterial occlusion.
Severe hypotension and venous insufficiency are less frequent
causes. The presentation is variable, depending on the different
vessels involved and the acuteness of the event. Diagnosis is
often difficult.
Acute small bowel ischaemia
An embolus from the heart or aorta to the superior mesenteric
artery is responsible for 40-50% of cases, thrombosis of underlying
atheromatous disease for approximately 25%, and non-occlusive
ischaemia due to hypotension complicating myocardial infarction,
heart failure, arrhythmias or sudden blood loss for approximately
25%. Vasculitis and venous occlusion are rare causes. The clinical
spectrum ranges from transient alteration of bowel function to
transmural haemorrhagic necrosis and gangrene. Patients usually
have evidence of cardiac disease and arrhythmia. Almost all
develop abdominal pain that is more impressive than the physical
findings. In the early stages, the only physical signs may be a
silent, distended abdomen or diminished bowel sounds, with
peritonitis developing only later.
Leucocytosis, metabolic acidosis, hyperphosphataemia
and hyperamylasaemia are typical. Plain abdominal X-rays
show ‘thumb-printing’ due to mucosal oedema. Mesenteric
or CT angiography reveals an occluded or narrowed major
artery with spasm of arterial arcades, although most patients
undergo laparotomy on the basis of a clinical diagnosis without
angiography. Resuscitation, management of cardiac disease
and intravenous antibiotic therapy, followed by laparotomy,
are key steps. If treatment is instituted early, embolectomy
and vascular reconstruction may salvage some small bowel.
In these rare cases, a ‘second look’ laparotomy should be
undertaken 24 hours later and further necrotic bowel resected.
In patients at high surgical risk, thrombolysis may sometimes
be effective. The results of therapy depend on early intervention;
patients treated late have a 75% mortality rate. Survivors often
have nutritional failure from short bowel syndrome (p. 708) and
require intensive nutritional support, including home parenteral
nutrition and anticoagulation. Small bowel transplantation can be
considered in selected patients. Patients with mesenteric venous
thrombosis also require surgery if there are signs of peritonitis
but are otherwise treated with anticoagulation. Investigations for
underlying prothrombotic disorders should be performed (p. 978).
Acute colonic ischaemia
The splenic flexure and descending colon have little collateral
circulation and lie in ‘watershed’ areas of arterial supply. The
spectrum of injury ranges from reversible colopathy to transient
colitis, colonic stricture, gangrene and fulminant pancolitis.
Arterial thromboembolism is usually responsible but colonic
ischaemia can also follow severe hypotension, colonic volvulus,
strangulated hernia, systemic vasculitis or hypercoagulable
states. Ischaemia of the descending and sigmoid colon is also
a complication of abdominal aortic aneurysm surgery (where
the inferior mesenteric artery is ligated). The patient is usually
elderly and presents with sudden onset of cramping, left-sided,
lower abdominal pain and rectal bleeding. Symptoms usually
resolve spontaneously over 24-48 hours and healing occurs in
2 weeks. Some may develop a fibrous stricture or segment of
colitis. A minority develop gangrene and peritonitis. The diagnosis
is established by colonoscopy within 48 hours of presentation;
otherwise, mucosal ulceration may have resolved. Resection is
required for peritonitis.
| Chronic mesenteric ischaemia
This results from atherosclerotic stenosis of the coeliac axis,
superior mesenteric artery and inferior mesenteric artery. At
least two of the three vessels must be affected for symptoms to
develop. The typical presentation is with dull but severe mid- or
upper abdominal pain developing about 30 minutes after eating.
Weight loss is common because patients are reluctant to eat
and some experience diarrhoea. Physical examination shows
evidence of generalised arterial disease. An abdominal bruit is
sometimes audible but is non-specific. The diagnosis is made by
mesenteric angiography. Treatment is by vascular reconstruction
or percutaneous angioplasty, if the patient’s clinical condition
permits. The condition is frequently complicated by intestinal
infarction, if left untreated.
Polyps and polyposis syndromes
Polyps may be neoplastic or non-neoplastic. The latter include
hamartomas, metaplastic (‘hyperplastic’) polyps and inflammatory
polyps. These have no malignant potential. Polyps may be
single or multiple and vary from a few millimetres to several
centimetres in size.
Colorectal adenomas are extremely common in the Western
world and the prevalence rises with age; 50% of people over
60 years of age have adenomas, and in half of these the polyps
are multiple. They are more common in the rectum and distal
colon and are either pedunculated or sessile. Histologically, they
are classified as either tubular, villous or tubulovillous, according to
the glandular architecture. Nearly all forms of colorectal carcinoma
develop from adenomatous polyps, although not all polyps carry
the same degree of risk. Features associated with a higher risk
of subsequent malignancy are listed in Box 21 .67.
Adenomas are usually asymptomatic and discovered
incidentally. Occasionally, they cause bleeding and anaemia.
Villous adenomas can secrete large amounts of mucus, causing
diarrhoea and hypokalaemia.
Discovery of a polyp at sigmoidoscopy is an indication for
colonoscopy because proximal polyps are present in 40-50%
of such patients. Colonoscopic polypectomy should be carried
out wherever possible, as this considerably reduces subsequent
colorectal cancer risk (Fig. 21 .55). Very large or sessile polyps
can sometimes be removed safely by endoscopic mucosal
resection (EMR) but many require surgery. Once all polyps have
been removed, surveillance colonoscopy should be undertaken at
3-5-year intervals, as new polyps develop in 50% of patients.
Patients over 75 years of age do not require repeated colon¬
oscopies, as their subsequent lifetime cancer risk is low.
21 .67 Risk factors for malignant change in
colonic polyps
• Large size (> 2 cm) • Villous architecture
• Multiple polyps • High-grade dysplasia
828 • GASTROENTEROLOGY
Fig. 21 .55 Large rectal adenomatous polyp. [A] Before colonoscopic polypectomy. \B} After polypectomy.
1 21.68 Gastrointestinal polyposis syndromes
Neoplastic
Non-neoplastic
Familial adenomatous
polyposis
Peutz-Jeghers
syndrome
Juvenile polyposis
Cronkhite-Canada
syndrome
Cowden’s disease
Inheritance
Autosomal dominant2
Autosomal dominant
Autosomal dominant
in one-third
None
Autosomal dominant
Oesophageal polyps
-
-
-
+
+
Gastric polyps
+
+
+
+++
+++
Small bowel polyps
++
+++
++
++
++
Colonic polyps
+++
++
++
+++
+
Other features
Colorectal cancer,
bleeding, extra-
intestinal features
(see Box 21 .69)
Pigmentation, bleeding,
intussusception, bowel
and other cancers
Colorectal cancer
Hair loss,
pigmentation,
nail dystrophy,
malabsorption
Many congenital
anomalies, oral
and cutaneous
hamartomas, thyroid
and breast tumours
- absent; + may occur; ++ common; +++ very common.
The polyps themselves are not neoplastic but cancer risk is increased in several syndromes.
Tare autosomal recessive variant MUTYH (see text).
Between 1 0% and 20% of polyps show histological evidence
of malignancy. When cancer cells are found within 2 mm of the
resection margin of the polyp, when the polyp cancer is poorly
differentiated or when lymphatic invasion is present, segmental
colonic resection is recommended because residual tumour
or lymphatic spread (in up to 10%) may be present. Malignant
polyps without these features can be followed up by surveillance
colonoscopy.
Polyposis syndromes are classified by histopathology (Box
21 .68). It is important to note that, while the hamartomatous
polyps in Peutz-Jeghers syndrome and juvenile polyposis are
not themselves neoplastic, these disorders are associated with
an increased risk of malignancy of the breast, colon, ovary and
thyroid.
Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is an uncommon autosomal
dominant disorder affecting 1 in 13 000 of the population and
accounting for 1 % of all colorectal cancers. It results from germline
mutation of the tumour suppressor APC gene, followed by
acquired mutation of the remaining allele (Ch. 3). The APC gene is
large and over 1400 different mutations have been reported, but
most are loss-of-function mutations resulting in a truncated APC
protein. This protein normally binds to and sequesters (3-catenin
but is unable to do so when mutated, allowing p-catenin to
translocate to the nucleus, where it up-regulates the expression
of many genes.
Around 20% of cases arise as new mutations and have no
family history. Hundreds to thousands of adenomatous colonic
polyps develop in 80% of patients by age 15 (Fig. 21 .56), with
symptoms such as rectal bleeding beginning a few years later.
In those affected, cancer will develop within 10-15 years of
the appearance of adenomas and 90% of patients will develop
colorectal cancer by the age of 50 years. Despite surveillance,
approximately 1 in 4 patients with FAP have cancer by the time
they undergo colectomy.
Disorders of the colon and rectum • 829
Fig. 21.56 Familial adenomatous polyposis. There are hundreds of
adenomatous polyps throughout the colon.
21 .69 Extra-intestinal features of familial
adenomatous polyposis
• Congenital hypertrophy of the retinal pigment epithelium (CHRPE,
70-80%)
• Epidermoid cysts (extremities, face, scalp)* (50%)
• Benign osteomas, especially skull and angle of mandible* (50-90%)
• Dental abnormalities (15-25%)*
• Desmoid tumours (10-15%)
• Other malignancies (brain, thyroid, liver, 1-3%)
*Gardner’s syndrome.
A second gene involved in base excision repair (MutY homolog,
MUTYH) has been identified and may give rise to colonic polyposis.
MUTYH displays autosomal recessive inheritance and leads to
tens to hundreds of polyps and proximal colon cancer. This
variant is referred to as MUTYH -associated polyposis (MAP).
Non-neoplastic cystic fundic gland polyps occur in the stomach
but adenomatous polyps also arise uncommonly. Duodenal
adenomas are found in over 90% and are most common around
the ampulla of Vater. Malignant transformation to adenocarcinoma
takes place in 1 0% and is the leading cause of death in those
who have had prophylactic colectomy. Many extra-intestinal
features are also seen in FAP (Box 21 .69).
Desmoid tumours occur in up to one-third of patients and
usually arise in the mesentery or abdominal wall. Although
benign, they may become very large, causing compression of
adjacent organs, intestinal obstruction or vascular compromise,
and are difficult to remove. They sometimes respond to hormonal
therapy with tamoxifen, and the NSAID sulindac may bring
about regression in some, by unknown mechanisms. Congenital
hypertrophy of the retinal pigment epithelium (CHRPE) occurs
in some cases and is seen as dark, round, pigmented retinal
lesions. When present in an at-risk individual, these are 100%
predictive of the presence of FAP. A variant, Turcot’s syndrome,
is characterised by FAP with primary CNS tumours (astrocytoma
or medulloblastoma).
Early identification of affected individuals before symptoms
develop is essential. The diagnosis can be excluded if
sigmoidoscopy is normal. In newly diagnosed cases, genetic
testing should be carried out to confirm the diagnosis and identify
the causal mutation. Subsequently, all first-degree relatives
should also undergo testing (p. 46). In families with known FAP,
adolescents should undergo mutation testing at 1 3-1 4 years of
Fig. 21.57 Peutz-Jeghers syndrome. Typical lip pigmentation.
age and patients who are found to have the mutation should be
offered colectomy after school or college education has been
completed. The operation of choice is total proctocolectomy with
ileal pouch-anal anastomosis. Periodic upper gastrointestinal
endoscopy every 1-3 years is recommended to detect and
monitor duodenal and periampullary adenomas. If large, these
may be amenable to endoscopic resection.
Peutz-Jeghers syndrome
Multiple hamartomatous polyps occur in the small intestine
and colon, as well as melanin pigmentation of the lips, mouth
and digits (Fig. 21 .57). Most cases are asymptomatic, although
chronic bleeding, anaemia or intussusception can occur. There
is a significant risk of small bowel or colonic adenocarcinoma
and of cancer of the pancreas, lung, testis, ovary, breast and
endometrium. Peutz-Jeghers syndrome is an autosomal dominant
disorder, most commonly resulting from truncating mutations in
a serine-threonine kinase gene on chromosome 19p (STK11).
Diagnosis requires two of the three following features:
• small bowel polyposis
• mucocutaneous pigmentation
• a family history suggesting autosomal dominant
inheritance.
The diagnosis can be made by genetic testing but this may
be inconclusive, since mutations in genes other than STK1 1 can
cause the disorder. Affected people should undergo regular upper
endoscopy, colonoscopy and small bowel and pancreatic imaging.
Polyps greater than 1 cm in size should be removed. Testicular
examination is essential for men, while women should undergo
pelvic examination, cervical smears and regular mammography.
Asymptomatic relatives of affected patients should also undergo
screening.
Juvenile polyposis
In juvenile polyposis, tens to hundreds of mucus-filled hamar¬
tomatous polyps are found in the colorectum. One-third of
cases are inherited in an autosomal dominant manner and up
to one-fifth develop colorectal cancer before the age of 40. The
criteria for diagnosis are:
• ten or more colonic juvenile polyps
• juvenile polyps elsewhere in the gut, or
• any polyps in those with a family history.
Germline mutations in the SMAD4 gene are often found, as
are PTEN mutations. Colonoscopy with polypectomy should
be performed every 1 -3 years and colectomy considered for
extensive involvement.
830 • GASTROENTEROLOGY
Ijtolorectal cancer
Although relatively rare in the developing world, colorectal cancer
is the second most common malignancy and the second leading
cause of cancer deaths in Western countries. In the UK, the
incidence is 50-60 per 100000, equating to 30000 cases per
year. The condition becomes increasingly common over the
age of 50 years.
Pathophysiology
Both environmental and genetic factors are important in colorectal
carcinogenesis (Fig. 21.58). Environmental factors account for
the wide geographical variation in incidence and the decrease in
risk seen in migrants who move from high- to low-risk countries.
Dietary factors are most important and these are summarised in
Box 21 .70; other recognised risk factors are listed in Box 21 .71 .
Colorectal cancer development results from the accumulation of
multiple genetic mutations. There are also associated epigenetic
influences, such as microRNA expression signature, and potential
influences from non-coding genetic variation. Currently, there are
three main pathways of genetic instability and each is associated
with histological, clinical and prognostic parameters:
• Chromosomal instability. Mutations or deletions of portions
of chromosomes arise, with loss of heterozygosity (LOH)
and inactivation of specific tumour suppressor genes. In
LOH, one allele of a gene is deleted but gene inactivation
occurs only when a subsequent unrelated mutation affects
the other allele. Chromosomal instability (CIN) occurs in
Fig. 21.58 Pathogenesis of colorectal cancer (CRC). (FAP = familial
adenomatous polyposis; HNPCC = hereditary non-polyposis colon cancer;
JPS = juvenile polyposis syndrome; MAP = MyTyft-associated polyposis;
PJS = Peutz-Jeghers syndrome)
around 85% of colorectal cancers. Figure 21 .59 outlines
some of the common genes affected by CIN.
• Microsatellite instability. This involves germline mutations in
one of six genes encoding enzymes involved in repairing
errors that occur normally during DNA replication (DNA
mismatch repair); these genes are designated hMSH2,
hMSH6, hMLHI , hMLH3, hPMSI and hPMS2. Replication
errors accumulate and can be detected in ‘microsatellites’
of repetitive DNA sequences. They also occur in important
regulatory genes, resulting in a genetically unstable
phenotype and accumulation of multiple somatic mutations
throughout the genome that eventually lead to cancer.
Around 1 5% of sporadic cancers develop this way, as do
most cases of hereditary non-polyposis colon cancer
(HNPCC).
• CpG island methylator phenotype (CIMP). This phenotype
is found in approximately 20-30% of colorectal cancers
and results in widespread gene hypermethylation. The
result is functional loss of tumour suppressor genes.
21.70 Dietary risk factors for colorectal cancer
Risk factor
Comments
Increased risk
Red meat*
High saturated fat and protein content
Carcinogenic amines formed during cooking
Saturated animal fat*
High faecal bile acid and fatty acid levels
May affect colonic prostaglandin turnover
Decreased risk
Dietary fibre*
Effects vary with fibre type; shortened transit
time, binding of bile acids and effects on
bacterial flora proposed
Fruit and vegetables
Green vegetables contain anticarcinogens,
such as flavonoids
Little evidence for protection from vitamins A,
C and E
Calcium
Binds and precipitates faecal bile acids
Folic acid
Reverses DNA hypomethylation
Omega-3 fatty acids
May be of modest benefit
Evidence is inconsistent and a clear relationship is unproven.
21 .71 Non-dietary risk factors for colorectal cancer
Medical conditions
• Colorectal adenomas (p. 827)
• Long-standing extensive ulcerative colitis or Crohn’s colitis (p. 813),
especially if associated with primary sclerosing cholangitis
• Ureterosigmoidostomy
• Acromegaly
• Pelvic radiotherapy
Others
• Obesity and sedentary lifestyle - may be related to diet
• Smoking (relative risk 1 .5-3.0)
• Alcohol (weak association)
• Cholecystectomy (effect of bile acids in right colon)
• Type 2 diabetes (hyperinsulinaemia)
• Use of aspirin or NSAIDs (COX-2 inhibition) and perhaps statins
associated with reduced risk
(COX-2 = cyclo-oxygenase 2; NSAIDs = non-steroidal anti-inflammatory drugs)
Disorders of the colon and rectum • 831
Normal
Early adenoma
Intermediate
adenoma
Late adenoma
Carcinoma
fMTMrMVirfTp
nns
mi
Further mutations
• Anchorage
independence
• Protease
synthesis
• Telomerase
synthesis
• Multidrug
resistance
• Evasion of
immune system
Key gene(s)
APC
(adenomatous
polyposis coli)
K-ras
DCC (deleted in
colon cancer)
SMAD4
TP53
Chromosome
5q
12p
1 8q
17p
Normal
function
Inhibits
translocation
of p-catenin to
nucleus and
suppresses
cell growth
Transmembrane
GTP-binding
protein mediating
mitogenic
signals (p21)
DCC regulates
apoptosis and has a
tumour suppressor
function
SMAD4 regulates
cell growth
Up-regulated during
cell damage to
arrest cell cycle and
allow DNA repair or
apoptosis to occur
Alteration
Truncating
mutations
Gain-of-function
mutations
Allelic deletion or
silencing (DCC)
Gain-of-function
mutations (SMAD4)
Allelic deletion;
gain-of-function
mutations
Effect
Progression to
early adenoma
development
Cell
proliferation
Enhanced tumour
growth, invasion
and metastasis
Cell proliferation;
impaired apoptosis
Fig. 21.59 The multistep origin of cancer: molecular events implicated
21.72 Modified Amsterdam criteria for hereditary
non-polyposis colon cancer
• Three or more relatives with colon cancer (at least one first-degree)
• Colorectal cancer in two or more generations
• At least one member affected under 50 years of age
• Familial adenomatous polyposis excluded
*These criteria are strict and may miss some families with mutations. Hereditary
non-polyposis colon cancer should also be considered in individuals with
colorectal or endometrial cancer under 45 years of age.
With the advent of sophisticated sequencing methodologies,
such as whole-exome or whole-genome sequencing, it is
becoming clear that colorectal cancer displays molecular
heterogeneity resulting from both common and rare genetic
variants, all displaying differing levels of penetrance.
About 5-10% of colon cancers are caused by HNPCC.
Pedigrees with this disorder have an autosomal dominant mode of
inheritance and a positive family history of colon cancer occurring
at a young age. The lifetime risk in affected individuals is 80%,
with a mean age at cancer development of 45 years. In contrast
to sporadic colon cancer, two-thirds of tumours occur proximally.
The diagnostic criteria are listed in Box 21 .72. In a subset of
patients, there is also an increased incidence of cancers of the
endometrium, ovary, urinary tract, stomach, pancreas, small
intestine and CNS, related to inheritance of different mismatch
repair gene mutations. Those who fulfil the criteria for HNPCC
should be referred for pedigree assessment, genetic testing (see
above) and colonoscopy. These should begin around 25 years
of age or 5-1 0 years earlier than the youngest case of cancer in
the family. Colonoscopy needs to be repeated every 1-2 years
but, even then, interval cancers can still occur.
in colorectal carcinogenesis. (GTP = guanine triphosphate)
A family history of colorectal cancer can be obtained in 20%
of patients who do not fulfil the criteria for HNPCC. In these
families, the lifetime risk of developing colon cancer is 1 in 12
and 1 in 6, respectively, when one or two first-degree relatives
are affected. The risk is even higher if relatives were affected
at an early age. The genes responsible for these cases are,
however, unknown.
Most colorectal cancers are ‘sporadic’ and arise from malignant
transformation of a benign adenomatous polyp. Over 65% occur
in the rectosigmoid and a further 15% occur in the caecum or
ascending colon. Synchronous tumours are present in 2-5% of
patients. Spread occurs through the bowel wall. Rectal cancers
may invade the pelvic viscera and side walls. Lymphatic invasion
is common at presentation, as is spread through both portal
and systemic circulations to reach the liver and, less commonly,
the lungs. Tumour stage at diagnosis is the most important
determinant of prognosis (Fig. 21 .60).
Clinical features
Symptoms vary, depending on the site of the carcinoma. In
tumours of the left colon, fresh rectal bleeding is common and
obstruction occurs early. Tumours of the right colon present
with anaemia from occult bleeding or with altered bowel habit,
but obstruction is a late feature. Colicky lower abdominal pain
is present in two-thirds of patients and rectal bleeding occurs
in 50%. A minority present with features of either obstruction
or perforation, leading to peritonitis, localised abscess or fistula
formation. Carcinoma of the rectum usually causes early bleeding,
mucus discharge or a feeling of incomplete emptying. Between
1 0% and 20% of patients present with iron deficiency anaemia
or weight loss. On examination, there may be a palpable mass,
signs of anaemia or hepatomegaly from metastases. Low rectal
tumours may be palpable on digital examination.
832 • GASTROENTEROLOGY
Dukes stage
Definition
Prevalence
at diagnosis (%)
10
35
30
25
5-year survival
rate (%)
>90
65
30-35
Fig. 21.60 Modified Dukes classification and survival in colorectal cancer.
<5
Investigations
Colonoscopy is the investigation of choice because it is
more sensitive and specific than barium enema. Furthermore,
lesions can be biopsied and polyps removed. Patients in whom
colonoscopy is incomplete and those who are at high risk of
complications can be investigated by CT colonography (virtual
colonoscopy). This is a sensitive and non-invasive technique for
diagnosing tumours and polyps of more than 6 mm diameter.
When the diagnosis of colon cancer has been made, CT of the
chest, abdomen and pelvis should be performed as a staging
investigation, particularly to detect hepatic metastases. Pelvic
MRI or endoanal ultrasound should be used for local staging of
rectal cancer. Measurement of serum carcinoembryonic antigen
(CEA) levels are of limited value in diagnosis, since values are
normal in many patients, but CEA testing can be helpful during
follow-up to monitor for recurrence.
Management
Surgery
All patients should be discussed at a multidisciplinary team
meeting. Those with locally advanced rectal cancer should
be offered neoadjuvant radiotherapy or chemoradiotherapy to
increase the subsequent chance of a complete (R0) surgical
resection. A 1 -week course of radiotherapy just prior to surgery
reduces the risk of local recurrence in operable rectal cancer.
The tumour should be removed, along with adequate resection
margins and pericolic lymph nodes. Continuity should be restored
by direct anastomosis, wherever possible. Carcinomas within
2 cm of the anal verge may require abdominoperineal resection
and formation of a colostomy. All patients should be counselled
pre-operatively about the possible need for a stoma. Total
mesorectal excision reduces recurrence rates and increases
survival in rectal cancer. Metastatic disease confined to liver or
lung should be considered for resection, as this can be potentially
curative if there is truly no disease at other sites. Post-operatively,
patients should undergo colonoscopy after 6-12 months and
then at 5 years to search for local recurrence or development
of new lesions, which occur in 6% of cases.
Adjuvant therapy
About 30-40% of patients have lymph node involvement at
presentation (Fig. 21.60) and are therefore at risk of recurrence.
Most recurrences are within 3 years of diagnosis and affect
the liver, lung, distant lymph nodes and peritoneum. Adjuvant
chemotherapy with 5-fluorouracil/folinic acid or capecitabine,
preferably in combination with oxaliplatin, can reduce the risk
of recurrence in patients with Dukes stage C cancers and some
high-risk Dukes B cancers. Post-operative radiotherapy reduces
the risk of local recurrence in rectal cancer if operative resection
margins are involved.
Palliation of advanced disease
Surgical resection of the primary tumour is appropriate for
some patients with metastases to treat obstruction, bleeding
or pain. Palliative chemotherapy with 5-fluorouracil/folinic acid,
capecitabine, oxaliplatin or irinotecan improves survival. Patients
with advanced metastatic disease may be treated with mono¬
clonal antibodies using bevacizumab or cetuximab, either alone
or together with chemotherapy. Pelvic radiotherapy is sometimes
useful for distressing rectal symptoms, such as pain, bleeding
or severe tenesmus. Endoscopic laser therapy or insertion of
an expandable metal stent can be used to relieve obstruction
(Fig. 21.61).
Prevention and screening
Secondary prevention aims to detect and remove lesions at an
early or pre-malignant stage by screening the asymptomatic
general population. Several potential methods exist:
• Population-based screening of people over the age of
50 years by regular faecal occult blood (FOB) testing
reduces colorectal cancer mortality and increases the
proportion of early cancers detected. The sensitivity
and specificity of these tests need to be improved.
Traditionally, serial stool testing with or without subsequent
colonoscopy is the screening method of choice
in the UK.
• Colonoscopy remains the gold standard and allows
preventative polypectomy but is expensive, requires bowel
preparation and carries risks (perforation approximately
1 : 1000). Many countries lack the resources to offer this
form of screening.
• Flexible sigmoidoscopy is an alternative option and has
been shown to reduce overall colorectal cancer mortality
by approximately 35% (70% for cases arising in the
Disorders of the colon and rectum • 833
Fig. 21.61 Placement of a colonic stent for an inoperable cancer with impending obstruction, [jj The contrast study demonstrates an obstruction.
HI The stent is deployed across the tumour. [C] A satisfactory position is demonstrated on subsequent CT scanning.
rectosigmoid). It is recommended in the USA every
5 years in all persons over the age of 50.
• Screening for high-risk patients by molecular genetic
analysis is an exciting prospect but is not yet available.
• CT colonography is fast and low-risk, and offers
equivalent sensitivity to colonoscopy. Disadvantages
include reduced sensitivity to detect polyps of less than
6 mm, the requirement for bowel preparation, exposure
to ionising radiation and its inability to offer therapeutic
intent.
Diverticulosis
Diverticula are acquired and are most common in the sigmoid
and descending colon of middle-aged people. Asymptomatic
diverticula (diverticulosis) are present in over 50% of people
above the age of 70 years. Symptomatic diverticular disease
supervenes in 10-25% of cases, while complicated diverticulosis
(acute diverticulitis, pericolic abscess, bleeding, perforation or
stricture) is uncommon.
Pathophysiology
A life-long refined diet with a relative deficiency of fibre is widely
thought to be responsible and the condition is rare in populations
with a high dietary fibre intake, such as in Asia, where it more
often affects the right side of the colon. It is postulated that
small-volume stools require high intracolonic pressures for
propulsion and this leads to herniation of mucosa between the
taeniae coli (Fig. 21.62). Diverticula consist of protrusions of
mucosa covered by peritoneum. There is commonly hypertrophy
of the circular muscle coat. Inflammation is thought to result
from impaction of diverticula with faecoliths. This may resolve
spontaneously or progress to cause haemorrhage, perforation,
local abscess formation, fistula and peritonitis. Repeated attacks
of inflammation lead to thickening of the bowel wall, narrowing
of the lumen and eventual obstruction.
Clinical features
Symptoms are usually the result of associated constipation
or spasm. Colicky pain is suprapubic or felt in the left iliac
fossa. The sigmoid colon may be palpable and, in attacks of
diverticulitis, there is local tenderness, guarding, rigidity (‘left-sided
appendicitis’) and sometimes a palpable mass. During these
episodes, there may be diarrhoea, rectal bleeding or fever. The
differential diagnosis includes colorectal cancer, ischaemic colitis,
Taenia
(longitudinal muscle)
Fig. 21.62 The human colon in diverticulosis. The colonic wall is weak
between the taeniae. The blood vessels that supply the colon pierce the
circular muscle and weaken it further by forming tunnels. Diverticula
usually emerge through these points of least resistance.
IBD and infection. Diverticular disease may be complicated by
perforation, pericolic abscess, fistula formation (usually colovesical)
or acute rectal bleeding. These complications are more common
in patients who take NSAIDs or aspirin. After one attack of
diverticulitis, the recurrence rate is around 3% per year. Over
10-30 years, perforation, obstruction or bleeding may occur,
each affecting 5% of patients.
Investigations
Investigations are usually performed to exclude colorectal
neoplasia. Diverticula can be seen during colonoscopy or on
imaging modalities such as CT scan, CT colonography or
barium enema (see Fig. 21 .12C, p. 773). In severe diverticulosis,
colonoscopy requires expertise and carries a risk of perforation.
CT is used to assess complications, such as perforation or
pericolic abscess.
834 • GASTROENTEROLOGY
Management
Diverticular disease that is asymptomatic and discovered
coincidentally requires no treatment. Constipation can be
relieved by a high-fibre diet, with or without a bulking laxative
(ispaghula husk, 1-2 sachets daily), taken with plenty of fluids.
Stimulant laxatives (see Box 21.73 below) should be avoided.
Antispasmodics may sometimes help. Acute attacks of diverticulitis
can be treated with antibiotics active against Gram-negative
and anaerobic organisms. Severe cases require intravenous
fluids, intravenous antibiotics, analgesia and nasogastric suction,
but randomised trials show no benefit from acute resection
compared to conservative management. Emergency surgery is
reserved for severe haemorrhage or perforation. Percutaneous
drainage of acute paracolic abscesses can be effective and avoids
the need for emergency surgery. Patients who have repeated
attacks of obstruction should undergo elective surgery once
the acute episode has settled, in order to resect the affected
segment of bowel with restoration of continuity by primary
anastomosis.
Constipation and disorders of defecation
The clinical approach to patients with constipation and its aetiology
have been described on page 786.
Simple constipation
Simple constipation is extremely common and does not signify
underlying organic disease. It usually responds to increased
dietary fibre or the use of bulking agents; an adequate fluid
intake is also essential. Many types of laxative are available, and
these are listed in Box 21 .73.
Severe idiopathic constipation
This occurs almost exclusively in young women and often begins
in childhood or adolescence. The cause is unknown but some
have ‘slow transit’ with reduced motor activity in the colon.
Others have ‘obstructed defecation’, resulting from inappropriate
contraction of the external anal sphincter and puborectalis muscle
(anismus). The condition is often resistant to treatment. Bulking
agents may exacerbate symptoms but prokinetic agents or
balanced solutions of polyethylene glycol ‘3350’ benefit some
patients with slow transit. Glycerol suppositories and biofeedback
techniques are used for those with obstructed defecation. Others
benefit from agents such as prucalopride or linaclotide. Rarely,
subtotal colectomy may be necessary as a last resort.
21.73 Laxatives
Class
Examples
Bulk-forming laxatives
Ispaghula husk, methylcellulose
Stimulants
Bisacodyl, dantron (only for terminally ill
patients), docusate, senna
Faecal softeners
Docusate, arachis oil enema
Osmotic laxatives
Lactulose, lactitol, magnesium salts
Others
Polyethylene glycol (PEG)*, phosphate
enema*
*Also used for bowel preparation prior to investigation or surgery.
Faecal impaction
In faecal impaction, a large, hard mass of stool fills the rectum.
This tends to occur in disabled, immobile or institutionalised
patients, especially the frail elderly or those with dementia.
Constipating drugs, autonomic neuropathy and painful anal
conditions also contribute. Megacolon, intestinal obstruction
and urinary tract infections may supervene. Perforation and
bleeding from pressure-induced ulceration are occasionally
seen. Treatment involves adequate hydration and careful digital
disimpaction after softening the impacted stool with arachis oil
enemas. Stimulants should be avoided.
I Melanosis coli and laxative
misuse syndromes
Long-term consumption of stimulant laxatives leads to accu¬
mulation of lipofuscin pigment in macrophages in the lamina
propria. This imparts a brown discoloration to the colonic mucosa,
often described as resembling ‘tiger skin’. The condition is
benign and resolves when the laxatives are stopped. Prolonged
laxative use may rarely result in megacolon or ‘cathartic colon’,
in which barium enema demonstrates a featureless mucosa,
loss of haustra and shortening of the bowel. Surreptitious
laxative misuse is a psychiatric condition seen in young women,
some of whom have a history of bulimia or anorexia nervosa
(pp. 1 203 and 1 204). They complain of refractory watery diarrhoea.
Laxative use is usually denied and may continue, even when
patients are undergoing investigation. Screening of urine for
laxatives may reveal the diagnosis.
Hirschsprung’s disease
This disease is characterised by constipation and colonic dilatation
(megacolon) due to congenital absence of ganglion cells in the
large intestine. The incidence is approximately 1 :5000. About
one-third of patients have a positive family history and, in these
families, the disease is inherited in an autosomal dominant manner
with incomplete penetrance. About 50% of familial cases and
1 5% of sporadic cases have mutations affecting the RET proto¬
oncogene, which is also implicated in multiple endocrine neoplasia
(MEN) types 2 and 3 (also known as MEN 2a and 2b, respectively;
p. 688). Unlike MEN 2 and 3, which are caused by activating RET
mutations, Hirschsprung’s disease is caused by loss-of-function
mutations. In some kindreds, Hirschsprung’s disease and MEN
can actually co-segregate and this presumably represents both
‘switch off and ‘switch on’ of RET in different tissues. Although
RET is the most important susceptibility gene, some patients with
(fx
• Evaluation: particular attention should be paid to immobility, dietary
fluid and fibre intake, drugs and depression.
• Immobility: predisposes to constipation by increasing the colonic
transit time; the longer this is, the greater the fluid absorption and
the harder the stool.
• Bulking agents: can make matters worse in patients with slow
transit times and should be avoided.
• Overflow diarrhoea: if faecal impaction develops, paradoxical
overflow diarrhoea may occur. If antidiarrhoeal agents are given,
the underlying impaction may worsen and result in serious
complications, such as stercoral ulceration and bleeding.
21.74 Constipation in old age
Disorders of the colon and rectum • 835
RET mutations do not develop clinical Hirschsprung’s disease,
and mutations in other genes have been identified that interact to
cause the disease. All of the genes implicated in Hirschsprung’s
disease are involved in the regulation of enteric neurogenesis,
and the mutations cause failure of migration of neuroblasts into
the gut wall during embryogenesis. Ganglion cells are absent
from nerve plexuses, most commonly in a short segment of
the rectum and/or sigmoid colon. As a result, the internal anal
sphincter fails to relax. Constipation, abdominal distension and
vomiting usually develop immediately after birth but a few cases
do not present until childhood or adolescence. The rectum is
empty on digital examination.
A plain abdominal X-ray or barium enema shows a small
rectum and colonic dilatation above the narrowed segment.
Full-thickness biopsies are required to demonstrate nerve plexuses
and confirm the absence of ganglion cells. Histochemical stains
for acetylcholinesterase are also used. Anorectal manometry
demonstrates failure of the rectum to relax with balloon distension.
Treatment involves resection of the affected segment.
Acquired megacolon
This may develop in childhood as a result of voluntary withholding
of stool during toilet training. In such cases, it presents after the
first year of life and is distinguished from Hirschsprung’s disease
by the urge to defecate and the presence of stool in the rectum.
It usually responds to osmotic laxatives.
In adults, acquired megacolon has several causes. It is seen
in patients with depression or dementia, either as part of the
condition or as a side-effect of antidepressant drugs. Prolonged
misuse of stimulant laxatives may cause degeneration of the
myenteric plexus, while interruption of sensory or motor innervation
may be responsible in a number of neurological disorders.
Patients taking large doses of opioid analgesics can develop
a megacolon: so-called ‘narcotic bowel syndrome’. Systemic
sclerosis and hypothyroidism are other recognised causes.
Most patients can be managed conservatively by treatment
of the underlying cause, high-residue diets, laxatives and the
judicious use of enemas. Prokinetics are helpful in a minority
of patients. Opioid-associated constipation can be treated with
the specific peripheral opioid receptor antagonist naloxegol.
Subtotal colectomy is a last resort for the most severely affected
patients.
Acute colonic pseudo-obstruction
Acute colonic pseudo-obstruction (Ogilvie’s syndrome) has
many causes (Box 21 .75) and is characterised by sudden onset
of painless, massive enlargement of the proximal colon; there
are no features of mechanical obstruction. Bowel sounds are
normal or high-pitched, rather than absent. Left untreated, it
may progress to perforation, peritonitis and death.
Abdominal X-rays show colonic dilatation with air extending to
the rectum. Caecal diameter greater than 10 cm is associated with
I 21 .75 Causes of acute colonic pseudo-obstruction
• Trauma, burns
• Electrolyte and acid-base
• Recent surgery
disorders
• Drugs (opiates,
• Diabetes mellitus
phenothiazines)
• Uraemia
• Respiratoryfailure
a high risk of perforation. Single-contrast or water-soluble barium
enemas demonstrate the absence of mechanical obstruction.
Management consists of treating the underlying disorder and
correcting any biochemical abnormalities. The anticholinesterase
neostigmine is effective in enhancing parasympathetic activity
and gut motility. Decompression, with either a rectal tube or
colonoscope, may be effective but needs to be repeated until
the condition resolves. In severe cases, surgical or fluoroscopic
defunctioning caecostomy is necessary.
Anorectal disorders
Faecal incontinence
The normal control of anal continence is described on page
770. Common causes of incontinence are listed in Box 21 .76.
High-risk patients include frail older people, women after childbirth
and those with severe neurological/spinal disorders, learning
difficulties or cognitive impairment.
Patients are often embarrassed to admit incontinence and may
complain only of ‘diarrhoea’. A careful history and examination,
especially of the anorectum and perineum, may help to establish
the underlying cause. Endoanal ultrasound is valuable for defining
the integrity of the anal sphincters, while anorectal physiology
and MR proctography are also useful investigations.
Management
This is often very difficult. Underlying disorders should be treated
and diarrhoea managed with loperamide, diphenoxylate or
codeine phosphate. Attention must be paid to a proper diet
and adequate fluid intake. Pelvic floor exercises, biofeedback
and bowel retraining techniques help some patients, and those
with confirmed anal sphincter defects may benefit from sphincter
repair operations. Where sphincter repair is not appropriate,
a trial of sacral nerve stimulation is undertaken with a view to
insertion of a permanent stimulator but, if unsuccessful, creation
of a neo-sphincter may be possible, by graciloplasty or by an
artificial anal sphincter.
Haemorrhoids
Haemorrhoids (commonly known as piles) arise from congestion
of the internal and/or external venous plexuses around the anal
canal. They are extremely common in adults. The aetiology is
unknown, although they are associated with constipation and
straining, and may develop for the first time during pregnancy.
First-degree piles bleed, while second-degree piles prolapse
but retract spontaneously. Third-degree piles are those that
require manual replacement after prolapsing. Bright red rectal
bleeding occurs after defecation. Other symptoms include pain,
pruritus ani and mucus discharge; thrombosis can occur in
prolapsed piles, which can be very painful (Fig. 21.63). Treatment
i
• Obstetric trauma: childbirth, hysterectomy
• Severe diarrhoea
• Faecal impaction
• Congenital anorectal anomalies
• Anorectal disease: haemorrhoids, rectal prolapse, Crohn’s disease
• Neurological disorders: spinal cord or cauda equina lesions,
dementia
21.76 Causes of faecal incontinence
836 • GASTROENTEROLOGY
Fig. 21.63 Thrombosed prolapsed haemorrhoids.
21 .77 Causes of pruritus ani
Local anorectal conditions
• Haemorrhoids • Poor hygiene
• Fistula, fissures
Infections
• Threadworms • Candidiasis
Skin disorders
• Contact dermatitis • Lichen planus
• Psoriasis
Other
• Diarrhoea or incontinence of • Irritable bowel syndrome
any cause • Anxiety
involves measures to prevent constipation and straining. Band
ligation is effective for many but a minority of patients require
haemorrhoidectomy, which is usually curative. Haemorrhoidal
artery ligation operation (HALO) procedures have been developed
and may replace surgery. HALO involves using Doppler ultra¬
sound to identify all the arteries feeding the haemorrhoids and
ligating them.
Pruritus ani
This is common and can stem from many causes (Box 21 .77),
most of which result in contamination of the perianal skin with
faecal contents.
Itching may be severe and results in an itch-scratch-itch cycle
that exacerbates the problem. When no underlying cause is
found, all local barrier ointments and creams must be stopped.
Good personal hygiene is essential, with careful washing after
defecation. The perineal area must be kept dry and clean.
Bulk-forming laxatives may reduce faecal soiling.
^Solitary rectal ulcer syndrome
This is most common in young adults and occurs on the anterior
rectal wall. It is thought to result from localised chronic trauma
and/or ischaemia associated with disordered puborectalis function
and mucosal prolapse. The ulcer is seen at sigmoidoscopy and
biopsies show a characteristic accumulation of collagen.
Symptoms include minor bleeding and mucus per rectum,
tenesmus and perineal pain. Treatment is often difficult but
avoidance of straining at defecation is important and treatment
of constipation may help. Marked mucosal prolapse is treated
surgically.
Anal fissure
In this common problem, traumatic or ischaemic damage to
the anal mucosa results in a superficial mucosal tear, most
commonly in the midline posteriorly. Spasm of the internal anal
sphincter exacerbates the condition. Severe pain occurs on
defecation and there may be minor bleeding, mucus discharge
and pruritus. The skin may be indurated and an oedematous
skin tag, or ‘sentinel pile’, adjacent to the fissure is common.
Avoidance of constipation with bulk-forming laxatives and
increased fluid intake is important. Relaxation of the internal
sphincter is normally mediated by nitric oxide, and 0.2% glyceryl
trinitrate, which donates nitric oxide and improves mucosal blood
flow, is effective in 60-80% of patients. Diltiazem cream (2%)
can be used as an alternative. Resistant cases may respond
to injection of botulinum toxin into the internal anal sphincter
to induce relaxation. Manual dilatation under anaesthesia leads
to long-term incontinence and should not be considered. The
majority of cases can be treated without surgery, but where
these measures fail, healing can be achieved surgically by lateral
internal anal sphincterotomy or advancement anoplasty.
Anorectal abscesses and fistulae
Perianal abscesses develop between the internal and external
anal sphincters and may point at the perianal skin. Ischiorectal
abscesses occur lateral to the sphincters in the ischiorectal fossa.
They usually result from infection of anal glands by normal intestinal
bacteria. Crohn’s disease (p. 813) is sometimes responsible.
Patients complain of extreme perianal pain, fever and/
or discharge of pus. Spontaneous rupture may lead to the
development of fistulae. These may be superficial or track through
the anal sphincters to reach the rectum. Abscesses are drained
surgically and superficial fistulae are laid open with care to avoid
sphincter damage.
Diseases of the peritoneal cavity
| Peritonitis
Surgical peritonitis occurs as the result of a ruptured viscus (for
details see this book’s companion text, Principles and Practice
of Surgery). Peritonitis may also complicate ascites in chronic
liver disease (spontaneous bacterial peritonitis, p. 864) or may
occur in children in the absence of ascites, due to infection with
Streptococcus pneumoniae or p- haemolytic streptococci (p. 253).
Chlamydial peritonitis is a complication of pelvic inflammatory
disease (p. 336). The patient presents with right upper quadrant
pain, pyrexia and a hepatic rub (the Fitz-Hugh-Curtis syndrome).
Tuberculosis may cause peritonitis and ascites (p. 588).
Ijumours
The most common is secondary adenocarcinoma from the
ovary or gastrointestinal tract. Mesothelioma is a rare tumour
complicating asbestos exposure. It presents as a diffuse
Diseases of the pancreas • 837
abdominal mass, due to omental infiltration, and with ascites.
The prognosis is extremely poor.
Other disorders
Endometriosis
Ectopic endometrial tissue can become embedded on the
serosal aspect of the intestine, most frequently in the sigmoid
and rectum. The overlying mucosa is usually intact. Cyclical
engorgement and inflammation result in pain, bleeding, diarrhoea,
constipation and adhesions or obstruction. Low backache is
frequent. The onset is usually between 20 and 45 years and
the condition is more common in nulliparous women. Bimanual
examination may reveal tender nodules in the pouch of Douglas.
Endoscopic studies reveal the diagnosis only if carried out during
menstruation, when a bluish mass with intact overlying mucosa
is apparent. In some patients, laparoscopy is required. Treatment
options include laparoscopic diathermy and hormonal therapy
with progestogens (e.g. norethisterone), gonadotrophin-releasing
hormone analogues or danazol.
Pneumatosis cystoides intestinalis
In this rare condition, multiple gas-filled submucosal cysts line
the colonic and small bowel walls. The cause is unknown but
the condition may be seen in patients with chronic cardiac or
pulmonary disease, pyloric obstruction, systemic sclerosis or
dermatomyositis. Most patients are asymptomatic, although
there may be abdominal cramp, diarrhoea, tenesmus, rectal
bleeding and mucus discharge. The cysts are recognised on
sigmoidoscopy, plain abdominal X-rays or barium enema.
Therapies reported to be effective include prolonged high-flow
oxygen, elemental diets and antibiotics.
Diseases of the pancreas
Acute pancreatitis
Acute pancreatitis accounts for 3% of all cases of abdominal
pain admitted to hospital. It affects 2-28 per 100000 of the
population and is increasing in incidence. It is a potentially serious
condition with an overall mortality of 10%. About 80% of all
cases are mild and have a favourable outcome. Approximately
98% of deaths from pancreatitis occur in the 20% of patients
with severe disease and about one-third of these arise within the
first week, usually from multi-organ failure. After this time, the
majority of deaths result from sepsis, especially that complicating
infected necrosis. At admission, it is possible to predict patients
at risk of these complications (Box 21 .78). Individuals who are
predicted to have severe pancreatitis (Box 21 .79) and those
with necrosis or other complications should be managed in a
specialist centre with an intensive care unit and multidisciplinary
hepatobiliary specialists.
Pathophysiology
Acute pancreatitis occurs as a consequence of premature
intracellular trypsinogen activation, releasing proteases that digest
the pancreas and surrounding tissue. Triggers for this are many,
including alcohol, gallstones and pancreatic duct obstruction (Fig.
21 .64). There is simultaneous activation of nuclear factor kappa
21.78 Glasgow criteria for prognosis in
acute pancreatitis
• Age >55 years
• P02 <8 kPa (60 mmHg)
• White blood cell count >15x1 09/L
• Albumin <32 g/L (3.2 g/dL)
• Serum calcium <2 mmol/L (8 mg/dL) (corrected)
• Glucose >10 mmol/L (180 mg/dL)
• Urea >16 mmol/L (45 mg/dL) (after rehydration)
• Alanine aminotransferase >200 U/L
• Lactate dehydrogenase >600 U/L
*Severity and prognosis worsen as the number of these factors increases. More
than three implies severe disease.
i
Initial assessment
• Clinical impression of severity
• Body mass index >30 kg/m2
• Pleural effusion on chest X-ray
• APACHE II score >8 (see Box 10.50, p. 214)
24 hours after admission
• Clinical impression of severity
• APACHE II score >8
• Glasgow score >3 (see Box 21 .78)
• Persisting organ failure, especially if multiple
• CRP > 1 50 mg/L
48 hours after admission
• Clinical impression of severity
• Glasgow score >3
• CRP >150 mg/L
• Persisting organ failure for 48 hours
• Multiple or progressive organ failure
(CRP = C-reactive protein)
B (NFkB), leading to mitochondrial dysfunction, autophagy and a
vigorous inflammatory response. The normal pancreas has only
a poorly developed capsule, and adjacent structures, including
the common bile duct, duodenum, splenic vein and transverse
colon, are commonly involved in the inflammatory process. The
severity of acute pancreatitis is dependent on the balance between
the activity of released proteolytic enzymes and antiproteolytic
factors. The latter comprise an intracellular pancreatic trypsin
inhibitor protein and circulating (32-macroglobulin, -antitrypsin
and Cl -esterase inhibitors. The causes of acute pancreatitis are
listed in Box 21 .80. Acute pancreatitis is often self-limiting, but
in some patients with severe disease, local complications, such
as necrosis, pseudocyst or abscess, occur, as well as systemic
complications that lead to multi-organ failure.
Clinical features
The typical presentation is with severe, constant upper abdominal
pain, of increasing intensity over 15-60 minutes, which radiates
to the back. Nausea and vomiting are common. There is marked
epigastric tenderness, but in the early stages (and in contrast to
a perforated peptic ulcer), guarding and rebound tenderness are
absent because the inflammation is principally retroperitoneal.
Bowel sounds become quiet or absent as paralytic ileus develops.
In severe cases, the patient becomes hypoxic and develops
hypovolaemic shock with oliguria. Discoloration of the flanks
21 .79 Features that predict severe pancreatitis
838 • GASTROENTEROLOGY
Fig. 21 .64 Pathophysiology of acute pancreatitis.
21.80 Causes of acute pancreatitis
Common (90% of cases)
• Gallstones
• Alcohol
• Idiopathic causes
• Post-ERCP
Rare
• Post-surgical (abdominal, cardiopulmonary bypass)
• Trauma
• Drugs (azathioprine/mercaptopurine, thiazide diuretics, sodium
valproate)
• Metabolic (hypercalcaemia, hypertriglyceridaemia)
• Pancreas divisum (p. 842)
• Sphincter of Oddi dysfunction
• Infection (mumps, Coxsackie virus)
• Hereditary factors
• Renal failure
• Organ transplantation (kidney, liver)
• Severe hypothermia
• Petrochemical exposure
(ERCP = endoscopic retrograde cholangiopancreatography)
Fig. 21.65 Computed tomogram showing large pancreatic
pseudocyst (C) compressing the stomach (S). The pancreas is atrophic
and calcified (arrows).
i
21 .81 Complications of acute pancreatitis
Complication
Cause
Systemic
Systemic inflammatory
Increased vascular permeability from
response syndrome
cytokine, platelet-aggregating factor and
(SIRS)
kinin release
Hypoxia
Acute respiratory distress syndrome (ARDS)
due to microthrombi in pulmonary vessels
Hyperglycaemia
Disruption of islets of Langerhans with
altered insulin/glucagon release
Hypocalcaemia
Sequestration of calcium in fat necrosis,
fall in ionised calcium
Reduced serum
Increased capillary permeability
albumin concentration
Pancreatic
Necrosis
Non-viable pancreatic tissue and
peripancreatic tissue death; frequently
infected
Abscess
Circumscribed collection of pus close to
the pancreas and containing little or no
pancreatic necrotic tissue
Pseudocyst
Disruption of pancreatic ducts
Pancreatic ascites or
Disruption of pancreatic ducts
pleural effusion
Gastrointestinal
Upper gastrointestinal
Gastric or duodenal erosions
bleeding
Variceal haemorrhage
Splenic or portal vein thrombosis
Erosion into colon
Erosion by pancreatic pseudocyst
Duodenal obstruction
Compression by pancreatic mass
Obstructive jaundice
Compression of common bile duct
(Grey Turner’s sign) or the periumbilical region (Cullen’s sign) is a
feature of severe pancreatitis with haemorrhage. The differential
diagnosis includes a perforated viscus, acute cholecystitis and
myocardial infarction. Various complications may occur and
these are listed in Box 21 .81 .
A collection of fluid and debris may develop in the lesser sac,
following inflammatory rupture of the pancreatic duct; this is known
as a pancreatic fluid collection. It is initially contained within a
poorly defined, fragile wall of granulation tissue, which matures
over a 6-week period to form a fibrous capsule (Fig. 21 .65). Such
‘pseudocysts’ are common and usually asymptomatic, resolving
as the pancreatitis recovers. Pseudocysts greater than 6 cm
in diameter seldom disappear spontaneously and can cause
constant abdominal pain and compress or erode surrounding
structures, including blood vessels, to form pseudoaneurysms.
Large pseudocysts can be detected clinically as a palpable
abdominal mass.
Pancreatic ascites occurs when fluid leaks from a disrupted
pancreatic duct into the peritoneal cavity. Leakage into the thoracic
cavity can result in a pleural effusion or a pleuro-pancreatic fistula.
Diseases of the pancreas • 839
Investigations
The diagnosis is based on raised serum amylase or lipase
concentrations and ultrasound or CT evidence of pancreatic
swelling. Plain X-rays should be taken to exclude other diagnoses,
such as perforation or obstruction, and to identify pulmonary
complications. Amylase is efficiently excreted by the kidneys
and concentrations may have returned to normal if measured
24-48 hours after the onset of pancreatitis. A persistently elevated
serum amylase concentration suggests pseudocyst formation.
Peritoneal amylase concentrations are massively elevated in
pancreatic ascites. Serum amylase concentrations are also
elevated (but less so) in intestinal ischaemia, perforated peptic
ulcer and ruptured ovarian cyst, while the salivary isoenzyme
of amylase is elevated in parotitis. If available, serum lipase
measurements are preferable to amylase, as they have greater
diagnostic accuracy for acute pancreatitis.
Ultrasound scanning can confirm the diagnosis, although in
the earlier stages the gland may not be grossly swollen. The
ultrasound scan is also useful because it may show gallstones,
biliary obstruction or pseudocyst formation.
Contrast-enhanced pancreatic CT performed 6-1 0 days after
admission can be useful in assessing viability of the pancreas if
persisting organ failure, sepsis or clinical deterioration is present,
since these features may indicate that pancreatic necrosis has
occurred. Necrotising pancreatitis is associated with decreased
pancreatic enhancement on CT, following intravenous injection
of contrast material. The presence of gas within necrotic
material (Fig. 21 .66) suggests infection and impending abscess
formation, in which case percutaneous aspiration of material
for bacterial culture should be carried out and appropriate
antibiotics prescribed. Involvement of the colon, blood vessels
and other adjacent structures by the inflammatory process is best
seen by CT.
Certain investigations stratify the severity of acute pancreatitis
and have important prognostic value at the time of presentation
(see Boxes 21 .78 and 21 .79). In addition, serial assessment of
CRP is a useful indicator of progress. A peak CRP of >21 0 mg/L
in the first 4 days predicts severe acute pancreatitis with 80%
accuracy. It is worth noting that the serum amylase concentration
has no prognostic value.
Fig. 21.66 Pancreatic necrosis. Lack of vascular enhancement of the
pancreas during contrast-enhanced computed tomography indicates
necrosis (arrow). The presence of gas suggests that infection has occurred.
Management
Management comprises several related steps:
• establishing the diagnosis and disease severity
• early resuscitation, according to whether the disease is
mild or severe
• detection and treatment of complications
• treatment of the underlying cause.
Opiate analgesics should be given to treat pain and
hypovolaemia should be corrected using normal saline or
other crystalloids. All severe cases should be managed in a
high-dependency or intensive care unit. A central venous line
and urinary catheter should be inserted to monitor patients
with shock. Oxygen should be given to hypoxic patients, and
those who develop systemic inflammatory response syndrome
(SIRS) may require ventilatory support. Flyperglycaemia should
be corrected using insulin and hypocalcaemia by intravenous
calcium injection.
Nasogastric aspiration is required only if paralytic ileus is
present. Enteral feeding, if tolerated, should be started at an
early stage in patients with severe pancreatitis because they are
in a severely catabolic state and need nutritional support. Enteral
feeding decreases endotoxaemia and so may reduce systemic
complications. Nasogastric feeding is just as effective as feeding
by the nasojejunal route. Prophylaxis of thromboembolism with
subcutaneous low-molecular-weight heparin is also advisable.
The use of prophylactic, broad-spectrum intravenous antibiotics
to prevent infection of pancreatic necrosis is not indicated, but
infected necrosis is treated with antibiotics that penetrate necrotic
tissue, e.g. carbapenems or quinolones, and metronidazole.
Patients who present with cholangitis or jaundice in association
with severe acute pancreatitis should undergo urgent ERCP to
diagnose and treat choledocholithiasis. In less severe cases of
gallstone pancreatitis, biliary imaging (using MRCP or EUS) can be
carried out after the acute phase has resolved. If the liver function
tests return to normal and ultrasound has not demonstrated
a dilated biliary tree, laparoscopic cholecystectomy with an
on-table cholangiogram is appropriate because any common
bile duct stones have probably passed. When the operative
cholangiogram detects residual common bile duct stones, these
should be removed by laparoscopic exploration of the duct or by
post-operative ERCP. Cholecystectomy should be undertaken
within 2 weeks of resolution of pancreatitis - and preferably
during the same admission - to prevent further potentially fatal
attacks of pancreatitis. Patients with infected pancreatic necrosis
or pancreatic abscess require urgent endoscopic drainage or
minimally invasive retroperitoneal pancreatic (MIRP) necrosectomy
to debride all cavities of necrotic material. Pancreatic pseudocysts
can be treated by drainage into the stomach or duodenum.
This is usually performed after an interval of at least 6 weeks,
once a pseudocapsule has matured, by surgical or endoscopic
cystogastrostomy.
Chronic pancreatitis
Chronic pancreatitis is a chronic inflammatory disease char¬
acterised by fibrosis and destruction of exocrine pancreatic
tissue. Diabetes mellitus occurs in advanced cases because
the islets of Langerhans are involved (p. 733).
Pathophysiology
Around 80% of cases in Western countries result from alcohol
misuse. In southern India, severe chronic calcific pancreatitis
840 • GASTROENTEROLOGY
occurs in non-alcoholics, possibly as a result of malnutrition,
deficiency of trace elements and micronutrients, and cassava
consumption. Other causes are listed in Box 21.82. The
pathophysiology of chronic pancreatitis is shown in Figure 21 .67.
Clinical features
Chronic pancreatitis predominantly affects middle-aged alcoholic
men. Almost all present with abdominal pain. In 50%, this
occurs as episodes of ‘acute pancreatitis’, although each attack
results in a degree of permanent pancreatic damage. Relentless,
slowly progressive chronic pain without acute exacerbations
affects 35% of patients, while the remainder have no pain but
21.82 Causes of chronic pancreatitis
Toxic-metabolic
• Alcohol • Hypercalcaemia
• Tobacco • Chronic kidney disease
Idiopathic
• Tropical • Early-/late-onset types
Genetic
• Hereditary pancreatitis • SPINK-1 mutation
(cationic trypsinogen mutation) • Cystic fibrosis
Autoimmune
• In isolation or as part of multi-organ problem
Recurrent and severe acute pancreatitis
• Recurrent acute pancreatitis • Post-necrotic
Obstructive
• Ductal adenocarcinoma • Pancreas divisum
• Intraductal papillary mucinous • Sphincter of Oddi stenosis
neoplasia
*These can be memorised by the mnemonic ‘TIGARO’. Gallstones do not cause
chronic pancreatitis but may be observed as an incidental finding.
present with diarrhoea. Pain is due to a combination of increased
pressure within the pancreatic ducts and direct involvement of
peri pancreatic nerves by the inflammatory process. Pain may be
relieved by leaning forwards or by drinking alcohol. Approximately
one-fifth of patients chronically consume opiate analgesics. Weight
loss is common and results from a combination of anorexia,
avoidance of food because of post-prandial pain, malabsorption
and/or diabetes. Steatorrhoea occurs when more than 90% of
the exocrine tissue has been destroyed; protein malabsorption
develops only in the most advanced cases. Overall, 30% of
patients have (secondary) diabetes but this figure rises to 70%
in those with chronic calcific pancreatitis. Physical examination
reveals a thin, malnourished patient with epigastric tenderness.
Skin pigmentation over the abdomen and back is common and
results from chronic use of a hot water bottle (erythema ab igne).
Many patients have features of other alcohol- and smoking-related
diseases. Complications are listed in Box 21 .83.
Investigations
Investigations (Box 21 .84 and Fig. 21 .68) are carried out to:
• make a diagnosis of chronic pancreatitis
• define pancreatic function
• demonstrate anatomical abnormalities prior to surgical
intervention.
i
• Pseudocysts and pancreatic ascites, which occur in both acute and
chronic pancreatitis
• Obstructive jaundice due to benign stricture of the common bile
duct as it passes through the diseased pancreas
• Duodenal stenosis
• Portal or splenic vein thrombosis leading to segmental portal
hypertension and gastric varices
• Peptic ulcer
21.83 Complications of chronic pancreatitis
Aetiology
Alcohol
Smoking
Mechanisms
Oxidative
stress
Idiopathic Genetic Autoimmune Obstructive
Normal
Acute
"pancreatitis
Recurrent
acute
pancreatitis
Chronic
* pancreatitis
Fig. 21.67 Pathophysiology of chronic
pancreatitis. Alcohol and other risk factors may
trigger acute pancreatitis through multiple
mechanisms. The first (or ‘sentinel’) episode of
acute pancreatitis initiates an inflammatory
response involving T-helper (Th) cells. Ongoing
exposure to alcohol drives further inflammation
but this is modified by regulatory T cells (Treg)
with subsequent fibrosis, via activation of
pancreatic stellate cells. A cycle of inflammation
and fibrosis ensues, with development of chronic
pancreatitis. Alcohol is the most relevant risk
factor, as it is involved at multiple steps.
Diseases of the pancreas • 841
21.85 Intervention in chronic pancreatitis
Endoscopic therapy
• Dilatation or stenting of pancreatic duct strictures
• Removal of calculi (mechanical or shock-wave lithotripsy)
• Drainage of pseudocysts
Surgical methods
• Partial pancreatic resection, preserving the duodenum
• Pancreatico-jejunostomy
21.84 Investigations in chronic pancreatitis
Tests to establish the diagnosis
• Ultrasound
• Computed tomography (may show atrophy, calcification or ductal
dilatation)
• Abdominal X-ray (may show calcification)
• Magnetic resonance cholangiopancreatography
• Endoscopic ultrasound
Tests to define pancreatic function
• Collection of pure pancreatic juice after secretin injection (gold
standard but invasive and seldom used)
• Pancreolauryl test (see Box 21 .12, p. 777)
• Faecal pancreatic elastase
Tests to demonstrate anatomy prior to surgery
• Magnetic resonance cholangiopancreatography
Fig. 21.68 Imaging in chronic pancreatitis. {k\ Computed tomogram
showing a grossly dilated and irregular duct with a calcified stone (arrow
A). Note the calcification in the head of the gland (arrow B). [§] Magnetic
resonance cholangiopancreatogram of the same patient showing marked
ductal dilatation with abnormal dilated side branches (arrows A). A small
cyst is also present (arrow B).
| Management
Alcohol misuse
Alcohol avoidance is crucial in halting progression of the disease
and reducing pain.
Pain relief
A range of analgesic drugs, particularly NSAIDs, are valuable but
the severe and unremitting nature of the pain often leads to opiate
use with the risk of addiction. Analgesics, such as pregabalin
and tricyclic antidepressants at a low dose, may be effective.
Oral pancreatic enzyme supplements suppress pancreatic
secretion and their regular use reduces analgesic consumption
in some patients. Patients who are abstinent from alcohol and
who have severe chronic pain that is resistant to conservative
measures should be considered for surgical or endoscopic
pancreatic therapy (Box 21.85). Coeliac plexus neurolysis
sometimes produces long-lasting pain relief, although relapse
occurs in the majority of cases. In some patients, MRCP does
not show a surgically or endoscopically correctable abnormality
and, in these individuals, the only surgical approach is total
pancreatectomy. Unfortunately, even after this operation, some
continue to experience pain. Moreover, the procedure causes
diabetes, which may be difficult to control, with a high risk of
hypoglycaemia (since both insulin and glucagon are absent) and
significant morbidity and mortality.
Malabsorption
This is treated by dietary fat restriction (with supplementary
medium-chain triglyceride therapy in malnourished patients) and
oral pancreatic enzyme supplements. A PPI is added to optimise
duodenal pH for pancreatic enzyme activity.
Management of complications
Surgical or endoscopic therapy may be necessary for the
management of pseudocysts, pancreatic ascites, common
bile duct or duodenal stricture and the consequences of
portal hypertension. Many patients with chronic pancrea¬
titis also require treatment for other alcohol- and smoking-
related diseases and for the consequences of self-neglect and
malnutrition.
Autoimmune pancreatitis
Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis
that can mimic cancer but which responds to glucocorticoids.
It is characterised by abdominal pain, weight loss or
obstructive jaundice, without acute attacks of pancreatitis.
Blood tests reveal increased serum IgG or lgG4 and the
presence of other autoantibodies. Imaging shows a diffusely
enlarged pancreas, narrowing of the pancreatic duct and
stricturing of the lower bile duct. AIP may occur alone or with
other autoimmune disorders, such as Sjogren’s syndrome,
primary sclerosing cholangitis or IBD. The response to
glucocorticoids is usually excellent but some patients require
azathioprine.
842 • GASTROENTEROLOGY
Congenital abnormalities affecting
the pancreas
Pancreas divisum
This is due to failure of the primitive dorsal and ventral ducts
to fuse during embryonic development of the pancreas. As a
consequence, most of the pancreatic drainage occurs through
the smaller accessory ampulla rather than through the major
ampulla. The condition occurs in 7-10% of the normal population
and is usually asymptomatic, but some patients develop acute
pancreatitis, chronic pancreatitis or atypical abdominal pain.
Annular pancreas
In this congenital anomaly, the pancreas encircles the second/
third part of the duodenum, leading to gastric outlet obstruction.
Annular pancreas is associated with malrotation of the intestine,
atresias and cardiac anomalies.
Cystic fibrosis
This disease is considered in detail on page 580. The major
gastrointestinal manifestations are pancreatic insufficiency and
meconium ileus. Peptic ulcer and hepatobiliary disease may also
occur. In cystic fibrosis, pancreatic secretions are protein- and
mucus-rich. The resultant viscous juice forms plugs that obstruct
the pancreatic ductules, leading to progressive destruction of
acinar cells. Steatorrhoea is universal and the large-volume bulky
stools predispose to rectal prolapse. Malnutrition is compounded
by the metabolic demands of respiratory failure and by diabetes,
which develops in 40% of patients by adolescence.
Nutritional counselling and supervision are important to
ensure intake of high-energy foods, providing 1 20-1 50% of the
recommended intake for normal subjects. Fats are an important
calorie source and, despite the presence of steatorrhoea, fat
intake should not be restricted. Supplementary fat-soluble vitamins
are also necessary. High-dose oral pancreatic enzymes are
required, in doses sufficient to control steatorrhoea and stool
frequency. A PPI aids fat digestion by producing an optimal
duodenal pH.
Meconium ileus
Mucus-rich plugs within intestinal contents can obstruct the small
or large intestine of a newborn child. Meconium ileus is treated
by the mucolytic agent A/-acetylcysteine, given either orally, by
Gastrografin enema or by gut lavage using polyethylene glycol.
In resistant cases of meconium ileus, surgical resection may
be necessary.
Tumours of the pancreas
Adenocarcinoma of the pancreas
Some 90% of pancreatic neoplasms are adenocarcinomas that
arise from the pancreatic ducts. These tumours involve local
structures and metastasise to regional lymph nodes at an early
stage. Most patients have advanced disease at the time of
presentation. Neuro-endocrine tumours also arise in the pancreas
but tend to grow more slowly and have a better prognosis; these
are discussed in detail on page 678. Pancreatic adenocarcinoma
affects 10-15 per 100000 in Western populations, rising to 100
per 1 00 000 in those over the age of 70. Men are affected twice
as often as women. The disease is associated with increasing
age, smoking and chronic pancreatitis. Between 5% and 10%
of patients have a genetic predisposition: hereditary pancreatitis,
HNPCC and familial atypical mole multiple melanoma syndrome
(FAMMM). Overall survival is only 3-5%, with a median survival
of 6-10 months for those with locally advanced disease and
3-5 months if metastases are present.
Clinical features
Many patients are asymptomatic until an advanced stage,
when they present with central abdominal pain, weight loss and
obstructive jaundice (Fig. 21 .69). The pain results from invasion
of the coeliac plexus and is characteristically incessant and
gnawing. It often radiates from the upper abdomen through to
the back and may be eased a little by bending forwards. Almost
all patients lose weight and many are cachectic. Around 60% of
tumours arise from the head of the pancreas, and involvement of
the common bile duct results in the development of obstructive
jaundice, often with severe pruritus. A few patients present with
diarrhoea, vomiting from duodenal obstruction, diabetes mellitus,
recurrent venous thrombosis, acute pancreatitis or depression.
Physical examination reveals clear evidence of weight loss. An
abdominal mass due to the tumour itself, a palpable gallbladder
or hepatic metastasis is commonly found. A palpable gallbladder
in a jaundiced patient is usually the consequence of distal biliary
obstruction by a pancreatic cancer (Courvoisier’s sign).
Investigations
The diagnosis is usually made by ultrasound and contrast-
enhanced CT (Fig. 21 .70). Diagnosis in non-jaundiced patients
is often delayed because presenting symptoms are relatively
non-specific. Fit patients with small, localised tumours should
undergo staging to define operability. EUS or laparoscopy with
laparoscopic ultrasound will define tumour size, involvement of
blood vessels and metastatic spread. In patients unsuitable for
surgery because of advanced disease, frailty or comorbidity,
EUS- or CT-guided cytology or biopsy can be used to confirm the
diagnosis (Fig. 21 .70). MRCP and ERCP are sensitive methods
of diagnosing pancreatic cancer and are valuable when the
diagnosis is in doubt, although differentiation between cancer
and localised chronic pancreatitis can be difficult. The main role
of ERCP is to insert a stent into the common bile duct to relieve
obstructive jaundice in inoperable patients.
Management
Surgical resection is the only method of effecting cure, and 5-year
survival in patients undergoing a complete resection is around
12%. Clinical trials have demonstrated improved survival (21-29%)
with adjuvant chemotherapy using gemcitabine. Unfortunately,
only 1 0-1 5% of tumours are resectable for cure, since most are
locally advanced at the time of diagnosis. For the great majority of
patients, treatment is palliative. Chemotherapy with FOLFIRINOX
(5-fluorouracil, leucovorin, irinotecan and oxaliplatin) improves
median survival to 1 1 months. Pain relief can be achieved using
analgesics but, in some patients, coeliac plexus neurolysis may
be required. Jaundice can be relieved by choledochojejunostomy
in fit patients, whereas percutaneous or endoscopic stenting is
preferable in the elderly and those with very advanced disease.
Ampullary or periampullary adenocarcinomas are rare neoplasms
that arise from the ampulla of Vater or adjacent duodenum. They
are often polypoid and may ulcerate; they frequently infiltrate
the duodenum but behave less aggressively than pancreatic
adenocarcinoma. Around 25% of patients undergoing resection
Diseases of the pancreas • 843
Fig. 21 .69 Features of pancreatic cancer.
Fig. 21 .70 Carcinoma of the pancreas. {K\ A computed tomogram showing a large, necrotic mass encasing the coeliac axis (arrows). [§] Endoscopic
ultrasound was subsequently performed to enhance staging and to obtain a fine needle aspiration biopsy, which confirmed pancreatic ductal adenocarcinoma.
844 • GASTROENTEROLOGY
of ampullary or periampullary tumours survive for 5 years, in
contrast to patients with pancreatic ductal cancer.
|jncidental pancreatic mass
Cystic neoplasms of the pancreas are increasingly being seen
with widespread use of CT. These are a heterogeneous group;
serous cystadenomas rarely, if ever, become malignant and
do not require surgery. Mucinous cysts occur more often in
women, are usually in the pancreatic tail and display a spectrum
of behaviour from benign to frankly malignant. Aspiration of the
cyst contents for cytology and measurement of CEA and amylase
concentrations in fluid obtained at EUS can help determine
whether a lesion is mucinous or not. In fit patients, all mucinous
lesions should be resected. A variant, called intraductal papillary
mucinous neoplasia (IPMN), is often discovered coincidentally
on CT, frequently in elderly men. This may affect the main
pancreatic duct with marked dilatation and plugs of mucus,
or may involve a side branch. The histology varies from villous
adenomatous change to dysplasia or carcinoma. Since IPMN
is a pre-malignant but indolent condition, the decision to resect
or to monitor depends on age and fitness of the patient and
location, size and evolution of lesions.
Further information
Books and journal articles
Canard JM, Letard J-C, Palazzo L, et al. Gastrointestinal endoscopy in
practice. Edinburgh: Churchill Livingstone; 201 1 .
Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s
Gastrointestinal and liver disease, 10th edn. Philadelphia: Elsevier
Saunders; 2015.
Websites
bsg.org.uk British Society of Gastroenterology.
crohnsandcolitis.org.uk Crohn’s and Colitis UK.
coeliac.org.uk Coeliac UK.
ecco-ibd.eu European Crohn’s and Colitis Organisation.
gastro.org American Gastroenterological Association and American
Digestive Health Foundation.
isg.org. in Indian Society of Gastroenterology.
Hepatology
QM Anstee
DEJ Jones
Clinical examination of the abdomen for liver and biliary disease 846
Liver tumours and other focal liver lesions 890
Functional anatomy and physiology 848
Applied anatomy 848
Hepatic function 850
Primary malignant tumours 890
Secondary malignant tumours 892
Benign tumours 893
Investigation of liver and hepatobiliary disease 852
Drugs and the liver 893
Liver blood biochemistry 852
Drug-induced liver injury 894
Haematological tests 853
Inherited liver diseases 895
Immunological tests 853
Haemochromatosis 895
Imaging 853
Wilson’s disease 896
Histological examination 855
Alpha! -antitrypsin deficiency 897
Non-invasive markers of hepatic fibrosis 855
Gilbert’s syndrome 897
Presenting problems in liver disease 855
Vascular liver disease 898
Acute liver failure 856
Hepatic arterial disease 898
Abnormal liver function tests 859
Portal venous disease 898
Jaundice 860
Hepatic venous disease 898
Hepatomegaly 862
Ascites 862
Hepatic encephalopathy 864
Variceal bleeding 865
Pregnancy and the liver 899
Intercurrent and pre-existing liver disease 900
Pregnancy-associated liver disease 900
Liver transplantation 900
Cirrhosis 866
Portal hypertension 868
Infections and the liver 871
Indications and contraindications 900
Complications 901
Prognosis 901
Viral hepatitis 871
Cholestatic and biliary disease 902
HIV infection and the liver 879
Chemical cholestasis 902
Liver abscess 879
Alcoholic liver disease 880
Non-alcoholic fatty liver disease 882
Autoimmune liver and biliary disease 885
Autoimmune hepatitis 886
Primary biliary cholangitis 887
Benign recurrent intrahepatic cholestasis 902
Intrahepatic biliary disease 902
Extrahepatic biliary disease 902
Secondary biliary cirrhosis 903
Gallstones 903
Cholecystitis 905
Choledocholithiasis 906
Primary sclerosing cholangitis 888
Tumours of the gallbladder and bile duct 907
lgG4-associated cholangitis 890
Miscellaneous biliary disorders 908
846 • HEPATOLOGY
Clinical examination of the abdomen for liver and biliary disease
2 Face
Jaundice
Spider naevi
Parotid swelling
A Xanthelasma and jaundiced
sclera in a patient with
chronic cholestasis
A Kayser-Fleischer rings
in Wilson’s disease
1 Hands
Clubbing
Dupuytren’s contracture
Leuconychia
Bruising
Flapping tremor (hepatic
encephalopathy)
A Palmar erythema
Observation
• Unkempt
• Smell of alcohol or fetor hepaticus
• Encephalopathy
• Weight loss
• Scratch marks from itching
3 Chest
Loss of body hair
AGynaecomastia
A Spider naevi
4 Abdomen: inspection
Scars
Distension
Veins
Testicular atrophy
A Aspiration of ascitic fluid
5 Abdomen: palpation/
percussion/auscultation
Hepatomegaly
Splenomegaly
Ascites
Palpable gallbladder
Hepatic bruit (rare)
Tumour
6 Legs
Bruising
Oedema
Insets (Spider naevi) From Hayes P, Simpson K. Gastroenterology and liver disease. Edinburgh: Churchill Livingstone, Elsevier Ltd; 1995; (Aspiration)
Strachan M. Davidson’s Clinical cases. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2008; (Palmar erythema) Goldman L, SchafterAI. Goldman’s Cecil
medicine, 24th edn. Philadelphia: WB Saunders, Elsevier Inc.; 2012.
Clinical examination of the abdomen for liver and biliary disease • 847
History and significance of abdominal signs
Presenting clinical features of liver disease
Effects of chronic liver injury (>6 months)
These represent the combined effects of:
Impairment of liver function and its
metabolic sequelae
• Jaundice (failure of bilirubin clearance)
• Encephalopathy (failure of clearance of
by-products of metabolism)
• Bleeding (impaired liver synthesis of clotting
factors)
• Hypoglycaemia
Ongoing presence of aetiological factors
(e.g. alcohol)
• Effects of aetiological agent, e.g.
intoxication, withdrawal, cognitive
impairment versus
• Effects of liver injury from agent, e.g.
encephalopathy
Catabolic status (± poor nutrition)
• Skin thinning (‘paper-money skin’)
• Loss of muscle bulk
• Leuconychia
Impaired albumin synthesis
• Reduced oncotic pressure (contributes to
ascites)
Reduced aldosterone clearance
• Na+ retention (contributes to ascites)
Reduced oestrogen clearance
• Mild feminisation of males (loss of body
hair, gynaecomastia)
Silent presentation of liver disease
It is important to note that patients with liver
disease can present silently following detection
of abnormality on screening investigation.
This occurs frequently in practice in three
settings:
Biochemical abnormality
• Liver enzyme abnormality detected during
health screening or drug monitoring
Radiological abnormality
• Observation of an unexpected structural
lesion (liver mass most usually) following
ultrasound, computed tomography or other
imaging assessment undertaken for reasons
unrelated to the liver
Serological abnormality
• Detection of a liver-related autoantibody
i
Ascites
Causes
Associated clinical findings
Exudative (high protein)
Carcinoma
Weight loss ± hepatomegaly
Tuberculosis
Weight loss ± fever
Transudative (low protein)
Cirrhosis
Hepatomegaly
Splenomegaly
Spider naevi
Renal failure (including nephrotic syndrome)
Generalised oedema
Peripheral oedema
Congestive heart failure
Elevated jugular venous pressure
5 Assessment of liver size
Clinical assessment of hepatomegaly is
important in diagnosing liver disease.
• Start in the right iliac fossa.
• Progress up the abdomen 2 cm with each
breath (through open mouth).
• Confirm the lower border of the liver by
percussion.
• Detect if smooth or irregular, tender or
non-tender; ascertain the shape.
• Identify the upper border by percussion.
i Assessment of
encephalopathy
Flapping tremor. Jerky forward movements
every 5-1 0 secs, when arms are
outstretched and hands are dorsiflexed,
suggest hepatic encephalopathy. The
movements are coarser than those seen in
tremor.
©
| ®
©
©
~ ©
©
@
® ”© i
© ®
©
©
©
8
>
® ®
©
End
©
©
© '
Number connection test. These 25
numbered circles can normally be joined
together within 30 secs. Serial observations
may provide useful information, as long as
the position of the numbers is varied to avoid
the patient learning their pattern.
Doctor Patient
Constructional apraxia. Drawing stars and
clocks may reveal marked abnormality.
848 • HEPATOLOGY
Functional anatomy and physiology
Applied anatomy
Normal liver structure and blood supply
The liver weighs 1 .2-1 .5 kg and has multiple functions, including
key roles in metabolism, control of infection, and elimination of
toxins and by-products of metabolism. It is classically divided
into left and right lobes by the falciform ligament, but a more
useful functional division is into the right and left hemilivers, based
on blood supply (Fig. 22.1). These are further divided into eight
segments, according to subdivisions of the hepatic and portal
veins. Each segment has its own branch of the hepatic artery and
Right hemiliver Left hemiliver
(RHL) (LHL)
= Portal vein
= Hepatic vein
Fig. 22.1 Liver blood supply.
biliary tree. The segmental anatomy of the liver has an important
influence on imaging and treatment of liver tumours, given the
increasing use of surgical resection. A liver segment is made
up of multiple smaller units known as lobules, comprised of a
central vein, radiating sinusoids separated from each other by
single liver cell (hepatocyte) plates, and peripheral portal tracts.
The functional unit of the liver is the hepatic acinus (Fig. 22.2).
Blood flows into the acinus via a single branch of the portal
vein and hepatic artery situated centrally in the portal tracts. Blood
flows outwards along the hepatic sinusoids into one of several
tributaries of the hepatic vein at the periphery of the acinus.
Bile, formed by active and passive excretion by hepatocytes
into channels called cholangioles, which lie between them, flows
in the opposite direction from the periphery of the acinus. The
cholangioles converge in interlobular bile ducts in the portal tracts.
The hepatocytes in each acinus lie in three zones, depending
on their position relative to the portal tract. Those in zone 1 are
closest to the terminal branches of the portal vein and hepatic
artery, and are richly supplied with oxygenated blood, and with
blood containing the highest concentration of nutrients and toxins.
Conversely, hepatocytes in zone 3 are furthest from the portal
tracts and closest to the hepatic veins, and are therefore relatively
hypoxic and exposed to lower concentrations of nutrients and
toxins compared to zone 1 . The different perfusion and toxin
exposure patterns, and thus vulnerability, of hepatocytes in the
different zones contribute to the often patchy nature of liver injury.
Liver cells
Hepatocytes comprise 80% of liver cells. The remaining 20%
are the endothelial cells lining the sinusoids, epithelial cells lining
the intrahepatic bile ducts, cells of the immune system (including
macrophages (Kupffer cells) and unique populations of atypical
lymphocytes), and a key population of non-parenchymal cells
called stellate or Ito cells.
E
Right Left
hepatic duct hepatic duct Liver
Portal vein
Hepatic artery
Bile duct
Gallbladder
Cystic duct
Pancreas
Pancreatic duct
Sphincter of Oddi
Bile
duct
Zone 2
Zone 1
(perivenous)
Good O2 supply
Gluconeogenesis
Bile salt formation
Cholangiole
I Zone 3
; (pericentral)
| Mono-oxygenation
; Glycolysis
■ Lipolysis
iGlucuronidation
Fig. 22.2 Liver structure and microstructure. [A] Liver anatomy showing relationship with pancreas, bile duct and duodenu|pj Hepatic lobule.
[C] Hepatic acinus.
Functional anatomy and physiology • 849
Endothelial cells line the sinusoids (Fig. 22.3), a network
of capillary vessels that differ from other capillary beds in the
body, in that there is no basement membrane. The endothelial
cells have gaps between them (fenestrae) of about 0.1 micron
in diameter, allowing free flow of fluid and particulate matter
Space of Disse Endothelial NK cell T cell
cell
Hepatocyte
Stellate
cell
Sinusoid Kupffer
lumen cell
Bcell
PMN cell
Fig. 22.3 Non-parenchymal liver cells. (B cell = B lymphocyte; NK cell
= natural killer cell; PMN cell = polymorphonuclear leucocyte; T cell = T
lymphocyte).
to the hepatocytes. Individual hepatocytes are separated from
the leaky sinusoids by the space of Disse, which contains
stellate cells that store vitamin A and play an important part in
regulating liver blood flow. They may also be immunologically
active and play a role in the liver’s contribution to defence against
pathogens. The key role of stellate cells in terms of pathology is
in the development of hepatic fibrosis, the precursor of cirrhosis.
They undergo activation in response to cytokines produced
following liver injury, differentiating into myofibroblasts, which
are the major producers of the collagen-rich matrix that forms
fibrous tissue (Fig. 22.4).
Blood supply
The liver is unique as an organ, as it has dual perfusion: it receives
a majority of its supply via the portal vein, which drains blood
from the gut via the splanchnic circulation and is the principal
route for nutrient trafficking to the liver, and a minority from
the hepatic artery. The portal venous contribution is 50-90%.
The dual perfusion system, and the variable contribution from
portal vein and hepatic artery, can have important effects on
the clinical expression of liver ischaemia (which typically exhibits
a less dramatic pattern than ischaemia in other organs, a fact
that can sometimes lead to it being missed clinically), and can
raise practical challenges in liver transplant surgery.
Biliary system and gallbladder
Hepatocytes provide the driving force for bile flow by creating
osmotic gradients of bile acids, which form micelles in bile (bile
Injured
hepatocyte
Fibrogenesis
(TGF-p,)
Matrix degeneration
(MMP2, TIMP1 + 2)
Chemotaxis
Vasoconstriction
(ET1)
Cytokine
production
(IL-10)
Initiation
Perpetuation
Fig. 22.4 Pathogenic mechanisms in hepatic fibrosis. Stellate cell activation occurs under the influence of cytokines released by other cell types in the
liver, including hepatocytes, Kupffer cells (tissue macrophages), platelets and lymphocytes. Once stellate cells become activated, they can perpetuate their
own activation by synthesis of transforming growth factor beta (TGF-fy), and platelet-derived growth factor (PDGF) through autocrine loops. Activated
stellate cells produce TGF-pi, stimulating the production of collagen matrix, as well as inhibitors of collagen breakdown. The inhibitors of collagen
breakdown, matrix metalloproteinase 2 and 9 (MMP2 and MMP9), are inactivated in turn by tissue inhibitors TIMP1 and TIMP2, which are increased in
fibrosis. Inflammation also contributes to fibrosis, with the cytokine profile produced by Th2 lymphocytes, such as interleukin-6 and 13 (IL-6 and IL-13).
Activated stellate cells also produce endothelin 1 (ET1), which may contribute to portal hypertension. (EGF = epidermal growth factor; IGFt = insulin-like
growth factor 1 ; ROS = reactive oxygen species)
850 • HEPATOLOGY
acid-dependent bile flow), and of sodium (bile acid-independent
bile flow). Bile is secreted by hepatocytes and flows from
cholangioles to the biliary canaliculi. The canaliculi join to form
larger intrahepatic bile ducts, which in turn merge to form the
right and left hepatic ducts. These ducts join as they emerge
from the liver to form the common hepatic duct, which becomes
the common bile duct after joining the cystic duct (see Fig. 22.2).
The common bile duct is approximately 5 cm long and 4-6 mm
wide. The distal portion of the duct passes through the head
of the pancreas and usually joins the pancreatic duct before
entering the duodenum through the ampullary sphincter (sphincter
of Oddi). It should be noted, though, that the anatomy of the
lower common bile duct can vary widely. Common bile duct
pressure is maintained by rhythmic contraction and relaxation
of the sphincter of Oddi; this pressure exceeds gallbladder
pressure in the fasting state, so that bile normally flows into
the gallbladder, where it is concentrated 1 0-fold by resorption
of water and electrolytes.
The gallbladder is a pear-shaped sac typically lying under the
right hemiliver, with its fundus located anteriorly behind the tip
of the 9th costal cartilage. Anatomical variation is common and
should be considered when assessing patients clinically and
radiologically. The function of the gallbladder is to concentrate,
and provide a reservoir for, bile. Gallbladder tone is maintained
by vagal activity, and cholecystokinin released from the duodenal
mucosa during feeding causes gallbladder contraction and
reduces sphincter pressure, so that bile flows into the duodenum.
The body and neck of the gallbladder pass posteromedially
towards the porta hepatis, and the cystic duct then joins it to the
common hepatic duct. The cystic duct mucosa has prominent
crescentic folds (valves of Heister), giving it a beaded appearance
on cholangiography.
Hepatic function
B Carbohydrate, amino acid and
lipid metabolism
The liver plays a central role in carbohydrate, lipid and amino
acid metabolism, and is also involved in metabolising drugs and
environmental toxins (Fig. 22.5). An important and increasingly
recognised role for the liver is in the integration of metabolic
pathways, regulating the response of the body to feeding
and starvation. Abnormality in metabolic pathways and their
regulation can play an important role both in liver disease
(e.g. non-alcoholic fatty liver disease, NAFLD) and in diseases
that are not conventionally regarded as diseases of the liver
(such as type 2 diabetes and inborn errors of metabolism).
Flepatocytes have specific pathways to handle each of the
nutrients absorbed from the gut and carried to the liver via the
portal vein:
• Amino acids from dietary proteins are used for synthesis
of plasma proteins, including albumin. The liver produces
8-1 4 g of albumin per day, and this plays a critical role in
maintaining oncotic pressure in the vascular space and in
the transport of small molecules like bilirubin, hormones
and drugs throughout the body. Amino acids that are not
required for the production of new proteins are broken
down, with the amino group being converted ultimately
to urea.
• Following a meal, more than half of the glucose absorbed
is taken up by the liver and stored as glycogen or
Nutrient metabolism
Carbohydrate
Protein
Lipids
Protein synthesis
Albumin
Coagulation factors
Complement factors
Haptoglobin
Caeruloplasmin
Transferrin
Protease inhibitors,
e.g. a-| -antitrypsin
Storage
Iron
Copper
Vitamins A, D and B-|2
Immune
functions
Local cells
(Kupffer cells)
Innate factors
(defensins etc.)
Excretion
Bile salts
Bilirubin
Drugs
Phospholipid
Cholesterol
Fig. 22.5 Important liver functions.
converted to glycerol and fatty acids, thus preventing
hyperglycaemia. During fasting, glucose is synthesised
(gluconeogenesis) or released from glycogen in the liver,
thereby preventing hypoglycaemia (p. 724).
• The liver plays a central role in lipid metabolism,
producing very low-density lipoproteins and further
metabolising low- and high-density lipoproteins (see
Fig. 14.13, p. 372). Dysregulation of lipid metabolism is
thought to have a critical role in the pathogenesis of
NAFLD. Lipids are now recognised to play a key part in
the pathogenesis of hepatitis C, facilitating viral entry into
hepatocytes.
Clotting factors
The liver produces key proteins that are involved in the coagulation
cascade. Many of these coagulation factors (II, VII, IX and X) are
post-translationally modified by vitamin K-dependent enzymes,
and their synthesis is impaired in vitamin K deficiency (p. 918).
Reduced clotting factor synthesis is an important and easily
accessible biomarker of liver function in the setting of liver
injury. Prothrombin time (PT; or the International Normalised
Ratio, INR) is therefore one of the most important clinical tools
available for the assessment of hepatocyte function. Note that
the deranged PT or INR seen in liver disease may not directly
equate to increased bleeding risk, as these tests do not capture
the concurrent reduced synthesis of anticoagulant factors,
including protein C and protein S. In general, therefore, correction
of PT using blood products before minor invasive procedures
should be guided by clinical risk rather than the absolute value
of the PT.
Bilirubin metabolism and bile
The liver plays a central role in the metabolism of bilirubin and
is responsible for the production of bile (Fig. 22.6). Between
425 and 510 mmol (250-300 mg) of unconjugated bilirubin is
produced from the catabolism of haem daily. Bilirubin in the
Functional anatomy and physiology • 851
blood is normally almost all unconjugated and, because it is not
water-soluble, is bound to albumin and does not pass into the
urine. Unconjugated bilirubin is taken up by hepatocytes at the
sinusoidal membrane, where it is conjugated in the endoplasmic
reticulum by UDP-glucuronyl transferase, producing bilirubin
mono- and diglucuronide. Impaired conjugation by this enzyme is
a cause of inherited hyperbilirubinaemias (see Box 22.17). These
bilirubin conjugates are water-soluble and are exported into the
bile canaliculi by specific carriers on the hepatocyte membranes.
The conjugated bilirubin is excreted in the bile and passes into
the duodenal lumen.
Once in the intestine, conjugated bilirubin is metabolised by
colonic bacteria to form stercobilinogen, which may be further
oxidised to stercobilin. Both stercobilinogen and stercobilin are
then excreted in the stool, contributing to its brown colour.
Biliary obstruction results in reduced stercobilinogen in the stool,
and the stools become pale. A small amount of stercobilinogen
(4 mg/day) is absorbed from the bowel, passes through the liver
and is excreted in the urine, where it is known as urobilinogen
or, following further oxidisation, urobilin. The liver secretes 1-2 L
of bile daily. Bile contains bile acids (formed from cholesterol),
phospholipids, bilirubin and cholesterol. Several biliary transporter
proteins have been identified (Fig. 22.7). Mutations in genes
encoding these proteins have been identified in inherited
intrahepatic biliary diseases presenting in childhood, and in
adult-onset disease such as intrahepatic cholestasis of pregnancy
and gallstone formation.
Storage of vitamins and minerals
Vitamins A, D and B12 are stored by the liver in large amounts,
while others, such as vitamin K and folate, are stored in smaller
amounts and disappear rapidly if dietary intake is reduced.
The liver is also able to metabolise vitamins to more active
compounds, e.g. 7-dehydrocholesterol to 25(OH) vitamin D.
Vitamin K is a fat-soluble vitamin and so the inability to absorb
Hepatocytes
NTCP
■^Bile acids
Bile -
canaliculus
BSEP
MDR3
OATP
^►Bilirubin and
organic
anions
-Sinusoid
Fig. 22.7 Biliary transporter proteins. On the hepatocyte basolateral
membrane, sodium taurocholate co-transporting polypeptide (NTCP)
mediates uptake of conjugated bile acids from portal blood. At the
canalicular membrane, these bile acids are secreted via the bile salt export
pump (BSEP) into bile. Multidrug resistance protein 3 (MDR3), also situated
on the canalicular membrane, transports phospholipid to the outer side of
the membrane. This solubilises bile acids, forming micelles and protecting
bile duct membranes from bile salt damage. Familial intrahepatic
cholestasis 1 (FIC1) moves phosphatidylserine from the inside to the
outside of the canalicular membrane; mutations result in familial
cholestasis syndrome in childhood. MDR2 (multidrug resistance 2)
regulates transport of glutathione. Multidrug resistance protein 2 (MRP2)
transports bilirubin and is induced by rifampicin. Organic anion transporter
protein (OATP) transports bilirubin and organic anions.
fat-soluble vitamins, as occurs in biliary obstruction, results in
a coagulopathy. The liver also stores minerals such as iron,
in ferritin and haemosiderin, and copper, which is excreted
in bile.
| Immune regulation
Approximately 9% of the normal liver is composed of immune
cells (see Fig. 22.3). Cells of the innate immune system include
Kupffer cells derived from blood monocytes, the liver macrophages
and natural killer (NK) cells, as well as ‘classical’ B and T cells
of the adaptive immune response (p. 67). An additional type of
atypical lymphocyte, with phenotypic features of both T cells and
NK cells, is thought to play an important role in host defence
through linking of innate and adaptive immunity. The enrichment
of such cells in the liver reflects the unique importance of the
liver in preventing microorganisms from the gut from entering
the systemic circulation.
Kupffer cells constitute the largest single mass of tissue-resident
macrophages in the body and account for 80% of the phagocytic
capacity of this system. They remove aged and damaged red
blood cells, bacteria, viruses, antigen-antibody complexes and
endotoxin. They also produce a wide variety of inflammatory
mediators that can act locally or may be released into the
systemic circulation.
The immunological environment of the liver is unique in that
antigens presented within it tend to induce immunological
tolerance. This is of importance in liver transplantation, where
classical major histocompatibility (MHC) barriers may be crossed,
and also in chronic viral infections, when immune responses may
be attenuated. The mechanisms that underlie this phenomenon
have not been fully defined.
852 • HEPATOLOGY
Investigation of liver and
hepatobiliary disease
Investigations play an important role in the management of liver
disease in three settings:
• identifying the presence of liver disease
• establishing the aetiology
• understanding disease severity (in particular, identification
of cirrhosis with its complications).
When planning investigations, it is important to be clear as to
which of these goals is being addressed.
Suspicion of the presence of liver disease is normally based on
blood biochemistry abnormality (‘liver function tests’, or ‘LFTs’).
Aetiology is typically established through a combination of
history, specific blood tests and, where appropriate, imaging
and liver biopsy.
Staging of disease (in essence, the identification of cirrhosis)
is largely histological, although there is increasing interest in non-
invasive approaches, including novel imaging modalities, serum
markers of fibrosis and the use of predictive scoring systems.
The aims of investigation in patients with suspected liver
disease are shown in Box 22.1 .
Liver blood biochemistry
Liver blood biochemistry (LFTs) includes the measurement
of serum bilirubin, aminotransferases, alkaline phosphatase,
y-glutamyl transferase and albumin. Most analytes measured by
LFTs are not truly ‘function’ tests but instead, given that they are
released by injured hepatocytes, provide biochemical evidence of
liver cell damage. Liver function per se is best assessed by the
serum albumin, PT and bilirubin because of the role played by
the liver in synthesis of albumin and clotting factors and in
clearance of bilirubin. Although LFT abnormalities are often
non-specific, the patterns are frequently helpful in directing further
investigations. In addition, levels of bilirubin and albumin and the
PT are related to clinical outcome in patients with severe liver
disease, reflected by their use in several prognostic scores: the
Child-Pugh and MELD scores in cirrhosis (see Boxes 22.29 and
22.30, pp. 867 and 868), the Glasgow score in alcoholic hepatitis
(see Box 22.47, p. 882) and the King’s College Hospital criteria
for liver transplantation in acute liver failure (see Box 22.11,
p. 858). These established predictive models, together with
emerging disease-specific scoring systems in conditions such
as non-alcoholic steatohepatitis (the NASH fibrosis score) and
primary biliary cholangitis (PBC, formerly known as primary biliary
cirrhosis; the UK-PBC risk score), systematise the approach to
assessing abnormal LFTs and can be important for the targeting
of more expensive and/or invasive confirmatory diagnostic tests.
22.1 Aims of investigations in patients with
suspected liver disease
• Detect hepatic abnormality
• Measure the severity of liver damage
• Detect the pattern of liver function test abnormality: hepatitic or
obstructive/cholestatic
• Identify the specific cause
• Investigate possible complications
Bilirubin and albumin
The degree of elevation of bilirubin can reflect the degree of
liver damage. A raised bilirubin often occurs earlier in the natural
history of biliary disease (e.g. PBC) than in disease of the liver
parenchyma (e.g. cirrhosis), where the hepatocytes are primarily
involved. Swelling of the liver within its capsule in inflammation
can, however, sometimes impair bile flow and cause an elevation
of bilirubin level that is disproportionate to the degree of liver
injury. Caution is therefore needed in interpreting the level of liver
injury purely on the basis of bilirubin elevation.
Serum albumin levels are often low in patients with liver disease.
This is due to a change in the volume of distribution of albumin,
and to reduced synthesis. Since the plasma half-life of albumin
is about 2 weeks, albumin levels may be normal in acute liver
failure but are almost always reduced in chronic liver failure.
I Alanine aminotransferase and
aspartate aminotransferase
Alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) are located in the cytoplasm of the hepatocyte; AST is
also located in the hepatocyte mitochondria. Although both
transaminase enzymes are widely distributed, expression of ALT
outside the liver is relatively low and this enzyme is therefore
considered more specific for hepatocellular damage. Large
increases of aminotransferase activity favour hepatocellular
damage, and this pattern of LFT abnormality is known as
‘hepatitic’.
I Alkaline phosphatase and
y-glutamyl transferase
Alkaline phosphatase (ALP) is the collective name given to several
different enzymes that hydrolyse phosphate esters at alkaline
pH. These enzymes are widely distributed in the body but the
main sites of production are the liver, gastrointestinal tract, bone,
placenta and kidney. ALPs are post-translationally modified,
resulting in the production of several different isoenzymes, which
differ in abundance in different tissues. ALP enzymes in the liver
are located in cell membranes of the hepatic sinusoids and the
biliary canaliculi. Accordingly, levels rise with intrahepatic and
extrahepatic biliary obstruction and with sinusoidal obstruction,
as occurs in infiltrative liver disease.
Gamma-glutamyl transferase (GGT) is a microsomal enzyme
found in many cells and tissues of the body. The highest
concentrations are located in the liver, where it is produced by
hepatocytes and by the epithelium lining small bile ducts. The
function of GGT is to transfer glutamyl groups from y-glutamyl
peptides to other peptides and amino acids.
The pattern of a modest increase in aminotransferase activity
and large increases in ALP and GGT activity favours biliary
obstruction and is commonly described as ‘cholestatic’ or
‘obstructive’ (Box 22.2). Isolated elevation of the serum GGT is
relatively common and may occur during ingestion of microsomal
enzyme-inducing drugs, including alcohol (Box 22.3), but also
in NAFLD.
Other biochemical tests
Other widely available biochemical tests may become altered in
patients with liver disease:
• Hyponatraemia occurs in severe liver disease due to
increased production of vasopressin (antidiuretic hormone,
Investigation of liver and hepatobiliary disease • 853
22.2 ‘Hepatitic’ and ‘cholestatic7‘obstructive’ liver
function tests
Pattern AST/ALT GGT ALP
Biliary obstruction T TT TTT
Hepatitis TTT T T
Alcohol/enzyme-inducing drugs N/T TT N
N = normal; T mild elevation (< twice normal); TT moderate elevation (2-5
times normal); TTT marked elevation (>5 times normal).
(ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate
aminotransferase; GGT = gamma-glutamyltransferase)
22.3 Drugs that increase levels
of y-glutamyltransferase
• Barbiturates • Griseofulvin
• Carbamazepine • Rifampicin
• Ethanol • Phenytoin
ADH; see Fig. 14.8, p. 359). Hyponatraemia can be a
significant clinical problem in liver disease with aspects
that are distinct from hyponatraemia of other causes.
• Serum urea may be reduced in hepatic failure, whereas
levels of urea may be increased following gastrointestinal
haemorrhage.
• When high levels of urea are accompanied by raised
bilirubin, high serum creatinine and low urinary sodium,
this suggests hepatorenal failure, which carries a grave
prognosis.
• Significantly elevated ferritin suggests haemochromatosis.
Modest elevations can be seen in inflammatory disease,
NAFLD and alcohol excess.
Haematological tests
Blood count
The peripheral blood count is often abnormal and can give a
clue to the underlying diagnosis:
• A normochromic normocytic anaemia may reflect recent
gastrointestinal haemorrhage, whereas chronic blood loss
is characterised by a hypochromic microcytic anaemia
secondary to iron deficiency. A high erythrocyte mean cell
volume (macrocytosis) is associated with alcohol misuse,
but target cells in any jaundiced patient also result in a
macrocytosis. Macrocytosis can persist for a long period
of time after alcohol cessation, making it a poor marker of
ongoing consumption.
• Leucopenia may complicate portal hypertension and
hypersplenism, whereas leucocytosis may occur with
cholangitis, alcoholic hepatitis and hepatic abscesses.
Atypical lymphocytes are seen in infectious
mononucleosis, which may be complicated by an acute
hepatitis.
• Thrombocytopenia is common in cirrhosis and is due to
reduced platelet production and increased breakdown
because of hypersplenism. Thrombopoietin, required for
platelet production, is produced in the liver and levels fall
with worsening liver function. Thus platelet levels are
usually more depressed than white cells and haemoglobin
in the presence of hypersplenism in patients with cirrhosis.
A low platelet count is often an indicator of chronic liver
disease, particularly in the context of hepatomegaly.
Thrombocytosis is unusual in patients with liver disease
but may occur in those with active gastrointestinal
haemorrhage and, rarely, in hepatocellular carcinoma.
Coagulation tests
These are often abnormal in patients with liver disease. The
normal half-lives of the vitamin K-dependent coagulation factors
in the blood are short (5-72 hours), and so changes in the PT
occur relatively quickly following liver damage; these changes
provide valuable prognostic information in patients with both
acute and chronic liver failure. An increased PT is evidence of
severe liver damage in chronic liver disease. Vitamin K does
not reverse this deficiency if it is due to liver disease, but will
correct the PT if the cause is vitamin K deficiency, as may occur
with biliary obstruction due to non-absorption of fat-soluble
vitamins.
Immunological tests
A variety of tests are available to evaluate the aetiology of
hepatic disease (Boxes 22.4 and 22.5). The presence of liver-
related autoantibodies can be suggestive of the presence of
autoimmune liver disease (although false-positive results can
occur in non-autoimmune inflammatory disease such as NAFLD).
Elevation in overall serum immunoglobulin levels can also indicate
autoimmunity (immunoglobulin G (IgG) and IgM). Elevated serum
IgA can be seen, often in more advanced alcoholic liver disease
and NAFLD, although the association is not specific.
i
22.4 Chronic liver disease screen
• Hepatitis B surface antigen
• Immunoglobulins
• Hepatitis C antibody
• Ferritin
• Liver autoantibodies
• arantitrypsin
(antinuclear antibody, smooth
muscle antibody,
antimitochondrial antibody)
• Caeruloplasmin
Imaging
Several imaging techniques can be used to determine the site
and general nature of structural lesions in the liver and biliary
tree. In general, however, imaging techniques are unable to
identify hepatic inflammation and have poor sensitivity for liver
fibrosis unless advanced cirrhosis with portal hypertension is
present.
Ultrasound
Ultrasound is non-invasive and most commonly used as a
‘first-line’ test to identify gallstones, biliary obstruction (Fig. 22.8)
or thrombosis in the hepatic vasculature. Ultrasound is good for
the identification of splenomegaly and abnormalities in liver texture
but is less effective at identifying diffuse parenchymal disease.
Focal lesions, such as tumours, may not be detected if they
are less than 2 cm in diameter and have similar echogenicity
to normal liver tissue. Bubble-based contrast media are now
used routinely and can enhance discriminant capability. Doppler
ultrasound allows blood flow in the hepatic artery, portal vein
854 • HEPATOLOGY
22 5 How t0 ^entity the cause of liver function test (LFT) abnormality
Diagnosis
Clinical clue
Initial test
Additional tests
Alcoholic liver disease
History
LFTs
AST > ALT; high MCV
Random blood alcohol
Non-alcoholic fatty liver
disease (NAFLD)
Metabolic syndrome (central obesity,
diabetes, hypertension)
LFTs
Liver biopsy
Chronic hepatitis B
Injection drug use; blood transfusion
HBsAg
HBeAg, HBeAb
HBV-DNA
Chronic hepatitis C
Injection drug use; blood transfusion
HCV antibody
HCV-RNA
Primary biliary cholangitis
Itching; raised ALP
AMA
Liver biopsy
Primary sclerosing cholangitis
Inflammatory bowel disease
MRCP
ANCA
Autoimmune hepatitis
Other autoimmune diseases
ASMA, ANA, LKM, immunoglobulin
Liver biopsy
Haemochromatosis
Diabetes/joint pain
Transferrin saturation, ferritin
HFE gene test
Wilson’s disease
Neurological signs; haemolysis
Caeruloplasmin
24-hour urinary copper
di-antitrypsin
Lung disease
di -antitrypsin level
oci -antitrypsin genotype
Drug-induced liver disease
Drug/herbal remedy history
LFTs
Liver biopsy
Coeliac disease
Malabsorption
Tissue transglutaminase
Duodenal biopsy
(ALP = alkaline phosphatase; ALT = alanine aminotransferase; AMA = antimitochondrial antibody; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody;
ASMA = anti-smooth muscle antibody; AST = aspartate aminotransferase; HBeAb = antibody to hepatitis B e antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B
surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HFE = haemochromatosis (high iron/Fe); LKM = liver-kidney microsomal antibody; MCV = mean cell
volume; MRCP = magnetic resonance cholangiopancreatography)
Fig. 22.8 Ultrasound showing a stone in the gallbladder (A) with
acoustic shadow (S).
and hepatic veins to be investigated. Endoscopic ultrasound
provides high-resolution images of the pancreas, biliary tree
and liver (see below and Fig. 22.46, p. 906).
Computed tomography and magnetic
resonance imaging
Computed tomography (CT) detects smaller focal lesions in
the liver, especially when combined with contrast injection (Fig.
22.9). Magnetic resonance imaging (MRI) can also be used to
localise and confirm the aetiology of focal liver lesions, particularly
primary and secondary tumours.
Fig. 22.9 Computed tomography in a patient with cirrhosis. The liver
is small and has an irregular outline (black arrow), the spleen is enlarged
(long white arrow), fluid (ascites) is seen around the liver, and collateral
vessels are present around the proximal stomach (short white arrow).
Hepatic angiography is seldom used nowadays as a diagnostic
tool, since CT and MRI are both able to provide images of hepatic
vasculature, but it still has a therapeutic role in the embolisation
of vascular tumours, such as hepatocellular carcinoma. Hepatic
venography is now rarely performed.
Cholangiography
Cholangiography can be undertaken by magnetic resonance
cholangiopancreatography (MRCP; Fig. 22.10), endoscopy
(endoscopic retrograde cholangiopancreatography, ERCP)
or the percutaneous approach (percutaneous transhepatic
Presenting problems in liver disease • 855
Fig. 22.10 Magnetic resonance cholangiopancreatography showing
a biliary stricture due to cholangiocarcinoma in the distal common
bile duct (arrow). The proximal common bile duct (CBD) is dilated but the
pancreatic duct (PD) is normal.
cholangiography, PTC). The latter does not allow the ampulla of
Vater or pancreatic duct to be visualised. Endoscopic ultrasound
can also provide high-quality biliary imaging safely (see below).
MRCP is as good as ERCP at providing images of the biliary
tree but is safer, and there is now little, if any, role for diagnostic
ERCP. Both endoscopic and percutaneous approaches allow
therapeutic interventions, such as the insertion of biliary stents
across bile duct strictures. The percutaneous approach is used
only if it is not possible to access the bile duct endoscopically.
Endoscopic ultrasound
Endoscopic ultrasound (EUS; p. 774) is complementary to
MRCP in the diagnostic evaluation of the extrahepatic biliary tree,
ampulla of Vater and pancreas. With the ultrasonic probe in the
duodenum, high-quality images are obtained, tissue sampling
can be performed and, increasingly, therapeutic drainage of
biliary obstruction can be performed. EUS has the advantage
over ERCP of not exposing patients to the risk of pancreatitis,
among other complications of bile duct cannulation.
Histological examination
An ultrasound-guided liver biopsy can confirm the severity of
liver damage and provide aetiological information. It is performed
percutaneously with aTrucut or Menghini needle, usually through
an intercostal space under local anaesthesia, or radiologically
using a transjugular approach.
Percutaneous liver biopsy is a relatively safe procedure if the
conditions detailed in Box 22.6 are met, but carries a mortality
of about 0.01%. The main complications are abdominal and/or
shoulder pain, bleeding and biliary peritonitis. Biliary peritonitis is
rare and usually occurs when a biopsy is performed in a patient
with obstruction of a large bile duct. Liver biopsies can be carried
out in patients with defective haemostasis if:
• the defect is corrected with fresh frozen plasma and
platelet transfusion
• the biopsy is obtained by the transjugular route, or
22.6 Conditions required for safe percutaneous
liver biopsy
• Cooperative patient
• Prothrombin time <4 secs prolonged
• Platelet count >80x1 09/L
• Exclusion of bile duct obstruction, localised skin infection, advanced
chronic obstructive pulmonary disease, marked ascites and severe
anaemia
• the procedure is conducted percutaneously under
ultrasound control and the needle track is then plugged
with procoagulant material.
In patients with potentially resectable malignancy, biopsy should
be avoided due to the potential risk of tumour dissemination.
Operative or laparoscopic liver biopsy may sometimes be valuable.
Although the pathological features of liver disease are complex,
with several features occurring together, liver disorders can be
broadly classified histologically into fatty liver (steatosis), hepatitis
(inflammation, ‘grade’) and cirrhosis (fibrosis, ‘stage’). The use of
special histological stains can help in determining aetiology. The
clinical features and prognosis of these changes are dependent
on the underlying aetiology and are discussed in the relevant
sections below.
Non-invasive markers of hepatic fibrosis
Non-invasive markers of liver fibrosis can reduce the need for
liver biopsy to assess the extent of fibrosis in some settings.
In general, they have high negative predictive value, being able
to exclude the presence of advanced fibrosis, but a relatively
low positive predictive value. It is important to note that many
of these tests have been validated only in certain aetiologies of
liver disease and therefore results cannot be extrapolated to all
other liver diseases. Alcohol-related liver disease is particularly
poorly served in this respect.
Serological markers of hepatic fibrosis, such as o^-macroglobulin,
haptoglobin and routine clinical biochemistry tests, are used in
the Fibrotest®. The Enhanced Liver Fibrosis (ELF®) serological
assay uses a combination of hyaluronic acid, procollagen peptide
III (PIIINP) and tissue inhibitor of metalloproteinase 1 (TIMP1).
These tests are good at differentiating severe fibrosis from
mild scarring but are limited in their ability to detect subtle
changes. A number of non-commercial scores based on
standard biochemical and anthropometric indices have also been
described that provide similar levels of sensitivity and specificity
(e.g. the FIB4 score, which is based on age, ALT/AST ratio and
platelet count).
An alternative to serological markers is vibration-controlled
transient elastography (Fibroscan®), in which ultrasound-based
shock waves are sent through the liver to measure liver stiffness
as a surrogate for hepatic fibrosis. Once again, this test is
good at differentiating severe fibrosis from mild scarring, but it
is limited in its ability to detect subtle changes and validity may
be affected by obesity. Similar techniques, including magnetic
resonance elastography, are promising but not yet widely
available.
Presenting problems in liver disease
Liver injury may be either acute or chronic. The main causes are
listed in Figure 22.1 1 and discussed in detail later in the chapter. In
856 • HEPATOLOGY
the UK, liver disease is the only one of the top causes of mortality
that is steadily increasing (Fig. 22.12). Mortality rates have risen
substantially over the last 30 years, with a near-fivefold increase
in liver-related mortality in people younger than 65 years. The
rate of increase is substantially higher in the UK than in other
countries in Western Europe.
• Acute liver injury may present with non-specific symptoms
of fatigue and abnormal LFTs, or with jaundice and acute
liver failure.
• Chronic liver injury is defined as hepatic injury,
inflammation and/or fibrosis occurring in the liver for more
than 6 months. In the early stages, patients can be
asymptomatic with fluctuating abnormal LFTs. With more
severe liver damage, however, the presentation can be
with jaundice, portal hypertension or other signs of
cirrhosis and hepatic decompensation (Box 22.7). Patients
with clinically silent chronic liver disease frequently present
when abnormalities in liver function are observed on
routine blood testing, or when clinical events, such as an
intercurrent infection or surgical intervention, cause the
liver to decompensate. Patients with compensated
cirrhosis can undergo most forms of surgery without
Acute liver injury
Chronic liver injury
Viral hepatitis
(A, B, E)
Chronic viral hepatitis
(B + C)
Alcoholic
liver disease*
Drugs
NAFLD
Haemochromatosis
Wilson
’s disease
ai -antitrypsin deficiency
Cryptogenic (unknown)
Autoimmune
hepatitis*
PBC
PSC
Fig. 22.11 Causes of acute and chronic liver injury. ^Although there is
often evidence of chronic liver disease at presentation, may present acutely
with jaundice. In alcoholic liver disease this is due to superimposed
alcoholic hepatitis. (NAFLD = non-alcoholic fatty liver disease; PBC =
primary biliary cholangitis; PSC = primary sclerosing cholangitis)
D 22.7
Presentation of liver disease
Severity
Acute liver injury
Chronic liver injury
Mild/moderate Abnormal liver
function tests
Abnormal liver function tests
Severe
Jaundice
Signs of cirrhosis ± portal
hypertension
Very severe
Acute liver failure
Chronic liver failure*
Jaundice
Ascites
Hepatic encephalopathy
Portal hypertension with
variceal bleeding
*May not occur until several years after cirrhosis has presented.
significantly increased risk, whereas decompensation can
be a complication in all cases and the presence of portal
hypertension with intra-abdominal varices can make
abdominal surgery more hazardous. The possibility of
undiagnosed liver disease should be borne in mind in all
patients in at-risk groups undergoing significant surgery.
Acute liver failure
Acute liver failure is an uncommon but serious condition
characterised by a relatively rapid progressive deterioration in
liver function. The presence of encephalopathy is a cardinal
feature, with mental changes progressing from delirium to coma.
The syndrome was originally defined further as occurring within
8 weeks of onset of the precipitating illness, in the absence
of evidence of pre-existing liver disease. This distinguishes it
from instances in which hepatic encephalopathy represents a
deterioration in chronic liver disease.
Liver failure occurs when there is insufficient metabolic and
synthetic function for the needs of the patient. Although the direct
cause is usually acute loss of functional hepatocytes, this can
occur in different settings, which have implications for outcome
and treatment. In a patient whose liver was previously normal
(fulminant liver failure), the level of injury needed to cause liver
Fig. 22.12 Standardised UK mortality rates
showing the rise in liver-related mortality.
From Williams R, Aspinall R, Beilis M, et al.
Addressing liver disease in the UK: a blueprint for
attaining excellence in health care and reducing
premature mortality from lifestyle issues of
excess consumption of alcohol, obesity, and viral
hepatitis. Reprinted with permission from Elsevier
(The Lancet 2014; 384:1953-1997).
Presenting problems in liver disease • 857
failure, and thus the patient risk, is very high. In a patient with
pre-existing chronic liver disease, the additional acute insult
needed to precipitate liver failure is much less. It is critical,
therefore, to understand whether liver failure is a true acute event
or an acute deterioration on a background of pre-existing injury
(which may itself not have been diagnosed). Although liver biopsy
may ultimately be necessary, it is the presence or absence of the
clinical features suggesting chronicity that guides the clinician.
More recently, newer classifications have been developed
to reflect differences in presentation and outcome of acute
liver failure. One such classification divides acute liver failure
into hyperacute, acute and subacute, according to the interval
between onset of jaundice and encephalopathy (Box 22.8).
Pathophysiology
Any cause of liver damage can produce acute liver failure, provided
it is sufficiently severe (Fig. 22.13). Acute viral hepatitis is the
most common cause worldwide, whereas paracetamol toxicity
(p. 137) is the most frequent cause in the UK. Acute liver failure
occurs occasionally with other drugs, or from Amanita phalloides
(mushroom) poisoning, in pregnancy, in Wilson’s disease, following
shock (p. 199) and, rarely, in extensive malignant disease of the
liver. In 10% of cases, the cause of acute liver failure remains
unknown and these patients are often labelled as having ‘non-A-E
viral hepatitis’ or ‘cryptogenic’ acute liver failure.
Clinical assessment
Cerebral disturbance (hepatic encephalopathy and/or cerebral
oedema) is the cardinal manifestation of acute liver failure, but in
the early stages this can be mild and episodic, and so its absence
does not exclude a significant acute liver injury. The initial clinical
features are often subtle and include reduced alertness and poor
concentration, progressing through behavioural abnormalities,
such as restlessness and aggressive outbursts, to drowsiness
and coma (Box 22.9). Cerebral oedema may occur due to
increased intracranial pressure, causing unequal or abnormally
reacting pupils, fixed pupils, hypertensive episodes, bradycardia,
hyperventilation, profuse sweating, local or general myoclonus,
focal fits or decerebrate posturing. Papilloedema occurs rarely
and is a late sign. More general symptoms include weakness,
nausea and vomiting. Right hypochondrial discomfort is an
occasional feature.
The patient may be jaundiced but jaundice may not be present
at the outset (e.g. in paracetamol overdose), and there are a
number of exceptions, including Reye’s syndrome, in which
jaundice is rare. Occasionally, death may occur in fulminant
cases of acute liver failure before jaundice develops. Fetor
hepaticus can be present. The liver is usually of normal size
but later becomes smaller. Hepatomegaly is unusual and, in
22.8
Classification of acute liver failure
Type
Time: jaundice to
encephalopathy
Cerebral
oedema
Common
causes
Hyperacute
<7 days
Common
Viral,
paracetamol
Acute
8-28 days
Common
Cryptogenic,
drugs
Subacute
29 days to
1 2 weeks
Uncommon
Cryptogenic,
drugs
22.9 How to assess clinical grade of
hepatic encephalopathy
Cryptogenic
(5-10%)
Non-A-E viral
hepatitis
Miscellaneous
(< 5%)
Clinical grade
Clinical signs
Grade 1
Poor concentration, slurred speech, slow mentation,
disordered sleep rhythm
Grade 2
Drowsy but easily rousable, occasional aggressive
behaviour, lethargic
Grade 3
Marked delirium, drowsy, sleepy but responds to
pain and voice, gross disorientation
Grade 4
Unresponsive to voice, may or may not respond to
painful stimuli, unconscious
Viral infections
(5%)
Wilson's disease
Acute fatty liver of pregnancy
Shock and cardiac failure
Budd-Chiari syndrome
Leptospirosis
Liver metastases
Lymphoma
Amanita phalloides
Paracetamol
Halothane
Antituberculous drugs
Methylenedioxymethamphetamine
(MDMA, 'ecstasy')
Herbal remedies
Fig. 22.13 Causes of acute liver failure in the UK. The relative frequency of the different causes varies according to geographical area.
858 • HEPATOLOGY
the presence of a sudden onset of ascites, suggests venous
outflow obstruction as the cause (Budd-Chiari syndrome, p. 898).
Splenomegaly is uncommon and never prominent. Ascites and
oedema are late developments and may be a consequence of
fluid therapy. Other features are related to the development of
complications (see below).
Investigations
The patient should be investigated to determine the cause of the
liver failure and the prognosis (Boxes 22.10 and 22.1 1). Hepatitis
B core IgM antibody is the best screening test for acute hepatitis
B infection, as liver damage is due to the immunological response
to the virus, which has often been eliminated, and the test for
hepatitis B surface antigen (HBsAg) may be negative. The PT
rapidly becomes prolonged as coagulation factor synthesis fails;
this is the laboratory test of greatest prognostic value and should
be carried out at least twice daily. Its prognostic importance
emphasises the necessity of avoiding the use of fresh frozen
plasma to correct raised PT in acute liver failure, except in the
setting of frank bleeding. Factor V levels can be used instead
of the PT to assess the degree of liver impairment. The plasma
22.10 Investigations to determine the cause of
acute liver failure
• Toxicology screen of blood and urine
• HBsAg, IgM anti-HBc
• IgM anti-HAV
• Anti-HEV, HCV, cytomegalovirus, herpes simplex, Epstein— Barr virus
• Caeruloplasmin, serum copper, urinary copper, slit-lamp eye
examination
• Autoantibodies: ANA, ASMA, LKM, SLA
• Immunoglobulins
• Ultrasound of liver and Doppler of hepatic veins
(ANA = antinuclear antibody; anti-HBc = antibody to hepatitis B core antigen;
ASMA = anti-smooth muscle antibody; HAV = hepatitis A virus; HBsAg =
hepatitis B surface antigen; HCV = hepatitis C virus; HEV = hepatitis E virus; IgM
= immunoglobulin M; LKM = liver-kidney microsomal antibody; SLA = soluble
liver antigen)
22.11 Adverse prognostic criteria in
acute liver failure
Paracetamol overdose
• H+ >50 nmol/L (pH <7.3) at or beyond 24 hours following the
overdose
Or
• Serum creatinine >300 pimol/L (=3.38 mg/dL) plus prothrombin
time >100 secs plus encephalopathy grade 3 or 4
Non-paracetamol cases
• Prothrombin time >100 secs
Or
• Any three of the following:
Jaundice to encephalopathy time >7 days
Age <10 or >40 years
Indeterminate or drug-induced causes
Bilirubin >300 pimol/L (=17.6 mg/dL)
Prothrombin time >50 secs
Or
• Factor V level <15% and encephalopathy grade 3 or 4
*Predict a mortality rate of >90% and are an indication for referral for possible
liver transplantation.
bilirubin reflects the degree of jaundice. Plasma aminotransferase
activity is particularly high after paracetamol overdose, reaching
1 00-500 times normal, but falls as liver damage progresses and
is not helpful in determining prognosis. Plasma albumin remains
normal unless the course is prolonged. Percutaneous liver
biopsy is contraindicated because of the severe coagulopathy,
but biopsy can be undertaken using the transjugular route if
appropriate.
Management
Patients with acute liver failure should be treated in a high-
dependency or intensive care unit as soon as progressive
prolongation of the PT occurs or hepatic encephalopathy is
identified (Box 22.1 2), so that prompt treatment of complications
can be initiated (Box 22.13). Conservative treatment aims to
maintain life in the hope that hepatic regeneration will occur,
but early transfer to a specialised transplant unit should always
be considered. N- acetylcysteine therapy may improve outcome,
particularly in patients with acute liver failure due to paracetamol
poisoning. Liver transplantation is an increasingly important
treatment option for acute liver failure, and criteria have been
developed to identify patients unlikely to survive without a
transplant (see Box 22.1 1). Patients should, wherever possible, be
transferred to a transplant centre before these criteria are met to
allow time for assessment and to maximise the time for a donor
liver to become available. Survival following liver transplantation
22.13 Complications of acute liver failure
• Encephalopathy and cerebral
• Renal failure
oedema
• Multi-organ failure
• Hypoglycaemia
(hypotension and respiratory
• Metabolic acidosis
failure)
• Infection (bacterial, fungal)
22.12 Monitoring in acute liver failure
Cardiorespiratory
• Pulse
• Blood pressure
• Central venous pressure
• Respiratory rate
Neurological
• Intracranial pressure monitoring (specialist units, p. 208)
• Conscious level
Fluid balance
• Hourly output (urine, vomiting, diarrhoea)
• Input: oral, intravenous
Blood analyses
• Arterial blood gases
• Peripheral blood count (including platelets)
• Sodium, potassium, HC03~, calcium, magnesium
• Creatinine, urea
• Glucose (2-hourly in acute phase)
• Prothrombin time
Infection surveillance
• Cultures: blood, urine, throat, sputum, cannula sites
• Chest X-ray
• Temperature
Presenting problems in liver disease • 859
for acute liver failure is improving and 1 -year survival rates of
about 60% can be expected. A number of artificial liver support
systems have been developed and evaluated for use as a bridge
to either transplantation or recovery. None, however, has entered
routine clinical use.
Abnormal liver function tests
Frequently, LFTs are requested in patients who have no symptoms
or signs of liver disease, as part of routine health checks, insurance
medicals or drug monitoring. When abnormal results are found,
it is important for the clinician to be able to interpret them and
to investigate appropriately. Many patients with chronic liver
disease are asymptomatic or have vague, non-specific symptoms.
Apparently asymptomatic abnormal LFTs are therefore a common
occurrence. When LFTs are measured routinely prior to elective
surgery, 3.5% of patients are discovered to have mildly elevated
transaminases. The prevalence of abnormal LFTs has been
reported to be as high as 10% in some studies. The most
common abnormalities are alcoholic (p. 880) or non-alcoholic
fatty liver disease (p. 882). Since effective medical treatments
are now available for many types of chronic liver disease, further
evaluation is usually warranted to make sure the patient does not
have a treatable condition. Although transient mild abnormalities
in LFTs may not be clinically significant, the majority of individuals
with persistently abnormal LFTs do have significant liver disease.
Biochemical abnormalities in chronic liver disease often fluctuate
over time; even mild abnormalities can therefore indicate significant
underlying disease and so warrant follow-up and investigation.
When abnormal LFTs are detected, a thorough history should
be compiled to determine the patient’s alcohol consumption, drug
use (prescribed drugs or otherwise), risk factors for viral hepatitis
(e.g. blood transfusion, injection drug use, tattoos), the presence
of autoimmune diseases, family history, neurological symptoms,
and the presence of features of the metabolic syndrome
(p. 730), including diabetes and/or obesity (see Box 22.5 and
Fig. 19.5, p. 698). The presence or absence of stigmata of
22.14 Common causes of elevated serum
transaminases
Minor elevation (<100 U/L )
• Chronic hepatitis C • Haemochromatosis
• Chronic hepatitis B • Fatty liver disease
Moderate elevation (100-300 U/L*)
As above plus:
• Alcoholic hepatitis • Autoimmune hepatitis
• Non-alcoholic steatohepatitis • Wilson’s disease
Major elevation (>300 U/L*)
• Drugs (e.g. paracetamol) • Toxins (e.g. Amanita
• Acute viral hepatitis phalloides poisoning)
• Autoimmune liver disease • Flare of chronic hepatitis B
• Ischaemic liver
These ranges are indicative but do not rigidly discriminate between different
aetiologies.
Fig. 22.14 Suggested management of abnormal liver function tests in asymptomatic patients. *No further investigation needed. (c^AT = alpha!
antitrypsin; BMI = body mass index; ERCP = endoscopic retrograde cholangiopancreatography; GGT = y-glutamyl transferase; HBsAg = hepatitis B surface
antigen; HCVAb = antibody to hepatitis C virus; MRCP = magnetic resonance cholangiopancreatography; NAFLD = non-alcoholic fatty liver disease)
860 • HEPATOLOGY
chronic liver disease does not reliably identify those individuals
with significant disease and investigations are indicated, even
in the absence of these signs.
Both the pattern of LFT abnormality (hepatitic or obstructive)
and the degree of elevation are helpful in determining the
cause of underlying liver disease (Boxes 22.14 and 22.15).
The investigations that make up a standard liver screen and
additional or confirmatory tests are shown in Boxes 22.4 and
22.5. An algorithm for investigating abnormal LFTs is provided
in Figure 22.14.
In haemolysis, destruction of red blood cells or their marrow
precursors causes increased bilirubin production. Jaundice due
to haemolysis is usually mild because a healthy liver can excrete
a bilirubin load six times greater than normal before unconjugated
bilirubin accumulates in the plasma. This does not apply to
newborns, who have less capacity to metabolise bilirubin.
The most common form of non-haemolytic hyperbilirubinaemia
is Gilbert’s syndrome, an inherited disorder of bilirubin metabolism
(Box 22.17). Other inherited disorders of bilirubin metabolism
are very rare.
Jaundice
Jaundice is usually detectable clinically when the plasma bilirubin
exceeds 40 jimol/L (~2.5 mg/dL). The causes of jaundice overlap
with the causes of abnormal LFTs discussed above. In a patient
with jaundice it is useful to consider whether the cause might
be pre-hepatic, hepatic or post-hepatic, and there are often
important clues in the history (Box 22.16).
Pre-hepatic jaundice
This is caused either by haemolysis or by congenital hyper¬
bilirubinaemia, and is characterised by an isolated raised bilirubin
level.
22.15 Causes of cholestatic jaundice
Intrahepatic
• Primary biliary cholangitis
• Primary sclerosing cholangitis
• Alcohol
• Drugs
• Hepatic infiltrations
(lymphoma, granuloma,
amyloid, metastases)
Extrahepatic
• Carcinoma:
Ampullary
Pancreatic
Bile duct
(cholangiocarcinoma)
Liver metastases
Cystic fibrosis
Severe bacterial infections
Pregnancy (p. 899)
Inherited cholestatic liver
disease, e.g. benign recurrent
intrahepatic cholestasis
Chronic right heart failure
Choledocholithiasis
Parasitic infection
Traumatic biliary strictures
Chronic pancreatitis
Hepatocellular jaundice
Hepatocellular jaundice results from an inability of the liver to
transport bilirubin into the bile, occurring as a consequence of
parenchymal disease. Bilirubin transport across the hepatocytes
may be impaired at any point between uptake of unconjugated
bilirubin into the cells and transport of conjugated bilirubin into
the canaliculi. In addition, swelling of cells and oedema resulting
from the disease itself may cause obstruction of the biliary
canaliculi. In hepatocellular jaundice, the concentrations of both
unconjugated and conjugated bilirubin in the blood increase.
i
Symptoms*
• Itching preceding jaundice
• Abdominal pain (suggests
stones)
• Weight loss (chronic liver
disease and malignancy)
Recent drug history
Other
• Exposure to intravenous drug or blood transfusions
• Travel history and country of birth
• Metabolic syndrome (increased body mass index ± type 2 diabetes/
hypertension)
• Autoimmune disease history
• Alcohol history
• Inflammatory bowel disease
• Family history of liver disease, autoimmune disease or the metabolic
syndrome
• Dark urine and pale stools
• Fever ± rigors
• Dry eyes/dry mouth
• Fatigue
22.16 Key history points in patients with jaundice
*Symptoms may be absent and abnormal liver function tests detected
incidentally.
22.17 Congenital non-haemolytic hyperbilirubinaemia
Syndrome
Inheritance
Abnormality
Clinical features
Treatment
Unconjugated hyperbilirubinaemia
iGlucuronyl transferase
Gilbert’s
Can be autosomal recessive
Mild jaundice, especially
None necessary
or dominant
iBilirubin uptake
with fasting
Crigler— Najjar:
Type 1
Autosomal recessive
Absent glucuronyl transferase
islGlucuronyl transferase
Rapid death in neonate
(kernicterus)
Type II
Autosomal recessive
Presents in neonate
Phenobarbital, phototherapy
or liver transplant
Conjugated hyperbilirubinaemia
^Canalicular excretion of organic
Dubin-Johnson
Autosomal recessive
Mild jaundice
None necessary
anions, including bilirubin
Pigmentation of liver biopsy tissue
Rotor’s
Autosomal recessive
iBilirubin uptake
^Intrahepatic binding
Mild jaundice
None necessary
Presenting problems in liver disease • 861
Hepatocellular jaundice can be due to acute or chronic injury
(see Fig. 22.11), and clinical features of acute or chronic liver
disease may be detected clinically (see Box 22.7).
Characteristically, jaundice due to parenchymal liver disease
is associated with increases in transaminases (AST, ALT), but
increases in other LFTs, including cholestatic enzymes (GGT,
ALP), may occur and suggest specific aetiologies (see below).
Acute jaundice in the presence of an ALT of > 1 000 U/L is highly
suggestive of an infectious cause (e.g. hepatitis A or B), drugs
(e.g. paracetamol) or hepatic ischaemia. Imaging is essential,
in particular to identify features suggestive of cirrhosis, define
the patency of the hepatic vasculature and obtain evidence
of portal hypertension. Liver biopsy has an important role in
defining the aetiology of hepatocellular jaundice and the extent of
liver injury.
Obstructive (cholestatic) jaundice
Cholestatic jaundice may be caused by:
• failure of hepatocytes to initiate bile flow
• obstruction of the bile ducts or portal tracts
• obstruction of bile flow in the extrahepatic bile ducts
between the porta hepatis and the papilla of Vater.
In the absence of treatment, cholestatic jaundice tends to
become progressively more severe because conjugated bilirubin is
unable to enter the bile canaliculi and passes back into the blood,
and also because there is a failure of clearance of unconjugated
bilirubin arriving at the liver cells. The causes of cholestatic
jaundice are listed in Box 22.15. Cholestasis may result from
defects at more than one of these levels. Those confined to
the extrahepatic bile ducts may be amenable to surgical or
endoscopic correction.
Clinical features (Box 22.18) comprise those due to cholestasis
itself, those due to secondary infection (cholangitis) and those
of the underlying condition (Box 22.19). Obstruction of the bile
duct drainage due to blockage of the extrahepatic biliary tree
is characteristically associated with pale stools and dark urine.
Pruritus may be a dominant feature and can be accompanied
by skin excoriations. Peripheral stigmata of chronic liver disease
are absent. If the gallbladder is palpable, the jaundice is unlikely
to be caused by biliary obstruction due to gallstones, probably
because a chronically inflamed, stone-containing gallbladder
cannot readily dilate. This is Courvoisier’s Law, and suggests
BS 22.18 Clinical features and complications of
cholestatic jaundice
Cholestasis
Early features
• Jaundice
• Pale stools
• Dark urine
• Pruritus
Late features
• Malabsorption (vitamins A, D,
• Xanthelasma and xanthomas
E and K): weight loss,
steatorrhoea, osteomalacia,
bleeding tendency
Cholangitis
• Fever
• Pain (if gallstones present)
• Rigors
Fig. 22.15 Investigation of jaundice. (ERCP = endoscopic retrograde cholangiopancreatography; LFTs = liver function tests; MRCP = magnetic
resonance cholangiopancreatography)
862 • HEPATOLOGY
22.19 Clinical features suggesting an underlying
cause of cholestatic jaundice
Clinical feature
Causes
Jaundice
Static or increasing
Carcinoma
Primary biliary cholangitis
Primary sclerosing cholangitis
Fluctuating
Choledocholithiasis
Stricture
Pancreatitis
Choledochal cyst
Primary sclerosing cholangitis
Abdominal pain
Choledocholithiasis
Pancreatitis
Choledochal cyst
Cholangitis
Stone
Stricture
Choledochal cyst
Abdominal scar
Stone
Stricture
Irregular hepatomegaly
Hepatic carcinoma
Palpable gallbladder
Carcinoma below cystic duct
(usually pancreas)
Abdominal mass
Carcinoma
Pancreatitis (cyst)
Choledochal cyst
Occult blood in stools
Ampullary tumour
*Each of these diseases can give rise to almost any of the clinical features shown
but the box indicates the most likely cause of the clinical features listed.
that jaundice is due to a malignant biliary obstruction (e.g.
pancreatic cancer). Cholangitis is characterised by ‘Charcot’s
triad’ of jaundice, right upper quadrant pain and fever. Cholestatic
jaundice is characterised by a relatively greater elevation of ALP
and GGT than the aminotransferases.
Ultrasound is indicated to determine whether there is evidence
of mechanical obstruction and dilatation of the biliary tree (Fig.
22.15). EUS provides an additional investigation modality for
investigation of lower common bile duct obstruction.
Management of cholestatic jaundice depends on the underlying
cause and is discussed in the relevant sections below.
Hepatomegaly
Hepatomegaly may occur as the result of a general enlargement
of the liver or because of primary or secondary liver tumour
i
Large liver (hepatomegaly)
• Liver metastases
• Multiple or large hepatic cysts
• Cirrhosis (early): non-alcoholic fatty liver disease, alcohol,
haemochromatosis
• Hepatic vein outflow obstruction
• Infiltration: amyloid
Small liver
• Cirrhosis (late)
(Box 22.20). The most common liver tumour in Western countries
is liver metastasis, whereas primary liver cancer complicating
chronic viral hepatitis is more common in the Far East. Unlike
carcinoma metastases, those from neuro-endocrine tumours
typically cause massive hepatomegaly but without significant
weight loss. Cirrhosis can be associated with either hepatomegaly
or reduced liver size in advanced disease. Although all causes
of cirrhosis can involve hepatomegaly, it is much more common
in alcoholic liver disease and haemochromatosis. Hepatomegaly
may resolve in patients with alcoholic cirrhosis when they stop
drinking.
Ascites
Ascites is present when there is accumulation of free fluid in the
peritoneal cavity. Small amounts of ascites are asymptomatic,
but with larger accumulations of fluid (>1 L) there is abdominal
distension, fullness in the flanks, shifting dullness on percussion
and, when the ascites is marked, a fluid thrill/fluid wave. Other
features include eversion of the umbilicus, herniae, abdominal
striae, divarication of the recti and scrotal oedema. Dilated
superficial abdominal veins may be seen if the ascites is due
to portal hypertension.
Pathophysiology
Ascites has numerous causes, the most common of which are
malignant disease, cirrhosis and heart failure. Many primary
disorders of the peritoneum and visceral organs can also cause
ascites, and these need to be considered even in a patient with
chronic liver disease (Box 22.21). Splanchnic vasodilatation is
thought to be the main factor leading to ascites in cirrhosis.
This is mediated by vasodilators (mainly nitric oxide) that are
released when portal hypertension causes shunting of blood
into the systemic circulation. Systemic arterial pressure falls due
to pronounced splanchnic vasodilatation as cirrhosis advances.
This leads to activation of the renin-angiotensin system with
secondary aldosteronism, increased sympathetic nervous activity,
increased atrial natriuretic hormone secretion and altered activity
22.21 Causes of ascites
Low SAAG (exudative)
High SAAG (transudative)
Common causes
Malignant disease:
Hepatic
Peritoneal
Cardiac failure
Hepatic cirrhosis
Other causes
Acute pancreatitis
Lymphatic obstruction
Infection:
Tuberculosis
Nephrotic syndrome
Hypoproteinaemia:
Protein-losing enteropathy
Malnutrition
Hepatic venous occlusion:
Budd-Chiari syndrome
Sinusoidal obstruction syndrome
(Veno-occlusive disease)
Rare causes
Hypothyroidism
Meigs’ syndrome*
Constrictive pericarditis
*Meigs’ syndrome is the association of a right pleural effusion with or without
ascites and a benign ovarian tumour. The ascites resolves on removal of the
tumour.
(SAAG = serum ascites albumin gradient; see text)
22.20 Causes of change in liver size
Presenting problems in liver disease • 863
Cirrhosis
Portal
hypertension
Reduced
albumin
pressure
Transudation
of fluid
Reduced
aldosterone
metabolism
Aldosterone
t
Activation of
renin-angiotensin
system
t
Under-filling
of circulation
l
Reduced
renal
blood flow
Splanchnic
vasodilatation
Salt Lymph
and water formation
retention exceeds
Fig. 22.16 Pathogenesis of ascites.
of the kallikrein-kinin system (Fig. 22.16). These systems tend to
normalise arterial pressure but produce salt and water retention.
In this setting, the combination of splanchnic arterial vasodilatation
and portal hypertension alters intestinal capillary permeability,
promoting accumulation of fluid within the peritoneum.
Investigations
Ultrasonography is the best means of detecting ascites, particularly
in the obese and those with small volumes of fluid. Paracentesis
(if necessary under ultrasonic guidance) can be used to obtain
ascitic fluid for analysis. The appearance of ascitic fluid may
point to the underlying cause (Box 22.22). Pleural effusions are
found in about 1 0% of patients, usually on the right side (hepatic
hydrothorax); most are small and identified only on chest X-ray,
but occasionally a massive hydrothorax occurs. Pleural effusions,
particularly those on the left side, should not be assumed to
be due to the ascites.
Measurement of the protein concentration and the serum-
ascites albumin gradient (SAAG) can be a useful tool to distin¬
guish ascites of different aetiologies. Cirrhotic patients typically
develop ascites with a low protein concentration (‘transudate’;
protein concentration <25 g/L (2.5 g/dL)) and relatively few cells.
In up to 30% of patients, however, the total protein concentration
is >30 g/L (3.0 g/dL). In these cases, it is useful to calculate the
SAAG by subtracting the concentration of the ascites fluid albumin
from the serum albumin. A gradient of > 1 1 g/L (1 .1 g/dL) is 96%
predictive that ascites is due to portal hypertension. Venous
outflow obstruction due to cardiac failure or hepatic venous
outflow obstruction can also cause a transudative ascites, as
22.22 Ascitic fluid: appearance and analysis
Cause/appearance
• Cirrhosis: clear, straw-coloured or light green
• Malignant disease: bloody
• Infection: cloudy
• Biliary communication: heavy bile staining
• Lymphatic obstruction: milky-white (chylous)
Useful investigations
• Total albumin (plus serum albumin) and protein*
• Amylase
• Neutrophil count
• Cytology
• Microscopy and culture
*To calculate the serum-ascites albumin gradient (SAAG).
indicated by an albumin gradient of >1 1 g/L (1 .1 g/dL) but, unlike
in cirrhosis, the total protein content is usually >25 g/L (2.5 g/dL).
High protein ascites (‘exudate’; protein concentration >25 g/L
(2.5 g/dL) or a SAAG of <1 1 g/L (1 .1 g/dL) raises the possibility
of infection (especially tuberculosis), malignancy, pancreatic
ascites or, rarely, hypothyroidism. Ascites amylase activity of
> 1 000 U/L identifies pancreatic ascites, whereas low ascites
glucose concentrations suggest malignant disease or tuberculosis.
Cytological examination may reveal malignant cells (one-third
of cirrhotic patients with a bloody tap have a hepatocellular
carcinoma). Polymorphonuclear leucocyte counts of >250 x 106/L
strongly suggest infection (spontaneous bacterial peritonitis; see
below). Laparoscopy can be valuable in detecting peritoneal
disease.
The presence of triglyceride at a level >1.1 g/L (110 mg/dL)
is diagnostic of chylous ascites and suggests anatomical or
functional abnormality of lymphatic drainage from the abdomen.
The ascites in this context has a characteristic milky-white
appearance.
Management
Successful treatment relieves discomfort but does not prolong
life; if over-vigorous, it can produce serious disorders of fluid
and electrolyte balance, and precipitate hepatic encephalopathy
(p. 864). Treatment of transudative ascites is based on restricting
sodium and water intake, promoting urine output with diuretics
and, if necessary, removing ascites directly by paracentesis.
Exudative ascites due to malignancy is treated with paracentesis
but fluid replacement is generally not required. During management
of ascites, the patient should be weighed regularly. Diuretics
should be titrated to remove no more than 1 L of fluid daily, so
body weight should not fall by more than 1 kg daily to avoid
excessive fluid depletion.
Sodium and water restriction
Restriction of dietary sodium intake is essential to achieve negative
sodium balance and a few patients can be managed satisfactorily
by this alone. Restriction of sodium intake to 100 mmol/24 hrs
(‘no added salt diet’) is usually adequate. Drugs containing
relatively large amounts of sodium, and those promoting sodium
retention, such as non-steroidal anti-inflammatory drugs (NSAIDs),
must be avoided (Box 22.23). Restriction of water intake to
1 .0-1 .5 L724 hrs is necessary only if the plasma sodium falls
below 125 mmol/L.
864 • HEPATOLOGY
^9 22.23 Some drugs containing relatively large
amounts of sodium or causing sodium retention
High sodium content
• Alginates
• Effervescent preparations (e.g.
• Antacids
aspirin, calcium, paracetamol)
• Antibiotics
• Sodium valproate
• Phenytoin
Sodium retention
• Carbenoxolone
• Non-steroidal anti¬
• Glucocorticoids
inflammatory drugs
• Metoclopramide
• Oestrogens
Diuretics
Most patients require diuretics in addition to sodium restriction.
Spironolactone (100-400 mg/day) is the first-line drug because
it is a powerful aldosterone antagonist; it can, however, cause
painful gynaecomastia and hyperkalaemia, in which case amiloride
(5-10 mg/day) can be substituted. Some patients also require
loop diuretics, such as furosemide, but these can lead to fluid
and electrolyte imbalance and renal dysfunction. Diuresis may
be improved if patients are rested in bed, perhaps because
renal blood flow increases in the horizontal position. Patients
who do not respond to doses of 400 mg spironolactone and
1 60 mg furosemide, or who are unable to tolerate these doses
due to hyponatraemia or renal impairment, are considered to
have refractory or diuretic-resistant ascites and should be treated
by other measures.
Paracentesis
First-line treatment of refractory ascites is large-volume paracen¬
tesis. Paracentesis to dryness is safe, provided the circulation is
supported with an intravenous colloid such as human albumin
(6-8 g per litre of ascites removed, usually as 1 00 mL of 20% or
25% human albumin solution (HAS) for every 1 .5-2 L of ascites
drained) or another plasma expander. Paracentesis can be used
as an initial therapy or when other treatments fail.
Transjugular intrahepatic portosystemic stent shunt
A transjugular intrahepatic portosystemic stent shunt (TIPSS;
p. 870) can relieve resistant ascites but does not prolong life; it
may be an option where the only alternative is frequent, large-
volume paracentesis. TIPSS can be used in patients awaiting
liver transplantation or in those with reasonable liver function,
but can aggravate encephalopathy in those with poor function.
Complications
Renal failure
Renal failure can occur in patients with ascites. It can be pre-renal
and due to vasodilatation from sepsis and/or diuretic therapy,
or due to hepatorenal syndrome.
Hepatorenal syndrome
This occurs in 10% of patients with advanced cirrhosis
complicated by ascites. There are two clinical types; both are
mediated by renal vasoconstriction due to under-filling of the
arterial circulation.
Type 1 hepatorenal syndrome This is characterised by progressive
oliguria, a rapid rise of the serum creatinine and a very poor
prognosis (without treatment, median survival is less than
1 month). There is usually no proteinuria, a urine sodium excretion
of less than 1 0 mmol/24 hrs and a urine/plasma osmolarity ratio
of more than 1 .5. Other non-functional causes of renal failure
must be excluded before the diagnosis is made. Treatment
consists of albumin infusions in combination with terlipressin (or
octreotide and midodrine where terlipressin is not approved for
use) and is effective in about two-thirds of patients. Haemodialysis
should not be used routinely because it does not improve the
outcome. Patients who survive should be considered for liver
transplantation, which, along with TIPSS, is an effective treatment
in appropriate patients.
Type 2 hepatorenal syndrome This usually occurs in patients with
refractory ascites, is characterised by a moderate and stable
increase in serum creatinine, and has a better prognosis.
Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis (SBP) may present with
abdominal pain, rebound tenderness, absent bowel sounds and
fever in a patient with obvious features of cirrhosis and ascites.
Abdominal signs are mild or absent in about one-third of patients,
and in these individuals hepatic encephalopathy and fever are the
main features. Diagnostic paracentesis may show cloudy fluid,
and an ascites neutrophil count of >250x106/L almost invariably
indicates infection. The source of infection cannot usually be
determined, but most organisms isolated are of enteric origin
and Escherichia coli is the most frequently found. Ascitic culture
in blood culture bottles gives the highest yield of organisms.
SBP needs to be differentiated from other intra-abdominal
emergencies, and the finding of multiple organisms on culture
should arouse suspicion of a perforated viscus.
Treatment should be started immediately with broad-spectrum
antibiotics, such as cefotaxime or piperacillin/tazobactam).
Recurrence of SBP is common but may be reduced with
prophylactic quinolones, such as norfloxacin or ciprofloxacin.
Prophylactic antibiotics reduce the incidence of SBP and improve
survival in cirrhotic patients with gastrointestinal bleeding. In
patients with a previous episode of SBP and continued ascites,
norfloxacin (400 mg/day) prevents recurrence.
Prognosis
Only 10-20% of patients survive for 5 years from the first
appearance of ascites due to cirrhosis. The outlook is not
universally poor, however, and is best in those with well-maintained
liver function and a good response to therapy. The prognosis is
also better when a treatable cause for the underlying cirrhosis is
present or when a precipitating cause for ascites, such as excess
salt intake, is found. The mortality at 1 year is 50% following the
first episode of bacterial peritonitis.
Hepatic encephalopathy
Hepatic encephalopathy is a neuropsychiatric syndrome caused
by liver disease. As it progresses, delirium is followed by coma.
Simple delirium needs to be differentiated from delirium tremens
and Wernicke’s encephalopathy, and coma from subdural
haematoma, which can occur in alcoholics after a fall (Box 22.24).
Features include changes of intellect, personality, emotions and
consciousness, with or without neurological signs. The degree of
encephalopathy can be graded from 1 to 4, depending on these
features, and this is useful in assessing response to therapy (see
Box 22.9). When an episode develops acutely, a precipitating
factor may be found (Box 22.25). The earliest features are very
Presenting problems in liver disease • 865
mild and easily overlooked, but as the condition becomes more
severe, apathy, inability to concentrate, delirium, disorientation,
drowsiness, slurring of speech and eventually coma develop.
Convulsions sometimes occur. Examination usually shows a
flapping tremor (asterixis), inability to perform simple mental
arithmetic tasks or to draw objects such as a star (constructional
apraxia; p. 847), and, as the condition progresses, hyper- ref lexia
and bilateral extensor plantar responses. Hepatic encephalopathy
rarely causes focal neurological signs; if these are present, other
causes must be sought. Fetor hepaticus, a sweet musty odour to
the breath, is usually present but is more a sign of liver failure and
portosystemic shunting than of hepatic encephalopathy. Rarely,
chronic hepatic encephalopathy (hepatocerebral degeneration)
gives rise to variable combinations of cerebellar dysfunction,
Parkinsonian syndromes, spastic paraplegia and dementia.
Pathophysiology
Hepatic encephalopathy is thought to be due to a disturbance of
brain function provoked by circulating neurotoxins that are normally
metabolised by the liver. Accordingly, most affected patients have
evidence of liver failure and portosystemic shunting of blood, but
the balance between these varies from individual to individual.
22.24 Differential diagnosis of
hepatic encephalopathy
i
• Drugs (especially sedatives, antidepressants)
• Dehydration (including diuretics, paracentesis)
• Portosystemic shunting
• Infection
• Hypokalaemia
• Constipation
• TProtein load (including gastrointestinal bleeding)
Some degree of liver failure is a key factor, as portosystemic
shunting of blood alone hardly ever causes encephalopathy.
The ‘neurotoxins’ causing encephalopathy are unknown but are
thought to be mainly nitrogenous substances produced in the
gut, at least in part by bacterial action. These substances are
normally metabolised by the healthy liver and excluded from the
systemic circulation. Ammonia has traditionally been considered
an important factor. Recent interest has focused on y-aminobutyric
acid (GABA) as a mediator, along with octopamine, amino acids,
mercaptans and fatty acids that can act as neurotransmitters.
The brain in cirrhosis may also be sensitised to other factors,
such as drugs that can precipitate hepatic encephalopathy (Box
22.25) . Disruption of the function of the blood-brain barrier is a
feature of acute hepatic failure and may lead to cerebral oedema.
Investigations
The diagnosis can usually be made clinically; when doubt exists,
an electroencephalogram shows diffuse slowing of the normal
alpha waves with eventual development of delta waves. The
arterial ammonia is usually increased in patients with hepatic
encephalopathy. Increased concentrations can, however, occur in
the absence of clinical encephalopathy, rendering this investigation
of little diagnostic value.
Management
The principles are to treat or remove precipitating causes (Box
22.25) and to suppress the production of neurotoxins by bacteria
in the bowel. Dietary protein restriction is rarely needed and is
no longer recommended as first-line treatment because it is
unpalatable and can lead to a worsening nutritional state in
already malnourished patients. Lactulose (15-30 mL 3 times
daily) is increased gradually until the bowels are moving twice
daily. It produces an osmotic laxative effect, reduces the pH of
the colonic content, thereby limiting colonic ammonia absorption,
and promotes the incorporation of nitrogen into bacteria. Rifaximin
(400 mg 3 times daily) is a well-tolerated, non-absorbed antibiotic
that acts by reducing the bacterial content of the bowel and has
been shown to be effective. It can be used in addition, or as an
alternative, to lactulose if diarrhoea becomes troublesome. Chronic
or refractory encephalopathy is one of the main indications for
liver transplantation.
Variceal bleeding
Acute upper gastrointestinal haemorrhage from gastro-oesophageal
varices (Fig. 22.1 7) is common in chronic liver disease. Investigation
• Intracranial bleed (subdural/extradural haematoma, p. 1133)
• Drug or alcohol intoxication (pp. 1194 and 1195)
• Delirium tremens/alcohol withdrawal (p. 1194)
• Wernicke’s encephalopathy (p. 1195)
• Primary psychiatric disorders (p. 1191)
• Hypoglycaemia (p. 738)
• Neurological Wilson’s disease (p. 1115)
• Post-ictal state
22.25 Factors precipitating hepatic encephalopathy
Fig. 22.17 Varices: endoscopic views. [A] Oesophageal varices (arrows) at the lower end of the oesophagus. [§] Gastric varices (arrows).
[C] Appearance of oesophageal varices following application of strangulating bands (band ligation, arrow).
866 • HEPATOLOGY
and management are discussed on page 780 and the specific
management of variceal bleeding on page 869.
Cirrhosis
Cirrhosis is characterised by diffuse hepatic fibrosis and nodule
formation. It can occur at any age, has significant morbidity and
is an important cause of premature death. It is the most common
cause of portal hypertension and its complications. Worldwide,
the most common causes are chronic viral hepatitis, prolonged
excessive alcohol consumption and NAFLD but any condition
leading to persistent or recurrent hepatocyte death may lead
to cirrhosis. The causes of cirrhosis are listed in Box 22.26.
Cirrhosis may also occur in prolonged biliary damage or
obstruction, as is found in primary biliary cholangitis (PBC), primary
sclerosing cholangitis (PSC) and post-surgical biliary strictures.
Persistent blockage of venous return from the liver, such as is
found in sinusoidal obstruction syndrome (SOS; veno-occlusive
disease) and Budd-Chiari syndrome, can also result in cirrhosis.
Pathophysiology
Following liver injury, stellate cells in the space of Disse (see
Fig. 22.3, p. 849) are activated by cytokines produced by
Kupffer cells and hepatocytes. This transforms the stellate cell
into a myofibroblast-like cell, capable of producing collagen,
pro- inflammatory cytokines and other mediators that promote
hepatocyte damage and tissue fibrosis (see Fig. 22.4, p. 849).
Cirrhosis is a histological diagnosis (Fig. 22.18). It evolves over
years as progressive fibrosis and widespread hepatocyte loss
lead to distortion of the normal liver architecture that disrupts the
hepatic vasculature, causing portosystemic shunts. These changes
usually affect the whole liver but in biliary cirrhosis (e.g. PBC)
they can be patchy. Cirrhosis can be classified histologically into:
• Micronodular cirrhosis, characterised by small nodules
about 1 mm in diameter and typically seen in alcoholic
cirrhosis.
• Macronodular cirrhosis, characterised by larger nodules of
various sizes. Areas of previous collapse of the liver
architecture are evidenced by large fibrous scars.
Clinical features
The clinical presentation is highly variable. Some patients are
asymptomatic and the diagnosis is made incidentally at ultrasound
or at surgery. Others present with isolated hepatomegaly,
splenomegaly, signs of portal hypertension (p. 868) or hepatic
insufficiency. When symptoms are present, they are often
22.26 Causes of cirrhosis
• Alcohol
• Chronic viral hepatitis (B or C)
• Non-alcoholic fatty liver
disease
• Immune:
Primary sclerosing
cholangitis
Autoimmune liver disease
• Biliary:
Primary biliary cholangitis
Secondary biliary cirrhosis
Cystic fibrosis
• Genetic:
Haemochromatosis
Wilson’s disease
-antitrypsin deficiency
• Cryptogenic (unknown - 1 5%)
• Chronic venous outflow
obstruction
• Any chronic liver disease
non-specific and include weakness, fatigue, muscle cramps,
weight loss, anorexia, nausea, vomiting and upper abdominal
discomfort (Box 22.27). Cirrhosis will occasionally present because
of shortness of breath due to a large right pleural effusion, or
with hepatopulmonary syndrome (p. 898).
Hepatomegaly is common when the cirrhosis is due to alcoholic
liver disease or haemochromatosis. Progressive hepatocyte
destruction and fibrosis gradually reduce liver size as the
disease progresses in other causes of cirrhosis. A reduction
in liver size is especially common if the cause is viral hepatitis
or autoimmune liver disease. The liver is often hard, irregular
and non-tender. Jaundice is mild when it first appears and is
due primarily to a failure to excrete bilirubin. Palmar erythema
Fig. 22.18 Histological features in normal liver, hepatic fibrosis and
cirrhosis. [A] Normal liver. Columns of hepatocytes 1-2 cells thick radiate
from the portal tracts (PT) to the central veins. The portal tract contains a
normal intralobular bile duct branch of the hepatic artery and portal venous
radical. [5] Bridging fibrosis (stained pink, arrows) spreading out around
the hepatic vein and single liver cells (pericellular) and linking adjacent
portal tracts and hepatic veins. |C ] A cirrhotic liver. The liver architecture
is disrupted. The normal arrangement of portal tracts and hepatic veins
is now lost and nodules of proliferating hepatocytes are broken up by
strands of pink-/orange-staining fibrous tissue (arrows) forming cirrhotic
nodules (CN).
Cirrhosis • 867
22.27 Clinical features of hepatic cirrhosis
• Hepatomegaly (although liver may also be small)
• Jaundice
• Ascites
• Circulatory changes: spider telangiectasia, palmar erythema,
cyanosis
• Endocrine changes: loss of libido, hair loss
Men: gynaecomastia, testicular atrophy, impotence
Women: breast atrophy, irregular menses, amenorrhoea
• Haemorrhagic tendency: bruises, purpura, epistaxis
• Portal hypertension: splenomegaly, collateral vessels, variceal
bleeding
• Hepatic (portosystemic) encephalopathy
• Other features: pigmentation, digital clubbing, Dupuytren’s
contracture
can be seen early in the disease but is of limited diagnostic
value, as it occurs in many other conditions associated with a
hyper-dynamic circulation, including normal pregnancy, as well
as being found in some healthy people. Spider telangiectasias
occur and comprise a central arteriole (that occasionally raises
the skin surface), from which small vessels radiate. They vary
in size from 1 to 2 mm in diameter and are usually found only
above the nipples. One or two small spider telangiectasias may be
present in about 2% of healthy people and may occur transiently
in greater numbers in the third trimester of pregnancy, but
otherwise they are a strong indicator of liver disease. Florid spider
telangiectasia, gynaecomastia and parotid enlargement are most
common in alcoholic cirrhosis. Pigmentation is most striking in
haemochromatosis and in any cirrhosis associated with prolonged
cholestasis. Pulmonary arteriovenous shunts also develop, leading
to hypoxaemia and eventually to central cyanosis, but this is a
late feature.
Endocrine changes are noticed more readily in men, who
show loss of male hair distribution and testicular atrophy.
Gynaecomastia is common and can be due to drugs such as
spironolactone. Easy bruising becomes more frequent as cirrhosis
advances.
Splenomegaly and collateral vessel formation are features
of portal hypertension, which occurs in more advanced
disease (see below). Ascites also signifies advanced disease.
Evidence of hepatic encephalopathy also becomes common
with disease progression. Non-specific features of chronic liver
disease include clubbing of the fingers and toes. Dupuytren’s
contracture is traditionally regarded as a complication of cir¬
rhosis but the evidence for this is weak. Chronic liver failure
develops when the metabolic capacity of the liver is exceeded.
It is characterised by the presence of encephalopathy and/
or ascites. The term ‘hepatic decompensation’ or ‘decom¬
pensated liver disease’ is often used when chronic liver failure
occurs.
Other clinical and laboratory features may be present (Box
22.28); these include peripheral oedema, renal failure, jaundice,
and hypoalbuminaemia and coagulation abnormalities due to
defective protein synthesis.
Management
This includes treatment of the underlying cause, maintenance
of nutrition and treatment of complications, including ascites,
hepatic encephalopathy, portal hypertension and varices. Once the
diagnosis of cirrhosis is made, endoscopy should be performed
22.28 Features of chronic liver failure
• Worsening synthetic liver
• Variceal bleeding
function:
• Hepatic encephalopathy
Prolonged prothrombin time
• Ascites:
Low albumin
Spontaneous bacterial
• Jaundice
peritonitis
• Portal hypertension
Hepatorenal failure
22.29 Child-Pugh classification of prognosis
in cirrhosis
Score
1
2
3
Encephalopathy
None
Mild
Marked
Bilirubin (p,mol/L {mg/dL))*
Primary biliary
cholangitis/sclerosing
<68 (4)
68-170 (4-10)
>170 (70)
cholangitis
Other causes of
cirrhosis
<34 (2)
34-50 (2-3)
>50 (3)
Albumin
(g/L nm)
>35 (3.5)
28-35 (2.8-3.5)
<28 (2.8)
Prothrombin time
(secs prolonged)
<4
4-6
>6
Ascites
None
Mild
Marked
Add the individual scores:
<7 = Child’s A, 7-9 = Child’s B, >9 = Child’s C
*To convert bilirubin in gmol/L to mg/dL, divide by 17.
to screen for oesophageal varices (p. 869) and repeated every
2 years. As cirrhosis is associated with an increased risk of
hepatocellular carcinoma, patients should be placed under
regular surveillance for it (p. 890).
Chronic liver failure due to cirrhosis can also be treated by liver
transplantation. This currently accounts for about three-quarters
of all liver transplants (p. 900).
Prognosis
The overall prognosis is poor. Many patients present with
advanced disease and/or serious complications that carry a
high mortality. Overall, only 25% of patients survive 5 years
from diagnosis, but where liver function is good, 50% survive
for 5 years and 25% for up to 1 0 years. The prognosis is more
favourable when the underlying cause can be corrected, as in
alcohol misuse, haemochromatosis or Wilson’s disease.
Laboratory tests give only a rough guide to prognosis in
individual patients. Deteriorating liver function, as evidenced by
jaundice, ascites or encephalopathy, indicates a poor prognosis
unless a treatable cause such as infection is found. Increasing
bilirubin, falling albumin (or an albumin concentration of <30 g/L
(3.0 g/d L)) , marked hyponatraemia (<120 mmol/L) not due to
diuretic therapy, and a prolonged PT are all bad prognostic
features (Box 22.29 and Fig. 22.19). The Child-Pugh and MELD
(Model for End-stage Liver Disease) scores can be used to
assess prognosis. The MELD is more difficult to calculate at the
bedside but, unlike the Child-Pugh score, includes renal function;
if this is impaired, it is known to be a poor prognostic feature in
end-stage disease (Box 22.30). Although these scores give a
guide to prognosis, the course of cirrhosis can be unpredictable,
as complications such as variceal bleeding may occur.
868 • HEPATOLOGY
Fig. 22.19 Survival in cirrhosis by Child-Pugh score.
22.30 One-year survival rate depending
on MELD score
1 -year survival (%)
MELD score
No complications
Complications
<9
97
90
10-19
90
85
20-29
70
65
30-39
70
50
MELD from SI units
10x(0.378 [In serum bilirubin (jimol/L) + 1.12 [In INR] + 0.957 [In
serum creatinine (pmol/L)] + 0.643)
MELD from non-SI units
3.8 [In serum bilirubin (mg/dL)] + 11.2 [In INR] + 9.3 [In serum
creatinine (mg/dL)] + 6.4
In = natural log. To calculate online, go to https://optn.transplant.hrsa
.gov/resources/allocation-calculators/meld-calculator/
"Complications’ means the presence of ascites, encephalopathy or variceal
bleeding.
(INR = International Normalised Ratio; MELD = Model for End-stage Liver
Disease)
Portal hypertension
Portal hypertension frequently complicates cirrhosis but has
other causes. The normal hepatic venous pressure gradient
(difference between the wedged hepatic venous pressure (WHVP)
and free hepatic venous pressure; see below) is 5-6 mmHg.
Clinically significant portal hypertension is present when the
gradient exceeds 1 0 mmHg and risk of variceal bleeding increases
beyond a gradient of 12 mmHg. Increased vascular resistance
is common. Causes are classified in accordance with the main
sites of obstruction to blood flow in the portal venous system (Fig.
22.20). Extrahepatic portal vein obstruction is the usual source of
portal hypertension in childhood and adolescence, while cirrhosis
causes at least 90% of cases of portal hypertension in adults
in developed countries. Schistosomiasis is the most common
cause of portal hypertension worldwide but is infrequent outside
endemic areas, such as Egypt (p. 294).
Clinical features
The clinical features result principally from portal venous
congestion and collateral vessel formation (Box 22.31).
Splenomegaly is a cardinal finding and a diagnosis of portal
hypertension is unusual when splenomegaly cannot be detected
clinically or by ultrasonography. The spleen is rarely enlarged
® Post-hepatic post-sinusoidal
Budd-Chiari syndrome
® Intrahepatic post-sinusoidal
Veno-occlusive disease
©Sinusoidal
Cirrhosis*
Polycystic liver disease
Nodular regenerative
hyperplasia
Metastatic malignant
disease
Heart
Liver
Blood
from gut
© Intrahepatic
pre-sinusoidal
Schistosomiasis*
Congenital hepatic
fibrosis
Drugs
Vinyl chloride
Sarcoidosis
© Pre-hepatic pre-sinusoidal
Portal vein thrombosis due to sepsis (umbilical,
portal pyaemia) or procoagulopathy or secondary
to cirrhosis
Abdominal trauma including surgery
Fig. 22.20 Classification of portal hypertension according to site of
vascular obstruction. *Most common cause. Note that splenic vein
occlusion can also follow pancreatitis, leading to gastric varices.
22.31 Complications of portal hypertension
• Variceal bleeding:
• Ascites
oesophageal, gastric, other
• Iron deficiency anaemia
(rare)
• Renal failure
• Congestive gastropathy
• Hepatic encephalopathy
• Hypersplenism
more than 5 cm below the left costal margin in adults but more
marked splenomegaly can occur in childhood and adolescence.
Collateral vessels may be visible on the anterior abdominal wall
and occasionally several radiate from the umbilicus to form a
‘caput medusae’ (p. 846). Rarely, a large umbilical collateral vessel
has a blood flow sufficient to give a venous hum on auscultation
(Cruveilhier-Baumgarten syndrome). The most important collateral
vessel formation occurs in the oesophagus and stomach, and
this can be a source of severe bleeding. Rectal varices also
cause bleeding and are often mistaken for haemorrhoids (which
are no more common in portal hypertension than in the general
population). Fetor hepaticus results from portosystemic shunting
of blood, which allows mercaptans to pass directly to the lungs.
Portal hypertension • 869
Ascites occurs as a result of renal sodium retention and portal
hypertension that may be due, for example, to post-hepatic
causes (hepatic outflow obstruction, p. 862) or cirrhosis.
The most important consequence of portal hypertension is
variceal bleeding, which commonly arises from oesophageal
varices located within 3-5 cm of the gastro-oesophageal junction,
or from gastric varices. The size of the varices, endoscopic
variceal features such as red spots and stripes, high portal
pressure and liver failure are all general factors that predispose
to bleeding. Drugs capable of causing mucosal erosion, such as
salicylates and NSAIDs, can also precipitate bleeding. Variceal
bleeding is often severe, and recurrent if preventative treatment is
not given.
Pathophysiology
Increased portal vascular resistance leads to a gradual reduction
in the flow of portal blood to the liver and simultaneously to the
development of collateral vessels, allowing portal blood to bypass
the liver and enter the systemic circulation directly. Portosystemic
shunting occurs, particularly in the gastrointestinal tract and
especially the distal oesophagus, stomach and rectum, in the
anterior abdominal wall, and in the renal, lumbar, ovarian and
testicular vasculature. Stomal varices can also occur at the site
of an ileostomy. As collateral vessel formation progresses, more
than half of the portal blood flow may be shunted directly to the
systemic circulation. Increased portal flow contributes to portal
hypertension but is not the dominant factor.
Investigations
The diagnosis is often made clinically. Portal venous pressure
measurements are rarely needed for clinical assessment
or routine management but can be used to confirm portal
hypertension and to differentiate sinusoidal and pre-sinusoidal
forms. Pressure measurements are made by using a balloon
catheter inserted using the transjugular route (via the inferior vena
cava into a hepatic vein and then hepatic venule) to measure the
WHVP. This is an indirect measurement of portal vein pressure.
Thrombocytopenia is common due to hypersplenism, and platelet
counts are usually in the region of 100x109/L; values below
50x1 09/L are uncommon. Leucopenia occurs occasionally but
anaemia is seldom attributed directly to hypersplenism; if anaemia
is found, a source of bleeding should be sought.
Endoscopy is the most useful investigation to determine
whether gastro-oesophageal varices are present (see Fig. 22.17).
Once the diagnosis of cirrhosis is made, endoscopy should be
performed to screen for oesophageal varices (and repeated
every 2 years). Ultrasonography often shows features of portal
hypertension, such as splenomegaly and collateral vessels, and
can sometimes indicate the cause, such as liver disease or portal
vein thrombosis. CT and magnetic resonance angiography can
identify the extent of portal vein clot and are used to identify
hepatic vein patency.
Management
Acute upper gastrointestinal haemorrhage from gastro-
oesophageal varices is a common manifestation of chronic
liver disease. In the presence of portal hypertension, the risk
of a variceal bleed occurring within 2 years varies from 7% for
small varices up to 30% for large varices. The mortality following
a variceal bleed has improved to around 15% overall but is still
about 45% in those with poor liver function (i.e. Child-Pugh C).
The management of portal hypertension is largely focused
on the prevention and/or control of variceal haemorrhage. It is
important to remember, though, that bleeding can also result
from peptic ulceration, which is more common in patients with
liver disease than in the general population. The investigation
and management of gastrointestinal bleeding are dealt with in
more detail on page 780.
Primary prevention of variceal bleeding
If non-bleeding varices are identified at endoscopy, (3-adrenoceptor
antagonist ((3-blocker) therapy with propranolol (80-1 60 mg/
day) or nadolol (40-240 mg/day) is effective in reducing portal
venous pressure. Administration of these drugs at doses that
reduce the heart rate by 25% has been shown to be effective
in the primary prevention of variceal bleeding. In patients with
cirrhosis, treatment with propranolol reduces variceal bleeding
by 47% (number needed to treat for benefit (NNTB) 10), death
from bleeding by 45% (NNTB 25) and overall mortality by 22%
(NNTb 16). The efficacy of (3-blockers in primary prevention
is similar to that of prophylactic banding, which may also be
considered, particularly in patients who are unable to tolerate or
adhere to (3-blocker therapy. Carvedilol, a non-cardioselective
vasodilating (3-blocker, is also effective and may be better tolerated
at doses of 6.25-12.5 mg/day). For these, dose should be
titrated, as tolerated, to achieve a heart rate of 50-55 beats/min,
if possible.
Management of acute variceal bleeding
The priority in acute bleeding is to restore the circulation with
blood and plasma, not least because shock reduces liver blood
flow and causes further deterioration of liver function. The source
of bleeding should always be confirmed by endoscopy because
about 20% of patients are bleeding from non-variceal lesions.
Management of acute variceal bleeding is described in Box
22.32 and illustrated in Figure 22.21. All patients with cirrhosis
and gastrointestinal bleeding should receive prophylactic broad-
spectrum antibiotics, such as oral ciprofloxacin or intravenous
cephalosporin or piperacillin/tazobactam, because sepsis is
common and treatment with antibiotics improves outcomes.
The measures used to control acute variceal bleeding include
vasoactive medications (e.g. terlipressin), endoscopic therapy
(banding or sclerotherapy), balloon tamponade, TIPSS and,
rarely, oesophageal transection.
22.32 Emergency management of bleeding
Management
Reason
Intravenous fluids
To replace extracellular volume
Vasopressor (terlipressin)*
To reduce portal pressure, acute
bleeding and risk of early rebleeding
Prophylactic antibiotics
(cephalosporin IV)
To reduce incidence of spontaneous
bacterial peritonitis
Emergency endoscopy
To confirm variceal rather than ulcer
bleed
Variceal band ligation
To stop bleeding
Proton pump inhibitor
To prevent peptic ulcers
Phosphate enema and/or
lactulose
To prevent hepatic encephalopathy
*Caution in patients with significant coronary artery, peripheral or other vascular
disease.
870 • HEPATOLOGY
Fig. 22.21 Management of acute bleeding from oesophageal
varices. (TIPSS = transjugular intrahepatic portosystemic stent shunt)
Pharmacological reduction of portal venous pressure Terlipressin is
a synthetic vasopressin analogue that, in contrast to vasopressin,
can be given by intermittent injection rather than continuous
infusion. It reduces portal blood flow and/or intrahepatic resistance
and hence brings down portal pressure. It lowers mortality in
the setting of acute variceal bleeding. The dose of terlipressin
is 2 mg IV 4 times daily until bleeding stops, and then 1 mg
4 times daily for up to 72 hours. Caution is needed in patients
with severe ischaemic heart disease or peripheral vascular
disease because of the drug’s vasoconstrictor properties. In
countries where terlipressin is not available, octreotide is a
frequently used alternative.
Variceal ligation (‘banding’) and sclerotherapy This is the most
widely used initial treatment and is undertaken, if possible, at
the time of diagnostic endoscopy (see Fig. 22.1 7C). It stops
variceal bleeding in 80% of patients and can be repeated if
bleeding recurs. Band ligation involves the varices being sucked
into a cap placed on the end of the endoscope, allowing
them to be occluded with a tight rubber band. The occluded
varix subsequently sloughs with variceal obliteration. Banding
is repeated every 2-4 weeks until all varices are obliterated.
Oesophageal
aspirate
Gastric aspirate
Gastric balloon
(clamped)
Gastric balloon
(inflated with 200-250 mL of air)
Fig. 22.22 Sengstaken-Blakemore tube.
Regular follow-up endoscopy is required to identify and treat any
recurrence of varices. Band ligation has fewer side-effects than
sclerotherapy, a technique in which varices are injected with a
sclerosing agent, and has largely replaced it. Banding is best
suited to the treatment of oesophageal varices. It is associated
with a lower risk of oesophageal perforation or stricturing than
sclerotherapy. Prophylactic acid suppression with proton pump
inhibitors reduces the risk of secondary bleeding from banding-
induced ulceration.
In the case of gastric fundal varices, banding is less effective
and so endoscopic therapy relies on injection of agents such as
thrombin or cyanoacrylate glue directly into the varix to induce
thrombosis. Although highly effective, cyanoacrylate injection
treatment may be complicated by ‘glue embolism’ to the lungs.
Active bleeding may make endoscopic therapy difficult.
Protection of the patient’s airway with endotracheal intubation
aids the endoscopist, facilitating therapy and significantly reducing
the risk of pulmonary aspiration.
Balloon tamponade This technique employs a Sengstaken-
Blakemore tube, which consists of two balloons that exert pressure
in the fundus of the stomach and in the lower oesophagus,
respectively (Fig. 22.22). Additional lumens allow contents to be
aspirated from the stomach and from the oesophagus above the
oesophageal balloon. This technique may be used in the event
of life-threatening haemorrhage if early endoscopic therapy is
not available or is unsuccessful.
Endotracheal intubation prior to tube insertion reduces
the risk of pulmonary aspiration. The tube should be passed
through the mouth and its presence in the stomach should be
checked by auscultating the upper abdomen while injecting
air and by confirming with radiology. The safest technique is
Infections and the liver • 871
to inflate the balloon in the stomach under direct endoscopic
vision. Gentle traction is essential to maintain pressure on the
varices. Initially, only the gastric balloon should be inflated, with
200-250 ml_ of air, as this will usually control bleeding. Inflation
of the gastric balloon must be stopped if the patient experiences
pain because inadvertent inflation in the oesophagus can cause
oesophageal rupture. If the oesophageal balloon needs to be used
because of continued bleeding, it should be deflated for about
1 0 minutes every 3 hours to avoid oesophageal mucosal damage.
Pressure in the oesophageal balloon should be monitored with a
sphygmomanometer and should not exceed 40 mmHg. Balloon
tamponade will almost always stop oesophageal and gastric
fundal variceal bleeding but is only a bridge to more definitive
therapy. Self-expanding removable oesophageal stents are a
new alternative in patients with bleeding oesophageal, but not
gastric, varices.
TIPSS This technique uses a stent placed between the portal vein
and the hepatic vein within the liver to provide a portosystemic
shunt and therefore reduce portal pressure (Fig. 22.23). It is carried
out under radiological control via the internal jugular vein; prior
patency of the portal vein must be determined angiographically,
coagulation deficiencies may require correction with fresh frozen
plasma, and antibiotic cover is provided. Successful shunt
placement stops and prevents further variceal bleeding, and is
an effective treatment for both oesophageal and gastric varices.
Further bleeding necessitates investigation and treatment (e.g.
angioplasty) because it is usually associated with shunt narrowing
or occlusion. Hepatic encephalopathy may occur following TIPSS
and is managed by reducing the shunt diameter. Although TIPSS
is associated with less rebleeding than endoscopic therapy,
survival is not improved.
Portosystemic shunt surgery Surgery prevents recurrent bleeding
but carries a high mortality and often leads to encephalopathy.
In practice, portosystemic shunts are now reserved for when
other treatments have not been successful and are offered only
to patients with good liver function.
Oesophageal transection Rarely, surgical transection of the varices
may be performed as a last resort when bleeding cannot be
controlled by other means but operative mortality is high.
Fig. 22.23 Transjugular intrahepatic portosystemic stent shunt
(TIPSS). X-ray showing placement of a TIPSS within the portal vein (PM),
allowing blood to flow from the portal vein into the hepatic vein (HV) and
then the inferior vena cava (IVC).
Secondary prevention of variceal bleeding
Beta-blockers are used as a secondary measure to prevent
recurrent variceal bleeding. Following successful endoscopic
therapy, patients should be entered into an oesophageal banding
programme with repeated sessions of therapy at 12-24-week
intervals until the varices are obliterated. In selected individuals,
TIPSS may also be considered in this setting.
| Congestive ‘portal hypertensive’ gastropathy
Long-standing portal hypertension causes chronic gastric
congestion, which is recognisable at endoscopy as multiple
areas of punctate erythema (‘portal hypertensive gastropathy’
or ‘snakeskin gastropathy’). Rarely, similar lesions occur more
distally in the gastrointestinal tract. These areas may become
eroded, causing bleeding from multiple sites. Acute bleeding
can occur but repeated minor bleeding causing iron deficiency
anaemia is more common. Anaemia may be prevented by oral
iron supplements but repeated blood transfusions can become
necessary. Reduction of the portal pressure using propranolol
(80-1 60 mg/day) is the best initial treatment. If this is ineffective,
a TIPSS procedure can be undertaken.
Infections and the liver
The liver may be subject to a number of different infections.
These include hepatotropic viral infections and bacterial and
protozoal infections. Each has specific clinical features and
requires targeted therapies.
Viral hepatitis
This must be considered in anyone presenting with hepatitic
liver blood tests (high transaminases). The causes are listed
in Box 22.33.
All these viruses cause illnesses that have similar clinical
and pathological features and are frequently anicteric or even
asymptomatic. They differ in their tendency to cause acute
and chronic infections. The features of the major hepatitis
viruses are shown in Box 22.34. Therapeutic developments
for viral hepatitis, in particular hepatitis C, are evolving very
rapidly, with several new classes of drugs entering clinical
practice.
Clinical features of acute infection
A non-specific prodromal illness characterised by headache,
myalgia, arthralgia, nausea and anorexia usually precedes the
development of jaundice by a few days to 2 weeks. Vomiting
and diarrhoea may follow and abdominal discomfort is common.
i
22.33 Causes of viral hepatitis
Common
• Hepatitis A
• Hepatitis C
• Hepatitis B ± hepatitis D
• Hepatitis E
Less common
• Cytomegalovirus
• Epstein— Barr virus
Rare
• Herpes simplex
• Yellow fever
872 • HEPATOLOGY
22.34 Features of the main hepatitis viruses
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis D
Hepatitis E
Virus
Group
Enterovirus
Hepadnavirus
Flavivirus
Incomplete virus
Calicivirus
Nucleic acid
RNA
DNA
RNA
RNA
RNA
Size (diameter)
27 nm
42 nm
30-38 nm
35 nm
27 nm
Incubation (weeks)
2-4
4-20
2-26
6-9
3-8
Spread
Faeces
Yes
No
No
No
Yes
Blood
Uncommon
Yes
Yes
Yes
No
Saliva
Yes
Yes
Yes
Unknown
Unknown
Sexual
Uncommon
Yes
Uncommon
Yes
Unknown
Vertical
No
Yes
Uncommon
Yes
No
Chronic infection
No
Yes
Yes
Yes
No (except immune-
compromised)
Prevention
Active
Vaccine
Vaccine
No
Prevented by hepatitis
B vaccination
No
Passive
Immune serum
Hyperimmune serum
No
No
globulin
globulin
*AII body fluids are potentially infectious, although some (e.g. urine) are less infectious than others.
22.35 Complications of acute viral hepatitis
• Acute liver failure
• Chronic liver disease and
• Cholestatic hepatitis
cirrhosis (hepatitis B and C)
(hepatitis A)
• Relapsing hepatitis
• Aplastic anaemia
Dark urine and pale stools may precede jaundice. There are
usually few physical signs. The liver is often tender but only
minimally enlarged. Occasionally, mild splenomegaly and cervical
lymphadenopathy are seen. These features are more frequent
in children or those with Epstein-Barr virus (EBV) infection.
Symptoms rarely last longer than 3-6 weeks. Complications
may occur but are rare (Box 22.35).
Investigations
A hepatitic pattern of LFTs develops, with serum transaminases
typically between 200 and 2000 U/L in an acute infection (usually
lower and fluctuating in chronic infections). The plasma bilirubin
reflects the degree of liver damage. The ALP rarely exceeds twice
the upper limit of normal. Prolongation of the PT indicates the
severity of the hepatitis but rarely exceeds 25 seconds, except
in rare cases of acute liver failure. The white cell count is usually
normal with a relative lymphocytosis. Serological tests confirm
the aetiology of the infection.
Management
Most individuals do not need hospital care. Drugs such as
sedatives and narcotics, which are metabolised in the liver,
should be avoided. No specific dietary modifications are required.
Alcohol should not be taken during the acute illness. Elective
surgery should be avoided in cases of acute viral hepatitis, as
there is a risk of post-operative liver failure.
Liver transplantation is very rarely indicated for acute viral
hepatitis complicated by liver failure, but is commonly performed
for complications of cirrhosis resulting from chronic hepatitis B
and C infection.
Hepatitis A
The hepatitis A virus (HA V) belongs to the picornavirus group
of enteroviruses. HAV is highly infectious and is spread by the
faecal-oral route. Infected individuals, who may be asymptomatic,
excrete the virus in faeces for about 2-3 weeks before the onset
of symptoms and then for a further 2 weeks or so. Infection is
common in children but often asymptomatic, and so up to 30%
of adults will have serological evidence of past infection but give
no history of jaundice. Infection is also more common in areas
of overcrowding and poor sanitation. In occasional outbreaks,
water and shellfish have been the vehicles of transmission. In
contrast to hepatitis B, a chronic carrier state does not occur.
Investigations
Only one HAV antigen has been found and infected people make
an antibody to this antigen (anti -HAV). Anti-HAV is important in
diagnosis, as HAV is present in the blood only transiently during
the incubation period. Excretion in the stools occurs for only
7-1 4 days after the onset of the clinical illness and the virus cannot
be grown readily. Anti-HAV of the IgM type, indicating a primary
immune response, is already present in the blood at the onset
of the clinical illness and is diagnostic of an acute HAV infection.
Titres of this antibody fall to low levels within about 3 months of
recovery. Anti-HAV of the IgG type is of no diagnostic value, as
HAV infection is common and this antibody persists for years
after infection, but it can be used as a marker of previous HAV
infection. Its presence indicates immunity to HAV.
Management
Infection in the community is best prevented by improving
social conditions, especially overcrowding and poor sanitation.
Individuals can be given substantial protection from infection by
active immunisation with an inactivated virus vaccine.
Immunisation should be considered for individuals with chronic
hepatitis B or C infections. Immediate protection can be provided
by immune serum globulin if this is given soon after exposure
to the virus. The protective effect of immune serum globulin
is attributed to its anti-HAV content. Immunisation should be
Infections and the liver • 873
considered for those at particular risk, such as close contacts
of HAV-infected patients, the elderly, those with other major
disease and perhaps pregnant women.
Immune serum globulin can be effective in an outbreak of
hepatitis, in a school or nursery, as injection of those at risk
prevents secondary spread to families. People travelling to
endemic areas are best protected by vaccination.
Acute liver failure is rare in hepatitis A (0.1%) and chronic
infection does not occur. Infection in patients with chronic liver
disease, however, may cause serious or life-threatening disease.
In adults, a cholestatic phase with elevated ALP levels may
complicate infection. There is no role for antiviral drugs in the
therapy of HAV infection.
Hepatitis B
The hepatitis B virus consists of a core containing DNA and a
DNA polymerase enzyme needed for virus replication. The core
of the virus is surrounded by surface protein (Fig. 22.24). The
virus, also called a Dane particle, and an excess of its surface
protein (known as hepatitis B surface antigen, HBsAg) circulate
in the blood. Humans are the only source of infection.
Hepatitis B is one of the most common causes of chronic liver
disease and hepatocellular carcinoma worldwide. Approximately
one-third of the world’s population have serological evidence
of past or current infection with hepatitis B and approximately
350-400 million people are chronic HBsAg carriers.
Hepatitis B may cause an acute viral hepatitis; however, acute
infection is often asymptomatic, particularly when acquired at birth.
Many individuals with chronic hepatitis B are also asymptomatic.
The risk of progression to chronic liver disease depends
on the source and timing of infection (Box 22.36). Vertical
transmission from mother to child in the perinatal period is
the most common cause of infection worldwide and carries
the highest risk of ongoing chronic infection. In this setting,
adaptive immune responses to HBV may be absent initially,
with apparent immunological tolerance. Several mechanisms
contribute towards this:
• Firstly, the introduction of antigen in the neonatal period is
tolerogenic.
• Secondly, the presentation of such antigen within the liver,
as described above, promotes tolerance; this is particularly
HBV-DNA
HBsAg polymerase
Fig. 22.24 Schematic diagram of the hepatitis B virus. Hepatitis B
surface antigen (HBsAg) is a protein that makes up part of the viral
envelope. Hepatitis B core antigen (HBcAg) is a protein that makes up the
capsid or core part of the virus (found in the liver but not in blood).
Hepatitis B e antigen (HBeAg) is part of the HBcAg that can be found in the
blood and indicates infectivity.
evident in the absence of a significant innate or
inflammatory response.
• Finally, very high loads of antigen may lead to so-called
‘exhaustion’ of cellular immune responses. The state of
tolerance is not permanent, however, and may be
reversed as a result of therapy, or through spontaneous
changes in innate responses, such as interferon alpha
(IFN-a) and NK cells, accompanied by host-mediated
immunopathology.
Chronic hepatitis can lead to cirrhosis or hepatocellular
carcinoma, usually after decades of infection (Fig. 22.25). Chronic
HBV infection is a dynamic process that can be divided into
five phases (Box 22.37); these are not necessarily sequential,
however, and not all patients will go through all phases. It is
important to remember that the virus is not directly cytotoxic to
cells; rather, it is an immune response to viral antigens displayed
on infected hepatocytes that initiates liver injury. This explains
why there may be very high levels of viral replication but little
hepatocellular damage during the ‘immune-tolerant’ phase.
Investigations
Serology
HBV contains several antigens to which infected persons can
make immune responses (Fig. 22.26); these antigens and their
antibodies are important in identifying HBV infection (Boxes 22.37
and 22.38), although the widespread availability of polymerase
chain reaction (PCR) techniques to measure viral DNA levels in
peripheral blood means that longitudinal monitoring is now also
frequently guided by direct assessment of viral load.
Hepatitis B surface antigen Hepatitis B surface antigen (HBsAg)
is an indicator of active infection, and a negative test for HBsAg
makes HBV infection very unlikely. In acute liver failure from
hepatitis B, the liver damage is mediated by viral clearance and
so HBsAg is negative, with evidence of recent infection provided
by the presence of hepatitis B core IgM. HBsAg appears in the
blood late in the incubation period but before the prodromal
phase of acute type B hepatitis; it may be present for a few
days only, disappearing even before jaundice has developed, but
usually lasts for 3-4 weeks and can persist for up to 5 months.
The persistence of HBsAg for longer than 6 months indicates
chronic infection. Antibody to HBsAg (anti-HBs) usually appears
after about 3-6 months and persists for many years or perhaps
permanently. Anti-HBs implies either a previous infection, in which
case anti-HBc (see below) is usually also present, or previous
vaccination, in which case anti-HBc is not present.
Hepatitis B core antigen Hepatitis B core antigen (HBcAg) is not
found in the blood, but antibody to it (anti-HBc) appears early
22.36 Source of hepatitis B infection and risk of
chronic infection
Horizontal transmission (10%)
• Injection drug use
• Infected unscreened blood products
• Tattoos/acupuncture needles
• Sexual transmission
• Close living quarters/playground play as a toddler (may contribute to
high rate of horizontal transmission in Africa)
Vertical transmission (90%)
• Hepatitis B surface antigen (HBsAg)-positive mother
874 • HEPATOLOGY
HBV-tolerant| HBV clearance! Latent phase
HBV mutant
Viral
load
infection
Liver Normal ► Chronic —►Minimal ►Chronic — ► Cirrhosis ^^Hepatocellular
histology hepatitis inflammation hepatitis carcinoma
Fig. 22.25 Natural history of chronic hepatitis B virus (HBV) infection. There is an initial immunotolerant phase with high levels of virus and normal
liver biochemistry. An immunological response to the virus then occurs, with elevation in serum transaminases, which causes liver damage: chronic
hepatitis. If this response is sustained over many years and viral clearance does not occur promptly, chronic hepatitis may result in cirrhosis. In individuals
with a successful immunological response, viral load falls, HBe antibody (HBeAg) develops and there is no further liver damage. Some individuals may
subsequently develop HBV-DNA mutants that escape from immune regulation, and viral load again rises with further chronic hepatitis. Mutations in the core
protein result in the virus’s inability to secrete HBe antigen despite high levels of viral replication; such individuals have HBeAg-negative chronic hepatitis.
(ALT = alanine aminotransferase; AST = aspartate aminotransferase)
22.37 The five phases of chronic hepatitis B virus (HBV) infection
Phase
HBsAg HBeAg
Anti-HBe Ab
Viral load
ALT
Histology
Notes
‘Immune-tolerant’
phase
+ +
+++
Normal/
low
Normal/minimal
necroinflammation
Prolonged in perinatally infected
individuals; may be short or absent
if infected as an adult. High viral
load and so very infectious
‘Immune-reactive’
HBeAg-positive
chronic hepatitis
phase
+ +
++
Raised
Moderate/severe
necroinflammation
May last weeks or years. High risk
of cirrhosis or HCC if prolonged.
Increased chance of spontaneous
loss of HBeAg with seroconversion
to anti-HBe antibody-positive state
‘Inactive carrier’
phase
+
+
-/+
Normal
Normal/minimal
necroinflammation
Low risk of cirrhosis or HCC in
majority
HBeAg-negative
chronic hepatitis
phase
+
+
Fluctuating
+/++
Raised/
fluctuating
Moderate/severe
necroinflammation
May represent late immune
reactivation or presence of ‘pre-core
mutant’ HBV. High risk of cirrhosis
or HCC
HBsAg-negative
phase
- -
+
-/+
Normal
Normal
Ultrasensitive techniques may detect
low-level HBV even after HBsAg loss
(HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HCC = hepatocellular carcinoma)
in the illness and rapidly reaches a high titre, which subsides
gradually but then persists. Anti-HBc is initially of IgM type, with
IgG antibody appearing later. Anti-HBc (IgM) can sometimes reveal
an acute HBV infection when the HBsAg has disappeared and
before anti-HBs has developed (see Fig. 22.26 and Box 22.38).
Hepatitis B e antigen Hepatitis B e antigen (HBeAg) is an
indicator of viral replication. In acute hepatitis B it may appear
only transiently at the outset of the illness; its appearance is
followed by the production of antibody (anti-HBe). The HBeAg
reflects active replication of the virus in the liver.
Infections and the liver • 875
Relative amount of product detectable
Fig. 22.26 Serological responses to hepatitis B virus infection.
(anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to
HBeAg; anti-HBs = antibody to HBsAg; HBeAg = hepatitis B e antigen;
HBsAg = hepatitis B surface antigen; IgM = immunoglobulin M)
IV
22.38 How to interpret the serological tests of
acute hepatitis B virus infection
Interpretation
HBsAg
Anti-HBc
IgM
Anti-HBc
IgG Anti-HBs
Incubation period
+
+
-
Acute hepatitis
Early
+
+
Established
+
+
+
Established
-
+
+
(occasional)
Convalescence
(3-6 months) - ± +
(6-9 months) - - +
±
+
Post-infection
±
Immunisation - -
without infection
+
+ = positive; - = negative; + = present at low titre or absent.
(anti-HBc IgM/IgG = antibody to hepatitis B core antigen of immunoglobulin M/G
type; anti-HBs = antibody to HBsAg; HBsAg = hepatitis B surface antigen)
Chronic HBV infection (see below) is marked by the presence
of HBsAg and anti-HBc (IgG) in the blood. Usually, HBeAg or
anti-HBe is also present; HBeAg indicates continued active
replication of the virus in the liver. The absence of HBeAg usually
implies low viral replication; the exception is HBeAg-negative
chronic hepatitis B (also called ‘pre-core mutant’ infection,
discussed below), in which high levels of viral replication, serum
HBV-DNA and hepatic necroinflammation are seen, despite
negative HBeAg.
Viral load and genotype
HBV-DNA can be measured by PCR in the blood. Viral loads are
usually in excess of 105 copies/mL in the presence of active viral
replication, as indicated by the presence of e antigen. In contrast,
in individuals with low viral replication, who are HBsAg- and
anti-HBe-positive, viral loads are less than 105 copies/mL. The
exception is in patients who have a mutation in the pre-core
protein, which means they cannot secrete e antigen into serum
(Fig. 22.27). Such individuals will be anti-HBe-positive but have
a high viral load and often evidence of chronic hepatitis. These
mutations are common in the Far East, and those patients
Fig. 22.27 The site of hepatitis B virus (HBV)-DNA mutations.
HBV-DNA encodes four proteins: a DNA polymerase needed for viral
replication (P), a surface protein (S), a core protein (C) and an X protein.
The pre-C and C regions encode a core protein and an e antigen. Although
mutations in the hepatitis B virus are frequent, certain mutations have
important clinical consequences. Pre-C encodes a signal sequence needed
for the C protein to be secreted from the liver cell into serum as e antigen.
A mutation in the pre-core region leads to a failure of secretion of e
antigen into serum, and so individuals have high levels of viral production
but no detectable e antigen in the serum. Mutations can also occur in the
surface protein and may lead to the failure of vaccination to prevent
infection, since surface antibodies are produced against the native S
protein. Mutations also occur in the DNA polymerase during antiviral
treatment with lamivudine.
affected are classified as having e antigen-negative chronic
hepatitis. They respond differently to antiviral drugs from those
with classical e antigen-positive chronic hepatitis.
Measurement of viral load is important in monitoring antiviral
therapy and identifying patients with pre-core mutants. Specific
HBV genotypes (A-H) can also be identified using PCR. In some
settings, these may be useful in guiding therapy, as genotype A
tends to respond better to pegylated interferon -alfa compared
to genotypes C and D.
Management of acute hepatitis B
Treatment is supportive with monitoring for acute liver failure,
which occurs in less than 1 % of cases. There is no definitive
evidence that antiviral therapy reduces the severity or duration
of acute hepatitis B.
Full recovery occurs in 90-95% of adults following acute HBV
infection. The remaining 5-10% develop a chronic hepatitis B
infection that usually continues for life, although later recovery
occasionally occurs. Infection passing from mother to child at birth
leads to chronic infection in the child in 90% of cases and recovery
is rare. Chronic infection is also common in immunodeficient
individuals, such as those with Down’s syndrome or human
immunodeficiency virus (HIV) infection. Fulminant liver failure due
to acute hepatitis B occurs in less than 1 % of cases.
Recovery from acute HBV infection occurs within 6 months
and is characterised by the appearance of antibody to viral
antigens. Persistence of HBeAg beyond this time indicates
chronic infection. Combined HBV and hepatitis delta virus (HDV)
infection causes more aggressive disease.
Management of chronic hepatitis B
Treatments are still limited, as no drug is consistently able
to eradicate hepatitis B infection completely (i.e. render the
876 • HEPATOLOGY
patient HBsAg-negative). The goals of treatment are HBeAg
seroconversion, reduction in HBV-DNA and normalisation of
the LFTs. The indication for treatment is a high viral load in the
presence of active hepatitis, as demonstrated by elevated serum
transaminases and/or histological evidence of inflammation and
fibrosis. The oral antiviral agents are more effective in reducing
viral loads in patients with e antigen-negative chronic hepatitis
B than in those with e antigen-positive chronic hepatitis B, as
the pre-treatment viral loads are lower.
Most patients with chronic hepatitis B are asymptomatic and
develop complications, such as cirrhosis and hepatocellular
carcinoma, only after many years (see Fig. 22.25). Cirrhosis
develops in 15-20% of patients with chronic HBV over 5-20 years.
This proportion is higher in those who are e antigen-positive.
Two different types of drug are used to treat hepatitis B:
direct-acting nucleoside/nucleotide analogues and pegylated
interferon-alfa.
Direct-acting nucleoside/nucleotide antiviral agents
Orally administered nucleoside/nucleotide antiviral agents are
the mainstay of therapy. These act by inhibiting the reverse
transcription of pre-genomic RNA to FIBV-DNA by FIBV-DNA
polymerase but do not directly affect the covalently closed
circular DNA (cccDNA) template for viral replication, and so
relapse is common if treatment is withdrawn. One major concern
is the selection of antiviral-resistant mutations with long-term
treatment. This is particularly important with some of the older
agents, such as lamivudine, as mutations induced by previous
antiviral exposure may also induce resistance to newer agents.
Entecavir and tenofovir (see below) are potent antivirals with a
high barrier to genetic resistance and so are the most appropriate
first- line agents.
Lamivudine Although effective, long-term therapy is often
complicated by the development of HBV-DNA polymerase
mutants (e.g. the ‘YMDD variant’), which lead to viral resistance.
These occur after approximately 9 months and are characterised
by a rise in viral load during treatment. Outside resource-limited
settings, this agent is now seldom used for the treatment of HBV
but may be used to prevent reactivation of HBV in previously
infected, HBsAg-negative patients if they are undergoing
chemotherapy.
Entecavir and tenofovir Monotherapy with entecavir or tenofovir
is substantially more effective than lamivudine in reducing viral
load in HBeAg -positive and HBeAg -negative chronic hepatitis.
Antiviral resistance mutations occur in only 1-2% after 3 years
of entecavir drug exposure. Both drugs have anti-HIV action and
so their use as monotherapy is contraindicated in HIV-positive
patients, as it may lead to HIV antiviral drug resistance. Current
European guidelines advise that the other nucleoside/nucleotide
antivirals should not be used as first-line monotherapy due to
the induction of viral mutations, unless more potent drugs with
a high barrier to resistance are not available or appropriate.
Interferon-alfa
This is most effective in patients with a low viral load and serum
transaminases greater than twice the upper limit of normal, in
whom it acts by augmenting a native immune response. In
HBeAg-positive chronic hepatitis, 33% lose e antigen after
4-6 months of treatment, compared to 12% of controls.
Response rates are lower in HBeAg -negative chronic hepatitis,
even when patients are given longer courses of treatment.
Interferon is contraindicated in the presence of cirrhosis, as it
may cause a rise in serum transaminases and precipitate liver
failure. Longer-acting pegylated interferons that can be given
once weekly have been evaluated in both HBeAg-positive and
HBeAg -negative chronic hepatitis. Side-effects are common and
include fatigue, depression, irritability, bone marrow suppression
and the triggering of autoimmune thyroid disease.
Liver transplantation
Historically, liver transplantation was contraindicated in hepatitis
B because infection often recurred in the graft. The use of post¬
liver transplant prophylaxis with direct-acting antiviral agents
and hepatitis B immunoglobulins has, however, reduced the
reinfection rate to 10% and increased 5-year survival to 80%,
making transplantation an acceptable treatment option.
Prevention
Individuals are most infectious when markers of continuing viral
replication, such as HBeAg, and high levels of HBV-DNA are
present in the blood. HBV-DNA can be found in saliva, urine,
semen and vaginal secretions (although urine is not usually
considered to be capable of transmitting infection). The virus is
about ten times more infectious than hepatitis C, which in turn
is about ten times more infectious than HIV.
A recombinant hepatitis B vaccine containing HBsAg is available
(Engerix) and is capable of producing active immunisation in
95% of normal individuals. The vaccine should be offered to
those at special risk of infection who are not already immune,
as evidenced by anti-HBs in the blood (Box 22.39). The vaccine
is ineffective in those already infected by HBV. Infection can
also be prevented or minimised by the intramuscular injection of
specific hepatitis B immunoglobulin (HBIg) prepared from blood
containing anti-HBs. This should be given within 48 hours, or at
most a week, of exposure to infected blood in circumstances
likely to cause infection (e.g. needlestick injury, contamination
of cuts or mucous membranes). Vaccine can be given together
with HBIg (active-passive immunisation).
Neonates born to hepatitis B-infected mothers should be
immunised at birth and given immunoglobulin. Hepatitis B serology
should then be checked at 1 2 months of age.
Co-infection with HIV
Around 10% of the HIV-infected population has concurrent HBV
and this figure may be as high as 25% in areas where both
viruses are prevalent. Up to half of injection drug users with HIV
are co-infected with HBV. Co-infection increases the morbidity
and mortality compared to either infection alone: there are greater
levels of HBV viraemia, faster progression to chronic infection
and greater risk of cirrhosis and hepatocellular carcinoma than
with HBV infection alone. The immunosuppression that is seen in
HIV infection can lead to loss of anti-HBs antibodies, reactivation
of infection and a poorer antibody response to HBV vaccination.
22.39 At-risk groups meriting hepatitis B vaccination
in low-endemic areas
• Parenteral drug users
• Men who have sex with men
• Close contacts of infected individuals:
Newborn of infected mothers
Regular sexual partners
• Patients on chronic haemodialysis
• Patients with chronic liver disease
• Medical, nursing and laboratory personnel
Infections and the liver • 877
Pregnancy poses particular problems in co-infected patients,
with increased risk of perinatal transmission of HBV to the child.
Treatment can also be problematic. Several nucleoside
analogues have dual antiviral activity and some regimens have
been associated with emergence of drug resistance. Co- infection
is also associated with diminished response to interferons and
increased resistance to lamivudine in some patients. Co-infection
should be managed by specialists with expertise in this area and
combinations of antiviral agents need to be thought through
carefully. Antiviral therapy should be considered for co-infected
pregnant women, using drugs with dual activity, e.g. tenofovir
with emtricitabine or lamivudine.
Globally, there is a need to identify co-infected patients earlier,
especially in endemic areas, as well as a need for early effective
interventions, particularly in pregnant women, to reduce perinatal
transmission.
Hepatitis D (Delta virus)
The hepatitis D virus (HDV) is an RNA-defective virus that has no
independent existence; it requires HBV for replication and has
the same sources and modes of spread. It can infect individuals
simultaneously with HBV or can superinfect those who are already
chronic carriers of HBV. Simultaneous infections give rise to
acute hepatitis, which is often severe but is limited by recovery
from the HBV infection. Infections in individuals who are chronic
carriers of HBV can cause acute hepatitis with spontaneous
recovery, and occasionally there is simultaneous cessation of
the chronic HBV infection. Chronic infection with HBV and HDV
can also occur, and this frequently causes rapidly progressive
chronic hepatitis and eventually cirrhosis.
HDV has a worldwide distribution. It is endemic in parts of
the Mediterranean basin, Africa and South America, where
transmission is mainly by close personal contact and occasionally
by vertical transmission from mothers who also carry HBV. In
non-endemic areas, transmission is mainly a consequence of
parenteral drug misuse.
Investigations
HDV contains a single antigen to which infected individuals make
an antibody (anti- HDV). Delta antigen appears in the blood only
transiently, and in practice diagnosis depends on detecting
anti-HDV. Simultaneous infection with HBV and HDV, followed
by full recovery, is associated with the appearance of low titres
of anti-HDV of IgM type within a few days of the onset of the
illness. This antibody generally disappears within 2 months but
persists in a few patients. Super-infection of patients with chronic
HBV infection leads to the production of high titres of anti-HDV,
initially IgM and later IgG. Such patients may then develop
chronic infection with both viruses, in which case anti-HDV titres
plateau at high levels.
Management
Effective management of hepatitis B prevents hepatitis D.
Hepatitis C
This is caused by an RNA flavivirus. Acute symptomatic infection
with hepatitis C is rare. Most individuals are unaware of when
they became infected and are identified only when they develop
chronic liver disease. Eighty per cent of individuals exposed to
the virus become chronically infected and late spontaneous
viral clearance is rare. There is no active or passive protection
against hepatitis C virus (HCV).
22.40 Risk factors for the acquisition of chronic
hepatitis C infection
• Intravenous drug misuse (95% of new cases in the UK)
• Unscreened blood products
• Vertical transmission (3% risk)
• Needlestick injury (3% risk)
• Iatrogenic parenteral transmission (e.g. contaminated vaccination
needles)
• Sharing toothbrushes/razors
Hepatitis C infection is usually identified in asymptomatic
individuals screened because they have risk factors for infection,
such as previous injecting drug use (Box 22.40), or have
incidentally been found to have abnormal liver blood tests.
Although most people remain asymptomatic until progression
to cirrhosis occurs, fatigue can complicate chronic infection
and is unrelated to the degree of liver damage. Hepatitis C is
the most common cause of what used to be known as ‘non-A,
non-B hepatitis’.
If hepatitis C infection is left untreated, progression from chronic
hepatitis to cirrhosis occurs over 20-40 years. Risk factors for
progression include male gender, immunosuppression (such as
co-infection with HIV), prothrombotic states and heavy alcohol
misuse. Not everyone with hepatitis C infection will necessarily
develop cirrhosis but approximately 20% do so within 20 years.
Once cirrhosis has developed, the 5- and 10-year survival rates
are 95% and 81%, respectively. One-quarter of people with
cirrhosis will develop complications within 10 years and, once
complications such as ascites develop, the 5-year survival is
around 50%. Once cirrhosis is present, 2-5% per year will
develop primary hepatocellular carcinoma.
Investigations
Serology and virology
The HCV genome encodes a large polypeptide precursor that
is modified post-translationally to at least ten proteins, including
several antigens that give rise to antibodies in an infected
person; these are used in diagnosis. It may take 6-12 weeks
for antibodies to appear in the blood following acute infection,
such as a needlestick injury. In these cases, hepatitis C RNA can
be identified in the blood as early as 2-4 weeks after infection.
Active infection is confirmed by the presence of serum hepatitis
C RNA in anyone who is antibody-positive. Anti-HCV antibodies
persist in serum even after viral clearance, whether spontaneous
or post-treatment.
Molecular analysis
There are six common viral genotypes, the distribution of which
varies worldwide. Genotype has no effect on progression of
liver disease but does affect response to treatment. Genotype
1 is most common in northern Europe and was less easy to
eradicate than genotypes 2 and 3 with traditional pegylated
interferon alf a-/ri bavi r i n - based treatments. Knowledge of viral
genotype still remains relevant in guiding selection of drugs to
treat HCV.
Liver function tests
LFTs may be normal or show fluctuating serum transaminases
between 50 and 200 U/L. Jaundice is rare and only usually
appears in end-stage cirrhosis.
878 • HEPATOLOGY
Liver histology
Serum transaminase levels in hepatitis C are a poor predictor of
the degree of liver fibrosis and so a liver biopsy may be required
to stage the extent of liver damage. The degree of inflammation
and fibrosis can be scored histologically. The most common way
of doing this in hepatitis C is the Metavir system, which scores
fibrosis from 1 to 4, the latter equating to cirrhosis. Recently,
non-invasive markers and fibrosis scoring systems have been
used routinely, with biopsy being reserved for cases where these
give conflicting results.
Management
The aim of treatment is to eradicate infection. In recent years,
there have been substantial advances, so much so that rates
of viral clearance achieved 6 months after finishing treatment
(termed sustained virological response, SVR) have risen from
less than 40% a decade ago to levels approaching 1 00% with
some of the newer direct-acting antivirals. The infection is cured
in more than 99% of patients who achieve an SVR. These newer
drugs are extremely expensive, however, and so their use is
placing substantial strain on the finite health-care resources of
developed countries and has severely limited their availability in
resource-poor settings.
Until 201 1 , the treatment of choice was dual therapy with
pegylated interferon-alfa, given as a weekly subcutaneous
injection, together with oral ribavirin, a synthetic nucleotide
analogue. Treatment was long - up to 12 months for genotype
1 infection, and both agents had significant side-effects that
limited tolerability: ribavirin induces haemolytic anaemia and is
teratogenic, while interferon induces influenza-like symptoms,
irritability and depression, all of which can affect quality of life. As
already mentioned, efficacy of these agents was poor (1 2 months’
treatment for genotype 1 resulted in only a 40% SVR, rising to an
SVR of over 70% for genotypes 2 or 3 after 6 months’ treatment).
22.41 Direct-acting antiviral agents for hepatitis C
Drug class
Therapeutic target
Selected drugs
Protease
Non-structural viral protein
Telaprevir
inhibitors (Pis)
NS3/4A (protease that
Boceprevir
cleaves the HCV polyprotein)
Simeprevir
Paritaprevir
Grazoprevir
Nucleoside
Non-structural viral protein
Sofosbuvir
polymerase
NS5B (RNA-dependent RNA
inhibitors (NPIs)
polymerase needed for viral
replication)
Non-nucleoside
Non-structural viral protein
Dasabuvir
polymerase
NS5B (RNA-dependent RNA
inhibitors (NNPIs)
polymerase needed for viral
replication)
NS5A replication
Non-structural viral protein
Daclatasvir
complex
NS5A (assembly of viral
Velpatasvir
inhibitors
replication complex)
Ledipasvir
Ombitasvir
Elbasvir
Host-targeting
Cyclophilin (pharmacological
Alisporivir
antiviral drugs
inhibitor targets host cell
(HTAs)
functions involved in the
HCV life cycle)
(HCV = hepatitis C virus)
Since 201 1 , new classes of direct-acting antiviral agents (DAAs)
have been developed. There are four main classes of DAA,
which are defined according to their mechanism of action and
therapeutic target (Box 22.41). These compounds are targeted
to specific steps in the hepatitis C viral life cycle to disrupt viral
replication (Fig. 22.28). Initially, DAAs were added to interferon-/
ribavirin -based regimens; more recently, however, combinations
of DAAs have increasingly been used in ‘interferon-free’ regimens.
This maximises treatment efficacy by directly interfering with
replication at multiple points in the viral life cycle without exposing
patients to the side-effect profile of interferon-alfa therapy.
For example, 1 2 weeks of treatment with oral sofosbuvir plus
ledipasvir plus ribavirin can achieve a 99% SVR in treatment-naive
genotype 1 patients. Sofosbuvir plus velpatasvir achieves similar
results and is pan-genotypic. Although not without side-effects,
DAAs are often orally administered, efficacious and, in general,
well tolerated.
Liver transplantation should be considered when complications
of cirrhosis occur, such as diuretic-resistant ascites. Unfortunately,
if the virus is not cleared, hepatitis C will infect the transplanted
liver and up to 1 5% of patients then develop cirrhosis in the liver
graft within 5 years of transplantation. This should no longer
happen, as modern antiviral therapy post-transplant achieves
excellent results.
Hepatitis E
Hepatitis E is caused by an RNA virus that is endemic in India
and the Middle East. Prevalence is now increasing across Asia
and Europe, especially south-west France, so it is important to
note that infection is no longer seen only in travellers from an
endemic area.
The clinical presentation and management of hepatitis E
are similar to those of hepatitis A. Disease is spread via the
faecal-oral route or through contaminated food; the virus is
commonly present in uncooked game and pig-liver sausage
in southern France, and this may be a route of infection. In
most cases, it presents as a self-limiting acute hepatitis and
does not usually cause chronic liver disease. There is increasing
recognition that hepatitis E may develop into chronic infection,
usually in immunocompromised patients and especially in
organ-transplant recipients, although this remains uncommon. If
treatment is required for chronic infection, agents such as ribavirin
may be used. Blood donations are now routinely screened for
hepatitis E.
Hepatitis E differs from hepatitis A in that infection during
pregnancy is associated with the development of acute liver failure,
which has a high mortality. In acute infection, IgM antibodies to
hepatitis E virus (HEV) are positive.
Other forms of viral hepatitis
Non-A, non-B, non-C (NANBNC) or non-A-E hepatitis is the
term used to describe hepatitis thought to be due to a virus
that is not HAV, HBV, HCV or HEV. Other viruses that affect
the liver probably exist but the viruses described above now
account for the majority of hepatitis infections. Cytomegalovirus
and EBV infection causes abnormal LFTs in most patients and
occasionally jaundice occurs. Herpes simplex is a rare cause
of hepatitis in adults, most of whom are immunocompromised.
Herpes simplex virus hepatitis can be very severe in pregnancy.
Abnormal LFTs are also common in chickenpox, measles, rubella
and acute HIV infection.
Infections and the liver • 879
1 Receptor
binding andl
endocytosis
2 Hepatocyte
entry
7 Lipoviral particle assembly
NS5A
inhibitors
3 Fusion and
aRNA coating
Endoplasmic
reticulum
4 Translation of
$ RNA into protein
6 RNA replication
by encoded
polymerase
NS5B
polymerase
inhibitors
po
/
5 Polyprotein cleaved
into functional
proteins by protease
NS3/4A
protease
inhibitors
HCV-RNA
■Region encoding polyprotein precursor-
Fig. 22.28 Direct-acting antiviral agents. These compounds are targeted to specific steps in the hepatitis C viral life cycle to disrupt replication.
(5'NTR = 5' non-translated region; HCV = hepatitis C virus; IFN = interferon)
i
22.42 Causes of abnormal liver blood tests
in HIV infection
Hepatitic blood tests
• Chronic hepatitis C
• Antiretroviral drugs
• Chronic hepatitis B
Cholestatic blood tests
• Cytomegalovirus
• Tuberculosis
• Sclerosing cholangitis due to
• Atypical mycobacterium
Cryptosporidia
HIV infection and the liver
Several causes of abnormal LFTs occur in HIV infection, as
shown in Box 22.42. This topic is discussed in more detail
on page 317. Co-infection with HIV and HBV is discussed on
page 876.
Liver abscess
Liver abscesses are classified as pyogenic, hydatid or amoebic.
Pyogenic liver abscess
Pyogenic liver abscesses are uncommon but important because
they are potentially curable, carry significant morbidity and
mortality if untreated, and are easily overlooked. The mortality
of liver abscesses is 20-40%; failure to make the diagnosis is
the most common cause of death. Older patients and those
with multiple abscesses have a higher mortality.
Pathophysiology
Infection can reach the liver in several ways (Box 22.43). Pyogenic
abscesses are most common in older patients and usually result
from ascending infection due to biliary obstruction (cholangitis) or
contiguous spread from an empyema of the gallbladder. They can
also complicate dental sepsis or colonic pathology, e.g. cancer,
I diverticulitis or inflammatory bowel disease causing portal pyaemia.
880 • HEPATOLOGY
22.43 Causes of pyogenic liver abscesses
• Biliary obstruction (cholangitis)
• Direct extension
• Haematogenous:
• Trauma:
Portal vein (intra-abdominal
Penetrating or
infections)
non-penetrating
Hepatic artery (bacteraemia)
• Infection of liver tumour or cyst
Abscesses complicating suppurative appendicitis used to be
common in young adults but are now rare. Immunocompromised
patients are particularly likely to develop liver abscesses. Single
lesions are more common in the right liver; multiple abscesses
are usually due to infection secondary to biliary obstruction.
Escherichia coli and various streptococci, particularly Strep,
milleri, are the most common organisms; anaerobes, including
streptococci and Bacteroides, can often be found when infection
has been transmitted from large bowel pathology via the portal
vein, and multiple organisms are present in one-third of patients.
Clinical features
Patients are generally ill with fever and sometimes rigors and
weight loss. Abdominal pain is the most common symptom
and is usually in the right upper quadrant, sometimes with
radiation to the right shoulder. The pain may be pleuritic in
nature. Tender hepatomegaly is found in more than 50% of
patients. Mild jaundice may be present, becoming severe if large
abscesses cause biliary obstruction. Atypical presentations are
common and explain the frequency with which the diagnosis is
made only at autopsy. This is a particular problem in patients
with gradually developing illnesses or pyrexia of unknown origin
without localising features. Necrotic colorectal metastases can
be misdiagnosed as hepatic abscess.
Investigations
Liver imaging is the most revealing investigation and shows 90%
or more of symptomatic abscesses. Needle aspiration under
ultrasound guidance confirms the diagnosis and provides pus for
culture. A leucocytosis is frequently found, plasma ALP activity
is usually increased, and the serum albumin is often low. The
chest X-ray may show a raised right diaphragm and lung collapse,
or an effusion at the base of the right lung. Blood cultures are
positive in 50-80%. Abscesses caused by gut-derived organisms
require active exclusion of significant colonic pathology, such as
a colonoscopy to exclude colorectal carcinoma.
Management
Pending the results of culture of blood and pus from the abscess,
treatment should be commenced with a combination of antibiotics,
such as ampicillin, gentamicin and metronidazole. Aspiration or
drainage with a catheter placed in the abscess under ultrasound
guidance is required if the abscess is large or if it does not
respond to antibiotics. Any associated biliary obstruction and
cholangitis require biliary drainage (preferably endoscopically).
Surgical abscess drainage is rarely undertaken, although hepatic
resection may be indicated for a chronic persistent abscess or
‘pseudotumour’.
Hydatid cysts and amoebic liver abscesses
These are described on pages 299 and 287.
Leptospirosis
This is described on page 257.
Alcoholic liver disease
Alcohol is one of the most common causes of chronic liver
disease worldwide, with consumption continuing to increase in
many countries. Patients with alcoholic liver disease (ALD) may
also have risk factors for other liver diseases (e.g. coexisting
NAFLD or chronic viral hepatitis infection), and these may interact
to increase disease severity.
In the UK, a unit of alcohol contains 8 g of ethanol (Box
22.44). An upper threshold of 14 units/week in women and
21 units/week in men is generally considered safe. Recently,
however, Public Health England advice has adopted a more
conservative threshold of 14 units/week for both men and women.
The risk threshold for developing ALD is variable but begins at
30 g/day of ethanol. There is no clear linear relationship between
dose and liver damage, however. For many, consumption of
more than 80 g/day, for more than 5 years, is required to confer
significant risk of advanced liver disease. The average alcohol
consumption of a man with cirrhosis is 160 g/day for over
8 years. Some of the risk factors for ALD are:
• Drinking pattern. ALD and alcohol dependence are not
synonymous; many of those who develop ALD are not
alcohol-dependent and most dependent drinkers have
normal liver function. Liver damage is more likely to occur
in continuous rather than intermittent or ‘binge’ drinkers,
as this pattern gives the liver a chance to recover. It is
therefore recommended that people should have at least
two alcohol-free days each week. The type of beverage
does not affect risk.
• Gender. The incidence of ALD is increasing in women,
who have higher blood ethanol levels than men after
consuming the same amount of alcohol. This may be
related to the reduced volume of distribution of alcohol.
• Genetics. Alcoholism is more concordant in monozygotic
than dizygotic twins. While polymorphisms in the genes
involved in alcohol metabolism, such as aldehyde
dehydrogenase, may alter drinking behaviour, they have
not been linked to ALD. The patatin-like phospholipase
domain-containing 3 (PNPLA3) gene, also known as
adiponutrin, has been implicated in the pathogenesis of
both ALD and NAFLD (p. 883).
• Nutrition. Obesity increases the incidence of liver-related
mortality by over fivefold in heavy drinkers. Ethanol itself
produces 7 kcal/g (29.3 kJ/g) and many alcoholic drinks
also contain sugar, which further increases the calorific
22.44 Amount of alcohol in an average drink
Alcohol type
% Alcohol
by volume
Amount
Units
Beer
3.5
568 mL (1 pint)
2
9
568 mL (1 pint)
4
Wine
10
125 mL
1
12
750 mL
9
‘Alcopops’
6
330 mL
2
Sherry
17.5
750 mL
13
Vodka/rum/gin
37.5
25 mL
1
Whisky/brandy
40
700 mL
28
*1 unit = 8 g.
Alcoholic liver disease • 881
r
Gut permeability
I
Endotoxin
1
Kupffer
cells
Tumour necrosis
factor alpha
lnterleukin-6
Inflammation
Acetaldehyde CYP2E1
I
Adducts
I
T Oxidative stress
• Lipid peroxidation
• Low glutathione
Immune
system
Alcoholic
Coexistent
disorders,
e.g. viral hepatitis
haemochromatosis
Genetic
J susceptibility
Fig. 22.29 Factors involved in the pathogenesis of alcoholic liver
disease.
value and may contribute to weight gain. Excess alcohol
consumption is frequently associated with nutritional
deficiencies that contribute to morbidity.
Pathophysiology
Alcohol reaches peak blood concentrations after about
20 minutes, although this may be influenced by stomach contents.
It is metabolised almost exclusively by the liver via one of two
pathways (Fig. 22.29).
Approximately 80% of alcohol is metabolised to acetaldehyde by
the mitochondrial enzyme, alcohol dehydrogenase. Acetaldehyde
is then metabolised to acetyl-CoA and acetate by aldehyde
dehydrogenase. This generates NADH from NAD (nicotinamide
adenine dinucleotide), which changes the redox potential of
the cell. Acetaldehyde forms adducts with cellular proteins in
hepatocytes that activate the immune system, contributing to
cell injury.
The remaining 20% of alcohol is metabolised by the microsomal
ethanol-oxidising system (MEOS) pathway. Cytochrome CYP2E1
is an enzyme that oxidises ethanol to acetate. It is induced by
alcohol, and during metabolism of ethanol it releases oxygen free
radicals, leading to lipid peroxidation and mitochondrial damage.
The CYP2E1 enzyme also metabolises acetaminophen, and
hence chronic alcoholics are more susceptible to hepatotoxicity
from low doses of paracetamol.
It is thought that pro-inflammatory cytokines may also be
involved in inducing hepatic damage in alcoholic hepatitis, since
endotoxin is released into the blood because of increased gut
permeability, leading to release of tumour necrosis factor alpha
(TNF-a) and interleukin 1 (IL-1), IL-2 and IL-8 from immune cells.
All of these cytokines have been implicated in the pathogenesis
of liver fibrosis (see Fig. 22.4, p. 849).
22.45 Pathological features of alcoholic liver disease
• Alcoholic hepatitis:
• Macrovesicular steatosis
Lipogranuloma
• Fibrosis and cirrhosis
Neutrophil infiltration
• Central hyaline sclerosis
Mallory’s hyaline
Pericellular fibrosis
22.46 Clinical syndromes of alcoholic liver disease
Fatty liver
• Asymptomatic abnormal liver
• Normal/large liver
biochemistry
Alcoholic hepatitis
• Jaundice
• Features of portal hypertension
• Malnutrition
(e.g. ascites, encephalopathy)
• Hepatomegaly
Cirrhosis
• Stigmata of chronic liver
• Large, normal or small
disease
liver
• Ascites/varices/
• Hepatocellular carcinoma
encephalopathy
The pathological features of ALD are shown in Box 22.45. In
about 80% of patients with severe alcoholic hepatitis, cirrhosis
will coexist at presentation. Iron deposition is common and does
not necessarily indicate haemochromatosis. Figure 22.30A below
shows the histological features of alcoholic liver disease, which
are identical to those of non-alcoholic steatohepatitis.
Clinical features
ALD has a wide clinical spectrum, ranging from mild abnormalities
of LFTs on biochemical testing to advanced cirrhosis. The liver
is often enlarged in ALD, even in the presence of cirrhosis.
Stigmata of chronic liver disease, such as palmar erythema,
are more common in alcoholic cirrhosis than in cirrhosis of
other aetiologies. Alcohol misuse may also cause damage of
other organs and this should be specifically looked for (see
Box 28.22, p. 1194). Three types of ALD are recognised (Box
22.46) but these overlap considerably, as do the pathological
changes seen in the liver.
Alcoholic fatty liver disease
Alcoholic fatty liver disease (AFLD) usually presents with elevated
transaminases in the absence of hepatomegaly. It has a good
prognosis and steatosis usually disappears after 3 months of
abstinence.
Alcoholic hepatitis
This presents with jaundice and hepatomegaly; complications
of portal hypertension may also be present. It has a significantly
worse prognosis than AFLD. About one-third of patients die in the
acute episode, particularly those with hepatic encephalopathy or
a prolonged PT. Cirrhosis often coexists; if not present, it is the
likely outcome if drinking continues. Patients with acute alcoholic
hepatitis often deteriorate during the first 1-3 weeks in hospital.
Even if they abstain, it may take up to 6 months for jaundice to
resolve. In patients presenting with jaundice who subsequently
abstain, the 3- and 5-year survival is 70%. In contrast, those
who continue to drink have 3- and 5-year survival rates of 60%
and 34%, respectively.
882 • HEPATOLOGY
Alcoholic cirrhosis
Alcoholic cirrhosis often presents with a serious complication,
such as variceal haemorrhage or ascites, and only half of such
patients will survive for 5 years from presentation. However,
most who survive the initial illness and who become abstinent
will survive beyond 5 years.
Investigations
Investigations aim to establish alcohol misuse, exclude alternative
or additional coexistent causes of liver disease, and assess the
severity of liver damage. The clinical history from patient, relatives
and friends is important to establish alcohol misuse duration
and severity. Biological markers, particularly macrocytosis in
the absence of anaemia, may suggest and support a history of
alcohol misuse. A raised GGT is not specific for alcohol misuse
and may also be elevated in the presence of other conditions,
including NAFLD. The level may therefore not return to normal
with abstinence if chronic liver disease is present, and GGT
should not be relied on as an indicator of ongoing alcohol
consumption. The presence of jaundice may suggest alcoholic
hepatitis. Determining the extent of liver damage often requires
a liver biopsy.
In alcoholic hepatitis, PT and bilirubin are used to calculate a
‘discriminant function’ (DF), also known as the Maddrey score,
which enables the clinician to assess prognosis (PT = prothrombin
time; serum bilirubin in jimol/L is divided by 17 to convert
to mg/dL):
DF = [4.6 x Increase in PT (sec)] + Bilirubin (mg/dL)
A value over 32 implies severe liver disease with a poor
prognosis and is used to guide treatment decisions (see below). A
second scoring system, the Glasgow score, uses the age, white
cell count and renal function, in addition to PT and bilirubin, to
assess prognosis and has a cut-off of 9 (Box 22.47).
Management
Cessation of alcohol consumption is the single most important
treatment and prognostic factor. Life-long abstinence is the
best advice. General health and life expectancy are improved
when this occurs, irrespective of the stage of liver disease.
Abstinence is even effective at preventing progression, hepatic
decompensation and death once cirrhosis is present. Treatment
of alcohol dependency is discussed on page 1195. In the acute
presentation of ALD it is important to identify and anticipate
alcohol withdrawal and Wernicke’s encephalopathy, which need
22.47 How to assess prognosis using the Glasgow
alcoholic hepatitis score
Score
1
2
3
Age
<50
>50
White cell count
(x 1 09/L)
<15
>15
Urea (mmol/L
(BUNmg/dl))
<5 (14)
>5 (14)
PT ratio
<1.5
1. 5-2.0
>2.0
Bilirubin (|imol/L
(mg/dL))
<125 (7.4)
125-250
(7.4-14.8)
>250 (14.8)
A score of >9 is associated with a 40% 28-day survival, compared to
80% for patients with a score of <9.
(BUN = blood urea nitrogen; PT = prothrombin time)
treating in parallel with the liver disease and any complications
of cirrhosis.
Nutrition
Good nutrition is very important, and enteral feeding via a fine-bore
nasogastric tube may be needed in severely ill patients.
Drug therapy
The optimum treatment of severe alcoholic hepatitis (Maddrey’s
discriminative score >32) has been debated for some time. The
STOPAH study was a large, multicentre, double-blind, randomised
trial to evaluate the relative merits of glucocorticoids and/or a
weak anti-TNF agent (pentoxifylline), alone or in combination. In a
cohort of 1 1 03 patients, no significant benefit from pentoxifylline
treatment was identified but treatment with prednisolone (40 mg
daily for 28 days) led to a modest reduction in short-term mortality,
from 17% in placebo-treated patients to 14% in the prednisolone
group. These findings were consistent with earlier studies where
an improvement in 28-day survival from 52% to 78% is seen
when glucocorticoids are given to those with a Glasgow score of
more than 9. Neither glucocorticoids nor pentoxifylline improved
survival at 90 days or 1 year, however. Sepsis is the main
side-effect of glucocorticoids, and existing sepsis and variceal
haemorrhage are the main contraindications to their use. If the
bilirubin has not fallen 7 days after starting glucocorticoids, the
drugs are unlikely to reduce mortality and should be stopped.
Liver transplantation
The role of liver transplantation in the management of ALD remains
controversial. In many centres, ALD is a common indication for
liver transplantation. The challenge is to identify patients with an
unacceptable risk of returning to harmful alcohol consumption.
Many programmes require a 6-month period of abstinence
from alcohol before a patient is considered for transplantation.
Although this relates poorly to the incidence of alcohol relapse
after transplantation, liver function may improve to the extent
that transplantation is no longer necessary. The outcome of
transplantation for ALD is good and if the patient remains abstinent
there is no risk of disease recurrence. Transplantation for alcoholic
hepatitis has been thought to have a poorer outcome and is
seldom performed due to concerns about recidivism; studies
to quantify this are ongoing.
Non-alcoholic fatty liver disease
Increasingly sedentary lifestyles and changing dietary patterns
mean that the prevalence of obesity and insulin resistance
has increased worldwide, and so fat accumulation in the liver
is a common finding during abdominal imaging studies and
on liver biopsy. In the absence of high alcohol consumption
(typically, a threshold of <20 g/day for women and <30 g/day
for men is adopted), this is called non-alcoholic fatty liver disease
(NAFLD).
NAFLD includes a spectrum of progressive liver disease
ranging from fatty infiltration alone (steatosis) to fatty infiltration
with inflammation (non-alcoholic steatohepatitis, NASH) and
may progress to cirrhosis and primary liver cancer (Fig. 22.30B).
NAFLD is considered by many to be the hepatic manifestation
of the ‘metabolic syndrome’ (p. 730), as it is strongly associated
with obesity, dyslipidaemia, type 2 diabetes and hypertension.
Estimates vary between populations, although one large European
study found NAFLD to be present in 94% of obese patients
Non-alcoholic fatty liver disease • 883
E
Steatosis >— C NASH J— Cirrhosis
T
TFA influx
iFA oxidation
TFA synthesis
iVLDL assembly
Insulin resistance
TNF-a
Oxidant stress
Endotoxin
Immune factors
TGF-(3
Stellate cell activation
Steatosis +
Fat infiltration > 5% necroinflammation
with or without (ballooning, Mallory
mild inflammation bodies,
megamitochondria)
Increasing fibrosis,
eventually leading
to cirrhosis
Fig. 22.30 Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). [A] Features. Rate of progression is determined by
environmental (dietary) and genetic factors. [§] The spectrum of NAFLD. (FA = fatty acid; TGF-p = transforming growth factor beta; TNF-a = tumour
necrosis factor alpha; VLDL = very low-density lipoprotein)
(body mass index (BMI) >30 kg/m2), 67% of overweight patients
(BMI >25 kg/m2) and 25% of normal-weight patients. The overall
prevalence of NAFLD in patients with type 2 diabetes ranges
from 40% to 70%. Histological NASH has been found in 3-16%
of apparently healthy potential living liver donors in Europe and
6-15% in the USA.
Overall, NAFLD is estimated to affect 20-30% of the general
population in Western countries and 5-18% in Asia, with about 1
in 10 NAFLD cases exhibiting NASH. The frequency of steatosis
varies with ethnicity (45% in Hispanics, 33% in whites and 24% in
blacks) and gender (42% white males versus 24% white females)
but only a minority of patients will progress to cirrhosis and
end-stage liver disease. However, because obesity is common
and the prevalence of NAFLD is rising, this still represents
a large number of patients, placing a substantial burden on
health-care resources. Over a median 12-year follow-up period
in a cohort of 619 NAFLD patients, an overall 33.2% risk of
death or liver transplantation was observed, with liver-related
mortality being the third most common cause of death after
cardiovascular disease and extra-hepatic malignancy. NAFLD is
the leading cause of liver dysfunction in the non-alcoholic, viral
hepatitis-negative population in Europe and North America, and
is predicted to become the main aetiology in patients undergoing
liver transplantation during the next 5 years.
Pathophysiology
The initiating events in NAFLD are based on the development
of obesity and insulin resistance, leading to increased hepatic
free fatty acid flux. This imbalance between the rate of import/
synthesis and the rate of export/catabolism of fatty acids in
the liver leads to the development of steatosis. This may be an
adaptive response through which hepatocytes store potentially
toxic lipids as relatively inert triglyceride. A ‘two-hit’ hypothesis
has been proposed to describe the pathogenesis of NAFLD,
the ‘first hit’ causing steatosis that then progresses to NASH if
a ‘second hit’ occurs. In reality, progression probably follows
hepatocellular injury caused by a combination of several different
‘hits’, including:
• oxidative stress due to free radicals produced during fatty
acid oxidation
• direct lipotoxicity from fatty acids and other metabolites in
the liver
• endoplasmic reticulum stress
• gut-derived endotoxin
• cytokine release (TNF-a etc.) and immune-mediated
hepatocellular injury.
Cellular damage triggers cell death and inflammation, which
leads to stellate cell activation and development of hepatic fibrosis
that culminates in cirrhosis (Fig. 22.30A). As with many other liver
diseases, subtle inter-patient genetic variations and environmental
factors interact to determine disease progression. Several genetic
modifiers of disease severity have been identified, with PNPLA3
and its product, adiponutrin, being the best validated.
This should not be confused with acute fatty liver, which
can occur in hepatic mitochondrial cytopathies, e.g. acute
fatty liver of pregnancy (p. 1283), or in other situations, e.g.
Reye’s syndrome (p. 241) or drug toxicity (sodium valproate,
tetracyclines), or with bacterial toxins (e.g. Bacillus cereus). In
these, defective mitochondrial beta-oxidation of lipids leads to fat
droplet accumulation in hepatocytes and microvesicular steatosis.
884 • HEPATOLOGY
Clinical features
NAFLD is frequently asymptomatic, although it may be associated
with fatigue and mild right upper quadrant discomfort. It is
commonly identified as an incidental biochemical abnormality
during routine blood tests or as a fatty liver during an ultrasound or
CT scan of the abdomen. Alternatively, patients with progressive
NASH may present late in the natural history of the disease with
complications of cirrhosis and portal hypertension, such as variceal
haemorrhage, or with hepatocellular carcinoma.
The average age of NASH patients is 40-50 years (50-60 years
for NASH-cirrhosis); however, the emerging epidemic of childhood
obesity means that NASH is present in increasing numbers
of younger patients. Recognised independent risk factors for
disease progression are age over 45 years, presence of diabetes
(or severity of insulin resistance), obesity (BMI >30 kg/m2) and
hypertension. These factors help with identification of ‘high-risk’
patient groups. NAFLD is also associated with polycystic ovary
syndrome, obstructive sleep apnoea and small-bowel bacterial
overgrowth.
Investigations
Investigation of patients with suspected NAFLD should be
directed first towards exclusion of excess alcohol consumption
and other liver diseases (including viral, autoimmune and other
metabolic causes) and then at confirming the presence of NAFLD,
discriminating simple steatosis from NASH and determining the
extent of any hepatic fibrosis that is present.
Biochemical tests
There is no single diagnostic blood test for NAFLD. Elevations
of serum ALT and AST are modest, and usually less than twice
the upper limit of normal. ALT levels fall as hepatic fibrosis
increases and the characteristic AST :ALT ratio of <1 seen in
NASH reverses (AST :ALT >1) as disease progresses towards
cirrhosis, meaning that steatohepatitis with advanced disease
may be present even in those with normal-range ALT levels.
Other laboratory abnormalities that may be present include
non-specific elevations of GGT, low-titre antinuclear antibody
(ANA) in 20-30% of patients and elevated ferritin levels.
Although routine blood tests are unable to determine the degree
of liver fibrosis/cirrhosis accurately, calculated scores, such as
the NAFLD Fibrosis Score and FIB-4 Score, which are based on
the results of routinely available blood tests and anthropometries,
have a high negative predictive value for advanced fibrosis/
cirrhosis (Box 22.48) and so can be used to rule out advanced
fibrosis in many NAFLD patients. This allows care to focus on
those most likely to have advanced disease.
Imaging
Ultrasound is most often used and provides a qualitative
assessment of hepatic fat content, as the liver appears ‘bright’
due to increased echogenicity; sensitivity is limited when fewer
than 33% of hepatocytes are steatotic, however. CT, MRI or
MR spectroscopy offer greater sensitivity for detecting lesser
degrees of steatosis, but these are resource-intensive and not
widely used. No routine imaging modality can distinguish simple
steatosis from steatohepatitis or accurately quantify hepatic
fibrosis short of cirrhosis.
Liver biopsy
Liver biopsy remains the ‘gold standard’ investigation for diagnosis
and assessment of degree of inflammation and extent of liver
fibrosis. The histological definition of NASH is based on a
combination of three lesions (steatosis, hepatocellular injury
and inflammation; see Fig. 22.30A) with a mainly centrilobular,
acinar zone 3 distribution. Specific features include hepatocyte
ballooning degeneration with or without acidophil bodies or
spotty necrosis and a mild, mixed inflammatory infiltrate. These
may be accompanied by Mallory-Denk bodies (also known
as Mallory’s hyaline). Perisinusoidal fibrosis is a characteristic
feature of NASH. Histological scoring systems are widely used
to assess disease severity semi-quantitatively.
It is important to note that hepatic fat content tends to diminish
as cirrhosis develops and so NASH is likely to be under-diagnosed
in the setting of advanced liver disease, where it is thought to be
the underlying cause of 30-75% of cases in which no specific
aetiology is readily identified (so-called ‘cryptogenic cirrhosis’).
Management
As it is a marker of the metabolic syndrome, identification of NAFLD
should prompt screening for and treatment of cardiovascular risk
factors in all patients. It is also necessary to assess whether
patients have progressive disease and advanced fibrosis so that
liver-targeted treatment can be focused particularly on those
patients. While liver biopsy is best able to do this, it is invasive
and unsuitable for widespread use outside the specialist care
setting. An example of an algorithm for the assessment and risk
stratification of patients with NAFLD is provided in Figure 22.31 .
Non-pharmacological treatment
Current treatment comprises lifestyle interventions to promote
weight loss and improve insulin sensitivity through dietary changes
22.48 Simple non-invasive scores for non-alcoholic fatty liver disease (NAFLD)/fibrosis
Thresholds
Test
Formula
Age <65 years
Age >65 years
NAFLD Fibrosis
Score (NFS)
-1 .675 + 0.037 x Age (years) + 0.094
x BMI (kg/m2) + 1 .13 x IFG or diabetes
(yes = 1 , no = 0) + 0.99 x AST/ALT ratio
- 0.013 x platelet count (x 109/L) - 0.66
x albumin (g/dL)
High risk (NFS >0.676)
Indeterminate risk (NFS -1.455-0.676)
Low risk (NFS <-1.455)
High risk (NFS >0.676)
Indeterminate risk
(NFS 0.12-0.676)
Low risk (NFS <0.12)
FIB-4 Score
Age (years) x AST (IU/L)/platelet count (x
107L) x VALT (IU/L)
High risk (FIB-4 >2.67)
Indeterminate risk (FIB-4 1.30-2.67)
Low risk (FIB-4 <1.30)
High risk (FIB-4 >2.67)
Indeterminate risk (2.00-2.67)
Low risk (FIB-4 <2.00)
*Predict advanced fibrosis and cirrhosis (F3-4). Simple scores like NFS and FIB-4 are based on the results of routinely available blood tests and anthropometries. Online
calculators for these are widely available.
(ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; IFG = impaired fasting glucose)
Autoimmune liver and biliary disease • 885
0
0
-Q
0
TD
C\J
0
CL
>*
0
CL
O
0
>
0
"O
0
CL
O
0
0
0
>*
LO
I
CO
_c
C/)
0
0
0
o
0
O
0
DC
Fig. 22.31 Assessment and risk stratification of patients with non-alcoholic fatty liver disease (NAFLD). (HCC = hepatocellular carcinoma;
M probe = medium probe; XL = large probe)
and physical exercise. Sustained weight reduction of 7-10%
is associated with significant improvement in histological and
biochemical NASH severity.
Pharmacological treatment
No pharmacological agents are currently licensed specifically
for NASH therapy. Treatment directed at coexisting metabolic
disorders, such as dyslipidaemia and hypertension, should be
given. Although use of HMG-CoA reductase inhibitors (statins)
does not ameliorate NAFLD, there does not appear to be
any increased risk of hepatotoxicity or other side-effects from
these agents, and so they may be used to treat dyslipidaemia.
Specific insulin-sensitising agents, in particular glitazones, may
help selected patients, while recent results with bezafibrate, a
lipid-lowering fibrate, have been encouraging. Positive results
with high-dose vitamin E (800 U/day) have been tempered by
evidence that high doses may be associated with an increased
risk of prostate cancer and all-cause mortality, which has limited
its use. Several new medicines are currently in late-phase clinical
trials and so liver-targeted pharmacological treatments are likely
to be available within the next few years.
Autoimmune liver and biliary disease
The liver is an important target for autoimmune injury. The clinical
picture is dictated by the nature of the autoimmune process
and, in particular, the target cell for immune injury. The disease
patterns are quite distinctive for primary hepatocellular injury
(in the context of autoimmune hepatitis) and biliary epithelial
cell injury (primary biliary cholangitis and primary sclerosing
cholangitis).
886 • HEPATOLOGY
Autoimmune hepatitis
Autoimmune hepatitis is a disease of immune-mediated liver
injury characterised by the presence of serum antibodies and
peripheral blood T lymphocytes reactive with self-proteins,
a strong association with other autoimmune diseases (Box
22.49), and high levels of serum immunoglobulins - in particular,
elevation of IgG. Although most commonly seen in women,
particularly in the second and third decades of life, it can develop
in either sex at any age. The reasons for the breakdown in
immune tolerance in autoimmune hepatitis remain unclear,
although cross- reactivity with viruses such as HAV and EBV
in immunogenetically susceptible individuals (typically those
with human leucocyte antigen (HLA)-DR3 and DR4, particularly
HLA-DRB3*0101 and HLA-DRB1*0401) has been suggested
as a mechanism.
Pathophysiology
Several subtypes of this disorder have been proposed that have
differing immunological markers. Although the different patterns
can be associated with variation in disease aspects, such as
response to immunosuppressive therapy, histological patterns are
similar in the different settings and the basic approach to treatment
(complete control of liver injury using immunosuppressive drugs
and maintained with appropriate therapy) is the same. The
formal classification into disease types has fallen out of favour
in recent years.
The most frequently seen autoantibody pattern is high titre
of antinuclear and anti-smooth muscle antibodies, typically
associated with IgG hyperglobulinaemia (type I autoimmune
hepatitis in the old classification), frequently seen in young adult
females. Disease characterised by the presence of anti-liver-kidney
microsomal (LKM) antibodies, recognising cytochrome P450-IID6
expressed on the hepatocyte membrane, is typically seen in
paediatric populations and can be more resistant to treatment
than ANA-positive disease. Adult onset of anti-LKM can be seen
in chronic HCV infection. This was classified as type II disease
in the old system. More recently, a pattern of antibody reactivity
with anti-soluble liver antigen (anti -SLA) has been described in
BS 22.49 Conditions associated with
autoimmune hepatitis
• Migrating polyarthritis
• Coombs-positive haemolytic
• Urticarial rashes
anaemia
• Lymphadenopathy
• Transient pulmonary infiltrates
• Hashimoto’s thyroiditis
• Ulcerative colitis
• Thyrotoxicosis
• Glomerulonephritis
• Myxoedema
• Nephrotic syndrome
• Pleurisy
typically adult patients, often with aggressive disease and usually
lacking autoantibodies of other specificities.
Clinical features
The onset is usually insidious, with fatigue, anorexia and eventually
jaundice. The non-specific nature of the early features can lead
to the diagnosis being missed in the early disease stages. In
about one-quarter of patients the onset is acute, resembling viral
hepatitis, but resolution does not occur. This acute presentation
can lead to extensive liver necrosis and liver failure. Other features
include fever, arthralgia, vitiligo and epistaxis. Amenorrhoea can
occur. Jaundice is mild to moderate or occasionally absent,
but signs of chronic liver disease, especially spider naevi and
hepatosplenomegaly, can be present. Associated autoimmune
disease, such as Hashimoto’s thyroiditis or rheumatoid arthritis,
is often present and can modulate the clinical presentation.
Investigations
Serological tests for autoantibodies are often positive (Box 22.50),
but low titres of these antibodies occur in some healthy people
and in patients with other inflammatory liver diseases. ANA also
occur in connective tissue diseases and other autoimmune
diseases (with an identical pattern of homogenous nuclear
staining) while anti-smooth muscle antibody has been reported
in infectious mononucleosis and a variety of malignant diseases.
Anti-microsomal antibodies (anti-LKM) occur particularly in children
and adolescents. Elevated serum IgG levels are an important
diagnostic and treatment response feature if present, but the
diagnosis is still possible in the presence of normal IgG levels. If
the diagnosis of autoimmune hepatitis is suspected, liver biopsy
should be performed. It typically shows interface hepatitis, with
or without cirrhosis. Scoring systems, such as the International
Autoimmune Hepatitis Group (IAIHG) criteria, are useful for
epidemiological study and for assessing trial eligibility but are
complex for normal clinical practice.
Management
Treatment with glucocorticoids is life-saving in autoimmune
hepatitis, particularly during exacerbations of active and
symptomatic disease. Initially, prednisolone (40 mg/day) is given
orally; the dose is then gradually reduced as the patient and
LFTs improve. Maintenance therapy should only be instituted
once LFTs are normal (as well as IgG if elevated). Approaches
to maintenance include reduced-dose prednisolone (ideally,
below 5-10 mg/day), usually in the context of azathioprine
(1.0-1 .5 mg/kg/day). Azathioprine can also be used as the
sole maintenance immunosuppressive agent in patients with
low-activity disease. Newer agents, such as mycophenolate mofetil
(MMF), are increasingly being used but formal evidence to inform
practice in this area is lacking. Patients should be monitored for
acute exacerbations (LFT and IgG screening with patients alerted
22.50 Frequency of autoantibodies in chronic non-viral liver diseases and in healthy people
Disease Antinuclear antibody (%) Anti-smooth muscle antibody (%) Antimitochondrial antibody
Healthy controls 5 1.5 0.01
Autoimmune hepatitis 80 70 15
Primary biliary cholangitis 25 35 95
Cryptogenic cirrhosis 40 30 15
*Patients with antimitochondrial antibody frequently have cholestatic liver function tests and may have primary biliary cholangitis (see text).
Autoimmune liver and biliary disease • 887
to the possible symptoms) and such exacerbations should be
treated with glucocorticoids. Although treatment can significantly
reduce the rate of progression to cirrhosis, end-stage disease
can be seen in patients despite treatment.
Primary biliary cholangitis
Primary biliary cholangitis (PBC, known as primary biliary cirrhosis
until 201 5, when the name was changed to reflect more accurately
the disease seen in the modern era) is a chronic, progressive
cholestatic liver disease that predominantly affects women
aged 30 and over. It is strongly associated with the presence
of antimitochondrial antibodies (AMA), which are diagnostic, and
is characterised by a granulomatous inflammation of the portal
tracts, leading to progressive damage and eventually loss of the
small and middle-sized bile ducts. This, in turn, leads to fibrosis
and cirrhosis of the liver. The condition can present with an
insidious onset of itching and/or tiredness; it may also frequently
be found incidentally as the result of routine blood tests.
Epidemiology
The prevalence of PBC varies across the world. It is relatively
common in northern Europe and North America but is rare in Africa
and Asia. There is a strong female-to-male predominance of 9 : 1 ;
it is also more common among cigarette smokers. Clustering of
cases has been reported, suggesting an environmental trigger
in susceptible individuals.
Pathophysiology
Immune mechanisms are clearly involved. The condition is
closely associated with other autoimmune non-hepatic diseases,
such as thyroid disease, and there is a genetic association with
HLA-DR8, together with polymorphisms in a number of other
genes regulating the nature of the immune response (e.g. IL-12
and its receptor). AMA is directed at pyruvate dehydrogenase
complex, a mitochondrial enzyme complex that plays a key
role in cellular energy generation. PBC-specific ANAs (such
as those directed at the nuclear pore antigen gp210) have a
characteristic staining pattern in immunofluorescence assays
(selectively binding to the nuclear rim or nuclear dots), which
means that they should not be mistaken for the homogenously
staining ANA seen in autoimmune hepatitis. Increases in serum
immunoglobulin levels are frequent but, unlike in autoimmune
hepatitis, it is typically IgM that is elevated.
Pathologically, chronic granulomatous inflammation destroys
the interlobular bile ducts; progressive lymphocyte-mediated
inflammatory damage causes fibrosis, which spreads from the
portal tracts to the liver parenchyma and eventually leads to
cirrhosis. A model of the natural history of the disease process
is shown in Figure 22.32.
Clinical features
Systemic symptoms such as fatigue are common and may
precede diagnosis by years. Pruritus, which can be a feature
of any cholestatic disease, is a common presenting complaint
and may precede jaundice by months or years. Jaundice is
rarely a presenting feature. The itching is usually worse on the
limbs. Although there may be right upper abdominal discomfort,
fever and rigors do not occur. Bone pain or fractures can rarely
result from osteomalacia (fat-soluble vitamin malabsorption) or,
more commonly, from osteoporosis (hepatic osteodystrophy).
Initially, patients are well nourished but weight loss can occur
as the disease progresses. Scratch marks may be found in
Genetic
Environmental
susceptibility
trigger factor(s)
Latent disease
(antimitochondrial Ab-positive,
normal LFTs)
Genetic
factors
Early disease
AMA-positive
(abnormal LFTs)
Genetic
factors
Late disease
(liver scarring/cirrhosis)
30% disease
recurrence
Liver decompensation
r
Death
3
Liver
transplant
Fig. 22.32 Natural history of primary biliary cholangitis.
(AMA = antimitochondrial antibody; LFTs = liver function tests)
patients with severe pruritus. Jaundice is prominent only late in
the disease and can become intense. Xanthomatous deposits
occur in a minority, especially around the eyes. Mild hepatomegaly
is common and splenomegaly becomes increasingly common
as portal hypertension develops. Liver failure may supervene.
Associated diseases
Autoimmune and connective tissue diseases occur with increased
frequency in PBC, particularly the sicca syndrome (p. 1038),
systemic sclerosis, coeliac disease (p. 805) and thyroid diseases.
Hypothyroidism should always be considered in patients with
fatigue.
Diagnosis and investigations
The LFTs show a pattern of cholestasis (see Box 22.2, p. 853).
Hypercholesterolaemia is common and worsens as disease
progresses but appears not to be associated with increased
cardiac risk. AMA is present in over 95% of patients; when it
is absent, the diagnosis should not be made without obtaining
histological evidence and considering cholangiography (typically,
MRCP) to exclude other biliary disease. ANA and anti-smooth
muscle antibodies are present in around 15% of patients (see
Box 22.50); autoantibodies found in associated diseases may
also be present. Ultrasound examination shows no sign of biliary
obstruction. Liver biopsy is necessary only if there is diagnostic
uncertainty. The histological features of PBC correlate poorly with
888 • HEPATOLOGY
the clinical features; portal hypertension can develop before the
histological onset of cirrhosis.
Management
The hydrophilic bile acid ursodeoxycholic acid (UDCA), at a
dose of 13-15 mg/kg/day, improves bile flow, replaces toxic
hydrophobic bile acids in the bile acid pool, and reduces
apoptosis of the biliary epithelium. Clinically, UDCA improves
LFTs, may slow down histological progression and has few
side-effects; it is therefore widely used in the treatment of PBC
and should be regarded as the optimal first-line treatment. Its use
is recommended in all clinical guidelines. A significant minority of
patients either fail to normalise their LFTs with UDCA or show an
inadequate response, and such individuals have an increased risk
of developing end -stage liver disease compared to those showing
a full response. Obeticholic acid (OCA) is a second-generation
bile acid therapeutic that acts as an agonist for the nuclear
farnesoid X receptor. It reduces hepatocyte synthesis of bile
acids and was approved in 201 6 for use in patients showing an
inadequate response to UDCA. Immunosuppressants, such as
glucocorticoids, azathioprine, penicillamine and ciclosporin, have
all been trialled in PBC. None shows overall benefit when given
to unselected patients. It is unclear whether these drugs offer
benefit to the specific subgroup of patients who do not respond
to UDCA and require second-line approaches to treatment.
Liver transplantation should be considered once liver failure
has developed and may be indicated in patients with intractable
pruritus. Serum bilirubin remains the most reliable marker of
declining liver function. Transplantation is associated with an
excellent 5-year survival of over 80%, although the disease will
recur in over one-third of patients at 10 years.
Pruritus
This is the main symptom requiring treatment. The cause is
unknown, but up-regulation of opioid receptors and increased
levels of endogenous opioids may play a role. First-line treatment
is with the anion-binding resin colestyramine, which probably acts
by binding potential pruritogens in the intestine and increasing
their excretion in the stool. A dose of 4-1 6 g/day orally is used.
The powder is mixed in orange juice and the main dose (8 g)
taken before and after breakfast, when maximal duodenal bile
acid concentrations occur. Colestyramine may bind other drugs
in the gut (most obviously UDCA) and adequate spacing should
be used between drugs. Colestyramine is sometimes ineffective,
especially in complete biliary obstruction, and can be difficult for
some patients to tolerate. Alternative treatments include rifampicin
(1 50 mg/day, titrated up to a maximum of 600 mg/day as required
and contingent on there being no deterioration in LFTs), naltrexone
(an opioid antagonist; 25 mg/day initially, increasing up to
300 mg/day), plasmapheresis and a liver support device (e.g. a
molecular adsorbent recirculating system, MARS).
Fatigue
Fatigue affects about one-third of patients with PBC. The cause
is unknown but it may reflect intracerebral changes due to
cholestasis. Unfortunately, once depression, hypothyroidism and
coeliac disease have been excluded, there is currently no specific
treatment. The impact on patients’ lives can be substantial.
Malabsorption
Prolonged cholestasis is associated with steatorrhoea and
malabsorption of fat-soluble vitamins, which should be replaced
as necessary. Coeliac disease should be excluded since its
incidence is increased in PBC.
Bone disease
Osteopenia and osteoporosis are common and normal post¬
menopausal bone loss is accelerated. Baseline bone density
should be measured (p. 989) and treatment started with
replacement calcium and vitamin D3. Bisphosphonates should
be used if there is evidence of osteoporosis. Osteomalacia is rare.
Overlap syndromes
AMA-negative PBC (‘autoimmune cholangitis’)
A few patients demonstrate the clinical, biochemical and
histological features of PBC but do not have detectable AMA
in the serum. Serum transaminases, serum immunoglobulin
levels and titres of ANA tend to be higher than in AMA-positive
PBC. The clinical course mirrors classical PBC, however, and
these patients should be considered as having a variant of PBC.
PBC/autoimmune hepatitis overlap
A few patients with AMA and cholestatic LFTs have elevated
transaminases, high serum immunoglobulins and interface hepatitis
on liver histology. In such individuals, a trial of glucocorticoid
therapy may be beneficial.
Primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is a cholestatic liver disease
caused by diffuse inflammation and fibrosis; it can involve
the entire biliary tree and leads to the gradual obliteration of
intrahepatic and extrahepatic bile ducts, and ultimately biliary
cirrhosis, portal hypertension and hepatic failure. Although
considered as an autoimmune disease, evidence for an
autoimmune pathophysiology is weaker than is the case for PBC
and autoimmune hepatitis. The incidence is about 6.3/100000
in Caucasians. Cholangiocarcinoma develops in about 1 0-30%
of patients during the course of the disease.
PSC is twice as common in young men. Most patients present
at age 25-40 years, although the condition may be diagnosed
at any age and is an important cause of chronic liver disease in
children. The generally accepted diagnostic criteria are:
• generalised beading and stenosis of the biliary system on
cholangiography (Fig. 22.33)
• absence of choledocholithiasis (or history of bile duct
surgery)
• exclusion of bile duct cancer, by prolonged follow-up.
The term ‘secondary sclerosing cholangitis’ is used to describe
the typical changes described above when a clear predisposing
factor for duct fibrosis can be identified. The causes of secondary
sclerosing cholangitis are shown in Box 22.51 .
Pathophysiology
The cause of PSC is unknown but there is a close association
with inflammatory bowel disease, particularly ulcerative colitis (Box
22.52). About two-thirds of patients have coexisting ulcerative
colitis, and PSC is the most common form of chronic liver disease
in ulcerative colitis. Between 3% and 10% of patients with
ulcerative colitis develop PSC, particularly those with extensive
colitis or pancolitis. The prevalence of PSC is lower in patients
with Crohn’s colitis (about 1%). Patients with PSC and ulcerative
colitis are at greater risk of colorectal neoplasia than those with
ulcerative colitis alone, and individuals who develop colorectal
neoplasia are at greater risk of cholangiocarcinoma.
It is currently believed that PSC is an immunologically mediated
disease, triggered in genetically susceptible individuals by toxic
Autoimmune liver and biliary disease • 889
Fig. 22.33 Magnetic resonance cholangiopancreatogram showing
typical changes of primary sclerosing cholangitis. There is intrahepatic
bile duct beading, stricturing and dilatation. The extrahepatic bile duct is
also diffusely strictured. Courtesy of Dr Dilip Patel, Royal Infirmary of
Edinburgh.
i
or infectious agents, which may gain access to the biliary tract
through a leaky, diseased colon. A close link with HLA haplotype
A1 -B8-DR3-DRW52A has been identified. This haplotype is
commonly found in association with other organ-specific
autoimmune diseases (e.g. autoimmune hepatitis).
The importance of immunological factors has been emphasised
by reports showing humoral and cellular abnormalities in PSC.
Perinuclear antineutrophil cytoplasmic antibodies (ANCA) have
been detected in the sera of 60-80% of patients with PSC with
or without ulcerative colitis, and in 30-40% of patients with
ulcerative colitis alone. The antibody is not specific for PSC and
is found in other chronic liver diseases (e.g. 50% of patients with
autoimmune hepatitis).
Fig- 22.34 Primary sclerosing cholangitis. Note onion skin scarring
(arrows) surrounding a bile duct.
Clinical features
The diagnosis is often made incidentally when persistently raised
serum ALP is discovered in an individual with ulcerative colitis.
Common symptoms include fatigue, intermittent jaundice, weight
loss, right upper quadrant abdominal pain and pruritus. Attacks
of acute cholangitis are uncommon and usually follow biliary
instrumentation. Physical examination is abnormal in about
50% of symptomatic patients; the most common findings are
jaundice and hepatomegaly/splenomegaly. The condition may
be associated with many other diseases (Box 22.52).
Investigations
Biochemical screening usually reveals a cholestatic pattern of
LFTs but ALP and bilirubin levels may vary widely in individual
patients during the course of the disease. For example, ALP and
bilirubin values increase during acute cholangitis, decrease after
therapy, and sometimes fluctuate for no apparent reason. Modest
elevations in serum transaminases are usually seen, whereas
hypoalbuminaemia and clotting abnormalities are found at a late
stage only. In addition to ANCA, low titres of serum ANA and
anti-smooth muscle antibodies may be found in PSC but have
no diagnostic significance; serum AMA is absent.
The key investigation is now MRCP, which is usually diagnostic
and reveals multiple irregular stricturing and dilatation (Fig. 22.33).
ERCP should be reserved for when therapeutic intervention is
likely to be necessary and should follow MRCP.
On liver biopsy, the characteristic early features of PSC are
periductal ‘onion skin’ fibrosis and inflammation, with portal
oedema and bile ductular proliferation resulting in expansion of
the portal tracts (Fig. 22.34). Later, fibrosis spreads, progressing
inevitably to biliary cirrhosis; obliterative cholangitis leads to the
so-called ‘vanishing bile duct syndrome’.
Management
There is no cure for PSC but management of cholestasis and
its complications and specific treatment of the disease process
are indicated. UDCA is widely used, although the evidence
to support this is limited. UDCA may have benefit in terms of
reducing colon carcinoma risk.
The course of PSC is variable. In symptomatic patients, median
survival from presentation to death or liver transplantation is about
12 years. About 75% of asymptomatic patients survive 15 years
or more. Most patients die from liver failure, about 30% die from
bile duct carcinoma, and the remainder die from colonic cancer
or complications of colitis. Immunosuppressive agents, including
22.51 Causes of secondary sclerosing cholangitis
• Previous bile duct surgery with stricturing and cholangitis
• Bile duct stones causing cholangitis
• Intrahepatic infusion of 5-fluorodeoxyuridine
• Insertion of formalin into hepatic hydatid cysts
• Insertion of alcohol into hepatic tumours
• Parasitic infections (e.g. Clonorchis)
• Autoimmune pancreatitis/immunoglobulin G4-associated cholangitis
• Acquired immunodeficiency syndrome (AIDS; probably infective as a
result of cytomegalovirus or Cryptosporidium)
BS 22.52 Diseases associated with
primary sclerosing cholangitis
•
Ulcerative colitis
• Angio-immunoblastic
•
Crohn’s colitis
lymphoma
•
Chronic pancreatitis
• Histiocytosis X
•
Retroperitoneal fibrosis
• Autoimmune haemolytic
•
Riedel’s thyroiditis
anaemia
•
Retro-orbital tumours
• Autoimmune pancreatitis/
•
Immune deficiency states
immunoglobulin G4-associated
•
Sjogren’s syndrome
cholangitis
890 • HEPATOLOGY
prednisolone, azathioprine, methotrexate and ciclosporin, have
been tried; results have generally been disappointing.
Symptomatic patients often have pruritus. Management is as
for PBC. Fatigue appears to be less prominent than in PBC,
although it is still present in some patients.
Management of complications
Broad-spectrum antibiotics (e.g. ciprofloxacin) should be given for
acute attacks of cholangitis but have no proven value in preventing
attacks. If cholangiography shows a well-defined obstruction
to the extrahepatic bile ducts (‘dominant stricture’), mechanical
relief can be obtained by placement of a stent or by balloon
dilatation performed at ERCP. It is important, in this situation, to
give active consideration to the possibility of cholangiocarcinoma
(the differential diagnosis for a dominant extrahepatic stricture).
Fat-soluble vitamin replacement is necessary in jaundiced patients.
Metabolic bone disease (usually osteoporosis) is a common
complication that requires treatment (p. 1044).
Surgical treatment
Surgical resection of the extrahepatic bile duct and biliary
reconstruction have a limited role in the management of non¬
cirrhotic patients with dominant extrahepatic disease. Orthotopic
transplantation is the only surgical option in patients with
advanced liver disease; 5-year survival is 80-90% in most centres.
Unfortunately, the condition may recur in the graft and there are
no identified therapies able to prevent this. Cholangiocarcinoma
is a contraindication to transplantation. Colon carcinoma risk can
be increased in patients following transplantation because of
the effects of immune suppression, and enhanced surveillance
should be instituted.
lgG4-associated cholangitis
This disease (as well as its nomenclature) is closely related to
autoimmune pancreatitis (which is present in more than 90%
of the patients; p. 841). lgG4-associated cholangitis (IAC) often
presents with obstructive jaundice (due to either hilar stricturing/
intrahepatic sclerosing cholangitis or a low bile duct stricture),
and cholangiographic appearances suggest PSC with or without
hilar cholangiocarcinoma. The serum lgG4 is often raised and liver
biopsy shows a lymphoplasmacytic infiltrate, with lgG4-positive
plasma cells. An important observation is that, compared to
PSC, IAC appears to respond well to glucocorticoid therapy.
Liver tumours and other focal
liver lesions
Identification of a hepatic mass lesion is common, both in
patients with known pre-existing liver disease and as a primary
presentation. Although primary and secondary malignant tumours
are important potential diagnoses, benign disease is frequent.
The finding of a liver mass, with its association in the minds of
patients with metastatic malignant disease, creates a high level
of anxiety, a factor that should always be borne in mind. The
critical steps to be taken in diagnosing hepatic mass lesions are:
• determining the presence, nature and severity of any
underlying chronic liver disease, as the differential
diagnosis is very different in patients with and those
without chronic liver disease
• using optimal (usually multiple) imaging modalities.
Primary malignant tumours
Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common primary liver
tumour, and the sixth most frequent cause of cancer worldwide.
Cirrhosis is present in 75-90% of individuals with HCC and is
an important risk factor for the disease. The risk is between
1 % and 5% in cirrhosis caused by hepatitis B and C. There is
also an increased risk in cirrhosis due to haemochromatosis,
alcohol, NASH and -antitrypsin deficiency. In northern Europe,
90% of those with HCC have underlying cirrhosis, compared
with 30% in Taiwan, where hepatitis B is the main risk factor.
The age-adjusted incidence rates vary from 28 per 1 00 000 in
South-east Asia (reflecting the prevalence of hepatitis B) to 1 0
per 100000 in southern Europe and 5 per 100000 in northern
Europe. Chronic hepatitis B infection increases the risk of HCC
1 00-fold and is the major risk factor worldwide. The risk of HCC is
0.4% per year in the absence of cirrhosis and 2-6% in cirrhosis.
The risk is four times higher in HBeAg- positive individuals than in
those who are HBeAg-negative. Hepatitis B vaccination has led
to a fall in HCC in countries with a high prevalence of hepatitis B.
The incidence in Europe and North America has risen recently,
probably related to the increased prevalence of hepatitis C and
NASH cirrhosis. The risk is higher in men and rises with age.
Macroscopically, the tumour usually appears as a single mass
in the absence of cirrhosis, or as a single nodule or multiple
nodules in the presence of cirrhosis. It takes its blood supply
from the hepatic artery and tends to spread by invasion into the
portal vein and its radicals. Lymph node metastases are common,
while lung and bone metastases are rare. Well-differentiated
tumours can resemble normal hepatocytes and can be difficult
to distinguish from normal liver.
Clinical features
Patients typically present with HCC in one of two ways. Commonly,
liver function deteriorates in those with underlying cirrhosis, with
worsening ascites and/or jaundice or variceal haemorrhage. Other
characteristic symptoms can include weight loss, anorexia and
abdominal pain. This often-rapid deterioration can, however,
be the event that leads to previously occult cirrhosis becoming
clinically apparent, meaning that absence of an established
diagnosis of cirrhosis does not preclude a diagnosis of HCC
complicating cirrhosis. Examination may reveal hepatomegaly or
a right hypochondrial mass. Tumour vascularity can lead to an
abdominal bruit, and hepatic rupture with intra-abdominal bleeding
may occur. The advanced nature of disease that presents in
this way makes curative therapy unlikely.
The second presentation is through screening of patients at
risk of HCC. The disease is typically detected much earlier in
its natural history, significantly increasing the treatment options.
Investigations
Serum markers
Alpha-fetoprotein (AFP) is produced by 60% of HCCs. Levels
increase with the size of the tumour and are often normal or
only minimally elevated in small tumours detected by ultrasound
screening. Serum AFP can also rise in the presence of active
hepatitis B and C viral replication; very high levels are seen in
acute hepatic necrosis, such as that following paracetamol
toxicity. AFP is used in conjunction with ultrasound in screening
but, in view of low sensitivity and specificity, levels need to
Liver tumours and other focal liver lesions • 891
be interpreted with caution. Nevertheless, in the absence of
a marked hepatic flare of disease, a progressively rising AFP,
or AFP of >400 ng/mL (330 lU/mL; normal is <10 ng/mL
(8 lU/mL), warrants an aggressive search for HCC. In HCC patients
with elevated AFP levels, serial measurements can be a useful
biomarker of disease progression or response to treatment.
Imaging
Ultrasound will detect focal liver lesions as small as 2-3 cm.
The use of ultrasound contrast agents has increased sensitivity
and specificity but is highly user-dependent. Ultrasound may
also show evidence of portal vein involvement and features of
coexistent cirrhosis. Multidetector row CT, following intravenous
contrast, identifies PICC by its classical hypervascular appearance
(Fig. 22.35). Small lesions of less than 2 cm can be difficult to
differentiate from hyperplastic nodules in cirrhosis. MRI can be
used instead. Angiography is now seldom performed and has
been superseded by the above techniques. A combination of
imaging modalities more accurately diagnoses and stages the
extent of disease, and use of at least two modalities (typically,
CT or MRI following initial screening ultrasound identification of
a mass lesion) is recommended.
Liver biopsy
Histological confirmation is advisable in patients with large tumours
who do not have cirrhosis or hepatitis B, in order to confirm
the diagnosis and exclude metastatic tumour. Biopsy should be
avoided in patients who may be eligible for transplantation or
surgical resection because there is a small (<2%) risk of tumour
seeding along the needle tract. In all cases of potential HCC
where biopsy is being considered, the impact that a confirmed
diagnosis will have on therapy must be weighed against the
risks of bleeding. If biopsy will not change management, then
its appropriateness should be considered carefully.
Role of screening
Screening for HCC, by ultrasound scanning and AFP measure¬
ments at 6-month intervals, is indicated in high-risk patients who
would be suitable for therapy if diagnosed with HCC. These
include individuals with cirrhosis caused by hepatitis B and C,
haemochromatosis, alcohol, NASH and oci -antitrypsin deficiency.
Fig. 22.35 Computed tomogram showing a large hepatocellular
carcinoma (arrows). Courtesy of Dr D. Redhead, Royal Infirmary of
Edinburgh.
Screening may also be indicated in those with chronic hepatitis
B (who carry an increased risk of HCC, even in the absence of
cirrhosis). Although no randomised controlled studies of outcome
have been undertaken, screening identifies smaller tumours,
often less than 3 cm in size, which are more likely to be cured
by surgical resection, local ablative therapy or transplantation.
The role of screening in other forms of chronic liver disease,
such as autoimmune hepatitis and PBC, is unclear. This is
compounded by the fact that disease staging by biopsy is no
longer standard practice in conditions such as PBC, so formal
documentation of the presence of cirrhosis, which might be the
trigger for commencement of HCC screening, rarely takes place.
Management
This is different for patients with cirrhosis and those without. In
the presence of cirrhosis, tumour size, multicentricity, extent of
liver disease (Child-Pugh score) and performance status dictate
therapy. An algorithm for managing those with cirrhosis is shown
in Figure 22.36.
Prognosis depends on tumour size, the presence of vascular
invasion, and liver function in those with cirrhosis. Screening has
improved the outlook through early detection.
Hepatic resection
This is the treatment of choice for non-cirrhotic patients. The
5-year survival in this group is about 50%. There is a 50%
recurrence rate at 5 years, however, which may be due to a
second de novo tumour or recurrence of the original tumour.
Few patients with cirrhosis are suitable for hepatic resection
because of the high risk of hepatic failure; nevertheless, surgery
is offered, particularly in the Far East, to some cirrhotic patients
with small tumours and good liver function (Child-Pugh A with
no portal hypertension).
Liver transplantation
Transplantation has the benefit of curing underlying cirrhosis
and removing the risk of a second, de novo tumour in an at-risk
patient. The requirement for immunosuppression creates its
own risks of reactivation, however, if residual or metastatic
disease is present, and assessment of patients for suitability
for liver transplantation focuses on the exclusion of extrahepatic
disease and vascular invasion. The 5-year survival following liver
transplantation is 75% for patients with single tumours of less
than 5 cm in size or three tumours smaller than 3 cm (the Milan
criteria). Unfortunately, the underlying liver disease, in particular
hepatitis C, may recur in the transplanted liver and can result in
recurrent cirrhosis that gives rise to a de novo HCC risk, now
complicated by the presence of immunosuppression.
Percutaneous therapy
Percutaneous ethanol injection into the tumour under ultrasound
guidance is efficacious (80% cure rate) for tumours of 3 cm or
less. Recurrence rates (50% at 3 years) are similar to those
following surgical resection. Radiofrequency ablation, using a
single electrode inserted into the tumour under radiological
guidance, is an alternative that takes longer to perform but
may cause more complete tumour necrosis. Improvements
in percutaneous therapy, with the combination of low patient
impact, relative efficacy and capacity for repeat treatment, are
making these approaches attractive, particularly when major
surgery would be inappropriate. Their role in primary therapy
as an alternative to curative resection or transplantation is yet
to be established.
892 • HEPATOLOGY
Hepatocellular carcinoma
PST 0, Child-Pugh A PST 0-2, Child-Pugh A-B
I i - 1 —
Very early stage
Single < 2 cm
E
Early stage
Single < 5 cm
1
Single
3 nodules < 3 cm
l
Portal pressure
h Increased Associated diseases
Normal No Yes
j i *
Intermediate stage
Multinodular; PST 0
PST > 2, Child-Pugh C
\ i
Advanced stage Terminal stage
Portal vein invasion;
N1, Ml; PST 1-2
Resection
Liver transplantation
RFA/PEI
TACE
Sorafenib
Best supportive
care
Curative treatment (30-40%)
Target: 20%
Target: 40%
Target: 10%
Median OS: > 60 months
OS: 20 months
OS: 11 months
OS: < 3 months
5-year survival: 40-70%
(14-45 months)
(6-14 months)
Fig. 22.36 Management of hepatocellular carcinoma complicating cirrhosis. Performance status (PST; see Box 33.3, p. 1322): 0 = fully active, no
symptoms; >2 = limited self-care, confined to bed or chair for 50% of waking hours. Child-Pugh score: see Box 22.29, p. 867. N1 , Ml : lymph node
involvement and metastases (for TNM classification, see Box 33.4, p. 1322) (OS = overall survival; PEI = percutaneous ethanol injection; RFA =
radiofrequency ablation; TACE = trans-arterial chemo-embolisation). Based on European Association for the Study of the Liver, European Organisation for
Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012; 56:908-943.
Trans-arterial chemo-embolisation
Hepatocellular cancers are not radiosensitive and the response
rate to chemotherapy with drugs, such as doxorubicin, is only
around 30%. In contrast, hepatic artery embolisation with
absorbable gelatin powder (Gelfoam) and doxorubicin is more
effective, with survival rates of 60% in cirrhotic patients with
unresectable HCC and good liver function (compared with 20% in
untreated patients) at 2 years. Unfortunately, any survival benefit
is lost at 4 years. Trans-arterial chemo-embolisation (TACE) is
contraindicated in decompensated cirrhosis and multifocal HCC.
TACE is now most frequently used as a holding first intervention
while the tumour is being assessed and the definitive management
plan is being developed.
Chemotherapy
Sorafenib improves survival from 7.9 to 10.7 months in cirrhotic
patients. The drug is a multikinase inhibitor with activity against
Raf, vascular endothelial growth factor (VEGF) and platelet-derived
growth factor (PDGF) signalling, and is the first systemic therapy
to prolong survival in HCC. The ultimate role of sorafenib in
HCC - in particular, when and how best to use it - is yet to
be established.
Fibrolamellar hepatocellular carcinoma
This rare variant differs from HCC in that it occurs in young
adults, equally in males and females, in the absence of hepatitis B
infection and cirrhosis. The tumours are often large at presentation
and the AFP is usually normal. Histology of the tumour reveals
malignant hepatocytes surrounded by a dense fibrous stroma.
The treatment of choice is surgical resection. This variant of HCC
has a better prognosis following surgery than an equivalent-sized
HCC, two-thirds of patients surviving beyond 5 years.
Other primary malignant tumours
These are rare but include haemangio-endothelial sarcomas.
Cholangiocarcinoma (bile duct cancer) typically presents with bile
duct obstruction rather than as a hepatic mass lesion, although
the latter occasionally occurs.
Secondary malignant tumours
These are common and usually originate from carcinomas in the
lung, breast, abdomen or pelvis. They may be single or multiple.
Peritoneal dissemination frequently results in ascites.
Clinical features
The primary neoplasm is asymptomatic in 50% of patients,
being detected on either radiological, endoscopic or blood
biochemistry screening. There is liver enlargement and weight
loss; jaundice may be present.
Investigations
A raised ALP activity is the most common biochemical abnormality
but LFTs may be normal. Ascitic fluid, if present, has a high
protein content and may be blood-stained; cytology sometimes
reveals malignant cells. Imaging shows filling defects (Fig. 22.37);
laparoscopy may reveal the tumour and facilitates liver biopsy.
Drugs and the liver • 893
Fig. 22.37 Computed tomogram showing multiple liver metastases
(arrows).
Management
Hepatic resection can improve survival for slow-growing tumours,
such as colonic carcinomas, and is an approach that should be
actively explored in patients who are fit for liver resection and
have had the primary tumour resected once extrahepatic disease
has been excluded. Patients with neuro-endocrine tumours, such
as gastrinomas, insulinomas and glucagonomas, and those with
lymphomas may benefit from surgery, hormonal treatment or
chemotherapy. Unfortunately, palliative treatment to relieve pain
is all that is available for most patients; this may include arterial
embolisation of the tumour masses.
Benign tumours
The increasing use of ultrasound scanning has led to more
frequent identification of incidental benign focal liver lesions.
Hepatic adenomas
These are rare vascular tumours that may present as an abdominal
mass, or with abdominal pain or intraperitoneal bleeding. They
are more common in women and may be caused by oral
contraceptives, androgens and anabolic glucocorticoids. Resection
is indicated for the relief of symptoms. Hepatic adenomas can
increase in size during pregnancy. Large or rapidly growing
adenomas can rarely rupture, causing intraperitoneal bleeding.
Haemangiomas
These are the most common benign liver tumours and are
present in 1-20% of the population. Most are smaller than
5 cm and rarely cause symptoms (Fig. 22.38). The diagnosis
is usually made by ultrasound but CT may show a low-density
lesion with delayed arterial filling. Surgery is needed only for very
large symptomatic lesions or where the diagnosis is in doubt.
Focal nodular hyperplasia
Focal nodular hyperplasia is common in women under the age
of 40. The lesions are usually asymptomatic but can be up to
10 cm in diameter; they can be differentiated from adenoma
by a focal central scar seen on CT or MRI. Histologically, they
Fig. 22.38 Magnetic resonance image showing a haemangioma
(arrows) in the liver. Courtesy of Dr D. Redhead, Royal Infirmary of
Edinburgh.
Fig. 22.39 Computed tomogram showing multiple cysts in the liver
and kidneys in polycystic disease.
consist of nodular regeneration of hepatocytes without fibrosis.
They may be multiple but only rarely need resection.
Cystic liver disease and liver abscess
Isolated or multiple simple cysts are common in the liver and are
a relatively frequent finding on ultrasound screening. They can
be associated with polycystic renal disease (Fig. 22.39). They
are intrinsically benign and require no therapy, other than in
rare cases where the mass effect of very large or multiple cysts
causes abdominal discomfort. In such cases, percutaneous or
surgical debulking can be attempted but recurrence is typical.
Liver abscesses are discussed on page 879.
Drugs and the liver
The liver is the primary site of drug metabolism and an important
target for drug-induced injury. Pre-existing liver disease may affect
the capacity of the liver to metabolise drugs and unexpected
toxicity may occur when patients with liver disease are given
drugs in normal doses (p. 32). Box 22.53 also shows drugs
that should be avoided in patients with cirrhosis, as they can
exacerbate known complications of cirrhosis. The possibility of
undiagnosed underlying liver injury should always be considered
in patients exhibiting unexpected effects following drug exposure.
894 • HEPATOLOGY
22.53 Drugs to be avoided in cirrhosis
Drug
Problem
Toxicity
Non-steroidal
anti-inflammatory
drugs
Reduced renal
blood flow
Mucosal ulceration
Hepatorenal failure
Bleeding varices
Angiotensin¬
converting enzyme
inhibitors
Reduced renal
blood flow
Hepatorenal failure
Codeine
Constipation
Hepatic encephalopathy
Narcotics
Constipation, drug
accumulation
Hepatic encephalopathy
Anxiolytics
Drug accumulation
Hepatic encephalopathy
Drug-induced liver injury
Drug toxicity should always be considered in the differential
diagnosis of patients presenting with acute liver failure, jaundice
or abnormal liver biochemistry. Some typical patterns of drug
toxicity are listed in Box 22.54; the most common picture is a
mixed cholestatic hepatitis. The presence of jaundice indicates
more severe liver damage. Although acute liver failure can occur,
most drug reactions are self-limiting and chronic liver damage
is rare. Abnormal LFTs often take weeks to normalise following
a drug-induced hepatitis, and it may be months before they
normalise after a cholestatic hepatitis. Occasionally, permanent
bile duct loss (ductopenia) follows a cholestatic drug reaction,
such as that due to co-amoxiclav, resulting in chronic cholestasis
with persistent symptoms such as itching.
The key to diagnosing acute drug-induced liver disease is to
take a detailed drug history (Box 22.55), looking for temporal
relationships between drug exposure and onset of liver abnormality
(bearing in mind the fact that liver injury can frequently take
weeks or even months to develop following exposure). A liver
biopsy should be considered if there is suspicion of pre-existing
liver disease or if blood tests fail to improve when the suspect
drug is withdrawn.
Where drug-induced liver injury is suspected or cannot be
excluded, the potential culprit drug should be discontinued
unless it is impossible to do so safely.
Types of liver injury
Different histological patterns of liver injury may occur with
drug injury.
Cholestasis
Pure cholestasis (selective interference with bile flow in the
absence of liver injury) can occur with oestrogens; this was
common when high concentrations of oestrogens (50 jig/day)
were used as contraceptives. Both the current oral contraceptive
pill and hormone replacement therapy can be safely used in
chronic liver disease.
Chlorpromazine and antibiotics such as flucloxacillin are
examples of drugs that cause cholestatic hepatitis, which is
characterised by inflammation and canalicular injury. Co-amoxiclav
is the most common antibiotic to cause abnormal LFTs but,
unlike other antibiotics, it may not produce symptoms until
10-42 days after it is stopped. Anabolic glucocorticoids used
by body-builders may also cause a cholestatic hepatitis. In some
KM 22.54 Examples of common causes of drug-induced
hepatotoxicity
Pattern
Drug
Cholestasis
Chlorpromazine
High-dose oestrogens
Cholestatic hepatitis
Non-steroidal anti-inflammatory
drugs
Co-amoxiclav
Statins
Acute hepatitis
Rifampicin
Isoniazid
Non-alcoholic steatohepatitis
Amiodarone
Venous outflow obstruction
Busulfan
Azathioprine
Fibrosis
Methotrexate
22.55 Diagnosing acute drug-induced
liver disease
• Tabulate the drugs taken:
Prescribed and self-administered
• Establish whether hepatotoxicity is reported in the literature
• Relate the time the drugs were taken to the onset of illness: 4 days
to 8 weeks (usual)
• Establish the effect of stopping the drugs on normalisation of liver
biochemistry:
Hepatitic liver function tests (2 months)
Cholestatic/mixed liver function tests (6 months)
N.B. Challenge tests with drugs should be avoided
• Exclude other causes:
Viral hepatitis
Biliary disease
• Consider liver biopsy
cases (e.g. NSAIDs and cyclo-oxygenase 2 (COX-2) inhibitors),
there is overlap with acute hepatocellular injury.
Hepatocyte necrosis
Many drugs cause an acute hepatocellular necrosis with high
serum transaminase concentrations; paracetamol is the best
known. Inflammation is not always present but does accompany
necrosis in liver injury due to diclofenac (an NSAID) and isoniazid
(an anti-tuberculous drug). Granulomas may be seen in liver injury
following the use of allopurinol. Acute hepatocellular necrosis has
also been described following the use of several herbal remedies,
including germander, comfrey and jin bu huan. Recreational
drugs, including cocaine and ecstasy, can also cause severe
acute hepatitis.
Steatosis
Microvesicular hepatocyte fat deposition, due to direct effects on
mitochondrial beta-oxidation, can follow exposure to tetracyclines
and sodium valproate. Macrovesicular hepatocyte fat deposition
has been described with tamoxifen, and amiodarone toxicity can
produce a similar histological picture to NASH.
Vascular/sinusoidal lesions
Drugs such as the alkylating agents used in oncology can
damage the vascular endothelium and lead to hepatic venous
Inherited liver diseases • 895
outflow obstruction. Chronic overdose of vitamin A can damage
the sinusoids and trigger local fibrosis that can result in portal
hypertension.
Hepatic fibrosis
Most drugs cause reversible liver injury and hepatic fibrosis is
very uncommon. Methotrexate, however, as well as causing
acute liver injury when it is started, can lead to cirrhosis when
used in high doses over a long period of time. Risk factors for
drug-induced hepatic fibrosis include pre-existing liver disease
and a high alcohol intake.
Inherited liver diseases
The inherited diseases are an important and probably under¬
diagnosed group of liver diseases. In addition to the ‘classical’
conditions, such as haemochromatosis and Wilson’s disease,
the important role played by the liver in the expression of
the inborn errors of metabolism should be remembered, as
should the potential for genetic underpinning for intrahepatic
cholestasis.
Haemochromatosis
Haemochromatosis is a condition in which the amount of total
body iron is increased; the excess iron is deposited in, and
causes damage to, several organs, including the liver. It may be
primary or secondary to other diseases (Box 22.56).
Hereditary haemochromatosis
In hereditary haemochromatosis (HHC), iron is deposited
throughout the body and total body iron may reach 20-60 g
(normally 4 g). The important organs involved are the liver,
pancreatic islets, endocrine glands, joints and heart. In the
liver, iron deposition occurs first in the periportal hepatocytes,
extending later to all hepatocytes. The gradual development of
fibrous septa leads to the formation of irregular nodules, and
finally regeneration results in macronodular cirrhosis. An excess
of liver iron can occur in alcoholic cirrhosis but this is mild in
comparison with haemochromatosis.
i
Primary haemochromatosis
• Hereditary haemochromatosis
• Congenital acaeruloplasminaemia
• Congenital atransferrinaemia
Secondary iron overload
• Parenteral iron loading (e.g. repeated blood transfusion)
• Iron-loading anaemia (thalassaemia, sideroblastic anaemia, pyruvate
kinase deficiency)
• Liver disease
Complex iron overload
• Juvenile haemochromatosis
• Neonatal haemochromatosis
• Alcoholic liver disease
• Porphyria cutanea tarda
• African iron overload (Bantu siderosis)
Pathophysiology
The disease is caused by increased absorption of dietary iron
and is inherited as an autosomal recessive trait. Approximately
90% of patients are homozygous for a single point mutation
resulting in a cysteine to tyrosine substitution at position 282
(C282Y) in the HFE protein, which has structural and functional
similarity to the HLA proteins. The mechanisms by which HFE
regulates iron absorption are unclear. It is believed, however,
that HFE normally interacts with the transferrin receptor in the
basolateral membrane of intestinal epithelial cells. In HHC, it
is thought that the lack of functional HFE causes a defect in
uptake of transferrin-associated iron, leading to up-regulation
of enterocyte iron-specific divalent metal transporters and
excessive iron absorption. A histidine-to-aspartic acid mutation
at position 63 (H63D) in HFE causes a less severe form of
haemochromatosis that is most commonly found in patients who
are compound heterozygotes also carrying a C282Y mutated
allele. Fewer than 50% of C282Y homozygotes will develop
clinical features of haemochromatosis; therefore other factors
must also be important. HHC may promote accelerated liver
disease in patients with alcohol excess or hepatitis C infection.
Iron loss in menstruation and pregnancy can delay the onset
of HHC in females.
Clinical features
Symptomatic disease usually presents in men over 40 years
of age with features of liver disease (often with hepatomegaly),
type 2 diabetes or heart failure. Fatigue and arthropathy are
early symptoms but are frequently absent. Leaden-grey skin
pigmentation due to excess melanin occurs, especially in exposed
parts, axillae, groins and genitalia: hence the term ‘bronzed
diabetes’. Once again, absence of this feature does not preclude
the diagnosis. Impotence, loss of libido and testicular atrophy
are recognised complications, as are early-onset osteoarthritis
targeting unusual sites such as the metacarpophalangeal joints,
chondrocalcinosis and pseudogout. Cardiac failure or cardiac
dysrhythmia may occur due to iron deposition in the heart.
Investigations
Serum iron studies show a greatly increased ferritin, a raised
plasma iron and saturated plasma iron-binding capacity.
Transferrin saturation of more than 45% is suggestive of iron
overload. Significant liver disease is unusual in patients with ferritin
lower than 1000 |ig/L (100 jig/dL). The differential diagnoses
for elevated ferritin are inflammatory disease or excess ethanol
consumption for modest elevations (<1000 |ig/L (100 jig/dL)).
Very significant ferritin elevation can be seen in adult Still’s disease.
In terms of imaging techniques, MRI has high specificity for iron
overload but poor sensitivity. Liver biopsy allows assessment of
fibrosis and distribution of iron (hepatocyte iron characteristic
of haemochromatosis). The Hepatic Iron Index (Hll) provides
quantification of liver iron (jimol of iron per g dry weight of
liver/age in years). An Hll of more than 1.9 suggests genetic
haemochromatosis (Fig. 22.40). Both the C282Y and the H63D
mutations can be identified by genetic testing, which is now in
routine clinical use.
Management
Treatment consists of weekly venesection of 500 mL blood
(250 mg iron) until the serum iron is normal; this may take
2 years or more. The aim is to reduce ferritin to under 50 pig/L
(5 jig/dL). Thereafter, venesection is continued as required to
keep the serum ferritin normal. Liver and cardiac problems
22.56 Causes of haemochromatosis
896 • HEPATOLOGY
Fig. 22.40 Liver histology: haemochromatosis. This Peris stain shows
accumulating iron within hepatocytes, which is stained blue. There is also
accumulation of large fat globules in some hepatocytes (macrovesicular
steatosis). Iron also accumulates in Kupffer cells and biliary epithelial cells.
improve after iron removal, but joint pain is less predictable and
can improve or worsen after iron removal. Type 2 diabetes does
not resolve after venesection. Other therapy includes that for
cirrhosis and diabetes. First-degree family members should be
investigated, preferably by genetic screening and also by checking
the plasma ferritin and iron-binding saturation. Liver biopsy is
indicated in asymptomatic relatives only if the LFTs are abnormal
and/or the serum ferritin is greater than 1000 jig/L (100 jig/d L)
because these features are associated with significant fibrosis
or cirrhosis. Asymptomatic disease should also be treated by
venesection until the serum ferritin is normal.
Pre-cirrhotic patients with HHC have a normal life expectancy,
and even cirrhotic patients have a good prognosis compared
with other forms of cirrhosis (three-quarters of patients are alive
5 years after diagnosis). This is probably because liver function is
well preserved at diagnosis and improves with therapy. Screening
for hepatocellular carcinoma (p. 890) is mandatory because
this is the main cause of death, affecting one-third of patients
with cirrhosis, irrespective of therapy. Venesection reduces but
does not abolish the risk of hepatocellular carcinoma in the
presence of cirrhosis.
Secondary haemochromatosis
Many conditions, including chronic haemolytic disorders,
sideroblastic anaemia, other conditions requiring multiple blood
transfusion (generally over 50 L), porphyria cutanea tarda, dietary
iron overload and occasionally alcoholic cirrhosis, are associated
with widespread secondary siderosis. The features are similar
to those of primary haemochromatosis but the history and
clinical findings point to the true diagnosis. Some patients are
heterozygotes for the HFE gene and this may contribute to the
development of iron overload.
Wilson’s disease
Wilson’s disease (hepatolenticular degeneration) is a rare but
important autosomal recessive disorder of copper metabolism
caused by a variety of mutations in the ATP7B gene on
chromosome 13. Total body copper is increased, with excess
copper deposited in, and causing damage to, several organs.
Pathophysiology
Normally, dietary copper is absorbed from the stomach and
proximal small intestine and is rapidly taken into the liver, where it
is stored and incorporated into caeruloplasmin, which is secreted
into the blood. The accumulation of excessive copper in the
body is ultimately prevented by its excretion, the most important
route being via bile. In Wilson’s disease, there is almost always
a failure of synthesis of caeruloplasmin; however, some 5% of
patients have a normal circulating caeruloplasmin concentration
and this is not the primary pathogenic defect. The amount of
copper in the body at birth is normal but thereafter it increases
steadily; the organs most affected are the liver, basal ganglia of
the brain, eyes, kidneys and skeleton.
The ATP7B gene encodes a member of the copper-transporting
P-type adenosine triphosphatase family, which functions to export
copper from various cell types. At least 200 different mutations
have been described. Most cases are compound heterozygotes
with two different mutations in ATP7B. Attempts to correlate
the genotype with the mode of presentation and clinical course
have not shown any consistent patterns. The large number of
culprit mutations means that, in contrast to haemochromatosis,
genetic diagnosis is not routine in Wilson’s disease, although it
may have a role in screening families following identification of
the genotype in an index patient.
Clinical features
Symptoms usually arise between the ages of 5 and 45 years.
Hepatic disease occurs predominantly in childhood and early
adolescence, although it can present in adults in their fifties.
Neurological damage causes basal ganglion syndromes and
dementia, which tends to present in later adolescence. These
features can occur alone or simultaneously. Other manifestations
include renal tubular damage and osteoporosis, but these are
rarely presenting features.
Liver disease
Episodes of acute hepatitis, sometimes recurrent, can occur,
especially in children, and may progress to fulminant liver failure.
The latter is characterised by the liberation of free copper into
the blood stream, causing massive haemolysis and renal
tubulopathy. Chronic hepatitis can also develop insidiously and
eventually present with established cirrhosis; liver failure and
portal hypertension may supervene. The possibility of Wilson’s
disease should be considered in any patient under the age of
40 presenting with recurrent acute hepatitis or chronic liver
disease of unknown cause, especially when this is accompanied
by haemolysis.
Neurological disease
Clinical features include a variety of extrapyramidal features,
particularly tremor, choreoathetosis, dystonia, parkinsonism
and dementia (Ch. 25). Unusual clumsiness for age may be an
early symptom. Neurological disease typically develops after
the onset of liver disease and can be prevented by effective
treatment started following diagnosis in the liver disease
phase. This increases the importance of diagnosis in the liver
phase beyond just allowing effective management of liver
disease.
Kayser-Fleischer rings
These constitute the most important single clinical clue to the
diagnosis and can be seen in 60% of adults with Wilson’s
disease (less often in children but almost always in neurological
Inherited liver diseases • 897
Wilson’s disease), albeit sometimes only by slit-lamp examination.
Kayser-Fleischer rings are characterised by greenish-brown
discoloration of the corneal margin appearing first at the upper
periphery (p. 846). They disappear with treatment.
Investigations
A low serum caeruloplasmin is the best single laboratory clue
to the diagnosis. Advanced liver failure from any cause can,
however, reduce the serum caeruloplasmin and occasionally it is
normal in Wilson’s disease. Other features of disordered copper
metabolism should therefore be sought; these include a high
free serum copper concentration, a high urine copper excretion
of greater than 0.6 |imol/24 hrs (38 (ng/24 hrs) and a very high
hepatic copper content. Measuring 24-hour urinary copper
excretion while giving D-penicillamine is a useful confirmatory
test; more than 25 (imol/24 hrs is considered diagnostic of
Wilson’s disease.
Management
The copper-binding agent penicillamine is the drug of choice.
The dose given must be sufficient to produce cupriuresis and
most patients require 1 .5 |ig/day (range 1-4 jig). The dose can
be reduced once the disease is in remission but treatment must
continue for life, even through pregnancy. Care must be taken to
ensure that re-accumulation of copper does not occur. Abrupt
discontinuation of treatment must be avoided because this may
precipitate acute liver failure. Toxic effects occur in one-third
of patients and include rashes, protein-losing nephropathy,
lupus-like syndrome and bone marrow depression. If these do
arise, trientine dihydrochloride (1 .2-2.4 jig/day) and zinc (50 mg
3 times daily) are potential alternatives.
Liver transplantation is indicated for fulminant liver failure
or for advanced cirrhosis with liver failure. The value of liver
transplantation in severe neurological Wilson’s disease is unclear.
Prognosis is excellent, provided treatment is started before
there is irreversible damage. Siblings and children of patients
with Wilson’s disease must be investigated and treatment
should be given to all affected individuals, even if they are
asymptomatic.
Alpharantitrypsin deficiency
Alpha^antitrypsin (oq-AT) is a serine protease inhibitor (Pi)
produced by the liver. One of its main anti-protease functions
is the breakdown of neutrophil elastase. The mutated form of
oq-AT (PiZ) cannot be secreted into the blood by liver cells
because it is retained within the endoplasmic reticulum of the
hepatocyte. Homozygous individuals (PiZZ) have low plasma oq-AT
concentrations, although globules containing oq-AT are found in
the liver, and these people may develop hepatic and pulmonary
disease. Liver manifestations include cholestatic jaundice in
the neonatal period (neonatal hepatitis), which can resolve
spontaneously; chronic hepatitis and cirrhosis in adults; and, in
the long term, HCC. AlpharAT deficiency is a not uncommon
exacerbating factor for liver disease of other aetiologies, and
the possibility of dual pathology should be considered when
severity of disease, such as ALD, appears disproportionate to
the level of underlying insult.
There are no clinical features that distinguish liver disease due
to oq-AT deficiency from liver disease due to other causes, and
the diagnosis is made from the low plasma oq-AT concentration
and genotyping for the presence of the mutation. AlpharAT-
containing globules can be demonstrated in the liver (Fig. 22.41)
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Fig. 22.41 Liver histology in ai -antitrypsin deficiency. Accumulation
of periodic acid— Schiff-positive granules (arrows) within individual
hepatocytes is shown in this section from a patient with oq-AT deficiency.
but this is not necessary to make the diagnosis. Occasionally,
patients with liver disease and minor reductions of plasma oq-AT
concentrations have oq-AT variants other than PiZZ, but the
relationship of these to liver disease is uncertain.
There is no specific treatment. The risk of severe and early-
onset emphysema means that all patients should be advised
to stop smoking.
Gilbert’s syndrome
Gilbert’s syndrome is by far the most common inherited disorder
of bilirubin metabolism (see Box 22.17, p. 860). It is an autosomal
recessive trait when caused by a mutation in the promoter region
of the gene for UDP-glucuronyl transferase enzyme (UGT1A1),
which leads to reduced enzyme expression. It can be inherited
in a dominant fashion when there is a missense mutation in the
gene. This results in decreased conjugation of bilirubin, which
accumulates as unconjugated bilirubin in the blood. The levels of
unconjugated bilirubin increase during fasting, as fasting reduces
levels of UDP-glucuronyl transferase.
Clinical features
The typical presentation is with isolated elevation of bilirubin,
typically, although not exclusively, in the setting of physical
stress or illness. There are no stigmata of chronic liver disease
other than jaundice. Increased excretion of bilirubin and hence
stercobilinogen leads to normal-coloured or dark stools, and
increased urobilinogen excretion causes the urine to turn dark
on standing as urobilin is formed. In the presence of haemolysis,
pallor due to anaemia and splenomegaly due to excessive
reticulo-endothelial activity are usually present.
Investigations
The plasma bilirubin is usually less than 100 jimol/L (~6 mg/
dL) and the LFTs are otherwise normal. There is no bilirubinuria
because the hyperbilirubinaemia is predominantly unconjugated.
Hepatic histology is normal and liver biopsy is not recommended
for the investigation of patients with possible Gilbert’s syndrome.
The condition is not associated with liver injury and thus has
an excellent prognosis, needs no treatment, and is clinically
important only because it may be mistaken for more serious
liver disease.
898 • HEPATOLOGY
Vascular liver disease
Metabolically, the liver is highly active and has large oxygen
requirements. This places it at risk of ischaemic injury in settings
of impaired perfusion. The risk is mitigated, however, by the dual
perfusion of the liver (via the portal vein as well as hepatic artery),
with the former representing a low-pressure perfusion system
that offers protection against the potential effects of arterial
hypotension. The single outflow through the hepatic vein and
the low-pressure perfusion system of the portal vein make the
liver vulnerable to venous thrombotic ischaemia in the context of
Budd-Chiari syndrome and portal vein thrombosis, respectively.
Hepatic arterial disease
Liver ischaemia
Liver ischaemic injury is relatively common during hypotensive or
hypoxic events and is under-diagnosed. The characteristic pattern
is one of rising transaminase values in the days following such an
event (e.g. prolonged seizures). Liver synthetic dysfunction and
encephalopathy are uncommon but can occur. Liver failure is very
rare. Diagnosis typically rests on clinical suspicion and exclusion
of other potential aetiologies. Treatment is aimed at optimising
liver perfusion and oxygen delivery. Outcome is dictated by the
morbidity and mortality associated with the underlying disease,
given that liver ischaemia frequently occurs in the context of
other organ ischaemia in high-risk patients.
Liver arterial disease
Hepatic arterial disease is rare outside the setting of liver
transplantation and is difficult to diagnose. It can cause
significant liver damage. Hepatic artery occlusion may result
from inadvertent injury during biliary surgery or may be caused by
emboli, neoplasms, polyarteritis nodosa, blunt trauma or radiation.
It usually causes severe upper abdominal pain with or without
signs of circulatory shock. LFTs show raised transaminases
(AST or ALT usually >1000 U/L), as in other causes of acute
liver damage. Patients usually survive if the liver and portal blood
supply are otherwise normal.
Hepatic artery aneurysms are extrahepatic in three-quarters
of cases and intrahepatic in one-quarter. Atheroma, vasculitis,
bacterial endocarditis and surgical or biopsy trauma are the
main causes. They usually lead to bleeding into the biliary tree,
peritoneum or intestine and are best diagnosed by angiography.
Treatment is radiological or surgical. Any of the vasculitides
can affect the hepatic artery but this rarely causes symptoms.
Hepatic artery thrombosis is a recognised complication of liver
transplantation and typically occurs in the early post-transplant
period. Clinical features are often related to bile duct rather than
liver ischaemia because of the dominant role of the hepatic artery
in extrahepatic bile duct perfusion. Manifestations can include
bile duct anastomotic failure with bile leak or the development
of late bile duct strictures. Diagnosis and initial intervention are
radiological in the first instance, with ERCP and biliary stenting
being the principal approaches to the treatment of bile duct injury.
Portal venous disease
Portal hypertension
See page 868.
|Portal vein thrombosis
Portal venous thrombosis as a primary event is rare but can
occur in any condition predisposing to thrombosis. It may also
complicate intra-abdominal inflammatory or neoplastic disease and
is a recognised cause of portal hypertension. Acute portal venous
thrombosis causes abdominal pain and diarrhoea, and may rarely
lead to bowel infarction, requiring surgery. Treatment is otherwise
based on anticoagulation, although there are no randomised data
that demonstrate efficacy. An underlying thrombophilia needs
to be excluded. Subacute thrombosis can be asymptomatic
but may subsequently lead to extrahepatic portal hypertension
(p. 868). Ascites is unusual in non-cirrhotic portal hypertension,
unless the albumin is particularly low.
Portal vein thrombosis can arise as a secondary event in
patients with cirrhosis and portal hypertension, and is a recognised
cause of decompensation in patients with previously stable
cirrhosis. In individuals showing such decompensation, portal
vein patency should be assessed by ultrasound with Doppler
flow studies.
Chronic portal vein thrombosis can be a cause of portal
hypertension.
Hepatopulmonary syndrome
This condition is characterised by resistant hypoxaemia (Pa02
<9.3 kPa (70 mmHg)), intrapulmonary vascular dilatation in
patients with cirrhosis, and portal hypertension. Clinical features
include finger clubbing, cyanosis, spider naevi and a characteristic
reduction in arterial oxygen saturation on standing. The hypoxia
is due to intrapulmonary shunting through direct arteriovenous
communications. Nitric oxide (NO) over-production may be
important in pathogenesis. The hepatopulmonary syndrome can
be treated by liver transplantation but, if severe (Pa02 <6.7 kPa
(50 mmHg)), is associated with an increased operative risk.
Ij’ortopulmonary hypertension
This unusual complication of portal hypertension is similar to
‘primary pulmonary hypertension’ (p. 621). It is defined as
pulmonary hypertension with increased pulmonary vascular
resistance and a normal pulmonary artery wedge pressure in
a patient with portal hypertension. The condition is caused by
vasoconstriction and obliteration of the pulmonary arterial system
and leads to breathlessness and fatigue.
Hepatic venous disease
Obstruction to hepatic venous blood flow can occur in the small
central hepatic veins, the large hepatic veins, the inferior vena
cava or the heart (see Fig. 22.20, p. 868). The clinical features
depend on the cause and on the speed with which obstruction
develops, and can mimic many other forms of chronic liver
disease, sometimes leading to delayed diagnosis. Congestive
hepatomegaly and ascites are, however, the most consistent
features. The possibility of hepatic venous obstruction should
always be considered in patients with an atypical liver presentation.
Budd-Chiari syndrome
This uncommon condition is caused by thrombosis of the larger
hepatic veins and sometimes the inferior vena cava. Many patients
have haematological disorders such as myelofibrosis, primary
proliferative polycythaemia, paroxysmal nocturnal haemoglobinuria,
Pregnancy and the liver • 899
or antithrombin III, protein C or protein S deficiencies (Ch. 23).
Pregnancy and oral contraceptive use, obstruction due to
tumours (particularly carcinomas of the liver, kidneys or adrenals),
congenital venous webs and occasionally inferior vena caval
stenosis are the other main causes. The underlying cause cannot
be found in about 50% of patients, although this percentage is
falling as molecular diagnostic tools (such as the JAK2 mutation
in myelofibrosis) increase our capacity to diagnose underlying
haematological disorders. Hepatic congestion affecting the
centrilobular areas is followed by centrilobular fibrosis, and
eventually cirrhosis supervenes in those who survive long enough.
Clinical features
Acute venous occlusion causes rapid development of upper
abdominal pain, marked ascites and occasionally acute liver
failure. More gradual occlusion causes gross ascites and, often,
upper abdominal discomfort. Hepatomegaly, frequently with
tenderness over the liver, is almost always present. Peripheral
oedema occurs only when there is inferior vena cava obstruction.
Features of cirrhosis and portal hypertension develop in those
who survive the acute event.
Investigations
The LFTs vary considerably, depending on the presentation, and
can show the features of acute hepatitis. Ascitic fluid analysis
shows a protein concentration above 25 g/L (2.5 g/dL) (exudate)
in the early stages; this often falls later in the disease, however.
Doppler ultrasound may reveal obliteration of the hepatic veins
and reversed flow or associated thrombosis in the portal vein.
CT may show enlargement of the caudate lobe, as this often
has a separate venous drainage system that is not involved in
the disease. CT and MRI may also demonstrate occlusion of the
hepatic veins and inferior vena cava. Liver biopsy demonstrates
centrilobular congestion with fibrosis, depending on the duration
of the illness. Venography is needed only if CT and MRI are
unable to demonstrate the hepatic venous anatomy clearly.
Management
Predisposing causes should be treated as far as possible; where
recent thrombosis is suspected, thrombolysis with streptokinase,
followed by heparin and oral anticoagulation, should be considered.
Ascites is initially treated medically but often with only limited
success. Short hepatic venous strictures can be treated with
angioplasty. In the case of more extensive hepatic vein occlusion,
many patients can be managed successfully by insertion of a
covered TIPSS, followed by anticoagulation. Surgical shunts,
such as portacaval shunts, are less commonly performed now
that TIPSS is available. Occasionally, a web can be resected or
an inferior vena caval stenosis dilated. Progressive liver failure is
an indication for liver transplantation and life-long anticoagulation.
Prognosis without transplantation or shunting is poor,
particularly following an acute presentation with liver failure. A
3-year survival of 50% is reported in those who survive the initial
event. The 1 - and 1 0-year survival following liver transplantation
is 85% and 69%, respectively, and this compares with a 5- and
10-year survival of 87% and 37%, respectively, following surgical
shunting.
I Sinusoidal obstruction syndrome
(veno-occlusive disease)
Sinusoidal obstruction syndrome (SOS; previously known
as veno-occlusive disease) is a rare condition characterised
by widespread occlusion of the small central hepatic veins.
Pyrrolizidine alkaloids in Senecio and Heliotropium plants used to
make teas, as well as cytotoxic drugs and hepatic irradiation, are
all recognised causes. SOS may develop in 1 0-20% of patients
following haematopoietic stem cell transplantation (usually within
the first 20 days) and carries a 90% mortality in severe cases.
Pathogenesis involves obliteration and fibrosis of terminal hepatic
venules due to deposition of red cells, haemosiderin-laden
macrophages and coagulation factors. In this setting, SOS is
thought to relate to pre-conditioning therapy with irradiation
and cytotoxic chemotherapy. The clinical features are similar to
those of the Budd-Chiari syndrome (see above). Investigations
show evidence of venous outflow obstruction histologically but,
in contrast to Budd-Chiari, the large hepatic veins appear patent
radiologically. Transjugular liver biopsy (with portal pressure
measurements) may facilitate the diagnosis. Traditionally, treatment
has been supportive but defibrotide shows promise (the drug
binds to vascular endothelial cells, promoting fibrinolysis and
suppressing coagulation).
J Cardiac disease
Hepatic damage, due primarily to congestion, may develop in all
forms of right heart failure (p. 461); usually, the clinical features are
predominantly cardiac. Very rarely, long-standing cardiac failure
and hepatic congestion give rise to cardiac cirrhosis. Severe
left ventricular dysfunction is a cause of ischaemic hepatitis.
Cardiac causes of acute and chronic liver disease are typically
under-diagnosed. Treatment is principally that of the underlying
heart disease with supportive treatment for the liver component.
Nodular regenerative hyperplasia of the liver
This is the most common cause of non-cirrhotic portal hyper¬
tension in developed countries; it is characterised by small
hepatocyte nodules throughout the liver without fibrosis, which
can result in sinusoidal compression. It is believed to be due
to damage to small hepatic arterioles and portal venules. It
occurs in older people and is associated with many conditions,
including connective tissue disease, haematological diseases and
immunosuppressive drugs, such as azathioprine. The condition
is usually asymptomatic but occasionally presents with portal
hypertension or with an abdominal mass. The diagnosis is made
by liver biopsy, which, in contrast to cirrhosis, shows nodule
formation in the absence of fibrous septa. Liver function is good
and the prognosis is very favourable. Management is based on
treatment of the portal hypertension.
Pregnancy and the liver
The inter-relationship between liver disease and pregnancy can
be a complex one and a source of real anxiety for both patient
and clinician. Three possibilities need to be borne in mind when
treating a pregnant woman with a liver abnormality:
• This represents a worsening of pre-existing chronic liver or
biliary disease (although pregnancy may be the first time a
woman’s liver biochemistry has been tested, so this may
not have previously been diagnosed).
• This represents a genuine first presentation of liver disease
that is not intrinsically related to pregnancy.
• This represents a genuine pregnancy-associated liver injury
process.
900 • HEPATOLOGY
It is critical to obtain information relating to liver disease risk
factors and pre-pregnancy liver status to establish whether any
abnormality was present before pregnancy. In general, the earlier
in pregnancy that liver abnormality presents, the more likely it is to
represent either pre-existing liver disease or non-pregnancy-related
acute liver disease. Equally, the best outcome for both mother
and baby results from optimising the physical condition of the
mother, and in situations of deteriorating liver function (which
can be steep in late pregnancy) consideration should always be
given to early delivery if the fetus is viable. Joint management
between hepatologists and obstetricians is essential.
Intercurrent and pre-existing liver disease
Acute hepatitis A can occur during pregnancy but has no effect on
the fetus. Chronic hepatitis B requires identification in pregnancy
because of long-term health implications for the mother and the
effectiveness of perinatal vaccination (with or without pre-delivery
maternal antiviral therapy) in reducing neonatal acquisition of
chronic hepatitis B. Maternal transmission of hepatitis C occurs
in 1 % of cases and there is no convincing evidence that the
mode of delivery affects this. Hepatitis E is reported to progress
to acute liver failure much more commonly in pregnancy, with a
20% maternal mortality. Pregnancy may be associated with either
worsening or improvement of autoimmune hepatitis, although
improvement during pregnancy and rebound post-partum is the
most common pattern seen. Complications of portal hypertension
may be a particular issue in the second and third trimesters.
Gallstones (p. 903) are more common during pregnancy and
may present with cholecystitis or biliary obstruction. The diagnosis
can usually be made with ultrasound. In biliary obstruction due
to gallstones, therapeutic ERCP can be safely performed but
lead protection for the fetus is essential and X-ray screening
must be kept to a minimum.
Pregnancy-associated liver disease
Several conditions occur only during pregnancy, may recur in
subsequent pregnancies and resolve after delivery of the baby,
and these are discussed on page 1283. The causes of abnormal
22.57 Abnormal liver function tests in pregnancy
• Liver function tests: alkaline phosphatase (ALP) levels and albumin
normally fall in pregnancy. ALP levels can rise due to the
contribution of placental ALP.
• Pre-existing liver disease: pregnancy is uncommon in cirrhosis
because cirrhosis causes relative infertility. Varices can enlarge in
pregnancy, and ascites should be treated with amiloride rather than
spironolactone. Penicillamine for Wilson’s disease and azathioprine
for autoimmune liver disease should be continued during pregnancy.
Autoimmune liver disease can flare up post-partum.
• Incidental: viral, autoimmune and drug-induced hepatitis must be
excluded in the presence of an elevated alanine aminotransferase
(ALT). Immunoglobulin/vaccination given to the fetus at birth prevents
transmission of hepatitis B to the fetus if the mother is infected.
Gallstones are more common in pregnancy and post-partum, and are
a cause of a raised ALP level. Biliary imaging with ultrasound and
magnetic resonance cholangiopancreatography is safe. Endoscopic
retrograde cholangiopancreatography to remove stones can be
performed safely with shielding of the fetus from radiation.
• Pregnancy-related liver diseases: occur predominantly in the
third trimester and resolve post-partum. Maternal and fetal mortality
and morbidity are reduced by expediting delivery.
LFTs in pregnancy, which include pregnancy-associated liver
disease, are shown in Box 22.57.
Liver transplantation
The outcome following liver transplantation has improved
significantly over the last decade so that elective transplantation
in low-risk individuals now has a 1 -year survival rate of more than
90% and is an effective treatment for end-stage liver disease. The
number of procedures is limited by cadaveric donor availability
and in many parts of the world this has led to living donor
transplant programmes. Despite this, 10% of those listed for
liver transplantation will die while awaiting a donor liver. The
main complications of liver transplantation relate to rejection,
complications of long-term immunosuppression and disease
recurrence in the liver graft.
Indications and contraindications
Currently, around 9500 liver transplants are undertaken in Europe
and the USA annually. About 1 0% are performed for acute liver
failure, 6% for metabolic diseases, 71% for cirrhosis and 11%
for hepatocellular carcinoma. Most patients are under 60 years
of age and only 10% are aged between 60 and 70 years.
Indications for elective transplant assessment are listed in Box
22.58. In North America, the most common indication is hepatitis
C cirrhosis, about 10-20% of transplants being for alcoholic
cirrhosis (Fig. 22.42). Patients with alcoholic liver disease need
to show a capacity for abstinence.
The main contraindications to transplantation are sepsis,
extrahepatic malignancy, active alcohol or other substance
misuse, and marked cardiorespiratory dysfunction.
Patients are matched for ABO blood group and size but do
not require HL4 matching with donors, as the liver is a relatively
immune-privileged organ compared with the heart or kidneys.
In many parts of the world, the MELD score (see Box 22.30,
p. 868) is used to identify and prioritise patients for transplantation.
In the UK, a similar system that also incorporates serum sodium,
the United Kingdom End-stage Liver Disease (UKELD) score,
is used to guide recipient selection. To be listed for elective
(non-super-urgent) transplantation in the UK, patients must have
a greater than 50% projected post-transplant 5-year survival and
must fall into one of three categories:
• Category 1: estimated 1-year mortality without
transplantation of more than 9% (equivalent to a UKELD
score of more than 49 points)
22.58 Indications for liver transplant assessment
for cirrhosis
Complications
• First episode of bacterial peritonitis
• Diuretic-resistant ascites
• Recurrent variceal haemorrhage
• Hepatocellular carcinoma <5 cm
• Persistent hepatic encephalopathy
Poor liver function
• Bilirubin >100 pmol/L (5.8 mg/dL) in primary biliary cholangitis
• MELD score >12 (Box 22.30, p. 868)
• Child-Pugh grade C (Box 22.29, p. 867)
(MELD = Model for End-stage Liver Disease)
Liver transplantation • 901
6%
11%
24%
11%
Hepatocellular
Primary biliary cholangitis
carcinoma
) Primary sclerosing cholangitis
Hepatitis C
Autoimmune liver disease
Alcohol
Cryptogenic
H Hepatitis B
■ Other
26%
Fig. 22.42 Indications for elective adult liver transplantation in the
UK, 2016.
• Category 2: HCC diagnosed radiologically by two
concordant modalities; based on CT, a single lesion of
less than 5 cm maximum diameter, or fewer than three
lesions each less than 3 cm in diameter, without
macrovascular invasion or metastases.
• Category 3: ‘variant syndromes’, including diuretic-resistant
ascites, hepatopulmonary syndrome, chronic hepatic
encephalopathy, intractable pruritus, familial amyloidosis,
primary hyperlipidaemia, polycystic liver disease and
recurrent cholangitis.
Super-urgent listing is reserved for patients with acute liver failure,
according to specific criteria.
Two types of transplant are increasingly used because of
insufficient cadaveric donors:
• Split liver transplantation. A cadaveric donor liver can be split
into two, with the larger right lobe used in an adult and
the smaller left lobe used in a child. This practice has led
to an increase in procedures despite a shortage of donor
organs.
• Living donor transplantation. This is normally performed using
the left lateral segment or the right lobe. The donor
mortality is significant at 0.5-1%. Pre-operative
assessment includes looking at donor liver size and
psychological status.
Complications
Early complications
Primary graft non-t unction
This is a state of hepatocellular dysfunction arising as a
consequence of liver paresis, which results from ischaemia
following removal from the donor and prior to reperfusion in
the recipient. Factors that increase the likelihood of primary
non-function include increasing donor age, degree of steatosis
in the liver and the length of ischaemia. Treatment is supportive
until recovery of function. Occasionally, recovery is not seen and
re-transplantation is necessary.
Technical complications
These include hepatic artery thrombosis, which may necessitate
re-transplantation. Anastomotic biliary strictures can also occur;
these may respond to endoscopic balloon dilatation and stenting,
or require surgical reconstruction. Portal vein thrombosis is rare.
Rejection
Less immunosuppression is needed following liver transplantation
than with kidney or heart/lung grafting. Initial immunosuppression
is usually with tacrolimus or ciclosporin, prednisolone and
azathioprine or mycophenolate. Some patients can eventually
be maintained on a single agent. Acute cellular rejection occurs
in 60-80% of patients, commonly at 5-1 0 days post-transplant
and usually within the first 6 weeks, but can arise at any point.
This normally responds to 3 days of high-dose intravenous
methylprednisolone.
Infections
Bacterial infections, such as pneumonia and wound infections, can
occur in the first few weeks after transplantation. Cytomegalovirus
(primary infection or reactivation) is a common infection in the
3 months after transplantation and can cause hepatitis. Patients
who have never had cytomegalovirus infection but who receive
a liver from a donor who has been exposed are at greatest risk
of infection and are usually given prophylactic antiviral therapy,
such as valganciclovir. Herpes simplex virus reactivation or, rarely,
primary infection may occur. Prophylaxis is given to recipients
who have had previous exposure to tuberculosis for the first
6 months after transplantation to prevent reactivation.
Late complications
These include recurrence of the initial disease in the graft and
complications due to the immunosuppressive therapy, such as
renal impairment from ciclosporin. Metabolic syndrome (p. 730) is
common, being described in about 50% of transplant recipients
within 6 months in the USA. Chronic vascular rejection is rare,
occurring in only 5% of cases.
Prognosis
The outcome following transplantation for acute liver failure is
worse than that for chronic liver disease because most patients
have multi-organ failure at the time of transplantation. The 1 -year
survival is 65% and falls only a little to 59% at 5 years. The
1-year survival for patients with cirrhosis is over 90%, falling to
70-75% at 5 years.
if\
• Alcoholic liver disease: 10% of cases present over the age of
70 years, when disease is more likely to be severe and has a worse
prognosis.
• Hepatitis A: causes more severe illness and runs a more protracted
course.
• Primary biliary cholangitis: one-third of cases are over 65 years.
• Liver abscess: more than 50% of all cases in the UK are over
60 years.
• Hepatocellular carcinoma: approximately 50% of cases in the UK
present over the age of 65 years.
• Surgery: older people are less likely to survive liver surgery
(including transplantation) because comorbidity is more prevalent.
22.59 Liver disease in old age
902 • HEPATOLOGY
Cholestatic and biliary disease
The concepts of biliary and cholestatic disease, and the important
distinctions between them, can be a source of confusion.
‘Cholestasis’ relates to a biochemical abnormality (typically,
elevation of ALP and elevation in serum bile acid levels and
bilirubin) that results from an abnormality in bile flow. The cause
can range from inherited or acquired dysfunction of transporter
molecules responsible for the production of canalicular bile to
physical obstruction of the extrahepatic bile duct. ‘Biliary disease’
relates to pathology at any level from the small intrahepatic
bile ducts to the sphincter of Oddi. Although there is very
significant overlap between cholestatic and biliary disease,
there are scenarios where cholestasis can exist without biliary
disease (transporter disease or pure drug-induced cholestasis)
and where biliary disease can exist without cholestasis (when
disease of the bile duct does not impact on bile flow). These
anomalies should always be borne in mind and cholestasis and
biliary disease always effectively distinguished.
Chemical cholestasis
Pure cholestasis can occur as an inherited condition (p. 895), as
a consequence of cholestatic drug reactions (p. 894) or as acute
cholestasis of pregnancy (p. 1284). A more frequent, but less
recognised, acquired biochemical cholestasis occurs in sepsis
(‘cholangitis lente’). This biochemical phenomenon is one of the
causes of LFT abnormality in sepsis, does not require specific
treatment, and has a prognostic significance conferred by the
underlying septic process.
Mutations in the biliary transporter proteins on the hepatocyte
canalicular membrane (familial intrahepatic cholestasis 1 , FIC1),
illustrated in Figure 22.7 (p. 851), have been shown to cause an
inherited intrahepatic biliary disease in childhood, characterised
by raised ALP levels and progression to a biliary cirrhosis. It is
also becoming increasingly clear that these proteins contribute
to intrahepatic biliary disease in adulthood.
Benign recurrent intrahepatic cholestasis
This rare condition usually presents in adolescence and is
characterised by recurrent episodes of cholestasis, lasting
1-6 months. It is now known to be mediated by mutations in the
ATP8B1 gene, which lies on chromosome 18 and encodes FIC1 .
Episodes start with pruritus, while painless jaundice develops
later. LFTs show a cholestatic pattern. Liver biopsy shows
cholestasis during an episode but is normal between episodes.
Treatment is required to relieve the symptoms of cholestasis,
such as pruritus, and the long-term prognosis is good.
Intrahepatic biliary disease
| Inflammatory and immune disease
The small intrahepatic bile ducts appear to be specifically
vulnerable to immune injury, and ductopenic injury (‘vanishing
bile duct syndrome’) can be a feature of a number of chronic
conditions, including graft-versus-host disease (GVHD), sarcoidosis
and, in the setting of liver transplantation, ductopenic rejection.
Intrahepatic small bile duct injury occurs most frequently in
primary biliary cholangitis, an autoimmune cholestatic disease,
and less frequently in primary sclerosing cholangitis (Box 22.60).
22.60 Comparison of primary biliary cholangitis
(PBC) and primary sclerosing cholangitis (PSC)
PBC
PSC
Gender (F:M)
10:1
1 :3
Age
Older: median age
50-55 years
Younger: median age
20-40 years
Disease
associations
Non-organ-specific
autoimmune disease
(e.g. Sjogren’s
syndrome) and
autoimmune thyroid
disease
Ulcerative colitis
Autoantibody
profile
90% AMA +ve
65-85% pANCA +ve
(but this is non-specific
and not diagnostic)
Predominant
bile-duct injury
Intrahepatic
Extrahepatic >
intrahepatic
(AMA = antimitochondrial antibody; pANCA = perinuclear antineutrophil
cytoplasmic antibody)
Caroli’s disease
This very rare disease is characterised by segmental saccular
dilatations of the intrahepatic biliary tree. The whole liver is
usually affected and extrahepatic biliary dilatation occurs in about
one-quarter of patients. Recurrent attacks of cholangitis (see Box
22.18, p. 861) may cause hepatic abscesses. Complications
include biliary stones and cholangiocarcinoma. Antibiotics are
required for episodes of cholangitis. Occasionally, localised
disease can be treated by segmental liver resection, and liver
transplantation may sometimes be required.
Congenital hepatic fibrosis
This is characterised by broad bands of fibrous tissue linking
the portal tracts in the liver, abnormalities of the interlobular
bile ducts and sometimes a lack of portal venules. The renal
tubules may show cystic dilatation (medullary sponge kidney;
p. 433), and eventually renal cysts may develop. The condition
can be inherited as an autosomal recessive trait. Liver involvement
causes portal hypertension with splenomegaly and bleeding from
oesophageal varices that usually presents in adolescence or in
early adult life. The prognosis is good because liver function is
preserved. Treatment may be required for variceal bleeding and
occasionally cholangitis. Patients can present during childhood
with renal failure if the kidneys are severely affected.
Cystic fibrosis
Cystic fibrosis (p. 580) is associated with biliary cirrhosis in
about 5% of individuals. Splenomegaly and an elevated ALP
are characteristic. Complications do not normally arise until late
adolescence or early adulthood, when bleeding due to variceal
haemorrhage may occur. UDCA improves liver blood tests but it
is not known whether the drug can prevent progression of liver
disease. Deficiency of fat-soluble vitamins (A, D, E and K) may
need to be treated in view of both biliary and pancreatic disease.
Extrahepatic biliary disease
Diseases of the extrahepatic biliary tree typically present with the
clinical features of impaired bile flow (obstructive jaundice and fat
Cholestatic and biliary disease • 903
Type I Type II Type III Type IV
(87%) (7%) (3%) (3%)
Fig. 22.43 Classification and frequency of choledochal cysts. From
Shearman DC, Finlayson NDC. Diseases of the gastrointestinal tract and
liver, 2nd edn. Edinburgh: Churchill Livingstone, Elsevier Ltd; 1989.
^9 22.61 Risk factors and mechanisms for
cholesterol gallstones
TCholesterol secretion
• Old age
• Obesity
• Female gender
• Rapid weight loss
• Pregnancy
Impaired gallbladder emptying
• Pregnancy
• Total parenteral nutrition
• Gallbladder stasis
• Spinal cord injury
• Fasting
4-Bile salt secretion
• Pregnancy
malabsorption). Obstructive disease is frequently a consequence
of stricturing following gallstone passage and associated infection
and inflammation or post-surgical intervention. PSC frequently
involves the extrahepatic biliary tree and its differential, lgG4
disease, is an important and potentially treatable cause of disease
(p. 890). Malignant diseases (cholangiocarcinoma or carcinoma
of the head of pancreas) should be considered in all patients
with extrahepatic biliary obstruction).
|j;holedochal cysts
This term applies to cysts anywhere in the biliary tree (Fig. 22.43).
The great majority cause diffuse dilatation of the common bile
duct (type I) but others take the form of biliary diverticula (type II),
dilatation of the intraduodenal bile duct (type III) and multiple biliary
cysts (type IV). The last type merges with Caroli’s disease (see
above). In the neonate, they may present with jaundice or biliary
peritonitis. Recurrent jaundice, abdominal pain and cholangitis may
arise in the adult. Liver abscess and biliary cirrhosis may develop
and there is an increased incidence of cholangiocarcinoma.
Excision of the cyst with hepatico-jejunostomy is the treatment
of choice.
Secondary biliary cirrhosis
Secondary biliary cirrhosis develops after prolonged large duct
biliary obstruction due to gallstones, benign bile duct strictures
or sclerosing cholangitis (see below). Carcinomas rarely cause
secondary biliary cirrhosis because few patients survive long
enough. The clinical features are those of chronic cholestasis
with episodes of ascending cholangitis or even liver abscess
(p. 879). Cirrhosis, ascites and portal hypertension are late
features. Relief of biliary obstruction may require endoscopic or
surgical intervention. Cholangitis dictates treatment with antibiotics,
which can be given continuously if attacks recur frequently.
Gallstones
Gallstone formation is the most common disorder of the biliary
tree and it is unusual for the gallbladder to be diseased in the
absence of gallstones. In developed countries, gallstones occur
in 7% of males and 15% of females aged 18-65 years, with an
overall prevalence of 11%. In individuals under 40 years there
is a 3 : 1 female preponderance, whereas in the elderly the sex
ratio is about equal. Gallstones are less frequent in India, the
Far East and Africa. There has been much debate over the role
of diet in cholesterol gallstone disease; an increase in dietary
22.62 Composition of and risk factors for
pigment stones
Black Brown
Composition
Polymerised calcium
bilirubinates*
Mucin glycoprotein
Calcium phosphate
Calcium carbonate
Cholesterol
Risk factors
Haemolysis
Age
Hepatic cirrhosis
Ileal resection/disease
*Major component.
cholesterol, fat, total calories and refined carbohydrate or lack
of dietary fibre has been implicated.
Pathophysiology
Gallstones are conventionally classified into cholesterol or
pigment stones, although the majority are of mixed composition.
Gallstones contain varying quantities of calcium salts, including
calcium bilirubinate, carbonate, phosphate and palmitate, which
are radio-opaque. Gallstone formation is multifactorial and the
factors involved are related to the type of gallstone (Boxes 22.61
and 22.62).
Cholesterol gallstones
Cholesterol is held in solution in bile by its association with bile
acids and phospholipids in the form of micelles and vesicles.
Biliary lipoproteins may also have a role in solubilising cholesterol.
In gallstone disease, the liver produces bile that contains an
excess of cholesterol because there is either a relative deficiency
of bile salts or a relative excess of cholesterol (‘lithogenic’ bile).
Abnormalities of bile salt synthesis and circulation, cholesterol
secretion and gallbladder function may make production of
lithogenic bile more likely.
Pigment stones
Brown, crumbly pigment stones are almost always the con¬
sequence of bacterial or parasitic biliary infection. They are
common in the Far East, where infection allows bacterial
(3-glucuronidase to hydrolyse conjugated bilirubin to its free form,
Calcium bilirubinate crystals*
Mucin glycoprotein
Cholesterol
Calcium palmitate/stearate
Infected bile
Stasis
904 • HEPATOLOGY
which then precipitates as calcium bilirubinate. The mechanism of
black pigment gallstone formation in developed countries is not
satisfactorily explained. Haemolysis is important as a contributing
factor for the development of black pigment stones that occur
in chronic haemolytic disease.
Biliary sludge
This describes gelatinous bile that contains numerous
microspheroliths of calcium bilirubinate granules and cholesterol
crystals, as well as glycoproteins; it is an important precursor
to the formation of gallstones in the majority of patients. Biliary
sludge is frequently formed under normal conditions but then
either dissolves or is cleared by the gallbladder; only in about
15% of patients does it persist to form cholesterol stones.
Fasting, parenteral nutrition and pregnancy are also associated
with sludge formation.
Clinical features
Only 1 0% of individuals with gallstones develop clinical evidence of
gallstone disease. Symptomatic stones within the gallbladder (Box
22.63) manifest as either biliary pain (‘biliary colic’) or cholecystitis
(see below). If a gallstone becomes acutely impacted in the cystic
duct, the patient will experience pain. The term ‘biliary colic’ is a
misnomer because the pain does not rhythmically increase and
decrease in intensity like other forms of colic. Typically, the pain
occurs suddenly and persists for about 2 hours; if it continues
for more than 6 hours, a complication such as cholecystitis or
pancreatitis may be present. Pain is usually felt in the epigastrium
(70% of patients) or right upper quadrant (20%) and radiates to
the interscapular region or the tip of the right scapula, but other
sites include the left upper quadrant and the lower chest. The
pain can mimic intrathoracic disease, oesophagitis, myocardial
infarction or dissecting aortic aneurysm.
Combinations of fatty food intolerance, dyspepsia and
flatulence not attributable to other causes have been referred
to as ‘gallstone dyspepsia’. These symptoms are not now
recognised as being caused by gallstones and are best regarded
as functional dyspepsia (p. 779). Acute and chronic cholecystitis
is described below.
A mucocele may develop if there is slow distension of the
gallbladder from continuous secretion of mucus; if this material
becomes infected, an empyema supervenes. Calcium may be
secreted into the lumen of the hydropic gallbladder, causing ‘limey’
bile, and if calcium salts are precipitated in the gallbladder wall,
the radiological appearance of ‘porcelain’ gallbladder results.
Gallstones in the gallbladder (cholecystolithiasis) migrate to the
common bile duct (choledocholithiasis; p. 906) in approximately
22.63 Clinical features and complications
of gallstones
15% of patients and cause biliary colic. Rarely, fistulae develop
between the gallbladder and the duodenum, colon or stomach. If
this occurs, air will be seen in the biliary tree on plain abdominal
X-rays. If a stone larger than 2.5 cm in diameter has migrated into
the gut, it may impact either at the terminal ileum or occasionally
in the duodenum or sigmoid colon. The resultant intestinal
obstruction may be followed by ‘gallstone ileus’. Gallstones
impacted in the cystic duct may cause stricturing of the common
hepatic duct and the clinical picture of extrahepatic biliary diseases
(‘Mirizzi’s syndrome’, with its important differential of malignant
bile duct stricture). The more common cause of jaundice due
to gallstones is a stone passing from the cystic duct into the
common bile duct (choledocholithiasis), which may also result in
cholangitis or acute pancreatitis. It is usually very small stones
that precipitate acute pancreatitis, due (it is thought) to oedema
at the ampulla as the stone passes into the duodenum (no
stone is seen within the bile duct in 80% of cases of presumed
gallstone pancreatitis, suggesting stone passage). Previous
stone passage is also the likely cause of most cases of benign
papillary fibrosis, which is most commonly seen in patients with
previous or present gallstone disease (it may present with jaundice,
obstructive LFTs with biliary dilatation, post-cholecystectomy
pain or acute pancreatitis).
Cancer of the gallbladder is growing in frequency (p. 907) but in
over 95% of cases is associated with the presence of gallstones.
Previously, the diagnosis was typically made as an incidental
histological finding following cholecystectomy for gallstone disease.
Increasing awareness of the risk of gallbladder carcinoma and
of the role played by polyps in the natural history has led to an
increase in screening activity and prospective diagnosis.
Investigations
Ultrasound is the investigation of choice for diagnosing gallstones.
Most stones are diagnosed by transabdominal ultrasound,
which has more than 92% sensitivity and 99% specificity for
gallbladder stones (see Fig. 22.8, p. 854). CT, MRCP (Fig.
22.44) and, increasingly, EUS are excellent modalities for
detecting complications of gallstones (distal bile duct stone or
gallbladder empyema) but are inferior to ultrasound in defining
Fig. 22.44 Magnetic resonance cholangiopancreatogram showing
multiple stones in the gallbladder (long arrow) and also within the
distal common bile duct (inset, arrow).
Clinical features
• Asymptomatic (80%)
• Biliary colic
Complications
• Empyema of the gallbladder
• Porcelain gallbladder
• Choledocholithiasis
• Acute pancreatitis
• Fistulae from gallbladder to
duodenum/colon
• Acute cholecystitis
• Chronic cholecystitis
• Pressure on/inflammation of
the common hepatic duct by a
gallstone in the cystic duct
(Mirizzi’s syndrome)
• Gallstone ileus
• Cancer of the gallbladder
Cholestatic and biliary disease • 905
i
their presence in the gallbladder. When recurrent attacks of
otherwise unexplained acute pancreatitis occur, they may result
from ‘microlithiasis’ in the gallbladder or common bile duct and
are best assessed by EUS.
Management
Asymptomatic gallstones found incidentally should not be
treated because the majority will never cause symptoms.
Symptomatic gallstones are best treated surgically by laparoscopic
cholecystectomy; the severity of symptoms should be balanced
against the individual patient surgical risk in order to decide
whether surgery is warranted. Various techniques can be used
to treat common bile duct stones (Box 22.64).
Cholecystitis
Acute cholecystitis
Pathophysiology
Acute cholecystitis is almost always associated with obstruction
of the gallbladder neck or cystic duct by a gallstone. Occasionally,
obstruction may be by mucus, parasitic worms or a biliary tumour,
or may follow endoscopic bile duct stenting. The pathogenesis
is unclear but the initial inflammation is possibly chemically
induced. This leads to gallbladder mucosal damage, which
releases phospholipase, converting biliary lecithin to lysolecithin, a
recognised mucosal toxin. At the time of surgery, approximately
50% of cultures of the gallbladder contents are sterile. Infection
occurs eventually, and in elderly patients or those with diabetes
mellitus a severe infection with gas-forming organisms can cause
emphysematous cholecystitis. Acalculous cholecystitis can occur
in the intensive care setting and in association with parenteral
nutrition, sickle cell disease and diabetes mellitus.
Clinical features
The cardinal feature is pain in the right upper quadrant but also
in the epigastrium, the right shoulder tip or the interscapular
region. Differentiation between biliary colic (p. 904) and acute
cholecystitis may be difficult; features suggesting cholecystitis
include severe and prolonged pain, fever and leucocytosis.
Examination shows right hypochondrial tenderness, rigidity
worse on inspiration (Murphy’s sign) and occasionally a gallbladder
mass (30% of cases). Fever is present but rigors are unusual.
Jaundice occurs in less than 1 0% of patients and is usually due to
passage of stones into the common bile duct, or to compression
or even stricturing of the common bile duct following stone
impaction in the cystic duct (Mirizzi’s syndrome). Gallbladder
perforation occurs in 10-15% of cases and gallbladder empyema
may arise.
Investigations
Peripheral blood leucocytosis is common, except in the elderly
patient, in whom the signs of inflammation may be minimal. Minor
increases of transaminases and amylase may be encountered.
Amylase should be measured to detect acute pancreatitis (p. 837),
which may be a potentially serious complication of gallstones.
Only when the amylase is higher than 1000 U/L can pain be
confidently attributed to acute pancreatitis, since moderately
elevated levels of amylase can occur with many other causes
of abdominal pain. Plain X-rays of the abdomen and chest may
show radio-opaque gallstones, and rarely intrabiliary gas due
to fistulation of a gallstone into the intestine; they are important
in excluding lower lobe pneumonia and a perforated viscus.
Ultrasonography detects gallstones and gallbladder thickening
due to cholecystitis but gallbladder empyema or perforation is
best assessed by CT.
Management
Medical
Medical management consists of bed rest, pain relief, antibiotics
and intravenous fluids. Moderate pain can be treated with NSAIDs
but more severe pain should be managed with opiates. A
cephalosporin (such as cefuroxime) or piperacillin/tazobactam
is the usual antibiotic of choice, but metronidazole is normally
added in severely ill patients and local prescribing practice
may vary. Nasogastric aspiration is needed only for persistent
vomiting. Cholecystitis usually resolves with medical treatment
but the inflammation may progress to an empyema or perforation
and peritonitis.
Surgical
Urgent surgery is the optimal treatment when cholecystitis
progresses in spite of medical therapy and when complications
such as empyema or perforation develop. Operation should
be carried out within 5 days of the onset of symptoms.
Delayed surgery after 2-3 months is no longer favoured. When
cholecystectomy may be difficult due to extensive inflammatory
change, percutaneous gallbladder drainage can be performed,
with subsequent cholecystectomy 4-6 weeks later. Recurrent
biliary colic or cholecystitis is frequent if the gallbladder is not
removed.
I Chronic cholecystitis
Chronic inflammation of the gallbladder is almost invariably
associated with gallstones. The usual symptoms are those
of recurrent attacks of upper abdominal pain, often at night
and following a heavy meal. The clinical features are similar to
those of acute calculous cholecystitis but milder. Patients may
recover spontaneously or following analgesia and antibiotics.
They are usually advised to undergo elective laparoscopic
cholecystectomy.
Acute cholangitis
Acute cholangitis is caused by bacterial infection of bile ducts
and occurs in patients with other biliary problems, such as
choledocholithiasis (see below), biliary strictures or tumours, or
after ERCP. Jaundice, fever (with or without rigors) and right
upper quadrant pain are the main presenting features (‘Charcot’s
triad’). Treatment is with antibiotics, relief of biliary obstruction
and removal (if possible) of the underlying cause.
22.64 Treatment of gallstones
Gallbladder stones
• Cholecystectomy: laparoscopic or open
• Oral bile acids: chenodeoxycholic or ursodeoxycholic (low rate of
stone dissolution)
Bile duct stones
• Lithotripsy (endoscopic or extracorporeal shock wave, ESWL)
• Endoscopic sphincterotomy and stone extraction
• Surgical bile duct exploration
906 • HEPATOLOGY
Fig. 22.45 Endoscopic retrograde cholangiopancreatogram showing
common duct stones (arrows).
Choledocholithiasis
Stones in the common bile duct (choledocholithiasis) occur in
10-15% of patients with gallstones (Fig. 22.45), which have
usually migrated from the gallbladder. Primary bile duct stones
are rare but can develop within the common bile duct many
years after a cholecystectomy, and are sometimes related to
biliary sludge arising from dysfunction of the sphincter of Oddi.
In Far Eastern countries, primary common bile duct stones
are thought to follow bacterial infection secondary to parasitic
infections with Clonorchis sinensis, Ascaris lumbricoides or
Fasciola hepatica (pp. 297 and 289 ). Common bile duct stones
can cause bile duct obstruction and may be complicated by
cholangitis due to secondary bacterial infection, sepsis, liver
abscess and biliary stricture.
Clinical features
Choledocholithiasis may be asymptomatic, may be found
incidentally by operative cholangiography at cholecystectomy,
or may manifest as recurrent abdominal pain with or without
jaundice. The pain is usually in the right upper quadrant, and
fever, pruritus and dark urine may be present. Rigors may be
a feature; jaundice is common and usually associated with
pain. Physical examination may show the scar of a previous
cholecystectomy; if the gallbladder is present, it is usually small,
fibrotic and impalpable.
Investigations
The LFTs show a cholestatic pattern and there is bilirubinuria.
If cholangitis is present, the patient usually has a leucocytosis.
The most convenient method of demonstrating obstruction to
the common bile duct is transabdominal ultrasound. This shows
dilated extrahepatic and intrahepatic bile ducts, together with
gallbladder stones (Fig. 22.46), but does not always reveal the
Fig. 22.46 Endoscopic ultrasound image in a patient with
cholangitis. The dilated common bile duct (CBD) contains a small stone
(arrow), which causes acoustic shadowing.
cause of the obstruction in the common bile duct; 50% of bile
duct stones are missed on ultrasound, particularly those in the
distal common bile duct. EUS is extremely accurate at identifying
bile duct stones. MRCP is non-invasive and is indicated when
intervention is not necessarily mandatory (e.g. the patient with
possible bile duct stones but no jaundice or sepsis).
Management
Cholangitis should be treated with analgesia, intravenous fluids and
broad-spectrum antibiotics, such as cefuroxime and metronidazole
(local prescribing practice may vary). Blood cultures should be
taken before the antibiotics are administered. Patients also require
urgent decompression of the biliary tree and stone removal.
ERCP with biliary sphincterotomy and stone extraction is the
treatment of choice and is successful in about 90% of patients. If
ERCP fails, other approaches include percutaneous transhepatic
drainage and combined (‘rendezvous’) endoscopic procedures,
extracorporeal shock wave lithotripsy (ESWL) and surgery.
Surgical treatment of choledocholithiasis is performed less
frequently than ERCP, and before the common bile duct is
explored the diagnosis of choledocholithiasis should be confirmed
by intraoperative cholangiography. If gallstones are found, the bile
duct is explored, either via the cystic duct or by opening it, all
stones are removed, clearance is checked by cholangiography
or choledochoscopy, and then primary closure of the duct is
performed if possible. External drainage of the common bile
duct by T-tube is rarely required nowadays. It is now possible
to achieve these goals laparoscopically in specialist centres.
|Recurrent pyogenic cholangitis
This disease occurs predominantly in South-east Asia. Biliary
sludge, calcium bilirubinate concretions and stones accumulate
in the intrahepatic bile ducts, with secondary bacterial infection.
Patients present with recurrent attacks of upper abdominal pain,
fever and cholestatic jaundice. Investigation of the biliary tree
demonstrates that both the intrahepatic and the extrahepatic
portions are filled with soft biliary mud. Eventually, the liver
becomes scarred and liver abscesses and secondary biliary
cirrhosis develop. The condition is difficult to manage and requires
Cholestatic and biliary disease • 907
drainage of the biliary tract with extraction of stones, antibiotics
and, in certain patients, partial resection of damaged areas of
the liver.
Tumours of the gallbladder and bile duct
|j!arcinoma of the gallbladder
This is an uncommon tumour, occurring more often in females
and usually in those over the age of 70 years. More than 90%
are adenocarcinomas; the remainder are anaplastic or, rarely,
squamous tumours. Gallstones are present in 70-80% of cases
and are thought to be important in the aetiology of the tumour.
Individuals with a calcified gallbladder (‘porcelain gallbladder’;
p. 904) are at high risk of malignant change, and gallbladder
polyps over 1 cm in size are associated with increased risk of
malignancy; preventative cholecystectomy should be considered
in such patients. Chronic infection with Salmonella, especially in
areas where typhoid is endemic, is also a risk factor.
Carcinoma of the gallbladder may be diagnosed incidentally
and is found in 1-3% of gallbladders removed at cholecystectomy
for gallstone disease. It may manifest as repeated attacks of
biliary pain and, later, persistent jaundice and weight loss. A
gallbladder mass may be palpable in the right hypochondrium.
LFTs show cholestasis, and porcelain gallbladder may be found
on X-ray. The tumour can be diagnosed by ultrasonography
and staged by CT. The treatment is surgical excision but local
extension of the tumour beyond the wall of the gallbladder into
the liver, lymph nodes and surrounding tissues is invariable and
palliative management is usually all that can be offered. Survival is
generally short, death typically occurring within 1 year in patients
presenting with symptoms.
Cholangiocarcinoma
Cholangiocarcinoma (CCA) is an uncommon tumour that can
arise anywhere in the biliary tree, from the intrahepatic bile ducts
(20-25% of cases) and the confluence of the right and left
hepatic ducts at the liver hilum (50-60%) to the distal common
bile duct (20%). It accounts for only 1 .5% of all cancers but
the incidence is increasing. The cause is unknown but the
tumour is associated with gallstones, primary and secondary
sclerosing cholangitis, Caroli’s disease and choledochal cysts
(see Fig. 22.43). In the Far East, particularly northern Thailand,
chronic liver fluke infection (Clonorchis sinensis) is a major risk
factor for the development of CCA in men. Primary sclerosing
cholangitis carries a lifetime risk of CCA of approximately 20%,
although only 5% of CCAs relate to primary sclerosing cholangitis.
Chronic biliary inflammation appears to be a common factor in
the development of biliary dysplasia and cancer that is shared
by all the predisposing causes.
Tumours typically invade the lymphatics and adjacent vessels,
with a predilection for spread within perineural sheaths. The
presentation is usually with obstructive jaundice. About 50% of
patients also have upper abdominal pain and weight loss. The
diagnosis is made using a combination of CT and MRI (see
Fig. 22.10, p. 855) but can be difficult to confirm in patients
with sclerosing cholangitis. Serum levels of the tumour marker
CA19-9 are elevated in up to 80% of cases, although this
may occur in biliary obstruction of any cause. In the setting of
biliary obstruction, ERCP may result in positive biliary cytology.
Endoscopic ultrasound-fine needle aspiration (EUS-FNA) of bile
duct masses is sometimes possible, and in specialist centres
single-operator cholangioscopy with biopsy is now established.
CCAs can be treated surgically in about 20% of patients, which
improves 5-year survival from less than 5% to 20-40%. Surgery
involves excision of the extrahepatic biliary tree with or without a
liver resection and a Roux loop reconstruction. However, most
patients are treated by stent insertion across the malignant
biliary stricture, using endoscopic or percutaneous transhepatic
techniques (Fig. 22.47). Combination chemotherapy is increasingly
used and palliation with endoscopic photodynamic therapy has
provided encouraging results.
| Carcinoma at the ampulla of Vater
Nearly 40% of all adenocarcinomas of the small intestine arise
in relationship to the ampulla of Vater and present with pain,
anaemia, vomiting and weight loss. Jaundice may be intermittent
or persistent. The diagnosis is made by duodenal endoscopy and
biopsy of the tumour but staging by CT/MRI and EUS is essential.
Ampullary carcinoma must be differentiated from carcinoma of
Fig. 22.47 Cholangiocarcinoma. [A] Endoscopic
retrograde cholangiopancreatogram showing a
malignant distal biliary stricture (arrow) and dilated duct
above this. |B A self-expanding metallic stent (SEMS)
has been placed across the stricture to relieve jaundice
(arrow).
908 • HEPATOLOGY
the head of the pancreas and a CCA because these last two
conditions both have a worse prognosis. Imaging may show a
‘double duct sign’ with stricturing of both the common bile duct
and pancreatic duct at the ampulla and upstream dilatation of
the ducts. EUS is the most sensitive method of assessing and
staging ampullary or periampullary tumours.
Curative surgical treatment can be undertaken by pan¬
creaticoduodenectomy and the 5-year survival may be as high
as 50%. If resection is impossible, palliative surgical bypass or
stenting may be necessary.
Benign gallbladder tumours
These are uncommon, often asymptomatic and usually found
incidentally at operation or postmortem. Cholesterol polyps,
sometimes associated with cholesterolosis, papillomas and
adenomas, are the main types.
I Functional biliary sphincter disorders
(‘sphincter of Oddi dysfunction’)
The sphincter of Oddi is a small smooth-muscle sphincter
situated at the junction of the bile duct and pancreatic duct
in the duodenum. It has been believed that sphincter of Oddi
dysfunction (SOD) was characterised by an increase in contractility
that produces a benign non-calculous obstruction to the flow
of bile or pancreatic juice. This may cause pancreaticobiliary
pain, deranged LFTs or recurrent pancreatitis. Classification
systems, based on clinical history, laboratory results, findings on
investigation and response to interventions, are difficult because
of the fluctuating nature of symptoms and the well -recognised
placebo effect of interventions. SOD was previously classified into
types l-lll but these have been replaced by newer terminology
(Boxes 22.66 and 22.67).
Clinical features
Patients with functional biliary sphincter disorders, who are
predominantly female, present with symptoms and signs
suggestive of either biliary or pancreatic disease:
• Patients with biliary sphincter disorders experience
recurrent, episodic biliary-type pain. They have often had a
cholecystectomy but the gallbladder may be intact.
• Patients with pancreatic sphincter disorders usually
present with unexplained recurrent attacks of pancreatitis.
Investigations
The diagnosis is established by excluding gallstones, including
microlithiasis, and by demonstrating a dilated or slowly draining
bile duct. The gold standard for diagnosis is sphincter of Oddi
manometry. This is not widely available, however, and is associated
with a high rate of procedure- related pancreatitis. Hepatobiliary
scintigraphy (e.g. hepatobiliary iminodiacetic acid) may have
value in the second-line investigation of post-cholecystectomy
syndrome.
22.66 Classification of biliary sphincter
of Oddi dysfunction (SOD)
Organic stenosis (formerly SOD type I)
• Biliary-type pain
• Abnormal liver enzymes (ALT/AST > twice normal on two or more
occasions)
• Dilated common bile duct (> 1 2 mm diameter)
• Delayed drainage of ERCP contrast beyond 45 mins
Functional sphincter of Oddi disorder (formerly SOD type II)
• Biliary-type pain with one or two of the above criteria
Functional biliary-type pain (formerly SOD type III)
• Biliary-type pain with no other abnormalities
22.67 Criteria for pancreatic sphincter
of Oddi dysfunction
• Recurrent attacks of acute pancreatitis - pancreatic-type pain with
amylase or lipase 3 times normal and/or imaging evidence of acute
pancreatitis
• Other aetiologies of acute pancreatitis excluded
• Normal pancreas at endoscopic ultrasound
• Abnormal sphincter manometry
Miscellaneous biliary disorders
Post-cholecystectomy syndrome
Dyspeptic symptoms following cholecystectomy (post¬
cholecystectomy syndrome) occur in about 30% of patients,
depending on how the condition is defined, how actively
symptoms are sought and what the original indication for
cholecystectomy was. The syndrome occurs most frequently
in women, in patients who have had symptoms for more than
5 years before cholecystectomy, and in cases when the operation
was undertaken for non-calculous gallbladder disease. An increase
in bowel habit resulting from bile acid diarrhoea occurs in about
5-1 0% of patients after cholecystectomy and often responds
to colestyramine (4-8 g daily). Severe post-cholecystectomy
syndrome occurs in only 2-5% of patients. The main causes
are listed in Box 22.65.
The usual symptoms include right upper quadrant pain,
flatulence, fatty food intolerance and occasionally jaundice and
cholangitis. The LFTs may be abnormal and sometimes show
cholestasis. Ultrasonography is used to detect biliary obstruction,
and EUS or MRCP to seek common bile duct stones. If retained
bile duct stones are excluded, sphincter of Oddi dysfunction
should be considered (see below). Other investigations that
may be required include upper gastrointestinal endoscopy, small
bowel radiology and pancreatic function tests. The possibility of
a functional illness should also be considered.
22.65 Causes of post-cholecystectomy symptoms
Immediate post-surgical
• Bleeding
•
Bile duct trauma/transection
• Biliary peritonitis
• Abscess
•
Fistula
Biliary
• Common bile duct stones
•
Disorders of the ampulla of
• Benign stricture
Vater (e.g. benign papillary
• Tumour
fibrosis; sphincter of Oddi
• Cystic duct stump syndrome
dysfunction)
Extrabiliary
• Functional dyspepsia
•
Gastro-oesophageal reflux
• Peptic ulcer
•
Irritable bowel syndrome
• Pancreatic disease
•
Functional abdominal pain
Further information • 909
• Gallstones: by the age of 70 years, prevalence is around 30% in
women and 19% in men.
• Acute cholecystitis: tends to be severe, may have few localising
signs and is associated with a high frequency of empyema and
perforation. If such complications supervene, mortality may reach
20%.
• Cholecystectomy: mortality after urgent cholecystectomy for acute
uncomplicated cholecystitis is not significantly higher than in
younger patients.
• Endoscopic sphincterotomy and removal of common duct
stones: well tolerated by older patients, with lower mortality than
surgical common bile duct exploration.
• Cancer of the gallbladder: a disease of old age, with a 1 -year
survival of 10%.
22.68 Gallbladder disease in old age
Management
All patients with organic stenosis are treated with endoscopic
sphincterotomy. The results are good but patients should be
warned that there is a high risk of complications, particularly
acute pancreatitis. Manometry should ideally be performed
in all suspected functional sphincter of Oddi disorder patients
(‘type II’), and results of sphincterotomy in those with high
pressures are good, but this should be avoided in patients with
functional biliary-type pain (‘type III’), as it is of no benefit. Medical
therapy with nifedipine and/or low-dose amitriptyline may be
tried. Pancreatic SOD can be treated with biliary sphincterotomy,
carried out in specialist centres, but this should be undertaken
with caution and careful consideration.
Routine prophylactic pancreatic duct stenting in patients
undergoing ERCP for sphincter of Oddi disorders is no longer
encouraged. Prophylactic administration of rectal NSAIDs
(e.g. diclofenac 100 mg) is recommended instead because
this significantly reduces the risk of procedure-related acute
pancreatitis.
Cholesterolosis of the gallbladder
In this condition, lipid deposits in the submucosa and epithelium
appear as multiple yellow spots on the pink mucosa, giving rise
to the description ‘strawberry gallbladder’. Cholesterolosis of
the gallbladder is usually asymptomatic but may occasionally
present with right upper quadrant pain. Small, fixed filling defects
may be visible on ultrasonography; the radiologist can usually
differentiate between gallstones and cholesterolosis. The condition
is usually diagnosed at cholecystectomy; if the diagnosis is made
radiologically, cholecystectomy may be indicated, depending
on symptoms.
Adenomyomatosis of the gallbladder
In this condition, there is hyperplasia of the muscle and mucosa of
the gallbladder. The projection of pouches of mucous membrane
through weak points in the muscle coat produces Rokitansky-
Aschoff sinuses. There is much disagreement over whether
adenomyomatosis is a cause of right upper quadrant pain or
other gastrointestinal symptoms. It may be diagnosed by oral
cholecystography, when a halo or ring of opacified diverticula
can be seen around the gallbladder. Other appearances include
deformity of the body of the gallbladder or marked irregularity
of the outline. Localised adenomyomatosis in the region of the
gallbladder fundus causes the appearance of a ‘Phrygian cap’.
Most patients are treated by cholecystectomy but only after other
diseases in the upper gastrointestinal tract have been excluded.
|jgG4-associated cholangitis
This recently reported disease often presents with obstructive
jaundice and is described on page 890.
Further information
Books and journal articles
Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes
mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol
Hepatol 2013; 10:330-344.
EASL Clinical practice guidelines: Autoimmune hepatitis. J Hepatol
2015; 63:971-1004.
EASL Clinical practice guidelines: Liver transplantation. J Hepatol
2016; 64:433-485.
EASL Recommendations on treatment of hepatitis C 2015. J Hepatol
2015; 63:199-236.
EASL-EASD-EASO Clinical practice guidelines for the management of
non-alcoholic fatty liver disease. J Hepatol 2016; 64:1388-1402.
Neuberger J, Gimson A, Davies M, et al. Selection of patients for liver
transplantation and allocation of donated livers in the UK. Gut 2008;
57:252-257.
Williams R, Aspinall R, Beilis M, et al. Addressing liver disease in the
UK: a blueprint for attaining excellence in health care and reducing
premature mortality from lifestyle issues of excess consumption of
alcohol, obesity, and viral hepatitis. Lancet 2014; 384:1953-1997.
Websites
aasld.org American Association for the Study of Liver Diseases
(guidelines available).
bsg.org.uk British Society of Gastroenterology (guidelines available).
easl.eu European Association for the Study of the Liver (guidelines
available).
eltr.org European Liver Transplant Registry.
unos.org United Network for Organ Sharing: US transplant register.
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HG Watson
DJ Culligan
LM Manson
Haematology and
transfusion medicine
Clinical examination in blood disease 912
Anaemias 940
Functional anatomy and physiology 914
Iron deficiency anaemia 940
Haematopoiesis 91 4
Anaemia of chronic disease 943
Blood cells and their functions 91 5
Megaloblastic anaemia 943
Haemostasis 91 7
Haemolytic anaemia 945
Investigation of diseases of the blood 919
Haemoglobinopathies 951
The full blood count 91 9
Sickle-cell anaemia 951
Blood film examination 920
Other abnormal haemoglobins 953
Bone marrow examination 920
Thalassaemias 953
Investigation of coagulation 920
Haematological malignancies 954
Presenting problems in blood disease 923
Leukaemias 954
Anaemia 923
Lymphomas 961
High haemoglobin 925
Paraproteinaemias 966
Leucopenia (low white cell count) 925
Aplastic anaemias 968
Leucocytosis (high white cell count) 926
Myeloproliferative neoplasms 969
Lymphadenopathy 927
Splenomegaly 927
Bleeding disorders 970
Bleeding 927
Disorders of primary haemostasis 970
Thrombocytopenia (low platelet count) 929
Coagulation disorders 971
Thrombocytosis (high platelet count) 929
Thrombotic disorders 975
Pancytopenia 930
Venous thromboembolic disease (venous thromboembolism) 975
Infection 930
Inherited and acquired thrombophilia and prothrombotic states 977
Principles of management of haematological disease 930
Blood products and transfusion 930
Chemotherapy 936
Haematopoietic stem cell transplantation 936
Anticoagulant and antithrombotic therapy 938
912 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Clinical examination in blood disease
4 Conjunctivae
Pallor
Jaundice
3 Mouth
Lips: angular stomatitis,
telangiectasia
Gum hypertrophy
Tongue: colour, smoothness
Buccal mucosa: petechiae
Tonsils: size
A Glossitis and angular
stomatitis in iron deficiency
A Gum hypertrophy in
acute myeloid leukaemia
A Hereditary haemorrhagic
telangiectasia
2 Pulse
Rate
1 Hands
Perfusion
Telangiectasia
Skin crease pallor
Koilonychia
A Koilonychia in iron
deficiency
5 Fundi
Hyperviscosity
Engorged veins
Papilloedema
Haemorrhage
AFundal haemorrhage in
thrombocytopenia
• General well-being
• Colour: pallor, plethora
• Breathlessness
6 Lymph nodes
(see opposite)
7 Skin
Purpura
Bruising
APurpura/petechiae in
thrombocytopenia
8 Abdomen
Masses
Ascites
Hepatomegaly
Splenomegaly
Inguinal and femoral lymph
nodes
9 Joints
Deformity
Swelling
Restricted movement
ASwollen joint in haemophilia
10 Feet
Peripheral circulation
Toes: gangrene
AGangrenous toe in
thrombocytosis
11 Urinalysis
Blood
Urobilinogen
Insets (Glossitis) From Hoff brand VA, John E, Pettit JE, I Jyas P. Color atlas of clinical hematology, 4th edn. Philadelphia: Mosby, Elsevier Inc.; 2010;
(Petechiae) Young NS, Gerson SL, High KA (eds). Clinical hematology. St Louis: Mosby, Elsevier Inc.; 2006.
Clinical examination in blood disease • 913
Abnormalities detected in the blood are
caused not only by primary diseases of
the blood and lymphoreticular systems but
also by diseases affecting other systems
of the body. The clinical assessment of
patients with haematological abnormalities
must include a general history and
examination, as well as a search for
symptoms and signs of abnormalities of
red cells, white cells, platelets, haemostatic
systems, lymph nodes and lymphoreticular
tissues.
Anaemia
Symptoms and signs help to indicate the
clinical severity of anaemia. A full history
and examination is needed to identify the
underlying cause.
6 Lymphadenopathy
Lymphadenopathy can be caused by benign or malignant disease. The clinical points to clarify are
shown in the box.
Supraclavicular
- — Axillary
-Epitrochlear
Inguinal
Femoral
Popliteal
fossa
Lymphadenopathy
History
• Speed of onset, rate of enlargement
• Painful or painless
• Associated symptoms: weight loss, night
sweats, itch
Examination
• Sites: localised, generalised
• Size (cm)
• Character: hard, soft, rubbery
• Fixed, mobile
• Search area that node drains for
abnormalities (e.g. dental abscess)
• Other general examination (e.g. joints,
rashes, finger clubbing)
Pre-auricular
Parotid
Submandibular
Submental
Anterior cervical
Posterior cervical
Supraclavicular
8 Examination of the spleen
• Move your hand up from the right iliac
fossa, towards the left upper quadrant on
expiration.
• Keep your hand still and ask the patient
to take a deep breath through the mouth
to feel the spleen edge being displaced
downwards.
• Place your left hand around the patient’s
lower ribs and approach the costal margin
to pull the spleen forwards.
• To help palpate small spleens, roll the
patient on to the right side and examine
as before.
i
• Notch
• Superficial
• Dull to percussion
• Cannot get examining hand between ribs
and spleen
• Moves well with respiration
Characteristics of the spleen
Anaemia
Non-specific symptoms
• Tiredness
• Lightheadedness
• Breathlessness
• Development/worsening of ischaemic
symptoms, e.g. angina or claudication
Non-specific signs
• Mucous membrane pallor
• Tachypnoea
• Raised jugular venous pressure
• Tachycardia
• Flow murmurs
• Ankle oedema
• Postural hypotension
Bleeding
Bleeding can be due to congenital or
acquired abnormalities in the clotting
system. History and examination help to
clarify the severity and the underlying cause
of the bleeding problem.
Bleeding
History
• Site of bleed
• Duration of bleed
• Precipitating causes, including previous
surgery or trauma
• Family history
• Drug history
• Age at presentation
• Other medical conditions, e.g. liver
disease
Examination
There are two main patterns of bleeding:
1 . Mucosal bleeding
Reduced number or function of platelets
(e.g. bone marrow failure or aspirin) or
von Willebrand factor (e.g. von Willebrand
disease)
Skin: petechiae, bruises
Gum and mucous membrane bleeding
Fundal haemorrhage
Post-surgical bleeding
2. Coagulation factor deficiency
(e.g. haemophilia or warfarin/
anticoagulant)
Bleeding into joints (haemarthrosis) or
muscles
Bleeding into soft tissues
Retroperitoneal haemorrhage
Intracranial haemorrhage
Post-surgical bleeding
914 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Disorders of the blood cover a wide spectrum of illnesses, ranging
from some of the most common disorders affecting humans
(anaemias) to relatively rare conditions such as leukaemias
and congenital coagulation disorders. Although the latter are
uncommon, advances in cellular and molecular biology have
had major impacts on their diagnosis, treatment and prognosis.
Haematological changes occur as a consequence of diseases
affecting any system and give important information in the
diagnosis and monitoring of many conditions.
Functional anatomy and physiology
Blood flows throughout the body in the vascular system, and
consists of:
• red cells, which transport oxygen from the lungs to the
tissues
• white cells, which defend against infection
• platelets, which interact with blood vessels and clotting
factors to maintain vascular integrity and prevent
bleeding
• plasma, which contains proteins with many functions,
including antibodies and coagulation factors.
Haematopoiesis
Haematopoiesis describes the formation of blood cells, an active
process that must maintain normal numbers of circulating cells
and be able to respond rapidly to increased demands such
as bleeding or infection. During development, haematopoiesis
occurs in the yolk sac, liver and spleen, and subsequently in red
bone marrow in the medullary cavity of all bones. In childhood,
red marrow is progressively replaced by fat (yellow marrow)
so that, in adults, normal haematopoiesis is restricted to the
vertebrae, pelvis, sternum, ribs, clavicles, skull, upper humeri and
proximal femora. However, red marrow can expand in response
to increased demands for blood cells.
Bone marrow contains a range of immature haematopoietic
precursor cells and a storage pool of mature cells for release
at times of increased demand. Haematopoietic cells interact
closely with surrounding connective tissue stroma, made up of
reticular cells, macrophages, fat cells, blood vessels and nerve
fibres (Fig. 23.1). In normal marrow, nests of red cell precursors
cluster around a central macrophage, which provides iron and
also phagocytoses nuclei from red cells prior to their release into
the circulation. Megakaryocytes are large cells that produce and
release platelets into vascular sinuses. White cell precursors are
clustered next to the bone trabeculae; maturing cells migrate into
the marrow spaces towards the vascular sinuses. Plasma cells
are antibody-secreting mature B cells that normally represent less
than 5% of the marrow population and are scattered throughout
the intertrabecular spaces.
Stem cells
All blood cells are derived from pluripotent haematopoietic stem
cells. These comprise only 0.01 % of the total marrow cells, but
they can self-renew (i.e. make more stem cells) or differentiate
to produce a hierarchy of lineage-committed progenitor cells.
The resulting primitive progenitor cells cannot be identified
morphologically, so they are named according to the types of cell
(or colony) they form during cell culture experiments. CFU-GM
(colony-forming unit - granulocyte, monocyte) is a progenitor
cell that produces granulocytic and monocytic lines, CFU-E
produce erythroid cells, and CFU-Meg produce megakaryocytes
and ultimately platelets (Fig. 23.2).
Growth factors, produced in bone marrow stromal cells
and elsewhere, control the survival, proliferation, differentiation
and function of stem cells and their progeny. Some, such as,
interleukin-3 (IL-3), stem cell factor (SCF) and granulocyte,
macrophage-colony-stimulating factor (GM-CSF), act on a wide
number of cell types at various stages of differentiation. Others,
such as erythropoietin, granulocyte-colony-stimulating factor
(G-CSF) and thrombopoietin (Tpo), are lineage-specific. Many of
these growth factors are now synthesised by recombinant DNA
technology and used as treatments: for example, erythropoietin to
correct renal anaemia and G-CSF to hasten neutrophil recovery
after chemotherapy.
The bone marrow also contains stem cells that can differentiate
into non -haematological cells. Mesenchymal stem cells differentiate
Vascular sinusoid
Fat cell
Myelocyte
Blast cells and
progenitor cells
Lymphocyte
Fig. 23.1 Structural organisation of normal bone marrow.
Functional anatomy and physiology • 915
IL-6
IL-11
Fig. 23.2 Stem cells and growth factors in haematopoietic cell development. (BFU-E = burst-forming unit - erythroid; CFU-E = colony-forming unit
- erythroid; CFU-GM = colony-forming unit - granulocyte, monocyte; CFU-Meg = colony-forming unit - megakaryocyte; Epo = erythropoietin; G-CSF =
granulocyte-colony-stimulating factor; GM-CSF = granulocyte, macrophage-colony-stimulating factor; IL = interleukin; M-CSF = macrophage-colony-
stimulating factor; SCF = stem cell factor; Tpo = thrombopoietin)
into skeletal muscle, cartilage, cardiac muscle, and fat cells while
others differentiate into nerves, liver and blood vessel endothelium.
This is termed stem cell plasticity and may have exciting clinical
applications in the future (Ch. 3).
Blood cells and their functions
Red cells
Red cell precursors formed in the bone marrow from the erythroid
(CFU-E) progenitor cells are called erythroblasts or normoblasts
(Fig. 23.3). These divide and acquire haemoglobin, which turns
the cytoplasm pink; the nucleus condenses and is extruded from
the cell. The first non-nucleated red cell is a reticulocyte, which
still contains ribosomal material in the cytoplasm, giving these
large cells a faint blue tinge (‘polychromasia’). Reticulocytes
lose their ribosomal material and mature over 3 days, during
which time they are released into the circulation. Increased
numbers of circulating reticulocytes (reticulocytosis) reflect
increased erythropoiesis. Proliferation and differentiation of red
cell precursors is stimulated by erythropoietin, a polypeptide
hormone produced by renal interstitial peritubular cells in response
to hypoxia. Failure of erythropoietin production in patients with
renal failure (p. 384) causes anaemia, which can be treated with
exogenous recombinant erythropoietin or similar pharmacological
agents called erythropoiesis-stimulating agents, e.g. darbepoetin.
Normal mature red cells circulate for about 120 days. They
are 8 jam biconcave discs lacking a nucleus but filled with
haemoglobin, which delivers oxygen to the tissues. In order to
pass through the smallest capillaries, the red cell membrane is
deformable, with a lipid bilayer to which a ‘skeleton’ of filamentous
proteins is attached via special linkage proteins (Fig. 23.4).
Inherited abnormalities of any of these proteins result in loss of
membrane as cells pass through the spleen, and the formation
of abnormally shaped red cells called spherocytes or elliptocytes
(see Fig. 23. 8D). Red cells are exposed to osmotic stress in the
pulmonary and renal circulation; in order to maintain homeostasis,
the membrane contains ion pumps, which control intracellular
levels of sodium, potassium, chloride and bicarbonate. In the
absence of mitochondria, the energy for these functions is
provided by anaerobic glycolysis and the pentose phosphate
pathway in the cytosol. Membrane glycoproteins inserted into
the lipid bilayer also form the antigens recognised by blood
grouping (see Fig. 23.4). The ABO and Rhesus systems are the
most commonly recognised (p. 931) but over 400 blood group
antigens have been described.
Haemoglobin
Haemoglobin is a protein specially adapted for oxygen transport.
It is composed of four globin chains, each surrounding an
iron-containing porphyrin pigment molecule termed haem.
Globin chains are a combination of two alpha and two non¬
alpha chains; haemoglobin A (aoc/(3|3) represents over 90%
of adult haemoglobin, whereas haemoglobin F (aa/yy) is the
predominant type in the fetus. Each haem molecule contains a
ferrous ion (Fe2+), to which oxygen reversibly binds; the affinity
for oxygen increases as successive oxygen molecules bind.
When oxygen is bound, the beta chains ‘swing’ closer together;
they move apart as oxygen is lost. In the ‘open’ deoxygenated
state, 2,3-bisphosphoglycerate (2,3-BPG), a product of red cell
916 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Myeloblast Promyelocyte Myelocyte Metamyelocyte Neutrophil
Myelocyte Metamyelocyte
Megakaryoblast
V _
Megakaryocyte
Fig. 23.3 Maturation pathway of red cells, granulocytes and platelets. The image on the right is a normal blood film.
RhD antigen
Fig. 23.4 Normal structure of red cell membrane. Red cell membrane flexibility is conferred by attachment of cytoskeletal proteins. Important
transmembrane proteins include band 3 (an ion transport channel) and glycophorin C (involved in cytoskeletal attachment and gas exchange, and a
receptor for Plasmodium falciparum in malaria). Antigens on the red blood cell determine an individual’s blood group. There are about 22 blood group
systems (groups of carbohydrate or protein antigens controlled by a single gene or by multiple closely linked loci); the most important clinically are the ABO
and Rhesus (Rh) systems (p. 931). The ABO genetic locus has three main allelic forms: A, B and 0. The A and B alleles encode g lycosy Itransferases that
introduce /V-acetylgalactosamine (open circle) and D-galactose (blue circle), respectively, on to antigenic carbohydrate molecules on the membrane surface.
People with the 0 allele produce an 0 antigen, which lacks either of these added sugar groups. Rh antigens are transmembrane proteins.
metabolism, binds to the haemoglobin molecule and lowers
its oxygen affinity. These complex interactions produce the
sigmoid shape of the oxygen dissociation curve (Fig. 23.5).
The position of this curve depends on the concentrations of
2,3-BPG, H+ ions and C02; increased levels shift the curve to
the right and cause oxygen to be released more readily, e.g.
when red cells reach hypoxic tissues. Haemoglobin F is unable
to bind 2,3-BPG and has a left-shifted oxygen dissociation
curve, which, together with the low pH of fetal blood, ensures
fetal oxygenation. Strong oxidising agents, such as dapsone,
can convert ferrous iron in haemoglobin to its ferric state (Fe3+).
The resultant methaemoglobin also has a left-shifted oxygen
dissociation curve, which can result in tissue hypoxia (p. 135).
Genetic mutations affecting the haem-binding pockets of globin
chains or the ‘hinge’ interactions between globin chains result
in haemoglobinopathies or unstable haemoglobins. Alpha globin
chains are produced by two genes on chromosome 1 6, and beta
globin chains by a single gene on chromosome 1 1 ; imbalance
in the production of globin chains results in the thalassaemias
(p. 951). Defects in haem synthesis cause the porphyrias (p. 378).
Functional anatomy and physiology • 917
mmHg 0 25 50 75 100
P02 (kPa or mmHg)
Fig. 23.5 The haemoglobin-oxygen dissociation curve. Factors are
listed that shift the curve to the right (more oxygen released from blood)
and to the left (less oxygen released) at given P02 ■ To convert kPa to
mmFIg, multiply by 7.5. (2,3-BPG = 2,3-bisphosphoglycerate)
Destruction
Red cells at the end of their lifespan of approximately 120 days
are phagocytosed by the reticulo-endothelial system. Amino
acids from globin chains are recycled and iron is removed
from haem for reuse in haemoglobin synthesis. The remnant
haem structure is degraded to bilirubin and conjugated with
glucuronic acid before being excreted in bile. In the small bowel,
bilirubin is converted to stercobilin; most of this is excreted, but
a small amount is reabsorbed and excreted by the kidney as
urobilinogen. Increased red cell destruction due to haemolysis
or ineffective haematopoiesis results in jaundice and increased
urinary urobilinogen. Free intravascular haemoglobin is toxic and
is normally bound by haptoglobins, which are plasma proteins
produced by the liver.
White cells
White cells or leucocytes in the blood consist of granulocytes
(neutrophils, eosinophils and basophils), monocytes and
lymphocytes (see Fig. 23.12). Granulocytes and monocytes
are formed from bone marrow CFU-GM progenitor cells during
myelopoiesis. The first recognisable granulocyte in the marrow
is the myeloblast, a large cell with a small amount of basophilic
cytoplasm and a primitive nucleus with open chromatin and
nucleoli. As the cells divide and mature, the nucleus segments
and the cytoplasm acquires specific neutrophilic, eosinophilic or
basophilic granules (see Fig. 23.3). This takes about 14 days.
The cytokines G-CSF, GM-CSF and M-CSF are involved in the
production of myeloid cells, and G-CSF can be used clinically to
hasten recovery of blood neutrophil counts after chemotherapy.
Myelocytes or metamyelocytes are normally found only in the
marrow but may appear in the circulation in infection or toxic
states. The appearance of more primitive myeloid precursors in
the blood is often associated with the presence of nucleated red
cells and is termed a ‘leucoerythroblastic’ picture; this indicates
a serious disturbance of marrow function.
Neutrophils
Neutrophils, the most common white blood cells in the blood
of adults, are 10-14 jim in diameter, with a multilobular nucleus
containing 2-5 segments and granules in their cytoplasm. Their
main function is to recognise, ingest and destroy foreign particles
and microorganisms (p. 64). A large storage pool of mature
neutrophils exists in the bone marrow. Every day, some 1011
neutrophils enter the circulation, where cells may be circulating
freely or attached to endothelium in the marginating pool.
These two pools are equal in size; factors such as exercise
or catecholamines increase the number of cells flowing in the
blood. Neutrophils spend 6-10 hours in the circulation before
being removed, principally by the spleen. Alternatively, they pass
into the tissues and either are consumed in the inflammatory
process or undergo apoptotic cell death and phagocytosis by
macrophages.
Eosinophils
Eosinophils represent 1-6% of the circulating white cells. They
are a similar size to neutrophils but have a bilobed nucleus and
prominent orange granules on Romanowsky staining. Eosinophils
are phagocytic and their granules contain a peroxidase capable
of generating reactive oxygen species and proteins involved
in the intracellular killing of protozoa and helminths (p. 233).
They are also involved in allergic reactions (e.g. atopic asthma,
p. 567; see also p. 84).
Basophils
These cells are less common than eosinophils, representing
less than 1 % of circulating white cells. They contain dense
black granules that obscure the nucleus. Mast cells resemble
basophils but are found only in the tissues. These cells are
involved in hypersensitivity reactions (p. 66).
Monocytes
Monocytes are the largest of the white cells, with a diameter
of 12-20 |im and an irregular nucleus in abundant pale blue
cytoplasm containing occasional cytoplasmic vacuoles. These
cells circulate for a few hours and then migrate into tissue, where
they become macrophages, Kupffer cells or antigen-presenting
dendritic cells. The former phagocytose debris, apoptotic cells
and microorganisms (see Box 4.1, p. 64).
Lymphocytes
Lymphocytes are derived from pluripotent haematopoietic stem
cells in the bone marrow. There are two main types: T cells (which
mediate cellular immunity) and B cells (which mediate humoral
immunity) (p. 68). Lymphoid cells that migrate to the thymus
develop into T cells, whereas B cells develop in the bone marrow.
The majority (about 80%) of lymphocytes in the circulation are
T cells. Lymphocytes are heterogeneous, the smallest being the
size of red cells and the largest the size of neutrophils. Small
lymphocytes are circular with scanty cytoplasm but the larger cells
are more irregular with abundant blue cytoplasm. Lymphocyte
subpopulations have specific functions and lifespan can vary
from a few days to many years. Cell surface antigens (‘cluster
of differentiation’ (CD) antigens), which appear at different points
of lymphocyte maturation and indicate the lineage and maturity
of the cell, are used to classify lymphomas and lymphoid
leukaemias.
Haemostasis
Blood must be maintained in a fluid state in order to function as
a transport system, but must be able to solidify to form a clot
following vascular injury in order to prevent excessive bleeding,
a process known as haemostasis. Successful haemostasis
918 • HAEMATOLOGY AND TRANSFUSION MEDICINE
is localised to the area of tissue damage and is followed by
removal of the clot and tissue repair. This is achieved by complex
interactions between the vascular endothelium, platelets, von
Willebrand factor, coagulation factors, natural anticoagulants
and fibrinolytic enzymes (Fig. 23.6). Dysfunction of any of these
components may result in haemorrhage or thrombosis.
Platelets
Platelets are formed in the bone marrow from megakaryocytes.
Megakaryocytic progenitor cells (CFU-Meg) divide to form
megakaryoblasts, which undergo a process called ‘endomitotic
reduplication’, in which there is division of the nucleus but not the
cell. This creates mature megakaryocytes, large cells with several
nuclei and cytoplasm containing platelet granules. Large numbers
of platelets then fragment off from each megakaryocyte into the
circulation. The formation and maturation of megakaryocytes
is stimulated by thrombopoietin produced in the liver. Platelets
circulate for 8-1 0 days before they are destroyed in the reticulo¬
endothelial system. Some 30% of peripheral platelets are normally
pooled in the spleen and do not circulate.
Under normal conditions, platelets are discoid, with a diameter
of 2-4 |im (Fig. 23.7). The surface membrane invaginates to
form a tubular network, the canalicular system, which provides a
conduit for the discharge of the granule content following platelet
activation. Drugs that inhibit platelet function and thrombosis
include aspirin (cyclo-oxygenase inhibitor), clopidogrel, prasugrel
and ticagrelor (adenosine diphosphate (ADP)-mediated activation
inhibitors), dipyridamole (phosphodiesterase inhibitor), and the
glycoprotein llb/llla inhibitors abciximab, tirofiban and eptifibatide
(which prevent fibrinogen binding; p. 500).
Clotting factors
The coagulation system consists of a cascade of soluble
inactive zymogen proteins designated by Roman numerals.
Fig. 23.6 The stages of normal haemostasis.
[A~| Stage 1. Pre-injury conditions encourage
flow. The vascular endothelium produces
substances (including nitric oxide, prostacyclin
and heparans) to prevent adhesion of platelets
and white cells to the vessel wall. Platelets and
coagulation factors circulate in a non-activated
state.
|~Bl Stage 2. Early haemostatic response:
platelets adhere; coagulation is activated. At the
site of injury, the endothelium is breached,
exposing subendothelial collagen. Small amounts
of tissue factor (TF) are released. Platelets bind
to collagen via a specific receptor, glycoprotein
la (GPIa), causing a change in platelet shape and
its adhesion to the area of damage by the
binding of other receptors (GPIb and GPIIb/llla)
to von Willebrand factor and fibrinogen,
respectively. Coagulation is activated by the
tissue factor (extrinsic) pathway, generating
small amounts of thrombin.
[Cl and [D] Stage 3. Fibrin clot formation:
platelets become activated and aggregate; fibrin
formation is supported by the platelet
membrane; stable fibrin clot forms. The adherent
platelets are activated by many pathways,
including binding of adenosine diphosphate
(ADP), collagen, thrombin and adrenaline
(epinephrine) to surface receptors. The
cyclo-oxygenase pathway converts arachidonic
acid from the platelet membrane into
thromboxane A2) which causes aggregation of
platelets. Activation of the platelets results in
release of the platelet granule contents,
enhancing coagulation further (see Fig. 23.7).
Thrombin plays a key role in the control of
coagulation: the small amount generated via the
TF pathway massively amplifies its own
production; the ‘intrinsic’ pathway becomes
activated and large amounts of thrombin are
generated. Thrombin directly causes clot
formation by cleaving fibrinopeptides (FPs) from
Investigation of diseases of the blood • 919
When proteolytically cleaved and activated, each is capable of
activating one or more components of the cascade. Activated
factors are designated by the suffix ‘a’. Some of these reactions
require phospholipid and calcium. Coagulation occurs by two
pathways: it is initiated by the extrinsic (or tissue factor) pathway
and amplified by the ‘intrinsic pathway’ (see Fig. 23. 6D).
Clotting factors are synthesised by the liver, although factor
V is also produced by platelets and endothelial cells. Factors
II, VII, IX and X require post -translational carboxylation to allow
them to participate in coagulation. The carboxylase enzyme
responsible for this in the liver is vitamin K-dependent. Vitamin K
is converted to an epoxide in this reaction and must be reduced
to its active form by a reductase enzyme. This reductase is
inhibited by warfarin, and this is the basis of the anticoagulant
effect of coumarins (p. 939). Congenital (e.g. haemophilia) and
acquired (e.g. liver failure) causes of coagulation factor deficiency
are associated with bleeding.
Investigation of diseases of the blood
The full blood count
To obtain a full blood count (FBC), anticoagulated blood is
processed through automated blood analysers that use a
variety of technologies (particle-sizing, radiofrequency and laser
instrumentation) to measure the haematological parameters. These
include numbers of circulating cells, the proportion of whole blood
volume occupied by red cells (the haematocrit, Hct), and the red
cell indices that give information about the size of red cells (mean
cell volume, MCV) and the amount of haemoglobin present in
the red cells (mean cell haemoglobin, MCH). Blood analysers
can differentiate types of white blood cell and give automated
counts of neutrophils, lymphocytes, monocytes, eosinophils
and basophils. It is important to appreciate, however, that a
E
Tissue
injury
Tissue factor
(extrinsic) pathway
• sss?-«
Common
pathway
Prothrombin —
-V
► Thrombin :
Intrinsic
pathway
■■
IXa < - IX
Villa
VIII
■ Amplification of coagulation by thrombin
E
Intrinsic pathway
Tissue factor pathway
inhibitor (TFPI)
Activated ; x — >xa j-.v.v;;
protein C, -ve . va
protein S
Prothrombin -
■■■■► Natural
-ve
* Thrombin
[ -ve r Antithrombin
Actions of thrombin
anticoagulant
actions
Fig. 23.6, cont’d fibrinogen to produce
fibrin. Fibrin monomers are cross-linked by
factor XIII, which is also activated by thrombin.
Having had a key role in clot formation and
stabilisation, thrombin then starts to regulate
clot formation in two main ways: (a) activation of
the protein C (PC) pathway (a natural
anticoagulant), which reduces further
coagulation; (b) activation of thrombin-activatable
fibrinolysis inhibitor (TAFI), which inhibits
fibrinolysis (see E and F).
[El Stage 4. Limiting clot formation: natural
anticoagulants reverse activation of coagulation
factors. Once haemostasis has been secured,
the propagation of clot is curtailed by
anticoagulants. Antithrombin is a serine protease
inhibitor synthesised by the liver, which destroys
activated factors such as Xla, Xa and thrombin
(lla). Its major activity against thrombin and Xa is
enhanced by heparin and fondaparinux,
explaining their anticoagulant effect. Tissue
factor pathway inhibitor (TFPI) binds to and
inactivates Vila and Xa. Activation of PC occurs
following binding of thrombin to membrane-
bound thrombomodulin; activated protein C (aPC)
binds to its co-factor, protein S (PS), and cleaves
Va and Villa. PC and PS are vitamin K-dependent
and are depleted by coumarin anticoagulants
such as warfarin.
l~Fl Stage 5. Fibrinolysis: plasmin degrades fibrin
to allow vessel recanalisation and tissue repair.
The insoluble clot needs to be broken down for
vessel recanalisation. Plasmin, the main
fibrinolytic enzyme, is produced when
plasminogen is activated, e.g. by tissue
plasminogen activator (t-PA) or urokinase in the
clot. Plasmin hydrolyses the fibrin clot, producing
fibrin degradation products, including the
D-dimer. This process is highly regulated; the
plasminogen activators are controlled by an
inhibitor called plasminogen activator inhibitor
(PAI), the activity of plasmin is inhibited by
a2-antiplasmin and a2-macroglobulin, and
fibrinolysis is further inhibited by the thrombin-
activated TAFI.
920 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Fig. 23.7 Normal platelet structure. The platelet surface is populated by glycoproteins, which bind to key structures including fibrinogen, collagen and
von Willebrand factor and cell surface receptors for thrombin, ADP and adrenaline (epinephrine). Through internal signalling pathways, platelet activation
causes degranulation of alpha and dense granules, which ultimately results in platelet aggregation. Blockade of these pathways by drugs such as aspirin,
clopidogrel, ticagrelor, tirofiban and abcixamab forms the basis of antiplatelet therapy. (ADP = adenosine diphosphate; GP = glycoprotein)
23.1 Spurious full blood count results
from autoanalysers
Result
Explanation
Increased haemoglobin
Lipaemia, jaundice, very high white
cell count
Reduced haemoglobin
Improper sample mixing, blood
taken from vein into which an
infusion is flowing
Increased red cell volume
(mean cell volume, MCV)
Cold agglutinins, non-ketotic
hyperosmolarity
Increased white cell count
Nucleated red cells present
Reduced platelet count
Clot in sample, platelet clumping
number of conditions can lead to spurious results (Box 23.1).
The reference ranges for a number of common haematological
parameters in adults are given in Chapter 35.
Blood film examination
Although technical advances in full blood count analysers have
resulted in fewer blood samples requiring manual examination,
scrutiny of blood components prepared on a microscope slide
(the ‘blood film’) can often yield valuable information (Box 23.2
and Fig. 23.8). Analysers cannot identify abnormalities of red
cell shape and content (e.g. Howell-Jolly bodies, basophilic
stippling, malaria parasites) or fully define abnormal white cells
such as blasts.
Bone marrow examination
In adults, bone marrow for examination is usually obtained from
the posterior iliac crest. After a local anaesthetic, marrow can
be sucked out from the medullary space, stained and examined
under the microscope (bone marrow aspirate). In addition, a
core of bone may be removed (trephine biopsy), fixed and
decalcified before sections are cut for staining (Fig. 23.9). A
bone marrow aspirate is used to assess the composition and
morphology of haematopoietic cells or abnormal infiltrates. Further
investigations may be performed, such as cell surface marker
analysis (immunophenotyping), chromosome and molecular
studies to assess malignant disease, or marrow culture for
suspected tuberculosis. A trephine biopsy is superior for assessing
marrow cellularity, marrow fibrosis, and infiltration by abnormal
cells such as metastatic carcinoma.
Investigation of coagulation
Bleeding disorders
In patients with clinical evidence of a bleeding disorder (p. 913),
there are recommended screening tests (Box 23.3). Physiological
activation of coagulation is predominantly by tissue factor, with
amplification of the process by the small amounts of thrombin
formed as a result. For ease of description, the terms extrinsic,
intrinsic and common pathways are still used (see Fig. 23. 6D).
Coagulation tests measure the time to clot formation in vitro in
a plasma sample after the clotting process is initiated by activators
and calcium. The result of the test sample is compared with
normal controls. The tissue factor (‘extrinsic’) pathway (see Fig.
23.6D) is assessed by the prothrombin time (PT), and the ‘intrinsic’
pathway by the activated partial thromboplastin time (APTT),
sometimes known as the partial thromboplastin time with kaolin
(PTTK). Coagulation is delayed by deficiencies of coagulation
factors and by the presence of inhibitors of coagulation, such
as heparin. The approximate reference ranges and causes of
abnormalities are shown in Box 23.3. If both the PT and APTT
are prolonged, this indicates either deficiency or inhibition of the
Investigation of diseases of the blood • 921
23.2 How to interpret red cell appearances
Microcytosis (reduced average cell size, MCV <76 fL ){K\
Nucleated red blood cells (normoblasts) {¥}
• Iron deficiency • Sideroblastic anaemia
• Thalassaemia
Macrocytosis (increased average cell size, MCV >100 fL) [B]
• Marrow infiltration • Myelofibrosis
• Severe haemolysis • Acute haemorrhage
Howell-Jolly bodies (small round nuclear remnants) [G]
• Vitamin B12 or folate deficiency • Drugs (e.g. zidovudine,
• Liver disease, alcohol trimethoprim, phenytoin,
• Hypothyroidism methotrexate,
• Myelodysplastic syndromes hydroxycarbamide)
Target cells (central area of haemoglobinisation) [C]
• Hyposplenism • Dyshaematopoiesis
• Post-splenectomy
Polychromasia (young red cells - reticulocytes present) [H]
• Haemolysis, acute • Increased red cell
haemorrhage turnover
• Liver disease • Post-splenectomy
• Thalassaemia • Haemoglobin C disease
Basophilic stippling (abnormal ribosomal RNA appears as
blue dots) \T\
Spherocytes (dense cells, no area of central pallor) [d]
• Autoimmune haemolytic • Post-splenectomy
anaemia • Hereditary spherocytosis
Red cell fragments (intravascular haemolysis) [E]
• Microangiopathic haemolysis, • Disseminated intravascular
e.g. haemolytic uraemic coagulation (DIC)
syndrome (HUS), thrombotic
thrombocytopenic purpura (TTP)
• Dyshaematopoiesis • Lead poisoning
Fig. 23.8 Appearance of red blood cells. [A] Microcytosis. \W\ Macrocytosis. [C] Target cells. [jj] Spherocytes. [e] Red cell fragments.^ Nucleated
red blood cells. [G] Howell-Jolly bodies, [jj] Polychromasia. \J] Basophilic stippling.
final common pathway (which includes factors X, V, prothrombin
and fibrinogen) or global coagulation factor deficiency involving
more than one factor, as occurs in disseminated intravascular
coagulation (DIC, pp. 196 and 978). Further specific tests may
be performed based on interpretation of the clinical scenario and
results of these screening tests. A mixing test with normal plasma
allows differentiation between a coagulation factor deficiency
(the prolonged time corrects) and the presence of an inhibitor
of coagulation (the prolonged time does not correct); the latter
may be a chemical (heparins) or an antibody (most often a
lupus anticoagulant but occasionally a specific inhibitor of one
of the coagulation factors, typically factor VIII). Von Willebrand
disease may present with a normal APTT; further investigation
of suspected cases is detailed on page 974.
Platelet function has historically been assessed by the
bleeding time, measured as the time to stop bleeding after a
standardised incision. However, most centres have abandoned
the use of this test. Platelet function can be assessed in vitro by
measuring aggregation in response to various agonists, such
as adrenaline (epinephrine), collagen, thrombin, arachidonic
acid and ADP, agglutination in response to ristocetin or by
measuring the constituents of the intracellular granules, e.g.
adenosine triphosphate, adenosine diphosphate and their ratio
to each other (ATP/ADP).
Coagulation screening tests are also performed in patients
with suspected DIC, when clotting factors and platelets are
consumed, resulting in thrombocytopenia and prolonged PT and
APTT. In addition, there is evidence of active coagulation with
922
HAEMATOLOGY AND TRANSFUSION MEDICINE
Fig. 23.9 Bone marrow aspirate and trephine. [A] Trephine biopsy needle. \&\ Macroscopic appearance of a trephine biopsy. [C] Microscopic
appearance of stained section of trephine. [6] Bone marrow aspirate needle. [|] Stained macroscopic appearance of marrow aspirate: smear (left) and
squash (right). [F] Microscopic appearance of stained marrow particles and trails of haematopoietic cells.
23.3 Coagulation screening tests
Investigation
Reference
range2
Situations in which tests
may be abnormal
Platelet count
1 50—400 x 1 09/L
Thrombocytopenia
Prothrombin
time (PT)
9-1 2 secs
Deficiencies of factors II, V, VII
or X
Severe fibrinogen deficiency
Activated
partial
thromboplastin
time (APTT)
26-36 secs
Deficiencies of factors II, V,
VIII, IX, X, XI, XII
Severe fibrinogen deficiency
Unfractionated heparin therapy
Antibodies against clotting
factors
Lupus anticoagulant
Multiple factor deficiency
(e.g. DIC)
Fibrinogen
concentration
1. 5-4.0 g/L
Hypofibrinogenaemia, e.g.
liver failure, DIC
^.B. International normalised ratio (INR) is used only to monitor coumarin
therapy and is not a coagulation screening test. 2Ranges are approximate and
may vary between laboratories.
(DIC = disseminated intravascular coagulation)
consumption of fibrinogen and generation of fibrin degradation
products (D-dimers). Note, however, that fibrinogen is an
acute phase protein that may also be elevated in inflammatory
disease (p. 70).
Monitoring anticoagulant therapy
The international normalised ratio (INR) is validated only to assess
the therapeutic effect of coumarin anticoagulants, including
warfarin. INR is the ratio of the patient’s PT to that of a normal
control, raised to the power of the international sensitivity index
of the thromboplastin used in the test (ISI, derived by comparison
with an international reference standard material). Concentrations
of the direct oral anticoagulants (DOACs) cannot be accurately
assessed from the PT or the APTT, with which they have a
variable and generally poor correlation.
Monitoring of heparin therapy is, on the whole, required only
with unfractionated heparins. Therapeutic anticoagulation prolongs
the APTT relative to a control sample by a ratio of approximately
1 .5-2.5. Low-molecular-weight heparins have such a predictable
dose response that monitoring of the anticoagulant effect is not
required, except in patients with renal impairment (glomerular
filtration rate less than 30 mLVmin). When monitoring is indicated,
an anti-Xa activity assay rather than APTT should be used.
Thrombotic disorders
Measurement of plasma levels of D-dimers derived from fibrin
degradation is useful in excluding the diagnosis of active venous
thrombosis in some patients (see Fig. 10.6, p. 187).
A variety of tests exist that may help to explain an underlying
propensity to thrombosis, especially venous thromboembolism
(thrombophilia) (Box 23.4). Examples of possible indications for
testing are given in Box 23.5. In most patients, the results do
not affect clinical management (p. 975) but they may influence
the duration of anticoagulation (e.g. antiphospholipid antibodies,
p. 977), justify family screening in inherited thrombophilias
(p. 975), or suggest additional management strategies to reduce
thrombosis risk (e.g. in myeloproliferative disease and paroxysmal
nocturnal haemoglobinuria; p. 950). Anticoagulants can interfere
with some of these assays; for example, warfarin reduces protein
C and S levels and affects measurement of lupus anticoagulant,
while heparin interferes with antithrombin and lupus anticoagulant
Presenting problems in blood disease • 923
23.4 Investigation of possible thrombophilia
Full blood count
Plasma levels
• Antithrombin
• Protein C
• Protein S (free)
• Antiphospholipid antibodies, lupus anticoagulant, anticardiolipin
antibody/anti-p2GP1
Thrombin/reptilase time (for dysfibrinogenaemia)
Genetic testing
• Factor V Leiden
• Prothrombin G20210A
• JAK-2 V61 7F mutation
• CALR mutations
Flow cytometry
• Screen for GPI-linked cell surface proteins (CD14, 16, 55, 59),
deficient in paroxysmal nocturnal haemoglobinuria
(CD = cluster of differentiation; GP1 = glycoprotein 1 ; GPI = glycerol
phosphatidyl inositol)
123.5 Possible indications for
thrombophilia testing
• Venous thrombosis <45 years
• Recurrent venous thrombosis
• Family history of unprovoked
or recurrent thrombosis
• Combined arterial and venous
thrombosis
• Venous thrombosis at an
unusual site:
Cerebral venous thrombosis
Hepatic vein (Budd-Chiari
syndrome)
Portal vein, mesenteric vein
*Antiphospholipid antibodies should be sought where clinical criteria for
antiphospholipid syndrome (APS) are fulfilled (p. 977). Thrombophilia testing may
explain the diagnosis without necessarily affecting management and this limits
the clinical value of such an approach.
ifx
• Blood cell counts and film components: not altered in general by
ageing alone, although haemoglobin concentrations fall with
increasing age.
• Ratio of bone marrow cells to marrow fat: falls.
• Neutrophils: maintained throughout life, although leucocytes may
be less readily mobilised by bacterial invasion in old age.
• Lymphocytes: functionally compromised by age due to a
T-cell-related defect in cell-mediated immunity.
• Clotting factors: no major changes, although mild congenital
deficiencies may be first noticed in old age.
• Erythrocyte sedimentation rate (ESR): raised above the reference
range but usually in association with chronic or subacute disease. In
truly healthy older people, the ESR range is very similar to that in
younger people.
23.6 Haematological investigations in old age
assays. Therefore these tests, when required, should be performed
when the patient is not taking anticoagulants.
Presenting problems in blood disease
Anaemia
Anaemia refers to a state in which the level of haemoglobin
in the blood is below the reference range appropriate for age
23.7 Causes of anaemia
Decreased or ineffective marrow production
• Lack of iron, vitamin B12 or • Invasion by malignant cells
folate • Renal failure
• Hypoplasia/myelodysplasia • Anaemia of chronic disease
Normal marrow production but increased removal of cells
• Blood loss • Hypersplenism
• Haemolysis
and sex. Other factors, including pregnancy and altitude, also
affect haemoglobin levels and must be taken into account when
considering whether an individual is anaemic. The clinical features
of anaemia reflect diminished oxygen supply to the tissues
(p. 912). A rapid onset of anaemia (e.g. due to blood loss) causes
more profound symptoms than a gradually developing anaemia.
Individuals with cardiorespiratory disease are more susceptible
to symptoms of anaemia.
The clinical assessment and investigation of anaemia should
gauge its severity and define the underlying cause (Box 23.7).
Clinical assessment
• Iron deficiency anaemia (p. 940) is the most common type
of anaemia worldwide. A thorough gastrointestinal history
is important, looking in particular for symptoms of blood
loss. Menorrhagia is a common cause of anaemia in
pre-menopausal females, so women should always be
asked about their periods.
• A dietary history should assess the intake of iron and folate,
which may become deficient in comparison to needs (e.g. in
pregnancy or during periods of rapid growth; pp. 712, 945
and 1284).
• Past medical history may reveal a disease that is known to
be associated with anaemia, such as rheumatoid arthritis
(anaemia of chronic disease), or previous surgery (e.g.
resection of the stomach or small bowel, which may lead
to malabsorption of iron and/or vitamin B12).
• Family history and ethnic background may raise suspicion
of haemolytic anaemias, such as the haemoglobinopathies
and hereditary spherocytosis. Pernicious anaemia may
also run in families but is not associated with a clear
Mendelian pattern of inheritance.
• A drug history may reveal the ingestion of drugs that
cause blood loss (e.g. aspirin and anti-inflammatory
drugs), haemolysis (e.g. sulphonamides) or aplasia (e.g.
chloramphenicol).
On examination, as well as the general physical findings of
anaemia shown on page 912, there may be specific findings
related to the aetiology of the anaemia; for example, a patient may
be found to have a right iliac fossa mass due to an underlying
caecal carcinoma. Haemolytic anaemias can cause jaundice.
Vitamin B12 deficiency may be associated with neurological signs,
including peripheral neuropathy, dementia and signs of subacute
combined degeneration of the cord (p. 1138). Sickle-cell anaemia
(p. 951) may result in leg ulcers, stroke or features of pulmonary
hypertension. Anaemia may be multifactorial and the lack of
specific symptoms and signs does not rule out silent pathology.
Investigations
Schemes for the investigation of anaemias are often based on
the size of the red cells, which is most accurately indicated by
the MCV in the FBC. Commonly, in the presence of anaemia:
924 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Investigate Check family
Fig. 23.10 Investigation of anaemia with normal or low mean cell volume (MCV). (Hb = haemoglobin; MCH = mean cell haemoglobin)
Fig. 23.11 Investigation of anaemia with high mean cell volume (MCV). (LDH = lactate dehydrogenase)
Presenting problems in blood disease • 925
• A normal MCV (normocytic anaemia) suggests either acute
blood loss or the anaemia of chronic disease, also known
as the anaemia of inflammation (ACD/AI) (Fig. 23.10).
• A low MCV (microcytic anaemia) suggests iron deficiency
or thalassaemia or sometimes ACD/AI (Fig. 23.10).
• A high MCV (macrocytic anaemia) suggests vitamin B12 or
folate deficiency or myelodysplasia (Fig. 23.1 1).
Specific types of anaemia and their management are described
later in this chapter (p. 940).
High haemoglobin
Patients with a persistently raised haematocrit (Hot) (>0.52 males,
>0.48 females) for more than 2 months should be investigated.
‘True’ polycythaemia (or absolute erythrocytosis) indicates an
excess of red cells, while ‘relative’, ‘apparent’ or ‘low-volume’
polycythaemia is due to a decreased plasma volume. Causes of
polycythaemia are shown in Box 23.8. These involve increased
erythropoiesis in the bone marrow, either due to a primary increase
in marrow activity, or in response to increased erythropoietin (Epo)
levels in chronic hypoxaemia, or due to inappropriate secretion of
Epo. Athletes who seek to benefit from increased oxygen -carrying
capacity have been known to use Epo to achieve this.
Apparent erythrocytosis with a raised Hot, normal red cell
mass (RCM) and reduced plasma volume may be associated
with hypertension, smoking, alcohol and diuretic use (Gaisbock’s
syndrome).
Clinical assessment and investigations
Males and females with Hot values of over 0.60 and over 0.56,
respectively, can be assumed to have an absolute erythrocytosis.
A clinical history and examination will identify most patients
with polycythaemia secondary to hypoxia. The presence of
hypertension, smoking, excess alcohol consumption and/or diuretic
use is consistent with low-volume polycythaemia (Gaisbock’s
syndrome). In polycythaemia rubra vera (PR V), a mutation in a
kinase, JAK-2 V617F, is found in over 90% of cases (p. 970).
Patients with PRV have an increased risk of arterial thromboses,
particularly stroke, and venous thromboembolism. They may
also have aquagenic pruritus (itching after exposure to water),
hepatosplenomegaly and gout (due to high red cell turnover).
If the JAK-2 mutation is absent and there is no obvious
secondary cause, a measurement of red cell mass is required
to confirm an absolute erythrocytosis, followed by further
investigations to exclude hypoxia, and causes of inappropriate
erythropoietin secretion.
Leucopenia (low white cell count)
A reduction in the total numbers of circulating white cells is called
leucopenia. This may be due to a reduction in all types of white
cell or in individual cell types (usually neutrophils or lymphocytes).
Leucopenia may occur in isolation or as part of a reduction in all
three haematological lineages (pancytopenia; p. 930).
Neutropenia
A reduction in neutrophil count (usually <1 .5x1 09/L but dependent
on age and race) is called neutropenia. The main causes are listed
in Box 23.9 and Figure 23.12. Drug-induced neutropenia is not
uncommon (Box 23.10). Clinical manifestations range from no
symptoms to overwhelming sepsis. The risk of bacterial infection
is related to the degree of neutropenia, with counts lower than
0.5x1 09/L considered to be critically low. Fever is the first and
often only manifestation of infection. A sore throat, perianal pain or
skin inflammation may be present. The lack of neutrophils allows
the patient to become septicaemic and shocked within hours if
immediate antibiotic therapy is not commenced. Management
is discussed on page 224.
|Lymphopenia
This is an absolute lymphocyte count of less than 1 x109/L.
The causes are shown in Box 23.9. Although minor reductions
may be asymptomatic, deficiencies in cell-mediated immunity
may result in infections (with organisms such as fungi, viruses
and mycobacteria) and a propensity to lymphoid and other
malignancies (particularly those associated with viral infections
such as Epstein-Barr virus (EBV), human papillomavirus (HPV)
23.8 Classification and causes of erythrocytosis
Absolute erythrocytosis
Relative (low-volume) erythrocytosis
Haematocrit
High
High
Red cell mass
High
Normal
Plasma volume
Normal
Low
Causes
Primary
Myeloproliferative disorder
Polycythaemia rubra vera (primary proliferative polycythaemia)
Secondary
High erythropoietin due to tissue hypoxia:
High altitude
Cardiorespiratory disease
High-affinity haemoglobins
Inappropriately increased erythropoietin:
Renal disease (hydronephrosis, cysts, carcinoma)
Other tumours (hepatoma, bronchogenic carcinoma, uterine
fibroids, phaeochromocytoma, cerebellar haemangioblastoma)
Exogenous testosterone therapy
Exogenous erythropoietin administration:
Performance-enhancing drug-taking in athletes
Diuretics
Smoking
Obesity
Alcohol excess
Gaisbock’s syndrome
926 • HAEMATOLOGY AND TRANSFUSION MEDICINE
23.9 How to interpret white blood cell results
Neutrophils [A]
Neutrophilia
• Infection: bacterial, fungal
• Trauma: surgery, burns
• Infarction: myocardial infarct, pulmonary embolus, sickle-cell crisis
• Inflammation: gout, rheumatoid arthritis, ulcerative colitis, Crohn’s
disease
• Malignancy: solid tumours, Hodgkin lymphoma
• Myeloproliferative disease: polycythaemia, chronic myeloid leukaemia
• Physiological: exercise, pregnancy
Neutropenia
• Infection: viral, bacterial (e.g. Salmonella), protozoal (e.g. malaria)
• Drugs: see Box 23.10
• Autoimmune: connective tissue disease
• Alcohol
• Bone marrow infiltration: leukaemia, myelodysplasia
• Congenital: Kostmann’s syndrome
• Constitutional: Afro-Caribbean and Middle Eastern descent
Eosinophils [B]
Eosinophilia
• Allergy: hay fever, asthma, eczema
• Infection: parasitic
• Drug hypersensitivity: e.g. gold, sulphonamides
• Vasculitis: e.g. eosinophilic granulomatosis with polyangiitis
(Churg-Strauss), granulomatosis with polyangiitis (Wegener’s)
• Connective tissue disease: polyarteritis nodosa
• Malignancy: solid tumours, lymphomas
• Primary bone marrow disorders: myeloproliferative disorders,
hypereosinophilic syndrome (HES), acute myeloid leukaemia
Basophils [C]
Basophilia
• Myeloproliferative disease: polycythaemia, chronic myeloid
leukaemia
• Inflammation: acute hypersensitivity, ulcerative colitis, Crohn’s
disease
• Iron deficiency
Monocytes [jj]
Monocytosis
• Infection: bacterial (e.g. tuberculosis)
• Inflammation: connective tissue disease, ulcerative colitis, Crohn’s
disease
• Malignancy: solid tumours, chronic myelomonocytic leukaemia
Lymphocytes [E]
Lymphocytosis
• Infection: viral, bacterial (e.g. Bordetella pertussis)
• Lymphoprol iterative disease: chronic lymphocytic leukaemia,
lymphoma
• Post-splenectomy
Lymphopenia
• Inflammation: connective tissue disease
• Lymphoma
• Renal failure
• Sarcoidosis
• Drugs: glucocorticoids, cytotoxics
• Congenital: severe combined immunodeficiency
• HIV infection
t *
Fig. 23.12 Appearance of white blood cells. [A] Neutrophil. [§] Eosinophil. [C] Basophil. [6] Monocyte. [E] Lymphocyte.
23.10 Drugs that can induce neutropenia
Group
Examples
Analgesics/anti¬
inflammatory agents
Gold, penicillamine, naproxen
Antithyroid drugs
Carbimazole, propylthiouracil
Anti-arrhythmics
Quinidine, procainamide
Antihypertensives
Captopril, enalapril, nifedipine
Antidepressants/
psychotropics
Amitriptyline, dosulepin, mianserin
Antimalarials
Pyrimethamine, dapsone, sulfadoxine,
chloroquine
Anticonvulsants
Phenytoin, sodium valproate,
carbamazepine
Antibiotics
Sulphonamides, penicillins, cephalosporins
Miscellaneous
Cimetidine, ranitidine, chlorpropamide,
zidovudine
*Many drugs can induce cytopenias. In suspected cases check drug summary of
product characteristics.
and human herpesvirus 8 (HHV-8)). Lymphopenia without any
obvious cause is common with advancing age.
Leucocytosis (high white cell count)
An increase in the total numbers of circulating white cells is called
leucocytosis. This is usually due to an increase in a specific type
of cell (see Box 23.9). It is important to realise that an increase
in a single type of white cell (e.g. eosinophils or monocytes) may
not increase the total white cell count (WCC) above the upper
limit of normal and will be apparent only if the ‘differential’ of
the white count is examined.
|Neutrophilia
An increase in the number of circulating neutrophils is called
a neutrophilia or a neutrophil leucocytosis. It can result from
an increased production of cells from the bone marrow or
redistribution from the marginated pool. The normal neutrophil
count depends on age, race and certain physiological parameters.
During pregnancy, not only is there an increase in neutrophils
but also earlier forms, such as metamyelocytes, can be found in
the blood. The causes of a neutrophilia are shown in Box 23.9.
Presenting problems in blood disease • 927
Eosinophilia
A high eosinophil count of more than 0.5x109/L is usually
secondary to infection (especially parasites; p. 233), allergy
(e.g. eczema, asthma, reactions to drugs; p. 84), immunological
disorders (e.g. polyarteritis, sarcoidosis) or malignancy (e.g.
lymphomas) (see Box 23.9). Usually, such eosinophilia is
short-lived.
In the rarer primary disorders, there is a persistently raised, often
clonal, eosinophilia, e.g. in myeloproliferative disorders, subtypes
of acute myeloid leukaemia and idiopathic hypereosinophilic
syndrome (HES). Recently, specific mutations in receptor tyrosine
kinase genes have been found in some primary eosinophilias
(e.g. causing rearrangements of platelet-derived growth factor
receptors a and (3 or c-kit), which allow diagnosis and, in some
cases, specific therapy with tyrosine kinase inhibitors such as
imatinib.
Eosinophil infiltration can damage many organs (e.g. heart,
lungs, gastrointestinal tract, skin, musculoskeletal system);
evaluation of eosinophilia therefore includes not only the
identification of any underlying cause and its appropriate treatment
but also assessment of any related organ damage.
|j.ymphocytosis
A lymphocytosis is an increase in circulating lymphocytes above
that expected for the patient’s age. In adults, this is greater than
3.5x1 09/L. Infants and children have higher counts; age-related
reference ranges should be consulted. Causes are shown in Box
23.9; the most common is viral infection.
Lymphadenopathy
Enlarged lymph glands may be an important indicator of
haematological disease but they are not uncommon in reaction
to infection or inflammation (Box 23.11). The sites of lymph
node groups, and symptoms and signs that may help elucidate
the underlying cause are shown on page 913. Nodes that
enlarge in response to local infection or inflammation (‘reactive
nodes’) usually expand rapidly and are painful, whereas those
due to haematological disease are more frequently painless.
Localised lymphadenopathy should elicit a search for a
i
Infective
• Bacterial: streptococcal, tuberculosis, brucellosis
• Viral: Epstein— Barr virus (EBV), human immunodeficiency
virus (HIV)
• Protozoal: toxoplasmosis
• Fungal: histoplasmosis, coccidioidomycosis
Neoplastic
• Primary: lymphomas, leukaemias
• Secondary: lung, breast, thyroid, stomach, melanoma
Connective tissue disorders
• Rheumatoid arthritis
• Systemic lupus erythematosus (SLE)
Sarcoidosis
Amyloidosis
Drugs
• Phenytoin
source of inflammation or primary malignancy in the appropriate
drainage area:
• the scalp, ear, mouth and throat, face, teeth or thyroid for
neck nodes
• the breast for axillary nodes
• the perineum or external genitalia for inguinal nodes.
Generalised lymphadenopathy may be secondary to infection,
often viral, connective tissue disease or extensive skin disease
(dermatopathic lymphadenopathy) but is more likely to signify
underlying haematological malignancy. Weight loss and drenching
night sweats that may require a change of nightclothes are
associated with haematological malignancies, particularly
lymphoma.
Initial investigations in lymphadenopathy include an FBC (to
detect neutrophilia in infection or evidence of haematological
disease), measurement of erythrocyte sedimentation rate (ESR)
and a chest X-ray (to detect mediastinal lymphadenopathy). If
the findings suggest malignancy, a formal cutting needle or
excision biopsy of a representative node is indicated to obtain
a histological diagnosis.
Splenomegaly
The spleen may be enlarged due to involvement by
lymphoproliferative disease, the resumption of extramedullary
haematopoiesis in myeloproliferative disease, enhanced reticulo¬
endothelial activity in autoimmune haemolysis, expansion of the
lymphoid tissue in response to infections, or vascular congestion
as a result of portal hypertension (Box 23.12). Hepatosplenomegaly
is suggestive of lympho- or myeloproliferative disease, liver disease
or infiltration (e.g. with amyloid). Associated lymphadenopathy
is suggestive of lymphoproliferative disease. An enlarged spleen
may cause abdominal discomfort, accompanied by back pain
and abdominal bloating and early satiety due to stomach
compression. Splenic infarction produces severe abdominal
pain radiating to the left shoulder tip, associated with a splenic
rub on auscultation. Rarely, spontaneous or traumatic rupture and
bleeding may occur.
Investigation should focus on the suspected cause. Imaging
of the spleen by ultrasound or computed tomography (CT) will
detect variations in density in the spleen, which may be a feature
of lymphoproliferative disease; it also allows imaging of the liver
and abdominal lymph nodes. Biopsy of enlarged abdominal or
superficial lymph nodes may provide the diagnosis, as might
a bone marrow biopsy in splenic lymphomas. A chest X-ray
or CT of the thorax will detect mediastinal lymphadenopathy.
An FBC may show pancytopenia secondary to hypersplenism,
when the enlarged spleen has become overactive, destroying
blood cells prematurely. If other abnormalities are present, such
as abnormal lymphocytes or a leucoerythroblastic blood film, a
bone marrow examination is indicated. Screening for infectious
or liver disease (p. 852) may be appropriate. If all investigations
are unhelpful, splenectomy may be diagnostic but is rarely carried
out in these circumstances.
Bleeding
Normal bleeding is seen following surgery and trauma. Pathological
bleeding occurs when structurally abnormal vessels rupture
or when a vessel is breached in the presence of a defect in
haemostasis. This may be due to a deficiency or dysfunction
of platelets, the coagulation factors or von Willebrand factor, or
23.1 1 Causes of lymphadenopathy
928 • HAEMATOLOGY AND TRANSFUSION MEDICINE
23.12 Causes of splenomegaly
Congestive
Portal hypertension
• Cirrhosis
• Stenosis or malformation of
• Hepatic vein occlusion
• Portal vein thrombosis
portal or splenic vein
Cardiac
• Chronic congestive cardiac
failure
• Constrictive pericarditis
Infective
Bacterial
• Endocarditis
• Brucellosis
• Sepsis
• Tuberculosis
• Salmonella
Viral
• Hepatitis
• Epstein— Barr
• Cytomegalovirus
Protozoal
• Malaria*
• Leishmaniasis (kala-azar)*
• Trypanosomiasis
Fungal
• Histoplasmosis
Inflammatory/granulomatous disorders
• Felty’s syndrome in
rheumatoid arthritis
• Sarcoidosis
• Systemic lupus erythematosus
Haematological
Red cell disorders
• Megaloblastic anaemia
• Haemoglobinopathies
Autoimmune haemolytic anaemias
• Hereditary spherocytosis
Myeloproliferative disorders
• Chronic myeloid leukaemia*
• Myelofibrosis*
• Polycythaemia rubra vera
• Essential thrombocythaemia
Neoplastic
• Leukaemias, including chronic
myeloid leukaemia*
• Lymphomas
Other malignancies
• Metastatic cancer - rare
Lysosomal storage diseases
• Gaucher’s disease
• Niemann-Pick disease
Miscellaneous
• Cysts, amyloid, thyrotoxicosis, haemophagocytic syndromes
*Causes of massive splenomegaly.
occasionally to excessive fibrinolysis, which is most commonly
observed following therapeutic thrombolysis (p. 500).
Clinical assessment
‘Screening’ blood tests (see Box 23.3) do not reliably detect all
causes of pathological bleeding (e.g. von Willebrand disease,
scurvy, certain anticoagulant drugs and the causes of purpura
listed in Box 23.13) and should not be used indiscriminately.
A careful clinical evaluation is the key to diagnosis of bleeding
disorders (p. 970). It is important to consider the following:
• Site of bleeding. Bleeding into muscle and joints, along
with retroperitoneal and intracranial haemorrhage, indicates
a likely defect in coagulation factors. Purpura, prolonged
23.13 Causes of non-thrombocytopenic purpura
• Senile purpura
• Paraproteinaemias
• Factitious purpura
• Purpura fulminans, e.g. in
• Henoch-Schonlein purpura
disseminated intravascular
(p. 1043)
coagulation secondary to
• Vasculitis (p. 1040)
sepsis
Fig. 23.13 Petechial purpura.
bleeding from superficial cuts, epistaxis, gastrointestinal
haemorrhage or menorrhagia is more likely to be due to
thrombocytopenia, a platelet function disorder or von
Willebrand disease. Recurrent bleeds at a single site
suggest a local structural abnormality rather than
coagulopathic bleeding.
• Duration of history. It may be possible to assess whether
the disorder is congenital or acquired.
• Precipitating causes. Bleeding arising spontaneously
indicates a more severe defect than bleeding that occurs
only after trauma.
• Surgery. Ask about operations. Dental extractions,
tonsillectomy and circumcision are stressful tests of the
haemostatic system. Immediate post-surgical bleeding
suggests defective platelet plug formation and primary
haemostasis; delayed haemorrhage is more suggestive of
a coagulation defect. However, in post-surgical patients,
persistent bleeding from a single site is more likely to
indicate surgical bleeding than a bleeding disorder.
• Family history. While a positive family history may be
present in patients with inherited disorders, the absence of
affected relatives does not exclude a hereditary bleeding
diathesis; about one-third of cases of haemophilia arise in
individuals without a family history, and deficiencies of
factor VII, X and XIII are recessively inherited. Recessive
disorders are more common in cultures where there is
consanguineous marriage.
• Drugs. Use of antithrombotic, anticoagulant and fibrinolytic
drugs must be elicited. Drug interactions with warfarin and
drug-induced thrombocytopenia should be considered.
Some ‘herbal’ remedies may result in a bleeding diathesis.
Clinical examination may reveal different patterns of skin
bleeding. Petechial purpura is minor bleeding into the dermis
that is flat and non-blanching (Fig. 23.13). Petechiae are typically
found in patients with thrombocytopenia or platelet dysfunction.
Presenting problems in blood disease • 929
Palpable purpura occurs in vasculitis. Ecchymosis, or bruising,
is more extensive bleeding into deeper layers of the skin. The
lesions are initially dark red or purple but become yellow as
haemoglobin is degraded. Retroperitoneal bleeding presents with
a flank or peri-umbilical haematoma. Telangiectasia of lips and
tongue points to hereditary haemorrhagic telangiectasia (p. 970).
Joints should be examined for evidence of haemarthroses. A full
examination is important, as it may give clues to an underlying
associated systemic illness such as a haematological or other
malignancy, liver disease, renal failure, connective tissue disease
and possible causes of splenomegaly.
Investigations
Screening investigations and their interpretation are described on
page 920. If the patient has a history that is strongly suggestive
of a bleeding disorder and all the preliminary screening tests
give normal results, further investigations, such as measurement
of von Willebrand factor and assessment of platelet function,
should be performed (p. 921).
Thrombocytopenia (low platelet count)
A reduced platelet count may arise by one of two mechanisms:
• decreased or abnormal production (bone marrow failure
and hereditary thrombocytopathies)
• increased consumption following release into the
circulation (immune-mediated, DIC or sequestration).
Spontaneous bleeding does not usually occur until the
platelet count falls below 20x109/L, unless their function is
also compromised. Purpura and spontaneous bruising are
characteristic but there may also be oral, nasal, gastrointestinal
or genitourinary bleeding. Severe thrombocytopenia (<10x1 09/L)
may result in retinal haemorrhage and potentially fatal intracranial
bleeding, but this is rare.
Investigations are directed at the possible causes listed in Box
23.14. A blood film is the single most useful initial investigation.
Examination of the bone marrow may reveal increased
megakaryocytes in consumptive causes of thrombocytopenia,
or the underlying cause of bone marrow failure in leukaemia,
hypoplastic anaemia or myelodysplasia.
Treatment (if required) depends on the underlying cause.
Platelet transfusion is rarely required and is usually confined to
patients with bone marrow failure and platelet counts below
10x109/L, or to clinical situations with actual or predicted serious
haemorrhage.
Thrombocytosis (high platelet count)
The most common reason for a raised platelet count is that it
is reactive to another process, such as infection, inflammation,
connective tissue disease, malignancy, iron deficiency, acute
haemolysis or gastrointestinal bleeding (Box 23.1 5). The presenting
clinical features are usually those of the underlying disorder
and haemostasis is rarely affected. Reactive thrombocytosis
is distinguished from the myeloproliferative disorders by the
presence of uniform small platelets, lack of splenomegaly, and
the presence of an associated disorder. The key to diagnosis is
the clinical history and examination, combined with observation
of the platelet count over time (reactive thrombocytosis gets
better with resolution of the underlying cause).
The platelets are a product of an abnormally expanding clone of
cells in the myeloproliferative disorders, chronic myeloid leukaemia
i
Decreased production
Marrow hypoplasia
• Childhood bone marrow failure syndromes, e.g. Fanconi’s
anaemia, dyskeratosis congenita, amegakaryocytic
thrombocytopenia
• Idiopathic aplastic anaemia
• Drug-induced: cytotoxics, anti metabolites
• Transfusion-associated graft-versus-host disease
Marrow infiltration
• Leukaemia
• Myeloma
• Carcinoma (rare)
• Myelofibrosis
Haematinic deficiency
• Vitamin B12 and/or folate deficiency
Familial (macro-)thrombocytopathies
• Myosin heavy chain abnormalities, e.g. Alport’s syndrome,
Fechtner’s syndrome, May— Hegglin anomaly
• Bernard-Soulier syndrome
• Montreal platelet syndrome
• Wiskott-Aldrich syndrome (small platelets)
• Mediterranean macrothrombocytopathy
Increased consumption
Immune mechanisms
• Idiopathic thrombocytopenic
purpura*
• Neonatal alloimmune
thrombocytopenia
Coagulation activation
• Disseminated intravascular coagulation (see Box 23.68,
p. 978)
Mechanical pooling
• Hypersplenism
Thrombotic microangiopathies
• Haemolytic uraemic syndrome
(HUS) and atypical HUS
• Liver disease
Others
• Gestational thrombocytopenia
• Type 2B von Willebrand disease
*Associated conditions include collagen vascular diseases (particularly systemic
lupus erythematosus), B-cell malignancy, HIV infection and antiphospholipid
syndrome.
23.15 Causes of a raised platelet count
Reactive thrombocytosis
• Acute and chronic
• Tissue damage
inflammatory disorders
• Haemolytic anaemias
• Infection
• Post-splenectomy
• Malignant disease
• Post-haemorrhage
Clonal thrombocytosis
• Primary thrombocythaemia
• Myelodysplastic syndromes
• Polycythaemia rubra
(MDSs; refractory anaemia
vera
with ring sideroblasts and
• Chronic myeloid leukaemia
thrombocytosis (RARS-T), MDS
• Myelofibrosis
with isolated deletion of 5q)
23.14 Causes of thrombocytopenia
• Osteopetrosis
• Lysosomal storage disorders,
e.g. Gaucher’s disease
• Post-transfusion purpura
• Drug-associated, especially
quinine, vancomycin and
heparin
• Thrombotic thrombocytopenic
purpura
• Pre-eclampsia
930 • HAEMATOLOGY AND TRANSFUSION MEDICINE
and some forms of myelodysplasia. As with PRV, patients with
essential thrombocythaemia may present with thrombosis or,
rarely, bleeding. Stroke, transient ischaemic attacks, amaurosis
fugax, digital ischaemia or gangrene, aquagenic pruritus,
splenomegaly and systemic upset are also features. Patients
with myeloproliferative disorders may also present with features
such as aquagenic pruritus, splenomegaly and systemic upset.
Pancytopenia
Pancytopenia refers to the combination of anaemia, leucopenia
and thrombocytopenia. It may be due to reduced production
of blood cells as a consequence of bone marrow suppression
or infiltration, or there may be peripheral destruction or splenic
pooling of mature cells. Causes are shown in Box 23.1 6. A bone
marrow aspirate and trephine are usually required to establish
the diagnosis.
i
Bone marrow failure
• Hypoplastic/aplastic anaemia (p. 968): inherited, idiopathic,
viral, drugs
Bone marrow infiltration
• Acute leukaemia
• Myeloma
• Lymphoma
• Carcinoma
• Haemophagocytic syndrome
• Myelodysplastic syndromes
Ineffective haematopoiesis
• Megaloblastic anaemia
• Acquired immunodeficiency syndrome (AIDS)
Peripheral pooling/destruction
• Hypersplenism: portal hypertension, Felty’s syndrome, malaria,
myelofibrosis
• Systemic lupus erythematosus
Infection
Infection is a major complication of haematological disorders.
It relates to the immunological deficit caused by the disease
itself, or its treatment with chemotherapy and/or immunotherapy
(pp. 224 and 925).
Principles of management of
haematological disease
Blood products and transfusion
Blood transfusion from an unrelated donor to a recipient inevitably
carries some risk, including adverse immunological interactions
between the host and infused blood (p. 931), and transmission
of infectious agents. Although there are many compelling clinical
indications for blood component transfusion, there are also many
clinical circumstances in which transfusion is conventional but
the evidence for its effectiveness is limited. In these settings,
allogeneic transfusion may be avoided by following protocols that
recommend the use of low haemoglobin thresholds for red cell
transfusion, perioperative blood salvage and antifibrinolytic drugs.
Blood products
Blood components are prepared from whole blood or specific
blood constituents collected from individual donors and include
red cells, platelets, plasma and cryoprecipitate (Box 23.17).
Plasma derivatives are licensed pharmaceutical products
produced on a factory scale from large volumes of human plasma
obtained from many people and treated to remove transmissible
infection. Examples include:
• Coagulation factors. Concentrates of factors VIII and IX are
used for the treatment of conditions such as haemophilia
A, haemophilia B and von Willebrand disease. Coagulation
factors made by recombinant DNA technology are now
preferred due to perceived lack of infection risk but
plasma-derived products are still used in many countries.
• Immunoglobulins. Intravenous immunoglobulin G (IVIgG) is
administered as regular replacement therapy to reduce
infective complications in patients with primary and
secondary immunodeficiency. A short, high-dose course
of IVIgG may also be effective in some immunological
disorders, including immune thrombocytopenia (p. 971)
and Guillain-Barre syndrome (p. 1140). IVIgG can cause
acute reactions and must be infused strictly according to
the manufacturer’s product information. There is a risk of
renal dysfunction in susceptible patients and, in these
circumstances, immunoglobulin products containing low or
no sucrose are preferred. Anti-zoster immunoglobulin has
a role in the prophylaxis of varicella zoster (p. 239).
Anti-Rhesus D immunoglobulin is used in pregnancy to
prevent haemolytic disease of the newborn (see Box 23.19
below).
• Human albumin. This is available in two strengths. The 5%
solution can be used as a colloid resuscitation fluid but it
is no more effective and is more expensive than crystalloid
solutions. Human albumin 20% solution is used in the
management of hypoproteinaemic oedema in nephrotic
syndrome (p. 395) and ascites in chronic liver disease
(p. 864). It is hyperoncotic and expands plasma volume by
more than the amount infused.
Blood components and their use are summarised in Box 23.1 7.
Blood donation
A safe supply of blood components depends on a well-organised
system with regular donation by healthy individuals who have no
excess risk of infections transmissible in blood (Fig. 23.14). Blood
donations are obtained by either venesection of a unit of whole
blood or collection of a specific component, such as platelets,
by apheresis. During apheresis, the donor’s blood is drawn via
a closed system into a machine that separates the components
by centrifugation and collects the desired fraction into a bag,
returning the rest of the blood to the donor. Each donation must
be tested for hepatitis B virus (HBV), hepatitis C virus (HCV), HIV
and human T-cell lymphotropic virus (HTLV) nucleic acid and/
or antibodies. Platelet concentrates may be tested for bacterial
contamination. The need for other microbiological tests depends
on local epidemiology. For example, testing for Trypanosoma
cruzi (Chagas’ disease; p. 279) is necessary in areas of South
America and the USA where infection is prevalent. Tests for West
Nile virus have been required in the USA since this agent became
23.16 Causes of pancytopenia
Principles of management of haematological disease • 931
23.17 Blood components and their use
Component
Major haemorrhage
Other indications
Red cell concentrate1
Most of the plasma is removed and replaced
with a solution of glucose and adenine in
saline to maintain viability of red cells
ABO compatibility with recipient essential
Replace acute blood loss: increase circulating
red cell mass to relieve clinical features
caused by insufficient oxygen delivery. Order
4-6 U initially to allow high red cell to FFP
transfusion ratios of (at least) 2 : 1
Severe anaemia
If no cardiovascular disease, transfuse to
maintain Fib at 70 g/L
If known or likely to have cardiovascular
disease, maintain Hb at 90 g/L
Platelet concentrate
One adult dose is made from four donations of
whole blood, or from a single platelet
apheresis donation
ABO compatibility with recipient preferable
Maintain platelet count >50x1 09/L, or in
multiple or central nervous system trauma
>100x1 09/L
If ongoing bleeding, order when platelets
< 1 00 x 1 09/L to allow for delivery time
Each adult dose has a minimum of 2.4X1011
platelets, which raises platelet count by
40 x 1 09/L unless there is consumptive
coagulopathy, e.g. disseminated intravascular
coagulation
Thrombocytopenia , e.g. in acute leukaemia
Maintain platelet count >10x1 09/L if not
bleeding
Maintain platelet count >20x109/L if minor
bleeding or at risk (sepsis, concurrent use of
antibiotics, abnormal coagulation)
Increase platelet count >50x109/L for minor
invasive procedure (e.g. lumbar puncture,
gastroscopy and biopsy, insertion of indwelling
lines, liver biopsy, laparotomy) or in acute,
major blood loss
Increase platelet count > 1 00 x 1 09/L for
operations in critical sites such as brain or eyes
Fresh frozen plasma2
150-300 mL plasma from one donation of
whole blood
ABO compatibility with recipient recommended
Dilutional coagulopathy with a PT prolonged
>50% is likely after replacement of 1-1 .5
blood volumes with red cell concentrate
Give initially in (at least) a ratio of 1 FFP:2 red
cell concentrate; order 15-20 mLVkg and allow
for thawing time. Further doses only if bleeding
continues and guided by PT and APTT
Replacement of coagulation factor deficiency
If no virally inactivated or recombinant product
is available
Thrombotic thrombocytopenic purpura
Plasma exchange (using virus- inactivated
plasma if available) is frequently effective
Cryoprecipitate
Fibrinogen and coagulation factor concentrated
from plasma by controlled thawing
10-20 mL pack contains:
Fibrinogen 150-300 mg
Factor VIII 80-1 20 U
von Willebrand factor 80-120 U
In UK supplied as pools of 5 U
Aim to keep fibrinogen >1.5 g/L. Pooled units
(of 10 donations) will raise fibrinogen by 1 g/L
von Willebrand disease and haemophilia
If virus- inactivated or recombinant products are
not available
1 Whole blood is an alternative to red cell concentrate. ABO compatibility with recipient essential. Tooled plasma can be treated with solvent and detergent or single units
treated with methylene blue as an additional viral inactivation step. Virus-inactivated plasma is indicated for large-volume exposure, as in treatment of thrombotic
thrombocytopenic purpura, and for treatment of children in the UK born after 1995.
(APTT = activated partial thromboplastin time; FFP = fresh frozen plasma; Fib = haemoglobin; PT = prothrombin time)
prevalent. Components for use in specific patient groups are
prepared from hepatitis E virus-negative donors in the UK, and
plasma donated in the UK is not used at present for producing
pooled plasma derivatives in view of concerns about transmission
of variant Creutzfeldt-Jakob disease (vCJD; p. 1127).
Adverse effects of transfusion
Death directly attributable to transfusion is rare, at less than
0.3 per 100 000 transfusions. Relatively minor symptoms of
transfusion reactions (fever, itch or urticaria) occur in up to 3%
of transfusions, and usually in patients who have had repeated
transfusions. Any symptoms or signs that arise during a transfusion
must be taken seriously, as they may be the first warnings of
a serious reaction. Figure 23.16 below outlines the symptoms
and signs, management and investigation of acute reactions to
blood components.
Red cell incompatibility
Red blood cell membranes contain numerous cell surface
molecules that are potentially antigenic (see Fig. 23.4). The
ABO and Rhesus D antigens are the most important in routine
transfusion and antenatal practice.
ABO blood groups
The frequency of the ABO antigens varies among different
populations. The ABO blood group antigens are oligosaccharide
chains that project from the red cell surface. These chains are
attached to proteins and lipids that lie in the red cell membrane.
The ABO gene encodes a glycosyltransferase that catalyses
the final step in the synthesis of the chain, which has three
common alleles: A, B and O. The O allele encodes an inactive
enzyme, leaving the ABO antigen precursor (called the H antigen)
unmodified. The A and B alleles encode enzymes that differ by
932 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Donor
Education Recruitment Selection
Donation
■\
Test for:
HIV
HTLV
Hepatitis B
Hepatitis C
Hepatitis E
Syphilis
ABO + RhD
Other blood
groups
Red cell
antibodies
450 ml_ whole blood
collected into 63 mL
anticoagulant/preservative
Process into blood components
Platelet
apheresis1
J
Plasma2
\
Fractionation
\
Plasma derivatives,
e.g. albumin,
immunoglobulin
Storage
4°C 35 days
Confirm compatibility
-30°C 36 months
Thaw
Patient
22°C 5 days (agitate)
J
Fig. 23.14 Blood donation, processing and storage. 1 Platelet apheresis involves circulating the donor’s blood through a cell separator to remove
platelets before returning other blood components to the donor. 2ln the UK, plasma for fractionation is imported as a precautionary measure against vCJD.
(vCJD = variant Creutzfeldt-Jakob disease; HIV = human immunodeficiency virus; HTLV = human T-cell lymphotropic virus)
four amino acids and hence attach different sugars to the end
of the chain. Individuals are tolerant to their own ABO antigens,
but do not suppress B-cell clones producing antibodies against
ABO antigens that they do not carry themselves (Box 23.18).
They are, therefore, capable of mounting a humoral immune
response to these ‘foreign’ antigens.
ABO-incompatible red cell transfusion
If red cells of an incompatible ABO group are transfused (especially
if a group O recipient is transfused with group A, B or AB red
cells), the recipient’s IgM anti-A, anti-B or anti-AB binds to the
transfused red cells. This activates the full complement pathway
(p. 66), creating pores in the red cell membrane and destroying
Principles of management of haematological disease • 933
23.18 ABO blood group antigens and antibodies
ABO blood Red cell A or
Antibodies in
UK frequency
group
B antigens
plasma
(%)
0
None
Anti-A and anti-B
46
A
A
Anti-B
42
B
B
Anti-A
9
AB
A and B
None
3
the transfused red cells in the circulation (intravascular haemolysis).
The anaphylatoxins C3a and C5a, released by complement
activation, liberate cytokines such as tumour necrosis factor (TNF),
interleukin 1 (IL-1) and IL-8, and stimulate degranulation of mast
cells with release of vasoactive mediators. All these substances
may lead to inflammation, increased vascular permeability and
hypotension, which may, in turn, cause shock and renal failure.
Inflammatory mediators can also cause platelet aggregation, lung
peribronchial oedema and smooth muscle contraction. About
20-30% of ABO-incompatible transfusions cause some degree of
morbidity, and 5-10% cause or contribute to a patient’s death.
The main reason for this relatively low morbidity is the lack of
potency of ABO antibodies in group A or B subjects; even if
the recipient is group O, those who are very young or very old
usually have weaker antibodies that do not lead to the activation
of large amounts of complement.
The Rhesus D blood group and haemolytic disease
of the newborn
About 1 5% of Caucasians are Rhesus-negative: that is, they
lack the Rhesus D (RhD) red cell surface antigen (see Fig. 23.4).
In other populations (e.g. in Chinese and Bengalis), only 1-5%
are Rhesus-negative. RhD-negative individuals do not normally
produce substantial amounts of anti-RhD antibodies. However,
if RhD-positive red cells enter the circulation of an RhD-negative
individual, IgG antibodies are produced. This can occur during
pregnancy if the mother is exposed to fetal cells via fetomaternal
haemorrhage, or following transfusion. If a woman is so sensitised,
during a subsequent pregnancy anti-RhD antibodies can cross
the placenta; if the fetus is RhD-positive, haemolysis with severe
fetal anaemia and hyperbilirubinaemia can result. This can cause
severe neurological damage or death due to haemolytic disease
of the newborn (HDN). Therefore, an RhD-negative female who
may subsequently become pregnant should never be transfused
with RhD-positive blood.
In RhD-negative women, administration of anti-RhD
immunoglobulin (anti-D) perinatally can block the immune response
to RhD antigen on fetal cells and is the only effective product for
preventing the development of Rhesus antibodies (Box 23.19).
HDN can also be caused by other alloantibodies against red
cell antigens, usually after previous pregnancies or transfusions.
These antigens include Rhc, RhC, RhE, Rhe, and the Kell,
Kidd and Duffy antigen systems. HDN can also occur if there
is fetomaternal ABO incompatibility, most commonly seen in a
group O mother with a group A fetus. The fetus is generally less
severely affected by ABO incompatibility than by RhD, Rhc or
Kell antigen mismatch, and the incompatibility is often picked
up coincidentally after birth.
Other immunological complications of transfusion
Rare but serious complications include transfusion-associated lung
injury (TRALI) and transfusion-associated graft-versus-host disease
23.19 Rhesus D blood groups in pregnancy
• Haemolytic disease of the newborn (HDN): occurs when the
mother has anti-red cell immunoglobulin G (IgG) antibodies that
cross the placenta and haemolyse fetal red cells.
• Screening for HDN in pregnancy: at the time of booking
(12-16 weeks) and again at 28-34 weeks’ gestation, every
pregnant woman should have a blood sample sent for determination
of ABO and Rhesus D (RhD) group and testing for red cell
alloantibodies that may be directed against paternal blood group
antigens present on fetal red cells.
• Anti-D immunoglobulin prophylaxis in a pregnant woman who
is RhD-negative: antenatal anti-D prophylaxis is offered at
28-34 weeks to RhD-negative pregnant women who have no
evidence of immune anti-D. This prevents the formation of
antibodies that could cause HDN. Following delivery of an
RhD-positive baby, the mother is given further anti-D within
72 hours; a maternal sample is checked for remaining fetal red
cells and additional anti-D is given if indicated. Additional anti-D is
also given after potential sensitising events antenatally (e.g. early
bleeding). Doses vary according to national recommendations.
(TA GVHD). The latter occurs when there is sharing of a human
leucocyte antigen (HL4) haplotype between donor and recipient,
which allows transfused lymphocytes to engraft, proliferate and
recognise the recipient as foreign, resulting in acute GVHD
(p. 937). Prevention is by gamma- or X-ray irradiation of blood
components before their administration to prevent lymphocyte
proliferation. Those at risk of TA GVHD, who must receive
irradiated blood components, include patients with congenital
T-cell immunodeficiencies or Hodgkin lymphoma, patients with
aplastic anaemia receiving immunosuppressive therapy with
antithymocyte globulin (ATG), recipients of haematopoietic stem
cell transplants or of blood from a family member, neonates
who have received an intrauterine transfusion, and patients
taking T-lymphocyte-suppressing drugs, such as fludarabine
and other purine analogues.
Transfusion-transmitted infection
Over the past 30 years, HBV, HIV-1 and HCV have been identified
and effective tests introduced to detect and exclude infected
donations. Where blood is from ‘safe’ donors and correctly tested,
the current risk of a donated unit being infectious is very small. By
2013 in the UK, the estimated chance that a unit of blood from
a ‘safe’ donor might transmit one of the viruses for which blood
is tested was 1 in 6.6 million units for HIV-1 , 1 in 51 .5 million
for HCV and 1 in 2.6 million for HBV. However, some patients
who received transfusions before these tests were available
suffered serious consequences from infection; this serves as a
reminder to avoid non-essential transfusion, since it is impossible
to exclude the emergence of new or currently unrecognised
transfusion-transmissible infection. Licensed plasma derivatives
that have been virus-inactivated do not transmit HIV, HTLV,
HBV, HCV, cytomegalovirus or other lipid-enveloped viruses.
Variant CJD is a human prion disease linked to bovine
spongiform encephalitis (BSE; p. 1127). The risk of a recipient
acquiring the agent of vCJD from a transfusion is uncertain,
but of 1 6 recipients of blood from donors who later developed
the disease, 3 have died with clinical vCJD and 1 other had
postmortem immunohistological features of infection.
Bacterial contamination of a blood component - usually
platelets - is extremely rare (1 proven case in the UK in 2015)
but can result in severe bacteraemia/sepsis in the recipient.
934 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Safe transfusion procedures
The proposed transfusion and any alternatives should be
discussed with the patient or, if that is not possible, with a
relative, and this should be documented in the case record. Some
patients, e.g. Jehovah’s Witnesses, may refuse transfusion and
require specialised management to survive profound anaemia
following blood loss.
Pre-transfusion testing
To ensure that red cells supplied for transfusion are compatible
with the intended recipient, the transfusion laboratory will perform
either a ‘group and screen’ procedure or a ‘cross-match’. In the
group and screen procedure, the red cells from the patient’s
blood sample are tested to determine the ABO and RhD type,
and the patient’s serum is also tested against an array of red
cells expressing the most important antigens to detect any
red cell antibodies. Any antibody detected can be identified by
further testing, so that red cell units that lack the corresponding
antigen can be selected. The patient’s sample can be held in the
laboratory for up to a week, so that the hospital blood bank can
quickly prepare compatible blood without the need for a further
patient sample. Conventional cross-matching consists of the
group and antibody screen, followed by direct confirmation of
the compatibility of individual units of red cells with the patient’s
serum. Full cross-matching takes about 45 minutes if no red
cell antibodies are present, but may require hours if a patient
has multiple antibodies.
Blood can be supplied by ‘electronic issue’, without the need
for compatibility cross-matching, if the laboratory’s computer
system shows that the patient’s ABO and RhD groups have been
identified and confirmed on two separate occasions and their
antibody screen is negative. This allows group-specific units to be
issued quickly and safely, for elective and emergency transfusion.
Bedside procedures for safe transfusion
Errors leading to patients receiving the wrong blood are an
important avoidable cause of mortality and morbidity. Most
incompatible transfusions result from failure to adhere to standard
procedures for taking correctly labelled blood samples from the
patient and ensuring that the correct pack of blood component
is transfused into the intended patient. In the UK in 2015, there
were 280 reports of transfusion of an incorrect blood component
(11 per 100000 units transfused). Every hospital where blood
is transfused should have a written transfusion policy used by
all staff who order, check or administer blood products (Fig.
23.15). Management of suspected transfusion reactions is
shown in Figure 23.16.
Ijransfusion in major haemorrhage
The successful management of a patient with major haemorrhage
requires frontline clinical staff to be trained to recognise significant
blood loss early and to intervene before shock is established.
Hospitals should have local major haemorrhage protocols and
all clinical staff must be familiar with their content. Good team
working and communication are essential to prevent poor clinical
outcome, suboptimal or inappropriate transfusion practice and
component wastage. Fresh frozen plasma (FFP) should be given
as part of initial resuscitation in (at least) a 1 : 2 ratio with red cell
concentrate (RCC) until coagulation results are available. If the
patient is bleeding, a ratio of FFP to RCC of 1 : 1 should be given
until laboratory results are available and use of cryoprecipitate
should be considered. Once the bleeding is under control, further
Taking blood for pre-transfusion testing
1* Positively identify the patient at the bedside
• Label the sample tube and complete
the request form clearly and accurately
after identifying the patient
• Do not write forms and labels in advance
Administering blood
► Positively identify the patient at the bedside
► Ensure that the identification of each blood pack j
matches the patient’s identification
► Check that the ABO and RhD groups of each
pack are compatible with the patient’s
► Check each pack for evidence of damage
► If in doubt, do not use and return to the blood bank
► Complete the forms that document the transfusion of each pack
1 Check the compatibility label on the pack against the patient’s wristband
Blood pack Patient’s wristband
r
_ F _ Qi irnamo
f| U I
U
ji " i
r'
31
l
-Date of birth
Unique identifier/
hospital number
JL
» Always involve
the patient by asking '
them to state their name
and date of birth, where possible
Record-keeping
• Record in the patient’s notes, the reason for transfusion, the product given, dose, any adverse effects
and the clinical respons
Observations
1* Transfusions should only be given when the patient can be observed
• Blood pressure, pulse and temperature should be monitored before and 15 minutes after starting each pack
• In conscious patients, further observations are only needed if the patient has symptoms or signs of a reaction
• In unconscious patients, check pulse and temperature at intervals during transfusion
• Signs of abnormal bleeding during the transfusion could be due to disseminated intravascular coagulation
resulting from an acute haemolytic reaction
Fig. 23.15 Bedside procedures for safe blood transfusion. The patient’s safety depends on adherence to standard procedures for taking samples for
compatibility testing, administering blood, record-keeping and observations.
Principles of management of haematological disease • 935
Fig. 23.16 Investigation and management of acute transfusion reactions. *Use size-appropriate dose in children. (ARDS = acute respiratory distress
syndrome; BP = blood pressure; CVP = central venous pressure; DIC = disseminated intravascular coagulation; FBC = full blood count; IV = intravenous)
936 • HAEMATOLOGY AND TRANSFUSION MEDICINE
23.20 Key points in transfusion medicine
• A restrictive strategy for red cell transfusion (Hb <70 g/L) is at least
as effective as a liberal strategy (<100 g/L).
• The majority of reports in haemovigilance schemes such as SHOT
relate to errors in the process of transfusion.
• Although transfusion-transmitted infection is a major concern for
patients receiving transfusion, it is rare.
• In patients with trauma or burns or those who have had surgery,
there is no evidence that resuscitation with albumin or other colloid
solutions reduces the risk of death compared to resuscitation with
crystalloid solutions.
• It is recommended that transfusion should be carried out at night
time only in unavoidable circumstances.
(SHOT = Serious Hazards of Transfusion)
FFP transfusion should be guided by laboratory results with
transfusion triggers of PT and/or APTT above 1 -5 times normal
for a standard dose of FFP (15-20 mL/kg). Cryoprecipitate
should be given if the fibrinogen level falls below 1 .5 g/L. Platelets
should be kept above 50x109/L; to allow for delivery time,
platelets should be requested if there is ongoing bleeding and
the platelet count has fallen below 100x109/L Blood component
use in major haemorrhage is summarised in Box 23.17 and key
points in transfusion medicine in Box 23.20.
Chemotherapy
Chemotherapy refers to the use of drugs to treat cancer (Box
23.21; see also Fig. 33.2, p. 1317). Many haematological
malignancies are sensitive to the effects of chemotherapy drugs
and, as such, chemotherapy is the mainstay of treatment for
most haematological cancers. There is a wide range of drugs
available that work by damaging DNA or disrupting cellular
metabolism, in such a way that natural apoptosis mechanisms,
such as TP53, are activated and the cell dies. Despite cancer
cells being more sensitive, chemotherapy is largely non-specific
and kills some normal cells as well as cancer cells. This leads
to common side-effects of treatment, such as transient bone
marrow failure, mucositis and infertility. The supportive care
of patients undergoing chemotherapy is critical in overcoming
these side-effects. It is this supportive care, including blood
product support, antibiotics, antifungal drugs, growth factors
and antiemetics, that has allowed specialist haematology units to
achieve the best possible results from intensive chemotherapy:
for example, when treating acute leukaemia.
The basic principles of chemotherapy include combining
several non-cross-reacting drugs in a regimen that kills a fixed
proportion of cancer cells with a given dose. Several cycles of
the combination are given to achieve gradual reduction of the
tumour burden, to induce remission and, in some instances, to
produce a cure (p. 1330).
In recent years, chemotherapy has been improved by the
addition of treatments that are more targeted to the cancer
cell, particularly monoclonal antibodies; for example, rituximab
(anti-CD20) has been added to CFIOP (cyclophosphamide
doxorubicin, vincristine, prednisolone) and other regimens,
significantly improving the outcome in a range of CD20-positive
B-cell lymphomas, including diffuse large B-cell lymphoma,
follicular lymphoma and mantle cell lymphoma. Chemotherapy
drugs can also be linked to a monoclonal antibody to allow
23.21 Examples of commonly used groups of
cancer drugs in haematology
Alkylating agents
• Cross-link double-stranded DNA by adding an alkyl group, e.g.
cyclophosphamide, melphalan, chlorambucil
Anthracyclines
• Intercalate between base pairs in the DNA molecule, e.g.
daunorubicin, doxorubicin, idarubicin
Antimetabolites
• Inhibit DNA and RNA synthesis, e.g. cytosine arabinoside,
fludarabine, methotrexate
Vinca alkaloids
• Cause disruption of tubulin, e.g. vincristine, vinblastine
Topoisomerase II inhibitors
• Prevent DNA repair, e.g. etoposide, daunorubicin, mitoxantrone
An example of a common combination regimen is CHOP, used in lymphoma:
cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine) and
prednisolone, given every 21 days for six cycles
targeting of the chemotherapy drug to the specific cancer cell.
Examples of such antibody-drug conjugates (ADCs) include
the linking of the intercalating antibiotic calicheamicin to
anti-CD33 (gemtuzumab ozogamicin) to treat acute myeloid
leukaemia, and to anti-CD22 (inotuzumab ozogamicin) to treat
acute lymphoblastic leukaemia. Small molecules targeted at
the mechanisms causing cancer are replacing chemotherapy
in some disease situations, such as tyrosine kinase inhibitors in
chronic myeloid leukaemia and inhibitors of B-cell signalling in
relapsed chronic lymphocytic leukaemia and lymphomas. More
details of specific chemotherapies are given later in the chapter.
Haematopoietic stem cell transplantation
Transplantation of haematopoietic stem cells (HSCT) has
offered the only hope of ‘cure’ in a variety of haematological
and non-haematological disorders (Box 23.22). As standard
treatment improves, the indications for HSCT are being refined
and extended, although its use remains most common in
haematological malignancies. The type of HSCT is defined
according to the donor and source of stem cells:
• In allogeneic HSCT, the stem cells come from a donor
- either a related donor (usually an HLA-identical
sibling) or a closely HLA-matched volunteer unrelated
donor (VU D).
• In an autologous transplant, the stem cells are harvested
from the patient and stored in the vapour phase of liquid
nitrogen until required. Stem cells can be harvested from
the bone marrow or from the blood.
23.22 Indications for allogeneic haematopoietic stem
cell transplantation
• Neoplastic disorders affecting stem cell compartments (e.g.
leukaemias)
• Failure of haematopoiesis (e.g. aplastic anaemia)
• Major inherited defects in blood cell production (e.g. thalassaemia,
immunodeficiency diseases)
• Inborn errors of metabolism with missing enzymes or cell lines
Principles of management of haematological disease • 937
Allogeneic HSCT
Healthy bone marrow or blood stem cells from a donor are
infused intravenously into the recipient, who has been suitably
‘conditioned’. The conditioning treatment (chemotherapy with
or without radiotherapy) is ‘myeloablative’ or, increasingly, ‘non-
myeloablative’. Myeloablative conditioning destroys malignant cells
and immunosuppresses the recipient, as well as ablating the
recipient’s haematopoietic tissues. Reduced intensity conditioning
(non-myeloablative) relies on intense immunosuppression to
provide ‘immunological space’ for transplanted stem cells. The
infused donor cells ‘home’ to the marrow, engraft and produce
enough erythrocytes, granulocytes and platelets for the patient’s
needs after about 3-4 weeks. During this period of aplasia,
patients are at risk of infection and bleeding, and require intensive
supportive care as described on page 957. It may take several
years to regain normal immunological function and patients remain
at risk from opportunistic infections, particularly in the first year.
An advantage of receiving allogeneic donor stem cells is that the
donor’s immune system can recognise residual recipient malignant
cells and destroy them. This immunological ‘graft-versus-disease’
effect is a powerful tool against many haematological tumours
and can be boosted post-transplantation by the infusion of T cells
taken from the donor: so-called donor lymphocyte infusion (DLI).
Considerable morbidity and mortality are associated with
HSCT. The best results are obtained in patients with minimal
residual disease, and in those under 20 years of age who have
an HLA-identical sibling donor. Reduced-intensity conditioning
has enabled treatment of older or less fit patients. In this form
of transplantation, rather than using very intensive myeloablative
conditioning, which causes morbidity from organ damage,
relatively low doses of chemotherapy drugs, such as fludarabine
and cyclophosphamide or busulfan, are used in combination
with antibodies such as alemtuzumab (which targets CD52
on mature lymphoid cells) or anti -thymocyte globulin (ATG) to
immunosuppress the recipient and allow donor stem cells to
engraft. The emerging donor immune system then eliminates
malignant cells via the ‘graft-versus-disease’ effect, which may
be boosted by the elective use of donor T-cell infusions post¬
transplant. Such transplants have produced long-term remissions
in some patients with acute leukaemia and myelodysplastic
syndromes aged 40-65 years, who would not previously have
been considered for a myeloablative allograft.
Complications
These are outlined in Boxes 23.23 and 23.24. The risks and
outcomes of transplantation depend upon several patient- and
disease-related factors. In general, 25% die from procedure-
related complications, such as infection and GVHD, and there
23.23 Complications of allogeneic haematopoietic
stem cell transplantation
Early
• Anaemia • Mucositis - pain, nausea,
• Infections diarrhoea
• Bleeding • Liver veno-occlusive disease
• Acute GVHD
Late
• Chronic GVHD • Cataracts
• Infertility • Second malignancy
(GVHD = graft-versus-host disease)
^9 23.24 Infections during recovery from
haematopoietic stem cell transplantation (HSCT)
Infection
Time after HSCT
Management
Herpes simplex
(p. 247)
0-4 weeks (aplastic
phase)
Aciclovir prophylaxis
and therapy
Bacterial, fungal
0-4 weeks (aplastic
phase)
As for acute leukaemia
(p. 956) - antibiotic and
antifungal prophylaxis
and therapy
Cytomegalovirus
(p. 242)
5-21 weeks
(cell-mediated
immune deficiency)
Antigen screening in
blood (PCR) and
pre-emptive therapy
(e.g. ganciclovir)
Varicella zoster
(p. 238)
After 1 3 weeks
Aciclovir prophylaxis
and therapy
Pneumocystis
jirovecii (p. 31 8)
8-26 weeks
Co-trimoxazole
Encapsulated
bacteria
8 weeks to years
(immunoglobulin
deficiency, prolonged
with GVHD)
Prophylaxis and
revaccination
(GVHD = graft-versus-host disease; PCR = polymerase chain reaction)
remains a significant risk of the haematological malignancy
relapsing. The long-term survival for patients undergoing allogeneic
HSCT in acute leukaemia is around 50%.
Graft-versus-host disease
GVHD is caused by the cytotoxic activity of donor T lymphocytes
that become sensitised to their new host, regarding it as foreign.
This may cause either an acute or a chronic form of GVHD.
Acute GVHD occurs in the first 100 days after transplant in
about one-third of patients. It can affect the skin, causing rashes,
the liver, causing jaundice, and the gut, causing diarrhoea, and
may vary from mild to lethal. Prevention includes HLA-matching
of the donor, immunosuppressant drugs, including methotrexate,
ciclosporin, alemtuzumab or ATG. Severe presentations are
very difficult to control and, despite high-dose glucocorticoids,
may result in death.
Chronic GVHD may follow acute GVHD or arise independently;
it occurs later than acute GVHD. It often resembles a connective
tissue disorder, although in mild cases a rash may be the only
manifestation. Chronic GVHD is usually treated with glucocorticoids
and prolonged immunosuppression with, for example, ciclosporin.
Chronic GVHD results in an increased infection risk. However,
associated with chronic GVHD are the graft-versus-disease
effect and a lower relapse rate of the underlying malignancy.
| Autologous HSCT
This procedure can also be used in haematological malignancies.
The patient’s own stem cells from blood or marrow are first
harvested and frozen. After conditioning myeloablative therapy,
the autologous stem cells are reinfused into the blood stream in
order to rescue the patient from the marrow damage and aplasia
caused by chemotherapy. Autologous HSCT may be used for
disorders that do not primarily involve the haematopoietic tissues,
or for patients in whom very good remissions have been achieved.
The most common indications are lymphomas and myeloma.
The preferred source of stem cells for autologous transplants
is peripheral blood (PBSCT). These stem cells engraft more
938 • HAEMATOLOGY AND TRANSFUSION MEDICINE
quickly, marrow recovery occurring within 2-3 weeks. There is
no risk of GVHD and no immunosuppression is required. Thus
autologous stem cell transplantation carries a lower procedure-
related mortality rate than allogeneic HSCT at around 5%, but
there is a higher rate of recurrence of malignancy because the
anti-malignancy effect is solely dependent on the conditioning
chemotherapy with no ‘graft-versus-disease’ effect.
Anticoagulant and antithrombotic therapy
There are numerous indications for anticoagulant and
antithrombotic medications (Box 23.25). The guiding principles are
outlined here but management in specific indications is discussed
elsewhere in the book. Broadly speaking, antiplatelet medications
are of greater efficacy in the prevention of arterial thrombosis
and of less value in the prevention of venous thromboembolism
(VTE). Thus, antiplatelet agents, such as aspirin, clopidogrel
and, increasingly, ticagrelor, are the drugs of choice in acute
coronary events (p. 498) and in ischaemic cerebrovascular
i
Heparin/LMWH/Fondaparinux
• Prevention and treatment of VTE
• Percutaneous coronary intervention
• Post-thrombolysis for Ml
• Unstable angina pectoris
• Non-Q wave Ml
• Acute peripheral arterial occlusion
• Cardiopulmonary bypass
• Haemodialysis and haemofiltration
Coumarins (warfarin etc.)
• Prevention and treatment of VTE
• Arterial embolism
• Atrial fibrillation with specific risk factors
for stroke (p. 472)
• Mobile mural thrombus post-MI
• Extensive anterior Ml
• Dilated cardiomyopathy
• Cardioversion
• Ischaemic stroke in antiphospholipid
syndrome
• Mitral stenosis and mitral regurgitation
with atrial fibrillation
• Recurrent venous thrombosis while on
warfarin
• Mechanical prosthetic cardiac valves
Rivaroxaban
• Prevention and treatment of VTE
• Atrial fibrillation with risk factors for stroke
Dabigatran etexilate
• Prevention of VTE
• Atrial fibrillation with risk factors for stroke
Apixaban
• Prevention of VTE
• Atrial fibrillation with risk factors for stroke
Edoxaban
• Treatment of VTE
• Atrial fibrillation with risk factors for stroke
(INR = international normalised ratio; LMWH = low-molecular-weight heparin;
Ml = myocardial infarction; VTE = venous thromboembolism)
disease, while warfarin and other anticoagulants are favoured
in VTE (p. 975) and management of atrial fibrillation (p. 471).
In some extremely prothrombotic situations, such as coronary
artery stenting, a combination of anticoagulant and antiplatelet
drugs is used (p. 491).
A wide range of anticoagulant and antithrombotic drugs
is used in clinical practice. These drugs and their modes of
action are given in Box 23.26. Newer agents allow predictable
anticoagulation without the need for frequent monitoring and
dose titration. Although warfarin remains the mainstay for
oral anticoagulation, newer oral anticoagulants (dabigatran,
rivaroxaban, edoxaban and apixaban), which can be given at
fixed doses with predictable effects and no need for monitoring,
have now been approved for the prevention of perioperative
VTE, the treatment of established VTE and the prevention of
cardioembolic stroke in patients with atrial fibrillation.
Heparins
Unfractionated heparin (UFH) and low-molecular-weight heparins
(LMWHs) act by binding via a specific pentasaccharide in the
heparin molecule to antithrombin. Fondaparinux is a synthetic
pentasaccharide, which also binds antithrombin and has
similar properties to LMWH. These agents enhance the natural
anticoagulant activity of antithrombin (see Fig. 23. 6E). Increased
cleavage of activated proteases, particularly factor Xa and
thrombin (lla), accounts for the anticoagulant effect. LMWHs
preferentially augment antithrombin activity against factor Xa.
For the licensed indications, LMWHs are at least as efficacious
as UFH but have several advantages:
• LMWHs are nearly 1 00% bioavailable and so produce
reliable dose-dependent anticoagulation.
• LMWHs do not require monitoring of their anticoagulant
effect (except possibly in patients with very low body
BS 23.26 Modes of action of anticoagulant and
antithrombotic drugs
Mode of action
Drug
Antiplatelet drugs
Cyclo-oxygenase (COX) inhibition
Aspirin
Adenosine diphosphate (ADP) receptor
inhibition
Clopidogrel
Prasugrel
Ticagrelor
Glycoprotein llb/llla inhibition
Abciximab
Tirofiban
Eptifibatide
Phosphodiesterase inhibition
Dipyridamole
Oral anticoagulants
Vitamin K antagonism
Warfarin/coumarins
Direct thrombin inhibition
Dabigatran
Direct Xa inhibition
Rivaroxaban
Apixaban
Edoxaban
Injectable anticoagulants
Antithrombin-dependent inhibition of
thrombin and Xa
Heparin
LMWH
Antithrombin-dependent inhibition of Xa
Fondaparinux
Danaparoid
Direct thrombin inhibition
Argatroban
Bivalirudin
23.25 Indications for anticoagulation
Therapeutic INR 2.5
| INR 3.5
Principles of management of haematological disease • 939
23.27 Treatments for emergencies in
haematological practice
• Reversal of life- and limb-threatening haemorrhage in
anticoagulated patients:
Warfarin: prothrombin complex concentrate and IV vitamin Kt
Unfractionated heparin: protamine sulphate
Dabigatran: idarucizumab
• Recognition of thrombotic thrombocytopenic purpura and treatment
with plasma exchange
• Recognition of coagulopathy associated with acute promyelocytic
leukaemia and treatment with all-trans-retinoic acid and fibrinogen
replacement
• Recognition of chest syndrome and stroke in patients with
sickle-cell anaemia and red cell transfusion or exchange transfusion
• Recognition of neutropenic sepsis in patients receiving
chemotherapy and early treatment with empirical broad-spectrum
antibiotics
weight and with a glomerular filtration rate below
30 mL7min).
• LMWHs have a half-life of around 4 hours when given
subcutaneously, compared with 1 hour for UFH. This permits
once-daily dosing by the subcutaneous route, rather than the
therapeutic continuous intravenous infusion or twice-daily
subcutaneous administration required for UFH.
• While rates of bleeding are similar between products,
the risk of osteoporosis and heparin-induced
thrombocytopenia is much lower for LMWH.
UFH is, however, more completely reversed by protamine
sulphate in the event of bleeding and at the end of cardiopulmonary
bypass, for which UFH remains the drug of choice (Box 23.27).
LMWHs are widely used for the prevention and treatment of
VTE, the management of acute coronary syndromes and for
most other scenarios listed in Box 23.25. In some situations,
UFH is still favoured by some clinicians, though there is little
evidence that it is advantageous, except when rapid reversibility
is required. UFH is useful in patients with a high risk of bleeding,
e.g. those who have peptic ulceration or who may require urgent
surgery. It is also favoured in the treatment of life-threatening
thromboembolism, e.g. major pulmonary embolism with significant
hypoxaemia, hypotension and right-sided heart strain. In this
situation, UFH is started with a loading intravenous dose of 80 U/
kg, followed by a continuous infusion of 18 U/kg/hr initially. The
level of anticoagulation should be assessed by the APTT after
6 hours and, if satisfactory, twice daily thereafter. It is usual to
aim for a patient APTT that is 1 .5-2.5 times the control time of
the test. Monitoring of UFH treatment by APTT is not without
difficulties and other assays, such as the specific anti-Xa assay,
may provide more accurate guidance.
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is a rare complication
of heparin therapy, caused by induction of anti-heparin/PF4
antibodies that bind to and activate platelets via an Fc receptor.
This results in platelet activation and a prothrombotic state,
with a paradoxical thrombocytopenia. HIT is more common in
surgical than medical patients (especially cardiac and orthopaedic
patients), with use of UFH rather than LMWH, and with higher
doses of heparin.
Clinical features
Patients present, typically 5-14 days after starting heparin
treatment, with a fall in platelet count of more than 30% from
baseline. The count may still be in the reference range. The
patient may be asymptomatic, or develop venous or arterial
thrombosis and skin lesions, including overt skin necrosis.
Affected patients may complain of pain or itch at injection sites
and of systemic symptoms, such as shivering, following heparin
injections. Patients who have received heparin in the preceding
100 days and who have preformed antibodies may develop
acute systemic symptoms and an abrupt fall in platelet count
in the first 24 hours after re-exposure.
Investigations
The pre-test probability of the diagnosis is assessed using the
4Ts scoring system. This assigns a score based on:
• the thrombocytopenia
• the timing of the fall in platelet count
• the presence of new thrombosis
• the likelihood of another cause for the thrombocytopenia.
Individuals at low risk need no further test. Those with
intermediate and high likelihood scores should have the
diagnosis confirmed or refuted using an anti-PF4 enzyme-linked
immunosorbent assay (ELISA).
Management
Heparin should be discontinued as soon as HIT is diagnosed and
an alternative anticoagulant that does not cross-react with the
antibody should be substituted. Argatroban (a direct thrombin
inhibitor) and danaparoid (a heparin analogue) are licensed for
use in the UK. In asymptomatic patients with HIT who do not
receive an alternative anticoagulant, around 50% will sustain a
thrombosis in the subsequent 30 days. Patients with established
thrombosis have a poorer prognosis.
Coumarins
Although several coumarin anticoagulants are used around the
world, warfarin is the most common.
Coumarins inhibit the vitamin K-dependent post-translational
carboxylation of factors II (prothrombin), VII, IX and X in the
liver (see Fig. 23. 6D). This results in anticoagulation due to an
effective deficiency of these factors. This is monitored by the INR,
a standardised test based on measurement of the prothrombin
time (p. 922). Recommended target INR values for specific
indications are given in Box 23.25.
Warfarin anticoagulation typically takes more than 3-5 days
to become established, even using loading doses. Patients
who require rapid initiation of therapy may receive higher
initiation doses of warfarin. A typical regime in this situation
is to give 10 mg warfarin on the first and second days, with
5 mg on the third day; subsequent doses are titrated against
the INR. Patients without an urgent need for anticoagulation
(e.g. atrial fibrillation) can have warfarin introduced slowly using
lower doses. Low-dose regimens are associated with a lower
risk of the patient developing a supratherapeutic INR, and
hence a lower bleeding risk. The duration of warfarin therapy
depends on the clinical indication, and while treatment of
deep vein thrombosis (DVT) or preparation for cardioversion
may require a limited duration, anticoagulation to prevent
cardioembolic stroke in atrial fibrillation or from heart valve disease
is long-term.
The major problems with warfarin are:
• a narrow therapeutic window
• metabolism that is affected by many factors
• numerous drug interactions.
940 • HAEMATOLOGY AND TRANSFUSION MEDICINE
23.28 How to assess risks of anticoagulation
Contraindications
• Recent surgery, especially to eye or central nervous system
• Pre-existing haemorrhagic state, e.g. advanced liver disease,
haemophilia, thrombocytopenia
• Pre-existing structural lesions, e.g. peptic ulcer
• Recent cerebral or gastrointestinal haemorrhage
• Uncontrolled hypertension
• Cognitive impairment
• Frequent falls
Bleeding risk score
• Several bleeding risk scores exist for different indications for
anticoagulation
• The validation of most bleeding risk scores has been poor
• Many risk factors for thrombosis are also risk factors for bleeding
• Following anticoagulant-related bleeding, reassessment of bleeding
and thrombosis risk is indicated
• In many cases, patients benefit from recommencing anticoagulants
after bleeding
Drug interactions are common through protein binding and
metabolism by the cytochrome P450 system. Inter-individual
differences in warfarin doses required to achieve a therapeutic INR
are mostly accounted for by naturally occurring polymorphisms
in the CYP2C9 and the VK0RC1 genes (which predict the
metabolism and function of warfarin, respectively) and dietary
intake of vitamin K.
Major bleeding is the most common serious side-effect
of warfarin and occurs in 1-2% of patients each year. Fatal
haemorrhage, which is most commonly intracranial, occurs
in about 0.25% per annum. There are scoring systems that
predict the annual bleeding risk and these can be used to help
compare the risks and benefits of warfarin for an individual patient
(Box 23.28). There are also some specific contraindications to
anticoagulation (Box 23.28). Management of warfarin includes
strategies for over-anticoagulation and for bleeding:
• If the INR is above the therapeutic level, warfarin should
be withheld or the dose reduced. If the patient is not
bleeding, it may be appropriate to give a small dose of
vitamin K either orally or intravenously (1-2.5 mg),
especially if the INR is greater than 8.
• In the event of bleeding, withhold further warfarin. Minor
bleeding can be treated with 1-2.5 mg of vitamin K IV.
Major haemorrhage should be treated as an emergency
with vitamin K 5-10 mg slowly IV, combined with
coagulation factor replacement (see Box 23.27). This
should optimally be a prothrombin complex concentrate
(30-50 U/kg) that contains factors II, VII, IX and X; if that is
not available, fresh frozen plasma (15-30 mLVkg) should
be given.
| Direct oral anticoagulants
The direct oral anticoagulants (DOACs) offer an alternative to
coumarins in the management of VTE and the prevention of
stroke and systemic embolism in patients with atrial fibrillation.
The DOACs are direct specific inhibitors of key proteases in the
common pathway. Dabigatran inhibits thrombin while rivaroxaban,
apixaban and edoxaban inhibit Xa. The key features of these drugs
include the fact that they are efficacious in fixed oral doses, have
a short half-life of around 1 0 hours, achieve peak plasma levels
2-4 hours after oral intake, have very few drug interactions and
are all moderately dependent on renal function for their excretion.
An initial perceived drawback was the lack of specific reversal
agents for these drugs but idarucizumab is a monoclonal antibody
now available for the reversal of dabigatran, and andexanet alfa, a
site-inactivated Xa molecule, is close to licensing for the reversal
of apixaban and rivaroxaban (see Box 23.27).
DOACs are now licensed for the prevention of VTE following
high-risk orthopaedic surgery (except edoxaban), the acute
management and prevention of recurrence of VTE, and the
prevention of stroke and systemic embolism in patients with atrial
fibrillation with risk factors. The general perception at present
is that in these indications they are at least as efficacious as
dose-adjusted coumarin and probably associated with less
clinically significant bleeding.
Anaemias
Around 30% of the total world population is anaemic and half
of these, some 600 million people, have iron deficiency. The
classification of anaemia by the size of the red cells (MOV)
indicates the likely cause (see Figs 23.10 and 23.1 1).
Red cells in the bone marrow must acquire a minimum level
of haemoglobin before being released into the blood stream (Fig.
23.17). While in the marrow compartment, red cell precursors
undergo cell division, driven by erythropoietin. If red cells cannot
acquire haemoglobin at a normal rate, they will undergo more
divisions than normal and will have a low MCV when finally
released into the blood. The MCV is low because component
parts of the haemoglobin molecule are not fully available: that
is, iron in iron deficiency, globin chains in thalassaemia, haem
ring in congenital sideroblastic anaemia and, occasionally, poor
iron utilisation in the anaemia of chronic disease/anaemia of
inflammation.
In megaloblastic anaemia, the biochemical consequence
of vitamin B12 or folate deficiency is an inability to synthesise
new bases to make DNA. A similar defect of cell division is
seen in the presence of cytotoxic drugs or haematological
disease in the marrow, such as myelodysplasia. In these states,
cells haemoglobinise normally but undergo fewer cell divisions,
resulting in circulating red cells with a raised MCV. The red cell
membrane is composed of a lipid bilayer that will freely exchange
with the plasma pool of lipid. Conditions such as liver disease,
hypothyroidism, hyperlipidaemia and pregnancy are associated
with raised lipids and may also cause a raised MCV. Reticulocytes
are larger than mature red cells, so when the reticulocyte
count is raised - e.g. in haemolysis - this may also increase
the MCV.
Iron deficiency anaemia
This occurs when iron losses or physiological requirements
exceed absorption.
Blood loss
The most common explanation in men and post-menopausal
women is gastrointestinal blood loss (p. 780). This may result
from occult gastric or colorectal malignancy, gastritis, peptic
ulceration, inflammatory bowel disease, diverticulitis, polyps
and angiodysplastic lesions. Worldwide, hookworm and
schistosomiasis are the most common causes of gut blood loss
(pp. 288 and 294). Gastrointestinal blood loss may be exacerbated
Anaemias
941
Normal
i
Marrow
Blood
O
Microcytosis
(i MCV)
Reticulocyte -
Marked
A reticulocytosis
t
o
Normal-sized
RBC
i
Macrocytosis
(TMCV)
Elevated plasma
lipid
Liver disease
Hypothyroidism
Alcohol
Hyperlipidaemia
Pregnancy
Fig. 23.17 Factors that influence the size of red cells in anaemia. In microcytosis, the MCV is <76 fL. In macrocytosis, the MCV is >100 fL.
(MCV = mean cell volume; RBC = red blood cell)
by the chronic use of aspirin or non-steroidal anti-inflammatory
drugs (NSAIDs), which cause intestinal erosions and impair
platelet function. In women of child-bearing age, menstrual blood
loss, pregnancy and breastfeeding contribute to iron deficiency
by depleting iron stores; in developed countries, one-third of
pre-menopausal women have low iron stores but only 3% display
iron-deficient haematopoiesis. Very rarely, chronic haemoptysis
or haematuria may cause iron deficiency.
Malabsorption
A dietary assessment should be made in all patients to ascertain
their iron intake (p. 716). Gastric acid is required to release iron
from food and helps to keep iron in the soluble ferrous state
(Fig. 23.18). Achlorhydria in the elderly or that due to drugs
such as proton pump inhibitors may contribute to the lack of
iron availability from the diet, as may previous gastric surgery.
Iron is absorbed actively in the upper small intestine and hence
can be affected by coeliac disease (p. 805).
Physiological demands
At times of rapid growth, such as infancy and puberty, iron
requirements increase and may outstrip absorption. In pregnancy,
iron is diverted to the fetus, the placenta and the increased
maternal red cell mass, and is lost with bleeding at parturition
(Box 23.29).
Investigations
Confirmation of iron deficiency
Serum ferritin is a measure of iron stores in tissues and is the
best single test to confirm iron deficiency (Box 23.30). It is a
23.29 Haematological physiology in pregnancy
• Full blood count: increased plasma volume (40%) lowers normal
haemoglobin (reference range reduced to >105 g/L at 28 weeks).
The mean cell volume (MCV) may increase by 5 fL. A progressive
neutrophilia occurs. Gestational thrombocytopenia (rarely
<60x1 09/L) is a benign phenomenon.
• Depletion of iron stores: iron deficiency is a common cause of
anaemia in pregnancy and, if present, should be treated with oral
iron supplement.
• Vitamin B12: serum levels are physiologically low in pregnancy but
deficiency is uncommon.
• Folate: tissue stores may become depleted, and folate
supplementation is recommended in all pregnancies (see
Box 19.29, p. 712).
• Coagulation factors: from the second trimester, procoagulant
factors increase approximately threefold, particularly fibrinogen, von
Willebrand factor and factor VIII. This causes activated protein C
resistance and a shortened activated partial thromboplastin time
(APTT), and contributes to a prothrombotic state.
• Anticoagulants: levels of protein C increase from the second
trimester, while levels of free protein S fall as C4b binding protein
increases.
very specific test; a subnormal level is due to iron deficiency or,
very rarely, hypothyroidism or vitamin C deficiency. Ferritin levels
can be raised in liver disease and in the acute phase response;
in these conditions, a ferritin level of up to 100 pig/L may still be
compatible with low bone marrow iron stores.
942 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Fig. 23.18 The regulation of iron absorption, uptake and distribution in the body. The transport of iron is regulated in a similar fashion to
enterocytes in other iron-transporting cells such as macrophages.
23.30 Investigations to differentiate anaemia of chronic disease from iron deficiency anaemia
Ferritin Iron TIBC Transferrin saturation Soluble transferrin receptor
Iron deficiency anaemia l l T l T
Anaemia of chronic disease T/Normal III i/Normal
(TIBC = total iron binding capacity)
Plasma iron and total iron binding capacity (TIBC) are measures
of iron availability; hence they are affected by many factors
besides iron stores. Plasma iron has a marked diurnal and
day-to-day variation and becomes very low during an acute
phase response but is raised in liver disease and haemolysis.
Levels of transferrin, the binding protein for iron, are lowered
by malnutrition, liver disease, the acute phase response and
nephrotic syndrome, but raised by pregnancy and the oral
contraceptive pill. A transferrin saturation (i.e. iron/TIBCxIOO)
of less than 1 6% is consistent with iron deficiency but is less
specific than a ferritin measurement.
All proliferating cells express membrane transferrin receptors to
acquire iron; a small amount of this receptor is shed into blood,
where it can be detected in a free soluble form. At times of poor
iron stores, cells up-regulate transferrin receptor expression and
the levels of soluble plasma transferrin receptor increase. This
can now be measured by immunoassay and used to distinguish
storage iron depletion in the presence of an acute phase response
or liver disease, when a raised level indicates iron deficiency.
In difficult cases, it may still be necessary to examine a bone
marrow aspirate for iron stores.
Investigation of the cause
This will depend on the age and sex of the patient, as well as
the history and clinical findings. In men and in post-menopausal
women with a normal diet, the upper and lower gastrointestinal
tract should be investigated by endoscopy or radiological studies.
Serum anti-transglutaminase antibodies and possibly a duodenal
biopsy are indicated (p. 806) to detect coeliac disease. Current
guidelines suggest exclusion of coeliac disease by antibody
testing at an early stage of investigation. In the tropics, stool
and urine should be examined for parasites (p. 233).
Anaemias • 943
Management
Unless the patient has angina, heart failure or evidence of cerebral
hypoxia, transfusion is not necessary and oral iron replacement
is appropriate. Ferrous sulphate 200 mg 3 times daily (195 mg
of elemental iron per day) is adequate and should be continued
for 3-6 months to replete iron stores. Many patients suffer
gastrointestinal side-effects with ferrous sulphate, including
dyspepsia and altered bowel habit. When this occurs, reduction
in dose to 200 mg twice daily or a switch to ferrous gluconate
300 mg twice daily (70 mg of elemental iron per day) or another
alternative oral preparation should be tried. Delayed-release
preparations are not useful, since they release iron beyond the
upper small intestine, where it cannot be absorbed.
The haemoglobin should rise by around 10 g/L every
7-10 days and a reticulocyte response will be evident within
a week. A failure to respond adequately may be due to
non-adherence, continued blood loss, malabsorption or an
incorrect diagnosis. Patients with malabsorption, chronic gut
disease or inability to tolerate any oral preparation may need
parenteral iron therapy. Previously, iron dextran or iron sucrose
was used, but new preparations of iron isomaltose and iron
carboxymaltose have fewer allergic effects and are preferred.
Doses required can be calculated based on the patient’s starting
haemoglobin and body weight. Observation for anaphylaxis
following an initial test dose is recommended.
Anaemia of chronic disease
Anaemia of chronic disease (ACD), also known as anaemia of
inflammation (Al), is a common type of anaemia, particularly in
hospital populations. It occurs in the setting of chronic infection,
chronic inflammation or neoplasia. The anaemia is not related
to bleeding, haemolysis or marrow infiltration, is mild, with
haemoglobin in the range of 85-1 1 5 g/L, and is usually associated
with a normal MCV (normocytic, normochromic), though this
may be reduced in long-standing inflammation. The serum iron
is low but iron stores are normal or increased, as indicated by
the ferritin or stainable marrow iron.
Pathogenesis
It has recently become clear that the key regulatory protein that
accounts for the findings characteristic of ACD/AI is hepcidin,
which is produced by the liver (see Fig. 23.1 8). Hepcidin production
is induced by pro-inflammatory cytokines, especially IL-6. Hepcidin
binds to ferroportin on the membrane of iron -exporting cells, such
as small intestinal enterocytes and macrophages, internalising the
ferroportin and thereby inhibiting the export of iron from these
cells into the blood. The iron remains trapped inside the cells
in the form of ferritin, levels of which are therefore normal or
high in the face of significant anaemia. Inhibition or blockade of
hepcidin is a potential target for treatment of this form of anaemia.
Diagnosis and management
It is often difficult to distinguish ACD associated with a low MCV
from iron deficiency. Box 23.30 summarises the investigations
and results. Examination of the marrow may ultimately be required
to assess iron stores directly. A trial of oral iron can be given
in difficult situations. A positive response occurs in true iron
deficiency but not in ACD. Measures that reduce the severity
of the underlying disorder generally help to improve the ACD.
Trials of higher-dose intravenous iron are under way to try to
bypass the hepcidin-induced blockade.
Megaloblastic anaemia
This results from a deficiency of vitamin B12 or folic acid, or from
disturbances in folic acid metabolism. Folate is an important
substrate of, and vitamin B12 a co-factor for, the generation
of the essential amino acid methionine from homocysteine.
This reaction produces tetrahydrofolate, which is converted to
thymidine monophosphate for incorporation into DNA. Deficiency
of either vitamin B12 or folate will therefore produce high plasma
levels of homocysteine and impaired DNA synthesis.
The end result is cells with arrested nuclear maturation but
normal cytoplasmic development: so-called nucleocytoplasmic
asynchrony. All proliferating cells will exhibit megaloblastosis;
hence changes are evident in the buccal mucosa, tongue, small
intestine, cervix, vagina and uterus. The high proliferation rate of
bone marrow results in striking changes in the haematopoietic
system in megaloblastic anaemia. Cells become arrested
in development and die within the marrow; this ineffective
erythropoiesis results in an expanded hypercellular marrow. The
megaloblastic changes are most evident in the early nucleated
red cell precursors, and haemolysis within the marrow results in
a raised bilirubin and lactate dehydrogenase (LDH), but without
the reticulocytosis characteristic of other forms of haemolysis
(p. 945). Iron stores are usually raised. The mature red cells are
large and oval, and sometimes contain nuclear remnants. Nuclear
changes are seen in the immature granulocyte precursors and
a characteristic appearance is that of ‘giant’ metamyelocytes
with a large ‘sausage-shaped’ nucleus. The mature neutrophils
show hypersegmentation of their nuclei, with cells having six or
more nuclear lobes. If severe, a pancytopenia may be present
in the peripheral blood.
Vitamin B12 deficiency, but not folate deficiency, is associated
with neurological disease in up to 40% of cases, although
advanced neurological disease due to B12 deficiency is now
uncommon in the developed world. The main pathological finding
is focal demyelination affecting the spinal cord, peripheral nerves,
optic nerves and cerebrum. The most common manifestations
are sensory, with peripheral paraesthesiae and ataxia of gait.
The clinical and diagnostic features of megaloblastic anaemia
are summarised in Boxes 23.31 and 23.32, and the neurological
features of B12 deficiency in Box 23.33.
Vitamin B12
Vitamin B12 absorption
The average daily diet contains 5-30 jig of vitamin B12, mainly
in meat, fish, eggs and milk - well in excess of the 1 jig daily
23.31 Clinical features of megaloblastic anaemia
Symptoms
• Malaise (90%)
•
Poor memory
• Breathlessness (50%)
•
Depression
• Paraesthesiae (80%)
•
Personality change
• Sore mouth (20%)
•
Hallucinations
• Weight loss
•
Visual disturbance
• Impotence
Signs
• Smooth tongue
•
Skin pigmentation
• Angular cheilosis
•
Heart failure
• Vitiligo
•
Pyrexia
944 • HAEMATOLOGY AND TRANSFUSION MEDICINE
23.32 Investigations in megaloblastic anaemia
Investigation
Result
Haemoglobin
Often reduced, may be very low
Mean cell volume
Usually raised, commonly >120 fL
Erythrocyte count
Low for degree of anaemia
Blood film
Oval macrocytosis, poikilocytosis, red cell
fragmentation, neutrophil hypersegmentation
Reticulocyte count
Low for degree of anaemia
Leucocyte count
Low or normal
Platelet count
Low or normal
Bone marrow
Increased cellularity, megaloblastic changes
in erythroid series, giant metamyelocytes,
dysplastic megakaryocytes, increased iron
in stores, pathological non-ring sideroblasts
Serum ferritin
Elevated
Plasma lactate
dehydrogenase
Elevated, often markedly
23.33 Neurological findings in B12 deficiency
Peripheral nerves
• Glove and stocking paraesthesiae
• Loss of ankle reflexes
Spinal cord
• Subacute combined degeneration of the cord
Posterior columns - diminished vibration sensation and
proprioception
Corticospinal tracts - upper motor neuron signs
Cerebrum
• Dementia
• Optic atrophy
Autonomic neuropathy
requirement. In the stomach, gastric enzymes release vitamin B12
from food and at gastric pH it binds to a carrier protein termed
R protein. The gastric parietal cells produce intrinsic factor, a
vitamin B12-binding protein that optimally binds vitamin B12 at
pH 8. As gastric emptying occurs, pancreatic secretion raises
the pH and vitamin B12 released from the diet switches from
the R protein to intrinsic factor. Bile also contains vitamin B12
that is available for reabsorption in the intestine. The vitamin
B12— intrinsic factor complex binds to specific receptors in the
terminal ileum, and vitamin B12 is actively transported by the
enterocytes to plasma, where it binds to transcobalamin II, a
transport protein produced by the liver, which carries it to the
tissues for utilisation. The liver stores enough vitamin B12 for
3 years and this, together with the enterohepatic circulation,
means that vitamin B12 deficiency takes years to become manifest,
even if all dietary intake is stopped or severe B12 malabsorption
supervenes.
Blood levels of vitamin B12 (cobalamin) provide a reasonable
indication of tissue stores, are usually diagnostic of deficiency and
remain the first-line tests for most laboratories. Additional tests
have been evaluated, including measurement of methylmalonic
acid, holotranscobalamin and plasma homocysteine levels, but do
not add much in most clinical situations. Levels of cobalamins fall
in normal pregnancy. Reference ranges vary between laboratories
but levels below 150 ng/L are common and, in the last trimester,
5-1 0% of women have levels below 1 00 ng/L. Spuriously low
B12 values occur in women using the oral contraceptive pill and
in patients with myeloma, in whom paraproteins can interfere
with vitamin B12 assays.
Causes of vitamin B12 deficiency
Dietary deficiency
This occurs only in strict vegans but the onset of clinical features
can occur at any age between 10 and 80 years. Less strict
vegetarians often have slightly low vitamin B12 levels but are not
tissue vitamin B12-deficient.
Gastric pathology
Release of vitamin B12 from food requires normal gastric acid
and enzyme secretion, and this is impaired by hypochlorhydria
in elderly patients or following gastric surgery. Total gastrectomy
invariably results in vitamin B12 deficiency within 5 years, often
combined with iron deficiency; these patients need life-long
3-monthly vitamin B12 injections. After partial gastrectomy, vitamin
B12 deficiency only develops in 10-20% of patients by 5 years;
an annual injection of vitamin B12 should prevent deficiency in
this group.
Pernicious anaemia
This is an organ-specific autoimmune disorder in which the gastric
mucosa is atrophic, with loss of parietal cells causing intrinsic
factor deficiency. In the absence of intrinsic factor, less than 1 %
of dietary vitamin B12 is absorbed. Pernicious anaemia has an
incidence of 25/100000 population over the age of 40 years in
developed countries, but an average age of onset of 60 years.
It is more common in individuals with other autoimmune disease
(Hashimoto’s thyroiditis, Graves’ disease, vitiligo or Addison’s
disease; Ch. 1 8) or a family history of these or pernicious anaemia.
The finding of anti-intrinsic factor antibodies in the context of B12
deficiency is diagnostic of pernicious anaemia without further
investigation. Antiparietal cell antibodies are present in over 90%
of cases but are also present in 20% of normal females over the
age of 60 years; a negative result makes pernicious anaemia
less likely but a positive result is not diagnostic. The Schilling
test, involving measurement of absorption of radio-labelled B12
after oral administration before and after replacement of intrinsic
factor, has fallen out of favour with the availability of autoantibody
tests, greater caution in the use of radioactive tracers, and limited
availability of intrinsic factor.
Small bowel pathology
One-third of patients with pancreatic exocrine insufficiency fail
to transfer dietary vitamin B12 from R protein to intrinsic factor.
This usually results in slightly low vitamin B12 values but no tissue
evidence of vitamin B12 deficiency.
Motility disorders or hypogammaglobulinaemia can result in
bacterial overgrowth, and the ensuing competition for free vitamin
B12 can lead to deficiency. This is corrected to some extent by
appropriate antibiotics.
A small number of people heavily infected with the fish
tapeworm (p. 297) develop vitamin B12 deficiency.
Inflammatory disease of the terminal ileum, such as Crohn’s
disease, may impair the absorption of vitamin B12— intrinsic factor
complex, as may surgery on that part of the bowel.
Anaemias • 945
Folate
Folate absorption
Folates are produced by plants and bacteria; hence dietary leafy
vegetables (spinach, broccoli, lettuce), fruits (bananas, melons)
and animal protein (liver, kidney) are a rich source. An average
Western diet contains more than the minimum daily intake of
50 pig but excess cooking destroys folates. Most dietary folate is
present as polyglutamates; these are converted to monoglutamate
in the upper small bowel and actively transported into plasma.
Plasma folate is loosely bound to plasma proteins such as albumin
and there is an enterohepatic circulation. Total body stores of
folate are small and deficiency can occur in a matter of weeks.
Folate deficiency
The causes and diagnostic features of folate deficiency are shown
in Boxes 23.34 and 23.35. The edentulous elderly or psychiatric
patient is particularly susceptible to dietary deficiency and this
is exacerbated in the presence of gut disease or malignancy.
Pregnancy-induced folate deficiency is the most common cause
of megaloblastosis worldwide and is more likely in the context
of twin pregnancies, multiparity and hyperemesis gravidarum.
Serum folate measurement is very sensitive to dietary intake;
a single folate-rich meal can normalise it in a patient with true
folate deficiency, whereas anorexia, alcohol and anticonvulsant
therapy can reduce it in the absence of megaloblastosis. For
this reason, red cell folate levels are a more accurate indicator
of folate stores and tissue folate deficiency.
| Management of megaloblastic anaemia
If a patient with a severe megaloblastic anaemia is very ill and
treatment must be started before vitamin B12 and red cell folate
i
Diet
• Poor intake of vegetables
Malabsorption
• e.g. Coeliac disease, small bowel surgery
Increased demand
• Cell proliferation, e.g. haemolysis
• Pregnancy
Drugs*
• Certain anticonvulsants (e.g. phenytoin)
• Contraceptive pill
• Certain cytotoxic drugs (e.g. methotrexate)
results are available, that treatment should always include both
folic acid and vitamin B12. The use of folic acid alone in the
presence of vitamin B12 deficiency may result in worsening of
neurological features.
Rarely, if severe angina or heart failure is present, transfusion
can be used in megaloblastic anaemia. The cardiovascular system
is adapted to the chronic anaemia present in megaloblastosis,
and the volume load imposed by transfusion may result in
decompensation and severe cardiac failure. In such circumstances,
exchange transfusion or slow administration of 1 U of red cells
with diuretic cover may be given.
Vitamin B12 deficiency
Vitamin B12 deficiency is treated with hydroxycobalamin. In
cases of uncomplicated deficiency, 1000 pig IM for 6 doses 2
or 3 days apart, followed by maintenance therapy of 1000 pig
every 3 months for life, is recommended. In the presence of
neurological involvement, a dose of 1000 jig on alternate days
until there is no further improvement, followed by maintenance
as above, is recommended. The reticulocyte count will peak
by the 5th— 1 0th day after starting replacement therapy. The
haemoglobin will rise by 10 g/L every week until normalised.
The response of the marrow is associated with a fall in plasma
potassium levels and rapid depletion of iron stores. If an initial
response is not maintained and the blood film is dimorphic (i.e.
shows a mixture of microcytic and macrocytic cells), the patient
may need additional iron therapy. A sensory neuropathy may
take 6-1 2 months to correct; long-standing neurological damage
may not improve.
Folate deficiency
Oral folic acid (5 mg daily for 3 weeks) will treat acute deficiency
and 5 mg once weekly is adequate maintenance therapy.
Prophylactic folic acid in pregnancy prevents megaloblastosis
in women at risk, and reduces the risk of fetal neural tube
defects (p. 712). Prophylactic supplementation is also given in
chronic haematological disease associated with reduced red cell
lifespan (e.g. haemolytic anaemias). There is some evidence that
supraphysiological supplementation (400 pig/day) can reduce
the risk of coronary and cerebrovascular disease by lowering
plasma homocysteine levels. This has led the US Food and
Drug Administration to introduce fortification of bread, flour and
rice with folic acid.
Haemolytic anaemia
Haemolysis indicates that there is shortening of the normal
red cell lifespan of 120 days. There are many causes, as
shown in Figure 23.19. To compensate, the bone marrow may
increase its output of red cells six- to eightfold by increasing
the proportion of red cells produced, expanding the volume of
active marrow, and releasing reticulocytes prematurely. Anaemia
occurs only if the rate of destruction exceeds this increased
production rate.
There are some general features of haemolysis and other
specific features that help to identify the reason for haemolysis.
Results of investigations that establish the presence of haemolysis
are shown in Box 23.36. Red cell destruction overloads pathways
for haemoglobin breakdown in the liver (p. 850), causing a
modest rise in unconjugated bilirubin in the blood and mild
jaundice. Increased reabsorption of urobilinogen from the gut
results in an increase in urinary urobilinogen (pp. 860 and 915).
Red cell destruction releases LDH into the serum. The bone
*Usually only a problem in patients deficient in folate from another cause.
i
Diagnostic findings
• Serum folate levels may be low but are difficult to interpret
• Low red cell folate levels indicate prolonged folate deficiency and
are probably the most relevant measure
Corroborative findings
• Macrocytic dysplastic blood picture
• Megaloblastic marrow
23.35 Investigation of folic acid deficiency
23.34 Causes of folate deficiency
946 • HAEMATOLOGY AND TRANSFUSION MEDICINE
E
Fig. 23.19 Causes and classification of haemolysis. [A] Inherited causes. \m Acquired causes. (CLL = chronic lymphocytic leukaemia;
DIC = disseminated intravascular coagulation; EBV = Epstein— Barr virus; G6PD = glucose-6-phosphate dehydrogenase; HUS = haemolytic uraemic
syndrome; PK = pyruvate kinase; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TTP = thrombotic thrombocytopenic purpura)
^9 23.36 Investigation results indicating
active haemolysis
Hallmarks of haemolysis
• ^Haemoglobin
• TReticulocytes
• TUnconjugated bilirubin
• TLactate dehydrogenase
• TUrinary urobilinogen
Additional features of intravascular haemolysis
• ^Haptoglobin
• Positive urinary haemosiderin
• TMethaemalbumin
• Haemoglobinuria
marrow compensation results in a reticulocytosis, and sometimes
nucleated red cell precursors appear in the blood. Increased
proliferation of the bone marrow can result in a thrombocytosis,
neutrophilia and, if marked, immature granulocytes in the blood,
producing a leucoerythroblastic blood film. The appearances of
the red cells may give an indication of the likely cause of the
haemolysis:
• Spherocytes are small, dark red cells that suggest
autoimmune haemolysis or hereditary spherocytosis.
• Sickle cells suggest sickle-cell disease.
• Red cell fragments indicate microangiopathic haemolysis.
• Bite cells (normal-sized red cells that look as if they have
been partially eaten) suggest oxidative haemolysis.
The compensatory erythroid hyperplasia may give rise to folate
deficiency, with megaloblastic blood features.
The differential diagnosis of haemolysis is determined by the
clinical scenario in combination with the results of blood film
examination and Coombs testing for antibodies directed against
red cells (see below and Fig. 23.19).
Extravascular haemolysis
Physiological red cell destruction occurs in the reticulo-endothelial
cells in the liver or spleen, so avoiding free haemoglobin in the
Anaemias • 947
plasma. In most haemolytic states, haemolysis is predominantly
extravascular.
To confirm the haemolysis, patients’ red cells can be labelled
with 51chromium. When re-injected, they can be used to determine
red cell survival; when combined with body surface radioactivity
counting, this test may indicate whether the liver or the spleen
is the main source of red cell destruction. However, it is seldom
performed in clinical practice.
Intravascular haemolysis
Less commonly, red cell lysis occurs within the blood stream
due to membrane damage by complement (ABO transfusion
reactions, paroxysmal nocturnal haemoglobinuria), infections
(malaria, Clostridium perfringens), mechanical trauma (heart valves,
DIC) or oxidative damage (e.g. enzymopathies such as glucose-
6-phosphate dehydrogenase deficiency, which may be triggered
by drugs such as dapsone and maloprim). When intravascular
red cell destruction occurs, free haemoglobin is released into the
plasma. Free haemoglobin is toxic to cells and binding proteins
have evolved to minimise this risk. Haptoglobin is an a2-globulin
produced by the liver, which binds free haemoglobin, resulting in
a fall in its levels during active haemolysis. Once haptoglobins are
saturated, free haemoglobin is oxidised to form methaemoglobin,
which binds to albumin, in turn forming methaemalbumin, which
can be detected spectrophotometrically in Schumm’s test.
Methaemoglobin is degraded and any free haem is bound to a
second binding protein called haemopexin. If all the protective
mechanisms are saturated, free haemoglobin may appear in
the urine (haemoglobinuria). When fulminant, this gives rise to
black urine, as in severe falciparum malaria infection (p. 274).
In smaller amounts, renal tubular cells absorb the haemoglobin,
degrade it and store the iron as haemosiderin. When the tubular
cells are subsequently sloughed into the urine, they give rise
to haemosiderinuria, which is always indicative of intravascular
haemolysis (Box 23.36).
Causes of haemolytic anaemia
These can be classified as inherited or acquired (Fig. 23.19).
• Inherited red cell abnormalities resulting in chronic
haemolytic anaemia may arise from pathologies of the red
cell membrane (hereditary spherocytosis or elliptocytosis),
haemoglobin (haemoglobinopathies), or protective
enzymes that prevent cellular oxidative damage, such as
glucose-6-phosphate dehydrogenase (G6PD).
• Acquired causes include auto- and alloantibody-mediated
destruction of red blood cells and other mechanical, toxic
and infective causes.
Red cell membrane defects
The structure of the red cell membrane is shown in Figure 23.4.
The basic structure is a cytoskeleton ‘stapled’ on to the lipid
bilayer by special protein complexes. This structure ensures
great deformability and elasticity; the red cell diameter is 8 jim
but the narrowest capillaries in the circulation are in the spleen,
measuring just 2 jam in diameter. When the normal red cell
structure is disturbed, usually by a quantitative or functional
deficiency of one or more proteins in the cytoskeleton, cells lose
their elasticity. Each time such cells pass through the spleen,
they lose membrane relative to their cell volume. This results in
an increase in mean cell haemoglobin concentration (MCHC),
abnormal cell shape (see Box 23.2) and reduced red cell survival
due to extravascular haemolysis.
Hereditary spherocytosis
This is usually inherited as an autosomal dominant condition,
although 25% of cases have no family history and represent new
mutations. The incidence is approximately 1 : 5000 in developed
countries but this may be an under-estimate, since the disease
may present de novo in patients aged over 65 years and is often
discovered as a chance finding on a blood count. The most
common abnormalities are deficiencies of beta spectrin or ankyrin
(see Fig. 23.4). The severity of spontaneous haemolysis varies.
Most cases are associated with an asymptomatic compensated
chronic haemolytic state with spherocytes present on the blood
film, a reticulocytosis and mild hyperbilirubinaemia. Pigment
gallstones are present in up to 50% of patients and may cause
symptomatic cholecystitis. Occasional cases are associated
with more severe haemolysis; these may be due to coincidental
polymorphisms in alpha spectrin or co-inheritance of a second
defect involving a different protein. These cases tend to present
earlier in life with symptomatic, sometimes transfusion-dependent
anaemia.
The clinical course may be complicated by crises:
• A haemolytic crisis occurs when the severity of haemolysis
increases; this is rare, and usually associated with infection.
• A megaloblastic crisis follows the development of folate
deficiency; this may occur as a first presentation of the
disease in pregnancy.
• An aplastic crisis occurs in association with parvovirus
(erythrovirus) infection (p. 237). Parvovirus causes a
common exanthem in children, but if individuals with
chronic haemolysis become infected, the virus directly
invades red cell precursors and temporarily switches off
red cell production. Patients present with severe anaemia
and a low reticulocyte count.
Investigations
The patient and other family members should be screened for
features of compensated haemolysis (see Box 23.36). This may
be all that is required to confirm the diagnosis. Haemoglobin
levels are variable, depending on the degree of compensation.
The blood film will show spherocytes but the direct Coombs
test (Fig. 23.20) is negative, excluding immune haemolysis. An
osmotic fragility test may show increased sensitivity to lysis in
hypotonic saline solutions but is limited by lack of sensitivity
and specificity. More specific flow cytometric tests, detecting
binding of eosin-5-maleimide to red cells, are recommended in
borderline cases.
Management
Folic acid prophylaxis, 5 mg daily, should be given for life. In
severe cases, consideration may be given to splenectomy,
which improves but does not normalise red cell survival.
Potential indications for splenectomy include moderate to severe
haemolysis with complications (anaemia and gallstones), although
splenectomy should be delayed where possible until after 6 years
of age in view of the risk of sepsis. Guidelines for the management
of patients after splenectomy are presented in Box 23.37.
Acute, severe haemolytic crises require transfusion support,
but blood must be cross-matched carefully and transfused
slowly as haemolytic transfusion reactions may occur (p. 935).
Hereditary elliptocytosis
This term refers to a heterogeneous group of disorders that
produce an increase in elliptocytic red cells on the blood film
and a variable degree of haemolysis. This is due to a functional
948 • HAEMATOLOGY AND TRANSFUSION MEDICINE
H Direct antiglobulin test (DAT) (Coombs test)
Detects the presence of antibody bound to
the red cell surface, e.g.
1. Autoimmune haemolytic anaemia
2. Haemolytic disease of newborn
3. Transfusion reactions
>
Y X
Antibodies to
human globulin
Red cell
agglutination
Key
Red blood cells
Red cell antigen
Antibody bound
to red cell antigen
Fig. 23.20 Direct and indirect antiglobulin tests.
[b] Indirect antiglobulin test (IAT) (indirect Coombs test)
Detects antibodies in the plasma, e.g.
1 . Antibody screen in pre-transfusion testing
2. Screening in pregnancy for antibodies that may cause
haemolytic disease of newborn
known antigen Ag - Ab complex
expression on cell surface
+ v* *
Y
Antibodies to
human globulin
Red cell
agglutination
i
abnormality of one or more anchor proteins in the red cell
membrane, e.g. alpha spectrin or protein 4.1 (see Fig. 23.4).
Inheritance may be autosomal dominant or recessive. Hereditary
elliptocytosis is less common than hereditary spherocytosis in
Western countries, with an incidence of 1/10000, but is more
common in equatorial Africa and parts of South-east Asia. The
clinical course is variable and depends on the degree of membrane
dysfunction caused by the inherited molecular defect(s); most
cases present as an asymptomatic blood film abnormality but
occasional cases result in neonatal haemolysis or a chronic
compensated haemolytic state. Management of the latter is the
same as for hereditary spherocytosis.
A characteristic variant of hereditary elliptocytosis occurs in
South-east Asia, particularly Malaysia and Papua New Guinea,
with stomatocytes and ovalocytes in the blood. This has a
prevalence of up to 30% in some communities because it
offers relative protection from malaria and thus has sustained a
high gene frequency. The blood film is often very abnormal and
immediate differential diagnosis is broad.
|Red cell enzymopathies
The mature red cell must produce energy via ATP to maintain
a normal internal environment and cell volume while protecting
itself from the oxidative stress presented by oxygen carriage.
ATP is generated by glycolysis, while the hexose monophosphate
shunt produces nicotinamide adenine dinucleotide phosphate
(NADPH) and glutathione to protect against oxidative stress.
The impact of functional or quantitative defects in the enzymes
in these pathways depends on the importance of the steps
affected and the presence of alternative pathways. In general,
defects in the hexose monophosphate shunt pathway result in
periodic haemolysis precipitated by episodic oxidative stress,
while those in the glycolysis pathway result in shortened red cell
survival and chronic haemolysis.
Glucose-6-phosphate dehydrogenase deficiency
The enzyme glucose-6-phosphate dehydrogenase (G6PD) is
pivotal in the hexose monophosphate shunt pathway. Deficiencies
result in the most common human enzymopathy, affecting 1 0%
of the world’s population, with a geographical distribution that
parallels the malaria belt because heterozygotes are protected
from malarial parasitisation. The enzyme is a heteromeric structure
made of catalytic subunits that are encoded by a gene on the
X chromosome. The deficiency therefore affects males and rare
23.37 Management of the splenectomised patient
• Vaccinate with pneumococcal, Haemophilus influenzae type B,
meningococcal group C and influenza vaccines at least 2-3 weeks
before elective splenectomy. Vaccination should be given after
emergency surgery but may be less effective
• Pneumococcal re-immunisation should be given at least 5-yearly
and influenza annually. Vaccination status must be documented
• Life-long prophylactic penicillin V (500 mg twice daily) is
recommended. In penicillin-allergic patients, consider a macrolide
• Patients should be educated regarding the risks of infection and
methods of prophylaxis
• A card or bracelet should be carried to alert health professionals to
the risk of overwhelming sepsis
• In sepsis, patients should be resuscitated and given IV antibiotics to
cover pneumococcus, Haemophilus and meningococcus, according
to local resistance patterns
• The risk of cerebral malaria is increased in the event of infection
• Animal bites should be promptly treated with local disinfection and
antibiotics, to prevent serious soft tissue infection and sepsis
Anaemias • 949
23.38 Glucose-6-phosphate dehydrogenase
deficiency
homozygous females (p. 48), but it is carried by females. Carrier
heterozygous females are usually only affected in the neonatal
period or in the presence of skewed X-inactivation (p. 49).
Over 400 subtypes of G6PD are described. The most common
types associated with normal activity are the B+ enzyme present
in most Caucasians and 70% of Afro-Caribbeans, and the A+
variant present in 20% of Afro-Caribbeans. The two common
variants associated with reduced activity are the A" variety in
approximately 10% of Afro-Caribbeans, and the Mediterranean
or ET variety in Caucasians. In East and West Africa, up to 20%
of males and 4% of females (homozygotes) are affected and
have enzyme levels of about 15% of normal. The deficiency
in Caucasian and East Asian populations is more severe, with
enzyme levels as low as 1%.
Clinical features and investigation findings are shown in
Box 23.38.
Management aims to stop the intake of any precipitant drugs
or foods and treat any underlying infection. Favism due to the
consumption of fava beans is the classically described precipitant
of haemolysis in patients with G6PD deficiency. Acute transfusion
support may be life-saving.
Pyruvate kinase deficiency
This is the second most common red cell enzyme defect. It
results in deficiency of ATP production and a chronic haemolytic
anaemia. It is inherited as an autosomal recessive trait. The
extent of anaemia is variable; the blood film shows characteristic
‘prickle cells’ that resemble holly leaves. Enzyme activity is only
5-20% of normal. Transfusion support may be necessary during
periods of haemolysis.
Pyrimidine 3 nucleotidase deficiency
The pyrimidine 5' nucleotidase enzyme catalyses the
dephosphorylation of nucleoside monophosphates and is
important during the degradation of RNA in reticulocytes. It is
inherited as an autosomal recessive trait and is as common as
pyruvate kinase deficiency in Mediterranean, African and Jewish
populations. The accumulation of excess ribonucleoprotein
results in coarse basophilic stippling (see Box 23.2), associated
with a chronic haemolytic state. The enzyme is very sensitive to
inhibition by lead and this is the reason why basophilic stippling
is a feature of lead poisoning.
Autoimmune haemolytic anaemia
This results from increased red cell destruction due to red cell
autoantibodies. The antibodies may be IgG or IgM, or more rarely
IgE or IgA. If an antibody avidly fixes complement, it will cause
intravascular haemolysis, but if complement activation is weak, the
haemolysis will be extravascular (in the reticulo-endothelial system).
Antibody-coated red cells lose membrane to macrophages in
the spleen and hence spherocytes are present in the blood. The
optimum temperature at which the antibody is active (thermal
specificity) is used to classify immune haemolysis:
• Warm antibodies bind best at 37°C and account for 80%
of cases. The majority are IgG and often react against
Rhesus antigens.
• Cold antibodies bind best at 4°C but can bind up to
37°C in some cases. They are usually IgM and bind
complement. To be clinically relevant, they must act within
the range of normal body temperatures. They account for
the other 20% of cases.
Warm autoimmune haemolysis
The incidence of warm autoimmune haemolysis is approximately
1/100000 population per annum; it occurs at all ages but is more
common in middle age and in females. No underlying cause is
identified in up to 50% of cases. The remainder are secondary
to a wide variety of other conditions (see Fig. 23.19B).
Investigations
There is evidence of haemolysis, spherocytes and polychromasia
on the blood film. The diagnosis is confirmed by the direct
Coombs or antiglobulin test (see Fig. 23.20). The patient’s red
cells are mixed with Coombs reagent, which contains antibodies
against human IgG/IgM/complement. If the red cells have been
coated by antibody in vivo, the Coombs reagent will induce their
agglutination and this can be detected visually. The relevant
antibody can be eluted from the red cell surface and tested
against a panel of typed red cells to determine against which
red cell antigen it is directed. The most common specificity is
for Rhesus antigens and most often anti-e; this is helpful when
choosing blood to cross-match. The direct Coombs test can
be negative in the presence of brisk haemolysis. A positive test
requires about 200 antibody molecules to attach to each red
cell; with a very avid complement-fixing antibody, haemolysis
may occur at lower levels of antibody-binding. The standard
Coombs reagent will miss IgA or IgE antibodies. Around 10%
of all warm autoimmune haemolytic anaemias are Coombs
test- negative.
Management
If the haemolysis is secondary to an underlying cause, this must
be treated and any implicated drugs stopped.
Clinical features
• Acute drug-induced haemolysis to (e.g.):
Analgesics: aspirin, phenacetin
Antimalarials: primaquine, quinine, chloroquine, pyrimethamine
Antibiotics: sulphonamides, nitrofurantoin, ciprofloxacin
Miscellaneous: quinidine, probenecid, vitamin K, dapsone
• Chronic compensated haemolysis
• Infection or acute illness
• Neonatal jaundice: may be a feature of the B~ enzyme
• Favism, i.e. acute haemolysis after ingestion of broad beans
( Vida fava)
Laboratory features
Non-spherocytic intravascular haemolysis during an attack
The blood film will show:
• Bite cells (red cells with a ‘bite’ of membrane missing)
• Blister cells (red cells with surface blistering of the membrane)
• Irregularly shaped small cells
• Polychromasia reflecting the reticulocytosis
• Denatured haemoglobin visible as Heinz bodies within the red cell
cytoplasm with a supravital stain such as methyl violet
G6PD level
• Can be indirectly assessed by screening methods that usually
depend on the decreased ability to reduce dyes
• Direct assessment of G6PD is made in those with low screening
values
• Care must be taken close to an acute haemolytic episode because
reticulocytes may have higher enzyme levels and give rise to a false
normal result
950 • HAEMATOLOGY AND TRANSFUSION MEDICINE
It is usual to treat patients initially with prednisolone (1 mg/kg
orally). A response is seen in 70-80% of cases but may take up
to 3 weeks; a rise in haemoglobin will be matched by a fall in
bilirubin, LDH and reticulocyte levels. Once the haemoglobin has
normalised and the reticulocytosis resolved, the glucocorticoid
dose can be reduced slowly over several weeks. Glucocorticoids
probably work by decreasing macrophage destruction of antibody-
coated red cells and reducing antibody production.
Transfusion support may be required for life-threatening
problems, such as the development of heart failure or rapid
unabated falls in haemoglobin. The least incompatible blood
should be used but this may still give rise to transfusion reactions
or the development of alloantibodies.
If the haemolysis fails to respond to glucocorticoids or can only
be stabilised by large doses, then second-line therapies should
be considered. These include immunomodulation/suppression
and splenectomy. Currently, there are fewer splenectomies
than previously and the second-line drug of choice in current
UK guidance is the anti-CD20 monoclonal antibody rituximab.
Splenectomy is associated with a good response in 50-60%
of cases. The operation can be performed laparoscopically with
reduced morbidity. If splenectomy is not appropriate, alternative
immunosuppressive therapy with azathioprine, ciclosporin,
mycophenolate or cyclophosphamide may be considered.
There are concerns about all modes of second-line therapy, as
long-term immunosuppression carries a risk of malignancy, while
splenectomy is associated with an excess of severe infection due
to the capsulate organisms pneumococcus and meningococcus
(see Box 23.40).
Cold agglutinin disease
This is mediated by antibodies, usually IgM, which bind to the
red cells at low temperatures and cause them to agglutinate.
It may cause intravascular haemolysis if complement fixation
occurs. This can be chronic when the antibody is monoclonal,
or acute or transient when the antibody is polyclonal.
Chronic cold agglutinin disease
This typically affects elderly patients and may be associated with
an underlying low-grade B-cell lymphoma. It causes a low-grade
intravascular haemolysis with cold, painful and often blue fingers,
toes, ears or nose (so-called acrocyanosis). The latter is due
to red cell agglutination in the small vessels in these colder,
exposed areas. The blood film shows red cell agglutination
and the MCV may be spuriously high because the automated
analysers detect red cell aggregates as single cells. Monoclonal
IgM usually has anti-l or, less often, anti-i specificity. Treatment
is primarily by transfusion support but may also be directed at
any underlying lymphoma. Patients must keep extremities warm,
especially in winter. Some patients respond to glucocorticoid
therapy and rituximab. Two considerations for patients requiring
blood transfusion is that the cross-match sample must be
placed in a transport flask at a temperature of 37°C and blood
administered via a blood-warmer. All patients should receive
folic acid supplementation.
Other causes of cold agglutination
Cold agglutination can occur in association with Mycoplasma
pneumoniae or with infectious mononucleosis. Paroxysmal
cold haemoglobinuria is a very rare cause seen in children, in
association with viral or bacterial infection. An IgG antibody binds
to red cells in the peripheral circulation but lysis occurs in the
central circulation when complement fixation takes place. This
antibody is termed the Donath-Landsteiner antibody and has
specificity against the P antigen on the red cells.
Alloimmune haemolytic anaemia
Alloimmune haemolytic anaemia is caused by antibodies against
non-self red cells. It has two main causes, occurring after:
• unmatched blood transfusion (p. 935)
• maternal sensitisation to paternal antigens on fetal cells
(haemolytic disease of the newborn, p. 933).
|jlon-immune haemolytic anaemia
Endothelial damage
Disruption of red cell membrane may occur in a number of
conditions and is characterised by the presence of red cell
fragments on the blood film and markers of intravascular
haemolysis:
• Mechanical heart valves. High flow through incompetent
valves or periprosthetic leaks through the suture ring
holding a valve in place result in shear stress damage.
• March haemoglobinuria. Vigorous exercise, such as
prolonged marching or marathon running, can cause red
cell damage in the capillaries in the feet.
• Thermal injury. Severe burns cause thermal damage to red
cells, characterised by fragmentation and the presence of
microspherocytes in the blood.
• Microangiopathic haemolytic anaemia. Fibrin deposition in
capillaries can cause severe red cell disruption. It may
occur in a wide variety of conditions: disseminated
carcinomatosis, malignant or pregnancy-induced
hypertension, haemolytic uraemic syndrome (p. 408),
thrombotic thrombocytopenic purpura (p. 979) and
disseminated intravascular coagulation (p. 978).
Infection
Plasmodium falciparum malaria (p. 274) may be associated with
intravascular haemolysis; when severe, this is termed blackwater
fever because of the associated haemoglobinuria. Clostridium
perfringens sepsis (p. 227), usually in the context of ascending
cholangitis or necrotising fasciitis, may cause severe intravascular
haemolysis with marked spherocytosis due to bacterial production
of a lecithinase that destroys the red cell membrane.
Chemicals or drugs
Dapsone and sulfasalazine cause haemolysis by oxidative
denaturation of haemoglobin. Denatured haemoglobin forms
Heinz bodies in the red cells, visible on supravital staining with
brilliant cresyl blue. Arsenic gas, copper, chlorates, nitrites and
nitrobenzene derivatives may all cause haemolysis.
| Paroxysmal nocturnal haemoglobinuria
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired,
non-malignant clonal expansion of haematopoietic stem cells
deficient in glycosylphosphatidylinositol (GPI) anchor protein.
GPI anchors several key molecules to cells and its absence
results in clinical outcomes that reflect this, causing intravascular
haemolysis and anaemia because of increased sensitivity of red
cells to lysis by complement. This happens because key defence
mechanisms that protect cells from complement-mediated lysis
(CD55 and CD59) are GPI-anchored to red cells under normal
circumstances. Episodes of intravascular haemolysis result in
haemoglobinuria, most noticeable in early morning urine, which
Haemoglobinopathies • 951
has a characteristic red-brown colour. The disease is associated
with an increased risk of venous and arterial thrombosis in
unusual sites, such as the liver or abdomen. PNH clones are
also associated with hypoplastic bone marrow failure, aplastic
anaemia and myelodysplastic syndrome (pp. 960 and 969).
Management is supportive with transfusion and folate supplements
and prophylaxis or treatment of thrombosis. Standard care now
includes the anti-complement C5 monoclonal antibody eculizimab.
This has been shown to be effective in reducing haemolysis,
transfusion requirements and thrombotic risk. Eculizumab carries
a risk of infection, particularly for Neisseria meningitidis, and
all treated patients must be vaccinated against this organism.
Haemoglobinopathies
These diseases are caused by mutations affecting the genes
encoding the globin chains of the haemoglobin molecule. Normal
haemoglobin is composed of two alpha and two non-alpha globin
chains. Alpha globin chains are produced throughout life, including
in the fetus, so severe mutations may cause intrauterine death.
Production of non-alpha chains varies with age; fetal haemoglobin
(HbF-aa/yy) has two gamma chains, while the predominant adult
haemoglobin (HbA-aa/p(3) has two beta chains. Thus, disorders
affecting the beta chains do not present until after 6 months of
age. A constant small amount of haemoglobin A2 (HbA2-aa/85,
usually less than 2%) is made from birth.
The geographical distribution of the common haemoglobin¬
opathies is shown in Figure 23.21. The haemoglobinopathies
can be classified into qualitative or quantitative abnormalities.
Qualitative abnormalities - abnormal haemoglobins
In qualitative abnormalities (called the abnormal haemoglobins),
there is a functionally important alteration in the amino acid
structure of the polypeptide chains of the globin chains. Several
hundred such variants are known; they were originally designated
by letters of the alphabet, e.g. S, C, D or E, but the more
recently described ones are known by names that usually taken
from the town or district in which they were first described. The
best-known example is haemoglobin S, found in sickle-cell
anaemia. Mutations around the haem-binding pocket cause the
haem ring to fall out of the structure and produce an unstable
haemoglobin. These substitutions often change the charge of
the globin chains, producing different electrophoretic mobility,
and this forms the basis for the diagnostic use of haemoglobin
electrophoresis to identify haemoglobinopathies.
Quantitative abnormalities - thalassaemias
In quantitative abnormalities (the thalassaemias), there are
mutations causing a reduced rate of production of one or other
of the globin chains, altering the ratio of alpha to non-alpha
chains. In alpha-thalassaemia excess beta chains are present,
while in beta-thalassaemia excess alpha chains are present. The
excess chains precipitate, causing red cell membrane damage
and reduced red cell survival due to haemolysis.
Sickle-cell anaemia
Sickle-cell disease results from a single glutamic acid to valine
substitution at position 6 of the beta globin polypeptide chain. It
is inherited as an autosomal recessive trait (p. 48). Homozygotes
only produce abnormal beta chains that make haemoglobin S
(HbS, termed SS), and this results in the clinical syndrome of
sickle-cell disease. Heterozygotes produce a mixture of normal
and abnormal beta chains that make normal HbA and HbS
(termed AS), and this results in sickle-cell trait; although this was
previously thought of as asymptomatic, it may be associated
with an increased risk of sudden and cardiovascular death.
Epidemiology
The heterozygote frequency is over 20% in tropical Africa (see
Fig. 23.21). In black American populations, sickle-cell trait
has a frequency of 8%. Individuals with sickle-cell trait are
relatively resistant to the lethal effects of falciparum malaria in
early childhood; the high prevalence in equatorial Africa can be
explained by the survival advantage it confers in areas where
falciparum malaria is endemic. However, homozygous patients
with sickle-cell anaemia do not have correspondingly greater
resistance to falciparum malaria.
Pathogenesis
When haemoglobin S is deoxygenated, the molecules of
haemoglobin polymerise to form pseudocrystalline structures
known as ‘factoids’. These distort the red cell membrane and
Fig. 23.21 The geographical distribution of the haemoglobinopathies. From Hoff brand AV, Pettit JE. Essential haematology, 3rd edn. Edinburgh:
Blackwell Science; 1992.
952 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Ocular
Background retinopathy
Proliferative retinopathy
Vitreous bleeds
Pulmonary
Sickle chest syndrome
Infection
Pulmonary hypertension
Osteomyelitis
DjQ
dn hc5 (5>tH
Autosomal recessive A
inheritance
Hepatic sequestration
Cholelithiasis
Renal
Enuresis
Haematuria
Papillary necrosis
Chronic renal failure
c-
Dactylitis
Arthropathy
Sickle cell'
fPl Nucleated
9 ] w red cell
<J?&P « ^
9m
Blood film A
Fig. 23.22 Clinical and laboratory features of sickle-cell disease.
CNS
Subarachnoid bleed
Fits
| Cerebrovascular
event
Cardiac
Sickle myocardium
Cardiomegaly
Transfusional iron overload
ASplenic infarction
Vertebral collapse
Osteoporosis
Avascular necrosis
HbC — ►
HbS — ►
•
HbA — ►
mm
HbF —
=n
I Z
tt>
2 1
D) 03 —
A Electrophoresis gel
produce characteristic sickle-shaped cells (Fig. 23.22). The
polymerisation is reversible when re-oxygenation occurs. The
distortion of the red cell membrane, however, may become
permanent and the red cell ‘irreversibly sickled’. The greater the
concentration of sickle-cell haemoglobin in the individual cell,
the more easily tactoids are formed, but this process may be
enhanced or retarded by the presence of other haemoglobins.
Thus the abnormal haemoglobin C variant participates in
polymerisation more readily than haemoglobin A, whereas
haemoglobin F strongly inhibits polymerisation.
Clinical features
Sickling is precipitated by hypoxia, acidosis, dehydration and
infection. Irreversibly sickled cells have a shortened survival and
plug vessels in the microcirculation. This results in a number of
acute syndromes, termed ‘crises’, and chronic organ damage
(Fig. 23.22):
• Painful vaso-occlusive crisis. Plugging of small vessels in
the bone produces acute severe bone pain. This affects
areas of active marrow: the hands and feet in children
(so-called dactylitis) or the femora, humeri, ribs, pelvis and
vertebrae in adults. Patients usually have a systemic
response with tachycardia, sweating and a fever. This is
the most common form of crisis.
• Stroke. The single most devastating consequence of
sickle-cell disease is stroke. Stroke or silent stroke occurs
in 10-15% of children with sickle-cell disease. Children at
risk of stroke can be identified by screening with
transcranial Doppler ultrasound, with fast flow associated
with increased stroke risk. These children may be offered
strategies such as transfusion or treatment with
hydroxycarbamide to reduce the risk of stroke.
• Sickle chest syndrome. This may follow a vaso-occlusive
crisis and is the most common cause of death in adult
sickle-cell disease. Bone marrow infarction results in fat
emboli to the lungs, which cause further sickling and
infarction, leading to ventilatory failure if not treated.
• Sequestration crisis. Thrombosis of the venous outflow
from an organ causes loss of function and acute painful
enlargement. In children, the spleen is the most common
site. Massive splenic enlargement may result in severe
anaemia, circulatory collapse and death. Recurrent sickling
in the spleen in childhood results in infarction and adults
may have no functional spleen. In adults, the liver may
undergo sequestration with severe pain due to capsular
stretching. Priapism is a complication seen in affected men.
• Aplastic crisis. Infection of adult sicklers with human
parvovirus B19 (erythrovirus) may result in a severe but
Haemoglobinopathies • 953
23.39 Sickle-cell disease in pregnancy
• Pre-conceptual counselling: advice on the effect of sickle-cell
disease on pregnancy, and vice versa, should be offered.
• Vaccination status: should be updated before conception.
• Testing of partner: testing for haemoglobinopathy status is advised.
• Folic acid: should be taken in high dose (5 mg daily) prior to and
throughout pregnancy.
• Hydroxycarbamide: should be discontinued 3 months prior to
conception.
• Angiotensin-converting enzyme (ACE) inhibitors: should be
discontinued prior to conception.
• Pulmonary hypertension: should be excluded prior to conception.
• Placental failure: women with sickle-cell disease have increased
rates, resulting in pre-eclampsia and intrauterine growth retardation.
• Aspirin 75 mg: should be given throughout pregnancy.
• Thromboprophylaxis after delivery: all women with sickle-cell
disease should receive thromboprophylaxis with low-molecular-
weight heparin for at least 10 days post vaginal delivery and for
6 weeks post caesarean section. Antenatal thromboprophylaxis
should be considered for women with additional risk factors for
venous thromboembolism (see Box 23.65).
• Transfusion: extended cross-matched blood for Rhesus and Kell
status should be provided. Blood should be cytomegalovirus¬
negative.
self-limiting red cell aplasia. This results in profound
anaemia, which may cause heart failure. Unlike in all other
sickle crises, the reticulocyte count is low.
• Pregnancy. Pregnancy in sickle-cell disease requires
planning and multidisciplinary management. Women with
sickle-cell disease have increased pregnancy-related
morbidity, which includes painful crisis, placental failure
and thrombosis (Box 23.39).
Investigations
Patients with sickle-cell disease have a compensated anaemia,
usually around 60-80 g/L. The blood film shows sickle cells,
target cells and features of hyposplenism from a young age.
A reticulocytosis is present. The presence of HbS can be
demonstrated by exposing red cells to a reducing agent such
as sodium dithionite; HbA gives a clear solution, whereas HbS
polymerises to produce a turbid solution. This forms the basis
of emergency screening tests before surgery in appropriate
ethnic groups but cannot distinguish between sickle-cell trait
and disease. The definitive diagnosis requires haemoglobin
electrophoresis to demonstrate the absence of HbA, 2-20%
HbF and the predominance of HbS. Both parents of the affected
individual will have sickle-cell trait.
Management
All patients with sickle-cell disease should receive prophylaxis with
daily folic acid, and appropriate management of the hyposplenic
state that is uniformly found in these patients from an early age
(see Box 23.37). Seasonal vaccination against influenza is also
advised in these patients.
Vaso-occlusive crises are managed by aggressive rehydration,
oxygen therapy, adequate analgesia (which often requires opiates)
and antibiotics. Transfusion should be with fully genotyped
blood wherever possible. Simple top-up transfusion may be
used in a sequestration or aplastic crisis. A regular transfusion
programme to suppress HbS production and maintain the HbS
level below 30% may be indicated in patients with recurrent
severe complications, such as cerebrovascular accidents in
children or chest syndromes in adults. Exchange transfusion,
in which a patient is simultaneously venesected and transfused
to replace HbS with HbA, may be used in life-threatening crises
or to prepare patients for surgery.
A high HbF level inhibits polymerisation of HbS and reduces
sickling. Patients with sickle-cell disease and high HbF levels
have a mild clinical course with few crises. Some agents are
able to increase synthesis of HbF and this has been used to
reduce the frequency of severe crises. The oral cytotoxic agent
hydroxycarbamide has been shown to have clinical benefit
with acceptable side-effects in children and adults who have
recurrent severe crises.
Relatively few allogeneic stem cell transplants from HLA-
matched siblings have been performed but this procedure
appears to be potentially curative (p. 937).
Prognosis
In Africa, few children with sickle-cell anaemia survive to adult
life without medical attention. Even with standard medical care,
approximately 15% die by the age of 20 years and 50% by the
age of 40 years.
Other abnormal haemoglobins
Another beta-chain haemoglobinopathy, haemoglobin C (HbC)
disease, is clinically silent but associated with microcytosis
and target cells on the blood film. Compound heterozygotes
inheriting one HbS gene and one HbC gene from their parents
have haemoglobin SC disease, which behaves like a mild form
of sickle-cell disease. SC disease is associated with a reduced
frequency of crises but is not uncommonly associated with
complications in pregnancy and retinopathy.
Thalassaemias
Thalassaemia is an inherited impairment of haemoglobin
production, in which there is partial or complete failure to
synthesise a specific type of globin chain. In alpha-thalassaemia,
disruption of one or both alleles on chromosome 1 6 may occur,
with production of some or no alpha globin chains. In beta-
thalassaemia, defective production usually results from disabling
point mutations causing no ((3°) or reduced ((3“) beta chain
production.
Beta-thalassaemia
Failure to synthesise beta chains (beta-thalassaemia) is the
most common type of thalassaemia, most prevalent in the
Mediterranean area. Heterozygotes have thalassaemia minor, a
condition in which there is usually mild microcytic anaemia and
little or no clinical disability, which may be detected only when
iron therapy for a mild microcytic anaemia fails. Homozygotes
(thalassaemia major) either are unable to synthesise haemoglobin
A or, at best, produce very little; after the first 4-6 months of
life, they develop profound transfusion-dependent hypochromic
anaemia. The diagnostic features are summarised in Box 23.40.
Intermediate grades of severity occur.
Management and prevention
See Box 23.41 . Cure is now a possibility for selected children,
with allogeneic HSCT (p. 937).
It is possible to identify a fetus with homozygous beta-
thalassaemia by obtaining chorionic villous material for DNA
954 • HAEMATOLOGY AND TRANSFUSION MEDICINE
23.40 Diagnostic features of beta-thalassaemia
Beta-thalassaemia major (homozygotes)
• Profound hypochromic anaemia
• Evidence of severe red cell dysplasia
• Erythroblastosis
• Absence or gross reduction of the amount of haemoglobin A
• Raised levels of haemoglobin F
• Evidence that both parents have thalassaemia minor
Beta-thalassaemia minor (heterozygotes)
• Mild anaemia
• Microcytic hypochromic erythrocytes (not iron-deficient)
• Some target cells
• Punctate basophilia
• Raised haemoglobin A2 fraction
23.41 Treatment of beta-thalassaemia major
Problem
Management
Erythropoietic failure
Allogeneic HSCT from
HLA-compatible sibling
Transfusion to maintain Hb
>100 g/L
Folic acid 5 mg daily
Iron overload
Iron therapy contraindicated
Iron chelation therapy
Splenomegaly causing mechanical
problems, excessive transfusion
needs
Splenectomy; see Box 23.37
(Hb = haemoglobin; HLA = human leucocyte antigen; HSCT = haematopoietic
stem cell transplantation)
23.42 Anaemia in old age
• Mean haemoglobin: falls with age in both sexes but remains well
within the reference range. When a low haemoglobin does occur, it
is generally due to disease.
• Anaemia can never be considered ‘normal’ in old age.
• Symptoms: may be subtle and insidious. Cardiovascular features
such as dyspnoea and oedema, and cerebral features such as
dizziness and apathy, tend to predominate.
• Ferritin: if lower than 45 jig/L in older people, is highly predictive
of iron deficiency. Conversely, ferritin may be raised by chronic
disease and so a normal ferritin does not exclude iron deficiency.
• Serum iron and transferrin: fall with age because of the
prevalence of other disorders, and are not reliable indicators of
deficiency.
• Most common cause of iron deficiency: gastrointestinal
blood loss.
• Most common cause of vitamin B12 deficiency: pernicious
anaemia, as the prevalence of chronic atrophic gastritis rises in
old age.
• Neuropsychiatric symptoms associated with vitamin B12
deficiency: well-established association but a causal relationship
has not been clearly shown. Dementia associated with vitamin B12
deficiency in the absence of haematological abnormalities is rare.
• Anaemia of chronic disease: frequent in old age because of the
rising prevalence of diseases that inhibit iron transport.
analysis sufficiently early in pregnancy to allow termination. This
examination is appropriate only if both parents are known to be
carriers (beta-thalassaemia minor) and will accept a termination.
Alpha-thalassaemia
Reduced or absent alpha-chain synthesis is common in South¬
east Asia. There are two alpha gene loci on chromosome 1 6
and therefore each individual carries four alpha gene alleles.
• If one is deleted, there is no clinical effect.
• If two are deleted, there may be a mild hypochromic
anaemia.
• If three are deleted, the patient has haemoglobin H
disease.
• If all four are deleted, the baby is stillborn (hydrops fetalis).
Haemoglobin H is a beta-chain tetramer, formed from the
excess of beta chains, which is functionally useless, so that
patients rely on their low levels of HbA for oxygen transport.
Treatment of haemoglobin H disease is similar to that of
beta-thalassaemia of intermediate severity, involving folic acid
supplementation, transfusion if required and avoidance of iron
therapy.
Haematological malignancies
Haematological malignancies arise when the processes controlling
proliferation or apoptosis are corrupted in blood cells because of
acquired mutations in key regulatory genes. If mature differentiated
cells are involved, the cells will have a low growth fraction and
produce indolent neoplasms, such as the low-grade lymphomas
or chronic leukaemias, when patients have an expected survival
of many years. In contrast, if more primitive stem or progenitor
cells are involved, the cells can have the highest growth fractions
of all human neoplasms, producing rapidly progressive, life-
threatening illnesses such as the acute leukaemias or high-grade
lymphomas. Involvement of pluripotent stem cells produces the
most aggressive acute leukaemias. In general, haematological
neoplasms are diseases of elderly patients, the exceptions being
acute lymphoblastic leukaemia, which predominantly affects
children, and Hodgkin lymphoma, which affects people aged
20-40 years. Management of young patients with haematological
malignancy is particularly challenging (Box 23.43).
Leukaemias
Leukaemias are malignant disorders of the haematopoietic stem
cell compartment, characteristically associated with increased
numbers of white cells in the bone marrow and/or peripheral
blood. The course of leukaemia may vary from a few days or
weeks to many years, depending on the type.
Epidemiology and aetiology
The incidence of leukaemia of all types in the population is
approximately 10/100000 per annum, of which just under half
are cases of acute leukaemia. Males are affected more frequently
than females, the ratio being about 3 : 2 in acute leukaemia, 2 : 1
in chronic lymphocytic leukaemia and 1 .3 : 1 in chronic myeloid
leukaemia. Geographical variation in incidence does occur, the
most striking being the rarity of chronic lymphocytic leukaemia in
Chinese and related races. Acute leukaemia occurs at all ages.
Acute lymphoblastic leukaemia shows a peak of incidence in
children aged 1-5 years. All forms of acute myeloid leukaemia
Haematological malignancies • 955
23.43 Consequences of haematological
malignancy in adolescence
• Tailored management protocols: the most effective treatment
schedules for leukaemia and lymphoma differ between children and
adults. Adolescent patients may be most appropriately managed in
specialist centres.
• Psychosocial effects: adolescents undergoing treatment for
haematological malignancy may suffer significant consequences for
their schooling and social development, and require support from a
multidisciplinary team.
• ‘Late effects’: adolescents who have been treated with
chemotherapy and/or radiotherapy in childhood may be at risk of a
wide range of complications, depending on the region irradiated,
radiation dose and the drugs used. Particularly relevant
complications in this age group include short stature, growth
hormone deficiency, delayed puberty, and cognitive dysfunction
affecting schooling (after cranial irradiation). Life-long follow-up is
often undertaken to detect and manage these late effects and to
deal with consequences such as infertility and second malignancy.
23.44 Risk factors for leukaemia
Ionising radiation
• After atomic bombing of Japanese cities (myeloid leukaemia)
• Radiotherapy
• Diagnostic X-rays of the fetus in pregnancy
Cytotoxic drugs
• Especially alkylating agents (myeloid leukaemia, usually after a
latent period of several years)
• Industrial exposure to benzene
Retroviruses
• Adult T-cell leukaemia/lymphoma (ATLL) caused by human T-cell
lymphotropic virus 1 (HTLV-1), most prevalent in Japan, the
Caribbean and some areas of Central and South America and Africa
Genetic
• Identical twin of patients with leukaemia
• Down’s syndrome and certain other genetic disorders
Immunological
• Immune deficiency states (e.g. hypogammaglobulinaemia)
have their lowest incidence in young adult life and there is a
striking rise over the age of 50. Chronic leukaemias occur mainly
in middle and old age.
The cause of the leukaemia is unknown in the majority of
patients. Several risk factors have been identified (Box 23.44).
Terminology and classification
Leukaemias are traditionally classified into four main groups:
• acute lymphoblastic leukaemia (ALL)
• acute myeloid leukaemia (AML)
• chronic lymphocytic leukaemia (CLL)
• chronic myeloid leukaemia (CML).
In acute leukaemia, there is proliferation of primitive stem
cells, with limited accompanying differentiation, leading to an
accumulation of blasts, predominantly in the bone marrow, which
causes bone marrow failure. In chronic leukaemia, the malignant
clone is able to differentiate, resulting in an accumulation of
more mature cells. Lymphocytic and lymphoblastic cells are
those derived from the lymphoid stem cell (B cells and T cells).
23.45 WHO classification of acute leukaemia
Acute myeloid leukaemia (AML) with recurrent
genetic abnormalities
• AML with t(8;21)(q22;q22.1), gene product RUNX1 -RUNX1T1
• AML with inv(1 6)(p13.1;q22), gene product CBFB-MYHL1
• Acute promyelocytic leukaemia t(1 5;1 7), gene product PML-RARA
• AML with t(9;11)(p21 .3;q23.3), gene product MLLT3-KMT2A
• AML with t(6;9)(p23;q34), gene product DEK-NUP214
• AML with inv(3)(q21 .3;q26.2) or t(3;3)(q21 .3;q26.2), gene products
GATA2, MECOM
• AML (megakaryoblastic) with t(1 ;22)(p1 3.3;q1 3.3), gene product
RBM15-MKL1
• AML with mutated NPM1
• AML with biallelic mutations of CEBPA
Acute myeloid leukaemia with myelodysplasia-related changes
• e.g. Following a myelodysplastic syndrome
Therapy-related myeloid neoplasms
• e.g. Alkylating agent or topoisomerase II inhibitor
Myeloid sarcoma
Myeloid proliferations related to Down’s syndrome
Acute myeloid leukaemia not otherwise specified
• e.g. AML with or without differentiation, acute myelomonocytic
leukaemia, erythroleukaemia, megakaryoblastic leukaemia
Acute lymphoblastic leukaemia (ALL)
• B-lymphoblastic leukaemia/lymphoma
• T-lymphoblastic leukaemia/lymphoma
Updated 2016; major subtypes.
Myeloid refers to the other lineages: that is, precursors of red
cells, granulocytes, monocytes and platelets (see Fig. 23.2).
The diagnosis of leukaemia is usually suspected from an
abnormal blood count, often a raised white count, and is
confirmed by examination of the bone marrow. This includes the
morphology of the abnormal cells, analysis of cell surface markers
(immunophenotyping), clone-specific chromosome abnormalities
and molecular changes. These results are incorporated in the
World Health Organisation (WHO) classification of tumours of
haematopoietic and lymphoid tissues; the subclassification of
acute leukaemias is shown in Box 23.45. The features in the
bone marrow not only provide an accurate diagnosis but also
give valuable prognostic information, increasingly allowing therapy
to be tailored to the patient’s disease.
Acute leukaemia
There is a failure of cell maturation in acute leukaemia. Proliferation
of cells that do not mature leads to an accumulation of primitive
cells that take up more and more marrow space at the expense of
the normal haematopoietic elements. Eventually, this proliferation
spills into the blood. Acute myeloid leukaemia (AML) is about
four times more common than acute lymphoblastic leukaemia
(ALL) in adults. In children, the proportions are reversed, the
lymphoblastic variety being more common. The clinical features
are usually those of bone marrow failure (anaemia, bleeding or
infection; pp. 923, 927 and 930).
Investigations
Blood examination usually shows anaemia with a normal or raised
MCV. The leucocyte count may vary from as low as 1 x 1 09/L
to as high as 500x1 09/L or more. In the majority of patients,
956 • HAEMATOLOGY AND TRANSFUSION MEDICINE
the count is below 100x109/L. Severe thrombocytopenia is
usual but not invariable. Frequently, blast cells are seen in the
blood film but sometimes the blast cells may be infrequent or
absent. A bone marrow examination will confirm the diagnosis.
The bone marrow is usually hypercellular, with replacement of
normal elements by leukaemic blast cells in varying degrees (but
more than 20% of the cells) (Fig. 23.23). The presence of Auer
rods in the cytoplasm of blast cells indicates a myeloblastic type
Fig. 23.23 Acute myeloid leukaemia. Bone marrow aspirate showing
infiltration with large blast cells, which display nuclear folding and
prominent nucleoli.
M
O
o
CD19- and CD10-
positive cells
/
*•1
1 ■ "
1 • ■
• * • jm ft "
* •
• *?• :
■
• •
10°
101
102
CD10
103
104
' X )! Uift >1
iWil(HI.'»l)c ((
e t a * I* ii &
H >H if u i( >iit
11 II IS IG 17 1ft
SI it mi 99 a
Fig. 23.24 Investigation of acute lymphoblastic leukaemia (ALL).
[ A] Flow cytometric analysis of blasts labelled with the fluorescent
antibodies anti-CDI 9 (y axis) and anti-CDIO (x axis). ALL blasts are
positive for both CD19 and CD10 (arrow). \W\ Chromosome analysis
(karyotype) of blasts showing additional chromosomes X, 4, 6, 7, 14, 18
and 21.
of leukaemia. Classification and prognosis are determined by
immunophenotyping and chromosome and molecular analysis,
as shown in Figure 23.24.
Management
The first decision must be whether or not to give specific treatment
to attempt to achieve remission. This is generally aggressive, has
numerous side-effects, and may not be appropriate for the very
elderly or patients with serious comorbidities (Chs 32 and 33).
In these patients, supportive treatment can effect considerable
improvement in well-being. Low-intensity chemotherapy, such
as low-dose cytosine arabinoside or, recently, azacitidine, is
frequently used in elderly and more frail patients but only induces
remission in less than 20% of patients.
Specific therapy
Ideally, whenever possible, patients with acute leukaemia should
be treated within a clinical trial. If a decision to embark on specific
therapy has been taken, the patient should be prepared as
recommended in Box 23.46. It is unwise to attempt aggressive
management of acute leukaemia unless adequate services are
available for the provision of supportive therapy.
The aim of treatment is to destroy the leukaemic clone of cells
without destroying the residual normal stem cell compartment
from which repopulation of the haematopoietic tissues will occur.
There are three phases:
• Remission induction. In this phase, a fraction of the
tumour is destroyed by combination chemotherapy. The
patient goes through a period of severe bone marrow
hypoplasia lasting 3-4 weeks and requires intensive
support and inpatient care from a specially trained
multidisciplinary team. The aim is to achieve remission, a
state in which the blood counts return to normal and the
marrow blast count is less than 5%. Quality of life is highly
dependent on achieving remission.
• Remission consolidation. If remission has been achieved,
residual disease is attacked by therapy during the
consolidation phase. This consists of a number of courses
of chemotherapy, again resulting in periods of marrow
hypoplasia. In poor-prognosis leukaemia, this may include
allogeneic HSCT.
• Remission maintenance. If the patient is still in remission
after the consolidation phase for ALL, a period of
maintenance therapy is given, with the individual as an
outpatient and treatment consisting of a repeating cycle of
drug administration. This may extend for up to 3 years if
relapse does not occur.
23.46 Preparation for specific therapy in
acute leukaemia
• Existing infections identified and treated (e.g. urinary tract infection,
oral candidiasis, dental, gingival and skin infections)
• Anaemia corrected by red cell concentrate transfusion
• Thrombocytopenic bleeding controlled by platelet transfusions
• If possible, central venous catheter (e.g. Hickman line) inserted to
facilitate access to the circulation for delivery of chemotherapy,
fluids, blood products and other supportive drugs
• Tumour lysis risk assessed and prevention started: fluids with
allopurinol or rasburicase
• Therapeutic regimen carefully explained to the patient and informed
consent obtained
• Consideration of entry into clinical trial
Haematological malignancies • 957
KM 23.47 Drugs commonly used in the treatment of
acute leukaemia
Phase
Acute lymphoblastic
leukaemia
Acute myeloid
leukaemia
Induction
Vincristine (IV)
Prednisolone (oral)
L- Asparaginase (IM)
Daunorubicin (IV)
Methotrexate (intrathecal)
Imatinib (oral)*
Daunorubicin (IV)
Cytarabine (IV)
Etoposide (IV and oral)
Gentuzumab
ozogamicin (IV)
k\\-trans retinoic acid
(ATRA) (oral)
Arsenic trioxide (ATO)
Consolidation
Daunorubicin (IV)
Cytarabine (IV)
Etoposide (IV)
Methotrexate (IV)
Imatinib (oral)*
Cytarabine (IV)
Amsacrine (IV)
Mitoxantrone (IV)
Maintenance
Prednisolone (oral)
Vincristine (IV)
Mercaptopurine (oral)
Methotrexate (oral)
Imatinib (oral)*
Relapse
Fludarabine
Cytarabine
Idarubicin
Fludarabine
Cytarabine
Arsenic trioxide (ATO)
Idarubicin
*lf Philadelphia chromosome-positive.
In patients with ALL, it is necessary to give prophylactic
treatment to the central nervous system, as this is a sanctuary
site where standard therapy does not penetrate. This usually
consists of a combination of cranial irradiation, intrathecal
chemotherapy and high-dose methotrexate, which crosses the
blood-brain barrier.
Thereafter, specific therapy is discontinued and the patient
observed.
The detail of the schedules for these treatments can be found
in specialist texts. The drugs most commonly employed are listed
in Box 23.47. Generally, if a patient fails to go into remission
with induction treatment, alternative drug combinations may be
tried, but the outlook is poor unless remission can be achieved.
Disease that relapses during treatment or soon after the end of
treatment carries a poor prognosis and is difficult to treat. The
longer after the end of treatment that relapse occurs, the more
likely it is that further treatment will be effective.
In some patients, alternative palliative chemotherapy, not
designed to achieve remission, may be used to curb excessive
leucocyte proliferation. Drugs used for this purpose include
hydroxycarbamide and mercaptopurine. The aim is to reduce
the blast count without inducing bone marrow failure.
Supportive therapy
Aggressive and potentially curative therapy, which involves
periods of severe bone marrow failure, would not be possible
without appropriate supportive care. The following problems
commonly arise.
Anaemia Anaemia is treated with red cell concentrate transfusions.
Bleeding Thrombocytopenic bleeding requires platelet
transfusions, unless the bleeding is trivial. Recent trials have
confirmed that in acute leukaemia prophylactic platelet transfusion
should be given to maintain the platelet count above 10x109/L.
Coagulation abnormalities occur and need accurate diagnosis and
treatment (p. 971).
Infection Fever (>38°C) lasting over 1 hour in a neutropenic
patient indicates possible sepsis (see also p. 218). Parenteral
broad -spectrum antibiotic therapy is essential. Empirical therapy is
given according to local bacteriological resistance patterns, such
as with a combination of an aminoglycoside (e.g. gentamicin)
and a broad-spectrum penicillin (e.g. piperacillin/tazobactam) or
a single-agent beta-lactam (e.g. meropenem). The organisms
most commonly associated with severe neutropenic sepsis are
Gram-positive bacteria, such as Staphylococcus aureus and
Staphylococcus epidermidis, which are present on the skin
and gain entry via cannulae and central lines. Gram-negative
infections often originate from the gastrointestinal tract, which
is affected by chemotherapy-induced mucositis; organisms
such as Escherichia coli, Pseudomonas and Klebsiella spp. are
likely to cause rapid clinical deterioration and must be covered
with initially empirical antibiotic therapy. Gram-positive infection
may require vancomycin or teicoplanin therapy. If fever has not
resolved after 3-5 days and there is evidence on CT scanning or
sensitive blood tests for a disseminated fungal infection, empirical
antifungal therapy (e.g. a liposomal amphotericin B preparation,
voriconazole or caspofungin) is added.
Patients with ALL are susceptible to infection with Pneumocystis
jirovecii (p. 318), which causes a severe pneumonia. Prophylaxis
with co-trimoxazole is given during chemotherapy. Diagnosis may
require either induced sputum, bronchoalveolar lavage or open
lung biopsy. Treatment is with high-dose co-trimoxazole, initially
intravenously, changing to oral treatment as soon as possible.
Oral and pharyngeal Candida infection is common. Fluconazole
is effective for the treatment of established local infection and for
prophylaxis against systemic candidaemia. Prophylaxis against
other systemic fungal infections, including Aspergillus, using
itraconazole or posaconazole, for example, is usual practice
during high-risk intensive chemotherapy. This is often used
along with sensitive markers of early fungal infection to guide
treatment initiation (a ‘pre-emptive approach’).
For systemic fungal infection with Candida or aspergillosis,
intravenous liposomal amphotericin, caspofungin or voriconazole
is required for at least 3 weeks. In systemic Candida infection
intravenous catheters should be removed.
Reactivation of herpes simplex infection (p. 247) occurs
frequently around the lips and nose during ablative therapy for
acute leukaemia, and is treated with aciclovir. This may also
be prescribed prophylactically to patients with a history of cold
sores or elevated antibody titres to herpes simplex. Herpes zoster
manifesting as chickenpox or, after reactivation, as shingles
(p. 239) should be treated in the early stage with high-dose
aciclovir, as it can be fatal in immunocompromised patients.
The value of isolation facilities, such as laminar flow rooms, is
debatable but may contribute to staff awareness of careful reverse
barrier nursing practice. The isolation can be psychologically
stressful for the patient.
Metabolic problems Frequent monitoring of fluid balance and renal,
hepatic and haemostatic function is necessary. Patients are often
severely anorexic and diarrhoea is common as a consequence
of the side-effects of therapy; they may find drinking difficult and
hence require intravenous fluids and electrolytes. Renal toxicity
occurs with some antibiotics (e.g. aminoglycosides) and antifungal
agents (amphotericin). Cellular breakdown during induction therapy
958 • HAEMATOLOGY AND TRANSFUSION MEDICINE
(tumour lysis syndrome; p. 1328) releases intracellular ions
and nucleic acid breakdown products, causing hyperkalaemia,
hyperuricaemia, hyperphosphataemia and hypocalcaemia. This
may lead to renal failure. Allopurinol and intravenous hydration
are given to try to prevent this. In patients at high risk of
tumour lysis syndrome, prophylactic rasburicase (a recombinant
urate oxidase enzyme) is used. Occasionally, dialysis may
be required.
Psychological problems Psychological support is a key aspect
of care. Patients should be kept informed, and their questions
answered and fears allayed as far as possible. A multidisciplinary
approach to patient care involves input from many services,
including psychology. Key members of the team include
haematology specialist nurses, who are often the central point
of contact for patients and families throughout the illness.
Haematopoietic stem cell transplantation
This is described on page 936. In patients with high-risk acute
leukaemia, allogeneic HSCT can improve 5-year survival from
20% to around 50%. Reduced-intensity conditioning has allowed
HSCT to be delivered to a higher proportion of patients with
acute leukaemias, up to the age of about 65 years.
Prognosis
Without treatment, the median survival of patients with acute
leukaemia is about 5 weeks. This may be extended to a number
of months with supportive treatment. Patients who achieve
remission with specific therapy have a better outlook. Around
80% of adult patients under 60 years of age with ALL or AML
achieve remission, although remission rates are lower for older
patients. However, the relapse rate continues to be high. Box
23.48 shows the survival in ALL and AML and the influence of
prognostic features. The level of detectable leukaemia cells, called
minimal residual disease (MRD), measured after induction therapy
in ALL by sensitive laboratory techniques, has been shown to be
a powerful prognostic tool that is now used routinely to direct
subsequent consolidation therapy.
Advances in treatment have led to steady improvement in
survival from leukaemia. They include the introduction of drugs
such as all -trans retinoic acid (ATRA) and arsenic trioxide (ATO)
23.48 Outcome in adult acute leukaemia
5-year overall
Disease/risk
Risk factors
survival
Acute myeloid leukaemia (AML)
Good risk
Promyelocytic leukaemia t(1 5;1 7)
90%
t(8;21)
65%
inv 16 or t(16;16)
70%
Poor risk
Cytogenetic abnormalities
-5, -7, del
5q, abn(3q), complex (>5)
21%
Intermediate risk
AML with none of the above
48%
Acute lymphoblastic leukaemia (ALL)
Poor risk
Philadelphia chromosome
High white count >100x1 09/L
Abnormal short arm of
chromosome
11 t(1 ; 1 9)
20%
Standard
ALL with none of the above
37%
in acute promyelocytic leukaemia, which has greatly reduced
induction deaths from bleeding in this good-risk leukaemia. A
chemotherapy-free schedule of ATRA and ATO has recently
produced cure rates of 90% in patients with low-risk acute
promyelocytic leukaemia. Current trials aim to improve survival,
especially in standard and poor-risk disease, with strategies that
include better use of allogeneic HSCT and targeted therapies
such as anti-CD33 monoclonal antibodies (Mylotarg) and FLT3
inhibitors. FLT3 is a cytokine receptor often expressed on AML
blast cells and whose expression is associated with a poorer
prognosis.
Chronic myeloid leukaemia
Chronic myeloid leukaemia (CML) is a myeloproliferative stem cell
disorder resulting in proliferation of all haematopoietic lineages but
manifesting predominantly in the granulocytic series. Maturation of
cells proceeds fairly normally. The disease occurs chiefly between
the ages of 30 and 80 years, with a peak incidence at 55 years.
It is rare, with an annual incidence in the UK of 1.8/100000,
and accounts for 20% of all leukaemias. It is found in all races.
The defining characteristic of CML is the chromosome
abnormality known as the Philadelphia (Ph) chromosome. This
is a shortened chromosome 22 resulting from a reciprocal
translocation of material with chromosome 9. The break on
chromosome 22 occurs in the breakpoint cluster region (BCR).
The fragment from chromosome 9 that joins the BCR carries
the abl oncogene, which forms a fusion gene with the remains
of the BCR. This BCR ABL fusion gene codes for a 210 kDa
protein with tyrosine kinase activity, which plays a causative role
in the disease as an oncogene (p. 1318), influencing cellular
proliferation, differentiation and survival. In some patients in
whom conventional chromosomal analysis does not detect a
Ph chromosome, the BCR ABL gene product is detectable by
molecular techniques.
Natural history
The disease has three phases:
• A chronic phase, in which the disease is responsive to
treatment and is easily controlled, which used to last
3-5 years. With the introduction of imatinib therapy, this
phase has been prolonged to encompass a normal life
expectancy in many patients.
• An accelerated phase (not always seen), in which disease
control becomes more difficult.
• Blast crisis, in which the disease transforms into an acute
leukaemia, either myeloblastic (70%) or lymphoblastic
(30%), which is relatively refractory to treatment. This is
the cause of death in the majority of patients; survival is
therefore dictated by the timing of blast crisis, which
cannot be predicted. Prior to imatinib therapy (see below),
approximately 10% of patients per year would transform.
In those treated with imatinib for up to 10 years, only
between 0.5 and 2.5% have transformed each year.
Clinical features
Symptoms at presentation may include lethargy, weight loss,
abdominal discomfort, gout and sweating, but about 25% of
patients are asymptomatic at diagnosis. Splenomegaly is present
in 90%; in about 10%, the enlargement is massive, extending
to over 15 cm below the costal margin. A friction rub may be
heard in cases of splenic infarction. Hepatomegaly occurs in
about 50%. Lymphadenopathy is unusual.
Haematological malignancies • 959
Investigations
FBC results are variable between patients. There is usually a
normocytic, normochromic anaemia. The leucocyte count can
vary from 10 to 600x1 09/L. In about one-third of patients, there
is a very high platelet count, sometimes as high as 2000x109/L.
In the blood film, the full range of granulocyte precursors, from
myeloblasts to mature neutrophils, is seen but the predominant
cells are neutrophils and myelocytes (see Fig. 23.3). Myeloblasts
usually constitute less than 10% of all white cells. There is
often an absolute increase in eosinophils and basophils, and
nucleated red cells are common. If the disease progresses through
an accelerated phase, the percentage of more primitive cells
increases. Blast transformation is characterised by a dramatic
increase in the number of circulating blasts. In patients with
thrombocytosis, very high platelet counts may persist during
treatment, in both chronic and accelerated phases, but usually
drop dramatically at blast transformation. Basophilia tends to
increase as the disease progresses.
Bone marrow should be obtained to confirm the diagnosis
and phase of disease by morphology, chromosome analysis to
demonstrate the presence of the Ph chromosome, and RNA
analysis to demonstrate the presence of the BCR ABL gene
product. Blood LDH levels are elevated and the uric acid level
may be high due to increased cell breakdown.
Management
Chronic phase
There are now five available tyrosine kinase inhibitors (TKIs) for
the treatment of CML (Box 23.49). These specifically inhibit BCR
ABL tyrosine kinase activity. Imatinib, nilotinib and dasatinib are
recommended as first-line therapy in chronic phase CML; they
usually normalise the blood count within a month and within
3-6 months produce complete cytogenetic response
(disappearance of the Ph chromosome) in some 90% of patients.
A sample of bone marrow is taken at 6 months to confirm
complete cytogenetic response, and patients are subsequently
monitored by 3-monthly real-time quantitative polymerase chain
reaction (PCR) for BCR ABL mRNA transcripts in blood. The
aim is to reduce the BCR ABL transcript levels by 3-5 logs from
baseline and this is called major molecular response (MR3-MR5).
A proportion of patients achieve a complete molecular response
where the transcripts are not detectable by PCR. It may be
possible for patients with a complete or major molecular response
23.49 Tyrosine kinase inhibition in chronic myeloid
leukaemia
Agents
First-line
• Imatinib
• Nilotinib
Second-line
• Imatinib
• Nilotinib
• Dasatinib
Outcomes
• 90% achieve complete cytogenetic response
• Responses faster with nilotinib and dasatinib
• Median survival comparable to normal population
*For patients with T315I kinase domain mutations use ponatinib.
to stop TKI therapy and this is being investigated in clinical
trials. For those failing to respond or who lose their response
and progress on first-line therapy, options include switching to
a different TKI (Box 23.49). Some patients develop detectable
mutations in the BCR ABL gene, which renders them resistant to
one or more of the TKIs. The T31 51 mutation has been particularly
problematic, as this provides wide-ranging resistance. The
third-generation TKI ponatinib is effective, however. Allogeneic
HSCT (p. 937) is now reserved for patients who fail TKI therapy.
Hydroxycarbamide and interferon were previously used for
control of disease. Hydroxycarbamide is still useful in palliative
situations and interferon is used in women planning pregnancy.
Accelerated phase and blast crisis
Management is more difficult. For patients in accelerated phase,
TKI therapy is indicated, most commonly with nilotinib or dasatinib.
When blast transformation occurs, the type of blast cell should be
determined. Response to appropriate acute leukaemia treatment
(see Box 23.49) is better if disease is lymphoblastic than if
myeloblastic. Second- or third-generation TKIs such as dasatinib
are used in combination with chemotherapy to try and achieve
remission. In younger and fitter patients an allogeneic HSCT is
appropriate therapy if a return to chronic phase is achieved.
Hydroxycarbamide can be an effective single agent and low-dose
cytarabine can also be used palliatively in older patients.
| Chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common variety
of leukaemia, accounting for 30% of cases. The male-to-female
ratio is 2 : 1 and the median age at presentation is 65-70 years.
In this disease, B lymphocytes, which would normally respond
to antigens by transformation and antibody formation, fail to
do so. An ever-increasing mass of immuno-incompetent cells
accumulates, to the detriment of immune function and normal
bone marrow haematopoiesis.
Clinical features
The onset is usually insidious. Indeed, in around 70% of patients,
the diagnosis is made incidentally on a routine FBC. Presenting
problems may be anaemia, infections, painless lymphadenopathy,
and systemic symptoms such as night sweats or weight loss;
these more often occur later in the course of the disease.
Investigations
The diagnosis is based on the peripheral blood findings of a mature
lymphocytosis (> 5 x 1 09/L) with characteristic morphology and cell
surface markers. Immunophenotyping reveals the lymphocytes
to be monoclonal B cells expressing the B-cell antigens CD19
and CD23, with either kappa or lambda immunoglobulin light
chains and, characteristically, an aberrant T-cel I antigen CD5. On
flow cytometry, some people are shown to have circulating CLL
cells at a level less than 5x109/L. This is known as monoclonal
B lymphocytosis of uncertain significance.
Other useful investigations in CLL include a reticulocyte count
and a direct Coombs test, as autoimmune haemolytic anaemia
may occur (p. 949). Serum immunoglobulin levels should be
estimated to establish the degree of hypogammaglobulinaemia,
which is common and progressive. Bone marrow examination
by aspirate and trephine is not essential for the diagnosis of
CLL, but may be helpful in difficult cases, for prognosis (patients
with diffuse marrow involvement have a poorer prognosis) and
to monitor response to therapy. The main prognostic factor is
• Dasatinib
• Bosutinib
• Ponatinib*
960 • HAEMATOLOGY AND TRANSFUSION MEDICINE
i
stage of disease (Box 23.50); however, loss of chromosome
1 7 p or mutation in the TP53 gene, which resides at this genetic
locus, is a powerful prognostic marker and predictor of response
to therapy. A mutation in TP53 is present in <10% of patients
at presentation but rises to 30% of cases at relapse. This test
should be performed in all patients prior to the initiation of therapy.
Management
No specific treatment is required for most clinical stage A patients,
unless progression occurs. Life expectancy is usually normal in
older patients. The patient should be offered clear information
about CLL and be reassured about the indolent nature of the
disease, as the diagnosis of leukaemia inevitably causes anxiety.
Treatment is required only if there is evidence of bone marrow
failure, massive or progressive lymphadenopathy or splenomegaly,
systemic symptoms such as weight loss or night sweats, a
rapidly increasing lymphocyte count, autoimmune haemolytic
anaemia or thrombocytopenia. Initial therapy for those requiring
treatment (progressive stage A and stages B and C) is based on
the age and fitness of the patient and the TP53 mutation status.
For patients who are under 70 years, fit and TP53 mutation¬
negative, fludarabine in combination with the alkylating agent
cyclophosphamide and the anti-CD20 monoclonal antibody
rituximab (FCR) is standard care. For older, less fit patients,
rituximab is combined with gentler chemotherapy: bendamustine
or oral chlorambucil. Recently, a more potent type 2 anti-CD20
antibody, obinutuzumab, has become available and produces
better responses in combination with chlorambucil than rituximab.
CLL cells are dependent on abnormal and persistent signalling
through the B-cell receptor (BCR) pathway. Drugs that can
inhibit this pathway are now available and show great promise.
Ibrutinib inhibits Bruton’s tyrosine kinase and idelalisib inhibits
PI3 kinase, both components of the BCR pathway. Ibrutinib
and idelalisib are licensed for relapsed CLL but crucially are
licensed and effective in 7P53-mutated disease at all stages
and are quickly becoming standard care in 7P53-mutated CLL.
Bone marrow failure or autoimmune cytopenias may respond
to glucocorticoid treatment.
Supportive care is increasingly required in progressive
disease, such as transfusions for symptomatic anaemia or
thrombocytopenia, prompt treatment of infections and, for
some patients with hypogammaglobulinaemia, immunoglobulin
replacement. Radiotherapy may be used for lymphadenopathy that
is causing discomfort or local obstruction, and for symptomatic
splenomegaly. Splenectomy may be required to improve low
blood counts due to autoimmune destruction or to hypersplenism,
and can relieve massive splenomegaly.
Prognosis
The majority of clinical stage A patients have a normal life
expectancy but patients with advanced CLL are more likely to
die from their disease or infectious complications. Survival is
influenced by prognostic features of the leukaemia, particularly
TP53 mutation status, and whether patients can tolerate and
respond to fludarabine-based treatment. In those able to
be treated with chemotherapy and rituximab, 90% are alive
4 years later. Rarely, CLL transforms to an aggressive high-grade
lymphoma, called Richter’s transformation.
| Prolymphocytic leukaemia
Prolymphocytic leukaemia (PLL) is a variant of chronic
lymphocytic leukaemia found mainly in males over the age
of 60 years; 25% of cases are of the T-cell variety. There is
typically massive splenomegaly with little lymphadenopathy
and a very high leucocyte count, often in excess of 400x1 09/L.
The characteristic cell is a large lymphocyte with a prominent
nucleolus. Treatment is generally unsuccessful and the prognosis
very poor. Leukapharesis, splenectomy and chemotherapy may
be tried. The anti-CD52 antibody alemtuzumab, when given
intravenously, has produced responses in some 90% of patients
with T-PLL.
Hairy cell leukaemia
This is a rare chronic B-cell lymphoproliferative disorder. The
male-to-female ratio is 6 : 1 and the median age at diagnosis
is 50 years. Presenting symptoms are general ill health and
recurrent infections. Splenomegaly occurs in 90% but lymph
node enlargement is unusual.
Severe neutropenia, monocytopenia and the characteristic
hairy cells in the blood and bone marrow are typical. These
cells usually have a B-lymphocyte immunotype but they also
characteristically express CD25 and CD103. Recently, all patients
with hairy cell leukaemia have been found to have a mutation
in the BRAF gene.
Over recent years, a number of treatments, including cladribine
and deoxycoformycin, have been shown to produce long-lasting
remissions.
Myelodysplastic syndromes
Myelodysplastic syndromes (MDSs) constitute a group of clonal
haematopoietic disorders with the common features of ineffective
blood cell production and a tendency to progress to AML. As
such, they are pre-leukaemic and represent genetic steps in the
development of leukaemia. These genetic abnormalities have
been identified and are present as a manifestation of clonal
haematopoiesis in about 3% of patients over the age of 80, at a
time when their blood counts are normal (clonal haematopoiesis of
indeterminate potential, CHIP). MDS presents with consequences
of bone marrow failure (anaemia, recurrent infections or bleeding),
usually in older people (median age at diagnosis is 73 years).
The overall incidence is 4/100000 in the population, rising to
more than 30/1 00 000 in the over-seventies. The blood film is
characterised by cytopenias and abnormal-looking (dysplastic)
blood cells, including macrocytic red cells and hypogranular
neutrophils with nuclear hyper- or hyposegmentation. The bone
marrow is hypercellular, with dysplastic changes in at least 10%
of cells of one or more cell lines. Blast cells may be increased
but do not reach the 20% level that indicates acute leukaemia.
Chromosome analysis frequently reveals abnormalities, particularly
23.50 Staging of chronic lymphocytic leukaemia
Clinical stage A (60% patients)
• No anaemia or thrombocytopenia and fewer than three areas of
lymphoid enlargement
Clinical stage B (30% patients)
• No anaemia or thrombocytopenia, with three or more involved areas
of lymphoid enlargement
Clinical stage C (10% patients)
• Anaemia and/or thrombocytopenia, regardless of the number of
areas of lymphoid enlargement
Haematological malignancies • 961
KM 23.51 WHO classification of myelodysplastic
syndromes (MDSs)
Disease
Bone marrow findings
MDS with single-lineage
dysplasia
<5% blasts and single-lineage
dysplasia only
MDS with ring
sideroblasts (MDS-RS)
>15% ring sideroblasts, or 6-14%
and presence of SF3B1 gene
mutation
MDS with multilineage
dysplasia
<5% blasts and dysplasia in 2 or
more lineages
MDS with excess blasts
5-1 9% blasts
MDS with isolated del(5q)
Myelodysplastic syndrome associated
with a del(5q) cytogenetic abnormality
<5% blasts
Often normal or increased blood
platelet count
MDS, unclassifiable
None of the above or inadequate
material
BV 23.52 Revised International Prognostic Scoring
System and outcomes in myelodysplasia
Median
25% progression
Overall
survival
to acute myeloid
Risk category
score
(years)
leukaemia (years)
Very low
<1.5
8.8
Not reached
Low
>1.5-3
5.3
10.8
Intermediate
>3-4.5
3.0
3.2
High
>4.5-6
1.6
1.4
Very high
>6
0.8
0.73
*The IPSS-R is based on three prognostic factors: the blast percentage in bone
marrow; karyotype; and number and degree of blood cytopenias. A score is
derived from which patients can be stratified into five risk categories for survival
and leukaemic transformation.
of chromosome 5 or 7. The WHO classification of MDS is shown
in Box 23.51 .
Prognosis
The natural history of MDS is progressive worsening of dysplasia
leading to fatal bone marrow failure or progression to AML in
30% of cases. The time to progression varies (from months to
years) with the subtype of MDS, being slowest in MDS with
ring sideroblasts and single-lineage dysplasia and most rapid
in MDS with excess blasts. The revised International Prognostic
Scoring System (IPSS-R) predicts clinical outcome based on
karyotype and cytopenias in blood, as well as percentage of
bone marrow blasts (Box 23.52). There are five prognostic
groups. The median survival for low-risk patients (IPSS-R very
low and low) is 5-9 years, that for the intermediate group is
3 years and that for high-risk patients (IPSS-R high and very
high) is 1-1 .5 years.
Management
For the vast majority of patients who are elderly, the disease
is incurable, and supportive care with red cell and platelet
transfusions is the mainstay of treatment. A trial of erythropoiesis
stimulating agents (ESA) and granulocyte-colony-stimulating
factor (G-CSF) is recommended in some patients with low-
risk MDS (IPSS-R very low, low and intermediate) to improve
haemoglobin or neutrophil counts. A rare subtype called MDS
with isolated del(5q) responds well to the immunomodulatory
drug lenalidomide, with two-thirds of anaemic patients becoming
transfusion-independent for up to 2 years. Allogeneic stem
cell transplantation may afford a cure in patients with a good
performance status and is considered in high-risk patients (IPSS-R
high and very high) and some low-risk patients. More recently,
the hypomethylating agent azacytidine has improved survival
by a median of 9 months for high-risk patients, and in the UK
is a recommended standard of care for those not eligible for
transplantation.
Lymphomas
These neoplasms arise from lymphoid tissues, and are diagnosed
from the pathological findings on biopsy as Hodgkin or non-
Hodgkin lymphoma. The majority are of B-cell origin. Non-Hodgkin
lymphomas are classified as low- or high-grade tumours on the
basis of their proliferation rate. The normal architecture of the
lymph node is outlined in Figure 23.25.
• High-grade tumours divide rapidly, are typically present for
a matter of weeks before diagnosis, and may be life-
threatening with frequent risk of extranodal involvement.
• Low-grade tumours divide slowly, may be present for
many months before diagnosis, and typically behave in an
indolent fashion.
Hodgkin lymphoma
The histological hallmark of Hodgkin lymphoma (HL) is the
presence of Reed-Sternberg cells: large, malignant lymphoid
cells of B-cell origin (Fig. 23.26). They are often present only in
small numbers but are surrounded by large numbers of reactive
non-malignant T cells, plasma cells and eosinophils.
The epidemiology of HL is shown in Box 23.53 and its
histological WHO classification in Box 23.54.
Nodular lymphocyte-predominant HL is slow-growing, localised
and rarely fatal. It has biological features, such as CD20-positive
Hodgkin cells, and clinical features that make it more akin to
a low-grade B-cell non-Hodgkin lymphoma. Classical HL is
divided into four histological subtypes from the appearance of the
Germinal centre B-cell follicle
Fig. 23.25 Schema of lymph node architecture. Different lymphocyte
populations reside in different areas of the node: B cells in the follicles,
T cells in the paracortex and plasma cells in the medulla. B cells are
selected for antigen in the follicle centre. Errors during this process result
in B-cell lymphomas, which are by far the most common type.
962 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Fig. 23.26 Hodgkin lymphoma. In the centre of this lymph node biopsy
is a large typical Reed-Stern berg cell with two nuclei containing a
prominent eosinophilic nucleolus.
23.53 Epidemiology and aetiology of
Hodgkin lymphoma
23.54 WHO pathological classification of Hodgkin
lymphoma (HL)
Type
Histology classification
Proportion of HL
Nodular lymphocyte-
predominant HL
5%
Classical HL
Nodular sclerosing
70%
Mixed cellularity
20%
Lymphocyte- rich
5%
Lymphocyte-depleted
Rare
Reed-Stern berg cells and surrounding reactive cells. The nodular
sclerosing type is more common in young patients and in women.
Mixed cellularity is more common in the elderly. Lymphocyte-rich
HL usually presents in men. Lymphocyte-depleted HL is rare
and probably represents large-cell or anaplastic non-Hodgkin
lymphoma.
Clinical features
There is painless, rubbery lymphadenopathy, usually in the neck
or supraclavicular fossae; the lymph nodes may fluctuate in
size. Young patients with nodular sclerosing disease may have
large mediastinal masses that are surprisingly asymptomatic
i
23.55 Clinical stages of Hodgkin lymphoma
(Ann Arbor classification)
Stage
Definition
1
Involvement of a single lymph node region (1) or
extralymphatic* site (lE)
II
Involvement of two or more lymph node regions (II) or an
extralymphatic site and lymph node regions on the same
side of (above or below) the diaphragm (llE)
III
Involvement of lymph node regions on both sides of the
diaphragm with (lllj or without (III) localised extralymphatic
involvement or involvement of the spleen (llls), or both (lllSE)
IV
Diffuse involvement of one or more extralymphatic tissues,
e.g. liver or bone marrow
Each stage is subclassified:
A
No systemic symptoms
B
Weight loss >10%, drenching sweats, fever
The lymphatic structures are defined as the lymph nodes, spleen, thymus,
Waldeyer’s ring, appendix and Peyer’s patches.
but may cause dry cough and some breathlessness. Isolated
subdiaphragmatic nodes occur in fewer than 1 0% at diagnosis.
Hepatosplenomegaly may be present but does not always
indicate disease in those organs. Spread is contiguous from
one node to the next, and extranodal disease, such as bone,
brain or skin involvement, is rare.
Investigations
Treatment of HL depends on the stage at presentation;
investigations therefore aim not only to diagnose lymphoma
but also to determine the extent of disease (Box 23.55).
• FBC may be normal. If a normochromic, normocytic
anaemia or lymphopenia is present, this is a poor
prognostic factor. An eosinophilia or a neutrophilia may be
present.
• ESR may be raised.
• Renal function tests are required to ensure function is
normal prior to treatment.
• Liver function may be abnormal in the absence of disease
or may reflect hepatic infiltration. An obstructive pattern
may be caused by nodes at the porta hepatis.
• LDH measurements showing raised levels are an adverse
prognostic factor.
• Chest X-ray may show a mediastinal mass.
• CT scan of chest, abdomen and pelvis permits staging.
Bulky disease (> 10 cm in a single node mass) is an
adverse prognostic feature.
• Positron emission tomography (PET) scanning identifies
nodes involved with HL, which are 18fluorodeoxyglucose
(FDG)-avid, and this allows more accurate staging and
monitoring of response (Fig. 23.27).
• Lymph node biopsy may be undertaken surgically or by
percutaneous needle biopsy under radiological guidance
(Fig. 23.28).
Management
Clinical trials have shown that patients with early-stage disease
(stages IA and IIA) have better outcomes if limited cycles of
chemotherapy are combined with radiotherapy, rather than using
radiotherapy alone.
Incidence
• Approximately 4 new cases/1 00 000 population/year
Sex ratio
• Slight male excess (1.5:1)
Age
• Median age 31 years; first peak at 20-35 years and second at
50-70 years
Aetiology
• Unknown
• More common in patients from well-educated backgrounds and
small families
• Three times more likely with a past history of infectious
mononucleosis but no definitive causal link to Epstein— Barr virus
infection proven
Haematological malignancies • 963
Fig. 23.27 Positron emission tomography (PET) scans in Hodgkin lymphoma, demonstrating response to treatment. [A] Chest X-ray from a young
man with Hodgkin lymphoma at presentation, showing a left-sided anterior-superior mediastinal mass with tracheal deviation to the right. \B\ Fused
PET-CT image showing intense fluorodeoxyglucose (FDG) uptake (avidity) in the mass at presentation. [C] Fused PET-CT image showing no FDG uptake
(PET negativity), representing complete response at the end of treatment.
Fig. 23.28 CT-guided percutaneous needle biopsy of retroperitoneal
nodes involved by lymphoma.
The ABVD regimen (doxorubicin, bleomycin, vinblastine and
dacarbazine) is widely used in the UK. Standard therapy for
early-stage patients without additional risk factors, such as bulk
disease or high ESR, is two cycles of ABVD combined with 20 Gy
radiotherapy to the involved sites of disease. Standard therapy
for early-stage patients with additional risk factors is four cycles
of ABVD combined with 30 Gy radiotherapy. Careful planning of
radiotherapy is required to limit the doses delivered to normal
tissues and new planning techniques continue to improve targeting
of radiotherapy. Nevertheless, the long-term risks of second
cancers and heart and lung disease within the radiation fields
remain a concern, especially for young people with a high cure
rate and decades of life ahead of them. Recent randomised trial
data from the UK RAPID study have suggested that early-stage
patients without bulk disease who have a negative PET scan
after three cycles of ABVD can safely omit radiotherapy. Young
women receiving breast irradiation during the treatment of chest
disease have an increased risk of breast cancer and should
participate in a screening programme. Patients continuing to
smoke after lung irradiation are at particular risk of lung cancer.
ABVD chemotherapy can cause cardiac and pulmonary toxicity,
due to doxorubicin and bleomycin, respectively. The incidence
of infertility and secondary myelodysplasia/AML is low with this
regimen.
Patients with advanced-stage disease are most commonly
managed with chemotherapy alone. Standard treatment in
the UK is 6-8 cycles of ABVD, followed by an assessment of
response. The recent UK RATHL trial has confirmed previous
data showing that achieving a PET-negative response after
two cycles of ABVD (interim PET-2 response) predicts a very
good outcome from continuing with up to six cycles of ABVD.
Indeed, the same outcome can be achieved by omitting the
bleomycin from the last four cycles and using just AVD, thus
reducing the risk of lung toxicity. Patients who are PET-positive
after two cycles, however, have a very high relapse risk if they
continue with ABVD, only 13% being relapse-free at 2 years.
The RATHL and other studies have demonstrated that changing
to a more intensive regimen, BEACOPP (bleomycin, etoposide,
adriamycin, cyclophosphamide, vincristine (oncovin), procarbazine,
prednisolone), in these patients improves the relapse-free survival
to approximately 65%.
Patients with relapsed disease that responds to salvage
chemotherapy and ideally becomes PET-negative should be
considered for autologous stem cell transplantation (p. 937).
Those with resistant disease might benefit from an allogeneic
964 • HAEMATOLOGY AND TRANSFUSION MEDICINE
23.57 Epidemiology and aetiology of
non-Hodgkin lymphoma
Incidence
• 1 2 new cases/1 00 000 people/year
Sex ratio
• Slight male excess
Age
• Median age 65-70 years
Aetiology
• No single causative abnormality described
• Lymphoma is a late manifestation of HIV infection (p. 322)
• Specific lymphoma types are associated with viruses:
e.g. Epstein— Barr virus (EBV) with post-transplant NHL,
human herpesvirus 8 (HHV8) with a primary effusion lymphoma,
and human T-cell lymphotropic virus (HTLV-1) with adult T-cell
leukaemia lymphoma
• Gastric lymphoma can be associated with Helicobacter pylori
infection
• Some lymphomas are associated with specific chromosomal
translocations:
The t(14;18) in follicular lymphoma results in the dysregulated
expression of the BCL-2 gene product, which inhibits apoptotic
cell death
The t(8;14) found in Burkitt lymphoma and the t(1 1 ; 1 4) in mantle
cell lymphoma alter function of c-myc and cyclin D1 ,
respectively, resulting in malignant proliferation
• Lymphoma occurs in congenital immunodeficiency states and in
immunosuppressed patients after organ transplantation
23.56 The Hasenclever prognostic index for
advanced Hodgkin lymphoma
Score 1 for each of the following risk factors present at diagnosis:
• Age >45 years
• Male gender
• Serum albumin <40 g/L
• Hb <105 g/L
• Stage IV disease
• White blood cell count >15x1 09/L
• Lymphopenia <0.6x1 09/L
Score
5-year rate of freedom
from progression (%)
5-year rate of overall
survival (%)
0-1
79
90
>2
60
74
>3
55
70
>4
47
59
stem cell transplant. Brentuximab vedotin is an antibody-drug
conjugate directed against CD30 on the Reed-Stern berg cell
surface. This antibody delivers the antimitotic toxin monomethyl
auristatin E to the Hodgkin cells and, as a single agent, can
produce good responses in patients who have failed, or are not
suitable for, an autologous transplant and can be a ‘bridge’ to
an allogeneic transplant.
Prognosis
Over 90% of patients with early-stage HL achieve complete
remission when treated with chemotherapy followed by involved
field radiotherapy, and the great majority are cured. The major
challenge is how to reduce treatment intensity, and hence
long-term toxicity, without reducing the excellent cure rates in
this group. Omitting radiotherapy in the majority of PET-negative
patients is one major step forward in this regard.
Historically, between 50 and 70% of those with advanced -stage
HL were cured. The Hasenclever index (Box 23.56) can be helpful
in assigning approximate chances of cure when discussing
treatment plans with patients. More recent data using the PET
scanner to direct therapy suggests that long-term survival is
improving to beyond 80%. Patients who fail to respond to initial
chemotherapy or relapse within a year of initial therapy have a
poor prognosis but some may achieve long-term survival after
autologous HSCT. Patients relapsing after 1 year may obtain
long-term survival with further chemotherapy alone, but fit patients
frequently proceed to autologous HSCT.
Non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL) represents a monoclonal
proliferation of lymphoid cells of B-cell (90%) or T-cell (10%)
origin. The incidence of these tumours increases with age, to
62.8/million population per annum at age 75 years, and the
overall rate is increasing at about 3% per year.
The epidemiology of NHL is shown in Box 23.57. Previous
classifications were based principally on histological appearances.
The current WHO classification stratifies according to cell lineage
(T or B cells) and incorporates clinical features, histology,
chromosomal abnormalities and concepts related to the biology
of the lymphoma. Clinically, the most important factor is grade,
which is a reflection of proliferation rate. High-grade NHL has
high proliferation rates, rapidly produces symptoms, is fatal if
untreated, but is potentially curable. Low-grade NHL has low
proliferation rates, may be asymptomatic for many months or
even years before presentation, runs an indolent course, but is
not curable by conventional therapy. Of all cases of NHL in the
developed world, over two-thirds are either diffuse large B-cell
NHL (high-grade) or follicular NHL (low-grade) (Fig. 23.29). Other
forms of NHL, including Burkitt lymphoma, mantle cell lymphoma,
mucosa-associated lymphoid tissue (MALT) lymphomas and
T-cell lymphomas, are less common.
Clinical features
Unlike Hodgkin lymphoma, NHL is often widely disseminated at
presentation, including in extranodal sites. Patients present with
lymph node enlargement (Fig. 23.30), which may be associated
with systemic upset: weight loss, sweats, fever and itching.
Hepatosplenomegaly may be present. Sites of extranodal
involvement include the bone marrow, gut, thyroid, lung, skin,
testis, brain and, more rarely, bone. Bone marrow involvement
is more common in low-grade (50-60%) than high-grade (1 0%)
disease. Compression syndromes may occur, including gut
obstruction, ascites, superior vena cava obstruction and spinal
cord compression.
The same staging system (see Box 23.55) is used for both
HL and NHL, but NHL is more likely to be stage III or IV at
presentation.
Investigations
These are as for HL, but in addition the following should be
performed:
• Bone marrow aspiration and trephine to identify bone
marrow involvement.
• Immunophenotyping of surface antigens to distinguish
T-cell from B-cell tumours. This may be done on blood,
marrow or nodal material.
Haematological malignancies • 965
Fig. 23.29 Histology of non-Hodgkin lymphoma. U (Low-grade)
follicular or nodular pattern. jjfj (High-grade) diffuse pattern.
• Cytogenetic analysis to detect chromosomal translocations
and molecular testing for T-cell receptor or immunoglobulin
gene rearrangements.
• Immunoglobulin determination. Some lymphomas are
associated with IgG or IgM paraproteins, which serve as
markers for treatment response.
• Measurement of uric acid levels .Some very agg ressi ve
high-grade NHLs are associated with very high urate levels,
which can precipitate renal failure when treatment is started.
• HIV testing. HIV is a risk factor for some lymphomas and
affects treatment decisions.
• Hepatitis B and C testing. This should be done prior to
therapy with rituximab.
Management
Low-grade NHL
The majority of patients (80%) present with advanced stage
disease and will run a relapsing and remitting course over several
years. Asymptomatic patients may not require therapy and are
managed by ‘watching and waiting’. Indications for treatment
include marked systemic symptoms, lymphadenopathy causing
discomfort or disfigurement, bone marrow failure or compression
syndromes. In follicular lymphoma, the options are:
• Radiotherapy. This can be used for localised stage I
disease, which is rare.
• Chemotherapy. Most patients will respond to oral therapy
with chlorambucil, which is well tolerated but not curative.
More intensive intravenous chemotherapy in younger
patients produces better quality of life but no survival benefit.
• Monoclonal antibody therapy. Humanised monoclonal
antibodies (‘biological therapy’; p. 960) can be used to
Fig. 23.30 Bulky axillary lymphadenopathy with distended
superficial veins in a patient presenting with high-grade lymphoma.
From Howard MR, Hamilton PJ. Haematology: An illustrated colour text,
4th edn. Edinburgh: Elsevier Ltd; 2013.
target surface antigens on tumour cells and to induce
tumour cell apoptosis directly. The anti-CD20 antibody
rituximab has been shown to induce durable clinical
responses in up to 60% of patients when given alone, and
acts synergistically when given with chemotherapy.
Rituximab (R) in combination with cyclophosphamide,
vincristine and prednisolone (R-CVP), cyclophosphamide,
doxorubicin, vincristine, prednisolone (R-CHOP) or
bendamustine (R-bendamustine) is commonly used as
first-line therapy. Randomised trials have also confirmed
that 2 years of maintenance therapy with single-agent
rituximab, following achievement of first or second
response, delays relapse and the time to next treatment.
As yet, however, rituximab maintenance has not shown a
survival benefit. New and more potent monoclonal
antibodies are also in development and trials of
obinutuzumab (p. 960) have been completed.
• Kinase inhibitors. Idelalisib is approved for relapsed follicular
lymphoma and ibrutinib (p. 960) is approved for relapsed
mantle cell lymphoma, a poor-prognosis lymphoma with
low-grade histology but aggressive clinical behaviour.
These targeted therapies are likely to become more widely
used in low-grade lymphomas in the near future.
• Transplantation. High-dose chemotherapy and autologous
HSCT can produce long remissions in patients with
relapsed disease. Decisions on the timing of such treatment
are complex in the context of rituximab maintenance and
newer targeted therapies. However, younger patients with
short first or second remissions or who relapse during
rituximab maintenance should be considered.
966 • HAEMATOLOGY AND TRANSFUSION MEDICINE
High-grade NHL
Patients with diffuse large B-cell NHL need treatment at initial
presentation:
• Chemotherapy. The majority (>90%) are treated with
intravenous combination chemotherapy, typically with the
CHOP regimen (cyclophosphamide, doxorubicin,
vincristine and prednisolone).
• Monoclonal antibody therapy. When combined with CHOP
chemotherapy, rituximab (R) increases the complete
response rates and improves overall survival. R-CHOP is
currently recommended as first-line therapy for those with
stage II or higher diffuse large B-cell lymphoma.
• Radiotherapy. Stage I patients without bulky disease are
treated with four cycles of CHOP or R-CHOP, followed by
involved site radiotherapy. Radiotherapy is also indicated
for a residual localised site of bulk disease after
chemotherapy, and for spinal cord and other compression
syndromes.
• HSCT. Autologous HSCT (p. 937) benefits patients with
relapsed disease that is sensitive to salvage
immunochemotherapy. As with HL, achieving PET
negativity prior to autologous transplantation is desirable.
Prognosis
Low-grade NHL runs an indolent remitting and relapsing course,
with an overall median survival of 12 years. Transformation to
a high-grade NHL occurs in 3% per annum and is associated
with poor survival.
In diffuse large B-cell NHL treated with R-CHOP, some 75%
of patients overall respond initially to therapy and 50% will have
disease-free survival at 5 years. The prognosis for patients with
NHL is further refined according to the international prognostic
index (IPI). For high-grade NHL, 5-year survival ranges from over
75% in those with low-risk scores (age <60 years, stage I or II,
one or fewer extranodal sites, normal LDH and good performance
status) to 25% in those with high-risk scores (increasing age,
advanced stage, concomitant disease and a raised LDH).
Relapse is associated with a poor response to further
chemotherapy (<10% 5-year survival), but in patients under
65 years HSCT improves survival.
Paraproteinaemias
A gammopathy refers to over-production of one or more classes of
immunoglobulin. It may be polyclonal in association with acute or
chronic inflammation, such as infection, sarcoidosis, autoimmune
disorders or some malignancies. Alternatively, a monoclonal
increase in a single immunoglobulin class may occur in association
with normal or reduced levels of the other immunoglobulins.
Such monoclonal proteins (also called M-proteins, paraproteins
or monoclonal gammopathies) occur as a feature of myeloma,
lymphoma and amyloidosis, in connective tissue disease such
as rheumatoid arthritis or polymyalgia rheumatica, in infection
such as HIV, and in solid tumours. In addition, they may be
present with no underlying disease. Gammopathies are detected
by plasma immunoelectrophoresis.
I Monoclonal gammopathy of
uncertain significance
In monoclonal gammopathy of uncertain significance (MGUS,
also known as benign monoclonal gammopathy), a paraprotein is
present in the blood but there are no other features of myeloma,
Waldenstrom macroglobulinaemia (see below), lymphoma or
related disease. It is a common condition associated with
increasing age; a paraprotein can be found in 1 % of the population
aged over 50 years, increasing to 5% over 80 years.
Clinical features and investigations
Patients are usually asymptomatic, and the paraprotein is found
on blood testing for other reasons. The routine blood count
and biochemistry are normal, the paraprotein is usually present
in small amounts with no associated immune paresis, and
there are no lytic bone lesions. The bone marrow may have
increased plasma cells but these usually constitute less than
10% of nucleated cells.
Prognosis
After follow-up of 20 years, only one-quarter of cases will progress
to myeloma or a related disorder (i.e. around 1% per annum).
There is no certain way of predicting progression in an individual
patient. However, an abnormal ratio of kappa to lambda light
chains (serum free light chain ratio, SFLR) increases the risk of
progression. Patients with an abnormal ratio should be monitored
for progression on an annual basis.
Waldenstrom macroglobulinaemia
This is a low-grade lymphoplasmacytic lymphoma associated
with an IgM paraprotein, causing clinical features of hyperviscosity
syndrome. It is a rare tumour occurring in the elderly and more
commonly affects males.
Patients classically present with features of hyperviscosity,
such as nosebleeds, bruising, delirium and visual disturbance.
However, presentation may be with anaemia, systemic symptoms,
splenomegaly or lymphadenopathy, or may be asymptomatic, with
an IgM paraprotein detected on routine screening. Patients are
found on investigation to have an IgM paraprotein associated with
a raised plasma viscosity. The bone marrow has a characteristic
appearance, with infiltration of lymphoid cells, plasma cells and
sometimes prominent mast cells. A high proportion of patients
have a mutation in the MYD88 gene.
Management
If patients show symptoms of hyperviscosity and anaemia,
plasmapheresis is required to remove IgM and make blood
transfusion possible. Chemotherapy with alkylating agents, such
as chlorambucil, has been the mainstay of treatment, controlling
disease in over 50%. Fludarabine may be more effective in this
disease but has more side-effects. Rituximab in combination
with chemotherapy is most commonly used; ibrutinib is very
effective and has recently been licensed for use. Rituximab alone
can cause a rapid release of IgM and increase in viscosity. The
median survival is 5 years.
Multiple myeloma
This is a malignant proliferation of plasma cells. Normal plasma
cells are derived from B cells and produce immunoglobulins
that contain heavy and light chains. Normal immunoglobulins
are polyclonal, which means that a variety of heavy chains are
produced and each may be of kappa or lambda light chain type
(p. 68). In myeloma, plasma cells produce immunoglobulin of a
single heavy and light chain, a monoclonal protein commonly
referred to as a paraprotein. In most cases an excess of light
chain is produced, and in some cases only light chain is produced;
Haematological malignancies • 967
Plasma cells in bone marrow A
Hyperviscosity
Retinal bleeds
Bruising
Heart failure
Cerebral ischaemia
Amyloid
‘Panda’ eyes
Nephrotic syndrome
Carpal tunnel syndrome
Bone pain/fracture
Lytic lesions
Engorged retinal veins A
in hyperviscosity
Abnormal blood tests
Anaemia -
Normo- or macrocytic
Pancytopenia-
Raised ESR-
Hypercalcaemia-
Renal impairment-
Paraproteinaemia-
Immune paresis
Bence Jones proteinuria
Serum free light chains
Bone marrow
Plasmacytosis > 10%
A Lytic lesion eroding A Lytic lesions in
right superior pubic skull
ramus and acetabulum
Renal failure due to:
Paraprotein deposition
Hypercalcaemia
Infection
NSAIDs
Amyloid
cord compression
Bony collapse
Extradural mass
Fig. 23.31 Clinical and laboratory features of multiple myeloma. (ESR = erythrocyte sedimentation rate; NSAIDs = non-steroidal anti-inflammatory
drugs)
23.58 Classification of multiple myeloma
Type of monoclonal (M)-protein
Relative frequency (%)
IgG
55
IgA
21
Light chain only
22
Others (D, E, non-secretory)
2
this appears in the urine as Bence Jones proteinuria and can
be measured in the urine or serum as free light chain. The
frequency of different isotypes of monoclonal protein in myeloma
is shown in Box 23.58.
Although a small number of malignant plasma cells are present
in the circulation, the majority are present in the bone marrow.
The malignant plasma cells produce cytokines, which stimulate
osteoclasts and result in net bone reabsorption. The resulting
lytic lesions cause bone pain, fractures and hypercalcaemia.
Marrow involvement can result in anaemia or pancytopenia.
Clinical features and investigations
The incidence of myeloma is 4/100000 new cases per annum,
with a male-to-female ratio of 2 : 1 . The median age at diagnosis is
60-70 years and the disease is more common in Afro-Caribbeans.
The clinical features are demonstrated in Figure 23.31 .
Diagnosis of myeloma requires two of the following criteria
to be fulfilled:
• increased malignant plasma cells in the bone marrow
• serum and/or urinary M-protein
• skeletal lytic lesions.
Bone marrow aspiration, plasma and urine electrophoresis,
and a skeletal survey are thus required. Normal immunoglobulin
levels, i.e. the absence of immunoparesis, should cast doubt
on the diagnosis. Paraproteinaemia can cause an elevated
ESR but this is a non-specific test; only approximately 5% of
patients with a persistently elevated ESR above 100 mm/hr
have underlying myeloma.
Management
If patients are asymptomatic with no evidence of end-organ
damage (e.g. to kidneys, bone marrow or bone), treatment may
not be required. So-called asymptomatic myeloma should be
monitored closely for the development of end-organ damage.
Immediate support
• High fluid intake to treat renal impairment and
hypercalcaemia (p. 661).
• Analgesia for bone pain.
968 • HAEMATOLOGY AND TRANSFUSION MEDICINE
• Bisphosphonates for hypercalcaemia and to delay other
skeletal related events (p. 1047).
• Allopurinol to prevent urate nephropathy.
• Plasmapheresis, if necessary, for hyperviscosity.
Chemotherapy with or without HSCT
Myeloma therapy has improved with the addition of novel agents,
initially thalidomide and more recently the proteasome inhibitor
bortezomib and the second-generation immunomodulatory drug
lenalidomide. For first-line therapy in older patients, thalidomide
combined with the alkylating agent melphalan and prednisolone
(MPT) has increased the median overall survival to more than
4 years. Lenalidomide is approved first-line treatment for patients
not eligible for transplantation and who are intolerant of, or
unsuitable for, thalidomide. Thalidomide and lenalidomide both
have anti-angiogenic effects against tumour blood vessels
and immunomodulatory effects. Both can cause somnolence,
constipation, peripheral neuropathy and thrombosis, though
lenalidomide has a better side-effect profile. It is vital that females
of child-bearing age use adequate contraception, as thalidomide
and lenalidomide are teratogenic. Treatment is administered until
paraprotein levels have stopped falling. This is termed ‘plateau
phase’ and can last for weeks or years.
In younger, fitter patients, standard treatment includes first-
line therapies, such as cyclophosphamide, thalidomide and
dexamethasone (CTD) or bortezomib (Velcade), thalidomide
and dexamethasone (VTD) to maximum response, and then
autologous HSCT, which improves quality of life and prolongs
survival but does not cure myeloma. In all patients who have
achieved maximal response, lenalidomide maintenance has been
shown to prolong the response.
When myeloma progresses, treatment is given to induce
a further plateau phase. In the UK, the proteosome inhibitor
bortezomib and lenalidomide have been used as second- and
third-line therapy, as appropriate. As they have been used more
frequently in the first or second line with prognostic benefit,
however, subsequent relapses are more difficult to treat. A
second-generation proteasome inhibitor, carfilzomib, and the
anti-CD38 antibody daratumumab show promise in relapsed/
refractory disease. Responding patients may benefit from a
second autologous HSCT.
Radiotherapy
This is effective for localised bone pain not responding to simple
analgesia and for pathological fractures. It is also useful for the
(fx
• Median age: approximately 70 years for most haematological
malignancies.
• Poor-risk biological features: adverse cytogenetics or the
presence of a multidrug resistance phenotype are more frequent.
• Prognosis: increasing age is an independent adverse variable in
acute leukaemia and aggressive lymphoma.
• Chemotherapy: may be less well tolerated. Older people are more
likely to have antecedent cardiac, pulmonary or metabolic problems,
tolerate systemic infection less well and metabolise cytotoxic drugs
differently.
• Cure rates: similar to those in younger patients, in those who do
tolerate treatment.
• Decision to treat: should be based on the individual’s biological
status, the level of social support available, and the patient’s wishes
and those of the immediate family, but not on chronological age alone.
emergency treatment of spinal cord compression complicating
extradural plasmacytomas.
Bisphosphonates
Long-term bisphosphonate therapy reduces bone pain and
skeletal events. These drugs protect bone (p. 1047) and may
cause apoptosis of malignant plasma cells. There is evidence
that intravenous zoledronate in combination with anti-myeloma
therapy confers a survival advantage over oral bisphosphonates.
Osteonecrosis of the jaw may be associated with long-term use
or poor oral hygiene and gum sepsis; regular dental review,
including a check before starting therapy, is therefore important.
Prognosis
The international staging system (ISS) identifies poor prognostic
features, including a high (32-microglobulin and low albumin at
diagnosis (ISS stage 3, median survival 29 months). Those
with a normal albumin and a low p2-microglobulin (ISS stage 1)
have a median survival of 62 months. Increasingly, cytogenetic
analysis is used to identify poor-risk patients, e.g. t(4; 1 4),
del(17/17p), t(14;16), t(14;20), non-hyperdiploidy and gain(lq).
Use of autologous HSCT and advances in drug therapy with the
newer agents have increased survival. Over one-third of patients
are now surviving for 5 years, compared with only one-quarter
10 years ago. The outlook may improve further with new drugs
and combinations of treatments.
Aplastic anaemias
Primary idiopathic acquired aplastic anaemia
This is a rare disorder in Europe and North America, with 2-4
new cases per million population per annum. The disease is
much more common in certain other parts of the world, e.g.
east Asia. The basic problem is failure of the pluripotent stem
cells because of an autoimmune attack, producing hypoplasia
of the bone marrow with a pancytopenia in the blood. The
diagnosis rests on exclusion of other causes of secondary
aplastic anaemia (see below) and rare congenital causes, such
as Fanconi’s anaemia.
Clinical features and investigations
Patients present with symptoms of bone marrow failure,
usually anaemia or bleeding, and less commonly, infections.
An FBC demonstrates pancytopenia, low reticulocytes and
often macrocytosis. Bone marrow aspiration and trephine
reveal hypocellularity. The severity of aplastic anaemia is graded
according to the Camitta criteria (Box 23.60).
23.60 Camitta criteria
Severe AA (SAA)
• Marrow cellularity <25% (or 25-50% with <30% residual
haematopoietic cells), plus at least two of:
Neutrophils <0.5x109/L
Platelets < 20 x109/L
Reticulocyte count <20x109/L
Very severe AA (VSAA)
• As for SAA but neutrophils < 0.2x1 09/L
Non-severe AA (NSAA)
• AA not fulfilling the criteria for SAA or VSAA
23.59 Haematological malignancy in old age
Myeloproliferative neoplasms • 969
Management
All patients will require blood product support and aggressive
management of infection. The prognosis of severe aplastic
anaemia managed with supportive therapy only is poor and more
than 50% of patients die, usually in the first year. The curative
treatment for patients under 35 years of age with severe idiopathic
aplastic anaemia is allogeneic HSCT if there is an available sibling
donor (p. 937). Older patients (35-50) may be candidates if they
have no comorbidities (p. 937). Those with a compatible sibling
donor should proceed to transplantation as soon as possible;
they have a 75-90% chance of long-term cure. In older patients
and those without a suitable donor, immunosuppressive therapy
(1ST) with anti -thymocyte globulin (ATG) and ciclosporin is the
treatment of choice and gives 5-year survival rates of 75%.
Unrelated donor allografts are considered for suitable patients
who fail 1ST. The thrombopoietin receptor agonist eltrombopag
(p. 971) has produced trilineage responses in patients who fail
1ST and is licensed for this indication. Non-transplanted patients
may relapse or other clonal disorders of haematopoiesis may
evolve, such as paroxysmal nocturnal haemoglobinuria (p. 950),
myelodysplastic syndrome (p. 960) and AML (p. 955). Patients
with aplastic anaemia must be followed up long-term.
The clinical features and methods of diagnosis are the same
as for primary idiopathic aplastic anaemia. An underlying cause
should be treated or removed, but otherwise management is
as for the idiopathic form.
Myeloproliferative neoplasms
These make up a group of chronic conditions characterised by
clonal proliferation of marrow precursor cells. Polycythaemia
rubra vera (PRV), essential thrombocythaemia and myelofibrosis
are the non-leukaemic myeloproliferative neoplasms. Although
the majority of patients are classifiable as having one of these
disorders, some have overlapping features and there is often
progression from one to another, e.g. PRV to myelofibrosis. The
recent discovery of the molecular basis of these disorders will
lead to changes in classification and treatment; a mutation in
the gene on chromosome 9 encoding the signal transduction
molecule JAK-2 has been found in more than 90% of PRV
cases and 50% of those with essential thrombocythaemia and
myelofibrosis. Mutations in the calreticulin gene (CALR), which
produces a chaperone protein that protects proteins moving from
the endoplasmic reticulin to the cytoplasm, have been found in
a further 25% of patients with essential thrombocythaemia. Less
commonly, mutations can be detected in the thrombopoietin
receptor gene MPL.
Myelofibrosis
In myelofibrosis, the marrow is initially hypercellular, with an excess
of abnormal megakaryocytes that release growth factors, such as
platelet-derived growth factor, to the marrow microenvironment,
resulting in a reactive proliferation of fibroblasts. As the disease
progresses, the marrow becomes fibrosed.
Most patients present over the age of 50 years, with lassitude,
weight loss and night sweats. The spleen can be massively
enlarged due to extramedullary haematopoiesis (blood cell
formation outside the bone marrow), and painful splenic infarcts
may occur.
The characteristic blood picture is leucoerythroblastic anaemia,
with circulating immature red blood cells (increased reticulocytes
and nucleated red blood cells) and granulocyte precursors
(myelocytes). The red cells are shaped like teardrops (teardrop
poikilocytes), and giant platelets may be seen in the blood. The
white count varies from low to moderately high and the platelet
count may be high, normal or low. Urate levels may be high due
to increased cell breakdown, and folate deficiency is common.
The marrow is often difficult to aspirate and a trephine biopsy
shows an excess of megakaryocytes, increased reticulin and
fibrous tissue replacement. The presence of a JAK-2 mutation
supports the diagnosis.
Management and prognosis
Median survival is 4 years from diagnosis, but ranges from 1 year
to over 20 years. Treatment is directed at control of symptoms,
e.g. red cell transfusions for anaemia. Folic acid should be given
to prevent deficiency. Cytotoxic therapy with hydroxycarbamide
may help control spleen size, the white cell count or systemic
symptoms. Splenectomy may be required for a grossly enlarged
spleen or symptomatic pancytopenia secondary to splenic
pooling of cells and hypersplenism. HSCT may be considered
for younger patients. Ruxolitinib, an inhibitor of JAK-2, is now
licensed in myelofibrosis and is effective at reducing systemic
symptoms and splenomegaly.
Essential thrombocythaemia
Uncontrolled proliferation of megakaryocytes results in a raised
level of circulating platelets that are often dysfunctional. Prior
to a diagnosis of essential thrombocythaemia being made,
reactive causes of thrombocytosis must be excluded (see Box
23.15). The presence of a JAK-2, CALR or, rarely, MPL mutation
supports the diagnosis but is not universal. Patients present at
a median age of 60 years with vascular occlusion or bleeding,
or with an asymptomatic isolated raised platelet count. A small
| Secondary aplastic anaemia
Causes of this condition are listed in Box 23.61 . It is not practical
to list all the drugs that have been suspected of causing aplasia.
It is important to check the reported side-effects of all drugs taken
over the preceding months. In some instances, the cytopenia
is more selective and affects only one cell line, most often the
neutrophils. Frequently, this is an incidental finding, with no
ill health. It probably has an immune basis but this is difficult
to prove.
23.61 Causes of secondary aplastic anaemia
• Drugs:
Cytotoxic drugs
Antibiotics - chloramphenicol, sulphonamides
Antirheumatic agents - penicillamine, gold, phenylbutazone,
indometacin
Antithyroid drugs - carbimazole, propylthiouracil
Anticonvulsants
Immunosuppressants - azathioprine
• Chemicals:
Benzene, toluene solvent misuse - glue-sniffing
Insecticides - chlorinated hydrocarbons (DDT), organophosphates
and carbamates (pp. 145 and 146)
• Radiation
• Viral hepatitis
• Pregnancy
• Paroxysmal nocturnal haemoglobinuria
970 • HAEMATOLOGY AND TRANSFUSION MEDICINE
percentage (around 5%) will transform to acute leukaemia and
others to myelofibrosis.
It is likely that most patients with essential thrombocythaemia
benefit from low-dose aspirin to reduce the risk of occlusive
vascular events. Low-risk patients (age <40 years, platelet count
<1500x109/L and no bleeding or thrombosis) may not require
treatment to reduce the platelet count. For those with a platelet
count above 1500x109/L, with symptoms, or with other risk
factors for thrombosis such as diabetes or hypertension, treatment
to control platelet counts should be given. Agents include oral
hydroxycarbamide or anagrelide, an inhibitor of megakaryocyte
maturation. Intravenous radioactive phosphorus (32P) may be
useful in old age and interferon-alfa has a role in younger patients.
Polycythaemia rubra vera
PRV occurs mainly in patients over the age of 40 years and
presents either as an incidental finding of a high haemoglobin,
or with symptoms of hyperviscosity, such as lassitude, loss of
concentration, headaches, dizziness, blackouts, pruritus and
epistaxis. Some patients present with manifestations of peripheral
arterial or cerebrovascular disease. Venous thromboembolism may
also occur. Peptic ulceration is common, sometimes complicated
by bleeding. Patients are often plethoric and many have a
palpable spleen at diagnosis.
Investigation of polycythaemia is discussed on page 925.
The diagnosis of PRV now rests on the demonstration of a high
haematocrit and the presence of the JAK-2 V617F mutation
(positive in 95% of cases). In the occasional JAK-2-negative
cases, a raised red cell mass and absence of causes of a
secondary erythrocytosis must be established. The spleen may
be enlarged and neutrophil and platelet counts are frequently
raised, an abnormal karyotype may be found in the marrow,
and in vitro culture of the marrow can be used to demonstrate
autonomous growth in the absence of added growth factors.
Management and prognosis
Aspirin reduces the risk of thrombosis. Venesection gives prompt
relief of hyperviscosity symptoms. Between 400 and 500 mL
of blood (less if the patient is elderly) are removed and the
venesection is repeated every 5-7 days until the haematocrit is
reduced to below 45%. Less frequent but regular venesection
will maintain this level until the haemoglobin remains reduced
because of iron deficiency.
Suppression of marrow proliferation with hydroxycarbamide
or interferon-alfa may reduce the risk of vascular occlusion,
control spleen size and reduce transformation to myelofibrosis.
Intravenous 32P, which is reserved for older patients as it increases
the risk of transformation to acute leukaemia by 6-10-fold, is
rarely used now in Europe and North America.
Median survival after diagnosis in treated patients exceeds
1 0 years. Some patients survive more than 20 years; however,
cerebrovascular or coronary events occur in up to 60% of patients.
The disease may convert to another myeloproliferative disorder,
with about 1 5% developing acute leukaemia or myelofibrosis.
Bleeding disorders
Disorders of primary haemostasis
The initial formation of the platelet plug (see Fig. 23. 6A, p. 918;
also known as ‘primary haemostasis’) may fail in thrombocytopenia
(p. 929), von Willebrand disease (p. 974), and also in platelet
function disorders and diseases affecting the vessel wall.
Vessel wall abnormalities
Vessel wall abnormalities may be:
• congenital, such as hereditary haemorrhagic telangiectasia
• acquired, as in a vasculitis (p. 1040) or scurvy.
Hereditary haemorrhagic teiangiectasia
Hereditary haemorrhagic telangiectasia (HHT) is a dominantly
inherited condition caused by mutations in the genes encoding
endoglin and activin receptor-like kinase, which are endothelial
cell receptors for transforming growth factor-beta (TGF-p), a
potent angiogenic cytokine. Telangiectasia and small aneurysms
are found on the fingertips, face and tongue, and in the nasal
passages, lung and gastrointestinal tract. A significant proportion
of these patients develop larger pulmonary arteriovenous
malformations (PAVMs) that cause arterial hypoxaemia due to
a right-to-left shunt. These predispose to paradoxical embolism,
resulting in stroke or cerebral abscess. All patients with HHT
should be screened for PAVMs; if these are found, ablation by
percutaneous embolisation should be considered.
Patients present either with recurrent bleeds, particularly
epistaxis, or with iron deficiency due to occult gastrointestinal
bleeding. Treatment can be difficult because of the multiple
bleeding points but regular iron therapy often allows the marrow
to compensate for blood loss. Local cautery or laser therapy
may prevent single lesions from bleeding. A variety of medical
therapies have been tried but none has been found to be
universally effective.
Ehlers-Danlos disease
Vascular Ehlers-Danlos syndrome (type 4) is a rare autosomal
dominant disorder (1/100 000) caused by a defect in type
3 collagen that results in fragile blood vessels and organ
membranes, leading to bleeding and organ rupture. Classical
joint hypermobility (p. 1059) is often limited in this form of the
disease but skin changes and facial appearance are typical.
The diagnosis should be considered when there is a history of
bleeding with normal laboratory tests.
Scurvy
Vitamin C deficiency affects the normal synthesis of collagen
and results in a bleeding disorder characterised by perifollicular
and petechial haemorrhage, bruising and subperiosteal bleeding.
The key to diagnosis is the dietary history (p. 715).
| Platelet function disorders
Bleeding may result from thrombocytopenia (see Box 23.14,
p. 929) or from congenital or acquired abnormalities of platelet
function. The most common acquired disorders are iatrogenic,
resulting from the use of aspirin, clopidogrel, ticagrelor,
dipyridamole and the glycoprotein llb/llla inhibitors to prevent
arterial thrombosis (see Box 23.26, p. 938). Inherited platelet
function abnormalities are relatively rare. Congenital abnormalities
may be due to deficiency of the membrane glycoproteins,
e.g. Glanzmann’s thrombasthenia (llb/llla) or Bernard-Soulier
syndrome (lb), or due to the presence of defective platelet
granules, e.g. a deficiency of dense (delta) granules (see Fig.
23.7, p. 920) giving rise to storage pool disorders. The congenital
macrothrombocytopathies that are due to mutations in the myosin
heavy chain gene MYH-9 are characterised by large platelets,
Bleeding disorders • 971
inclusion bodies in the neutrophils (Dohle bodies) and a variety
of other features, including sensorineural deafness and renal
abnormalities. Other familial thrombocytopathies are important,
as they can be associated with somatic features, and some are
associated with a propensity for development of bone marrow
failure or dysplasia (e.g. RUNX- 1 -associated thrombocytopenia).
Apart from Glanzmann’s thrombasthenia, these conditions are
mild disorders, with bleeding typically occurring after trauma or
surgery, but rarely spontaneous. Glanzmann’s thrombasthenia
is an autosomal recessive condition associated with a variable
but often severe bleeding disorder. These conditions are usually
managed by local mechanical measures, but antifibrinolytics, such
as tranexamic acid, may be useful and, in severe bleeding, platelet
transfusion may be required. Recombinant Vila is licensed for the
treatment of resistant bleeding in Glanzmann’s thrombasthenia.
| Thrombocytopenia
Thrombocytopenia occurs in many disease processes, as listed
in Box 23.14 (p. 929), many of which are discussed elsewhere
in this chapter.
Idiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura (ITP) is immune-mediated
with involvement of autoantibodies, most often directed against
the platelet membrane glycoprotein llb/llla, which sensitise the
platelet, resulting in premature removal from the circulation by
cells of the reticulo-endothelial system. It is not a single disorder;
some cases occur in isolation while others are associated with
underlying immune dysregulation in conditions such as connective
tissue diseases, HIV infection, B-cell malignancies, pregnancy and
certain drug therapies. The clinical presentation and pathogenesis
are similar, however, whatever the cause of ITP.
Clinical features and investigations
The presentation depends on the degree of thrombocytopenia.
Spontaneous bleeding typically occurs only when the platelet
count is below 20x1 09/L. At higher counts, the patient may
complain of easy bruising or sometimes epistaxis or menorrhagia.
Many cases with counts of more than 50x109/L are discovered
by chance.
In adults, ITP more commonly affects females and may have
an insidious onset. Unlike ITP in children, it is unusual for there to
be a history of a preceding viral infection. Symptoms or signs of
a connective tissue disease may be apparent at presentation or
emerge several years later. Patients aged over 65 years should
be considered for a bone marrow examination to look for an
accompanying B-cell malignancy, and appropriate autoantibody
testing performed if a diagnosis of connective tissue disease
is likely. HIV testing should be considered because a positive
result will have major implications for appropriate therapy. The
peripheral blood film is normal, apart from a greatly reduced
platelet number, while the bone marrow reveals an obvious
increase in megakaryocytes.
Management
Many patients with stable compensated ITP and a platelet
count of more than 30x109/L do not require treatment to raise
the platelet count, except at times of increased bleeding risk,
such as surgery and biopsy. First-line therapy for patients with
spontaneous bleeding is with high doses of glucocorticoids,
either prednisolone (1 mg/kg daily) or dexamethasone (40 mg
daily for 4 days), to suppress antibody production and inhibit
phagocytosis of sensitised platelets by reticulo-endothelial cells.
Administration of intravenous immunoglobulin can raise the platelet
count by blocking antibody receptors on reticulo-endothelial cells,
and is combined with glucocorticoid therapy if there is severe
haemostatic failure, especially with evidence of significant mucosal
bleeding or a slow response to glucocorticoids alone. Persistent
or potentially life-threatening bleeding should be treated with
platelet transfusion in addition to the other therapies.
The condition may become chronic, with remissions and
relapses. Relapses should be treated by re-introducing
glucocorticoids. If a patient has two relapses or primary
refractory disease, second-line therapies are considered. The
options for second-line therapy include the thrombopoietin
receptor agonists (TPO-RA) eltrombopag and romiplostim,
splenectomy and immunosuppression. Where splenectomy
is considered, the precautions shown in Box 23.40 need to
be in place. Splenectomy produces complete remission in
about 70% of patients and improvement in a further 20-25% in
favourable cases. The TPO-RAs induce response in around 75%
of cases, usually within 10-14 days. Low-dose glucocorticoid
therapy and immunosuppressants such as rituximab, ciclosporin,
mycophenolate and tacrolimus may also produce remissions.
The order in which therapies should be used is not entirely clear,
although the TPO-RAs are licensed for this indication while the
immunosuppressive agents are not.
Coagulation disorders
Normal coagulation is explained in Figure 23.6 (p. 918).
Coagulation factor deficiency may be congenital or acquired, and
may affect one or several of the coagulation factors (Box 23.62).
Inherited disorders are almost uniformly related to decreased
synthesis, as a result of mutation in the gene encoding a key
protein in coagulation. Von Willebrand disease is the most
common inherited bleeding disorder. Haemophilia A and B are
the most common single coagulation factor deficiencies but
inherited deficiencies of all the other coagulation factors are
seen. Acquired disorders may be due to under-production (e.g.
in liver failure), increased consumption (e.g. in DIC) or inhibition
of function of coagulation factors (such as heparin therapy or
immune inhibitors of coagulation, e.g. acquired haemophilia A).
Haemophilia A
Factor VIII deficiency resulting in haemophilia A affects 1/10000
individuals. It is the most common congenital coagulation factor
deficiency. Factor VIII is primarily synthesised by the liver and
endothelial cells and has a half-life of about 12 hours. It is
protected from proteolysis in the circulation by binding to von
Willebrand factor (vWF).
Genetics
The factor VIII gene is located on the X chromosome. Haemophilia
is associated with a range of mutations in the factor VIII gene;
these include major inversions, large deletions and missense,
nonsense and splice site abnormalities. As the factor VIII gene
is on the X chromosome, haemophilia A is a sex-linked disorder
(p. 48). Thus all daughters of a patient with haemophilia are
obligate carriers and they, in turn, have a 1 in 4 chance of each
pregnancy resulting in the birth of an affected male baby, a
normal male baby, a carrier female or a normal female. Antenatal
diagnosis by chorionic villous sampling is possible in families with a
known mutation.
972 • HAEMATOLOGY AND TRANSFUSION MEDICINE
i
23.63 Severity of haemophilia (ISTH criteria)
Severity
Factor VIII or IX level
Clinical presentation
Severe
<0.01 U/mL
Spontaneous haemarthroses
and muscle haematomas
Moderate
0.01-0.05 U/mL
Mild trauma or surgery
causes bleeding
Mild
> 0.05-0.4 U/mL
Major injury or surgery results
in excess bleeding
(ISTH = International Society on Thrombosis and Haemostasis)
Haemophilia ‘breeds true’ within a family; all members have
the same factor VIII gene mutation and a similarly severe or mild
phenotype. Female carriers of haemophilia may have reduced
factor VIII levels because of random inactivation of their normal
X chromosome in the developing fetus (p. 49). This can result
in a mild bleeding disorder; thus all known or suspected carriers
of haemophilia A should have their factor VIII level measured.
Clinical features
The extent and patterns of bleeding are closely related to residual
factor VIII levels (Box 23.63). Patients with severe haemophilia
(factor VIII levels <0.01 U/mL) present with spontaneous bleeding
into skin, muscle and joints. Retroperitoneal and intracranial
bleeding is also a feature. Babies with severe haemophilia have
an increased risk of intracranial haemorrhage and, although there
is insufficient evidence to recommend routine caesarean section
for these births, it is appropriate to avoid head trauma and to
perform imaging of the newborn within the first 24 hours of life.
Individuals with moderate and mild haemophilia (factor VIII levels
0.01-0.4 U/mL) present with the same pattern of bleeding but
usually after trauma or surgery, when bleeding is disproportionate
to the severity of the insult.
The major morbidity of recurrent bleeding in severe haemophilia
is musculoskeletal. Bleeding is typically into large joints, especially
knees, elbows, ankles and hips. Muscle haematomas are also
characteristic, most commonly in the calf and psoas muscles.
If early treatment is not given to arrest bleeding, a hot, swollen
and very painful joint or muscle haematoma develops. Recurrent
bleeding into joints leads to synovial hypertrophy, destruction of
the cartilage and chronic haemophilic arthropathy (Fig. 23.32).
Complications of muscle haematomas depend on their location.
A large psoas bleed may extend to compress the femoral nerve;
calf haematomas may increase pressure within the inflexible
fascial sheath, causing a compartment syndrome with ischaemia,
necrosis, fibrosis, and subsequent contraction and shortening
of the Achilles tendon.
Management
The key to the management of severe haemophilia A (and B;
p. 974) in more affluent countries is prophylactic coagulation factor
replacement. The aim of this treatment is to maintain trough levels
of factor VIII (or IX in the case of haemophilia B) above 0.02 U/mL.
Doing this substantially reduces the number of bleeding episodes
for men with severe haemophilia and so reduces the rate of
deterioration of joints, which is the major long-term morbidity.
Prophylaxis can be provided in many different ways: daily,
on alternate days, or on information from pharmacokinetic
studies that inform on the best way of scheduling prophylaxis.
Practice in haemophilia A and B is in the process of changing
somewhat due to the introduction of a variety of recombinant
factor concentrates that have been manipulated to alter their
half-life. In addition to standard half-life recombinant factor VIII,
there are new products produced by Fc fusion and pegylation/
glycopegylation that extend the half-life of factor VIII to the degree
that it can be used to alter dosing schedules for prophylaxis.
The alternative approach, which still needs to be used in less
affluent countries, is to treat on demand. In severe haemophilia
A, bleeding episodes should be treated by raising the factor VIII
level, usually by intravenous infusion of factor VIII concentrate.
Factor VIII concentrates are freeze-dried and stable at 4°C
and can therefore be stored in domestic refrigerators, allowing
patients to treat themselves at home at the earliest indication
of bleeding. Factor VIII concentrate prepared from blood donor
plasma is now screened for HBV, HCV and HIV, and undergoes
two separate virus inactivation processes during manufacture;
these preparations have a good safety record. However, factor
VIII concentrates prepared by recombinant technology are now
widely available and, although more expensive, are perceived as
being safer than those derived from human plasma in relation
to infection risk. In addition to raising factor VIII concentrations,
resting of the bleeding site with either bed rest or a splint reduces
continuing haemorrhage. Once bleeding has settled, the patient
should be mobilised and physiotherapy used to restore strength
to the surrounding muscles. All non-immune potential recipients
23.62 Causes of coagulopathy
Congenital
X-linked
• Haemophilia A and B
Autosomal
• Von Willebrand disease
• Factor II, V, VII, X, XI and XIII deficiencies
• Combined II, VII, IX and X deficiency
• Combined V and VIII deficiency
• Hypofibrinogenaemia
• Dysfibrinogenaemia
Acquired
Under-production
• Liver failure
• Vitamin K deficiency
Increased consumption
• Coagulation activation:
Disseminated intravascular coagulation (DIC)
• Immune-mediated:
Acquired haemophilia and von Willebrand disease
• Others:
Acquired factor X deficiency (in amyloid)
Acquired von Willebrand disease in Wilms’ tumour
Acquired factor VII deficiency in sepsis
Drug-induced
• Inhibition of function:
Heparins
Argatroban
Bivalirudin
Fondaparinux
Rivaroxaban
Apixaban
Dabigatran
Edoxaban
• Inhibition of post-translational modification:
Warfarin
Bleeding disorders • 973
Haemophilia B in the descendants of Queen Victoria
Albert [
| Victoria
■nr
| Affected with Numerical value = age at death • Carrier for
haemophilia (male) haemophilia (female)
A X-linked inheritance of haemophilia B
A Massive retroperitoneal haemorrhage
A X-ray of advanced
haemophilic arthropathy
A Massive bruising
Hepatoma in cirrhotic liver
secondary to HCV infection
contracted from coagulation
factor concentrate
A Left thigh muscle haematoma
in severe haemophilia
A Chronic haemophilic
arthropathy with joint swelling
and muscle wasting on left
Fig. 23.32 Clinical manifestations of haemophilia. On the knee X-ray, repeated bleeds have led to broadening of the femoral epicondyles, and there is
no cartilage present, as evidenced by the close proximity of the femur and tibia (A); sclerosis (B), osteophyte (C) and bony cysts (D) are present. (HCV =
hepatitis C virus) Inset (Massive bruising) From Hoff brand I/A Color atlas of clinical hematology, 3rd edn. Philadelphia: Mosby, Elsevier Inc.; 2000.
of pooled blood products should be offered hepatitis A and B
immunisation.
The vasopressin receptor agonist desmopressin (p. 688)
raises the vWF and factor VIII levels 3-4 -fold, which is useful in
arresting bleeding in patients with mild or moderate haemophilia
A. The dose required for this purpose is higher than that used in
diabetes insipidus, usually 0.3 pg/kg, and is given intravenously
or subcutaneously. Alternatively, the same effect can be achieved
by intranasal administration of 300 pg. Following repeated
administration of desmopressin, patients need to be monitored
for evidence of water retention, which can result in significant
hyponatraemia. Desmopressin is contraindicated in patients
with a history of severe arterial disease because of a propensity
to provoke a thrombotic event, and in young children where
hyponatraemia can result in fits.
Complications of coagulation factor therapy
Before 1986, coagulation factor concentrates from human
plasma were not virally inactivated and many patients became
infected with HIV and HBV/HCV. In patients with haemophilia
treated with pooled concentrates that were not virally inactivated
before 1988, infection with HCV is almost universal, 80-90%
have evidence of HBV exposure, and 60% became HIV-positive.
Management is described in Chapters 22 and 12.
Concern that the infectious agent that causes vCJD (p. 1 1 27)
might be transmissible by blood and blood products has been
confirmed in recipients of red cell transfusion (p. 931), and in
one recipient of factor VIII. Pooled plasma products, including
factor VIII concentrate, are now manufactured from plasma
collected in countries with a low incidence of bovine spongiform
encephalopathy.
Another serious complication of factor VIII infusion is the
development of anti-factor VIII antibodies, which arise in about
20% of those with severe haemophilia. Such antibodies rapidly
neutralise therapeutic infusions, making treatment relatively
ineffective. Infusions of activated clotting factors, e.g. Vila or
factor VIII inhibitor bypass activity (FEIBA), may stop bleeding.
Haemophilia B (Christmas disease)
Aberrations of the factor IX gene, which is also present on
the X chromosome, result in a reduction of the plasma factor
IX level, giving rise to haemophilia B. This disorder is clinically
indistinguishable from haemophilia A but is less common. The
974 • HAEMATOLOGY AND TRANSFUSION MEDICINE
frequency of bleeding episodes is related to the severity of the
deficiency of the plasma factor IX level. Treatment is with a factor
IX concentrate, used in much the same way as factor VIII for
haemophilia A. The new extended half-life recombinant factor
IX products made by Fc fusion, albumin fusion and pegylation
offer the possibility of prophylaxis on a once-weekly or even
two- weekly schedule. Although factor IX concentrates shared the
problems of virus transmission seen with factor VIII, they do not
commonly induce inhibitor antibodies (<1% patients); when this
does occur, however, it may be heralded by the development
of a severe allergic-type reaction.
|Von Willebrand disease
Von Willebrand disease is a common but usually mild bleeding
disorder caused by a quantitative (types 1 and 3) or qualitative
(type 2) deficiency of von Willebrand factor (vWF). This protein
is synthesised by endothelial cells and megakaryocytes, and is
involved in both platelet function and coagulation. It normally
forms a multimeric structure that is essential for its interaction
with subendothelial collagen and platelets (see Fig. 23.7,
p. 920). vWF acts as a carrier protein for factor VIII, to which it
is non-covalently bound; deficiency of vWF lowers the plasma
factor VIII level. vWF also forms bridges between platelets and
subendothelial components (e.g. collagen; see Fig. 23. 6B, p. 918),
allowing platelets to adhere to damaged vessel walls; deficiency
of vWF therefore leads to impaired platelet plug formation. Blood
group antigens (A and B) are expressed on vWF, reducing its
susceptibility to proteolysis; as a result, people with blood group
O have lower circulating vWF levels than individuals with non-0
groups. This needs to be borne in mind when making a diagnosis
of von Willebrand disease.
Most patients with von Willebrand disease have a type 1
disorder, characterised by a quantitative decrease in a normal
functional protein. Patients with type 2 disorders inherit vWF
molecules that are functionally abnormal. The type of abnormality
depends on the site of the mutation in the vWD gene and how it
affects binding to platelets, collagen and factor VIII. Patients with
type 2A disease have abnormalities in vWF-dependent platelet
adhesion; those with mutations in the platelet glycoprotein lb
binding site, resulting in increased affinity for glycoprotein 1 b, have
type 2B disease; those with mutations in the factor VIII binding
site have type 2N disease; and those with other abnormalities
in platelet binding but with normal vWF multimeric structure
have type 2M disease. The patterns of laboratory abnormality
accompanying these types are described in Box 23.64. The
gene for vWF is located on chromosome 12 and the disease is
usually autosomal dominantly inherited, except in type 2N and
type 3, where inheritance is autosomal recessive.
Clinical features
Patients present with haemorrhagic manifestations similar to
those in individuals with reduced platelet function. Superficial
bruising, epistaxis, menorrhagia and gastrointestinal haemorrhage
are common. Bleeding episodes are usually much less frequent
than in severe haemophilia, and excessive haemorrhage may
be observed only after trauma or surgery. Within a single family,
the disease has variable penetrance, so that some members
may have quite severe and frequent bleeds, whereas others are
relatively asymptomatic.
Investigations
The disorder is characterised by reduced activity of vWF and
factor VIII. The disease can be classified using a combination of
i
23.64 Classification of von Willebrand disease
Type
Defect
Inheritance
Investigations/patterns
1
Partial
quantitative
AD
Parallel decrease in vWF:Ag,
RiCoF and Vllhc
2A
Qualitative
AD
Absent HWM of vWF
Ratio of vWF activity to antigen
<0.7
2B
Qualitative
AD
Reduced HWM of vWF
Enhanced platelet agglutination
(RIPA)
2M
Qualitative
AD
Ratio of vWF activity to antigen
0.7
Normal multimers of vWF
Abnormal vWF/platelet
interactions
2N
Qualitative
AR
Defective binding of vWF to VIII
Low VIII
3
Severe
quantitative
AR or CH
Very low vWF and Vllhc activity
Absent multimers
(AD = autosomal dominant; AR = autosomal recessive; CH = compound
heterozygote; HWM = high-weight multimers of vWF; RiCoF = ristocetin
co-factor; RIPA = ristocetin-induced platelet agglutination; Vlll:c = coagulation
factor VIII activity in functional assay; vWF = von Willebrand factor; vWF:Ag =
vWF antigen measured by ELISA)
assays that include functional and antigenic measures of vWF,
multimeric analysis of the protein, and specific tests of function
to determine binding to platelet glycoprotein lb (RIPA) and factor
VIII (Box 23.64). In addition, analysis for mutations in the vWF
gene is informative in most cases.
Management
Many episodes of mild haemorrhage can be successfully treated
by local means or with desmopressin, which raises the vWF
level, resulting in a secondary increase in factor VIII. Tranexamic
acid may be useful in mucosal bleeding. For more serious or
persistent bleeds, haemostasis can be achieved with selected
factor VIII concentrates, which contain considerable quantities
of vWF in addition to factor VIII. Young children and patients
with severe arterial disease should not receive desmopressin,
and patients with type 2B disease develop thrombocytopenia
that may be troublesome following desmopressin. Bleeding in
type 3 patients responds only to factor VIII/vWF concentrate.
|Rare inherited bleeding disorders
Severe deficiencies of factor VII, X and XIII occur as autosomal
recessive disorders. They are rare but are associated with severe
bleeding. Typical features include haemorrhage from the umbilical
stump and intracranial haemorrhage. Factor XIII deficiency in
women is typically associated with recurrent fetal loss.
Factor XI deficiency may occur in heterozygous or homozygous
individuals. Bleeding is very variable and is not accurately predicted
by coagulation factor levels. In general, severe bleeding is confined
to patients with levels below 15% of normal.
Acquired bleeding disorders
DIC is an important cause of bleeding that begins with exaggerated
and inappropriate intravascular coagulation. It is discussed under
thrombotic disease on page 978.
Thrombotic disorders • 975
Liver disease
Although, traditionally, severe parenchymal liver disease
(Ch. 22) has been described as a state associated with an excess
of bleeding, it is now clear that these patients also have an
increased risk of venous thrombosis. Although there is reduced
hepatic synthesis of procoagulant factors, this is balanced to a
degree by the reduced production of natural anticoagulant proteins
and reduced fibrinolytic activity in patients with advanced liver
disease. In severe parenchymal liver disease, bleeding may arise
from many different causes. Pathological sources of potential
major bleeding, such as oesophageal varices or peptic ulcer, are
common. There is reduced hepatic synthesis, for example, of
factors V, VII, VIII, IX, X, XI, prothrombin and fibrinogen. Clearance
of plasminogen activator is reduced. Thrombocytopenia may
occur secondary to hypersplenism in portal hypertension. In
cholestatic jaundice, there is reduced vitamin K absorption, leading
to deficiency of factors II, VII, IX and X, but also of proteins C
and S. Treatment with plasma products or platelet transfusion
should be reserved for acute bleeds or to cover interventional
procedures such as liver biopsy. Vitamin K deficiency can be
readily corrected with parenteral administration of vitamin K.
Renal failure
The severity of the haemorrhagic state in renal failure is proportional
to the plasma urea concentration. Bleeding manifestations are
those of platelet dysfunction, with gastrointestinal haemorrhage
being particularly common. The causes are multifactorial and
include anaemia, mild thrombocytopenia and the accumulation
of low-molecular-weight waste products, normally excreted by
the kidney, that inhibit platelet function. Treatment is by dialysis
to reduce the urea concentration. Rarely, in severe or persistent
bleeding, platelet concentrate infusions and red cell transfusions
are indicated. Increasing the concentration of vWF, either by
cryoprecipitate or by desmopressin, may promote haemostasis.
Thrombotic disorders
Venous thromboembolic disease
(venous thromboembolism)
While the most common presentations of venous thromboembolism
(VTE) are deep vein thrombosis (DVT) of the leg (p. 1 86) and/or
pulmonary embolism (PE; see also p. 619), similar management
principles apply to rarer manifestations such as jugular vein
thrombosis, upper limb DVT, cerebral sinus thrombosis
(p. 1128) and intra-abdominal venous thrombosis (e.g. Budd-
Chiari syndrome; p. 898).
VTE has an annual incidence of approximately 1 : 1000
in Western populations. The relative incidence of DVT: PE is
approximately 2:1. Mortality 30 days after DVT is approximately
1 0%, compared to 1 5% for PE. All forms of VTE are increasingly
common with age and many of the deaths are related to coexisting
medical conditions, such as active cancer or inflammatory
disease, which predispose the patient to thrombosis in the
first place. Risk factors for VTE are often present (Box 23.65)
and it is appropriate to seek evidence of these risk factors in
determining the long-term management strategy. Figure 23.33
illustrates some of the causes and consequences of VTE. The
diagnosis of DVT and PE are discussed on pages 187 and
619, respectively.
i
Patient factors
• Increasing age
• Obesity
• Varicose veins
• Previous deep vein thrombosis
• Family history, especially of unprovoked venous thromboembolism
when young
• Transient additional risk factors:
Pregnancy/puerperium
Oestrogen-containing oral contraceptives and hormone
replacement therapy
Immobility, e.g. long-distance travel (>4 hrs)
Intravenous drug use involving the femoral vein
Surgery (see below)
Medical illnesses (see below)
Surgical conditions
• Major surgery, especially if >30 mins’ duration
• Abdominal or pelvic surgery, especially for cancer
• Major lower limb orthopaedic surgery, e.g. joint replacement and
hip fracture surgery
Medical conditions
• Myocardial infarction/heart failure
• Inflammatory bowel disease
• Malignancy (anti-cancer chemotherapy increases the risk of venous
thromboembolism compared with cancer alone)
• Nephrotic syndrome
• Chronic obstructive pulmonary disease
• Pneumonia
• Neurological conditions associated with immobility, e.g. stroke,
paraplegia, Guillain— Barre syndrome
• Any high-dependency admission
Haematological disorders
• Polycythaemia rubra vera
• Essential thrombocythaemia
• Deficiency of natural anticoagulants: antithrombin, protein C, protein S
• Paroxysmal nocturnal haemoglobinuria
• Gain-of-function prothrombotic mutations: factor V Leiden,
prothrombin gene G20210A
• Myelofibrosis
Antiphospholipid syndrome
Management of VTE
The mainstay of treatment for all forms of VTE is anticoagulation.
This can be achieved in several ways. One option is to use LMWH
followed by a coumarin anticoagulant, such as warfarin. Treatment
of acute VTE with LMWH should continue for a minimum of
5 days. Patients treated with warfarin should achieve a target INR
of 2.5 (range 2-3; pp. 922 and 938) with LMWH continuing until
the INR is above 2. Alternatively, patients may be treated with
a DOAC. Rivaroxaban and apixaban may be used immediately
from diagnosis without the need for LMWH, while the licences for
dabigatran and edoxaban include initial treatment with LMWH for
a minimum of 5 days before commencing the DOAC. In patients
with active cancer and VTE, there is evidence that maintenance
anticoagulation with LMWH is associated with a lower recurrence
rate than warfarin. Patients who have had VTE and have a strong
contraindication to anticoagulation and those who continue to
have new pulmonary emboli despite therapeutic anticoagulation
should have an inferior vena cava (IVC) filter inserted to prevent
life-threatening PE (p. 619).
The optimal initial period of anticoagulation is between
6 weeks and 6 months. Patients with a provoked VTE in the
23.65 Factors predisposing to venous thrombosis
976 • HAEMATOLOGY AND TRANSFUSION MEDICINE
Pathological
Lateral sinus
thrombosis is an
uncommon form of
venous thrombosis
at an unusual site
Postmortem
fatal massive
pulmonary
embolism
Absent IVC
predisposes
to lower
limb DVT
Iatrogenic
Fatal intracerebral
haemorrhage is the
most common cause
of haemorrhagic death
in patients on warfarin
Post-thrombotic syndrome
complicates 30% of
cases of lower limb DVT.
Severe cases
are complicated
by ulceration
Soleus muscle sinus
Anterior tibial vein
Fig. 23.33 Causes and consequences of venous thromboembolic disease and its treatment. (DVT = deep vein thrombosis; IVC = inferior vena
cava)
presence of a temporary risk factor, which is then removed, can
usually be treated for short periods (e.g. 3 months), and indeed
anticoagulation for more than 6 months does not alter the rate
of recurrence following discontinuation of therapy. If there are
ongoing risk factors that cannot be alleviated, such as active
cancer, long-term anticoagulation is usually recommended,
provided that the risk of bleeding is not deemed excessive.
For patients with unprovoked VTE, the optimum duration of
anticoagulation can be difficult to establish. Recurrence of VTE
is about 2-3% per annum in patients who have a temporary
medical risk factor at presentation and about 7-1 0% per annum
in those with apparently unprovoked VTE. This plateaus at around
30-40% recurrence at 5 years. As such, many patients who have
had unprovoked episodes of VTE will benefit from long-term
anticoagulation. Several factors predict risk of recurrence following
an episode of unprovoked VTE. The strongest predictors of
recurrence are male sex and a positive D-dimer assay measured
1 month after stopping anticoagulant therapy. These factors are
incorporated into scoring systems to predict recurrence such as
the DASH score and the Vienna prediction model.
The management of DVT of the leg should also include
elevation and analgesia; in limb-threatening DVT, thrombolysis
may also be considered. Thrombolysis for PE is discussed on
page 621. Post-thrombotic syndrome is due to damage of
venous valves by the thrombus. It occurs in around 30% of
patients who sustain a proximal lower limb DVT and results in
persistent leg swelling, heaviness and discoloration. The most
severe complication of this syndrome is ulceration around the
medial malleolus (Fig. 23.33). Recent trial evidence suggests that
use of elastic compression stockings following a DVT does not
reduce the incidence of post-thrombotic syndrome.
Prophylaxis of VTE
All patients admitted to hospital should be assessed for their
risk of developing VTE and appropriate prophylactic measures
should be put in place. Both medical and surgical patients are at
increased risk. A summary of the risk categories is given in Box
23.66. Early mobilisation of patients is important to prevent DVT,
and those at medium or high risk require additional antithrombotic
measures; these may be pharmacological or mechanical. There
Thrombotic disorders • 977
i
Indications
Patients in the following categories should be considered for specific
antithrombotic prophylaxis:
Moderate risk of DVT
• Major surgery:
In patients > 40 years or with other risk factor for VTE
• Major medical illness, e.g.:
Heart failure
Myocardial infarction with complications
Sepsis
Inflammatory conditions, including inflammatory bowel disease
Active malignancy
Nephrotic syndrome
Stroke and other conditions leading to lower limb paralysis
High risk of DVT
• Major abdominal or pelvic surgery for malignancy or with history of
DVT or known thrombophilia (see Box 23.4, p. 923)
• Major hip or knee surgery
• Neurosurgery
Methods of VTE prophylaxis
Mechanical
• Intermittent pneumatic
compression
• Mechanical foot pumps
Pharmacological
• LMWHs
• Unfractionated heparin
• Fondaparinux
• Dabigatran
(DVT = deep vein thrombosis; VTE = venous thromboembolism)
• Graduated compression
stockings
• Rivaroxaban
• Apixaban
• Warfarin
23.66 Antithrombotic prophylaxis
is increasing evidence in high-risk groups, such as patients who
have had major lower limb orthopaedic surgery and abdominal
or pelvic cancer surgery, for protracted thromboprophylaxis for
as long as 30 days or so after the procedure. Particular care
should be taken with the use of pharmacological prophylaxis
in patients with a high risk of bleeding or with specific risks of
haemorrhage related to the site of surgery or the use of spinal
or epidural anaesthesia.
Inherited and acquired thrombophilia and
prothrombotic states
Several inherited conditions predispose to VTE (see Box 23.65),
and have several points in common that are worth noting:
• None of them is strongly associated with arterial
thrombosis.
• All are associated with a slightly increased incidence of
adverse outcome of pregnancy, including recurrent early
fetal loss, but there are no data to indicate that any
specific intervention changes that outcome.
• Apart from in antithrombin deficiency and homozygous
factor V Leiden, most carriers of these genes will never
have an episode of VTE; if they do, it will be associated
with the presence of an additional temporary risk factor.
• There is little evidence that detection of these
abnormalities predicts recurrence of VTE.
• None of these conditions per se requires treatment with
anticoagulants. Patients with thrombosis should receive
anticoagulation, as discussed on page 975. Patients who
are deemed to be at high risk of thrombosis, e.g. those
with antithrombin deficiency in pregnancy, should receive
treatment or prophylactic doses of heparin to cover the
period of risk only.
Antithrombin deficiency
Antithrombin (AT) is a serine protease inhibitor (SERPIN) that
inactivates the activated coagulation factors lla, IXa, Xa and
Xla. Heparins and fondaparinux achieve their therapeutic effect
by potentiating the activity of AT. Familial deficiency of AT is
inherited in an autosomal dominant manner; homozygosity
for mutant alleles is not compatible with life. Around 70% of
affected individuals will have an episode of VTE before the age
of 60 years and the relative risk for thrombosis compared with
the background population is 10-20. Pregnancy is a high-risk
period for VTE and this requires fairly aggressive management
with doses of LMWH that are greater than the usual prophylactic
doses (>100 U/kg/day). AT concentrate (either plasma-derived
or recombinant) is available; this is required for cardiopulmonary
bypass and may be used as an adjunct to heparin in surgical
prophylaxis and in the peripartum period.
Protein C and S deficiencies
Protein C and its co-factor protein S are vitamin K-dependent
natural anticoagulants involved in switching off coagulation factor
activation (factors Va and Villa) and thrombin generation (see
Fig. 23. 6F, p. 919). Inherited deficiency of either protein C or
S results in a prothrombotic state with a fivefold relative risk of
VTE compared with the background population.
Factor V Leiden
Factor V Leiden results from a gain-of-function, single-base-pair
mutation which prevents the cleavage and hence inactivation
of activated factor V. This results in a relative risk of venous
thrombosis of 5 in heterozygotes and 50 or more in rare
homozygotes. The mutation is found in about 5% of Northern
Europeans, 2% of Hispanics, 1 .2% of African-Americans, 0.5%
of Asian-Americans and 1 .25% of Native Americans, and is rare
in Chinese and Malay people.
Prothrombin G20210A
This gain-of-function mutation in the non-coding 3' end of the
prothrombin gene is associated with an increased plasma level of
prothrombin. It is present in about 2% of Northern Europeans but
is rare in native populations of Korea, China, India and Africa. In
the heterozygous state, it is associated with a 2-3-fold increase
in risk of VTE compared with the background population.
| Antiphospholipid syndrome
Antiphospholipid syndrome (APS) is a clinicopathological entity in
which a constellation of clinical conditions, alone or in combination,
is found in association with a persistently positive test for an
antiphospholipid antibody. The antiphospholipid antibodies are
heterogeneous and typically are directed against proteins that
bind to phospholipids (Box 23.67). Although causal roles for these
antibodies have been proposed, the mechanisms underlying the
clinical features of APS are not clear. In clinical practice, two
types of test are used, which detect:
• antibodies that bind to negatively charged phospholipid on
an ELISA plate (called an anticardiolipin antibody test).
These assays usually contain p2-glycoprotein 1 (p2-GP1 )
978 • HAEMATOLOGY AND TRANSFUSION MEDICINE
23.67 Antiphospholipid syndrome (APS)
Clinical manifestations
• Adverse pregnancy outcome
Recurrent first trimester abortion (>3)
Unexplained death of morphologically normal fetus after
1 0 weeks’ gestation
Severe early pre-eclampsia
• Venous thromboembolism
• Arterial thromboembolism
• Livedo reticularis, catastrophic APS, transverse myelitis, skin
necrosis, chorea
Conditions associated with secondary APS
• Systemic lupus erythematosus
• Behget’s disease
• Rheumatoid arthritis
• Temporal arteritis
• Systemic sclerosis
• Sjogren’s syndrome
Targets for antiphospholipid antibodies
• (^-glycoprotein 1
• Prothrombin (may result in
• Protein C
haemorrhagic presentation)
• Annexin V
• those that interfere with phospholipid-dependent
coagulation tests like the APTT or the dilute Russell viper
venom time (DRWT; called a lupus anticoagulant test).
The term antiphospholipid antibody encompasses both a
lupus anticoagulant and an anticardiolipin antibody/ anti-p2-GP1 ;
individuals may be positive for one, two or all three of these
activities. It has been shown that patients who are ‘triple-positive’
have an increased likelihood of thrombotic events.
Clinical features and management
APS may present in isolation (primary APS) or in association with
one of the conditions shown in Box 23.67, most typically systemic
lupus erythematosus (secondary APS). Most patients present
with a single manifestation and APS is now most frequently
diagnosed in women with adverse outcomes of pregnancy.
It is extremely important to make the diagnosis in patients
with APS, whatever the manifestation, because it affects the
prognosis and management of arterial thrombosis, VTE and
pregnancy.
Arterial thrombosis, typically stroke, associated with APS
should probably be treated with warfarin, as opposed to aspirin.
APS-associated VTE is one of the situations in which the
predicted recurrence rate is high enough to indicate long-term
anticoagulation after a first event. In women with obstetric
presentations of APS, intervention with heparin and aspirin is
almost routinely prescribed, although there is little evidence
from clinical trials that it is an effective therapy in increasing the
chance of a successful pregnancy outcome.
| Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) may complicate a
range of illnesses (Box 23.68). It is characterised by systemic
activation of the pathways involved in coagulation and its
regulation. This may result in the generation of intravascular fibrin
clots causing multi-organ failure, with simultaneous coagulation
factor and platelet consumption, causing bleeding. The systemic
coagulation activation is induced either through cytokine
pathways, which are activated as part of a systemic inflammatory
23.68 Disseminated intravascular coagulation (DIC)
Underlying conditions
• Infection/sepsis
• Trauma
• Obstetric, e.g. amniotic fluid embolism, placental abruption,
pre-eclampsia
• Severe liver failure
• Malignancy, e.g. solid tumours and leukaemias
• Tissue destruction, e.g. pancreatitis, burns
• Vascular abnormalities, e.g. vascular aneurysms, liver
haemangiomas
• Toxic/immunological, e.g. ABO incompatibility, snake bites,
recreational drugs
ISTH scoring system for diagnosis of DIC
Presence of an associated
disorder
Platelets (x 109/L)
Elevated fibrin degradation
products
Prolonged prothrombin time
Fibrinogen
Essential
>100 = 0
<100 = 1
<50 = 2
No increase = 0
Moderate = 2
Strong = 3
<3 secs = 0
>3 secs but <6 secs = 1
>6 secs = 2
>1 g/L = 0
<1 g/L = 1
Total score
>5 = Compatible with overt DIC
<5 = Repeat monitoring over 1-2 days
(ISTH = International Society for Thrombosis and Haemostasis)
• Thrombocytopenia: not uncommon because of the rising
prevalence of disorders in which it may be a secondary feature, and
also because of the greater use of drugs that can cause it.
• ‘Senile’ purpura: presumed to be due to an age-associated loss of
subcutaneous fat and the collagenous support of small blood
vessels, making them more prone to damage from minor trauma.
• Thrombosis: incidence of thromboembolic disease rises with
increasing age. This may be due to stasis and concurrent illness, to
which older people are prone; some studies show increased platelet
aggregation with age, and others age-associated hyperactivity of the
haemostatic system, which could contribute to a prothrombotic state.
• Thromboprophylaxis: should be considered in all older patients
who are immobile as a result of acute illness. Prophylaxis is not
required in chronic immobility without a medical cause, as there is
no associated increase in thromboembolism.
• Anticoagulation: older patients are more sensitive to the
anticoagulant effects of warfarin, partly due to the concurrent use of
other drugs and the presence of other pathology. Life-threatening or
fatal bleeds on warfarin are significantly more common in those
over 80 years.
23.69 Haemostasis and thrombosis in old age
response, or by the release of procoagulant substances such
as tissue factor. In addition, suboptimal function of the natural
anticoagulant pathways and dysregulated fibrinolysis contribute
to DIC. There is consumption of platelets, coagulation factors
(notably factors V and VIII) and fibrinogen. The lysis of fibrin
Further information • 979
clot results in production of fibrin degradation products (FDPs),
including D-dimers.
Investigations
DIC should be suspected when any of the conditions listed in Box
23.68 are met. Measurement of coagulation times (APTT and PT;
p. 920), along with fibrinogen, platelet count and FDPs, helps in
the assessment of prognosis and aids clinical decision-making
with regard to both bleeding and thrombotic complications.
Management
Therapy is primarily aimed at the underlying cause. These patients
will often require intensive care to deal with concomitant issues,
such as acidosis, dehydration, renal failure and hypoxia. Blood
component therapy, such as fresh frozen plasma, cryoprecipitate
and platelets, should be given if the patient is bleeding or
to cover interventions with a high bleeding risk, but should
not be prescribed routinely based on coagulation tests and
platelet counts alone. Prophylactic doses of heparin should
be given, unless there is a clear contraindication. Established
thrombosis should be treated cautiously with therapeutic doses
of unfractionated heparin, unless clearly contraindicated. Patients
with DIC should not, in general, be treated with antifibrinolytic
therapy, e.g. tranexamic acid.
| Thrombotic thrombocytopenic purpura
Like DIC and also heparin-induced thrombocytopenia (p. 938),
thrombotic thrombocytopenic purpura (TTP) is a disorder in which
thrombosis is accompanied by paradoxical thrombocytopenia.
TTP is characterised by a pentad of findings, although few
patients have all five components:
• thrombocytopenia
• microangiopathic haemolytic anaemia
• neurological sequelae
• fever
• renal impairment.
It is an acute autoimmune disorder mediated by antibodies
against ADAMTS-13 (a disintegrin and metalloproteinase with
a thrombospondin type 1 motif).
This enzyme normally cleaves vWF multimers to produce normal
functional units, and its deficiency results in large vWF multimers
that cross-link platelets. The features are of microvascular
occlusion by platelet thrombi affecting key organs, principally
brain and kidneys. It is a rare disorder (1 in 750000 per annum),
which may occur alone or in association with drugs (ticlopidine,
ciclosporin), HIV, shiga toxins (p. 263) and malignancy. It should
be treated by emergency plasma exchange. Glucocorticoids,
aspirin and rituximab also have a role in management.
Untreated mortality rates are 90% in the first 10 days, and
even with appropriate therapy, the mortality rate is 20-30% at
6 months.
Further information
Websites
bcshguidelines.com British Committee for Standards in Haematology
guidelines.
cibmtr.org International Bone Marrow Transplant Registry.
transfusionguidelines.org.uk Contains the UK Transfusion Services’
Handbook of Transfusion Medicine and links to other relevant sites.
ukhcdo.org UK Haemophilia Centre Doctors’ Organisation.
23
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GPR Clunie
SH Ralston
Rheumatology and
bone disease
Clinical examination of the musculoskeletal system 982
Osteoarthritis 1007
Functional anatomy and physiology 984
Crystal-induced arthritis 012
Bone 984
Fibromyalgia 1018
Joints 986
Skeletal muscle 987
Bone and joint infections 1019
Investigation of musculoskeletal disease 988
Rheumatoid arthritis 1021
Joint aspiration 988
Juvenile idiopathic arthritis 1026
Imaging 988
Spondyloarthropathies 1027
Blood tests 990
Axial spondyloarthropathy 1 028
Tissue biopsy 992
Reactive arthritis 1 031
Electromyography 992
Psoriatic arthritis 1 032
Presenting problems in musculoskeletal disease 992
Enteropathic (spondylo)arthritis 1034
Acute monoarthritis 992
Autoimmune connective tissue diseases 034
Polyarthritis 993
Vasculitis 1040
Fracture 994
Generalised musculoskeletal pain 995
Diseases of bone 1044
Back pain 995
Osteoporosis 1 044
Regional musculoskeletal pain 997
Osteomalacia, rickets and vitamin D deficiency 1 049
Neck pain 997
Paget’s disease of bone 1053
Shoulder pain 997
Other bone diseases 1 055
Elbow pain 998
Bone and joint tumours 1056
Hand and wrist pain 998
Rheumatological involvement in other diseases 1057
Hip pain 998
Miscellaneous conditions 1058
Knee pain 998
Ankle and foot pain 999
Muscle pain and weakness 1 000
Principles of management 000
Education and lifestyle interventions 1 000
Non-pharmacological interventions 1001
Pharmacological treatment 1 002
982 • RHEUMATOLOGY AND BONE DISEASE
Clinical examination of the musculoskeletal system
2 Extensor surfaces
Rheumatoid nodules
Swollen bursa
Psoriasis rash
A Rheumatoid nodules
1 Hands
Swelling
Deformity
Nail changes
Tophi
Raynaud’s
A Nail dystrophy in
psoriatic arthritis
A Synovitis and deformity
in rheumatoid arthritis
3 Face
Rash
Alopecia
Mouth ulcers
Eyes
A Butterfly rash in systemic
lupus erythematosus
AScleritis in rheumatoid
arthritis
4 Trunk
Kyphosis
Scoliosis
Tender spots (fibromyalgia,
enthesitis)
5 Legs
Deformity
Swelling
Restricted movement
A Bone deformity in
Paget’s disease
A Heberden and Bouchard
nodes in osteoarthritis
Observation
• General appearance
• Gait
• Deformity
• Swelling
• Redness
• Rash
6 Feet
Deformity
Swelling (gout, dactylitis)
Redness
A Acute gout
Clinical examination of the musculoskeletal system • 983
General Assessment of Locomotor System (GALS) and Schober’s test
1 Gait
2 Arms
Inspect
hands for
swelling or
deformity
Ask patient to
make a fist and
open and close
fingers (tests
hand function)
Squeeze
metacarpals
(tests for
inflammation)
Press over supraspinatus
(tests for hyperalgesia)
Patient turns palms up and
down with elbows at side (tests
supination and pronation
of wrists and elbow)
Ask patient to put hands behind
head (tests shoulder movements)
Patient flexes elbows to touch
shoulder (tests elbow flexion)
/VSh
m u
V" 'A
Patient looks at ceiling
Ask patient to try to put
and then puts chin on
ear on shoulder (tests
chest (tests flexion and
lateral flexion cervical
extension cervical spine)
spine)
Patient slides hand down
leg to knee (tests lateral
spine flexion)
5 Schober’s test
Mark skin with pen in
midline about 4 cm
below superior iliac
crest. Make another
mark in midline 10 cm
above first. Ask patient
to bend forwards.
Normally, distance
between marks should
increase to 15 cm
Inspect spine from behind and side,
looking for scoliosis, kyphosis or
localised deformity. Ask patient to
touch toes
Stand behind
patient and hold
their pelvis.
Ask them to turn
from side to side
without moving
their feet (tests
thoracolumbar
rotation)
984 • RHEUMATOLOGY AND BONE DISEASE
Disorders of the musculoskeletal system affect all ages and ethnic
groups. In the UK, about 25% of new consultations in general
practice are for musculoskeletal symptoms. Musculoskeletal
diseases may arise from processes affecting bones, joints,
muscles, or connective tissues such as skin and tendon. The
principal manifestations are pain and impairment of locomotor
function.
Diseases of the musculoskeletal system tend to be more
common in women and most increase in frequency with increasing
age. They are the most common cause of physical disability in
older people and account for one-third of physical disability at
all ages.
Functional anatomy and physiology
The musculoskeletal system is responsible for movement of the
body, provides a structural framework to protect internal organs,
and acts as a reservoir for storage of calcium and phosphate in
the regulation of mineral homeostasis. The main components of
the musculoskeletal system are depicted in Figure 24.1.
Bone
Bones fall into two main types, based on their embryonic develop¬
ment. Flat bones, such as the skull, develop by intramembranous
ossification, in which embryonic fibroblasts differentiate directly
into bone within condensations of mesenchymal tissue during
early fetal life. Long bones, such as the femur and radius,
develop by endochondral ossification from a cartilage template.
During development, the cartilage is invaded by vascular tissue
containing osteoprogenitor cells and is gradually replaced by
bone from centres of ossification situated in the middle and
at the ends of the bone. A thin remnant of cartilage called the
growth plate or epiphysis remains at each end of long bones, and
chondrocyte proliferation here is responsible for skeletal growth
during childhood and adolescence. At the end of puberty, the
increased levels of sex hormones halt cell division in the growth
plate. The cartilage remnant then disappears as the epiphysis
fuses and longitudinal bone growth ceases.
Two types of bone tissue are present in the normal skeleton
(Fig. 24.1). Cortical bone is formed from Haversian systems,
comprising concentric lamellae of bone tissue surrounding a
central canal that contains blood vessels. Cortical bone is dense
and forms a hard envelope around the long bones. Trabecular or
cancellous bone fills the centre of the bone and consists of an
interconnecting meshwork of trabeculae, separated by spaces
filled with bone marrow. The most important cell types in bone are:
• Osteoclasts: multinucleated cells of haematopoietic origin,
responsible for bone resorption.
• Osteoblasts: mononuclear cells of derived from marrow
stromal cells responsible for bone formation.
Muscle
Articular cartilage
Chondrocytes Calcified
^rtilage
Subchondral
bone
Bone
Calcified zone
Growth
plate Hypertrophic zone
^Proliferative zone
Bone
Synovial
lining cells Joint
capsule
Myofilament
Myofibril
Fascicle
Haversian system
Synovium
Cortical bone
Epiphyseal plate
Tendon
Enthesis
Trabecular bone
Osteoblasts
Osteocytes
Osteoclasts
Fig. 24.1 Structure of the major musculoskeletal tissues.
Functional anatomy and physiology • 985
• Osteocytes : cells that differentiate from osteoblasts that
become embedded in bone matrix during bone formation.
They are responsible for sensing and responding to
mechanical stimuli and for coordinating osteoclast and
osteoblast activity.
• Bone marrow stromal cells: cells that produce receptor
activator of nuclear factor kappa B ligand (RANKL) and
macrophage colony-stimulating factor (M-CSF), which
stimulate osteoclast formation, and other cytokines that
support haematopoiesis (p. 914).
• Bone lining cells: flattened cells lining the bone surface
that differentiate from osteoblasts when bone formation is
complete.
Bone matrix and mineral
The most abundant protein of bone is type I collagen, which is
formed from two al peptide chains and one a2 chain wound
together in a triple helix. Type I collagen is proteolytically processed
inside the cell before being laid down in the extracellular space,
releasing propeptide fragments that can be used as biochemical
markers of bone formation. Subsequently, the collagen fibrils
become ‘cross-linked’ to one another by pyridinium molecules, a
process that enhances bone strength. When bone is broken down
by osteoclasts, the cross-links are released into the circulation.
These can be measured biochemically and are sometimes used
clinically to assess levels of bone resorption. Bone is normally
laid down in an orderly fashion, but when bone turnover is
high, as in Paget’s disease or severe hyperparathyroidism, it
is laid down in a chaotic pattern, giving rise to ‘woven bone’
that is mechanically weak. Bone matrix also contains growth
factors, other structural proteins and proteoglycans, thought to
be involved in helping bone cells attach to bone matrix and in
regulating bone cell activity. The other major component of bone
is mineral, comprised of calcium and phosphate crystals deposited
between the collagen fibrils in the form of hydroxyapatite [Ca10
(P04)6 (OH)^ Mineralisation is essential for bone’s rigidity and
strength but over-mineralisation causes the bone to become
brittle. In clinical practice, increased mineralisation can occur
in some types of osteogenesis imperfecta and in response to
long-term bisphosphonate therapy.
Bone remodelling
Bone remodelling is required for renewal and repair of the
skeleton throughout life. This is a cyclical process that has four
phases; quiescence, resorption, reversal and formation, as
illustrated in Figure 24.2. Remodelling starts with the attraction
of osteoclast precursors in peripheral blood to the target site,
probably by local release of chemotactic factors from areas of
microdamage. The osteoclasts resorb bone and, after about
10 days, undergo programmed cell death (apoptosis), heralding
the start of the reversal phase, when osteoblast precursors
are recruited to the resorption site. The osteoblast precursors
differentiate into mature osteoblasts and form new bone during
the formation phase. Initially, the matrix is unmineralised (osteoid)
but eventually becomes mineralised to form mature bone. Some
osteoblasts become trapped in bone matrix and differentiate
into osteocytes, which play a key regulatory role in coordinating
bone formation and resorption, whereas others differentiate into
bone-lining cells.
The cellular and molecular mediators of this bone remodelling
are shown in more detail in Figure 24.3. Osteoclast precursors
are derived from haematopoietic stem cells and differentiate
Bone-lining cells
Fig. 24.2 The bone remodelling cycle. Bone is renewed and repaired
by the process of bone remodelling. This begins by removal of old and
damaged bone by osteoclasts during the phase of bone resorption. After
about 10 days, the osteoclasts undergo programmed cell death (apoptosis)
and during the reversal phase are replaced by osteoclasts, which begin to
fill in the resorbed area with new bone matrix, heralding the start of bone
formation. The bone matrix is initially uncalcified (osteoid) but then
becomes mineralised to form mature bone.
into mature osteoclasts in response to M-CSF, produced by
bone marrow stromal cells, and RANKL, produced by both
osteocytes and bone marrow stromal cells. The RANKL binds
to and activates a receptor called RANK (receptor activator of
nuclear factor kappa B) on osteoclast precursors, promoting
osteoclast differentiation and bone resorption. This effect is
blocked by osteoprotegerin (OPG), which is a decoy receptor for
RANKL that inhibits osteoclast formation. Once formed, mature
osteoclasts attach to the bone surface by a tight sealing zone
and secrete hydrochloric acid and proteolytic enzymes, including
cathepsin K, into the space underneath, which is known as the
Howship’s lacuna. The acid dissolves the mineral and cathepsin
K degrades collagen. Osteocytes also produce sclerostin (SOST),
which is a potent inhibitor of bone formation. Under conditions
of mechanical loading, sclerostin production by osteocytes is
inhibited, allowing bone formation to proceed, stimulated by
members of the Wnt family of signalling proteins. The Wnt
molecules stimulate bone formation by activating members
of the lipoprotein receptor-related protein (LRP) family, the
most important of which are LRP4, LRP5 and LRP6. Sclerostin
antagonises the effects of Wnt family members by blocking
their interaction with LRP family members. Finally, osteocytes
play a critical role in phosphate homeostasis by producing
the hormone FGF23, which regulates renal tubular phosphate
reabsorption. Key regulators of bone remodelling are summarised
in Box 24.1 .
Mineralisation of bone is critically dependent on the enzyme
alkaline phosphatase (ALP), which is produced by osteoblasts
and degrades pyrophosphate, an inhibitor of mineralisation. Bone
remodelling is predominantly regulated at a local level but can
be influenced by circulating hormones or mechanical loading,
which can up-regulate or down-regulate remodelling across the
whole skeleton (Box 24.1).
986 • RHEUMATOLOGY AND BONE DISEASE
Fig. 24.3 Cellular and molecular regulators of bone remodelling Osteoclast precursors are derived from haematopoietic stem cells. They differentiate
into mature osteoclasts in response to the receptor activator of nuclear factor kappa B ligand (RANKL), which is produced by osteocytes, bone marrow
stromal cells and activated T cells (not shown), and macrophage colony-stimulating factor (M-CSF), which is produced by bone marrow stromal cells.
Osteoprotegerin (OPG) is also produced in the bone microenvironment, where it inhibits osteoclastic bone resorption by blocking the effect of RANKL.
Osteoblasts, which are derived from bone marrow stromal cells, are responsible for bone formation. Osteoblast activity is stimulated by signalling molecules
in the Wnt family but inhibited by sclerostin (SOST), which is produced by osteocytes. In addition to their role in regulating osteoclast and osteoblast
activity, osteocytes have an endocrine function in regulating phosphate homeostasis by producing fibroblast growth factor 23 (FGF23), which acts on the
kidney to promote phosphate excretion.
24.1 Key regulators of bone remodelling
Mediator
Source
Effects
Comment
RANKL
Osteocytes
Stromal cells
Activated T cells
Stimulates bone resorption
Activates RANK
Osteoprotegerin
Stromal cells
Lymphocytes
Inhibits bone resorption
Acts as decoy receptor for RANKL
Wnt
Stromal cells
Stimulates bone formation
Activates LRP receptors
Sclerostin
Osteocytes
Inhibits bone formation
Blocks effect of Wnt on LRP receptors
Parathyroid hormone
Parathyroid glands
Increases bone resorption and formation
Thyroid hormone
Thyroid gland
Increases bone resorption and formation
Oestrogen
Ovary
Inhibits bone resorption
Glucocorticoid
Adrenal gland
Exogenous
Inhibits bone formation
(LRP = lipoprotein receptor- related protein; RANKL = receptor activator of nuclear factor kappa B ligand)
Joints
There are three main types of joint: fibrous, fibrocartilaginous
and synovial (Box 24.2).
Fibrous and fibrocartilaginous joints
These comprise a simple bridge of fibrous or fibrocartilaginous
tissue joining two bones together where there is little requirement
for movement. The intervertebral disc is a special type of
fibrocartilaginous joint in which an amorphous area, called the
nucleus pulposus, lies in the centre of the fibrocartilaginous bridge.
The nucleus has a high water content and acts as a cushion to
improve the disc’s shock-absorbing properties.
24.2 Types of joint
Type
Range of
movement
Examples
Fibrous
Minimal
Skull sutures
Fibrocartilaginous
Limited
Symphysis pubis
Costochondral
junctions
Intervertebral discs
Sacroiliac joints
Synovial
Large
Most limb joints
Temporomandibular
Costovertebral
Functional anatomy and physiology • 987
Synovial joints
These are complex structures containing several cell types. They
are found where a wide range of movement is needed (Fig. 24.4).
Articular cartilage
This avascular tissue covers the bone ends in synovial joints.
Cartilage cells (chondrocytes) are responsible for synthesis and
turnover of cartilage, which consists of a mesh of type II collagen
fibrils that extend through a hydrated ‘gel’ of proteoglycan
molecules. The most important proteoglycan is aggrecan, which
consists of a core protein to which several glycosaminoglycan
(GAG) side chains are attached (Fig. 24.5). The GAGs are
polysaccharides that consist of long chains of disaccharide
repeats comprising one normal sugar and an amino sugar. The
most abundant GAGs in aggrecan are chondroitin sulphate and
keratan sulphate. Hyaluronan is another important GAG that
binds to aggrecan molecules to form very large complexes with
a total molecular weight of more than 100 million. Aggrecan has
a strong negative charge and avidly binds water molecules to
assume a shape that occupies the maximum possible volume
available. The expansive force of the hydrated aggrecan, combined
with the restrictive strength of the collagen mesh, gives articular
cartilage excellent shock-absorbing properties.
With ageing, the concentration of chondroitin sulphate
decreases, whereas that of keratan sulphate increases, resulting
Bone-
Skin and
subcutaneous
tissue
Bursa
Tendon
Tendon
sheath
Ligamentous
thickening
of capsule
Muscle
Bursa
Synoviu
Fibrocartilage
pad
Joint space
Hyaline articular
Fig. 24.4 Structure of a synovial joint.
Flyaluronan -
Fig. 24.5 Ultrastructure of articular cartilage.
Type II collagen
fibrils
Aggrecan
Link protein
Keratan
sulphate
Chondroitin
sulphate
Core protein
in reduced water content and shock-absorbing properties.
These changes differ from those found in osteoarthritis
(p. 1007), where there is abnormal chondrocyte division, loss
of proteoglycan from matrix and an increase in water content.
Cartilage matrix is constantly turning over and in health there is a
perfect balance between synthesis and degradation. Degradation
of cartilage matrix is carried out by aggrecanases and matrix
metalloproteinases, responsible for the breakdown of proteins
and proteoglycans, and by glycosidases, responsible for the
breakdown of GAGs. Pro-inflammatory cytokines, such as
interleukin-1 (IL-1) and tumour necrosis factor (TNF), which are
released during inflammation, stimulate production of aggrecanase
and metalloproteinases, causing cartilage degradation.
Synovial fluid
The surfaces of articular cartilage are separated by a space filled
with synovial fluid (SF), a viscous liquid that lubricates the joint.
It is an ultrafiltrate of plasma, into which synovial cells secrete
hyaluronan and proteoglycans.
Intra-articular discs
Some joints contain fibrocartilaginous discs within the joint space
that act as shock absorbers. The most clinically important are the
menisci of the knee. These are avascular structures that remain
viable because of diffusion of oxygen and nutrients from the SF.
Synovial membrane, joint capsule and bursae
The bones of synovial joints are connected by the joint capsule,
a fibrous structure richly supplied with blood vessels, nerves
and lymphatics that encases the joint. Ligaments are discrete,
regional thickenings of the capsule that act to stabilise joints (see
Fig. 24.4). The inner surface of the joint capsule is the synovial
membrane, comprising an outer layer of blood vessels and loose
connective tissue that is rich in type I collagen, and an inner
layer 1-4 cells thick consisting of two main cell types. Type A
synoviocytes are phagocytic cells derived from the monocyte/
macrophage lineage and are responsible for removing particulate
matter from the joint cavity; type B synoviocytes are fibroblast-like
cells that secrete SF. Most inflammatory and degenerative joint
diseases associate with thickening of the synovial membrane
and infiltration by lymphocytes, polymorphs and macrophages.
Bursae are hollow sacs lined with synovium and contain a small
amount of SF. They help tendons and muscles move smoothly
in relation to bones and other articular structures.
Skeletal muscle
Skeletal muscles are responsible for body movements and
respiration. Muscle consists of bundles of cells (myocytes)
embedded in fine connective tissue containing nerves and
blood vessels. Myocytes are large, elongated, multinucleated
cells formed by fusion of mononuclear precursors (myoblasts) in
early embryonic life. The nuclei lie peripherally and the centre of
the cell contains actin and myosin molecules, which interdigitate
with one another to form the myofibrils that are responsible
for muscle contraction. The molecular mechanisms of skeletal
muscle contraction are the same as for cardiac muscle (p. 446).
Myocytes contain many mitochondria that provide the large
amounts of adenosine triphosphate (ATP) necessary for muscle
contraction and are rich in the protein myoglobin, which acts as
a reservoir for oxygen during contraction.
Individual myofibrils are organised into bundles (fasciculi) that
are bound together by a thin layer of connective tissue (the
988 • RHEUMATOLOGY AND BONE DISEASE
perimysium). The surface of the muscle is surrounded by a thicker
layer of connective tissue, the epimysium, which merges with
the perimysium to form the muscle tendon. Tendons are tough,
fibrous structures that attach muscles to a point of insertion on
the bone surface called the enthesis.
Investigation of
musculoskeletal disease
Clinical history and examination usually provide sufficient informa¬
tion for the diagnosis and management of many musculoskeletal
diseases. Investigations are helpful in confirming the diagnosis,
assessing disease activity and indicating prognosis.
Joint aspiration
Joint aspiration with examination of SF is pivotal in patients
suspected of having septic arthritis, crystal arthritis or intra-articular
bleeding. It should be carried out in all individuals with acute
monoarthritis, and samples should be sent for microbiology and
clinical chemistry.
It is possible to obtain SF by aspiration from most peripheral
joints and only a small amount is required for diagnostic purposes.
Normal SF is present in small volume, is clear and either colourless
or pale yellow, and has a high viscosity. It contains few cells.
With joint inflammation, the volume increases, the cell count
and the proportion of neutrophils rise (causing turbidity), and the
viscosity reduces (due to enzymatic degradation of hyaluronan
and aggrecan). Turbid fluid with a high neutrophil count occurs in
sepsis, crystal arthritis and reactive arthritis. High concentrations
of urate crystals or cholesterol can make SF appear white.
Non-uniform blood-staining usually reflects needle trauma to
the synovium. Uniform blood-staining is most commonly due to
a bleeding diathesis, trauma or pigmented villonodular synovitis
(p. 1059) but can occur in severe inflammatory synovitis. A lipid
layer floating above blood-stained fluid is diagnostic of intra-articular
fracture and is caused by release of bone marrow fat into the joint.
Crystals can be identified by compensated polarised light
microscopy of fresh SF (to avoid crystal dissolution and
post-aspiration crystallisation). Urate crystals are long and
needle-shaped, and show a strong light intensity and negative
birefringence (Fig. 24. 6A). Calcium pyrophosphate crystals are
Fig. 24.6 Compensated polarised light microscopy of synovial fluids
(x400). [A] Monosodium urate crystals show bright negative birefringence
under polarised light and needle-shaped morphology. [§] Calcium
pyrophosphate crystals show weak positive birefringence under polarised
light and are few in number. They are more difficult to detect than urate
crystals.
smaller, rhomboid in shape and usually less numerous than urate
crystals; they have weak intensity and positive birefringence
(Fig. 24.6B).
They are of diagnostic value in osteoarthritis (OA), where they
demonstrate joint space narrowing that tends to be focal rather
than widespread, as in inflammatory arthritis. Other features of OA
detected on X-rays include osteophytes, subchondral sclerosis,
bone cysts and calcified loose bodies within the synovium (see
Fig. 24.21, p. 1010). Erosions and sclerosis of the sacroiliac
joints and syndesmophytes in the spine may be observed in
patients with spondyloarthritis (SpA; see Fig. 24.40, p. 1030). In
peripheral joints, proliferative erosions, associated with new bone
formation and periosteal reaction, occur in SpA. In tophaceous
gout, well-defined punched-out erosions may occur (see Fig.
24.27, p. 1015). Calcification of cartilage, tendons and soft tissues
or muscle occurs mainly in chondrocalcinosis (see Fig. 24.28,
p. 1016), calcium-containing crystal diseases, tumoral calcinosis
and autoimmune connective tissue diseases.
X-rays are of limited value in the diagnosis of rheumatoid
arthritis (RA) because features such as erosions, joint space
narrowing and periarticular osteoporosis may be detectable
only after several months or even years. The main indication for
X-rays in RA is in the assessment of disease over time when
structural damage to the joints is suspected.
Bone scintigraphy
Bone scintigraphy is useful in the diagnosis of metastatic bone
disease and Paget’s disease of bone. Abnormalities may also
be observed in primary bone tumours, complex regional pain
syndrome, osteoarthritis and inflammatory arthritis. It involves
Imaging
| Plain X-rays
X-rays show structural changes that are of value in the differential
diagnosis and monitoring of many bone and joint diseases
(Box 24.3).
24.3 Radiographic abnormalities in selected
rheumatic diseases
Rheumatoid arthritis
• Periarticular osteoporosis
•
Joint subluxation
• Marginal joint erosions
•
Joint space narrowing
Osteoporosis
• Osteopenia
•
Non-vertebral fractures
• Vertebral fractures
•
Cortical thinning
Paget’s disease
• Bone expansion
•
Osteosclerosis and lysis
• Abnormal trabecular pattern
•
Pseudofractures
Psoriatic arthritis
• Sacroiliitis
•
Proliferative enthesis erosions
• Syndesmophytes
•
Enthesophytes
• Bone sclerosis
•
Juxta-articular new bone
Osteoarthritis
• Joint space narrowing
•
Joint deformity
• Osteophytes
•
Subchondral cysts
• Subchondral sclerosis
Investigation of musculoskeletal disease • 989
24.4 Conditions identified by 99mTc-labelled
bisphosphonate bone scintigraphy
• Skeletal metastases
• Paget’s disease of bone
• Stress fractures and osteomalacia (e.g. Looser’s zones)
• Complex regional pain syndrome (p. 1055)
• Sclerosing bone disorders (e.g. hypertrophic pulmonary
osteoarthropathy; p. 1 057)
• Spondyloarthritides (abnormalities at sacroiliac joints and tendon/
ligament insertions)
gamma-camera imaging following an intravenous injection of
99mTc-labelled bisphosphonate. Early post-injection images
reflect blood flow and can show increased perfusion of inflamed
synovium, Pagetic bone or primary or secondary bone tumours.
Delayed images taken a few hours later reflect bone remodelling as
the 99mTc-labelled bisphosphonate localises to sites of active bone
turnover. Scintigraphy has a high sensitivity for detecting important
bone and joint pathology that is not apparent on X-rays (Box
24.4). Single photon emission computed tomography (SPECT)
combines radionuclide imaging with computed tomography. It
can provide accurate anatomical localisation of abnormal tracer
uptake within the bone and is of particular value in the assessment
of patients with chronic low back pain of unknown cause.
Magnetic resonance imaging
Magnetic resonance imaging (MRI) gives detailed information on
anatomy, allowing three-dimensional visualisation of bone and soft
tissues that cannot be adequately assessed by plain X-rays. The
technique is valuable in the assessment and diagnosis of many
musculoskeletal diseases (Box 24.5). T1 -weighted sequences are
useful for defining anatomy, whereas T2-weighted sequences
are useful for assessing tissue water content, which is often
increased in synovitis and other inflammatory disorders (Fig.
24.7). MRI sequences that suppress signal from fat, such as
short Tl inversion recovery (STIR), are helpful when evaluating
inflammatory disease. Contrast agents, such as gadolinium,
can be administered to increase sensitivity in detecting erosions
and synovitis.
Ultrasonography
Ultrasonography is a useful investigation for confirmation of small
joint synovitis and erosions, for anatomical location of periarticular
lesions, for characterisation of tendon lesions and for guided
injection of joints and bursae. Ultrasound is more sensitive than
clinical examination for the detection of early synovitis and is used
increasingly in the diagnosis and assessment of patients with
suspected inflammatory arthritis. In addition to locating synovial
thickening and effusions, ultrasound can detect increased blood
flow within synovium using power Doppler imaging, an option
that is available on most modern ultrasound machines (Fig. 24.8).
^Computed tomography
Computed tomography (CT) is used selectively for assessing
patients with bone and joint disease. CT may be used when
skeletal configuration needs defining, when calcific lesions are
being assessed (crowned dens syndrome, p. 1017), when MRI
is contraindicated, or when articular regions are being evaluated
in which an adjacent joint replacement creates signal artefacts
on MRI, using specific metal artefact reduction algorithms.
^9 24.5 Conditions detected by magnetic
resonance imaging
• Osteonecrosis
• Malignancy
• Intervertebral disc disease
• Fractures
• Nerve root entrapment
• Meniscal disease
• Spinal cord compression
• Synovitis
• Spinal stenosis
• Sacroiliitis and enthesitides
• Sepsis
• Inflammatory myositis
• Complex regional pain
• Rotator cuff tears, bursitis and
syndrome
tenosynovitis
f f yf '7 **)
Ml A /
1 *■ J - W m .1
1
T //'if
;Vt Y*“1 \
\ • :%■
U-'-i
y Jt v ^ 'J
s' X -
*
y
0
Fig. 24.7 Magnetic resonance image showing joint synovitis. Coronal
post-contrast Tl -weighted image shows extensive enhancement consistent
with synovitis (white areas, arrowed) in both wrists, at the second
metacarpophalangeal joint and proximal interphalangeal joints of the right
hand. Courtesy of Dr I. Beggs.
Effusion
P
Fig. 24.8 Ultrasound image showing synovitis. Lateral image of a
metacarpophalangeal joint in inflammatory arthritis. The periosteum (P) of
the phalanx shows as a white line. The dark, hypo-echoic area indicates
an effusion. The coloured areas demonstrated by power Doppler indicate
increased vascularity. The inset shows a transverse image of the same
joint. Courtesy of Dr N. McKay.
| Dual X-ray absorptiometry
Estimation of bone mineral density (BMD) has a key role in the
diagnosis and management of osteoporosis and is best made
using dual X-ray absorptiometry (DXA). Measurements at lumbar
spine, hip and sometimes forearm are obtained. DXA works on
the principle that calcium in bone attenuates passage of X-rays
through the tissue in proportion to the amount of mineral present:
the more bone mineral present, the higher the BMD value.
990 • RHEUMATOLOGY AND BONE DISEASE
Bone density measurements are often presented as T-scores,
which measure of the number of standard deviations by which
the patient’s BMD value differs from that in a young healthy
control (Fig. 24.9). Osteoporosis is defined in postmenopausal
women and men of more than 50 years old by a T-score of 2.5
or below (shaded red in the figure); osteopenia is diagnosed
20 40 60 80
Age (years)
Fig. 24.9 Typical output from a dual X-ray absorptiometry (DXA)
scan. [A] Image from hip DXA scan. [§] Bone mineral density (BMD)
values plotted in g/cm2 (left axis) and as the T-score values (right axis).
The solid line represents the population average plotted against age, and
the interrupted lines are ±2 standard deviations. The BMD T-score result
from the patient shown aged 70 years (arrow) is -3.0, indicating
osteoporosis. Note that, while the patient’s BMD is below average, it lies
within the reference range for someone of that age, since BMD normally
falls with age.
when the T-score lies between -1.0 and -2.5 (shaded pink).
BMD values above -1 .0 and below +2.5 are considered normal
(yellow/green), whereas values above +2.5 indicate high bone
mass, the most common cause being OA. The results need to
be interpreted carefully and in reference to coexisting conditions,
such as aortic calcification, vertebral fractures, degenerative disc
disease and OA, all of which can artefactually raise BMD results.
Radiographic correlation is then advisable.
Blood tests
Haematology
Abnormalities in the full blood count (FBC) often occur in
inflammatory rheumatic diseases but changes are usually non¬
specific. Examples include neutrophilia in crystal arthritides and
sepsis; neutropenia in lupus; and lymphopenia in autoimmune
rheumatic and connective tissue diseases. Reduced levels of
haemoglobin and raised platelets are a common and important
finding in active inflammatory rheumatological disorders. Many
synthetic and biologic disease-modifying antirheumatic drugs
(DMARDs) can cause marrow toxicity and require regular
monitoring of the FBC. Additional tests that are useful in assessing
rheumatic diseases include the direct antiglobulin test (which can
indicate intravascular haemolysis in systemic lupus erythematosus
(SLE); p. 948) and the dilute Russell viper venom test (a functional
assay for a lupus anticoagulant; p. 978).
Biochemistry
Routine biochemistry is useful for assessing metabolic bone
disease, muscle diseases and gout, and is essential in monitoring
DMARDs and biologic drugs (renal and hepatic function). Several
bone diseases, including Paget’s disease, renal bone disease
and osteomalacia, give a characteristic pattern that can be
helpful diagnostically (Box 24.6). Serum levels of uric acid are
usually raised in gout but a normal level does not exclude it,
especially during an acute attack, when urate levels temporarily
fall. Equally, an elevated serum uric acid does not confirm the
diagnosis, since most hyperuricaemic people never develop
gout. Levels of C-reactive protein (CRP) are a useful marker
of infection and inflammation, and are more specific than
the erythrocyte sedimentation rate (ESR). An exception is in
autoimmune connective tissue diseases, such as SLE and
systemic sclerosis, where CRP may be normal but the ESR
raised in active disease. Accordingly, an elevated CRP in a patient
with lupus or systemic sclerosis suggests an intercurrent illness,
such as sepsis, rather than active disease. More detail on the
24.6 Typical biochemical abnormalities in various skeletal diseases (in serum)
Calcium
Phosphate
ALP
PTH
FGF23
25(0H)D
Osteoporosis
N
N
N (T after fracture)
Nort
N
N or i
Paget’s disease
N
N
tt
N or T
N
N or i
Renal osteodystrophy
N or i
Nort
t
tt
tt
N or i
Vitamin D-deficient osteomalacia N or i
N or l
t
tt
N or i
u
Hypophosphataemic rickets
N
u
t
N or T
tt
N or i
Primary hyperparathyroidism
t/tt
N or i
Nort
tt
Nort
N or i
(ALP = alkaline phosphatase; FGF23 = fibroblast growth factor 23; PTH = parathyroid hormone)
(N = normal; single arrow = increased or decreased; double arrow = greatly increased or decreased)
Investigation of musculoskeletal disease • 991
i
24.7 Causes of an elevated serum creatinine
phosphokinase (CPK)
• Inflammatory myositis ±
• Trauma, strenuous exercise,
vasculitis
prolonged immobilisation after
• Muscular dystrophy
a fall
• Motor neuron disease
• Hypothyroidism, metabolic
• Alcohol, drugs (especially
myopathy
statins)
• Myocardial infarction*
• Viral myositis
*The CK-MB cardiac-specific isoform is disproportionately elevated compared
with total CPK.
interpretation of CRP and ESR changes is given on page 72.
Serum creatine phosphokinase levels are useful in the diagnosis
of myopathy or myositis, but specificity and sensitivity are poor
and raised levels may occur in some conditions (Box 24.7).
| Immunology
Autoantibody tests are widely used in the diagnosis of rheumatic
diseases. Whatever test is used, the results must be interpreted
in light of the clinical picture and the different detection and
assay systems used in different hospitals.
Rheumatoid factor
Rheumatoid factor (RF) is an antibody directed against the Fc
fragment of human immunoglobulin. In routine clinical practice,
immunoglobulin M (IgM) RF is usually measured, although different
methodologies allow measurement of IgG and IgA RFs too.
Positive RF occurs in a wide variety of diseases and some normal
adults (Box 24.8), particularly with increasing age. Although the
specificity is poor, about 70% of patients with RA test positive.
High RF titres are associated with more severe disease and
extra-articular disease.
Anti-citrullinated peptide antibodies
Anti-citrullinated peptide antibodies (ACPAs) recognise peptides
in which the amino acid arginine has been converted to citrulline
by peptidylarginine deiminase, an enzyme abundant in inflamed
synovium and in a variety of mucosal structures. ACPAs have
similar sensitivity to RF for RA (70%) but much higher specificity
(>95%), and should be used in preference to RF in the diagnosis of
RA. ACPAs are associated with more severe disease progression
HI 24.8 Conditions associated with a positive
rheumatoid factor
Condition
Approximate
frequency (%)
Rheumatoid arthritis with nodules and
extra-articular manifestations
100
Rheumatoid arthritis (overall)
70
Sjogren’s syndrome
90
Mixed essential cryoglobulinaemia
90
Primary biliary cholangitis
50
Infective endocarditis
40
Systemic lupus erythematosus
30
Tuberculosis
15
Age >65 years
20
*Normal healthy people can be positive for rheumatoid factor.
and can be detected in asymptomatic patients several years
before the development of RA. Their pathological role is still
debated but it is likely that they amplify the synovial response
to an inflammatory stimulus.
Antinuclear antibodies
Antinuclear antibodies (ANAs) are directed against one or more
components of the cell nucleus, including nucleic acids themselves
and the proteins concerned with the processing of DNA or RNA.
They occur in many inflammatory rheumatic diseases but are
also found at low titre in normal individuals and in other diseases
(Box 24.9). ANAs are not associated with disease severity or
activity. The most common indication for ANA testing is in patients
suspected of having SLE or other autoimmune connective
tissue diseases. ANA has high sensitivity for SLE (100%) but
low specificity (10-40%). A negative ANA virtually excludes SLE
but a positive result does not confirm it.
Anti-DNA antibodies bind to double-stranded DNA (dsDNA)
and are useful in SLE monitoring as very high titres are associated
with more severe disease, including renal or central nervous
system (CNS) involvement, and an increase in antibody titre may
precede relapse. Anti-DNA antibodies are routinely tested by
enzyme-linked immunosorbent assay (ELISA; see also p. 1036).
Antibodies to extractable nuclear antigens (ENAs) act as
markers for certain autoimmune connective tissue diseases and
some complications of SLE but sensitivity and specificity are poor
(Box 24.1 0). For example, antibodies to Sm are found in a minority
of patients with SLE but are associated with renal involvement.
Antibodies to Ro occur in SLE and in Sjogren’s syndrome (in
association with anti-La antibodies), and are associated with
a photosensitive rash and congenital heart block. Antibodies
to ribonucleoprotein (RNP) occur in SLE and also in mixed
connective tissue disease, where features of lupus, myositis
and systemic sclerosis coexist. Anti-topoisomerase 1 (also
termed Scl-70) antibodies occur in diffuse systemic sclerosis,
whereas anti-centromere antibodies are more specific for limited
systemic sclerosis.
Antiphospholipid antibodies
Antiphospholipid antibodies bind to a number of phospholipid
binding proteins but the most clinically relevant are those that
target beta2-glycoprotein 1 ((32GP1). They may be detected in
HI 24.9 Conditions associated with a positive
antinuclear antibody
Condition
Approximate
frequency (%)
Systemic lupus erythematosus
100%
Systemic sclerosis
60-80%
Sjogren’s syndrome
40-70%
Dermatomyositis or polymyositis
30-80%
Mixed connective tissue disease
100%
Autoimmune hepatitis
100%
Rheumatoid arthritis
30-50%
Autoimmune thyroid disease
30-50%
Malignancy
Varies widely
Infectious diseases
Varies widely
*Low-titre positive antinuclear antibody can occur in people without autoimmune
disease, without obvious clinical consequences, particularly in the elderly.
992 • RHEUMATOLOGY AND BONE DISEASE
^9 24.10 Conditions associated with antibodies to
extractable nuclear antigens
Antibody (target/other
name)
Disease association
Anti-centromere
antibody
Localised cutaneous systemic sclerosis
(sensitivity 60%, specificity 98%)
Anti-histone antibody
Drug-induced lupus (80%)
Anti-Jo-1
(anti-histidyl-tRNA
synthetase)
Polymyositis, dermatomyositis or
polymyositis-systemic sclerosis overlap
(20-30%)
Particularly associated with interstitial
lung disease
Anti-La antibody
(anti-SS-B)
Sjogren’s syndrome (60%)
SLE (20-60%)
Anti-ribonucleoprotein
antibody
(anti-RNP)
Mixed connective tissue disease (100%)
SLE (25-50%), usually in conjunction
with anti-Sm antibodies
Anti-Ro antibody
(anti-SS-A)
SLE (35-60%): associated with
photosensitivity, thrombocytopenia and
subacute cutaneous lupus
Maternal anti-Ro antibodies associated
with neonatal lupus and congenital heart
block
Sjogren’s syndrome (40-80%)
Anti-RNA polymerase
Diffuse systemic sclerosis (1 5%)
Anti Sm
(anti-Smith antibody)
SLE (15-30%); associated with renal
disease
Anti-Scl-70
(anti-topoisomerase 1
antibody)
Diffuse systemic sclerosis (15%);
associated with more severe organ
involvement, including pulmonary fibrosis
(SLE = systemic lupus erythematosus)
SLE and other autoimmune connective tissue diseases and are
key in diagnosing antiphospholipid antibody syndrome (p. 977).
Antineutrophil cytoplasmic antibodies
Antineutrophil cytoplasmic antibodies (ANCAs) are IgG antibodies
directed against the cytoplasmic constituents of granulocytes and
are useful in the diagnosis and monitoring of systemic vasculitis.
Two common patterns are described by immunofluorescence:
cytoplasmic fluorescence (c-ANCA), which is caused by antibodies
to proteinase-3 (PR3); and perinuclear fluorescence (p-ANCA),
which is caused by antibodies to myeloperoxidase (MPO) and
other proteins, such as lactoferrin and elastase. These antibodies
are not specific for vasculitis and positive results may be found
in autoimmune liver disease, malignancy, infection (bacterial
and human immunodeficiency virus, HIV), inflammatory bowel
disease, RA, SLE and pulmonary fibrosis.
Complement
Low complement C3 is an indicator of active SLE, owing to
‘consumption’ of complement by immune complexes (see Fig.
4.4, p. 66). Low C4 is less specific for SLE activity. High C3 and
functional measures of complement activation are non-specific
features of inflammation.
Tissue biopsy
Tissue biopsy is useful in confirming the diagnosis in certain
musculoskeletal diseases.
Synovial biopsy can be useful in selected patients with chronic
inflammatory monoarthritis or tenosynovitis to rule out chronic
infectious causes, especially mycobacterial infections. Synovial
biopsy can be obtained arthroscopically (by conventional means
or by use of needle arthroscope) or by using ultrasound guidance
under local anaesthetic.
Temporal artery biopsy can be of value in patients suspected
of having temporal arteritis, especially when the presentation is
atypical, but a negative result does not exclude the diagnosis.
Biopsies of affected tissues, such as skin, lung, nasopharynx,
gut, kidney and muscle, should be sought by default in confirming
a diagnosis of systemic vasculitis.
Muscle biopsy plays an important role in the investigation of
myopathy and inflammatory myositis. It is usually taken from
the quadriceps or deltoid through a small skin incision under
local anaesthetic. Since myositis can be patchy in nature,
MRI is sometimes used to localise the best site for biopsy.
Immunohistochemical staining, together with plain histology, gives
information on primary and secondary muscle and neuromuscular
disease. Repeat biopsies are sometimes used to monitor the
response to treatment.
Bone biopsy is occasionally required where non-invasive tests
give inconclusive results, in the diagnosis of infiltrative disorders,
in patients with renal bone disease, suspected chronic infection
or malignancy, and rarely to confirm or exclude the presence
of osteomalacia. Bone is taken from the iliac crest using a
large-diameter (8 mm) trephine needle under local anaesthetic
and processed without demineralisation. For focal lesions, the
biopsy should be taken under X-ray guidance or at open surgery,
from an affected site.
Electromyography
Electromyography (p. 1076) is of value in the investigation of
suspected myopathy and inflammatory myositis, when it shows
the diagnostic triad of:
• spontaneous fibrillation
• short-duration action potentials in a polyphasic
disorganised outline
• repetitive bouts of high-voltage oscillations on needle
contact with diseased muscle.
Presenting problems in
musculoskeletal disease
Acute monoarthritis
The most important causes of acute arthritis in a single joint are
crystal arthritis, sepsis, SpA and oligoarticular juvenile idiopathic
arthritis (JIA; p. 1026). Other potential causes are shown in
Box 24.11.
Clinical assessment
The clinical history, pattern of joint involvement, speed of onset,
and age and gender of the patient all give clues to the most likely
diagnosis. Gout classically affects the first metatarsophalangeal
(MTP) joint, whereas pseudogout, which can be a presenting
feature of calcium pyrophosphate dihydrate (CPPD) disease,
can affect the hand/wrist, ankle, knee or hip. A very rapid
onset (6-1 2 hours) is suggestive of crystal arthritis; joint sepsis
develops more slowly and continues to progress until treated.
Presenting problems in musculoskeletal disease • 993
24.1 1 Causes of acute monoarthritis
Common
• Gout
•
Spondyloarthritis
• Pseudogout
•
Psoriatic arthritis
• Trauma
•
Reactive arthritis
• Haemarthrosis
•
Enteropathic arthritis
Less common
• Rheumatoid arthritis
•
Tuberculosis
• Juvenile idiopathic arthritis
•
Leukaemia*
• Pigmented villonodular
•
Gonococcal infection
synovitis
• Foreign body reaction
•
Osteomyelitis*
*ln children, both leukaemia and osteomyelitis may present with monoarthritis.
Haemarthrosis typically causes a large effusion, in the absence
of periarticular swelling or skin change, in a patient who has
suffered an injury. Pigmented villonodular synovitis (p. 1059) also
presents with synovial swelling and a large effusion, although the
onset is gradual. A previous diarrhoeal illness or genital infection
suggests reactive arthritis, whereas intercurrent illness, dehydration
or surgery may act as a trigger for crystal-induced arthritis.
Rheumatoid arthritis seldom presents with monoarthritis but
psoriatic arthritis (PsA) can typically present this way. Osteoarthritis
can present with pain and stiffness affecting a single joint, but the
onset is gradual and there is usually no evidence of significant joint
swelling unless it is complicated by crystal -induced inflammation.
Investigations
Aspiration of the affected joint is mandatory. If sepsis is suspected
in a large joint, arthroscopic washout is advisable. The fluid should
be sent for culture and Gram stain to seek the presence of
organisms and should be checked by polarised light microscopy
for crystals. Blood cultures should also be taken in patients
suspected of having septic arthritis. CRP levels and ESR are raised
in sepsis, crystal arthritis and reactive arthritis, and this can be
useful in assessing the response to treatment. Serum uric acid
measurements may be raised in gout but a normal level does not
exclude the diagnosis. Ruling out primary hyperparathyroidism
is essential if there is pseudogout.
Management
If there is any suspicion of sepsis, intravenous antibiotics (see Box
24.50, p. 1020) should be given promptly, pending the results
of cultures. Unless atypical infections/tuberculosis (requiring
prolonged or special culture) are suspected, intra-articular
glucocorticoid injection may be considered after 48 hours of
negative synovial fluid culture. Otherwise, management should
be directed towards the underlying cause.
Polyarthritis
This term is used to describe pain and swelling affecting five
or more joints or joint groups. The possible causes are listed
in Box 24.12.
Clinical assessment
The hallmarks of inflammatory arthritis are early-morning
stiffness and worsening of symptoms with inactivity, along
with synovial swelling and tenderness on examination. Clinical
features in other systems can be helpful in determining the
24.12 Common causes of polyarthritis
Cause
Characteristics
Rheumatoid arthritis
Symmetrical, small and large joints, upper
and lower limbs
Viral arthritis
Symmetrical, small joints; may be
associated with rash and prodromal illness;
self-limiting
Osteoarthritis
Symmetrical, targets PIP, DIP and first
CMC joints in hands, knees, hips, back
and neck; associated with Heberden’s and
Bouchard’s nodes
Psoriatic arthritis
Asymmetrical, targets all joints and
entheses; associated with nail pitting/
onycholysis, dactylitis
Axial spondyloarthritis
and enteropathic
arthritis
Tends to affect midsize and large joints
and entheses, lower more than upper
limbs; history of inflammatory back pain
Systemic lupus
erythematosus
Symmetrical, typically affecting small joints;
clinical evidence of synovitis unusual
Juvenile idiopathic
arthritis
Various patterns (p. 1026): polyarticular,
oligoarticular and systemic but also
enthesitis-predominant
Chronic gout
Affects distal more than proximal joints;
history of acute attacks
Chronic sarcoidosis
(p. 608)
Varies: small and large joints, often
involves ankles
Calcium
pyrophosphate
arthritis
Chronic polyarthritis with involvement of
wrists, ankles, knees and oligoarticular
small hand joints
(CMC = carpometacarpal; DIP
interphalangeal)
= distal interphalangeal; PIP = proximal
underlying cause (Box 24.13). The most important diagnoses
to consider are PsA, RA and inflammatory small joint OA. RA is
characterised by symmetrical involvement of the small joints of
the hands and feet, wrists, ankles and knees. PsA is strongly
associated with enthesitis. Viral arthritis (p. 1020), Poncet’s
disease (in regions where tuberculosis is highly prevalent;
p. 588), polyarticular JIA (in children) and post-streptococcal
arthritis should also be considered.
The pattern of involvement can be helpful in reaching a
diagnosis (Fig. 24.10). Asymmetry, lower limb predominance,
enthesitis and greater involvement of large joints are characteristic
of the SpAs. In PsA there may be involvement of the proximal
and distal interphalangeal (PIP and DIP) joints, as opposed
to the metacarpophalangeal (MCP) and PIP joints in RA.
Inflammatory OA can appear similar to small-joint PsA in the
pattern of joint involvement. In PsA there may be nail pitting or
early onycholysis. Psoriasis may not be present. SLE can be
associated with polyarthritis but more usually causes polyarthralgia
and tenosynovitis, mainly of distal limb joints/tendons (p. 1035).
Investigations
Blood samples should be taken for routine haematology, bio¬
chemistry, ESR, CRP, viral serology and an immunological
screen, including ANA, RF and ACPA. Ultrasound examination
or MRI may be required to confirm the presence of synovitis, if
this is not obvious clinically.
994 • RHEUMATOLOGY AND BONE DISEASE
Fig. 24.10 Patterns of joint involvement in different forms of polyarthritis. {k\ Rheumatoid arthritis typically targets the metacarpophalangeal and
proximal interphalangeal joints of the hands and metatarsophalangeal joints of the feet, as well as other joints, in a symmetrical pattern. [§] Psoriatic
arthritis targets proximal and distal interphalangeal joints of the hands, entheses and larger joints in an asymmetrical pattern. Sacroiliitis (often
asymmetrical) may occur. [C] Axial spondyloarthritis/ankylosing spondylitis targets the spine, sacroiliac joints, entheses and large peripheral joints in an
asymmetrical pattern. [D] Osteoarthritis targets the proximal and distal interphalangeal joints of the hands, first carpometacarpal joint at the base of the
thumb, knees, hips, lumbar and cervical spine.
24.13 Extra-articular features of
inflammatory arthritis
Clinical feature
Disease association
Skin, nails and mucous
Psoriasis, nail pitting and
dystrophy
Raynaud’s phenomenon
Photosensitivity
Livedo reticularis
Splinter haemorrhages,
nail-fold infarcts, purpuric
lesions
Urticaria and erythemas
Oral ulcers
Nodules
Xerostomia, dry skin,
various rashes
membranes
Psoriatic arthritis
Systemic sclerosis, antiphospholipid
syndrome, SLE
SLE
SLE, antiphospholipid syndrome
Vasculitis
SLE, adult-onset Still’s disease,
systemic JIA, rheumatic fever
SLE, reactive arthritis, Behget’s disease
RA (mainly extensor surfaces), gout
(tophi; eccentric, white deposits within),
rheumatic fever
Primary Sjogren’s syndrome
Eyes
Uveitis
Conjunctivitis
Episcleritis, scleritis
SpA, sarcoid, JIA, Behget’s disease
Reactive arthritis
RA, vasculitis
Heart, lungs
Pleuro-pericarditis
SLE, RA, rheumatic fever
Aortic valve/root disease
HLA-B27-related SpA
Interstitial lung disease
RA, SLE, primary Sjogren’s syndrome
Abdominal organs
Hepatosplenomegaly
RA, SLE
Haematuria, proteinuria
SLE, vasculitis, systemic sclerosis
Urethritis
Reactive arthritis and SpA (sterile)
Fever, lymphadenopathy
Infection, systemic JIA, rheumatic fever
(HLA = human leucocyte antigen; JIA = juvenile idiopathic arthritis;
RA = rheumatoid arthritis; SLE =
SpA = spondyloarthritis)
systemic lupus erythematosus;
Management
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and
analgesics will help. Systemic glucocorticoids can be considered
if symptoms are very severe or having a great functional impact,
but early immunotherapy (DMARDs) is required in RA and in
some cases of PsA. An early accurate and specific diagnosis
is very important.
Fracture
Fractures are a common presenting symptom of osteoporosis but
they also occur in other bone diseases, in osteopenia and in some
patients with normal bone.
Clinical assessment
The presentation is with localised bone pain, which is worsened
by movement of the affected limb or region. There is usually a
history of trauma but spontaneous fractures can occur in the
absence of trauma in severe osteoporosis. Fractures can be
divided into several subtypes, based on the precipitating event
and presence or absence of an underlying disease (Box 24.14).
The main differential diagnosis is soft tissue injury but fracture
should be suspected when there is marked pain and swelling,
abnormal movement of the affected limb, crepitus or deformity.
Femoral neck fractures typically produce a shortened, externally
rotated leg that is painful to move. The pain from vertebral fracture
is variable and a high index of suspicion is key to making the
diagnosis by imaging, as discussed below.
Investigations
X-rays of the affected site should be taken in at least two planes
and examined for discontinuity of the cortical outline (Box 24.1 5).
In addition to demonstrating the fracture, X-rays may also show
evidence of an underlying disorder, such as osteoporosis, Paget’s
disease or osteomalacia. If the X-ray fails to show evidence of
a fracture but clinical suspicion remains high, MRI should be
Presenting problems in musculoskeletal disease • 995
24.14 Characteristics of different fracture types
obtained. Patients who are over the age of 50 and present with
fragility fractures should be screened for osteoporosis by DXA.
Management
Management of fracture in the acute stage requires adequate
pain relief, with opiates if necessary, reduction of the fracture
to restore normal anatomy, and immobilisation of the affected
limb to promote healing. This can be achieved either by the
use of an external cast or splint, or by internal fixation. Femoral
neck fractures present a special management problem since
non-union and avascular necrosis are common. This is especially
true with intracapsular hip fractures, which should be treated by
joint replacement surgery. Following the fracture, rehabilitation
is required with physiotherapy and a supervised exercise
programme. If the DXA scan shows evidence of osteoporosis or
other metabolic bone disease, this should be treated appropriately
(p. 1046). Options for management of painful vertebral fracture
are discussed on page 1002.
Generalised musculoskeletal pain
Clinical assessment
Clinical history and examination need to be wide-ranging (Box
24.16). Relentlessly progressive pain occurring in association with
weight loss suggests malignant disease with bone metastases.
Generalised bone pain may also arise in severe osteomalacia,
primary hyperparathyroidism and polyostotic Paget’s disease.
Widespread pain can occur in PsA if there is enthesial as
well as, or instead of, joint involvement; fatigue is also often
present. Polyarticular RA or OA pains tend to be localised to
sites of involvement, such as the lumbar spine, hips, knees and
hands. Fibromyalgia (FM) syndrome (p. 1018) presents with
generalised pain that particularly affects the trunk, back and neck.
Accompanying features include fatigue, poor concentration and
focal areas of hyperalgesia. Widespread pain may also occur
i
• Myopathies
• Psoriatic arthritis (enthesopathic)
• Fibromyalgia
• Parvovirus arthromyalgia
• Rheumatic fever/post-streptococcal infection
• Metastatic cancer
• Severe osteomalacia
in association with hypermobility, most notably Ehlers-Danlos
syndrome hypermobility subtype (hEDS; p. 1059).
Investigations
Bone scintigraphy is of value in patients suspected of having
osteomalacia, bone metastases or Paget’s disease, and in
characterising lesions at joints and/or entheses in SpAs,
including PsA. Myeloma (p. 966) should be screened for with
an FBC, measurement of CRP, and plasma and urinary protein
electrophoresis. If these results are positive, a radiological skeletal
survey should be obtained. Routine biochemistry, vitamin D and
parathyroid hormone (PTH) should be measured if osteomalacia
is suspected. In Paget’s disease, ALP may be elevated but can
be normal in localised disease. Any persistently elevated ESR,
CRP, angiotensin-converting enzyme (ACE), immunoglobulins,
C3/C4 or platelets invariably indicates inflammatory disease.
Laboratory investigations are normal in patients with FM alone
and in hEDS.
Management
Management should be directed towards the underlying cause.
Chronic pain of unknown cause and that associated with FM
respond poorly to analgesics and NSAIDs, but may respond
partially to antineuropathic agents, such as amitriptyline,
duloxetine, gabapentin and pregabalin.
Back pain
Back pain is a common symptom that affects 60-80% of people
at some time in their lives. Although the prevalence has not
increased, reported disability from back pain has risen significantly
in the last 30 years. In Western countries, back pain is the most
common cause of sickness-related work absence. In the UK, 7%
of adults consult their GP each year with back pain. Globally, low
back pain is thought to affect about 9% of the population. The
most important causes are summarised in Box 24.17.
Clinical assessment
The main purpose of clinical assessment is to differentiate the
self-limiting disorder of acute mechanical back pain from serious
spinal pathology, as summarised in Figure 24.1 1 . Mechanical back
pain is the most common cause of acute back pain in people
aged 20-55. This accounts for more than 90% of episodes,
and is usually acute and associated with lifting or bending. It
is exacerbated by activity and is generally relieved by rest (Box
24.18). It is usually confined to the lumbar-sacral region, buttock
or thigh, is asymmetrical and does not radiate beyond the knee
(which would imply nerve root irritation). On examination, there may
be asymmetric local paraspinal muscle spasm and tenderness,
and painful restriction of some, but not all, movements. Low back
pain is more common in manual workers, particularly those in
occupations that involve heavy lifting and twisting. The prognosis
Fracture type
Precipitation factor
Disease
Fragility fracture
Fall from standing
height or less
Osteoporosis
Osteopenia
Vertebral fracture
Bending, lifting, falling
Osteoporosis
Stress fracture
Running, excessive
training
Normal
High-energy fracture
Major trauma
Normal
Pathological fracture
Spontaneous, minimal
trauma
Malignancy
Paget’s disease
Osteomalacia
24.15 How to investigate a suspected fracture
• Order X-rays in two projections at right angles to one another
• Include the whole bone and the joints at either end (this may reveal
an additional unsuspected fracture)
• Check for evidence of displacement
• Check for a break in the cortex
• In suspected vertebral fracture, check for depression of the end plate
• If clinical suspicion is high but no fracture is seen, request magnetic
resonance imaging
24.16 Some common causes of generalised pain
996 • RHEUMATOLOGY AND BONE DISEASE
is generally good. After 2 days, 30% are better and 90% have
recovered by 6 weeks. Recurrences of pain may occur and
about 10-15% of patients go on to develop chronic back pain
that may be difficult to treat. Psychological elements, such as
job dissatisfaction, depression and anxiety, are important risk
factors for the transition to chronic pain and disability.
Back pain secondary to serious spinal pathology has different
characteristics (Box 24.19). If there is clinical evidence of spinal
cord or nerve root compression, sepsis including tuberculosis,
or a cauda equina lesion (Box 24.20), urgent investigation is
needed. Spinal stenosis presents insidiously with leg discomfort
on walking that is relieved by rest, bending forwards or walking
24.17 Causes of low back pain
• Mechanical (soft-tissue lesion)
• Paget’s disease
back pain
• Axial spondyloarthritis
• Intervertebral disc lesions (e.g.
• Spondylodiscitis
prolapse, disc degeneration)
• Bone metastases
• Facet joint disease
• Spondylolisthesis (p. 1059)
(osteoarthritis, psoriatic
• Scheuermann’s disease
arthritis)
(p. 1055)
• Vertebral fracture (p. 994)
24.18 Features of mechanical low back pain
• Pain varies with physical activity (improved with rest)
• Onset often sudden and precipitated by lifting or bending
• Recurrent episodes
• Pain limited to back or upper leg
• No clear-cut nerve root distribution
• No systemic features
• Prognosis good (90% recovery at 6 weeks)
uphill. Patients may adopt a characteristic simian posture,
with a forward stoop and slight flexion at hips and knees. The
most common cause is the gradual development of coexisting
contributing lesions such as facet joint arthritis, ligament flavum
thickening or degenerative spondylolisthesis.
Degenerative disc disease is a common cause of chronic low
back pain in middle-aged adults. Prolapse of an intervertebral disc
presents when discs are still well hydrated (in young and early
middle age) with nerve root pain, which can be accompanied
by a sensory deficit, motor weakness and asymmetrical reflexes.
Examination may reveal a positive sciatic or femoral stretch
test. About 70% of patients improve by 4 weeks. Inflammatory
back pain (IBP) due to axial spondyloarthritis (axSpA) or PsA
has a gradual onset and almost always occurs before the age
of 40. It is associated with morning stiffness and improves with
movement. Spondylolisthesis (p. 1 059) may cause back pain that
24.19 Red flags for possible spinal pathology
History
• Age: presentation <20 years or >55 years
• Character: constant, progressive pain unrelieved by rest
• Location: thoracic pain
• Past medical history: carcinoma, tuberculosis, HIV, systemic
glucocorticoid use, osteoporosis
• Constitutional: systemic upset, sweats, weight loss
• Major trauma
Examination
• Painful spinal deformity
• Severe/symmetrical spinal deformity
• Saddle anaesthesia
• Progressive neurological signs/muscle-wasting
• Multiple levels of root signs
Clinical assessment
(Box 24.20)
Fig. 24.11 Initial triage assessment of back pain.
Presenting problems in musculoskeletal disease • 997
24.20 Clinical features of radicular pain
Nerve root pain
• Unilateral leg pain worse than low back pain
• Pain radiates beyond knee
• Paraesthesia in same distribution
• Nerve irritation signs (reduced straight leg raising that reproduces
leg pain)
• Motor, sensory or reflex signs (limited to one or adjacent nerve
roots)
• Prognosis reasonable (50% recovery at 6 weeks)
Cauda equina syndrome
• Difficulty with micturition
• Loss of anal sphincter tone or faecal incontinence
• Saddle anaesthesia
• Gait disturbance
• Pain, numbness or weakness affecting one or both legs
is typically aggravated by standing and walking. Occasionally,
diffuse idiopathic skeletal hyperostosis (DISH; p. 1058) can cause
back pain but it is usually asymptomatic. Arachnoiditis is a rare
cause of chronic severe low back pain. It is caused by chronic
inflammation of the nerve root sheaths in the spinal canal and
can complicate meningitis, spinal surgery or myelography with
oil -based contrast agents.
Investigations
Investigations are not required in patients with acute mechanical
back pain. Those with persistent pain (>6 weeks) or red flags
(see Box 24.19) should undergo further investigation. MRI is
the investigation of choice because it can demonstrate spinal
stenosis, cord compression or nerve root compression, as well
as inflammatory changes in axSpA, malignancy and sepsis.
Plain X-rays can be of value in patients suspected of having
vertebral compression fractures, OA and degenerative disc
disease. If metastatic disease is suspected, bone scintigraphy
should be considered. Additional investigations that may be
required include routine biochemistry and haematology, ESR and
CRP (to screen for sepsis and inflammatory disease), protein
and urinary electrophoresis (for myeloma), human leucocyte
antigen (HLA)-B27 status in IBP and prostate-specific antigen
(for prostate carcinoma).
Management
Education is important in patients with mechanical back pain. It
should emphasise the self-limiting nature of the condition and
the fact that exercise is helpful rather than damaging. Regular
analgesia and/or NSAIDs may be required to improve mobility
and facilitate exercise. Return to work and normal activity should
take place as soon as possible. Bed rest is not helpful and may
increase the risk of chronic disability. Referral for physical therapy
should be considered if a return to normal activities has not been
achieved by 6 weeks. Low-dose tricyclic antidepressant drugs
may help pain, sleep and mood.
Other treatment modalities that are occasionally used include
epidural and facet joint injection, traction and lumbar supports,
though there is limited randomised controlled trial evidence to
support their use. Malignant disease, osteoporosis, Paget’s
disease and SpAs require specific treatment of the underlying
condition.
Surgery is required in less than 1% of patients with low
back pain but may be needed in progressive spinal stenosis,
in spinal cord compression and in some patients with nerve
root compression.
Regional musculoskeletal pain
Regional musculoskeletal pain is a common presenting complaint,
usually occurring as the result of age-related degenerative disease
of tendons and ligaments, OA and trauma.
Neck pain
Neck pain is a common symptom that can occur following an
injury or falling asleep in an awkward position, as a result of
stress or in association with OA of the spine. The causes are
shown in Box 24.21 . Most cases resolve spontaneously or with
a short course of NSAIDs or analgesics and some exercise
therapy. Patients with persistent pain that follows a nerve root
distribution and those with upper or lower limb neurological
signs should be investigated by MRI and, if necessary, referred
for a neurosurgical opinion.
24.21 Typical causes of neck pain
Mechanical
• Postural
•
Facet joint
• Whiplash injury
•
Cervical spondylosis
Inflammatory
• Infections
•
Rheumatoid arthritis
• Axial spondyloarthritis
•
Polymyalgia rheumatica
• Psoriatic arthritis
•
Discitis
Metabolic
• Axial calcium pyrophosphate
•
Fibrous dysplasia
di hydrate disease
•
Paget’s disease
Neoplastic
• Metastases
•
Lymphoma
• Myeloma
•
Intrathecal tumours
Other
• Fibromyalgia
•
Torticollis
Referred
• Pharynx
•
Aortic aneurysm
• Cervical lymph nodes
•
Pancoast tumour
• Teeth
•
Diaphragm
• Angina pectoris
Shoulder pain
Shoulder pain is a common complaint over the age of 40 (Box
24.22). Varying pain patterns associated with common lesions
are shown in Figure 24.12. For most shoulder lesions, general
management is with analgesics, NSAIDs, local glucocorticoid
injections and physiotherapy aimed at restoring normal movement
and function. Surgery may be required in patients who have
debilitating or persistent symptoms in association with rotator
cuff lesions or severe acromioclavicular joint arthritis. If there is
subacromial impingement, without evidence of a rotator cuff tear
on MRI, subacromial glucocorticoid injection and physiotherapy
constitute a reasonable first step. Calcific supraspinatus tendonitis
unresponsive to glucocorticoid injection can be treated with
barbotage (needle disruption of deposit under ultrasound
guidance). Complete rotator cuff tears in people under 40 years
of age may respond well to full surgical repair but results are
998 • RHEUMATOLOGY AND BONE DISEASE
24.22 Clinical findings in shoulder pain
Acromioclavicular Rotator cuff and
Fig. 24.12 Pain patterns around the shoulder. The dark shading
indicates sites of maximum pain.
less good in older people. Adhesive capsulitis (frozen shoulder)
presents with pain associated with marked restriction of elevation
and external rotation. Adhesive capsulitis is commonly associated
with diabetes mellitus and neck/radicular lesions. Treatment
in the early stage is with analgesia, intra- and extracapsular
glucocorticoid injection, and regular ‘pendulum’ exercises of
the arm to mobilise. Complete recovery sometimes takes up to
2 years. For severe or persistent symptoms, joint distension and
manipulation under anaesthesia are surgical options.
Elbow pain
The most common causes are repetitive trauma causing lateral
epicondylitis (tennis elbow) and medial epicondylitis (golfer’s elbow)
(Box 24.23). SpAs, including psoriatic disease, can present with
the same symptoms (tendon insertion enthesitis). Management
is by rest, analgesics and topical or systemic NSAIDs. Local
glucocorticoid injections may be required in resistant cases.
Olecranon bursitis can also follow local repetitive trauma but
other causes include infections and gout.
Hand and wrist pain
Pain from hand or wrist joints is well localised to the affected
joint, except for pain from the first carpometacarpal (CMC) joint,
commonly targeted by OA or PsA; although maximal at the thumb
base, the pain often radiates down the thumb and to the radial
aspect of the wrist. Non-articular causes of hand pain include:
24.23 Typical local causes of elbow pain
Lesion
Pain
Examination findings
Lateral humeral
epicondylitis
(e.g. traumatic ‘tennis
elbow’ or SpA-related
enthesitis)
Lateral epicondyle
Radiation to
extensor forearm
Tenderness over
epicondyle
Pain reproduced by
resisted active wrist
extension
Medial humeral
epicondylitis
(e.g. traumatic
‘golfer’s elbow’ or
SpA-related enthesitis)
Medial epicondyle
Radiation to flexor
forearm
Tenderness over
epicondyle
Pain reproduced by
resisted active wrist
flexion
Olecranon bursitis
(e.g. gout, rheumatoid
arthritis or infective,
as in tuberculosis)
Olecranon
Tender swelling
(SpA = spondyloarthritis)
• Tenosynovitis: affects flexor or extensor digital tendons.
Pain and tenderness are well localised to the tendon
lesions. There is often early-morning ‘claw-like’ digit
stiffness. De Quervain’s tenosynovitis involves the tendon
sheaths of abductor pollicis longus and extensor pollicis
brevis. It produces pain maximal over the radial aspect of
the distal forearm and wrist and marked pain on forced
ulnar deviation of the wrist with the thumb held across the
patient’s palm (Finkelstein’s sign). This test is not specific
for this lesion alone.
• Raynaud’s phenomenon : digital vasospasm triggered
mostly by cold (p. 1035).
• C6, C7 or C8 radiculopathy.
• Carpal tunnel syndrome: hand position-dependent and/or
nocturnal pain, numbness and paraesthesia of thumb and
second to fourth digits.
Hip pain
Pain from the hip joint is usually felt deep in the groin, with
variable radiation to the buttock, anterolateral thigh or knee (Fig.
24.13). Patients who report ‘hip pain’ sometimes point to greater
trochanter or buttock areas. Greater trochanter pain syndrome
is usually due to either gluteus medius insertional tendonitis/
enthesitis, trochanteric bursitis or referred pain (Box 24.24).
Pain at this site may also be referred from the lumbosacral
spine. A differential diagnosis of hip joint conditions (groin pain)
is symphysitis (SpAs, including psoriasis disease, need ruling
out). Other less common causes of pain in the hip/groin area
include inguinal hernia, adductor tendonitis and enthesitis of
anterior superior/inferior iliac spines.
Knee pain
In middle and older age, the most common cause of knee pain is
OA, the features of which are described on page 1008. Pain that
is associated with locking of the knee (sudden painful inability to
extend fully) is usually due to a meniscal tear or osteochondritis
dissecans. Referred pain from the hip may present at the knee and
is reproduced by hip, not knee, movement. Pain from periarticular
lesions is well localised to the involved structure (Box 24.25).
Anterior knee pain may be due to patellar ligament or retinacular
lesions (enthesitis, tendonitis, fat-pad syndrome) occurring typically
Rotator cuff and subacromial lesions
• Pain reproduced by resisted active movement:
Abduction: supraspinatus
External rotation: infraspinatus, teres minor
Internal rotation: subscapularis
Acromioclavicular joint
• Pain on full abduction and adduction (at 90° of forward elevation)
Bicipital (long head) tendinitis
• Tenderness over bicipital groove
• Pain reproduced by resisted active wrist supination or elbow flexion
Presenting problems in musculoskeletal disease • 999
24.24 Local causes of hip pain
Lesion
Pain
Examination findings
Gluteus medius enthesitis
Upper lateral thigh, worse on lying on
that side at night
Tenderness over greater trochanter
Trochanteric bursitis
As above
As above
Adductor tendinitis
(usually an SpA-enthesitis or
sports- related trauma lesion)
Upper inner thigh
Tenderness over adductor origin/tendon/muscle
Pain reproduced by resisted active hip adduction
Ischiogluteal enthesitis/bursitis
Buttock, worse on sitting
Tenderness over ischial prominence
Pubic symphysitis
(can mimic intra-articular hip lesions)
Medial groin pain, can radiate to inner
or even outer upper thighs
Tenderness over symphysis joint
If pain is worse on trunk curl/rectus activation under symphysis¬
resting hand, it may be insertional rectus enthesitis (SpAs)
(SpA = spondyloarthritis)
Trochanteric Hip
bursitis disease
Fig. 24.13 Pain patterns of hip disease and trochanteric pain
syndrome. The dark shading indicates sites of maximum pain.
from overuse and/or an SpA condition. Anterior knee pain is
relatively common in adolescents and may be the result of
patellar articular cartilage or ligament insertion osteochondritis.
Ankle and foot pain
Pain from the ankle (tibiotalar) joint due to OA or osteochondral
defect is felt between the malleoli and is worse on weight-bearing.
Pain from the subtalar joint (from the same lesions) is also worse
on weight-bearing. Inflammatory arthritis of either of these joints
(RA, PsA, CPPD arthritis or gout) often worsens and swells
with rest. These diagnoses can be associated with hindfoot
tenosynovitis (peroneal or posterior tibial). Pain under the heel is
typically due to plantar fasciitis. This can occur as the result of
overuse, which case it may respond to rest, padded footwear
and local glucocorticoid injections, but can also arise in SpA as
24.25 Local causes of knee pain
Lesion
Pain
Examination findings
Pre-patellar bursitis
Over patella
Tender fluctuant swelling
in front of patella
Superficial and deep
infrapatellar bursitis
and fat- pad syndrome
Anterior knee,
inferior to
patella
Tenderness in front of
(superficial) or behind
(deep) patellar tendon
Pain on full flexion
Anserine bursitis/
enthesitis
Upper medial
tibia
Tenderness (± swelling)
over upper medial tibia
Medial collateral
ligament lesions
(e.g. enthesitis)
Upper medial
tibia
Localised tenderness of
upper medial tibia
Pain reproduced by
valgus stress on partly
flexed knee
Popliteal cyst
(Baker’s cyst)
Popliteal fossa
Tender swelling of
popliteal fossa
Patellar ligament
enthesopathy
Anterior upper
tibia
Tenderness over tibial
tubercle
Osteochondritis of
patellar ligament
(Osgood-Schlatter
disease)
Anterior upper
tibia
Adolescents are affected
Pain on resisted active
knee extension
a manifestation of enthesitis. Pain affecting the back of the heel
may be due to Achilles tendinitis or enthesitis. The MTP joints
of the feet are commonly involved symmetrically in RA. The
presentation is with pain on walking felt below the metatarsal
heads, often described as ‘walking on marbles’. Patients with
active inflammation of the MTP joints have pain when the forefoot
is squeezed (p. 982). Involvement of the first MTP joint is common
in OA or PsA and is associated, respectively, with hallux valgus
and dactylitis. The hallux also a classical target in acute gout.
Morton’s neuroma is a neuropathy of an interdigital nerve and is
usually located between the third and fourth metatarsal heads.
Women are most commonly affected (tight shoes can be to
blame). Local sensory loss and a palpable tender swelling between
the metatarsal heads may be detected. Footwear adjustment,
with or without a local glucocorticoid injection, often helps but
surgical decompression may be required if symptoms persist.
1000 • RHEUMATOLOGY AND BONE DISEASE
Muscle pain and weakness
Muscle pain and weakness can arise from a variety of causes.
It is important to distinguish between a subjective feeling of
generalised weakness occurring with fatigue, and an objective
weakness with loss of muscle power and function. The former
is a non-specific manifestation of many systemic conditions.
Clinical assessment
Proximal muscle weakness suggests the presence of a myopathy
or myositis, which typically causes difficulty with standing from a
seated position, walking up steps, squatting and lifting overhead.
The causes are shown in Box 24.26. Worsening of symptoms on
exercise and post-exertional cramps suggest a metabolic myopathy,
such as glycogen storage disease (p. 370). A strong family history
and onset in childhood or early adulthood suggest muscular
dystrophy (p. 1143). Alcohol excess can cause an inflammatory
myositis and atrophy of type 2 muscle fibres. Proximal myopathy
may be a complication of glucocorticoid therapy, prolonged/severe
hypercalcaemia and osteomalacia. Myopathy and myositis can also
occur in association with many drugs (see ‘ Further information’ , p.
1060) and viral infections, including HIV; in the latter case, it may
be due to HIV itself or to treatment with zidovudine. Polymyositis
and dermatomyositis (p. 1 039) are associated with coexisting/
co-presenting malignancy, especially gonadal tumours. Clinical
examination should document the presence, pattern and severity of
muscle weakness (p. 1 081 ), assessed using the Medical Research
Council (MRC) scale (no power (0) to full power (5)).
Investigations
Investigations should include routine biochemistry and haematol¬
ogy, ESR, CRP, creatine kinase, serum 25(OH)-vitamin D, PTH,
parvovirus, hepatitis B/C, HIV and streptococcus serology,
24.26 Causes of proximal muscle pain or weakness
Inflammatory
• Polymyositis
•
Inclusion body myositis
• Dermatomyositis
•
Sarcoid
• Other autoimmune connective
•
Myasthenia gravis
tissue disease
Endocrine (Ch. 18)
• Hypothyroidism
•
Cushing’s syndrome
• Hyperthyroidism
•
Addison’s disease
Metabolic (Ch. 14)
• Myophosphorylase deficiency
•
Carnitine deficiency
• Phosphofructokinase
•
Osteomalacia (p. 1049)
deficiency
• Hypokalaemia
•
Hypercalcaemia
Genetic
• Muscular dystrophy (various; p. 1143)
Drugs/toxins
• Alcohol
•
Tumour necrosis factor
• Cocaine
inhibitors
• Glucocorticoids
• Statins and fibrates
•
Zidovudine
Infections (Ch. 11)
• Viral (HIV, cytomegalovirus,
•
Bacterial ( Clostridium
rubella, Epstein— Barr, echo)
perfringens , staphylococci,
• Parasitic (schistosomiasis,
tuberculosis, Mycoplasma)
cysticercosis, toxoplasmosis)
serum and urine protein electrophoresis, serum ACE, ANAs/
ENAs, RF, complement and myositis-specific autoantibodies
such as Jo-1 . Open muscle biopsy (site guided by MRI detection
of abnormal muscle) and electromyography (EMG) are usually
required to make the diagnosis. The initial imaging screening
for malignancy is usually a CT scan of the chest, abdomen and
pelvis; upper gastrointestinal endoscopy and colonoscopy may
also be considered.
Management
Management is determined by the cause but all patients with
muscle disease should benefit from physiotherapy and graded
exercises to maximise muscle function after the initial inflammation
is controlled.
Principles of management
The management of rheumatological disorders should be tailored
to the underlying diagnosis. Certain aspects are common to many
disorders, however, and the general principles are discussed
here. The therapeutic aims are:
• to educate patients about their disease
• to control pain, if it is present
• to optimise function
• to modify the disease process where this is possible
• to identify and treat comorbidity.
These aims are interrelated and success in one area often
benefits others. Successful management requires careful
assessment of the person as a whole. The management plan
should be individualised and patient-centred, should involve
relevant members of the multidisciplinary team, and should be
agreed and understood by both the patient and all the practitioners
that are involved. It must also take into account:
• the patient’s activity requirements and occupational and
recreational aspirations
• risk factors that may influence the disease
• the patient’s perceptions and knowledge of the condition
• medications and coping strategies that have already been
tried
• comorbid disease and its therapy
• the availability, costs and logistics of appropriate evidence-
based interventions.
The simplest and safest interventions should be tried first.
Symptoms and signs may change with time, so the management
plan for most patients will require regular review and re-adjustment.
Core interventions that should be considered for everyone with
a painful musculoskeletal condition are listed in Box 24.27. There
are also other non-pharmacological and drug options, the choice
of which depends on the nature and severity of the diagnosis.
Education and lifestyle interventions
Education
Patients must always be informed about the nature of their
condition and its investigation, treatment and prognosis, since
education can improve outcome. Information and therapist
contact can reduce pain and disability, improve self-efficacy and
reduce the health-care costs of many musculoskeletal conditions,
including OA and RA. The mechanisms are unclear but in part
may result from improved adherence. Benefits are modest but
potentially long-lasting, safe and cost-effective. Education can
be provided through one-to-one discussion, written literature,
Principles of management • 1001
KM 24.27 Interventions for patients with
rheumatic diseases
Core interventions
• Education
•
Reduction of adverse
• Aerobic conditioning
mechanical factors
• Muscle strengthening
•
Pacing of activities
• Simple analgesics
•
Appropriate footwear
• Disease-modifying therapy
•
Weight reduction if obese
Other options
• Other analgesic drugs:
•
Local glucocorticoid injections
Oral non-steroidal
•
Physical treatments:
anti-inflammatory drugs
Heat, cold, aids, appliances
Topical agents
•
Surgery
Opioid analgesics
•
Coping strategies (see Box
Amitriptyline
24.28)
Gabapentin/pregabalin
patient-led group education classes and interactive computer
programs. Inclusion of the patient’s partner or carer is often
appropriate; this is essential for childhood conditions but also
helps in many chronic adult conditions, such as RA and FM.
For children and adolescents with chronic diseases such as
JIA, education and support of the whole family, schooling and
psychological support is essential and best delivered through a
multidisciplinary team.
Exercise
Several types of exercise can be prescribed:
• Aerobic fitness training can produce long-term reduction in
pain and disability. It improves well-being, encourages
restorative sleep and benefits common comorbidity, such
as obesity, diabetes, chronic heart failure and hypertension.
• Local strengthening exercise for muscles that act over
compromised joints also reduces pain and disability,
with improvements in the reduced muscle strength,
proprioception, coordination and balance that associate
with chronic arthritis. ‘Small amounts often’ of
strengthening exercise are better than protracted sessions
performed infrequently.
• Weight-bearing exercise is of value in osteoporosis, where
it can result in modest increases in bone density and slow
bone loss.
| Joint protection
Excessive impact-loading and adverse repetitive use of a
compromised joint or periarticular tissue can worsen symptoms
in patients with arthritis. This can be mitigated by cessation of
contact sports and by pacing of activities by dividing physical
tasks into shorter segments with brief breaks in between. Other
strategies include adaptations to machinery or tools at the
workplace; the use of shock-absorbing footwear with thick soft
soles, which can reduce impact-loading through feet, knees, hips
and back; and the use of a walking stick on the contralateral
side to a painful hip, knee or foot.
Non-pharmacological interventions
Physical and occupational therapy
Local heat, ice packs, wax baths and other local external applica¬
tions can induce muscle relaxation and provide temporary relief
of symptoms in a range of rheumatic diseases.
Hydrotherapy induces muscle relaxation and facilitates
enhanced movement in a warm, pain-relieving environment
without the restraints of gravity and normal load-bearing. Various
manipulative techniques may also help improve restricted
movement. The combination of these with education and therapist
contact enhances their benefits.
Splints can give temporary rest and support for painful joints
and periarticular tissues, and can prevent harmful involuntary
postures during sleep. Prolonged rest must be avoided, however.
Orthoses are more permanent appliances used to reduce instability
and excessive abnormal movement. They include working wrist
splints, knee orthoses, and iron and T-straps to control ankle
instability. Orthoses are particularly suited to severely disabled
patients in whom a surgical option is inappropriate and often
need to be custom-made for the individual.
Aids and appliances can provide dignity and independence
for patients with respect to activities of daily living. Common
examples are a raised toilet seat, raised chair height, extended
handles on taps, a shower instead of a bath, thick-handled
cutlery, and extended ‘hands’ to pull on tights and socks. Full
assessment and advice from an occupational therapist maximise
the benefits of these (Box 24.27).
Self-help and coping strategies
These help patients to cope better with, and adjust to, chronic
pain and disability. They may be useful at any stage but are
particularly so for patients with incurable problems, who have
tried all available treatment options. The aim is to increase
self-management through self-assessment and problem-solving,
so that patients can recognise negative but potentially remediable
aspects of their mood (stress, frustration, anger or low self-esteem)
and their situation (physical, social, financial). These may then
be addressed by changes in attitude and behaviour, as shown
in Box 24.28.
Involvement of the spouse or partner in mutual goal-setting
can improve partnership adjustment. Such approaches are often
an element of group education classes and pain clinics but may
require more formal clinical psychological input.
Tailored multidisciplinary approaches are required for patients
with JIA and other chronic childhood diseases, dependent on
age and maturity. Adolescents and young adults have specific
demands, different to those of young children and adults, which
are influenced by many issues in their lives impinging on the
disease process, its impact and their ability to cope with it.
Weight control
Obesity aggravates pain at most sites through increased
mechanical strain and is a risk factor for progression of joint
damage in patients with OA and other types of arthritis. This
should be explained to obese patients and strategies offered
i
• Yoga and relaxation techniques to reduce stress
• Avoidance of negative situations or activities that produce stress
and increase in pleasant activities that give satisfaction
• Information and discussion to alter beliefs about and perspectives
on disease
• Reduction or avoidance of catastrophising and maladaptive pain
behaviour
• Imagery and distraction techniques for pain
• Expansion of social contact and better use of social services
24.28 Self-help and coping strategies
1002 • RHEUMATOLOGY AND BONE DISEASE
on how to lose and maintain an appropriate weight (p. 700).
Excessive weight loss can be counterproductive and adults
with a BMI of <20 kg/m2 are at increased risk of fractures.
Patients should therefore be advised to maintain BMI within
the 20-25 g/m2 range.
Surgery
A variety of surgical interventions can relieve pain and conserve
or restore function in patients with bone, joint and periarticular
disease (Box 24.29). Soft tissue release and tenosynovectomy
can reduce inflammatory symptoms, improve function and
prevent or retard tendon damage for variable periods, sometimes
indefinitely. Synovectomy does not prevent disease progression
but may be indicated for pain relief when drugs, physical
Bl 24.29 Surgical procedures in rheumatology and
bone disease
Procedure
Indication
Soft tissue release
Carpal tunnel
Tarsal tunnel
Flexor tenosynovectomy
Ulnar nerve transposition
Fasciotomy
Median nerve compression
Posterior tibial nerve entrapment
Relief of ‘trigger’ fingers
Ulnar nerve entrapment at elbow
Severe Dupuytren’s contracture
Tendon repairs and transfers
Fland extensor tendons
Thumb and finger flexor tendons
Extensor tendon rupture
Flexor tendon rupture
Synovectomy
Wrist and extensor tendon
sheath (+ excision of radial
head)
Knee synovectomy
Pain relief and prevention of
extensor tendon rupture in RA,
resistant inflammatory synovitis
Resistant inflammatory synovitis
Osteotomy
Femoral osteotomy
Tibial osteotomy
Early 0A of hip
Unicompartmental knee 0A
Deformed tibia in OA or Paget’s
disease
Excision arthroplasty
First metatarsophalangeal joint
(Keller’s procedure)
Radial head
Lateral end of clavicle
Metatarsal head
Painful hallux valgus
Painful distal radio-ulnar joint
Painful acromioclavicular joint
Painful subluxed
metatarsophalangeal joints
Joint replacement arthroplasty
Knee, hip, shoulder, elbow
Painful damaged joints in OA
and RA
Arthrodesis
Wrist
Ankle/subtalar joints
Damaged joint: pain relief,
improvement of grip
Damaged joint: pain relief,
stabilisation of hindfoot
Fracture repair
Flip arthroplasty
External fixation
Intramedullary nailing
Screw, plating and wiring
Fractured neck of femur
Multiple fractures, open fractures
Tibial and femur fractures
Wrist and other fractures
Other procedures
Nerve root decompression
Kyphoplasty
Vertebroplasty
Spinal stenosis, nerve entrapment
Painful vertebral fracture (evidence
base poor)
Painful vertebral fracture (evidence
base poor)
therapy and intra-articular injections have provided insufficient
relief. The main approaches for damaged joints are osteotomy
(cutting bone to alter joint mechanics and load transmission),
excision arthroplasty (removing part or all of the joint), joint
replacement (insertion of prosthesis in place of the excised
joint) and arthrodesis (joint fusion). Surgical fixation of fractures
is frequently required in patients with osteoporosis and other
bone diseases.
The main aims of surgery are to provide pain relief and improve
function and quality of life. If surgery is to be successful, the aims
and consequences of each operation should be considered as
part of an integrated programme of management and rehabilitation
by multidisciplinary teams of surgeons, allied health professionals
and physicians, and carefully explained to the patient. Assessment
of motivation, social support and environment is no less important
than careful consideration of patients’ general health, their risks for
major surgery, the extent of disease in other joints, and their ability
to mobilise following surgery. For some severely compromised
people, pain relief and functional independence are better served
by provision of a suitable wheelchair, home adjustments and
social services than by surgery that is technically successful but
following which the patient cannot mobilise.
Pharmacological treatment
Analgesics
Paracetamol (1 g up to 4 times daily) is the oral analgesic of
first choice for mild to moderate pain. It is thought to work by
inhibiting prostaglandin synthesis in the brain while having little
effect on peripheral prostaglandin production. It is well tolerated
and has few adverse effects and drug interactions. An increased
risk of gastrointestinal events and cardiovascular disease has
been reported with chronic usage in observational studies,
but this may be due to channelling of patients at higher risk of
these events for treatment with paracetamol rather than NSAID.
Paracetamol can be combined with codeine (co-codamol) or
di hydrocodeine (co-dydramol). These compound analgesics are
more effective than paracetamol but have more side-effects,
including constipation, headache and delirium, especially in
the elderly. The centrally acting opioid analgesics tramadol and
meptazinol may be useful for temporary control of severe pain
unresponsive to other measures but can cause nausea, bowel
upset, dizziness and somnolence, and withdrawal symptoms
after chronic use. The non-opioid analgesic nefopam (30-90 mg
3 times daily) can help moderate pain, though side-effects
(nausea, anxiety, dry mouth) often limit its use. Patients with
severe or intractable pain may require strong opioid analgesics,
such as oxycodone and morphine.
|jlon-steroidal anti-inflammatory drugs
NSAIDs are among the most widely prescribed drugs but their use
has declined over recent years because long-term prescription
is associated with an increased risk of cardiovascular disease.
Oral NSAIDs are useful in the treatment of a range of rheumatic
diseases with an inflammatory component. There is variability in
response and patients who do not gain benefit from one NSAID
may well do so with another. They inhibit the cyclo-oxygenase
(COX) and prostaglandin H synthase enzymes, which convert
arachidonic acid, derived from membrane phospholipids, to
prostaglandins and leukotrienes by the COX and 5-lipoxygenase
pathways, respectively (Fig. 24.14). There are two COX isoforms,
Principles of management • 1003
Membrane
phospholipid
Phospholipase A2
Arachidonic
acid
Prostaglandins NSAID
Prostaglandins
I
Mucosal integrity
Platelet aggregation
Renal blood flow
i
Pain
Inflammation
Fig. 24.14 Mechanism of action of non-steroidal anti-inflammatory
drugs.
encoded by different genes. The COX-1 enzyme is constitutively
expressed in gastric mucosa, platelets and kidneys, and
production of prostaglandins at these sites protects against
mucosal damage and regulates platelet aggregation and renal
blood flow. The COX-2 enzyme is induced at sites of inflammation,
producing prostaglandins that cause local pain and swelling.
Inflammation also up-regulates COX-2 in the spinal cord, where
it modulates pain perception. Ibuprofen, diclofenac and naproxen
are non-selective drugs that inhibit both COX enzymes, whereas
celecoxib and etoricoxib are selective inhibitors of COX-2. While
NSAIDs have anti-inflammatory activity, they are not thought to
have a disease-modifying effect in either OA or inflammatory
rheumatic diseases.
Non-selective NSAIDs can damage the gastric and duodenal
mucosal barrier and are associated with an increased risk of
upper gastrointestinal ulceration, bleeding and perforation. The
adjusted increased risk (odds ratio) of bleeding or perforation from
non-selective NSAIDs is 4-5, though differences exist between
NSAIDs (Box 24.30). Dyspepsia is a poor guide to the presence
of NSAID-associated ulceration and bleeding, and the principal
risk factors are shown in Box 24.31 . Co-prescription of a proton
pump inhibitor (PPI) or misoprostol (200 pig twice or 3 times daily)
reduces the risk of NSAID-induced ulceration and bleeding but
H2-antagonists in standard doses are ineffective. The COX-2
selective NSAIDs are much less likely to cause gastrointestinal
toxicity but benefit is attenuated in patients on low-dose aspirin.
The National Institute for Health and Care Excellence (NICE)
guidelines advise that a PPI should be co-prescribed with all
NSAIDs, including COX-2-selective NSAIDs, even though the
risk of gastrointestinal events with these is low. Since chronic
PPI therapy is associated with an increased risk of hip fracture,
the merits of giving PPI therapy with a COX-2-selective drug
need to be weighed up carefully.
Other side-effects of NSAIDs include fluid retention and renal
impairment due to inhibition of renal prostaglandin production,
^9 24.30 Commonly used NSAIDs and their risk of
gastrointestinal bleeding and perforation
Idiosyncratic
Daily adult
Doses/
side-effects,
Drug
dose
day
comments
Low risk
Celecoxib
1 00-200 mg
1-2
Selective C0X-2
inhibitor
Etoricoxib
60-120 mg
1
Selective C0X-2
inhibitor
Medium risk
Ibuprofen
1600-2400 mg
3-4 1
Gastrointestinal adverse
Naproxen
500-1 000 mg
1-2
1 effects more likely than
Diclofenac
75-150 mg
2-3 J
with COX-2 inhibitors,
even with PPI therapy
High risk
Indometacin
50-200 mg
3-4 1
i High incidence of
Ketoprofen
100-200 mg
2-4 J
i dyspepsia and CNS
side-effects
Piroxicam
20-30 mg
1-2
Restricted use in those
>60 years
(CNS = central nervous system; COX
= cyclo-oxygenase; PPI = proton pump
inhibitor)
24.31 Risk factors for NSAID-induced ulcers
• Age >60 years*
• Past history of peptic ulcer*
• Past history of adverse event with NSAID
• Concomitant glucocorticoid use
• High-dose or multiple NSAIDs
• High-risk NSAID (see Box 24.30)
*The most important risk factors.
24.32 Recommendations for the use of NSAIDs
• Use the lowest dose for the shortest time possible to control
symptoms
• Avoid NSAIDs in patients on warfarin
• Allow 2-3 weeks to assess efficacy. If response is inadequate,
consider a trial of another NSAID
• Never prescribe more than one NSAID at a time
• Co-prescribe a proton pump inhibitor for patients with risk factors
for gastrointestinal adverse effects (see Box 24.31)
• Avoid in patients with vascular disease
non-ulcer-associated dyspepsia, abdominal pain and altered
bowel habit, and rashes. Interstitial nephritis, asthma and
anaphylaxis can also occur but are rare. Recommendations for
NSAID prescribing are summarised in Box 24.32. Because of
the risk of adverse effects, NSAIDs should be used with great
care in the elderly (Box 24.33).
Ijopical agents
Topical NSAID creams and gels and capsaicin cream (chilli
extract; 0.025%) can help in the treatment of OA and superficial
periarticular lesions affecting hands, elbows and knees. They may
be used as monotherapy or as an adjunct to oral analgesics.
Topical NSAIDs can penetrate superficial tissues and even
1004 • RHEUMATOLOGY AND BONE DISEASE
reach the joint capsule, though intrasynovial levels mainly reflect
blood-borne drug delivery. Capsaicin selectively binds to the
protein transient receptor potential vanilloid type 1 (TRPV1),
which is a heat-activated calcium channel on the surface of
peripheral type C nociceptor fibres. Initial application causes
a burning sensation but continued use depletes presynaptic
substance P, with subsequent pain reduction that is optimal
after a period of 1-2 weeks.
| Disease-modifying antirheumatic drugs
Disease-modifying antirheumatic drugs (DMARDs) are a group
of small-molecule inhibitors of the immune response. They are
employed in a range of inflammatory rheumatic diseases, as well
as in other chronic inflammatory conditions. The most common
indications are summarised in Box 24.34. Most of these drugs
have the potential to cause bone marrow suppression or liver
dysfunction and they require regular blood monitoring. Monitoring
requirements for commonly used DMARDs are also summarised
in Box 24.34. If toxicity occurs, treatment may need to be
stopped temporarily and resumed at a lower dose. If toxicity
is severe, therapy may have to be withdrawn completely and
another drug substituted.
• Gastrointestinal complications: age is a strong risk factor for
bleeding and perforation, and for peptic ulceration. Elderly patients
are more likely to die if they suffer NSAID-associated bleeding or
perforation.
• Cardiovascular disease: use NSAIDs with caution in patients with
cardiovascular disease. Therapy with NSAIDs may exacerbate
hypertension and heart failure.
• Renal disease: use of NSAIDs may cause renal impairment.
Methotrexate
Methotrexate (MTX) is the core DMARD in RA, JIA and
PsA. It inhibits folic acid reductase, preventing formation of
tetrahydrofolate, which is necessary for DNA synthesis in
leucocytes and other cells. It is given orally in a starting dose
of 10-15 mg weekly and escalated in 2.5 mg increments every
2-4 weeks to a maximum of 25 mg weekly until benefit or toxicity
occurs. Folic acid (5 mg/week) should be co-prescribed to be
taken the day after MTX since it reduces adverse effects without
impairing efficacy. Benefit is usually observed after 4-8 weeks
but treatment should continue for 3 weeks before the conclusion
is reached that MTX has been ineffective. The most common
adverse effects are nausea, vomiting and malaise, which usually
occur one 1-2 days after the weekly dose. Individuals who
experience these effects can sometimes be successfully treated
with subcutaneous MTX. Patients should be warned of drug
interaction with sulphonamides and the importance of avoiding
excess alcohol, which enhances MTX hepatotoxicity. Acute
pulmonary toxicity (pneumonitis) is rare but can occur at any
time during treatment, and patients should be warned to stop
therapy and seek advice if they develop any new respiratory
symptoms. If pneumonitis occurs, treatment should be withdrawn
and high-dose glucocorticoids given. MTX must be co-prescribed
with robust contraception in women of child-bearing potential
and treatment must be stopped for 3 months in advance of
planning a pregnancy.
Sulfasalazine
Sulfasalazine (SSZ) can be used alone and or combination with
MTX and another DMARD. Its mechanism of action is incompletely
understood. Nausea and gastrointestinal intolerance are the main
adverse effects but leucopenia, abnormal LFTs and rashes may
also occur. The usual starting dose is 500 mg daily, escalating
in 500 mg increments every 2 weeks to a maintenance dose
of 2-4 g daily until benefit or toxicity occurs. Benefit may be
24.33 Use of oral NSAIDs in old age
24.34 Disease-modifying antirheumatic drugs
Drug
Maintenance dose
FBC
Monitoring
LFs
Other
Indications
Methotrexate
10-25 mg weekly orally
y
y
RA, PsA, AxSpA, JIA
Sulfasalazine
2-4 g daily orally
y
y
RA, PsA, AxSpA, JIA
Hydroxychloroquine
200-400 mg daily orally
-
-
Visual function
RA, SLE
Leflunomide
10-20 mg daily orally
y
y
BP
RA, JIA, PsA
Azathioprine
1-2.5 mg/kg daily orally
y
y
SLE, S V
Apremilast
30 mg twice daily orally
-
-
-
PsA
Tofacitinib
5 mg twice daily orally
y
y
Infection
RA
Baricitinib
2-4 mg daily orally
y
y
Infection
RA
Cyclophosphamide
2 mg/kg daily orally
1 5 mg/kg IV
y
y
eGFR
SLE, S V
Mycophenolate mofetil (MMF)
2-4 g daily orally
y
y
-
SLE, S V
Gold (myocrisin)
50 mg 4-weekly IM
y
-
Urinalysis
RA
Penicillamine
500-1500 mg daily orally
y
y
Urinalysis
RA
Ciclosporin A
3-5 mg/kg daily orally
-
-
BP, eGFR
RA, PsA
*Monitoring tests are usually done every 2 weeks on initiation of treatment for 6 weeks, then monthly for 3 months, then 3-monthly.
(AxSpA = axial spondyloarthritis; BP = blood pressure; eGFR = estimated glomerular filtration rate; FBC = full blood count; IM = intramuscular; IV = intravenous; JIA =
juvenile idiopathic arthritis; LFTs = liver function tests; PsA = psoriatic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; S V = systemic vasculitis)
Principles of management • 1005
observed after 4-8 weeks but treatment should be continued
for 3 months before the conclusion is reached that it has been
ineffective. Orange staining of urine and contact lenses may occur.
Hydroxychloroquine
Hydroxychloroquine (HCQ) is used in the treatment of RA and
SLE in a dose of 200-400 mg daily. Its mechanism of action
is incompletely understood. A wide range of side-effects can
potentially occur but HCQ is usually well tolerated in practice.
With long-term use, there is a risk of ocular toxicity due to
accumulation in the retina, although this is uncommon. It is usual
to check visual function before starting treatment and to repeat
this periodically while treatment is continued. HCQ is generally
considered to be safe during pregnancy
Leflunomide
Leflunomide can be used alone or in combination with other drugs
in a dose of 10-20 mg/day. It works by inhibiting dihydro-orotate
dehydrogenase, an enzyme used by activated lymphocytes to
synthesise pyrimidines necessary for DNA synthesis. It has low
marrow toxicity but may cause liver dysfunction, hypertension and
hirsutism. It must be co-prescribed with robust contraception in
women of child-bearing potential. Treatment must be stopped
for a period of 2 years in advance of planning a pregnancy.
Azathioprine
Azathioprine is most commonly used in vasculitis and SLE.
It is metabolised to 6-mercaptopurine (6-MP), which blocks
lymphocyte proliferation by inhibiting DNA synthesis. The typical
starting dose is 1 mg/kg body weight per day, increasing to
2.5 mg/kg until a response is observed or toxicity occurs.
Bone marrow suppression is the most important side-effect but
nausea may also occur. Genetic polymorphisms in the enzyme
thiopurine S-methyltransferase (TPMT) influence catabolism of
6-MP and sometimes genetic testing for TPMT variants is done
to guide dosages. Allopurinol inhibits catabolism of azathioprine,
necessitating a 75% reduction in azathioprine dose.
Apremilast
Apremilast is used in the treatment of PsA. It works by inhibiting
phosphodiesterase D4 in leucocytes, which in turn suppresses
production of pro-inflammatory cytokines, thereby reducing
inflammation. Apremilast is given orally in a dose of 30 mg twice
daily. The main adverse effects are gastrointestinal upset, weight
loss and an increased risk of depression.
Janus-activated kinase inhibitors
Janus-activated kinase (JAK) inhibitors work by inhibiting JAK
enzymes, which are a family of intracellular signalling molecules
that play a key role in transducing the effects of several pro-
inflammatory cytokines. They are indicated for patients with RA
who have responded inadequately to standard DMARDs and
provide an alternative to biologic treatments. Two JAK inhibitors
are currently available: tofacitinib, which is given orally in a dose
of 5 mg twice daily, and baricitinib, which is given orally in a
dose of 2-4 mg once daily. The main adverse effects are an
increased risk of opportunistic infections, hepatotoxicity and
haematological toxicity.
Cyclophosphamide
Cyclophosphamide is a cytotoxic alkylating agent that cross-links
DNA and halts cell division, causing immunosuppression. It is
mainly used to induce remission in life-threatening systemic
vasculitis and SLE. It can be given orally in a dose of 2 mg/kg/
day for 3-6 months or intravenously in a dose of 1 5 mg/kg every
3-4 weeks on 6-8 occasions. Adverse effects include nausea,
anorexia, vomiting, bone marrow suppression, cardiac toxicity,
alopecia and haemorrhagic cystitis. The risk of cystitis can be
mitigated by co-administration of mesna (2-mercaptoethane
sulfonate, which binds its urotoxic metabolites) and a high
fluid intake.
Mycophenolate mofetil
Mycophenolate mofetil (MMF) works by inhibiting inosine
monophosphate dehydrogenase, a rate-limiting enzyme in the
synthesis of guanosine nucleotides in lymphocytes. MMF is
frequently used in SLE and vasculitis in doses of 2-4 g daily
orally. Haematological toxicity is the main adverse effect.
Other DMARDs
Gold, penicillamine and ciclosporin A have been superseded
by more effective alternatives but are still occasionally used.
Gold (sodium aurothiomalate, myocrisin) is indicated for RA. Its
mechanism of action is unknown. It is given by intramuscular
injection of 50 mg weekly after an initial test dose of 10 mg.
Treatment is continued for up to 6 months until there is clinical
benefit or adverse effects occur. If there is benefit, the frequency
of injections is reduced to two-weekly and then monthly, providing
that the response is maintained. Penicillamine is indicated for RA
but is poorly tolerated. It is given in a starting dose of 1 25-250 mg
daily on an empty stomach, and increased in 125 mg increments
every 6 weeks to a maximum dose of 1 500 mg daily until there
is clinical benefit or adverse effects occur. Ciclosporin A is a
calcineurin inhibitor that inhibits lymphocyte activation. It is
occasionally used in RA at a dose of 2.5-4 mg/kg/day orally.
Glucocorticoids
Glucocorticoids have powerful anti-inflammatory and
immunosuppressive effects. They promote apoptosis of many
immune cells and activation of a wide range of pro-inflammatory
signalling pathways. They are used orally, intravenously,
intramuscularly and by intra-articular injection in the treatment
of a wide range of inflammatory rheumatic diseases, as well as
by local injection in patients with soft tissue rheumatism (p. 1026).
Systemic glucocorticoids
Systemic glucocorticoids are widely used in moderate to
high doses to induce remission in early RA and in systemic
and polyarticular JIA. They are also used at lower doses for
maintenance therapy and in the treatment of flares in RA, PsA and
axSpA with peripheral joint involvement. Glucocorticoids should
be used with caution in PsA because of a rebound increase in
activity of psoriasis when the effects wear off. Glucocorticoids
are also used to induce remission and to maintain disease
control in giant cell arteritis, polymyalgia rheumatica, vasculitis
and SLE.
Intra-articular and intramuscular glucocorticoids
Intra-articular glucocorticoids are employed in the treatment of a
wide range of inflammatory arthritides and are primarily indicated
when there are one or two problem joints with persistent synovitis
despite good general control of the disease. Methylprednisolone
is one of the most widely used, typically in doses of 40-80 mg.
Intramuscular methylprednisolone (80-120 mg) is a useful way
of controlling inflammatory arthritis while waiting for the effects
of a newly introduced DMARD to take effect, and is also helpful
1006 • RHEUMATOLOGY AND BONE DISEASE
in patients with stable disease who have a disease flare where a
major change in DMARD strategy is not thought to be necessary.
Biologies
The term ‘biologic’ refers to a group of medications that includes
monoclonal antibodies, fusion proteins and decoy receptors,
which are used in the treatment of several inflammatory rheumatic
diseases. They are targeted towards specific cytokines, receptors
and other cell-surface molecules regulating the immune response
(Fig. 24.15). The main adverse effect of the biologies used
in inflammatory diseases is an increased risk of infections.
Biologies are not carcinogenic, but patients who develop cancer
while on treatment may exhibit accelerated progression of the
tumour due to suppression of the immune response. Treatment
costs are much higher than with DMARDs and many countries
have set guidelines restricting their use to patients who have
active disease despite having had an adequate trial of standard
therapies. Their mechanisms of action, dosages and indications
are summarised in Box 24.35.
Anti-TNF therapy
A variety of inhibitors of the pro-inflammatory cytokine TNF have
been developed. Most are monoclonal antibodies that bind to and
neutralise TNF, but etanercept is a decoy receptor that prevents
TNF binding to its receptor. Anti-TNF therapy has traditionally
been used as the first-line biological drug in RA when DMARD
therapy has been incompletely effective. It has also traditionally
been used as the first-line biologic in PsA and AxSpA, but anti
IL-1 7A therapy (see below) has emerged as an equally effective
alternative. Anti-TNF therapy is usually co-prescribed with MTX in
RA and PsA as this increases efficacy, but TNF inhibitors are also
effective as monotherapy. They are usually given as monotherapy
in AxSpA unless there is peripheral joint involvement. Anti-TNF
therapy is contraindicated in patients with active infections such
as untreated tuberculosis and those with indwelling catheters,
due to the high risk of infection. Other contraindications are
severe heart failure and multiple sclerosis, both of which may
be worsened by treatment.
Rituximab
Rituximab is an antibody directed against the CD20 receptor,
which is expressed on B lymphocytes and immature plasma
cells. It causes profound B-cell lymphopenia for several months
due to complement-mediated lysis of cells that express CD20.
Rituximab is indicated in patients with RA who have not responded
adequately to first-line therapy but is typically employed as a
third-line treatment when TNF inhibitors have been ineffective. It
is also used in place of cyclophosphamide to induce remission
in patients with ANCA-positive vasculitis. In RA, the treatment
can be repeated when signs of improvement are wearing off
(anything from 6 months to 1 year or longer). In ANCA-positive
vasculitis, a single cycle of treatment may last for up to 1 8 months.
Rituximab is sometimes used off-label in SLE, even though
clinical trials did not show efficacy. Adverse effects include
hypogammaglobulinaemia, infusion reactions, an increased risk of
infections and, rarely, progressive multifocal leucoencephalopathy
(PML; p. 1123), a serious and potentially fatal infection of the
CNS caused by reactivation of JC virus.
Belimumab
Belimumab is indicated in SLE. It is a monoclonal antibody that
blocks the effects of the cytokine B-cell-activating factor of the
TNF family (BAFF), which is required for B-cell survival and
function. It is usually given when patients have had an inadequate
response to glucocorticoids and hydroxychloroquine. The main
Fig. 24.15 Targets for biologic therapies in
inflammatory rheumatic diseases. Biologic
treatments for inflammatory rheumatic diseases
work by targeting key cytokines and other
molecules involved in regulating the immune
response. See page 64 for more details. (BAFF
= B-cell-activating factor of the TNF family;
CD = cluster of differentiation; IL = interleukin;
TNF-a = tumour necrosis factor alpha;
TNFi = inhibitor of tumour necrosis factor)
Osteoarthritis • 1007
24.35 Biological drugs for inflammatory
rheumatic disease
Maintenance
Mechanism of
Drug
dose
action
Indications
Etanercept
50 mg weekly
Decoy receptor
RA, PsA,
SC
for TNF-a
AxSpA, JIA
Infliximab
3-5 mg/kg
8-weekly IV
Adalimumab
40 mg
2-weekly SC
1 Antibody to
RA, PsA,
Certolizumab
200 mg
2-weekly SC
1 TNF-a
AxSpA, JIA
Golimumab
50 mg
4-weekly SC -
Rituximab
2x1 g
Antibody to
RA,
2 weeks apart
CD20; destroys
vasculitis
IV
B cells
Belimumab
1 0 mg/kg
Antibody to
SLE
4-weekly IV
BAFF; inhibits
B-cell activation
Abatacept
125 mg
Inhibits T-cell
RA
weekly SC or
1 0 mg/kg
4-weekly IV
activation
Tocilizumab
1 62 mg weekly
Blocks IL-6
RA, JIA
SC or
8 mg/kg
8-weekly IV
receptor
Ustekinumab
45 mg
Antibody to
PsA
1 2-weekly SC
IL-12 and IL-23
Secukinumab
150 mg
Antibody to
PsA, AxSpA
4-weekly SC
IL-17A
Anakinra
100 mg daily
Decoy receptor
RA, CAPS,
SC
for IL-1
A0SD
Canakinumab
1 50 mg or
Antibody to
CAPS, sJIA,
2 mg/kg
8-weekly SC
IL-1 (3
A0SD, gout
(A0SD = adult-onset Still’s disease; AxSpA = axial spondyloarthritis; BAFF =
B-cell-activating factor of the TNF family; CAPS = cryopyrin-associated periodic
syndromes; CD =
cluster of differentiation; IL = interleukin; IV =
intravenous;
JIA = juvenile idiopathic arthritis; PsA =
psoriatic arthritis; RA =
rheumatoid
arthritis; SC = subcutaneous; sJIA = systemic juvenile inflammatory arthritis;
SLE = systemic lupus erythematosus; TNF-a = tumour necrosis factor alpha)
adverse effects are an increased risk of infection, leucopenia
and infusion reactions.
Abatacept
Abatacept is a fusion protein in which the Fc domain of IgG
has been combined with the extracellular domain of CTLA4,
which blocks T-cell activation by acting as a decoy for CD28,
a co-stimulatory molecule necessary for T-cell activation
(p. 69). It is indicated in patients with RA who have not responded
adequately to first-line therapy but is typically employed as a
third-line treatment when TNF inhibitors have been ineffective.
The main adverse effect is an increased risk of infections.
Tocilizumab
Tocilizumab is a monoclonal antibody to the IL-6 receptor. It is
indicated in patients with RA who have not responded adequately
to first-line therapy or to TNF inhibitors. It is sometimes employed
as a third-line treatment when TNF inhibitors have been ineffective.
An exception is when patients are MTX-intolerant, in which case
it is often used as a first-line therapy, based on a randomised
trial in which it showed greater efficacy than the TNF inhibitor
adalimumab. Adverse effects include leucopenia, abnormal
LFTs, hypercholesterolaemia, hypersensitivity reactions and an
increase risk of diverticulitis.
Ustekinumab
Ustekinumab is an antibody to the p40 protein, which is a
subunit of IL-23 and IL-12. It is indicated in patients with PsA
who have not responded adequately to first-line therapy with
other biologies. Adverse effects include an increased risk of
infections, hypersensitivity reactions and an exfoliative dermatitis.
Secukinumab
Secukinumab is a monoclonal antibody to IL-1 7A. It is indicated in
patients with PsA and axSpA, including ankylosing spondylitis, and
who have not responded adequately to first-line therapy. Adverse
effects include an increased risk of infections, nasopharyngitis
and headache.
Anakinra
Anakinra is a decoy receptor for IL-1. It is occasionally used
in RA but is less effective than other biological drugs. A more
frequent indication is for the treatment of adult-onset Still’s
disease (p. 1 040) and in cryopirin-associated periodic syndromes
(p. 81). Adverse effects include an increased risk of infections,
hypersensitivity reactions and neutropenia.
Canakinumab
Canakinumab is indicated for the treatment of systemic JIA (Still’s
disease), adult-onset Still’s disease, familial fever syndromes and
acute flares of gout resistant to other treatments. It is a monoclonal
antibody directed against the pro- inflammatory cytokine IL-1 (3.
The usual maintenance dose in adults is 1 50-300 mg SC every
8 weeks. Adverse effects include an increased risk of infections,
hypersensitivity reactions and neutropenia.
Osteoarthritis
Osteoarthritis (OA) is by far the most common form of arthritis
and is a major cause of pain and disability in older people. It
is characterised by focal loss of articular cartilage, subchondral
osteosclerosis, osteophyte formation at the joint margin, and
remodelling of joint contour with enlargement of affected joints.
Epidemiology
The prevalence rises progressively with age and it has been
estimated that 45% of all people develop knee OA and 25% hip
OA at some point during life. Although some are asymptomatic,
the lifetime risk of having a total hip or knee replacement for OA
in someone aged 50 is about 1 1 % for women and 8% for men
in the UK. There are major ethnic differences in susceptibility:
the prevalence of hip OA is lower in Africa, China, Japan and
the Indian subcontinent than in European countries, and that
of knee OA is higher.
Pathophysiology
OA is a complex disorder with both genetic and environmental
components (Box 24.36). Genetic factors are recognised as
playing a key role in the pathogenesis of OA. Family-based
studies have estimated that the heritability of OA ranges from
about 43% at the knee to between 60% and 65% at the hip and
1008 • RHEUMATOLOGY AND BONE DISEASE
24.36 Risk factors for osteoarthritis
Genetics
Adverse biomechanics
• Skeletal dysplasias
• Meniscectomy
• Polygenic inheritance
• Ligament rupture
Developmental abnormalities
• Paget’s disease
• Developmental dysplasia of
Obesity
the hip
Trauma
• Slipped femoral epiphysis
Hormonal
Repetitive loading
• Oestrogen deficiency
• Farmers
• Aromatase inhibitors
• Miners
• Elite athletes
hand, respectively. In most cases, the inheritance is polygenic
and mediated by several genetic variants of small effect. OA can,
however, be a component of multiple epiphyseal dysplasias, which
are caused by mutations in the genes that encode components
of cartilage matrix. Structural abnormalities, such as slipped
femoral epiphysis and developmental dysplasia of the hip, are also
associated with a high risk of OA, presumably due to abnormal
load distribution across the joint. Similar mechanisms probably
explain the increased risk of OA in patients with limb deformity
secondary to Paget’s disease of bone. Biomechanical factors
play an important role in OA related to certain occupations, such
as farmers (hip OA), miners (knee OA) and elite or professional
athletes (knee and ankle OA). It has been speculated that the
higher prevalence of knee OA in the Indian subcontinent and East
Asia might be accounted for by squatting. There is also a high
risk of OA in people who have had destabilising injuries, such as
cruciate ligament rupture, and those who have had meniscetomy.
For most individuals, however, participation in recreational sport
does not appear to increase the risk significantly. There is a
strong association between obesity and OA, particularly of the
hip. This is thought to be due partly to biomechanical factors
but it has also been speculated that cytokines released from
adipose tissue may play a role. Oestrogen appears to play a
role; lower rates of OA have been observed in women who use
hormone replacement therapy (HRT), and women who receive
aromatase inhibitor therapy for breast cancer often experience
a flare in symptoms of OA.
Degeneration of articular cartilage is the defining feature of
OA. Under normal circumstances, chondrocytes are terminally
differentiated cells but in OA they start dividing to produce
nests of metabolically active cells (Fig. 24.16A). Initially, matrix
components are produced by these cells at an increased rate, but
at the same time there is accelerated degradation of the major
structural components of cartilage matrix, including aggrecan
and type II collagen (see Fig. 24.5, p. 987). Eventually, the
concentration of aggrecan in cartilage matrix falls and makes the
cartilage vulnerable to load-bearing injury. Fissuring of the cartilage
surface (‘fibrillation’) then occurs, leading to the development
of deep vertical clefts (Fig. 24.1 6B), localised chondrocyte
death and decreased cartilage thickness. This is initially focal,
mainly targeting the maximum load-bearing part of the joint,
but eventually large parts of the cartilage surface are damaged.
Calcium pyrophosphate and basic calcium phosphate crystals
often become deposited in the abnormal cartilage.
OA is also accompanied by abnormalities in subchondral bone,
which becomes sclerotic and the site of subchondral cysts (Fig.
24.16C). Fibrocartilage is produced at the joint margin, which
undergoes endochondral ossification to form osteophytes. Bone
Fig. 24.16 Pathological changes in osteoarthritis. [A] Abnormal nests
of proliferating chondrocytes (arrows) interspersed with matrix devoid of
normal chondrocytes. [B Fibrillation of cartilage in OA. [C] X-ray of knee
joint affected by OA, showing osteophytes at joint margin (white arrows),
subchondral sclerosis (black arrows) and a subchondral cyst (open arrow).
remodelling and cartilage thinning slowly alter the shape of the
OA joint, increasing its surface area. It is almost as though
there is a homeostatic mechanism operative in OA that causes
enlargement of the failing joint to spread the mechanical load
over a greater surface area.
Patients with OA also have higher BMD values at sites
distant from the joint and this is particularly associated with
osteophyte formation. This is in keeping with observations made
in epidemiological studies that show that patients with OA are
partially protected from developing osteoporosis and vice versa.
This is likely to be due to the fact that the genetic factors that
predispose to osteoporosis might be protective for OA.
The synovium in OA is often hyperplastic and may be the site
of inflammatory change, but to a much lesser extent than in RA
and other inflammatory arthropathies. Osteochondral bodies
commonly occur within the synovium, reflecting chondroid
metaplasia or secondary uptake and growth of damaged cartilage
fragments. The outer capsule also thickens and contracts,
usually retaining the stability of the remodelling joint. The muscles
surrounding affected joints commonly show evidence of wasting
and non-specific type II fibre atrophy.
Clinical features
OA has a characteristic distribution, mainly targeting the hips,
knees, PIP and DIP joints of the hands, neck and lumbar spine
(see Fig. 24.10). The main presenting symptoms are pain and
functional restriction. The causes of pain in OA are not completely
understood but may relate to increased pressure in subchondral
bone (mainly causing night pain), trabecular microfractures,
capsular distension and low-grade synovitis. Pain may also
result from bursitis and enthesopathy secondary to altered joint
mechanics. Typical OA pain has the characteristics listed in Box
24.37. For many people, functional restriction of the hands,
knees or hips is an equal, if not greater, problem than pain.
The clinical findings vary according to severity but are principally
those of joint damage.
Osteoarthritis • 1009
24.37 Symptoms and signs of osteoarthritis
Pain
• Insidious onset over months or years
• Variable or intermittent nature over time (‘good days, bad days’)
• Mainly related to movement and weight-bearing, relieved by rest
• Only brief (< 1 5 mins) morning stiffness and brief (<5 mins)
‘gelling’ after rest
• Usually only one or a few joints painful
Clinical signs
• Restricted movement due to capsular thickening or blocking by
osteophyte
• Palpable, sometimes audible, coarse crepitus due to rough articular
surfaces
• Bony swelling around joint margins
• Deformity, usually without instability
• Joint-line or periarticular tenderness
• Muscle weakness and wasting
• Mild or absent synovitis
24.38 Characteristics of generalised
nodal osteoarthritis
• Polyarticular finger interphalangeal joint osteoarthritis
• Heberden’s (± Bouchard’s) nodes
• Marked female preponderance
• Peak onset in middle age
• Good functional outcome for hands
• Predisposition to osteoarthritis at other joints, especially knees
• Strong genetic predisposition
The correlation between the presence of structural change, as
assessed by imaging, and symptoms such as pain and disability
varies markedly according to site. It is stronger at the hip than
at the knee, and poor at most small joints. This suggests that
the risk factors for pain and disability may differ from those for
structural change. At the knee, for example, reduced quadriceps
muscle strength and adverse psychosocial factors (anxiety,
depression) correlate more strongly with pain and disability than
the degree of radiographic change.
Radiological evidence of OA is very common in middle-aged
and older people, and the disease may coexist with other
conditions, so it is important to remember that pain in a patient
with OA may be due to another cause.
Generalised nodal OA
Characteristics of this common form of OA are shown in Box
24.38. Some patients are asymptomatic whereas others develop
pain, stiffness and swelling of one or more PIP and DIP joints of
the hands from the age of about 40 years onwards. Gradually,
these develop posterolateral swellings on each side of the
extensor tendon, which slowly enlarge and harden to become
Heberden’s (DIP) and Bouchard’s (PIP) nodes (Fig. 24.17).
Typically, each joint goes through a phase of episodic symptoms
(1-5 years) while the node evolves and OA develops. Once OA
is fully established, symptoms may subside and hand function
often remains good. Affected joints are enlarged as a result
of osteophyte formation and often show characteristic lateral
deviation, reflecting the asymmetric focal cartilage loss of OA
(Fig. 24.18). Involvement of the first CMC joint is also common,
leading to pain on trying to open bottles and jars, and functional
Fig. 24.17 Nodal osteoarthritis. Heberden’s nodes and lateral (radial/
ulnar) deviation of distal interphalangeal joints, with mild Bouchard’s nodes
at the proximal interphalangeal joints.
Fig. 24.18 X-ray appearances in hand osteoarthritis. There is joint
space narrowing affecting the proximal interphalangeal (PIP) and distal
interphalangeal (DIP) joints in both hands. There are typical articular
subchondral and ‘gullwing’ appearances to some osteoarthritis-affected
joints, as well as osteophyte formation that is most marked at the second
DIP joints bilaterally and the first PIP joint on the right hand (arrows).
impairment. Clinically, it may be detected by the presence of
crepitus on joint movement, and squaring of the thumb base.
Generalised nodal OA has a very strong genetic component:
the daughter of an affected mother has a 1 in 3 chance of
developing nodal OA herself. People with nodal OA are also at
increased risk of OA at other sites, especially the knee.
Knee OA
At the knee, OA principally targets the patello-femoral and medial
tibio-femoral compartments but eventually spreads to affect
the whole of the joint (Fig. 24.19). It may be isolated or occur
as part of generalised nodal OA. Most patients have bilateral
and symmetrical involvement. In men, trauma is often a more
important risk factor and may result in unilateral OA.
The pain is usually localised to the anterior or medial aspect
of the knee and upper tibia. Patello-femoral pain is usually
worse going up and down stairs or inclines. Posterior knee pain
suggests the presence of a complicating popliteal cyst (Baker’s
cyst). Prolonged walking, rising from a chair, getting in or out of
1010 • RHEUMATOLOGY AND BONE DISEASE
Fig. 24.19 X-ray appearances in knee osteoarthritis. [A] Advanced
osteoarthritis showing almost complete loss of joint space affecting both
compartments and sclerosis of subchondral bone. [§] Skyline view of the
patella femoral joint in a patient with severe patello-femoral osteoarthritis.
There is almost complete loss of joint space and lateral displacement of
the patella.
Fig. 24.20 Typical varus knee deformity resulting from marked
medial tibio-femoral osteoarthritis.
a car, or bending to put on shoes and socks may be difficult.
Local examination findings may include:
• a jerky, asymmetric (antalgic) gait with less time weight¬
bearing on the painful side
• a varus (Fig. 24.20) or, less commonly, valgus and/or a
fixed flexion deformity
• joint-line and/or periarticular tenderness (secondary
anserine bursitis and medial ligament enthesopathy (see
Box 24.25), causing tenderness of the upper medial tibia)
• weakness and wasting of the quadriceps muscle
• restricted flexion and extension with coarse crepitus
• bony swelling around the joint line.
CPPD crystal deposition in association with OA is common
at the knee. This may result in a more overt inflammatory
component (stiffness, effusions) and super-added acute attacks
of synovitis (‘pseudogout’; p. 1016), which may be associated
with more rapid radiographic and clinical progression.
Hip OA
Hip OA most commonly targets the superior aspect of the
joint (Fig. 24.21). It is often unilateral at presentation, frequently
progresses with superolateral migration of the femoral head,
and has a poor prognosis. The less common central (medial)
OA shows more central cartilage loss and is largely confined to
women. It is often bilateral at presentation and can be associated
with generalised nodal OA. It has a better prognosis than superior
hip OA and progression to axial migration of the femoral head
is uncommon.
The hip shows the best correlation between symptoms and
radiographic change. Hip pain is usually maximal deep in the
anterior groin, with variable radiation to the buttock, anterolateral
thigh, knee or shin. Lateral hip pain, worse on lying on that side
with tenderness over the greater trochanter, suggests secondary
trochanteric bursitis. Common functional difficulties are the same
as for knee OA; in addition, restricted hip abduction in women
may cause pain during sexual intercourse. Examination may reveal:
• an antalgic gait
• weakness and wasting of quadriceps and gluteal muscles
• pain and restriction of internal rotation with the hip
flexed - the earliest and most sensitive sign of hip OA;
other movements may subsequently be restricted and
painful
• anterior groin tenderness just lateral to the femoral pulse
• fixed flexion, external rotation deformity of the hip
• ipsilateral leg shortening with severe joint attrition and
superior femoral migration.
Obesity is associated with more rapid progression of hip OA.
Fig. 24.21 X-ray of hip showing changes of osteoarthritis. Note the
superior joint space narrowing (N), subchondral sclerosis (S), marginal
osteophytes (0) and cysts (C).
Osteoarthritis • 1011
Fig. 24.22 X-ray of spine showing typical changes of osteoarthritis.
Cervical spondylosis showing disc space narrowing between C6 and C7,
osteophytes at the anterior vertebral body margins (thin arrows) and
osteosclerosis at the apophyseal joints (thick arrow).
Spine OA
The cervical and lumbar spine are the sites most often targeted
by OA, where it is referred to as cervical spondylosis and lumbar
spondylosis, respectively (Fig. 24.22). Spine OA may occur in
isolation or as part of generalised OA. The typical presentation is
with pain localised to the low back region or the neck, although
radiation of pain to the arms, buttocks and legs may also occur
due to nerve root compression. The pain is typically relieved
by rest and worse on movement. On physical examination, the
range of movement may be limited and loss of lumbar lordosis
is typical. The straight leg-raising test or femoral stretch test may
be positive and neurological signs may be seen in the legs where
there is complicating spinal stenosis or nerve root compression.
Early-onset OA
Unusually, typical symptoms and signs of OA may present before
the age of 45. In most cases, a single joint is affected and there
is a clear history of previous trauma. However, specific causes
of OA need to be considered in people with early-onset disease
affecting several joints, especially those not normally targeted
by OA, in which case rare causes need to be considered (Box
24.39). Kash in-Beck disease is a rare form of OA that occurs in
children, typically between the ages of 7 and 13, in some regions
of China. The cause is unknown but suggested predisposing
factors are selenium deficiency and contamination of cereals
with mycotoxin-producing fungi.
Erosive OA
This term is used to describe an unusual group of patients with
hand OA who have a more prolonged symptom phase, more overt
inflammation, more disability and worse outcome than those with
nodal OA. Distinguishing features include preferential targeting of
PIP joints, subchondral erosions on X-rays, occasional ankylosis
of affected joints and lack of association with OA elsewhere. It
is unclear whether erosive OA is part of the spectrum of hand
OA or a discrete subset.
Investigations
A plain X-ray of the affected joint should be performed and often
this will show one or more of the typical features of OA (see Figs
24.18-24.22). In addition to providing diagnostic information,
X-rays are of value in assessing the severity of structural change,
which is helpful if joint replacement surgery is being considered.
Non-weight-bearing postero-anterior views of the pelvis are
adequate for assessing hip OA. Patients with suspected knee
OA should have standing anteroposterior X-rays taken to assess
tibio-femoral cartilage loss, and a flexed skyline view to assess
patello-femoral involvement. Spine OA can often be diagnosed
on a plain X-ray, which typically shows evidence of disc space
narrowing and osteophytes. If nerve root compression or spinal
stenosis is suspected, MRI should be performed.
Routine biochemistry, haematology and autoantibody tests
are usually normal, though OA is associated with a moderate
acute phase response. Synovial fluid aspirated from an affected
joint is viscous with a low cell count.
Unexplained early-onset OA requires additional investigation,
guided by the suspected underlying condition. X-rays may show
typical features of dysplasia or avascular necrosis, widening of
joint spaces in acromegaly, multiple cysts, chondrocalcinosis
and MOP joint involvement in haemochromatosis (p. 895), or
disorganised architecture in neuropathic joints.
Management
Treatment follows the principles outlined on pages 1000-1007.
Measures that are pertinent in older people are summarised in
Box 24.40.
Education
It is important to explain the nature of the condition fully, outlining
the role of relevant risk factors such as obesity, heredity and
(fx
• Pain and disability: osteoarthritis is the principal cause in old age.
• Calcium phosphate deposition disease: may cause acute attacks
of synovitis (pseudogout) on a background of chronic osteoarthritis.
• Falls: reduced muscle strength and pain associated with lower limb
osteoarthritis increase the risk.
• Muscle-strengthening exercises: safely reduce the pain and
disability of knee osteoarthritis with accompanying improvements in
balance and reduced tendency to fall.
• Oral paracetamol and topical non-steroidal anti-inflammatory
drugs: safe in older people, with no important drug interactions or
contraindications.
• Intra-articular injection of glucocorticoid: a very safe and often
effective treatment, particularly useful for tiding a patient over a
special event.
• Total joint replacement: an excellent cost-effective treatment for
severe disabling knee or hip osteoarthritis in older people. There is
no age limit for joint replacement surgery.
24.40 Osteoarthritis in old age
1012 • RHEUMATOLOGY AND BONE DISEASE
trauma. The patent should be informed that established structural
changes are permanent and that, although a cure is not possible at
present, pain and function can often be improved. The prognosis
should also be discussed, mentioning that it is generally good
for nodal hand OA and better for knee than hip OA.
Lifestyle advice
Weight loss has a substantial beneficial effect on symptoms if
the patient is obese and is probably one of the most effective
treatments available for OA of the lower limbs. Strengthening and
aerobic exercises also have beneficial effects in OA and should be
advised, preferably with reinforcement by a physiotherapist (see
Box 24.27). Quadriceps strengthening exercises are particularly
beneficial in knee OA. Shock-absorbing footwear, pacing of
activities, use of a walking stick for painful knee or hip OA,
and provision of built-up shoes to equalise leg lengths can all
improve symptoms.
Non-pharmacological therapy
Acupuncture and transcutaneous electrical nerve stimulation
(TENS) have been shown to be effective in knee OA. Local
physical therapies, such as heat or cold, can sometimes give
temporary relief.
Pharmacological therapy
If symptoms do not respond to non-pharmacological measures,
paracetamol should be tried. Addition of a topical NSAID, and
then capsaicin, for knee and hand OA can also be helpful.
Oral NSAIDs should be considered in patients who remain
symptomatic. These drugs are significantly more effective than
paracetamol and can be successfully combined with paracetamol
or compound analgesics if the pain is severe. Strong opiates
may occasionally be required. Antineuropathic drugs, such as
amitriptyline, gabapentin and pregabalin, are sometimes used
in patients with symptoms that are difficult to control but the
evidence base for their use is poor. Neutralising antibodies to
nerve growth factor have been developed and are a highly
effective treatment for pain in OA but they are not yet licensed
for routine clinical use.
Intra-articular injections
Intra-articular glucocorticoid injections are effective in the treatment
of knee OA and are also used for symptomatic relief in the
treatment of OA at the first CMC joint. The duration of effect is
usually short but trials of serial glucocorticoid injections every
3 months in knee OA have shown efficacy for up to 1 year.
Intra-articular injections of hyaluronic acid are effective in knee OA
but the treatment is expensive and the effect short-lived. In the
UK they have not been considered to be cost-effective by NICE.
Neutraceuticals
Chondroitin sulphate and glucosamine sulphate have been used
alone and in combination for the treatment of knee OA. There
is evidence from randomised controlled trials that these agents
can improve knee pain to a small extent (3-5%) compared
with placebo.
Surgery
Surgery should be considered for patients with OA whose
symptoms and functional impairment impact significantly on
their quality of life despite optimal medical therapy and lifestyle
advice. Total joint replacement surgery is by far the most common
surgical procedure for patients with OA. It can transform the
quality of life for people with severe knee or hip OA and is
indicated when there is significant structural damage on X-ray.
Although surgery should not be undertaken at an early stage
during the development of OA, it is important to consider it
before functional limitation has become advanced since this
may compromise outcome. Patient-specific factors, such as
age, gender, smoking and presence of obesity, should not be
barriers to referral for joint replacement.
Only a small proportion of patients with OA progress to the
extent that total joint replacement is required but OA is by far the
most frequent indication for this. Over 95% of joint replacements
continue to function well into the second decade after surgery
and most provide life-long, pain-free function. Up to 20% of
patients are not satisfied with the outcome, however, and a
few experience little or no improvement in pain. Other surgical
procedures are performed much less frequently. Osteotomy is
occasionally carried out to prolong the life of malaligned joints
and to relieve pain by reducing intraosseous pressure. Cartilage
repair is sometimes performed to treat focal cartilage defects
resulting from joint injury.
Crystal-induced arthritis
A variety of crystals can deposit in and around joints and cause
an acute inflammatory arthritis, as well as a more chronic arthritis
associated with progressive joint damage (Box 24.41). Crystals
can be the primary pathogenic agent, as in gout, or an accessory
factor, as in calcium pyrophosphate deposition disease, in which
crystals are deposited in joints that are already abnormal. Several
factors influence crystal formation (Fig. 24.23). There must
be sufficient concentration of the chemical components (ionic
product), but whether a crystal then forms depends on the balance
of tissue factors that promote and inhibit crystal nucleation and
growth. The inflammatory potential of crystals resides in their
physical irregularity and high negative surface charge, which
can induce inflammation and damage cell membranes. Crystals
may also cause mechanical damage to tissues and act as wear
particles at the joint surface. They can reside in cartilage or tendon
for years without causing inflammation or symptoms, and it is
only when they are released that they trigger inflammation. This
may occur spontaneously but can also result from local trauma,
rapid changes in the concentration of the components that
form crystals, or in association with an acute phase response
triggered by intercurrent illness or surgery. In the longer term,
a reduction in concentrations of the solutes that form crystals
causes dissolution of crystals and remission of the arthritis.
Gout
Gout is the most common inflammatory arthritis in men and in
older women. It is caused by deposition of monosodium urate
monohydrate crystals in and around synovial joints.
Epidemiology
The prevalence of gout is approximately 1-2%, with a greater
than 5 : 1 male preponderance. Gout has become progressively
more common over recent years in affluent societies due to
the increased prevalence of obesity and metabolic syndrome
(p. 730), of which hyperuricaemia is an integral component.
The risk of developing gout increases with age and with serum
uric acid (SUA) levels. These are normally distributed in the
general population and hyperuricaemia is defined as an SUA
of more than 2 standard deviations above the mean for the
Crystal-induced arthritis • 1013
i
24.41 Crystal-associated arthritis and deposition in
connective tissue
Crystal
Associations
Common
Monosodium urate
Acute gout
monohydrate
Chronic tophaceous gout
Calcium pyrophosphate
Acute ‘pseudogout’
di hydrate
Chronic (pyrophosphate) arthropathy
Chondrocalcinosis
Basic calcium phosphates
Calcific periarthritis
Calcinosis
Uncommon
Cholesterol
Chronic effusions in rheumatoid arthritis
Calcium oxalate
Acute arthritis in dialysis patients
Extrinsic crystals/
semi-crystalline particles:
Synthetic crystals
Acute synovitis
Plant thorns/sea urchin
Chronic monoarthritis, tenosynovitis
spines
Solute excess
[Ca2+] + [P04] [Na+] + [Urate]
pH
Temperature
Pressure
Inhibitors of
crystal growth
^ < - Nucleating
factors
Growth-promoting
factors
Dissolution
Shedding
Fig. 24.23 Mechanisms of crystal formation.
population. SUA levels are higher in men, increase with age and
are positively associated with body weight. Levels are higher
in some ethnic groups (such as Maoris and Pacific islanders).
Although hyperuricaemia is strong risk factor for gout, only a
minority of hyperuricaemic individuals actually develop gout.
Pathophysiology
About one-third of the body uric acid pool is derived from dietary
sources and two-thirds from endogenous purine metabolism (Fig.
24.24). The concentration of uric acid in body fluids depends on
24.42 Causes of hyperuricaemia and gout
Diminished renal excretion
• Increased renal tubular
• Drugs:
reabsorption*
Thiazide and loop diuretics
• Renal failure
Low-dose aspirin
• Lead toxicity
Ciclosporin
• Lactic acidosis
Pyrazinamide
• Alcohol
Increased intake
• Game
• Offal
• Seafood
• Red meat
Increased production
• Myeloproliferative and
• Inherited disorders:
lymphoproliferative disease
Lesch-Nyhan syndrome
• Psoriasis
(HPRT mutations)
• High fructose intake
Phosphoribosyl
• Glycogen storage disease
pyrophosphate synthetase
(p. 370)
1 mutations
*Usually genetically determined (see text).
(HPRT = hypoxanthine guanine phosphoribosyl transferase)
Game, seafood,
oily fish, offal
Purine salvage
pathway
De novo
synthesis
Dietary purines
(-400 mg/24 hrs)
Endogenous purines
(-800 mg/24 hrs)
nr I nosine
Inhibition
of pathway
Stimulation
of pathway
Uricosuric
drugs
Hypoxanthine
Xanthine oxidase
I
Xanthine
\
Allopurinol
Febuxostat
♦ /
Xanthine oxidase x
Uric acid
(-1200 mg)
n
Allantoin
Pegloticase
Renal excretion acid
(-800 mg/24 hrs)
Intestinal excretion acid
(-400 mg/24 hrs)
Fig. 24.24 Uric acid metabolism. The main pathways for uric acid
production and elimination are shown, along with the site of action for
urate-lowering therapies.
the balance between endogenous synthesis, and elimination by
the kidneys (two-thirds) and gut (one-third). Purine nucleotide
synthesis and degradation are regulated by a network of enzyme
pathways, but xanthine oxidase plays a pivotal role in catalysing
the conversion of hypoxanthine to xanthine and xanthine to
uric acid.
The causes of hyperuricaemia are shown in Box 24.42. In
over 90% of patients, the main abnormality is reduced uric acid
1014 • RHEUMATOLOGY AND BONE DISEASE
excretion by the kidney, which is genetically determined. Impaired
renal excretion of urate also accounts for the occurrence of
hyperuricaemia in chronic renal failure, and for hyperuricaemia
associated with thiazide diuretic therapy.
Other risk factors for gout include metabolic syndrome, high
alcohol intake (predominantly beer, which contains guanosine),
generalised OA, and a diet relatively high in game, offal, seafood,
red meat and fructose, or low in vitamin C. Lead poisoning may
cause gout (saturnine gout). The association between OA and
gout is thought to be due to a reduction in levels of proteoglycan
and other inhibitors of crystal formation in osteoarthritic cartilage,
predisposing to crystal formation.
Some patients develop gout because they over-produce
uric acid. The mechanisms are poorly understood, except
in the case of a few single gene disorders where there are
mutations in genes that regulate purine metabolism (Box
24.42). Lesch-Nyhan syndrome is an X-linked recessive form
of gout that is also associated with mental retardation, self-
mutilation and choreoathetosis. An inherited cause should
be suspected if other clinical features are present or there
is an early age at onset with a positive family history. Severe
hyperuricaemia can also occur in patients with haematological
and other cancers who are undergoing chemotherapy due to
increased purine turnover (tumour lysis syndrome). This is seldom
connected with gout but can be associated with acute kidney
injury (p. 411).
Clinical features
The classical presentation is with an acute monoarthritis, which
affects the first MTP joint in over 50% of cases (Fig. 24.25).
Other common sites are the ankle, midfoot, knee, small joints
of hands, wrist and elbow. The axial skeleton and large proximal
joints are rarely involved. Typical features include:
• rapid onset, reaching maximum severity in 2-6 hours, and
often waking the patient in the early morning
• severe pain, often described as the ‘worst pain ever’
• extreme tenderness, such that the patient is unable to
wear a sock or to let bedding rest on the joint
Fig. 24.25 Podagra. Acute gout causing swelling, erythema and extreme
pain and tenderness of the first metatarsophalangeal joint.
• marked swelling with overlying red, shiny skin
• self-limiting over 5-14 days, with complete resolution.
During the attack, the joint shows signs of marked synovitis,
swelling and erythema. There may be accompanying fever, malaise
and even delirium, especially if a large joint such as the knee
is involved. As the attack subsides, pruritus and desquamation
of overlying skin are common. The main differential diagnosis is
septic arthritis, infective cellulitis or reactive arthritis. Acute attacks
may also manifest as bursitis, tenosynovitis or cellulitis, which
have the same clinical characteristics. Many patients describe
milder episodes lasting just a few days. Some have attacks in
more than one joint. Others have further attacks in other joints
a few days later (cluster attacks), the first possibly acting as a
trigger. Simultaneous polyarticular attacks are unusual.
Some people never have a second episode and in others
several years may elapse before the next one. In many, however,
a second attack occurs within 1 year and may progress to chronic
gout, with chronic pain and joint damage, and occasionally severe
deformity and functional impairment. Patients with uncontrolled
hyperuricaemia who suffer multiple attacks of acute gout may
also progress to chronic gout.
The presentation of gout in the elderly may be atypical with
chronic symptoms rather than acute attacks (Box 24.43).
Crystals may be deposited in the joints and soft tissues
to produce irregular firm nodules called tophi. These have a
predilection for the extensor surfaces of fingers, hands, forearm,
elbows, Achilles tendons and sometimes the helix of the ear.
Tophi have a white colour (Fig. 24.26), differentiating them from
rheumatoid nodules. Tophi can ulcerate, discharging white
gritty material, become infected or induce a local inflammatory
response, with erythema and pus in the absence of secondary
infection. They are usually a feature of long-standing gout but
can sometimes develop within 1 2 months in patients with chronic
renal failure. Occasionally, tophi may develop in the absence of
previous acute attacks, especially in patients on thiazide therapy
who have coexisting OA.
In addition to causing musculoskeletal disease, chronic
hyperuricaemia may be complicated by renal stone formation
(p. 431) and, if severe, renal impairment due to the development
of interstitial nephritis as a result of urate deposition in the kidney.
This is particularly common in patients with chronic tophaceous
gout who are on diuretic therapy.
Investigations
The diagnosis of gout can be confirmed by the identification of
urate crystals in the aspirate from a joint, bursa or tophus (see
Fig. 24. 6A, p. 988). In acute gout, the synovial fluid may be
6
• Aetiology: a higher proportion of older patients have gout
secondary to diuretic use and chronic kidney disease. Gout is often
associated with osteoarthritis.
• Presentation: may be atypical, with painful tophi and chronic
symptoms, rather than acute attacks. Joints of the upper limbs are
more frequently affected.
• Management: acute attacks are best treated by aspiration and
intra-articular injection of glucocorticoids, followed by early
mobilisation. Non-steroidal anti-inflammatory drugs and colchicine
should be used with caution because of increased risk of toxicity.
Low doses of allopurinol (50 mg/day) should be given and increased
gradually to avoid toxicity.
24.43 Gout in old age
Crystal-induced arthritis • 1015
Fig. 24.26 Tophus with white monosodium urate monohydrate
crystals visible beneath the skin. Diuretic-induced gout in a patient with
pre-existing nodal osteoarthritis.
Fig. 24.27 Erosive arthritis in chronic gout. Punched-out (‘Lulworth
Cove’) erosions (arrows) in association with a destructive arthritis affecting
the first metatarsophalangeal joint.
turbid due to an elevated neutrophil count. In chronic gout, the
appearance is more variable but occasionally the fluid appears
white due to the presence of urate crystals. Between attacks,
aspiration of an asymptomatic first MTP joint or knee may still
reveal crystals.
A biochemical screen, including renal function, uric acid,
glucose and lipid profile, should be performed because of the
association with metabolic syndrome. Hyperuricaemia is usually
present in gout but levels may be normal during an attack because
serum urate falls during inflammation. Acute gout is characterised
by an elevated ESR and CRP and with a neutrophilia, all of
which return to normal as the attack subsides. Tophaceous
gout may be accompanied by a modest but chronic elevation
in ESR and CRP.
X-rays are usually normal in acute gout but well-demarcated
erosions may be seen in patients with chronic or tophaceous
gout (Fig. 24.27). Tophi may also be visible on X-rays as soft
tissue swellings. In late disease, destructive changes may occur
that are similar to those in other forms of advanced inflammatory
arthritis.
Management
Management should focus on first dealing with the acute attack
and then giving prophylaxis to lower SUA and prevent further
attacks.
Acute gout
Oral colchicine given in doses of 0.5 mg twice or 3 times daily is
the treatment of first choice in acute gout. It works by inhibiting
microtubule assembly in neutrophils. The most common adverse
effects are nausea, vomiting and diarrhoea. Oral NSAIDs are also
effective but are used less commonly since many patients affected
by acute gout have coexisting cardiovascular, cerebrovascular
or chronic kidney disease. Oral prednisolone (15-20 mg daily) or
intramuscular methylprednisolone (80-1 20 mg daily) for 2-3 days
are highly effective and are a good choice in elderly patients where
there is an increased risk of toxicity with colchicine and NSAID
(Box 24.43). The IL-lp inhibitor canakinumab (see Box 24.35)
is effective but extremely expensive and so seldom given. Local
ice packs can also be used for symptomatic relief. Patients with
recurrent episodes can keep a supply of an NSAID, colchicine or
prednisolone and take it as soon as the first symptoms occur,
continuing until the attack resolves. Joint aspiration can give
pain relief, particularly if a large joint is affected, and may be
combined with an intra-articular glucocorticoid injection if the
diagnosis is clear and infection can be excluded.
Prophylaxis
Patients who have had a single attack of gout do not necessarily
need to be given urate-lowering therapy, but individuals who
have more than one acute attack within 1 2 months and those
with complications such as tophi or erosions should be offered it
(Box 24.44). The long-term therapeutic aim is to prevent attacks
occurring by bringing uric acid levels below the level at which
monosodium urate monohydrate crystals form. A therapeutic
target of 360 p,mol/L (6 mg/dL) is recommended in the British
Society of Rheumatology guidelines, whereas the European
League Against Rheumatism guidelines recommend a threshold
of 300 |imol/L (5 mg/dL).
Allopurinol is the drug of first choice. It inhibits xanthine oxidase,
which reduces the conversion of hypoxanthine and xanthine to
uric acid. The recommended starting dose is 100 mg daily, or
50 mg in older patients and in renal impairment. The dose of
allopurinol should be increased by 1 00 mg every 4 weeks (50 mg
in the elderly and those with renal impairment) until the target
uric acid level is achieved, side-effects occur or the maximum
recommended dose is reached (900 mg/day). Acute flares of gout
often follow initiation of urate- lowering therapy. The patient should
be warned about this and told to continue therapy, even if an
attack occurs. The risk of flares can be reduced by prophylaxis
with oral colchicine (0.5 mg twice daily) or an NSAID for the
first few months. Alternatively, patients can be given a supply
of colchicine, an NSAID or prednisolone to be taken at the first
24.44 Indications for urate-lowering drugs
• Recurrent attacks of acute
• Tophi
gout
• Renal impairment
• Evidence of bone or joint
• Nephrolithiasis
damage
1016 • RHEUMATOLOGY AND BONE DISEASE
sign of an acute attack. In the longer term, annual monitoring of
uric acid levels is recommended. In most patients, urate-lowering
therapy needs to be continued indefinitely.
Febuxostat also inhibits xanthine oxidase. It is typically
used in patients with an inadequate response to allopurinol,
and when allopurinol is contraindicated or causes adverse
effects. Febuxostat undergoes hepatic metabolism and no
dose adjustment is required for renal impairment. It is more
effective than allopurinol but commonly provokes acute attacks
when therapy is initiated. The usual starting dose is 80 mg
daily, increasing to 120 mg daily in patients with an inadequate
response. Prophylaxis against acute attacks should be given on
initiating therapy, as described for allopurinol.
Uricosuric drugs, such as probenecid, sulfinpyrazone and
benzbromarone, lower urate levels but are seldom used in routine
clinical practice. They are contraindicated in over-producers and
those with renal impairment or urolithiasis and require patients
to maintain a high fluid intake to avoid uric acid crystallisation
in the renal tubules.
Pegloticase is a biological treatment in which the enzyme uricase
(oxidises uric acid to 5-hydroxyisourate, which is then converted
to allantoin) has been conjugated to monomethoxypolyethylene
glycol. It is indicated for the treatment of tophaceous gout resistant
to standard therapy and is administered as an intravenous
infusion every 2 weeks for up to 6 months. It is highly effective
at controlling hyperuricaemia and can cause regression of tophi.
The main adverse effects are infusion reactions (which can
be treated with antihistamines or glucocorticoids) and flares
of gout during the first 3 months of therapy. A limiting factor
for longer-term treatment is the development of antibodies to
pegloticase, which occur in a high proportion of cases and are
associated with an impaired therapeutic response.
Lifestyle measures are equally important as drug therapy in
the treatment of gout. Patients should be advised to lose weight
where appropriate and to reduce excessive alcohol intake,
especially beer. Several antihypertensive drugs, including thiazides,
fLblockers and ACE inhibitors, increase uric acid levels, whereas
losartan has a uricosuric effect and should be substituted for
other drugs if possible. Patients should be advised to avoid large
amounts of seafood and offal, which have a high purine content,
but a highly restrictive diet is not necessary.
Calcium pyrophosphate dihydrate crystal
deposition disease
This condition is associated with deposition of calcium
pyrophosphate dihydrate (CPPD) crystals within articular and
hyaline cartilage and is often referred to as ‘pseudogout’. It
is rare under the age of 55 years but occurs in 10-15% of
people between 65 and 75 and 30-60% of those over 85. The
knee (hyaline cartilage and menisci) is by far the most common
site, followed by the wrist (triangular fibrocartilage) and pelvis
(symphysis pubis). Risk factors are shown in Box 24.45. In many
patients, chondrocalcinosis is asymptomatic and an incidental
finding on X-ray. A proportion of patients present with an acute
inflammatory arthritis (pseudogout) or a chronic inflammatory
arthropathy superimposed on a background of OA, especially
at the knee (Fig. 24.28), associated with joint damage and
functional limitation.
Pathophysiology
The underlying mechanisms of crystal deposition are poorly
understood. Clinical studies have shown that pyrophosphate
24.45 Risk factors for chondrocalcinosis
Common
• Age
• Osteoarthritis*
• Primary hyperparathyroidism
Rare
• Familial factors*
• Plypomagnesaemia
• Flaemochromatosis*
• Hypophosphatasia
• Wilson’s disease
*May be associated with structural damage to affected joints.
Fig. 24.28 Chondrocalcinosis of the knee. The X-ray shows
calcification of the fibrocartilaginous menisci (M) and articular hyaline
cartilage (H). There is also narrowing (N) of the medial tibio-femoral
compartment and osteophyte (0) formation.
levels are raised in patients with CPPD crystal deposition disease,
possibly due to over-production, but why this happens is unclear.
In hypophosphatasia (see Box 24.75, p. 1050), the predisposing
factor is thought to be impaired degradation of pyrophosphate
due to deficiency of ALP. In OA, it is thought that a reduction
in the amounts of proteoglycan and other natural inhibitors of
crystal formation in the abnormal cartilage also predispose to
crystal deposition (see Fig. 24.23).
Clinical features
The typical presentation is with a swollen tender joint that is
warm and erythematous with a large effusion. Fever is common
and the patient may appear confused and ill. The knee is most
commonly affected, followed by the wrist, shoulder, ankle
and elbow. Trigger factors include trauma, intercurrent illness,
dehydration and surgery. Septic arthritis and gout are the main
differential diagnoses.
Chronic arthropathy may also occur in association with CPPD
crystal deposition disease, affecting the same joints that are
involved in acute pseudogout. The presentation is with chronic
pain, early morning stiffness, inactivity gelling and functional
impairment. Acute attacks of pseudogout may be superimposed.
Affected joints usually show features of OA, with varying degrees
of synovitis. Effusion and synovial thickening are usually most
apparent at knees and wrists. Wrist involvement may result in
carpal tunnel syndrome and second and third MCP joints can be
Crystal-induced arthritis • 1017
affected. Inflammatory features may be sufficiently pronounced to
suggest RA. Inflammatory changes can occur at entheses and
may involve tendons and the ligamentum flavum. Inflammation
around the odontoid may occur secondary to CPPD deposition,
leading to crowned dens syndrome; this presents clinically with
neck pain. Severe damage and instability of knees or shoulders
can mimic a neuropathic joint but no neurological abnormalities
will be found.
Investigations
The pivotal investigation is joint aspiration, followed by examination
of synovial fluid using compensated polarised microscopy to
demonstrate CPPD crystals (see Fig. 24. 6B, p. 988) and to
permit distinction from gout. The aspirated fluid is often turbid
and may be uniformly blood-stained, reflecting the severity of
inflammation. Since sepsis and pseudogout can coexist, Gram
stain and culture of the fluid should be performed to exclude
sepsis, even if CPPD crystals are identified in synovial fluid.
X-rays of the affected joint may show evidence of calcification
in hyaline cartilage and/or fibrocartilage, although absence of
calcification does not exclude the diagnosis. Signs of OA are
frequently present. Screening for secondary causes (Box 24.45)
should be undertaken, especially in patients who present under
the age of 25 and those with polyarticular disease.
Management
Joint aspiration can sometimes provide symptomatic relief in
pseudogout and in a few patients no further treatment is required.
People with persistent symptoms can be treated with intra-articular
glucocorticoids, colchicine or an NSAID. Since most patients
with pseudogout are elderly, NSAIDs and colchicine must be
used with caution. Early active mobilisation is also important.
Chronic pyrophosphate-induced arthropathy should be managed
as for OA (p. 1011).
Basic calcium phosphate deposition disease
Basic calcium phosphate (BCP) deposition disease is caused
by the deposition of hydroxyapatite or apatite crystals and
other basic calcium phosphate salts (octacalcium phosphate,
tricalcium phosphate) in soft tissues. The main affected sites
are tendons, ligaments and hyaline cartilage in patients with
degenerative disease, and skeletal muscle and subcutaneous
tissues in connective tissue diseases.
Pathophysiology
Under normal circumstances, inhibitors of mineralisation, such
as pyrophosphate and proteoglycans, prevent calcification of
soft tissues. When these protective mechanisms break down,
abnormal calcification occurs. There are many causes (Box
24.46). In most situations calcification is of no consequence, but
when the crystals are released an inflammatory reaction may be
initiated, causing local pain and inflammation.
Calcific periarthritis
This occurs as the result of deposition of BCP in tendons,
which provokes an acute inflammatory response. The most
commonly affected site is the supraspinatus tendon (Fig. 24.29)
but other sites may also be involved, including the tendons
around the hip, feet and hands. The presentation is with acute
pain, swelling and local tenderness that develops rapidly over
4-6 hours. The overlying skin may be hot and red, raising the
possibility of infection. Attacks sometimes occur spontaneously
but can also be triggered by trauma. Modest systemic upset
^9 24.46 Rheumatic diseases associated with basic
calcium phosphate deposition
Disease
Site of calcification
Calcific periarthritis
Tendons and ligaments
Dermatomyositis and polymyositis
Subcutaneous tissue
Systemic sclerosis (IcSScI)
Subcutaneous tissue
Mixed connective tissue disease
Subcutaneous tissue
Paget’s disease of bone
Blood vessels
Ankylosing spondylitis
Ligaments
Fibrodysplasia ossificans progressiva
Subcutaneous tissues
and muscle
Milwaukee shoulder syndrome
Tendons and ligaments
Albright’s hereditary osteodystrophy
(p. 664)
Muscle
(IcSScI = localised cutaneous systemic sclerosis)
Fig. 24.29 Shoulder X-ray showing supraspinatus tendon
calcification (arrow).
and fever are common. Tendon calcification may be seen on
X-ray. If the affected joint or bursa is aspirated, inflammatory fluid
containing many calcium-staining (alizarin red S) aggregates may
be obtained. During an acute attack, there may be a neutrophilia
with an elevation in ESR and CRP. Routine biochemistry is
normal. Treatment is with analgesics and NSAIDs. Attacks may
also respond to a local injection of glucocorticoid. The condition
usually resolves spontaneously over 1-3 weeks and this is often
accompanied by dispersal and disappearance of calcific deposits
on X-ray. Large deposits sometimes accumulate, causing limitation
of joint movement, and may require surgical removal.
Acute inflammatory arthritis
Deposition of BCP occurs commonly in OA, both alone and
in combination with CPPD crystals, in which case it is referred
to as mixed crystal deposition disease. It may present with
pseudogout or be an incidental finding.
Milwaukee shoulder syndrome
This is a rare syndrome, in which extensive deposition of BCP
crystals in large joints is associated with progressive joint
destruction. It is more common in women than in men. The
onset is gradual with joint pain, sometimes precipitated by injury
1018 • RHEUMATOLOGY AND BONE DISEASE
or overuse. The disease progresses over a few months to cause
severe pain and disability, associated with joint destruction.
X-rays show joint space narrowing, osteophytes and calcification.
Aspiration yields large volumes of relatively non-inflammatory
fluid containing abundant BCP aggregates and often cartilage
fragments. The differential diagnosis is end-stage avascular
necrosis, chronic sepsis or neuropathic joint. There is no acute
phase response and synovial fluid cultures are negative.
Treatment is with analgesics, intra-articular injection of
glucocorticoids, local physical treatments and physiotherapy.
The clinical outcome is poor, however, and most patients require
joint replacement. The cause is incompletely understood but it
has been speculated that deposition of BCP crystals activates
collagenase and other proteases in articular cells, which are
responsible for the tissue damage.
Autoimmune connective tissue disease
Deposition of BCP may occur in the subcutaneous tissues
and muscle of patients with systemic sclerosis and other
autoimmune connective tissue diseases. Usually, the deposits
are asymptomatic but they may be associated with pain and
local ulceration. The mechanism by which this occurs is unclear
and there is no specific treatment.
Fibromyalgia
Fibromyalgia (FM) is a condition of generalised pain and
consequent disability. It is frequently associated with medically
unexplained symptoms in other systems (p. 1 1 87). The prevalence
in the UK and US is about 2-3%. Although FM can occur at
any age, including adolescence, it increases in prevalence with
age, to reach a peak of 7% in women aged over 70. There is a
strong female predominance of around 10:1. Risk factors include
life events that cause (unresolved) psychosocial distress relating
to previous abuse, marital disharmony, alcoholism or illness in
the family, poor sleep health, previous injury or assault, and low
income. FM arises in a variety of races and cultures.
Pathophysiology
The cause of FM is poorly understood but two abnormalities
that may be interrelated (Fig. 24.30) and have been consistently
reported in affected patients are disturbed, non-restorative sleep
and pain sensitisation, probably caused by abnormal central
pain processing.
Clinical features
The main presenting feature is widespread pain, which is often
worst in the neck and back (Box 24.47). It is characteristically
diffuse and unresponsive to analgesics and NSAIDs. Physiotherapy
often makes FM pain worse. Fatiguability, most prominent in the
morning, is another major problem and disability is often marked.
Although people can usually dress, feed and groom themselves,
they may be unable to perform tasks such as shopping or
housework. They may have experienced major difficulties at
work or may even retire because of pain and fatigue.
Examination is unremarkable, apart from the presence of
hyperalgesia on moderate digital pressure (enough just to whiten
the nail) over multiple sites (Fig. 24.31).
Investigations and management
There are no abnormalities on routine blood tests or imaging but
it is important to screen for other conditions that could account
Regional pain Disease Anxiety
syndrome Illness Life crisis
i
Sleep disturbance
Fig. 24.30 Possible causative mechanisms in fibromyalgia.
24.47 The spectrum of symptoms in fibromyalgia
Usual symptoms
• Widespread pain
• Fatiguability
• Disability
• Broken, non -restorative sleep
• Low affect, irritability, poor concentration
Variable locomotor symptoms
• Early-morning stiffness
• Feeling of swelling in hands
• Distal finger tingling
Additional, variable, non-locomotor symptoms
• Non-throbbing bifrontal headache (tension headache)
• Colicky abdominal pain, bloating, variable bowel habit (irritable
bowel syndrome)
• Bladder fullness, nocturnal frequency (irritable bladder)
• Hyperacusis, dyspareunia, discomfort when touched (allodynia)
• Frequent side-effects with drugs (chemical sensitivity)
for all or some of the patient’s symptoms (Box 24.48). Extensive
imaging is not recommended but bone scintigraphy can identify
many conditions that can contribute to widespread pain and is
a useful ‘negative’ test.
The aims of management are to educate the patient about the
condition, address unresolved psychological issues, achieve pain
control and improve sleep. Wherever possible, education should
include the spouse, family or carer. It should be acknowledged
that the cause of FM is not fully understood but the widespread
pain does not reflect inflammation, tissue damage or disease. The
model of a self-perpetuating cycle of poor sleep and pain (see
Fig. 24.30) is a useful framework for problem-based management.
Understanding the diagnosis can often help the patient come
to terms with the symptoms. Repeat or drawn-out investigation
may reinforce beliefs in occult serious pathology and should
be avoided.
Low-dose amitriptyline (10-75 mg at night), with or without
fluoxetine, may help by encouraging delta sleep and reducing
Bone and joint infections • 1019
Fig. 24.31 Typical tender points in fibromyalgia.
B9 24.48 Laboratory investigations recommended
before finalising a diagnosis of fibromyalgia
Test
Condition screened for
Full blood count, liver and renal function
tests
General disease indicators
Erythrocyte sedimentation rate,
C-reactive protein, serum amyloid A,
immunoglobulins
Inflammatory disease
Thyroid function
Hypo-/hyperthyroidism
Calcium, albumin, phosphate, alkaline
phosphatase, parathyroid hormone,
25-hydroxyvitamin-D, serum
angiotensin-converting enzyme
Hyperparathyroidism ,
osteomalacia, sarcoid
Antinuclear antibodies, extractable
nuclear antigens, rheumatoid factor,
anti-cyclic citrullinated peptide
antibodies, complement C3 and C4,
lupus anticoagulant, anti-cardiolipin
antibodies, streptococcal antibodies
Autoinflammatory and
autoimmune diseases
spinal cord wind-up. Many people with FM, however, are
intolerant of even small doses of amitriptyline. There is limited
evidence for the use of tramadol, serotonin-noradrenaline
(norepinephrine) re-uptake inhibitors (SNRIs) such as duloxetine,
and the anticonvulsants pregabalin and gabapentin. A graded
increase in aerobic exercise can improve well-being and sleep
quality. The use of self-help strategies and a cognitive behavioural
approach with relaxation techniques should be encouraged.
Sublimated anxiety relating to distressing life events should be
specifically explored with appropriate counselling. There are
patient organisations that provide additional information and
support. Although treatment may improve quality of life and
ability to cope, most people remain symptomatic for many years.
Septic arthritis is the most rapid and destructive joint disease.
The incidence is 2-10 per 100000 in the general population and
30-70 per 100000 in those with pre-existing joint disease or
joint replacement. Septic arthritis is associated with significant
morbidity and still has a mortality of about 1 0% despite advances
in antimicrobial therapy. The most important risk factor for
mortality is increasing age.
Pathogenesis
Septic arthritis usually occurs as a result of haematogenous
spread from infections of the skin or upper respiratory tract;
infection from direct puncture wounds or secondary to joint
aspiration is uncommon. Risk factors include increasing age,
pre-existing joint disease (principally RA), diabetes mellitus,
immunosuppression (by drugs or disease) and intravenous
drug misuse. In RA, the skin is a frequent portal of entry
because of maceration of skin between the toes due to joint
deformity and difficulties with foot hygiene caused by hand
deformity. Box 24.49 describes the particular considerations
in old age.
Clinical features
The usual presentation is with acute or subacute monoarthritis
and fever. The joint is usually swollen, hot and red, with pain
at rest and on movement. Although any joint can be affected,
lower limb joints, such as the knee and hip, are most commonly
1020 • RHEUMATOLOGY AND BONE DISEASE
ff\
targeted. Patients with pre-existing arthritis may present with
multiple joint involvement.
In adults, the most likely organism is Staphylococcus aureus,
particularly in patients with RA and diabetes. In young, sexually
active adults, gonococcus may be responsible. Disseminated
gonococcal infection occurs in up to 3% of patients with untreated
gonorrhoea. This usually presents with migratory arthralgia,
low-grade fever and tenosynovitis, which may precede the
development of an oligo- or monoarthritis. Painful pustular skin
lesions may also be present. Gram-negative bacilli or group B, C
and G streptococci are important causes among the elderly and
intravenous drug users. Less commonly, septic arthritis may be
caused by group A streptococci, pneumococci, meningococci
and Haemophilus influenzae.
Investigations
The pivotal investigation is joint aspiration but blood cultures
should also be taken. The synovial fluid is usually turbid or blood¬
stained but may appear normal. If the joint is not readily accessible,
aspiration should be performed under imaging guidance or in
theatre. Prosthetic joints should only be aspirated in theatre.
Synovial fluid should be sent for Gram stain and culture; cultures
are positive in around 90% of cases but the Gram stain is positive
in only 50%. In contrast, synovial fluid culture is positive in only
30% of gonococcal infections, making it important to obtain
concurrent cultures from the genital tract (positive in 70-90%
of cases). There is a leucocytosis with raised ESR and CRP in
most patients, but these features may be absent in elderly or
immunocompromised patients, or early in the disease course.
Serial measurements of CRP and ESR are useful in following
the response to treatment.
Management
The principles of management are summarised in Box 24.50.
The patient should be admitted to hospital for pain relief and
administration of parenteral antibiotics. Flucloxacillin (2 g IV
4 times daily) is the antibiotic of first choice pending the results of
cultures, since it will cover most staphylococcal and streptococcal
infections. If there is reason to suspect meticillin-resistant
Staphylococcus aureus (such as a known carrier), vancomycin
should be used instead while awaiting cultures. If a Gram-negative
infection is suspected, gentamicin or vancomycin should be
considered as first-line treatments. Cephalosporins are a potential
alternative for Gram-negative infections but carry a high risk of
Clostridium difficile infection in those aged over 65. Whatever
antibiotic is chosen, the regimen may need to be changed,
24.50 Emergency management of suspected
septic arthritis
Admit patient to hospital
Perform urgent investigations
• Aspirate joint:
Send synovial fluid for Gram stain and culture
Use imaging guidance if required
• Send blood for culture, routine biochemistry and haematology,
including erythrocyte sedimentation rate and C-reactive protein
• Consider sending other samples (sputum, urine, wound swab) for
culture, depending on patient history, to determine primary source
of infection
Commence intravenous antibiotic*
• Flucloxacillin (2 g 4 times daily)
• If penicillin-allergic:
Clindamycin (450-600 mg 4 times daily in younger patients)
Intravenous vancomycin (1 g twice daily if age >65 years)
• If high risk of Gram-negative sepsis (recurrent urinary tract
infection):
Intravenous gentamicin (5 mg/kg once daily) or vancomycin
(750-1000 mg twice daily)
Relieve pain
• Oral and/or intravenous analgesics
• Consider local ice-packs
Aspirate joint
• Perform serial needle aspiration to dryness (1-3 times daily or as
required)
• Consider arthroscopic drainage if needle aspiration difficult
Arrange physiotherapy
• Early regular passive movement, progressing to active movements
once pain controlled and effusion not re-accumulating
*The evidence base for choice of antibiotic selection is poor. Local guidelines
should be followed where available.
depending on the organism that is isolated. Microbiology advice
should always be sought in complicated situations, such as
when treating intravenous drug users, patients in intensive care
and those who might be colonised by resistant organisms. It is
traditional to continue intravenous antibiotics for 2 weeks and to
follow this with oral treatment for another 4 weeks, but there is
no evidence to support the optimal duration of treatment. Joint
aspiration should be performed using a large-bore needle once
or twice daily. If this is not possible, arthroscopic or open surgical
drainage may be needed performed. Regular passive movement
should be undertaken from the outset, and active movements
encouraged once the condition has stabilised. Infected prosthetic
joints require management by the orthopaedic team, but prolonged
antibiotic treatment on its own is often ineffective and removal of
the prosthesis is required for eradication of the infection.
Arthritis may be a feature of Lyme disease caused by members
of the Borrelia species of microorganisms (p. 255). It is generally
a late manifestation, which usually affects large joints. Brucellosis
presents with an acute febrile illness, followed in some cases
by the development of localised infection, which can result in
arthritis, bursitis, osteomyelitis, sacroiliitis and paravertebral
or psoas abscesses. These conditions are discussed on
pages 254 and 255.
| Viral arthritis
The usual presentation is with acute polyarthritis following a febrile
illness, which may be accompanied by a rash. Most cases of
24.49 Joint and bone infection in old age
• Vertebral infection: more common. Recognition may be delayed,
as symptoms may be attributed to compression fractures caused by
osteoporosis.
• Peripheral vascular disease: leads to more frequent involvement
of the bones of the feet, and diabetic foot ulcers are also commonly
complicated by osteomyelitis.
• Prosthetic joint infections: now more common because of the
increased frequency of prosthetic joint insertion in older people.
• Gram-negative bacilli: more frequent pathogens than in younger
people.
• Cephalosporins: contraindicated due to the high risk of Clostridium
difficile.
• Septic arthritis: mortality is high in elderly patients.
Rheumatoid arthritis • 1021
24.51 Musculoskeletal manifestations of HIV
Condition
Comment
Non-specific arthralgia
Most common; intermittent and
polyarticular
Reactive arthritis
Psoriatic arthritis
Idiopathic lower limb
inflammatory arthritis
Especially in men who have sex
with men
Osteonecrosis
Myositis
Vasculitis
Sjogren’s-like disease
Unclear if related to HIV, its
treatment or intercurrent disease
viral arthritis are self-limiting and settle down within 4-6 weeks.
Human parvovirus arthropathy (mainly B19; p. 237) is the most
common in Europe; adults may not have the characteristic
‘slapped cheek’ facial rash seen in children. The diagnosis can
be confirmed by a rise in specific IgM. Polyarthritis may also
occur rarely with hepatitis B and C, rubella (including rubella
vaccination) and HIV infection. A variety of mosquito-borne viruses
may cause epidemics of acute polyarthritis, including Ross River
(Australia, Pacific), Chikungunya and O’nyong-nyong (Asia, Africa),
and Mayaro viruses (South America). A wide variety of articular
symptoms have been associated with HIV, mainly in the later
stages of infection (Box 24.51). Management is symptomatic,
with NSAIDs and analgesics.
Osteomyelitis
In osteomyelitis, the primary sites of infection are bone and
bone marrow. Any part of a bone may be involved but there is
preferential targeting of the juxta-epiphyseal regions of long bones
adjacent to joints. The risk of osteomyelitis increases with age;
the incidence is about 8.8 cases per 100000 person-years in
those under 18, rising to 40.8 cases in those aged 60-69 and
88.3 cases in those above the age of 80.
Pathogenesis
Haematogenous spread is the most common cause in children
but contiguous spread of infection from adjacent soft tissues or
as the result of surgery is more important in adults. Diabetes
is a particularly important risk factor, accounting for about
30% of cases in recent series. Other risk factors include
immunosuppressive therapy, HIV infection and sickle-cell disease,
which particularly increases the risk of Salmonella infection. The
organisms most frequently implicated are Staph, aureus, Staph,
epidermidis and streptococci. The infection often results in a florid
inflammatory response, with a greatly increased intraosseous
pressure. If untreated, the condition may cause localised areas
of osteonecrosis, leading to the development of a fragment of
necrotic bone that is called a sequestrum. Eventual perforation of
the cortex by pus stimulates local new bone formation (involucrum)
in the periosteum, often leading to the development of sinuses
that discharge through the skin.
Clinical features
The presentation is with localised bone pain and tenderness,
often accompanied by malaise, night sweats and pyrexia. The
adjacent joint may be painful to move and may develop a sterile
effusion or secondary septic arthritis.
Investigations
Patients suspected of having osteomyelitis should have an MRI,
which is more sensitive than X-ray for detecting early changes.
Where possible, cultures should be obtained by open or imaging-
guided biopsy of the lesion. Evidence of osteopenia, localised
osteolysis and osteonecrosis may be seen on X-ray. Blood
cultures should be taken, which may also reveal the causative
organism. Routine bloods typically show evidence of an acute
phase response with a neutrophilia and raised ESR and CRP.
Management
Early recognition is critical as once osteomyelitis becomes
established and chronic, it may prove very hard to eradicate
with antibiotics alone. The principles are those followed for septic
arthritis, with parenteral antibiotics for 2 weeks, followed by oral
antibiotics for at least 4 weeks. An exception is in localised
osteomyelitis of the toes and fingers, which can often be treated
successfully with a prolonged course of oral antibiotics. Resection
of the infected bone and subsequent reconstruction may be
required. Complications of chronic osteomyelitis include secondary
amyloidosis (p. 81) and skin malignancy at the margin of a
discharging sinus (Marjolin’s ulcer).
| Discitis
Discitis is an unusual condition in which there is infection of the
intervertebral disc, often extending into the epidural space or
paravertebral soft tissues. Staph, aureus is the most common
pathogen. Risk factors include diabetes mellitus, immunodeficiency
or immunosuppressive therapy, and intravenous drug use. The
presentation is with back pain accompanied by fever, and an
acute phase response with high ESR and CRP and a neutrophilia.
If the diagnosis is suspected, an MRI should be performed and
blood cultures taken. If blood cultures are negative, open or
imaging-guided biopsy of the lesion should be performed to try to
identify the organism responsible. Management is with supportive
care and parenteral antibiotics followed by oral antibiotics, as
described for osteomyelitis.
| Tuberculosis
Tuberculosis can affect the musculoskeletal system, usually
targeting the spine (Pott’s disease) or large joints such as the
hip, knee or ankle. The presentation is with pain, swelling and
fever. The X-ray changes are non-specific and mycobacteria are
seldom identified in the synovial fluid, so tissue biopsy is required
for a definitive diagnosis. Medical management is described on
page 592. In some cases, surgical debridement may be required
for extensive joint disease, and spinal involvement may require
surgical stabilisation and decompression.
Rheumatoid arthritis
Rheumatoid arthritis (RA) is a common form of inflammatory
arthritis, occurring throughout the world and in all ethnic groups.
The prevalence of RA is approximately 0.8-1 .0% in Europe
and the Indian subcontinent, with a female-to-male ratio of 3 : 1 .
The prevalence is lower in South-east Asia (0.4%). The highest
prevalence in the world is in Pima Indians (5%). It is a chronic
disease characterised by a clinical course of exacerbations and
remissions.
1022 • RHEUMATOLOGY AND BONE DISEASE
Pathophysiology
RA is a complex disease with both genetic and environmental
components. The importance of genetic factors is demonstrated
by higher concordance of RA in monozygotic (1 2-1 5%) compared
with dizygotic twins (3%), and an increased frequency of disease
in first-degree relatives of patients. Genome-wide association
studies have detected nearly 1 00 loci that are associated with
the risk of developing RA. The strongest association is with
variants in the HLA region. Recent studies have shown that the
association with HLA is determined by variations in three amino
acids in the HLA-DRpI molecule (positions 1 1 , 71 and 74) and
single variants HLA-B (at position 9) and HL4-DP(31 (at position
9). The non-HLA loci generally lie within or close to genes involved
in regulating the immune response. It is currently believed that RA
occurs when an environmental stimulus, such as infection, triggers
autoimmunity in a genetically susceptible host by modifying
host proteins through processes like citrullination so that they
become immunogenic. However, no single specific pathogen
has been identified as a cause. An important environmental
risk factor is cigarette smoking, which is also associated with
more severe disease and reduced responsiveness to treatment.
Remission may occur during pregnancy and sometimes RA first
presents post-partum. This is likely to be due to suppression of
the immune response during pregnancy but hormonal changes
may also play a role.
The disease is characterised by infiltration of the synovial
membrane with lymphocytes, plasma cells, dendritic cells and
macrophages. There is evidence that CD4+ T lymphocytes
and B cells play important roles in the pathogenesis of RA by
interacting with other cells in the synovium, as illustrated in
Figure 24.32. Lymphoid follicles form within the synovial membrane
in which T- and B-cell interactions occur, causing activation of T
cells to produce cytokines and activation of B cells to produce
autoantibodies, including RF and ACPA. Synovial macrophages
are activated by TNF and interferon gamma (IFN-y), produced
by T cells. The macrophages produce several pro-inflammatory
cytokines, including TNF, IL-1 and IL-6, which act on synovial
fibroblasts to produce further cytokines, setting up a positive
feedback loop. The synovial fibroblasts proliferate, causing
synovial hypertrophy and producing matrix metalloproteinases
and the proteinase ADAMTS-5, which degrade soft tissues and
cartilage. Prostaglandins and nitric oxide produced within the
inflamed synovium cause vasodilatation, resulting in swelling
and pain. Systemic release of IL-6 triggers production of acute
phase proteins by the liver. At the joint margin, the inflamed
synovium (pannus) directly invades bone and cartilage to cause
joint erosions. A key pathogenic factor in bone erosions and
periarticular osteoporosis is osteoclast activation, stimulated by the
production of M-CSF by synovial cells and RANKL by activated
T cells (Fig. 24.32). New blood-vessel formation (angiogenesis)
occurs, causing the inflamed synovium to become highly vascular.
Fig. 24.32 Pathophysiology of rheumatoid arthritis. Some of the cytokines and cellular interactions believed to be important in rheumatoid arthritis are
shown. (ADAMTS5 = aggrecanase; IL = interleukin; M-CSF = macrophage colony-stimulating factor; MMP = matrix metalloproteinase; RANKL = receptor
activator of nuclear factor kappa B ligand; TNF = tumour necrosis factor)
Rheumatoid arthritis • 1023
i
Criterion Score
Joints affected
1 large joint 0
2-1 0 large joints 1
1-3 small joints 2
4-10 small joints 3
> 1 0 joints (at least 1 small joint) 5
Serology
Negative RF and ACPA 0
Low positive RF or ACPA 2
High positive RF or ACPA 3
Duration of symptoms
<6 weeks 0
>6 weeks 1
Acute phase reactants
Normal CRP and ESR 0
Abnormal CRP or ESR 1
Patients with a score >6 are considered to have definite RA.
*European League Against Rheumatism/American College of Rheumatology 201 0
criteria.
(ACPA = anti-citrullinated peptide antibody; CRP = C-reactive protein;
ESR = erythrocyte sedimentation rate; RF = rheumatoid factor)
Within these blood vessels, pro-inflammatory cytokines activate
endothelial cells, which support recruitment of yet more leucocytes
to perpetuate the inflammatory process.
Later, fibrous or bony ankylosis may occur. Muscles adjacent
to inflamed joints atrophy and may be infiltrated with lymphocytes.
This leads to progressive biomechanical dysfunction and may
further amplify destruction.
Rheumatoid nodules occur in patients who are RF- or ACPA-
positive and primarily affect extensor tendons. They consist of
a central area of fibrinoid material surrounded by a palisade of
proliferating mononuclear cells. Granulomatous lesions may
occur in the pleura, lung, pericardium and sclera.
Clinical features
The typical presentation is with pain, joint swelling and stiffness
affecting the small joints of the hands, feet and wrists in a
symmetrical fashion. Large joint involvement, systemic symptoms
and extra-articular features may also occur. Clinical criteria for
the diagnosis of RA are shown in Box 24.52.
Sometimes RA has an acute onset, with severe early morning
stiffness, polyarthritis and pitting oedema. This occurs more
commonly in old age. Another presentation is with proximal muscle
stiffness mimicking polymyalgia rheumatica (p. 1 042). Occasionally,
the onset is palindromic, with relapsing and remitting episodes of
pain, stiffness and swelling that last for only a few hours or days.
Examination typically reveals swelling and tenderness of the
affected joints. Erythema is unusual and its presence suggests
coexistent sepsis. Characteristic deformities may develop
with long-standing uncontrolled disease, although these have
become less common over recent years with more aggressive
management. They include ulnar deviation of the fingers, ‘swan
neck’ deformity, the boutonniere or ‘button hole’ deformity, and
a Z deformity of the thumb (Fig. 24.33). Dorsal subluxation of
the ulna at the distal radio-ulnar joint may occur and contribute
to rupture of the fourth and fifth extensor tendons. Triggering
of fingers may occur because of nodules in the flexor tendon
Fig. 24.33 The hand in rheumatoid arthritis. [A] Ulnar deviation of the
fingers with wasting of the small muscles of the hands and synovial swelling
at the wrists, the extensor tendon sheaths, the metacarpophalangeal and
proximal interphalangeal joints. [B] ‘Swan neck’ deformity of the fingers.
sheaths. Subluxation of the MTP joints of the feet may result in
‘cock-up’ toe deformities, causing pain on weight-bearing on
the exposed MTP heads and the development of secondary
adventitious bursae and callosities. In the hindfoot, a valgus
deformity of the calcaneus may be observed as the result of
damage to the ankle and subtalar joints. This is often associated
with loss of the longitudinal arch (flat foot) due to rupture of the
tibialis posterior tendon. Popliteal (Baker’s) cysts may occur in
patients with knee synovitis, in which synovial fluid communicates
with the cyst but is prevented from returning to the joint by a
valve-like mechanism; this is not specific to RA. Rupture may be
induced by knee flexion, leading to calf pain and swelling that may
mimic a deep venous thrombosis (DVT). These joint deformities
tend to be observed in older patients with long-standing disease
but are becoming much less common with more aggressive
treatment of RA in its early stages.
Systemic features
Anorexia, weight loss and fatigue may occur throughout the
disease course. Osteoporosis is a common complication
(p. 1 044) and muscle-wasting may occur as the result of systemic
inflammation and reduced activity. Extra-articular features are
most common in patients with long-standing seropositive erosive
disease but may occasionally occur at presentation, especially in
men. Most are due to serositis, granuloma and nodule formation
or vasculitis (Box 24.53).
Nodules
Rheumatoid nodules occur almost exclusively in RF- or ACPA-
positive patients, usually in extensor tendons (Fig. 24.34). They
24.52 Criteria for diagnosis of rheumatoid arthritis
1024 • RHEUMATOLOGY AND BONE DISEASE
24.53 Extra-articular manifestations of
rheumatoid disease
Systemic
• Fever
• Fatigue
• Weight loss
• Susceptibility to infection
Musculoskeletal
• Muscle- wasting
• Bursitis
• Tenosynovitis
• Osteoporosis
Haematological
• Anaemia
• Eosinophilia
• Thrombocytosis
Lymphatic
• Felty’s syndrome (see
• Splenomegaly
Box 24.54)
Nodules
• Sinuses
• Fistulae
Ocular
• Episcleritis
• Scleromalacia
• Scleritis
• Keratoconjunctivitis sicca
Vasculitis
• Digital arteritis
• Mononeuritis multiplex
• Ulcers
• Visceral arteritis
• Pyoderma gangrenosum
Cardiac
• Pericarditis
• Conduction defects
• Myocarditis
• Coronary vasculitis
• Endocarditis
• Granulomatous aortitis
Pulmonary
• Nodules
• Bronchiolitis
• Pleural effusions
• Caplan’s syndrome (p. 611)
• Fibrosing alveolitis
Neurological
• Cervical cord compression
• Peripheral neuropathy
• Compression neuropathies
• Mononeuritis multiplex
Amyloidosis (p. 81)
Fig. 24.34 Rheumatoid nodules and olecranon bursitis. Nodules were
palpable within, as well as outside, the bursa.
are frequently asymptomatic but some may be complicated by
ulceration and secondary infection.
Vasculitis
This is uncommon but may occur in seropositive patients. The
presentation is with systemic symptoms, such as fatigue and fever
and nail-fold infarcts. Rarely, cutaneous ulceration, skin necrosis
and mesenteric, renal or coronary artery occlusion may occur.
Ocular involvement
The most common symptom is dry eyes (keratoconjunctivitis
sicca) due to secondary Sjogren’s syndrome (p. 1038). Scleritis
and peripheral ulcerative keratitis are uncommon but more serious
and potentially sight-threatening complications that usually present
with pain and redness. Clinical features and management are
discussed in more detail on page 1172.
Serositis
Serositis is usually asymptomatic but may present with pleural
or pericardial pain and breathlessness. Pericardial effusion and
constrictive pericarditis may rarely occur.
Cardiac involvement
Heart block, cardiomyopathy, coronary artery occlusion and
aortic regurgitation have all been reported but are rare. The risk
of cardiovascular disease is increased due to a combination of
conventional risk factors, such as high cholesterol, smoking,
hypertension, reduced physical activity, NSAIDs, glucocorticoids
and the effects of inflammatory cytokines on vascular endothelium.
Pulmonary involvement
Pulmonary fibrosis may occur but is often asymptomatic. There
is some evidence that the risk of pulmonary fibrosis is increased
by anti-TNF therapy, although its uncertain whether this is causal
or a marker of more severe disease in patients who require
anti-TNF treatment.
Peripheral neuropathy
Entrapment neuropathies may result from compression by
hypertrophied synovium or by joint subluxation. Median nerve
compression is the most common and bilateral carpal tunnel
syndrome can occur as a presenting feature of RA. Other
syndromes include ulnar nerve compression at the elbow or
wrist, compression of the lateral popliteal nerve at the head
of the fibula, and tarsal tunnel syndrome (entrapment of the
posterior tibial nerve in the flexor retinaculum), which causes
burning, tingling and numbness in the distal sole and toes. Diffuse
symmetrical peripheral neuropathy and mononeuritis multiplex
may occur in patients with rheumatoid vasculitis.
Spinal cord compression
This rare complication is caused by compression of the spinal cord
from subluxation of the cervical spine at the atlanto-axial joint or
at a subaxial level (Fig. 24.35). Atlanto-axial subluxation is due to
erosion of the transverse ligament posterior to the odontoid peg.
It can lead to cord compression or sudden death following minor
trauma or manipulation. It should be suspected in any RA patient
who describes new onset of occipital headache, particularly if
symptoms of paraesthesia or electric shock are present in the
arms. The onset is often insidious, with subtle loss of function
that may initially be attributed to active disease. Reflexes and
power can be difficult to assess in patients with extensive joint
disease and therefore sensory or upper motor signs are most
important. Patients with evidence of spinal cord compression
require urgent neurosurgical referral for stabilisation and fixation.
Other complications
Amyloidosis is a rare complication of long-standing disease
that usually presents with nephrotic syndrome. Microcytic
anaemia can occur due to iron deficiency resulting from NSAID-
induced gastrointestinal blood loss, whereas normochromic,
normocytic anaemia with thrombocytosis occurs in patients
Rheumatoid arthritis • 1025
Fig. 24.35 Subluxation of cervical spine. [A] Flexion, showing widening
of the space (arrow) between the odontoid peg of the axis (behind) and the
anterior arch of the atlas (in front). [1] Extension, showing reduction in this
space.
24.55 Investigations and monitoring of
rheumatoid arthritis
To establish diagnosis
• Clinical criteria • Rheumatoid factor and
• Erythrocyte sedimentation rate anti-citrullinated peptide
and C-reactive protein antibodies
• Ultrasound or magnetic
resonance imaging
To monitor disease activity and drug efficacy
• Pain (visual analogue scale) • Joint swelling
• Early morning stiffness • DAS28 score (see Fig. 24.36)
(minutes) • Erythrocyte sedimentation rate
• Joint tenderness and C-reactive protein
To monitor disease damage
• X-rays • Functional assessment
To monitor drug safety
• Urinalysis • Urea and creatinine
• Full blood count • Liver function tests
• Chest X-ray
24.54 Felty’s syndrome
with active disease. Felty’s syndrome is a rare complication of
seropositive RA in which splenomegaly occurs in combination
with neutropenia and thrombocytopenia (Box 24.54). Localised
or generalised lymphadenopathy can occur in patients with
active disease but persistent lymphadenopathy may indicate the
development of lymphoma, which is more common in patients with
long-standing RA.
Investigations
The diagnosis of RA is essentially clinical but investigations
are useful in confirming the diagnosis and assessing disease
activity (Box 24.55). The ESR and CRP are usually raised but
normal results do not exclude the diagnosis, especially if only
a few joints are involved. Tests for ACPA are positive in about
70% of cases and are highly specific for RA, occurring in many
patients before clinical onset of the disease. Similarly, RF is also
positive in about 70% of cases, most of whom also test positive
for ACPA. RF is less specific than ACPA, however, and positive
tests can occur in other diseases (p. 991).
Ultrasound examination and MRI are not routinely required but
can be value in patients with symptoms suggestive of RA where
there is clinical uncertainty about the presence of synovitis. Plain
X-rays of the hands, wrist and feet are usually normal in early RA
but periarticular osteoporosis and marginal joint erosions may be
observed with more advanced disease. The main indication for
an X-ray is in the assessment of patients with painful joints to
determine whether significant structural damage has occurred.
Patients who are suspected of having atlanto-axial disease
should have lateral X-rays taken in flexion and extension, and
an MRI. In those with suspected Baker’s cyst, ultrasound may
be required to establish the diagnosis.
DAS28 is widely used to assess disease activity, response to
treatment and need for biological therapy. It involves counting
the number of swollen and tender joints in the upper limbs
and knees, and combining this with the ESR and the patient’s
assessment of the activity of their arthritis on a visual analogue
scale, where 0 indicates no symptoms and 100 the worst
symptoms possible. This data are entered into a calculator to
generate a numerical score. The higher the value, the more
active the disease (Fig. 24.36).
Management
The treatment goal is to suppress inflammation, control symptoms
and prevent joint damage. This involves a combination of
pharmacological and non-pharmacological therapies. When RA
occurs in women of child-bearing age, additional considerations
need to be taken into account and these are summarised in
Box 24.56.
Pharmacological therapy
DMARD therapy should be introduced in all patients as this
improves outcome. A typical algorithm is shown in Figure 24.37.
On first diagnosis, prednisolone should be started in a dose of
30 mg daily gradually reducing in 5 mg increments every 2 weeks
until therapy is withdrawn after about 1 2 weeks. At the same time,
methotrexate should be started in an initial dose of 1 5 mg weekly,
along with folic acid 5 mg weekly, and escalated up to a maximum
of 25 mg weekly, depending on the response. If the patient fails
to respond adequately or dose-limiting toxicity occurs, then an
additional DMARD should be commenced in combination with
MTX. The most common combination is triple therapy, in which
Risk factors
• Age of onset 50-70 years
•
Deforming but inactive disease
• Female > male
•
Seropositive for rheumatoid
• Caucasians > blacks
• Long-standing rheumatoid
arthritis
factor
Common clinical features
• Splenomegaly
•
Keratoconjunctivitis sicca
• Lymphadenopathy
•
Vasculitis, leg ulcers
• Weight loss
•
Recurrent infections
• Skin pigmentation
Laboratory findings
•
Nodules
• Normochromic, normocytic
•
Thrombocytopenia
anaemia
•
Impaired T- and B-cell
• Neutropenia
• Abnormal liver function
immunity
1026 • RHEUMATOLOGY AND BONE DISEASE
Calculation
• Count swollen joints
• Count tender joints
• Measure erythrocyte
sedimentation rate*
• Note patient global health
assessment (1-100)
• Enter data into calculator:
www.4s-dawn.com/das28
Interpretation
•>5.1 High activity
• 2.6-5. 1 Moderate activity
•<2.6 Remission
Fig. 24.36 Calculation of the Disease Activity Score 28 (DAS28).
^Erythrocyte sedimentation rate or C-reactive protein can be used for the
calculation.
24.56 Rheumatoid arthritis in pregnancy
• Immunological changes in pregnancy: many patients with
rheumatoid arthritis go into remission during pregnancy.
• Conception: methotrexate should be discontinued for at least
3 months and leflunomide discontinued for at least 24 months
before trying to conceive.
• Paracetamol: the oral analgesic of choice during pregnancy.
• Oral non-steroidal anti-inflammatory drugs and selective
cyclo-oxygenase 2 (COX-2) inhibitors: can be used from
implantation to 20 weeks’ gestation.
• Glucocorticoids: may be used to control disease flares; the main
maternal risks are hypertension, glucose intolerance and
osteoporosis.
• Disease-modifying antirheumatic drugs (DMARDs) that may be
used: sulfasalazine, hydroxychloroquine and azathioprine if required
to control inflammation.
• DMARDs that must be avoided: methotrexate, leflunomide,
cyclophosphamide, mycophenolate and gold.
• Biologic therapies: experience is limited but they may be
relatively safe during pregnancy. The main theoretical risk is
immunosuppression in the neonate, except for certolizumab, which
does cross the placenta in negligible amounts.
• Breastfeeding: methotrexate, leflunomide and cyclophosphamide
are contraindicated.
methotrexate, sulfasalazine and hydroxychloroquine are combined
(Fig. 24.37). Other DMARDs can be substituted or added, along
with a low-dose glucocorticoid such as prednisolone (5-1 0 mg
daily) if the patient fails to respond fully. If disease activity remains
high (DAS28 >5.1) despite triple therapy, however, it is usual to
progress to biologic therapy. The most commonly used first-line
biologies in RA are TNF inhibitors, although several other options
are available (p. 1006). When the patient has been stabilised on
biologic treatment for 12 months or more, a reduction in dose
should be considered, since it is possible to reduce the dose
in up to 50% of patients without loss of therapeutic effect. The
JAK inhibitors tofacitinib and baricitinib have efficacy in patients
who fail to respond adequately to other DMARDs and provide
an alternative to biologic therapies.
RA is a chronic disease and flares can occur even in patients
who are established on DMARD and biologic therapy. Transient
New diagnosis of
rheumatoid arthritis
Increase dose
over 12 weeks
MTX
+
Prednisolone]
Decrease dose
over 12 weeks
DAS28
<2.6
DAS28
>2.6
Continue
MTX
Add SSZ
+ HCQ
l
*
DAS28
<2.6
DAS28
2.6-5. 1
DAS28
>5.1
I I I
Continue
triple
therapy
Change
DMARD or
add low-dose
prednisolone
Add
biologic
Fig. 24.37 Algorithm for the management of rheumatoid arthritis.
(DAS28 = Disease Activity Score 28; DMARD = disease- modifying
antirheumatic drug; HCQ = hydroxychloroquine; MTX = methotrexate;
SSZ = sulfasalazine)
flares can be dealt with by intra-articular glucocorticoid injections
or a short course of oral glucocorticoids, but if a sustained flare
occurs, a change in systemic DMARD and/or biologic therapy
may need to be considered.
Non-pharmacological therapy
Physical and occupational therapy play important roles and
it is vital for all patients to be assessed by an occupational
therapist and physiotherapist and the appropriate advice and
treatment provided.
Surgery
Synovectomy can be helpful in joints that have failed to respond
adequately to systemic therapy and intra-articular injections. Joint
replacement surgery may be required but the need for this has
diminished over recent years, presumably as the result of more
aggressive medical management. Other surgical procedures that
can be helpful are excision of the metatarsal heads in patients
with subluxation of the MTP joints; neurosurgery in patients
with atlanto-axial subluxation; and fusion or the wrist or ankle in
patients with joint damage (see Box 24.29, p. 1002).
Juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA) is the term, accepted by the
international community, for several forms of arthritis defined by
the International League of Associations for Rheumatology 2001
criteria (Box 24.57). This includes juvenile forms of psoriatic arthritis
(JPsA), rheumatoid arthritis (JRA) and more undifferentiated forms
of inflammatory arthritis. The majority of patients with JIA have
a phenotype that is distinct from adult inflammatory arthritis
Spondyloarthropathies • 1027
24.57 Clinical features of juvenile idiopathic arthritis
Subtype
Frequency
Clinical features
Immunology
Systemic juvenile idiopathic arthritis
5%
Fever, rash, arthralgia, hepatosplenomegaly
Autoantibody-negative
Oligoarthritis (<4 joints)
60%
Large-joint arthritis, uveitis
ANA-positive
Polyarthritis (>5 joints)
20%
Polyarthritis; may be extended form of oligoarthritis
ANA-positive
Enthesis-related
5%
Sacroiliitis, enthesopathy
FILA-B27-positive
RF-positive
5%
Polyarthritis, similar to RA
RF-positive, ACPA-positive
Psoriatic arthritis
5%
Same as adult disease (p. 1032)
Autoantibody-negative
(ACPA = anti-citrullinated peptide antibody; ANA =
antinuclear antibody; HLA = human leucocyte antigen; RA = rheumatoid arthritis; RF =
rheumatoid factor)
and includes a strong association with uveitis. JIA affects about
1 : 1 000 children and young people up to 1 6 years of age - similar
to the prevalence of diabetes (1 : 700). The annual incidence is
approximately 1 per 10000 children and young people.
Whereas joint restriction is attributed to damage in adults,
in children it indicates inflammatory activity. Arthritis in children
affects limb growth and has a negative effect on height and
weight attainment. In young children, effective disease control
can repair joint damage before puberty.
Oligoarthritis is the most common form of JIA, accounting
for about 60% of cases. It is more common in females and
tends to affect large joints in an asymmetrical pattern. There is
an association with uveitis and many patients are ANA-positive.
Polyarticular JIA is heterogeneous: some patients are RF- and/
or ACPA-positive, while others are negative for autoantibodies.
Systemic juvenile idiopathic arthritis (sJIA, formerly known
as Still’s disease) is characterised by fever, rash, arthritis,
hepatosplenomegaly and serositis in association with anaemia
and a raised ESR and CRP. Autoantibody tests are negative.
This form of JIA is associated with haemophagocytic syndrome.
Many cases of enthesitis-related arthritis (ERA) are likely to
be self-limiting forms of spondyloarthritis. ERA can progress
over time into a more obviously defined spondyloarthropathy.
Investigations
ESR and CRP do not correlate well with the extent or severity of
inflammation and may be normal. A very high ESR may indicate
the presence of inflammatory bowel disease or (very rarely)
leukaemia. Low haemoglobin is likely to be due to anaemia
of chronic disease rather than iron deficiency. A positive ANA
occurs in 40-75% of cases of JIA and indicates an increased
risk of eye disease. Ultrasound is the radiological investigation of
choice to confirm synovitis or tenosynovitis. The false-negative
rate is higher in foot and ankle disease than in other joints.
Arthroscopy should be avoided unless a biopsy is required.
Synovial fluid aspiration, but not arthroscopy, is essential when
considering sepsis and tuberculosis.
Management
The key approach is to gain early rapid control of inflammation,
minimise the adverse effects of treatment and support the
general physical and mental health of the patient, which requires
full multidisciplinary team input. The standard immunotherapy
is methotrexate (subcutaneous methotrexate is typically used
in the young child). Alternative treatment includes leflunomide,
sulfasalazine and hydroxychloroquine. Azathioprine and ciclosporin
can be used to treat JIA with uveitis. Mycophenolate and
tacrolimus are considered to have a specific role in treating
R
• Uveitis: may be clinically silent and persist into adulthood. All (not
just those who are ANA-positive) need ophthalmic screening for eye
involvement.
« Persistence into adulthood: occurs in 50% of cases, especially in
systemic disease. Specific supportive management through
transition from adolescence to adulthood should be planned.
« Reduced peak bone mass: common in polyarthritis and systemic
juvenile idiopathic arthritis but there are few data on fracture risk
and the evidence base for treatment is poor.
« Therapy: methotrexate is standard treatment, used after NSAIDs
alone are insufficient. Anti-TNF therapy is effective in all forms of
juvenile idiopathic arthritis but long-term safety remains unclear.
(ANA = antinuclear antibody; NSAIDs = non-steroidal anti-inflammatory drugs;
TNF = tumour necrosis factor)
uveitis alone. Drug combinations are not well studied in JIA.
Biologic therapies, including anti-TNF, are effective in JIA and
are now a standard treatment in the presence of refractory
disease or intolerance of methotrexate or other non-biologic
immunotherapies. Tocilizumab is also effective in sJIA, and has
been approved by NICE for use in the UK.
Prognosis
Suboptimal outcomes are associated with delayed diagnosis
and referral to the specialist multidisciplinary team, inadequate
disease control, presentation with uveitis, sJIA in males and poor
engagement with services. Psychological support of affected
children and their families is associated with improved outcome.
Oligo-JIA often resolves at puberty. Polyarticular disease and sJIA
remain active into adulthood in about 50% of cases. Common
issues around the transition of adolescent patients into adulthood
are shown in Box 24.58.
Spondyloarthropathies
Spondyloarthropathies (SpAs) comprise a group of related
inflammatory musculoskeletal diseases that show overlap in their
clinical features and have a shared immunogenetic association
with HLA-B27 (Box 24.59). They include:
• axial spondyloarthritis
• ankylosing spondylitis
• reactive arthritis
• psoriatic arthritis
24.58 Juvenile idiopathic arthritis in adolescence
1028 • RHEUMATOLOGY AND BONE DISEASE
• arthritis with inflammatory bowel disease (enteropathic
spondyloarthritis).
In axial spondylitis and ankylosing spondylitis, the axial skeleton
(i.e. the central core skeleton) is predominantly affected. In
contrast to RA, in the SpAs there are frequent and notable
non-synovial musculoskeletal lesions - mainly inflammatory in
nature - of ligaments, tendons, periosteum and other bone
lesions. A hallmark lesion of all SpAs is enthesitis, which is
inflammation at the site of a ligament or tendon insertion into
bone. Dactylitis, inflammation of a whole finger or toe, may also
occur (see Fig. 24.43).
It has been estimated that about 1 % of the adult population in
the USA may have an SpA (about 2.7 million). There is a striking
association with HL4-B27, particularly for ankylosing spondylitis
(>95%). Additionally, SpAs are thought to arise as the result of
an aberrant host response to infection and abnormal mucosal
immunity mediated through changes in the IL-12, IL-23 and
i
• Asymmetrical inflammatory oligoarthritis (lower > upper limb)
• History of inflammatory back pain
• Sacroiliitis and spinal osteitis
• Enthesitis (e.g. gluteus medius insertion, plantar fascia origin)
• Tendency for familial aggregation
• HLA-B27 association
• Psoriasis (of skin and/or nails)
• Uveitis
• Sterile urethritis and/or prostatitis
• Inflammatory bowel disease
• Aortic root lesions (aortic incompetence, conduction defects)
(HLA = human leucocyte antigen)
Th17 axis (p. 65). In some situations, a triggering organism can
be identified, as in reactive arthritis following bacterial dysentery
or chlamydial urethritis, but in others the environmental trigger
remains obscure. Familial clustering not only is common to the
specific condition occurring in the proband, but also may extend
to other diseases in the spondyloarthropathy group.
Axial spondyloarthropathy
Axial spondyloarthropathy includes classical ankylosing spondylitis
(AS) as well as axial spondyloarthritis (axSpA). Inflammatory
changes in the entire axial skeleton are characteristic of axSpA
and can be visualised by MRI; structural alterations, such as new
bone formation with syndesmophytes and ankylosis, develop
later in the course of the disease. Accordingly, the criteria for
diagnosing AS (Box 24.60), which require evidence of sacroiliitis
on X-ray, are often only able to be applied many years after a
patient’s symptoms started. Not all patients with axSpA will go
on to develop AS.
Pathophysiology
Axial SpA and AS arise from an interaction between environmental
pathogens and the host immune system in genetically susceptible
individuals. Increased faecal carriage of Klebsiella aerogenes has
been reported in patients with established AS and may relate to
exacerbation of both joint and eye disease. There is increasing
evidence that axSpA and AS are due to an abnormal host
response to the intestinal microbiota with involvement of Th17
cells, which have a key role in mucosal immunity. This leads to
production of various inflammatory cytokines, including IL-12,
IL-23, IL-17 and TNF-a, which play vital roles in the pathogenesis
of enthesitis and other inflammatory lesions (Fig. 24.38).
There a strong association between axial spondyloarthropathy
and carriage of the major histocompatibility complex (MHC)
24.59 Features common to spondyloarthropathies
24.60 Comparison of diagnostic criteria for axial spondyloarthritis (ASAS) and ankylosing spondylitis (modified New York)
Axial spondyloarthritis Ankylosing spondylitis
Imaging Sacroiliitis on MRI only Bilateral sacroiliitis on X-ray, even if changes are mild
Unilateral sacroiliitis on X-ray if changes are definite
History Back pain >3 months that has four of the Low back pain >3 months improved by exercise and not relieved by rest
following characteristics:
1. improved by exercise
2. not relieved by rest
3. insidious onset
4. night pain
5. age at onset < 45
Good response of back pain to NSAID
Family history of spondyloarthritis
History of inflammatory bowel disease
Clinical Arthritis Limitation of lumbar spine movement in sagittal and frontal planes
examination Enthesitis Chest expansion reduced
Uveitis
Dactylitis
Psoriasis
Investigations HLA-B27-positive
Elevated CRP
Axial spondyloarthritis is diagnosed from: sacroiliitis on MRI + one other feature on history, clinical examination or investigation.
The diagnosis can also be made in HLA-B27-positive patients with >1 clinical feature in the absence of sacroiliitis
Ankylosing spondylitis can be diagnosed on X-ray evidence of sacroiliitis with one other feature on history or examination
(ASAS = Assessment of Spondylitis International Society; CRP = C-reactive protein; HLA = human leucocyte antigen; MRI = magnetic resonance imaging; NSAID =
non-steroidal anti-inflammatory drug)
Spondyloarthropathies
1029
Gut Activation of Tissue immune
epithelium immune cells cells
in submucosa
Fig. 24.38 Pathophysiology of axial spondyloarthropathy. In genetically susceptible individuals, it is thought that bacterial components penetrate the
mucosal barrier to activate macrophages and dendritic cells in the intestinal submucosa. These cells produce increased amounts of interleukin 23 (IL-23),
which acts on T cells, neutrophils and mast cells to make IL-17; IL-17 in turn has a pivotal role in driving inflammation, causing sacroiliitis and enthesitis.
Presentation of antigen by dendritic cells also plays a pathogenic part in activating T cells, and tumour necrosis factor (TNF), produced by macrophages
and activated T cells, contributes to the pathogenesis of inflammation. Production of IL-22 by T cells is thought to be involved in causing the new bone
formation that is typical of axial spondyloarthropathy.
class I molecule HLA-B27. This is particularly striking in patients
defined as having AS, more than 95% of whom are positive
for HLA-B27. Other susceptibility genes also implicated in
susceptibility to AS include ERAP-1 (an endoplasmic reticulum
protein with a role facilitating intracellular antigen processing
and binding with its presenting MHC molecule HLA-B27), the
IL-23 receptor and downstream signalling molecules involved
in directing Th17 cell responses, such as STAT3 (see Fig. 4.3,
p. 65). The HLA-B27 molecule itself is implicated through its
antigen-presenting function or because of its propensity to form
homodimers that activate leucocytes. HLA-B27 molecules may
also misfold, causing increased endoplasmic reticulum stress.
This could lead to inflammatory cytokine release by macrophages
and dendritic cells, thus triggering inflammatory disease.
| Axial spondyloarthritis
Clinical features
The cardinal feature of axSpA is inflammatory back pain and early
morning stiffness, with low back pain radiating to the buttocks
or posterior thighs if the sacroiliac joints are involved. Symptoms
are exacerbated by inactivity and relieved by movement.
Musculoskeletal symptoms may be prominent at entheses, may
be episodic and, if persistent, can present as widespread pain
and be mistaken for fibromyalgia. Fatigue is common. A history
of psoriasis (current, previous or in a first-degree relative) and
inflammatory bowel symptoms (current or previous) are important
clues. Physical signs include a reduced range of lumbar spine
movements in all directions, pain on sacroiliac stressing and a
high enthesitis index. Entheses that are typically affected include
Achilles’ insertion, plantar fascia origin, patellar ligament entheses,
gluteus medius insertion at the greater trochanter and tendon
attachments at humeral epicondyles. A number of validated
clinical questionnaires, such as the Bath Ankylosing Spondylitis
Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis
Functional Index (BASFI) and Ankylosing Spondylitis Disease
Activity Score (ASDAS-CRP), can be used to assess disease
activity and functional status in AS, though newer assessment
tools are being developed that are more specific to a diagnosis of
axSpA, such as the Assessment of Spondyloarthritis International
Society Health Index (ASAS-H).
Investigations
The diagnosis is aided by ultrasound or MRI of entheses, or by
MRI of the sacroiliac joints and spine (Fig. 24.39). Other findings
Fig. 24.39 Magnetic resonance imaging appearances in sacroiliitis.
Coronal MRI short T1 inversion recovery (STIR) sequence showing bilateral
sacroiliitis in axial spondyloarthritis. Bone marrow oedema (circles) is
present around both sacroiliac joints, which show irregularities due to
erosions (arrows).
1030 • RHEUMATOLOGY AND BONE DISEASE
may include raised ESR and CRP (although these can be normal),
anaemia and positive HLA-B27. Faecal calprotectin is a useful
screening test for associated inflammatory bowel disease.
Management
Patient education, NSAID use (optimally, once daily or slow release
taken at bedtime) and physical therapy are key interventions at the
outset. For severe and/or persistent peripheral musculoskeletal
features of SpA, both sulfasalazine and methotrexate are
reasonable therapy choices. These medications have no impact
on spinal symptoms or disease progression. In patients who
fail to respond adequately or who cannot tolerate NSAIDs,
progression to biologic therapy with either TNF inhibitors or the
IL-7A inhibitor secukinumab should be considered (see Box
24.35, p. 1007). Anti-TNF therapy is effective for both the axial
and peripheral lesions of axSpA, but it is as yet unclear whether
anti-TNF therapy modifies the natural history of the disease.
Prognosis
With such a recent definition of disease, the markers of prognosis
in patients diagnosed with axSpA are not fully understood. It
is clear that axSpA can remain mild and/or episodic in many
patients for many years. HLA-B27 positivity, high persistent CRP
and high functional incapacity are likely to be markers of poor
prognosis, if not markers of extension ultimately to AS.
| Ankylosing spondylitis
Ankylosing spondylitis (AS) is defined by the presence of sacroiliitis
on X-ray and other structural changes on spine X-rays, which
may eventually progress to bony fusion of the spine. There is a
male-to-female ratio of about 3:1. In Europe, more than 90%
of those affected are HLA-B27-positive (Caucasian HLA-B27
population prevalence is 9%). The overall prevalence of AS
is below 0.5% in most populations. Over 75% of patients are
able to remain in employment and enjoy a good quality of life.
Even if severe ankylosis develops, functional limitation may not
be marked, as long as the spine is fused in an erect posture.
Clinical features
Clinical features are the same as in axSpA. AS typically evolves
slowly, with fluctuating symptoms of spinal inflammation; ankylosis
develops in many patients over a period of many years. Secondary
osteoporosis of the vertebral bodies frequently occurs, leading
to an increased risk of vertebral fracture.
In AS, spinal fusion varies in its extent and in most cases
does not cause a gross flexion deformity, but a few patients
develop marked kyphosis of the dorsal and cervical spine that
may interfere with forward vision. This may prove incapacitating,
especially when associated with fixed flexion contractures of
hips or knees.
Up to 40% of patients also have peripheral musculoskeletal
lesions (asymmetrical, affecting entheses of large joints, such
as the hips, knees, ankles and shoulders).
Fatigue is a major complaint and is common to all SpAs, but
its cause is unknown. Acute anterior uveitis is the most common
extra-articular feature, which occasionally precedes joint disease.
Other extra-articular features are occasionally observed but are
rare (Box 24.61).
Investigations
In AS, X-rays of the sacroiliac joint show irregularity and loss of
cortical margins, widening of the joint space and subsequently
sclerosis, joint space narrowing and fusion. Lateral thoracolumbar
spine X-rays may show anterior ‘squaring’ of vertebrae due to
erosion and sclerosis of the anterior corners and periostitis of
the waist. Bridging syndesmophytes may also be seen. These
are areas of calcification that follow the outermost fibres of the
annulus (Fig. 24.40). In advanced disease, ossification of the
anterior longitudinal ligament and facet joint fusion may also
be visible. The combination of these features may result in the
24.61 Extra-articular features of axial
spondyloarthritis and ankylosing spondylitis
• Fatigue, anaemia
• Anterior uveitis (25%)
• Prostatitis (80% of men) and sterile urethritis
• Inflammatory bowel disease (up to 50% have IBD lesions)
• Osteoporosis
• Cardiovascular disease (aortic valve disease 20%)
• Amyloidosis (rare)
• Atypical upper lobe pulmonary fibrosis (very rare)
Fig. 24.40 Radiographic changes in spondyloarthritis. [A] Fine symmetrical marginal syndesmophytes typical of ankylosing spondylitis (arrow).
[§] Coarse, asymmetrical non-marginal syndesmophytes typical of psoriatic spondylitis (arrow).
Spondyloarthropathies • 1031
Fig. 24.41 ‘Bamboo’ spine of advanced ankylosing spondylitis. Note
the symmetrical marginal syndesmophytes (arrows), sacroiliac joint fusion
and generalised osteopenia.
typical ‘bamboo’ spine (Fig. 24.41). Erosive changes may be
seen in the symphysis pubis, ischial tuberosities and peripheral
joints. Osteoporosis is common and vertebral fractures may
occur. Atlanto-axial dislocation can arise as a late feature. MRI
is more sensitive for detection of early sacroiliitis than X-rays
(see Fig. 24.39) and can also detect inflammatory changes in
the lumbar spine. DXA scanning is important as part of a fragility
fracture assessment.
As in axSpA, ESR and CRP are usually raised in active disease
but may be normal; anaemia is often present. Autoantibodies,
such as RF, ACPA and ANA, are negative.
Management
The aims of management are the same as in axSpA: to relieve
pain and stiffness, maintain a maximal range of skeletal mobility
and avoid the development of deformities. Mobilising exercises
are important and are shown on many online resource sites (e.g.
National Ankylosing Spondylitis Society, UK). A long-acting NSAID
at night is helpful for alleviation of morning stiffness. Anti-TNF or
anti-IL-17A therapy should be considered in patients who are
inadequately controlled on standard therapy, as described for
axSpA. Biologic therapies are often highly effective at improving
symptoms but it is not clear whether they prevent ankylosis or
alter the natural history of the disease.
Local glucocorticoid injections can be useful for persistent
plantar fasciitis, other enthesopathies and peripheral arthritis.
Oral glucocorticoids may be required for acute uveitis but do
not help spinal disease. Severe hip, knee or shoulder arthritis
with secondary OA may require arthroplasty. Spinal osteotomy,
to correct stoop and make eyeline/posture ‘more normal’, can
make a significant difference to patients with severe ankylosed
kyphotic spines.
Reactive arthritis
Reactive (spondylo)arthritis (ReA) is a ‘reaction’ to a number of
bacterial triggers with clinical features in keeping with all SpA
conditions. The known triggers are Chlamydia, Campylobacter,
Salmonella, Shigella and Yersinia. Notably, non-SpA-related
reactive arthritis can occur following infection with many viruses,
Mycoplasma, Borrelia, streptococci and mycobacteria, including
M. leprae, which causes leprosy (Hansen’s disease); however, the
‘reaction’ in these instances consists typically of myoarthralgias,
is not associated with HLA-B27 and is generally not chronic.
The arthritis associated with rheumatic fever (p. 515) is also an
example of a reactive arthritis that is not associated with HL4-B27.
Sexually acquired reactive arthritis (SARA) is predominantly
a disease of young men, with a male preponderance of 15:1.
This may reflect a difficulty in diagnosing the condition in young
women, in whom Chlamydia infection is often asymptomatic
and is hard to detect in practical terms. Between 1 % and 2%
of patients with non-specific urethritis seen at genitourinary
medicine clinics have SARA (p. 1031). The syndrome of chlamydial
urethritis, conjunctivitis and reactive arthritis was formerly known
as Reiter’s disease.
With enteric triggering infections (enteropathic ReA), HL4-B27
may predict the reactive arthritis and its severity, though the
condition occurs in H LA- B2 7- negative people. The incidence
of specific triggering infections causing reactive arthritis around
the world varies, depending on the epidemiology of the infection
and prevalence of HLA-B27 in the local population.
Clinical features
The onset is typically acute, with an inflammatory enthesitis,
oligoarthritis and/or spinal inflammation. Lower limb joints and
entheses are predominantly affected. In all types of ReA, there
may be considerable systemic disturbance, with fever and weight
loss. Achilles insertional enthesitis/tendonitis or plantar fasciitis may
also be present. The first attack of arthritis is usually self-limiting,
but recurrent or chronic arthritis can develop and about 1 0% still
have active disease 20 years after the initial presentation. Low
back pain and stiffness due to enthesitis and osteitis are common
and 1 5-20% of patients develop sacroiliitis. Many extra-articular
features in ReA involve the skin, especially in SARA:
• circinate balanitis, which starts as vesicles on the coronal
margin of the prepuce and glans penis, later rupturing to
form superficial erosions with minimal surrounding
erythema, some coalescing to give a circular pattern
• keratoderma blennorrhagica, which begins as discrete
waxy, yellow-brown vesico-papules with desquamating
margins, occasionally coalescing to form large crusty
plaques on the palms and soles of the feet
• pustular psoriasis
• nail dystrophy with subungual hyperkeratosis
• mouth ulcers
• conjunctivitis
• uveitis, which is rare with the first attack but arises in 30%
of patients with recurring or chronic arthritis.
Other complications in ReA are very rare but include aortic
incompetence, conduction defects, pleuro-pericarditis, peripheral
neuropathy, seizures and meningoencephalitis.
Investigations
The diagnosis is usually made clinically but joint aspiration may
be required to exclude crystal arthritis and articular infection.
1032 • RHEUMATOLOGY AND BONE DISEASE
ESR and CRP are raised, urethritis may be confirmed in the
‘two-glass test’ by demonstration of mucoid threads in the
first-void specimen that clear in the second. High vaginal swabs
may reveal Chlamydia on culture. Except for post -Salmonella
arthritis, stool cultures are usually negative by the time the arthritis
presents but serology may help confirm previous dysentery. RF,
ACPA and ANA are negative.
In chronic or recurrent disease, X-rays show periarticular
osteoporosis; proliferative erosions, notably at entheses; periostitis,
especially of metatarsals, phalanges and pelvis; and large, ‘fluffy’
calcaneal spurs. In contrast to AS, radiographic sacroiliitis is often
asymmetrical and sometimes unilateral, and syndesmophytes
are predominantly coarse and asymmetrical, often extending
beyond the contours of the annulus (‘non-marginal’) (see Fig.
24.40B). Radiographic changes in the peripheral joints and spine
are identical to those seen in psoriasis.
Management
Acute ReA should be treated with rest, NSAIDs and analgesics.
Intra-articular or systemic glucocorticoids may be required in
patients with severe monarticular synovitis or polyarticular disease,
respectively. There is no convincing evidence for the use of
antibiotics unless a triggering infection is identified. If chlamydial
urethritis is diagnosed, it should be treated empirically with a short
course of doxycycline or a single dose of azithromycin. Treatment
with DMARDs (usually sulfasalazine or methotrexate) should
be considered for patients with persistent marked symptoms,
recurrent arthritis or severe keratoderma blennorrhagica. Anterior
uveitis is a medical emergency requiring topical, subconjunctival
or systemic glucocorticoids. For DMARD-recalcitrant cases,
anti-TNF therapy should be considered.
Psoriatic arthritis
In the UK and Denmark the estimated population prevalence
of psoriatic arthritis (PsA) from registry and coding data is
approximately 0.2%. It is likely the true prevalence is considerably
higher but this has not been extensively studied. The prevalence
of PsA in psoriasis patients, based on clinical assessment, is
variable but may be up to 40%. Early PsA may present as
axSpA. The onset is usually between 25 and 40 years of age
but juvenile forms exist. Occasionally, the arthritis and psoriasis
develop synchronously but the onset of musculoskeletal and skin
disease is frequently separated by many years. Classification of
PsA requires key assessments of family history and screening
for enthesitis (Box 24.62).
i
Inflammatory articular disease (joint, spine or enthesis) with >3 points
from the following (1 point each unless stated):
• Current psoriasis (scores 2 points)
• History of psoriasis in first- or second-degree relative
• Psoriatic nail dystrophy
• Negative IgM rheumatoid factor1
• Current dactylitis
• History of dactylitis
• Juxta-articular new bone2
Established by any method except latex. 2lll-defined ossification near joint
margins (excluding osteophytes) on X-rays of hands or feet.
(CASPAR = ClASsification for Psoriatic ARthritis)
Pathophysiology
Genetic factors have an important role in PsA and family studies
have suggested that heritability may exceed 80%. Variants in
the HLA-B and HLA-C genes are the strongest genetic risk
factors but more than 30 other variants also play a part. Many
of these variants overlap with those implicated in psoriasis
(p. 1247), where there are more than 40 susceptibility loci.
These lie within or close to genes in the IL-12, IL-23 and nuclear
factor kappa B (NFkB) signalling pathways. It is thought that an
environmental trigger, probably infectious in nature, triggers the
disease in genetically susceptible individuals, leading to immune
activation involving dendritic cells and T cells. CD8+ T cells (which
recognise antigen presented in the context of HLA class I) are
more abundant than CD4+ T cells within the joint, which is in
keeping with the genetic association between PsA and HLA-C
and B variants. There is increasing evidence that the IL-23/
IL-17 pathway plays a pivotal role in PsA. It is thought that the
triggering stimulus causes over-production of IL-23 by dendritic
cells, which in turn promotes differentiation and activation of
Th17 cells, which produce the pro-inflammatory cytokine IL-17A.
This, along with Thl cytokines like IFN-y and TNF-a, acts on
macrophages and tissue-resident stromal cells at entheses, in
bone and within the joint to produce additional pro-inflammatory
cytokines and other mediators, which contribute to inflammation
and tissue damage, as shown in Figure 24.42.
Clinical features
The presentation is with pain and stiffness affecting joints, tendons,
spine and entheses. Joints are typically not swollen; however,
several patterns of joint involvement are recognised (see below),
including an oligoarticular form. These patterns are not mutually
exclusive. Marked variation in disease patterns exists, including
a disease course of intermittent exacerbation and remission.
Destructive arthritis and disability are uncommon, except in the
case of arthritis mutilans.
Asymmetrical inflammatory mono-/oligoarthritis
This often presents abruptly with a combination of synovitis and
adjacent periarticular inflammation. It occurs most characteristically
in the hands and feet, when synovitis of a finger or toe is coupled
with tenosynovitis, enthesitis and inflammation of intervening tissue
to give a ‘sausage digit’ or dactylitis (Fig. 24.43A). Large joints,
such as the knee and ankle, may also be involved, sometimes
with very large effusions.
Symmetrical polyarthritis
This accounts for about 25% of cases. It predominates in women
and may resemble RA, with symmetrical involvement of small
and large joints in both upper and lower limbs. Nodules and
other extra-articular features of RA are absent and arthritis is
generally less extensive and more benign.
Distal interphalangeal joint arthritis
This is quite a common pattern and can be difficult to distinguish
from inflammatory generalised OA. PsA DIP joint disease is
associated with psoriatic nail disease (Fig. 24.43B).
Psoriatic spondylitis
This type presents with inflammatory back or neck pain and
prominent stiffness symptoms. Any structure in the spine can be
involved, including intervertebral disc entheses and facet joints. It
may occur alone or with any of the other clinical patterns described
above and is typically unilateral or asymmetric in severity.
24.62 The CASPAR criteria for psoriatic arthritis
Spondyloarthropathies • 1033
factor; RANKL = RANK ligand)
Arthritis mutilans
This is a deforming erosive arthritis targeting the fingers and
toes; it occurs in 5% of cases of PsA. Prominent cartilage and
bone destruction results in marked instability. The encasing skin
appears invaginated and ‘telescoped’ (‘main en lorgnette’) and
the finger can be pulled back to its original length.
Enthesitis-predominant
This form of disease presents with pain and stiffness at the
insertion sites of tendons and ligaments into bone (enthesitis).
Symptoms can be extensive or localised. Typically affected
entheses include Achilles tendon insertions, plantar fascia origins,
patellar ligament attachments, hip abductor complex insertion
at lateral femoral condyle, gluteus medius insertion at greater
trochanter, humeral epicondyle tendon attachments, deltoid
origin at acromial edge, intercostal muscle attachments at ribs,
and pelvic ligament attachments.
Nail changes include pitting, onycholysis, subungual
hyperkeratosis and horizontal ridging, which are found in 85%
of patients with PsA and can occur in the absence of skin
disease. The characteristic rash of psoriasis (p. 1247) may be
widespread, or confined to the scalp, natal cleft, umbilicus and
genitals, where it is easily overlooked. Obtaining a history of
psoriasis in a first-degree relative can be tricky but is important,
given that a positive response contributes to making a diagnosis.
Investigations
The diagnosis is made on clinical grounds. Autoantibodies
are generally negative and acute phase reactants, such as
ESR and CRP, are raised in only a proportion of patients with
active disease. X-rays may be normal or show erosive change
with joint space narrowing. Features that favour PsA over RA
include the characteristic distribution (see Fig. 24.10, p. 994) of
proliferative erosions with marked new bone formation, absence
of periarticular osteoporosis and osteosclerosis. Imaging of the
axial skeleton often reveals features similar to those in chronic
ReA, with coarse, asymmetrical, non-marginal syndesmophytes
and asymmetrical sacroiliitis. MRI and ultrasound with power
Doppler are increasingly employed to detect synovial inflammation
and inflammation at the entheses.
Management
Therapy with NSAIDs and analgesics may be sufficient to
manage symptoms in mild disease. Intra-articular glucocorticoid
injections can control isolated synovitis or enthesitis. Splints and
prolonged rest should be avoided because of the tendency to
fibrous and bony ankylosis. Patients with spondylitis should
be prescribed the same exercise and posture regime as in
axSpA/AS. Therapy with DMARDs should be considered for
persistent synovitis unresponsive to conservative treatment.
Methotrexate is the drug of first choice and is also effective
1034 • RHEUMATOLOGY AND BONE DISEASE
Fig. 24.43 Psoriatic arthropathy. [A] Dactylitis, jglliistal interphalangeal
joint pattern with accompanying nail dystrophy (pitting and onycholysis).
for skin disease (see EULAR guidelines, ‘Further information’,
p. 1060). Other DMARDs may also be helpful, including
sulfasalazine, ciclosporin and leflunomide. Particular attention
should be paid to monitoring liver function in patients treated
with DMARDs, since abnormalities are common in PsA.
Hydroxychloroquine is generally avoided, as it can cause
exfoliative skin reactions; it may, however, be tried in the small
subset of patients who have mild PsA but no psoriasis and
are ANA-positive. Anti-TNF treatment should be considered
for individuals with active synovitis who respond inadequately
to standard DMARDs, and treatment is effective for both PsA
and psoriasis. Ustekinumab, a monoclonal antibody that binds
to and neutralises the p40 subunit of IL-12 and IL-23, improves
joint, dactylitis and enthesitis lesions in PsA. Secukinumab, a
monoclonal antibody that targets IL-1 7A, has similar efficacy to
TNF inhibitors in PsA. Apremilast is an oral small-molecule inhibitor
of phosphodiesterase 4 (PDE4), which is effective in PsA when
DMARD therapy fails, although it appears to be less efficacious
than biologic treatment. Adverse effects include weight loss,
depression and suicidal ideation.
Enteropathic (spondylo)arthritis
The overall prevalence of inflammatory musculoskeletal disease
in inflammatory bowel diseases (IBDs: Crohn’s disease and
ulcerative colitis) is not well known, as studies have not adequately
assessed enthesitis and osteitis lesions, but the musculoskeletal
manifestations are in keeping with an SpA phenotype. Involvement
of the peripheral joints is seen in about 20% of IBD patients.
Oligoarticular disease predominantly affects the large lower
limb joints (knees, ankles and hips). Radiographic evidence
of sacroiliitis is present in about 20-25% of IBD patients.
In Crohn’s disease, more than in colitis, the arthritis usually
coincides with exacerbations of the underlying bowel disease
and the arthritis improves with effective treatment of the bowel
disease. There is some suggestion that the severity and onset of
inflammatory musculoskeletal symptoms can vary in association
with changes in the integrity of the ileocaecal valve, raising the
possibility that changes in gut flora may act as triggers for the
associated SpA.
NSAIDs are best avoided, since they can exacerbate IBD.
Instead, judicious use of glucocorticoids, sulfasalazine and
methotrexate may be considered. Liaison is necessary between
gastroenterologist and rheumatologist with regard to choice of
therapy. Anti-TNF therapy is effective in enteropathic arthritis but
etanercept should be avoided, as it has no efficacy in IBD. When
musculoskeletal symptoms worsen despite anti-TNF therapy, it
is wise to exclude bacterial overgrowth as a triggering cause
(blind-loop syndrome).
Autoimmune connective
tissue diseases
Autoimmune connective tissue diseases (AlCTDs) share many
clinical features and are characterised by dysregulation of immune
responses, autoantibody production that is often directed at
components of the cell nucleus, and tissue damage.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE, ‘lupus’) is a rare disease
with a prevalence that ranges from about 0.03% in Caucasians
to 0.2% in Afro-Caribbeans. Some 90% of affected patients are
female and the peak age at onset is between 20 and 30 years.
SLE is associated with considerable morbidity and a fivefold
increase in mortality compared to age- and gender-matched
controls, mainly because of an increased risk of premature
cardiovascular disease.
Pathophysiology
The cause of SLE is incompletely understood but genetic
factors play an important role. There is a higher concordance
in monozygotic twins and the disease is strongly associated with
polymorphic variants at the HLA\ locus. In a few instances, SLE is
associated with inherited mutations in complement components
Clq, C2 and C4, in the immunoglobulin receptor FcyRIIIb or in
the DNA exonuclease TREX1. Genome-wide association studies
have identified common polymorphisms near several other genes
that predispose to SLE, most of which are involved in regulating
immune cell function. From an immunological standpoint, the
characteristic feature of SLE is autoantibody production. These
autoantibodies have specificity for a wide range of targets but
many are directed against antigens present within the cell or
within the nucleus. This has led to the hypothesis that SLE
may occur because of defects in apoptosis or in the clearance
of apoptotic cells, which causes inappropriate exposure of
intracellular antigens on the cell surface, leading to polyclonal
B- and T-cell activation and autoantibody production. This is
supported by the fact that environmental factors that cause
flares of lupus, such as ultraviolet light and infections, increase
oxidative stress and cause cell damage. Whatever the underlying
cause, autoantibody production and immune complex formation
are thought to be important mechanisms of tissue damage in
active SLE, leading to vasculitis and organ damage.
Autoimmune connective tissue diseases • 1035
Clinical features
Symptoms such as fever, weight loss and mild lymphadenopathy
may occur during flares of disease activity, whereas others such
as fatigue and low-grade joint pains can be constant and not
particularly associated with active inflammatory disease.
Arthritis
Arthralgia is a common symptom, occurring in 90% of patients,
and is often associated with early morning stiffness. Tenosynovitis
may also occur but clinically apparent synovitis with joint swelling
is rare. Joint deformities may arise (Jaccoud’s arthropathy) as
the result of tendon damage but joint erosions are not a feature.
Raynaud’s phenomenon
Raynaud’s phenomenon (p. 504) is common and may antedate
other symptoms by months or years. SLE can present with
Raynaud’s phenomenon, along with arthralgia or arthritis.
Secondary Raynaud’s phenomenon associated with SLE and
other AlCTDs needs to be differentiated from primary Raynaud’s
phenomenon, which is common in the general population (up to
5%). Features in favour of secondary Raynaud’s phenomenon
include age at onset of over 25 years, absence of a family
history of Raynaud’s phenomenon, and occurrence in a male.
Examination of capillary nail-fold loops using an ophthalmoscope
(and oil placed on the skin) can show loss of the normal loop
pattern, with capillary ‘fallout’ and dilatation and branching of
loops; these features support either a diagnosis of systemic
sclerosis or severe primary Raynaud’s phenomenon. If Raynaud’s
phenomenon is severe, digital ulceration can occur (Fig. 24.44).
Skin
The skin is commonly involved in SLE, and many SLE skin
eruptions are precipitated by exposure to ultraviolet light. The
main types of skin involvement are:
• The classic facial rash (up to 20% of patients). This is
erythematous, raised and painful or itchy, and occurs over
the cheeks with sparing of the nasolabial folds (Fig. 24.45).
Rosacea is a mimic of this rash.
• A discoid rash characterised by hyperkeratosis and
follicular plugging, with scarring alopecia if it occurs on the
scalp.
• Diffuse, usually non-scarring alopecia, which may also
occur with active disease.
• Urticarial eruptions.
• Livedo reticularis (Fig. 24.46), which is also a feature of
antiphospholipid syndrome (p. 977) and can become
frankly vasculitic, if severe.
Kidney
Renal involvement is one of the main determinants of prognosis
and regular monitoring of urinalysis and blood pressure is essential.
The typical renal lesion is a proliferative glomerulonephritis
(p. 397), characterised by heavy haematuria, proteinuria and
casts on urine microscopy.
Cardiovascular
The most common manifestation is pericarditis. Myocarditis and
Libman-Sacks endocarditis can also occur. The endocarditis
is due to accumulation on the heart valves of sterile fibrin-
containing vegetations, which is thought to be a manifestation
of hypercoagulability associated with antiphospholipid antibodies.
The risk of atherosclerosis is greatly increased, as is the risk of
stroke and myocardial infarction. This is thought to be multifactorial
Fig. 24.44 Severe secondary Raynaud’s phenomenon leading to
digital ulceration.
Fig. 24.45 Malar rash of systemic lupus erythematosus, sparing the
nasolabial folds. The rash is notably similar to rosacea, which may itself
be associated with inflammatory joint diseases such as psoriatic arthritis.
due to the adverse effects of inflammation on the endothelium,
chronic glucocorticoid therapy and the procoagulant effects of
antiphospholipid antibodies.
Lung
Lung involvement is common and most frequently manifests
as pleuritic pain (serositis) or pleural effusion. Other features
include pneumonitis, atelectasis, reduced lung volume and
pulmonary fibrosis that leads to breathlessness. The risk of
thromboembolism is increased, especially in patients with
antiphospholipid antibodies.
Neurological
Fatigue, headache and poor concentration are common and
often occur in the absence of laboratory evidence of active
disease. More specific features of cerebral lupus include visual
hallucinations, chorea, organic psychosis, transverse myelitis
and lymphocytic meningitis.
Haematological
Neutropenia, lymphopenia, thrombocytopenia and haemolytic
anaemia may occur, due to antibody-mediated destruction of
1036 • RHEUMATOLOGY AND BONE DISEASE
Fig. 24.46 Livedo reticularis (systemic lupus erythematosus and
anti-phospholipid syndrome).
peripheral blood cells. The degree of lymphopenia is a good
guide to disease activity.
Gastrointestinal
Mouth ulcers may occur and may or may not be painful. Peritoneal
serositis can cause acute pain. Mesenteric vasculitis is a serious
complication, which can present with abdominal pain, bowel
infarction or perforation. Hepatitis is a recognised, though rare,
feature.
Paediatric disease
Renal disease and cutaneous manifestations are more frequent
in juvenile-onset SLE compared to disease in adults. Similarly,
there is subsequently a higher incidence of renal disease,
malar rash, Raynaud’s phenomenon, cutaneous vasculitis and
neuropsychiatric manifestations than in adults.
Investigations
The diagnosis is based on a combination of clinical features and
laboratory abnormalities. To fulfil the classification criteria for SLE,
at least 4 of the 1 1 factors shown in Box 24.63 must be present
or have occurred in the past. Checking of ANAs, antibodies to
ENAs and complement, routine haematology, biochemistry and
urinalysis are mandatory. Patients with active SLE test positive
for ANA. Some authorities believe that ANA-negative SLE occurs
(e.g. in the presence of antibodies to Ro) but others regard SLE
as necessarily ANA-positive; the issue may be more to do with
sensitivity of the ANA assay at any given time in a disease course.
Anti-dsDNA antibodies are positive in many, but not all, patients
and are tested at the time of diagnosis by most laboratories
using ELISA. ELISAs have low specificity, whereas testing for
anti-dsDNA antibodies using Crithidia luciliae is highly specific.
Patients with active disease tend to have low levels of C3 due
to complement consumption, but in some people low C3 and
C4 may be the result of inherited complement deficiency in
Cl , C2 or C4 that predisposes to SLE (p. 66). Studies of other
family members can help to differentiate inherited deficiency
from complement consumption. A raised ESR, leucopenia and
lymphopenia are typical of active SLE, along with anaemia,
haemolytic anaemia and thrombocytopenia. CRP is often normal
in active SLE, except in the presence of serositis; thus an elevated
CRP suggests infection.
Management
The therapeutic goals are to educate the patient about the
nature of the illness, to control symptoms and to prevent organ
^9 24.63 Criteria for the classification of systemic
lupus erythematosus
Features
Characteristics
Malar rash
Fixed erythema, flat or raised, sparing the
nasolabial folds
Discoid rash
Erythematous raised patches with adherent
keratotic scarring and follicular plugging
Photosensitivity
Rash due to unusual reaction to sunlight
Oral ulcers
Oral or nasopharyngeal ulceration, which may be
painless
Arthritis
Non-erosive, involving two or more peripheral joints
Serositis
Pleuritis (history of pleuritic pain or rub, or pleural
effusion) or pericarditis (rub, electrocardiogram
evidence or effusion)
Renal disorder
Persistent proteinuria >0.5 g/24 hrs or cellular
casts (red cell, granular or tubular)
Neurological
disorder
Seizures or psychosis, in the absence of provoking
drugs or metabolic derangement
Haematological
disorder
Haemolytic anaemia or leucopenia* (< 4 x 1 09/L) or
lymphopenia* (<1 x109/L) or thrombocytopenia*
(<100x1 09/L) in the absence of offending drugs
Immunological
Anti-DNA antibodies in abnormal titre or presence
of antibody to Sm antigen or positive
antiphospholipid antibodies
Antinuclear
antibody (ANA)
Abnormal titre of ANA by immunofluorescence
An adult has SLE if any 4 of 1 1 features are present
serially or simultaneously
*0n two separate occasions.
damage and maintain normal function. Patients should be advised
to avoid sun and ultraviolet light exposure and to employ sun
blocks (sun protection factor 25-50).
Mild to moderate disease
Patients with mild disease restricted to skin and joints can
sometimes be managed with analgesics, NSAIDs and hydroxy¬
chloroquine. Frequently, however, glucocorticoids are also
necessary (prednisolone 5-20 mg/day), often in combination
with immunosuppressants such as methotrexate, azathioprine or
mycophenolate mofetil (MMF). Increased doses of glucocorticoids
may be required for flares in activity or complications such as
pleurisy or pericarditis. The monoclonal antibody belimumab,
which targets the (3-cell growth factor BLyS, has recently been
shown to be effective in patients with active SLE who have
responded inadequately to standard therapy.
Severe and life-threatening disease
High-dose glucocorticoids and immunosuppressants are
required for the treatment of renal, CNS and cardiac involvement.
A commonly used regimen is pulsed methylprednisolone
(10 mg/kg IV) plus cyclophosphamide (15 mg/kg IV), repeated
at 2-3-weekly intervals for six cycles. Cyclophosphamide may
cause haemorrhagic cystitis but the risk can be minimised by
good hydration and co-prescription of mesna (2-mercaptoethane
sulfonate), which binds its urotoxic metabolites. Because of the
risk of azoospermia and premature menopause, sperm or oocyte
collection and storage need to be considered prior to treatment
with cyclophosphamide.
Autoimmune connective tissue diseases • 1037
MMF has been used successfully with high-dose glucocorticoids
for renal involvement with results similar to those of pulsed
cyclophosphamide but fewer adverse effects. Belimumab in
combination with standard therapy significantly decreases disease
activity in SLE patients and is safe and well tolerated. Its role
in patients with renal and neurological disease is still under
investigation.
Rituximab has been reported as being effective in selected
cases, though randomised controlled trials have not shown
significant overall efficacy.
Maintenance therapy
Following control of acute disease, a typical maintenance regimen
is oral prednisolone in a dose of 40-60 mg daily, gradually
reducing to 1 0-1 5 mg/day or less by 3 months. Azathioprine
(2-2.5 mg/kg/day), methotrexate (10-25 mg/week) or MMF
(2-3 g/day) should also be prescribed. The long-term
aim is to continue the lowest dose of glucocorticoid and
immunosuppressant to maintain remission. Cardiovascular risk
factors, such as hypertension and hyperlipidaemia, should be
controlled and patients should be advised to stop smoking.
Patients with SLE and the antiphospholipid antibody
syndrome, who have had previous thrombosis, require life-long
warfarin therapy. SLE patients are at risk of osteoporosis and
hypovitaminosis D, and should be screened with biochemistry
and DXA scanning accordingly.
Systemic sclerosis
Systemic sclerosis (SScI) is an autoimmune disorder of connective
tissue, which results in fibrosis affecting the skin, internal organs
and vasculature. It is characterised typically by Raynaud’s
phenomenon, digital ischaemia (Fig. 24.47), sclerodactyly, and
cardiac, lung, gut and renal disease. The peak age of onset is
in the fourth and fifth decades and overall prevalence is 10-20
per 100000, with a 4:1 female-to-male. It is subdivided into
diffuse cutaneous systemic sclerosis (dcSScI: 30% of cases)
and limited cutaneous systemic sclerosis (IcSScI: 70% of cases).
Some patients with IcSScI have calcinosis and telangiectasia.
The prognosis in dcSScI is poor (5-year survival about 70%).
Features that associate with a poor prognosis include older
age, diffuse skin disease, proteinuria, high ESR, a low gas
transfer factor for carbon monoxide (TLCO) and pulmonary
hypertension.
Fig. 24.47 Systemic sclerosis. Hands showing tight, shiny skin,
sclerodactyly, flexion contractures of the fingers and thickening of the left
middle finger extensor tendon sheath.
Pathophysiology
The cause of SScI is not completely understood. There is evidence
for a genetic component and associations with alleles at the HLA
locus have been found. The disease occurs in all ethnic groups
and race may influence severity. Isolated cases have been reported
in which an SScl-like disease has been triggered by exposure to
silica dust, vinyl chloride, epoxy resins and trichloroethylene. There
is clear evidence of immunological dysfunction: T lymphocytes,
especially those of the Thl 7 subtype, infiltrate the skin and there
is abnormal fibroblast activation, leading to increased production
of extracellular matrix in the dermis, primarily type I collagen. This
results in symmetrical thickening, tightening and induration of the
skin (scleroderma). Arterial and arteriolar narrowing occurs due
to intimal proliferation and vessel wall inflammation. Endothelial
injury causes release of vasoconstrictors and platelet activation,
resulting in further ischaemia, which is thought to exacerbate the
fibrotic process.
Clinical features
Skin
Initially, there is non-pitting oedema of fingers and flexor tendon
sheaths. Subsequently, the skin becomes shiny and taut, and
distal skin creases disappear. There can be capillary loss. The
face and neck are often involved, with thinning of the lips and
radial furrowing. In some patients, skin thickening stops at this
stage. Skin involvement restricted to sites distal to the elbow
or knee (apart from the face) is thus classified as IcSScI (Fig.
24.48). Involvement proximal to the knee and elbow and on the
trunk is classified as ‘diffuse disease’ (dcSScI).
Raynaud’s phenomenon
This is a universal feature and can precede other features by
many years. Involvement of small blood vessels in the extremities
may cause critical tissue ischaemia, leading to localised distal
skin infarction and necrosis.
Musculoskeletal features
Arthralgia and flexor tenosynovitis are common. Restricted hand
function is due to skin rather than joint disease and erosive
arthropathy is uncommon. Muscle weakness and wasting can
result from myositis.
Gastrointestinal involvement
Smooth muscle atrophy and fibrosis in the lower two-thirds
of the oesophagus lead to reflux with erosive oesophagitis.
Fig. 24.48 Typical facial appearance showing telangiectasias in
localised cutaneous systemic sclerosis.
1038 • RHEUMATOLOGY AND BONE DISEASE
Dysphagia and odynophagia may also occur. Involvement of the
stomach causes early satiety and occasionally outlet obstruction.
Recurrent occult upper gastrointestinal bleeding may indicate
a ‘watermelon’ stomach (antral vascular ectasia; up to 20% of
patients). Small intestine involvement may lead to malabsorption
due to bacterial overgrowth and intermittent bloating, pain or
constipation. Dilatation of bowel due to autonomic neuropathy
may cause pseudo-obstruction with nausea, vomiting, abdominal
discomfort and distension, often worse after food (symptoms can
mimic those of an acute abdomen and can lead to erroneous
laparotomy).
Pulmonary involvement
Pulmonary hypertension complicates long-standing disease
and is six times more prevalent in IcSSci than in dcSScl. It
usually presents with insidiously evolving exertional dyspnoea
and signs of right heart failure. Interstitial lung disease is common
in patients with dcSScl who have topoisomerase 1 antibodies
(Scl70). Dyspnoea can evolve slowly over time or rapidly in
occasional cases.
Renal involvement
One of the main causes of death is hypertensive renal crisis,
characterised by rapidly developing accelerated phase
hypertension (p. 514) and renal failure. Hypertensive renal crisis
is much more likely to occur in dcSScl than in IcSSci, and in
patients with topoisomerase 1 and RNP antibodies.
Investigations
As SScI can affect multiple organs, routine haematology, renal,
liver and bone function tests and urinalysis are essential. ANA is
positive in about 70%. About 30% of patients with dcSScl have
antibodies to topoisomerase 1 (Scl70). About 60% of patients
with IcSSci syndrome have anticentromere antibodies (p. 991).
Chest X-ray, transthoracic echocardiography and lung function
tests are recommended to assess for interstitial lung disease
and pulmonary hypertension (low corrected transfer factor may
indicate early pulmonary hypertension). High-resolution lung CT is
recommended if interstitial lung disease suspected. If pulmonary
hypertension is suspected, right heart catheter measurements
should be arranged at a specialist cardiac centre. A barium
swallow can assess oesophageal involvement. A hydrogen breath
test can indicate bacterial overgrowth (p. 808).
Management
No treatments are available that halt or reverse the fibrotic
changes that underlie the disease. The focus of management,
therefore, is to slow the effects of the disease on target organs.
• Raynaud’s phenomenon and digital ulcers. Avoidance of
cold exposure, use of thermal insulating gloves/socks
and maintenance of a high core temperature all help. If
symptoms are persistent, calcium channel blockers,
losartan, fluoxetine and sildenafil have efficacy. Courses of
intravenous prostacyclin are used for severe disease and
critical ischemia (e.g. 6-8 hours daily for 5 days). The
endothelin-1 antagonist bosentan is licensed for treating
ischaemic digital ulcers, and digital tip tissue health can be
maintained with regular use of fucidin-hydrocortisone cream.
• Gastrointestinal complications. Oesophageal reflux should
be treated with proton pump inhibitors and anti-reflux
agents. Rotating courses of antibiotics may be required for
bacterial overgrowth (e.g. rifaximin, a tetracycline and
metronidazole), while metoclopramide or domperidone
may help patients with symptoms of dysmotility/
pseudo-obstruction.
• Hypertension. Aggressive treatment with ACE inhibitors is
needed, even if renal impairment is present.
• Joint involvement. This may be treated with analgesics
and/or NSAIDs. If synovitis is present and both RA (i.e. an
‘overlap’ condition, which needs treatment on its own
merit) and OA have been ruled out, low-dose methotrexate
can be of value.
• Progressive pulmonary hypertension. Early treatment with
bosentan is required. In severe or progressive disease,
heart-lung transplant may be considered.
• Interstitial lung disease. Glucocorticoids and (pulse
intravenous) cyclophosphamide are the mainstays of
treatment in patients who have progressive interstitial lung
disease.
Mixed connective tissue disease
Mixed connective tissue disease (MCTD) is a condition in which
some clinical features of SScI, myositis and SLE all occur in the
same patient. It commonly presents with indolent puffiness of the
fingers (the appearance is between that of SpA-type dactylitis
and sclerodactyly) with Raynaud’s phenomenon and myalgias.
Most patients have anti-RNP antibodies. Management focuses
on treating the components of the disease (see other sections).
| Primary Sjogren’s syndrome
Primary Sjogren’s syndrome (PSS) is characterised by lymphocytic
infiltration of salivary and lacrimal glands, leading to glandular
fibrosis and exocrine failure. The typical age of onset is between
40 and 50, with a 9 : 1 female-to-male ratio. The disease may
occur with other autoimmune diseases (secondary Sjogren’s
syndrome).
Clinical features
The eye symptoms, termed keratoconjunctivitis sicca, are due to
a lack of lubricating tears, which reflects inflammatory infiltration
of the lacrimal glands. Conjunctivitis and blepharitis are frequent,
and may lead to filamentary keratitis due to binding of tenacious
mucous filaments to the cornea and conjunctiva. Oral involvement
manifests as a dry mouth (xerostomia). There is a high incidence
of dental caries and high risk of dental failure. Other sites of
extraglandular involvement are listed in Box 24.64. Often the
most disabling symptom is fatigue. There may be an association
with inflammatory small-joint OA (clinical suspicion, though formal
studies have not been done). Sialadenitis, osteoarthritis and
xerostomia (SOX) syndrome has been described; this may occur
independently of PSS or, more likely, constitute a mild form.
Both interstitial lung disease and interstitial nephritis (sometimes
complicated by renal tubular acidosis) require proactive screening.
PSS is associated with a 40-fold increased lifetime risk of
lymphoma, though the complication is still very rare.
Investigations
The diagnosis can be established by the Schirmer tear test,
which measures tear flow over 5 minutes using absorbent
paper strips placed on the lower eyelid; a normal result is more
than 6 mm of wetting. Staining with rose bengal may show
punctate epithelial abnormalities over the area not covered by
the open eyelid. If the diagnosis remains in doubt, it can be
confirmed by demonstrating focal lymphocytic infiltrate in a minor
salivary gland biopsy. Most patients have an elevated ESR and
Autoimmune connective tissue diseases • 1039
24.64 Features of primary Sjogren’s syndrome
Risk factors
• Age of onset 40-60
• Female > male
•
HLA-B8/DR3
Common clinical features
• Keratoconjunctivitis sicca
•
Non-erosive arthralgia
• Xerostomia
•
Generalised osteoarthritis
• Salivary gland enlargement
•
Raynaud’s phenomenon
• Rashes/skin irritation
•
Fatigue
Less common features
• Low-grade fever
•
Peripheral neuropathy
• Interstitial lung disease
•
Lymphadenopathy
• Anaemia, leucopenia
•
Lymphoreticular lymphoma
• Thrombocytopenia
•
Glomerulonephritis
• Cryoglobulinaemia
•
Interstitial nephritis
• Vasculitis
•
Renal tubular acidosis
Autoantibodies frequently detected
• Rheumatoid factor
•
SS-B (anti-La)
• Antinuclear antibody
•
Gastric parietal cell
• SS-A (anti-Ro)
•
Thyroid
Associated autoimmune disorders
• Systemic lupus erythematosus
•
Primary biliary cholangitis
• Systemic sclerosis
•
Chronic active hepatitis
• Coeliac disease
•
Myasthenia gravis
(HLA = human leucocyte antigen)
hypergammaglobulinaemia, and one or more autoantibodies,
including ANA and RF. ANA-negative disease exists. Anti-Ro
and anti-La antibodies are commonly present (see Box 24.10,
p. 992). Patients with joint pain, fatigue and RF (with or without
ANA) need careful assessment because a number of possibilities
exist: PSS and inflammatory OA; RA with incidental ANA; RA/
SLE overlap; or RA/PSS overlap. Knowing ACPA status can help
(it is positive in RA). Interstitial lung disease complicates PSS in
a sizable minority of patients (persistent dry cough, dyspnoea,
coarse ‘Velcro’ crackles on lung auscultation). A chest X-ray
and lung function tests should be performed.
Management
No treatments that have disease-modifying effects have yet
been identified and management is symptomatic. Lacrimal
substitutes, such as hypromellose, should be used during the day
in combination with more viscous lubricating application at night.
Soft contact lenses can be useful for corneal protection in patients
with filamentary keratitis, and occlusion of the lacrimal ducts is
occasionally needed. Artificial saliva sprays, saliva-stimulating
tablets, and pastilles and oral gels can be tried for xerostomia but
often chewing gum is most effective. Adequate postprandial oral
hygiene and prompt treatment of oral candidiasis are essential.
Vaginal dryness is treated with lubricants. A trial of systemic
pilocarpine (5-30 mg daily in divided doses) is worthwhile in early
disease to amplify glandular function. Hydroxychloroquine (200 mg
twice daily) is often used to address skin and musculoskeletal
features and may help fatigue. Immunosuppression does not
improve sicca symptoms but is essential for progressive interstitial
lung disease (e.g. glucocorticoids and cyclophosphamide) and
for interstitial nephritis (if hydroxychloroquine is ineffective alone).
If non-resolving lymphadenopathy or salivary gland enlargement
develops, biopsy should be undertaken to exclude malignancy.
Fig. 24.49 Typical eyelid appearance in dermatomyositis. Note the
oedema and telangiectasia.
Polymyositis and dermatomyositis
Polymyositis (PM) and dermatomyositis (DM) are characterised
by proximal skeletal and (cardiac and gut) smooth muscle
inflammation. In DM, characteristic skin changes also occur.
Both diseases are rare, with an incidence of 2-10 cases per
million/year. They can occur in isolation or in association with
other autoimmune diseases, and both are notably connected
with (either previously diagnosed or undisclosed) malignancy.
Clinical features
The typical presentation of PM and DM is with symmetrical
proximal muscle weakness over a few weeks, usually affecting
the lower limbs more than the upper, in adults between 40
and 60 years of age. Patients report difficulty rising from a
chair, climbing stairs and lifting, often (though not always) with
muscle pain. Systemic features of fever, weight loss and fatigue
are common. Respiratory or pharyngeal muscle involvement
can lead to ventilatory failure or aspiration that requires urgent
treatment. Interstitial lung disease occurs in up to 30% of patients
and is strongly associated with the presence of antisynthetase
(Jo-1) antibodies.
In DM, the skin lesions include Gottron’s papules, which are
scaly, erythematous or violaceous, psoriasiform plaques occurring
over the extensor surfaces of PIP and DIP joints, and a heliotrope
rash that is a violaceous discoloration of the eyelid in combination
with periorbital oedema (Fig. 24.49). Similar rashes occur on the
upper back, chest and shoulders (‘shawl’ distribution). Periungual
nail-fold capillaries are often enlarged and tortuous.
Investigations
Muscle biopsy is the pivotal investigation and shows the typical
features of fibre necrosis, regeneration and inflammatory cell
infiltrate (Fig. 24.50). Occasionally, however, a biopsy may be
normal, particularly if myositis is patchy so, invariably, MRI should
be used to identify areas of abnormal muscle for biopsy. Serum
levels of creatine kinase are typically raised and are a useful
measure of disease activity, although a normal creatine kinase
does not exclude the diagnosis, particularly in juvenile myositis.
Electromyography is very useful for highlighting non-autoimmune/
non-inflammatory myopathies. Screening for underlying malignancy
should be undertaken routinely (full examination, chest X-ray,
serum urine and protein electrophoresis, CT of chest/abdomen/
pelvis; prostate-specific antigen should be included in men, and
mammography in women).
1040 • RHEUMATOLOGY AND BONE DISEASE
Fig. 24.50 Muscle biopsy from a patient with polymyositis.
The sample shows an intense inflammatory cell infiltrate in an area
of degenerating and regenerating muscle fibres.
Management
Oral glucocorticoids (prednisolone 1 mg/kg daily) are the mainstay
of initial treatment of PM and DM but high-dose intravenous
methylprednisolone (1 g/day for 3 days) may be required in
patients with respiratory or pharyngeal weakness. If there is a good
response, glucocorticoids should be reduced by approximately
25% per month to a maintenance dose of 5-7.5 mg. Although
most patients respond well to glucocorticoids, many need
additional immunosuppressive therapy. Methotrexate and MMF
are the first choices of many but azathioprine and ciclosporin are
also used as alternatives. Rituximab appears to show efficacy in
a majority of patients, although the only controlled study (which
was criticised for its suboptimal design) was negative. In clinical
practice, rituximab is an option for use with glucocorticoids, to
maintain an early glucocorticoid-induced remission. Intravenous
immunoglobulin (IVIg) may be effective in refractory cases.
Mepacrine or hydroxychloroquine has been used for skin-
predominant disease to some good effect in certain cases.
One risk of treatment is glucocorticoid-induced myopathy. If the
initial response to treatment is poor, further biopsy then shows
type II fibre atrophy in glucocorticoid myopathy (compared with
fibre necrosis and regeneration in active myositis).
| Juvenile dermatomyositis
Juvenile dermatomyositis (JDM) is by far the most common
inflammatory myopathy in children and adolescents, and typically
does not require a search for malignancy. The incidence is 2-4
per million (USA and UK) with a median age of onset of 7 years
(25% are below 4 years at diagnosis). Many clinical features are
similar to those in the adult disease. JDM can be monocyclic,
lasting up to 3 years (25-40%), or polycyclic, with periods of
remission and relapse (60-75%). In some cases, polycyclic JDM
can be chronic and life-long. It is ulcerative in 10-20%. As in
adults, calcinosis occurs in about 30%.
Intravenous methylprednisolone, then oral glucocorticoids
and methotrexate produce a rapid response in many cases.
Cyclophosphamide is used for lesional ulceration. IVIg is given
in resistant cases.
I Undifferentiated autoimmune connective
tissue disease
In some patients, clinical features of AICTD occur, either
simultaneously or sequentially, but at any one time the features
and results of investigations do not allow a clear diagnosis to be
made on the basis of conventional criteria. However, recognising
that autoimmunity is present (‘autoimmune diathesis’) without
making a specific diagnosis can help patients move forwards
with chronic symptomology. Some of these individuals will
progress to having a recognisable AICTD with time; others will
continue to have an undifferentiated disease that remains the
same for many years, and in others the symptoms will recede.
Clinical monitoring and periodic autoimmune serological testing
of all patients is sensible.
Adult-onset Still’s disease
Adult-onset Still’s disease is a rare systemic inflammatory disorder
of unknown cause, possibly triggered by infection; it is similar
to sJIA. It presents with intermittent fever, rash and arthralgia,
and has been associated with pregnancy and the postpartum
period and with high levels of IL-18. Splenomegaly, hepatomegaly
and lymphadenopathy may be present. Investigations typically
provide evidence of an acute phase response, with a markedly
elevated serum ferritin. Tests for RF and ANA are negative and
so adult-onset Still’s disease may be better classified as an
autoinflammatory rather than an autoimmune disease. Most
patients respond to glucocorticoids but immunosuppressants,
such as azathioprine or MMF, can be added when response is
inadequate. Canakinumab or anakinra can be used for patients
with resistant disease.
Vasculitis
Vasculitis is characterised by inflammation and necrosis of
blood-vessel walls, with associated damage to skin, kidney, lung,
heart, brain and gastrointestinal tract. There is a wide spectrum of
involvement and severity, ranging from mild and transient disease
affecting only the skin, to life-threatening fulminant disease with
multiple organ failure. Principal sites of involvement for the main
types of vasculitis are summarised in Figure 24.51 . The clinical
features result from a combination of local tissue ischaemia
(due to vessel inflammation and narrowing) and the systemic
effects of widespread inflammation. Systemic vasculitis should
be considered in any patient with fever, weight loss, fatigue,
Behget’s ■
disease
Takayasu arteritis
Kawasaki
disease
Eosinophilic
granulomatosis
with polyangiitis
Polyarteritis
nodosa
Giant cell arteritis
iitis with
Microscopic
polyangiitis
lobulinaemic
vasculitis
-Schonlein
purpura
Behget’s disease
Fig. 24.51 Types of vasculitis. The anatomical targets of different forms
of vasculitis are shown.
Vasculitis • 1041
24.65 Clinical features of systemic vasculitis
Systemic
• Malaise
• Weight loss with arthralgia
• Fever
and myalgia
• Night sweats
Rashes
• Palpable purpura
• Ulceration
• Pulp infarcts
• Livedo reticularis
Ear, nose and throat
• Epistaxis
• Deafness
• Recurrent sinusitis
Respiratory
• Haemoptysis
• Poorly controlled asthma
• Cough
Gastrointestinal
• Abdominal pain (due to
• Mouth ulcers
mucosal inflammation or
• Diarrhoea
enteric ischaemia)
Neurological
• Sensory or motor neuropathy
evidence of multisystem involvement, rashes, raised inflammatory
markers and abnormal urinalysis (Box 24.65).
Antineutrophil cytoplasmic
antibody-associated vasculitis
Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is
a life-threatening disorder characterised by inflammatory infiltration
of small blood vessels, fibrinoid necrosis and the presence of
circulating antibodies to antineutrophil cytoplasmic antibody
(ANCA). The combined incidence is about 10-15/1 000 000.
Two main subtypes are recognised. Microscopic polyangiitis is a
necrotising small-vessel vasculitis found with rapidly progressive
glomerulonephritis, often in association with alveolar haemorrhage.
Cutaneous and gastrointestinal involvement is common and other
features include neuropathy (15%) and pleural effusions (15%).
Patients are usually myeloperoxidase (MPO) antibody-positive.
Secondly, granulomatosis with polyangiitis (formerly known
as Wegener’s granulomatosis) is characterised by granuloma
formation, mainly affecting the nasal passages, airways and
kidney. A minority of patients present with glomerulonephritis. The
most common presentation of granulomatosis with polyangiitis is
with epistaxis, nasal crusting and sinusitis, but haemoptysis and
mucosal ulceration may also occur. Deafness may be a feature
due to inner ear involvement, and proptosis may occur because
of inflammation of the retro-orbital tissue (Fig. 24.52). This causes
diplopia due to entrapment of the extra-ocular muscles, or loss
of vision due to optic nerve compression. Disturbance of colour
vision is an early feature of optic nerve compression. Untreated
nasal disease ultimately leads to destruction of bone and cartilage.
Migratory pulmonary infiltrates and nodules occur in 50% of
patients (as seen on high-resolution CT of lungs). Patients with
granulomatosis with polyangiitis are usually proteinase-3 (PR3)
antibody-positive (ELISA).
Patients with active disease usually have a leucocytosis with
elevated CRP, ESR and PR3. Complement levels are usually
normal or slightly elevated. Imaging of the upper airways or chest
Fig. 24.52 Eye involvement in antineutrophil cytoplasmic antibody-
associated vasculitis.
with MRI can be useful in localising abnormalities but, where
possible, the diagnosis should be confirmed by biopsy of the
kidney or lesions in the sinuses and upper airways.
Management for organ-threatening or acute-severe disease
is with high-dose glucocorticoids (e.g. daily pulse intravenous
methylprednisolone 0.5-1 g for 3 days, then oral prednisolone
0.5 mg/kg) and intravenous cyclophosphamide (e.g. 0.5-1 g
every 2 weeks for 3 months), followed by maintenance therapy
with lower-dose glucocorticoids and azathioprine, methotrexate
or MMF. Plasmapheresis should be considered for fulminant lung
disease. Rituximab in combination with high-dose glucocorticoids
is equally effective as oral cyclophosphamide at inducing remission
in AAV. Glucocorticoids and methotrexate are an effective
combination for treating limited AAV where there is indolent
sinus, lung or skin disease. AAV has a tendency to relapse and
patients must be followed on a regular and long-term basis,
monitoring urinalysis for blood and protein, plasma creatinine,
ESR, CRP, lung function and PR3 or MPO antibody titres.
| Takayasu arteritis
Takayasu arteritis affects the aorta, its major branches and
occasionally the pulmonary arteries. The typical age at onset is
25-30 years, with an 8 : 1 female-to-male ratio. It has a worldwide
distribution but is most common in Asia. Takayasu arteritis is
characterised by granulomatous inflammation of the vessel wall,
leading to occlusion or weakening of the vessel wall. It presents
with claudication, fever, arthralgia and weight loss. Clinical
examination may reveal loss of pulses, bruits, hypertension and
aortic incompetence. Investigation will identify an acute phase
response and normocytic, normochromic anaemia but the
diagnosis is based on angiography, which reveals coarctation,
occlusion and aneurysmal dilatation. Treatment is with high-dose
glucocorticoids and immunosuppressants, as described for
ANCA-associated vasculitis. With successful treatment, the
5-year survival is 83%.
Kawasaki disease
Kawasaki disease is a vasculitis that mostly involves the coronary
vessels. It presents as an acute systemic disorder, usually affecting
children under 5 years. It occurs mainly in Japan and other Asian
countries, such as China and Korea, but other ethnic groups may
also be affected. Presentation is with fever, generalised rash,
including palms and soles, inflamed oral mucosa and conjunctival
injection resembling a viral exanthem. The cause is unknown but
1042 • RHEUMATOLOGY AND BONE DISEASE
Fig. 24.53 Rash of systemic vasculitis (palpable purpura).
is thought to be an abnormal immune response to an infectious
trigger. Cardiovascular complications include coronary arteritis,
leading to myocardial infarction, transient coronary dilatation,
myocarditis, pericarditis, peripheral vascular insufficiency and
gangrene. Treatment is with aspirin (5 mg/kg daily for 14 days)
and IVIg (400 mg/kg daily for 4 days).
Polyarteritis nodosa
Polyarteritis nodosa has a peak incidence between the ages
of 40 and 50, with a male-to-female ratio of 2 : 1 . The annual
incidence is about 2/1 000000. Hepatitis B is an important risk
factor and the incidence is 1 0 times higher in the Inuit of Alaska,
in whom hepatitis B infection is endemic. Presentation is with
fever, myalgia, arthralgia and weight loss, in combination with
manifestations of multisystem disease. The most common skin
lesions are palpable purpura (Fig. 24.53), ulceration, infarction and
livedo reticularis (see Fig. 24.46). Pathological changes comprise
necrotising inflammation and vessel occlusion, and in 70% of
patients arteritis of the vasa nervorum leads to neuropathy, which
is typically symmetrical and affects both sensory and motor
function. Severe hypertension and/or renal impairment may occur
due to multiple renal infarctions but glomerulonephritis is rare (in
contrast to microscopic polyangiitis). The diagnosis is confirmed
by conventional or magnetic resonance angiography, which shows
multiple aneurysms and smooth narrowing of mesenteric, hepatic
or renal systems, or by muscle or sural nerve biopsy, which
reveals the histological changes described above. Treatment is
with high-dose glucocorticoids and immunosuppressants, as
described for ANCA-associated vasculitis.
Giant cell arteritis and
polymyalgia rheumatica
Giant cell arteritis (GCA) is a granulomatous arteritis that
affects any large (including aorta) and medium-sized arteries.
It is commonly associated with polymyalgia rheumatica (PMR),
which presents with symmetrical, immobility-associated neck and
shoulder girdle pain and stiffness. Since many patients with GCA
24.66 Conditions that can mimic
polymyalgia rheumatica
• Calcium pyrophosphate •
Lambert-Eaton syndrome
disease
(P- 1143)
• Spondyloarthritis •
Multiple separate lesions
• Hyper-/hypothyroidism
(cervical spondylosis, cervical
• Psoriatic arthritis
radiculopathy, bilateral
(enthesopathic)
subacromial impingement,
• Systemic vasculitis
facet joint arthritis,
• Myeloma
osteoarthritis of the
• Inflammatory myopathy
acromioclavicular joint)
(particularly inclusion body
myositis, p. 1059)
have symptoms of PMR, and many patients with PMR go on to
develop GCA if untreated, many rheumatologists consider them
to be different manifestations of the same underlying disorder.
Both diseases are rare under the age of 60 years. The average
age at onset is 70, with a female-to-male ratio of about 3:1.
The overall prevalence is about 20 per 100000 in those over
the age of 50 years.
Clinical features
The cardinal symptom of GCA is headache, which is often localised
to the temporal or occipital region and may be accompanied by
scalp tenderness. Jaw pain develops in some patients, brought
on by chewing or talking. Visual disturbance can occur (most
specifically amaurosis) and a catastrophic presentation is with
blindness in one eye due to occlusion of the posterior ciliary artery.
On fundoscopy, the optic disc may appear pale and swollen
with haemorrhages, but these changes may take 24-36 hours
to develop and the fundi may initially appear normal. Rarely,
neurological involvement may occur, with transient ischaemic
attacks, brainstem infarcts and hemiparesis.
In GCA, constitutional symptoms, such as weight loss, fatigue,
malaise and night sweats, are common. With PMR, there may
be stiffness and painful restriction of active shoulder movements
on waking. Muscles are not otherwise tender, and weakness
and muscle-wasting are absent. Other conditions that cause
PMR-like symptoms are shown in Box 24.66.
Investigations
The typical laboratory abnormality is an elevated ESR, often
with a normochromic, normocytic anaemia. CRP may also be
elevated and abnormal liver function can occur. Rarely, PMR and
GCA can present with a normal ESR. More objective evidence
for GCA should be obtained whenever possible. There are three
investigations to consider: temporal artery biopsy, ultrasound of
the temporal arteries and 19fluorodeoxyglucose positron emission
tomography (19FDG PET scan). Characteristic biopsy findings are
fragmentation of the internal elastic lamina with necrosis of the
media in combination with a mixed inflammatory cell infiltrate.
Diagnostic yield is highest with multiple biopsies and multiple
section analysis (to detect ‘skip’ lesions). A negative biopsy
does not exclude the diagnosis. On ultrasound examination,
affected temporal arteries show a ‘halo’ sign. A strongly positive
19FDG PET scan is highly specific but sensitivity is low. Caution
is needed in interpreting weakly positive images. Low-grade
vascular uptake may occur in atheromatous arterial disease.
Management
Prednisolone should be commenced urgently in suspected
GCA because of the risk of visual loss (Box 24.67). Response
Vasculitis • 1043
24.67 Emergency management of giant cell arteritis
• Take blood for CRP, ESR, FBC, bone/liver/renal function, serum
protein electrophoresis, CPK, RF, ACPA, ANA, ANCA, complement
C3 and C4, immunoglobulins, PTH, TSH, vitamin D and urine
electrophoresis
• Commence prednisolone (40-60 mg daily), and simultaneously,
a weekly oral bisphosphonate and calcium with vitamin D
supplements
• Consider urgent ophthalmology examination and temporal artery
biopsy in patients with visual symptoms
• Consider obtaining temporal artery ultrasound or 19FDG-PET scan
• Review within 1 week and adjust glucocorticoid doses according to
clinical response and results of investigations
(ACPA = anti-citrullinated peptide antibody; ANA = antinuclear antibody;
ANCA = antineutrophil cytoplasmic antibody; CPK = creatine phosphokinase;
CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; FBC = full blood
count; 19FDG-PET = 1 9f I uorodeoxyg I ucose positron emission tomography;
PTH = parathyroid hormone; RF = rheumatoid factor; TSH = thyroid-stimulating
hormone)
is dramatic, such that symptoms will completely resolve within
48-72 hours of starting therapy in virtually all patients. It is
customary to use higher doses in GCA (60-80 mg prednisolone)
than in PMR (15-20 mg), although the evidence base for this
is weak. In both conditions, the glucocorticoid dose should be
progressively reduced, guided by symptoms and ESR, with the
aim of reaching a dose of 10-15 mg by about 8 weeks. The
rate of reduction should then be slowed by 1 mg per month. If
symptoms recur, the dose should be increased to that which
previously controlled the symptoms, and reduction attempted
again in another few weeks. Most patients need glucocorticoids
for an average of 12-24 months. For advice on prophylaxis
against giant cell-induced osteoporosis, see page 1047.
Eosinophilic granulomatosis with polyangiitis
(Churg-Strauss syndrome)
Eosinophilic granulomatosis with polyangiitis (formerly known
as Churg-Strauss syndrome) is a small-vessel vasculitis with
an incidence of about 1-3 per 1 000000. It is associated with
eosinophilia. Some patients have a prodromal period for many
years, characterised by allergic rhinitis, nasal polyposis and
late-onset asthma that is often difficult to control. The typical acute
presentation is with a triad of skin lesions (purpura or nodules),
asymmetric mononeuritis multiplex and eosinophilia. Pulmonary
infiltrates and pleural or pericardial effusions due to serositis may
be present. Up to 50% of patients have abdominal symptoms
provoked by mesenteric vasculitis. Patients with active disease
have raised levels of ESR and CRP and an eosinophilia. Although
antibodies to MPO or PR3 can be detected in up to 60% of cases,
eosinophilic granulomatosis with polyangiitis is considered to be
a distinct disorder from the other ANCA-associated vasculitides.
Biopsy of an affected site reveals a small-vessel vasculitis with
eosinophilic infiltration of the vessel wall. Management is with
high-dose glucocorticoids and cyclophosphamide, followed
by maintenance therapy with low-dose glucocorticoids and
azathioprine, methotrexate or MMF.
Henoch-Schonlein purpura
Henoch-Schonlein purpura is a small-vessel vasculitis caused
by immune complex deposition following an infectious trigger.
It is predominantly a disease of children and young adults. The
usual presentation is with purpura over the buttocks and lower
legs, accompanied by abdominal pain, gastrointestinal bleeding
and arthralgia. Nephritis can also occur and may present up to
4 weeks after the onset of other symptoms. Biopsy of affected
tissue shows a vasculitis with IgA deposits in the vessel wall.
Henoch-Schonlein purpura is usually a self-limiting disorder that
settles spontaneously without specific treatment. Glucocorticoids
and immunosuppressive therapy may be required in patients with
more severe disease, particularly in the presence of nephritis.
| Cryoglobulinaemic vasculitis
This is a small-vessel vasculitis that occurs when immunoglobulins
precipitate out in the cold. Cryoglobulins are classified into three
types (see Box 4.21 , p. 84). Types II and III are associated
with vasculitis. The typical presentation is with a vasculitic rash
over the lower limbs, arthralgia, Raynaud’s phenomenon and
neuropathy. Some cases are secondary to hepatitis C infection
and others are associated with other autoimmune diseases.
Affected patients should be screened for evidence of hepatitis B
and C infection, and if the results are positive, these should be
treated appropriately (pp. 875 and 878). There is no consensus as
to how best to treat cryoglobulinaemic vasculitis in the absence
of an obvious trigger. Glucocorticoids and immunosuppressive
therapy are often used empirically but their efficacy is uncertain.
In severe cases, plasmapheresis can be considered.
Behget’s disease
This is a vasculitis of unknown aetiology that characteristically
targets small arteries and venules. It is rare in Western Europe but
more common in ‘Silk Route’ countries, around the Mediterranean
and in Japan, where there is a strong association with HL4-B51 .
Oral ulcers are universal (Fig. 24.54). Unlike aphthous ulcers,
they are usually deep and multiple, and last for 10-30 days.
Genital ulcers are also a common problem, occurring in 60-80%
of cases. The usual skin lesions are erythema nodosum or
acneiform lesions but migratory thrombophlebitis and vasculitis
also occur. Ocular involvement is common and may include
anterior or posterior uveitis or retinal vasculitis. Neurological
involvement occurs in 5% and mainly involves the brainstem,
Fig. 24.54 Oral ulceration in Behget’s disease.
1044 • RHEUMATOLOGY AND BONE DISEASE
i
although the meninges, hemispheres and cord can also be
affected, causing pyramidal signs, cranial nerve lesions, brainstem
symptoms or hemiparesis. Recurrent thromboses also occur.
Renal involvement is extremely rare.
The diagnosis is primarily made on clinical grounds (Box 24.68)
but one characteristic feature that can be of diagnostic value is
the pathergy test, which involves pricking the skin with a needle
and looking for evidence of pustule development within 48 hours.
Oral ulceration can be managed with topical glucocorticoid
preparations (soluble prednisolone mouthwashes, glucocorticoid
pastes). Colchicine can be effective for erythema nodosum
and arthralgia. Thalidomide (100-300 mg per day for 28 days
initially) is very effective for resistant oral and genital ulceration
but is teratogenic and neurotoxic. Glucocorticoids and
immunosuppressants are indicated for uveitis and neurological
disease.
Relapsing polychondritis
Relapsing polychondritis is a rare inflammatory disease of cartilage
that classically presents with acute pain and swelling of one or
both ear pinnae, sparing the lower non-cartilaginous portion.
Around 30% of patients have coexisting autoimmune or connective
tissue disease. Involvement of tracheobronchial cartilage leads
to a hoarse voice, cough, stridor or expiratory wheeze. Other
manifestations include collapse of the bridge of the nose, scleritis,
hearing loss and cardiac valve dysfunction. Cartilage biopsy
shows an inflammatory infiltrate in the perichondrium. Both
ESR and CRP are raised in active disease. Pulmonary function
tests, including flow-volume loops, should be performed to
assess the degree of laryngotracheal disease, since this is an
important cause of mortality. Mild disease usually responds
to low-dose glucocorticoids or NSAIDs, whereas major
tracheobronchial involvement requires high-dose glucocorticoids
and immunosuppressants, as described for SLE.
Osteoporosis is the most common bone disease. It has been
estimated that more than 8.9 million fractures occur annually
worldwide and most of these occur in patients with osteopenia
or osteoporosis. About one-third of all women and one-fifth of
men aged 50 and above suffer fractures at some point in life.
The burden of osteoporosis-related fractures is predicted to
increase by two- to threefold by 2050 on a worldwide basis, due
to ageing of the population. Osteoporosis is under-diagnosed and
under-treated in Asia and the Indian subcontinent, particularly
in rural areas, due to low provision of technologies like DXA,
which are required to make the diagnosis. Fractures in patients
with osteoporosis can affect any bone but common sites are the
forearm (Colles’ fracture), spine (vertebral fractures), humerus and
hip. All of these fractures become more common with increasing
age (Fig. 24.55). Since only about one-third of vertebral fractures
come to medical attention (clinical vertebral fractures), the true
number of patients with vertebral fracture is much greater than
that shown in Figure 24.55. Of these, hip fractures are the most
serious and have an immediate mortality of about 1 2% and a
continued increase in mortality of about 20% when compared with
age-matched controls. Treatment of hip fracture accounts for the
majority of the health-care costs associated with osteoporosis.
Pathophysiology
The defining feature of osteoporosis is reduced bone density,
which causes micro-architectural deterioration of bone tissue
and leads to an increased risk of fracture, in response to minor
trauma. The risk of fracture increases markedly with age in
both genders (Fig. 24.55). This is mostly attributable to an
increased risk of falling with age (p. 1308) but is also due in part
to an age-related decline in bone mass, especially in women
(Fig. 24.56). Bone mass increases during growth to reach a peak
between the ages of 20 and about 45 years, but falls thereafter
in both genders with an accelerated phase of bone loss after
the menopause in women due to oestrogen deficiency. The
loss of bone with ageing is caused by an imbalance in the bone
remodelling cycle, whereby the amount of new bone formed by
osteoblasts cannot keep pace with the amount that is removed
by osteoclasts (see Fig. 24.2, p. 985). The reduction in bone
formation is thought to be partly due to differentiation of bone
marrow stem cells to adipocytes, as opposed to osteoblasts.
Osteoporosis sometimes occurs because of failure to attain
adequate levels of peak bone mass but is more commonly due
to age-related bone loss.
Osteoporosis is a complex disease that can occur in association
with a wide variety of risk factors, as summarised in Box 24.69.
Genetic factors account for up to 80% of variation in bone
density, and genome-wide association studies have shown that
susceptibility is determined in part by a large number of common
variants, some of which are involved in the RANK and Wnt
signalling pathways (see Fig. 24.3, p. 986). Rarely, osteoporosis
may be caused by mutations in single genes. Environmental
factors, such as exercise and calcium intake during growth
and adolescence, are important in maximising peak bone mass
and in regulating rates of post-menopausal bone loss. Smoking
has a detrimental effect on BMD and is associated with an
increased fracture risk, partly because female smokers have an
earlier menopause than non-smokers. Heavy alcohol intake is a
recognised cause of osteoporosis and fractures but moderate
intake does not substantially alter risk.
Idiopathic osteoporosis
The term idiopathic osteoporosis is frequently used to describe
the occurrence of osteoporosis in patients with no specific
underlying cause. It is slightly misleading, since most, if not
all, patients in this category have age-related osteoporosis or
osteoporosis associated with inheritance of genetic variants that
regulate bone density.
Secondary osteoporosis
Osteoporosis can occur in association with a variety of diseases
and drug treatments, and in many cases more than one disease
24.68 Criteria for the diagnosis of Behget’s disease
Recurrent oral ulceration: minor aphthous, major aphthous or
herpetiform ulceration at least three times in 12 months plustm of
the following:
• Recurrent genital ulceration
• Eye lesions: anterior uveitis, posterior uveitis, cells in vitreous on
slit-lamp examination, retinal vasculitis
• Skin lesions: erythema nodosum, pseudofolliculitis, papulopustular
lesions, acneiform nodules
• Positive pathergy test
Diseases of bone • 1045
Age
Age
Fig. 24.55 Fractures associated with osteoporosis. {K\ X-ray of wrist. [B] Vertebrae. [C] Humerus. [D] Hip. [e] and {¥] The changing incidence of
each of these fractures with age in women and men, respectively. From Curtis EM, van der Velde R, Moon RJ, et al. Epidemiology of fractures in the
United Kingdom 1988-2012: variation with age, sex, geography, ethnicity and socioeconomic status. Bone 2016; 87:19-26.
Fig. 24.56 Changes in bone mass and microstructure with age.
Changes in men (blue line) and women (red line).
or risk factor is operative. The most important causes are
summarised in Box 24.69. Secondary causes of osteoporosis
are particularly common in men, occurring in up to 50% of
patients. Hypogonadism, glucocorticoid use (see below) and
alcohol excess are the most important predisposing factors.
Glucocorticoid-induced osteoporosis
Glucocorticoid-induced osteoporosis is a common problem
in patients with systemic inflammatory and chronic pulmonary
diseases. The risk of osteoporosis is related to dose and duration
of glucocorticoid therapy and increases substantially in patients
who have taken more than 7.5 mg of prednisolone daily for more
than 3 months (or an equivalent dose of another glucocorticoid).
Inhaled glucocorticoids can reduce bone density but the risk
of osteoporosis is much lower than with systemic therapy.
Glucocorticoids mainly cause osteoporosis by inhibiting bone
formation and causing apoptosis of osteoblasts and osteocytes.
Other contributory mechanisms include inhibition of intestinal
calcium absorption, increased renal excretion of calcium and
secondary hyperparathyroidism, which stimulates osteoclastic
bone resorption.
Pregnancy-associated osteoporosis
This is a rare form of osteoporosis that typically presents with
back pain and multiple vertebral fractures during the second
or third trimester. The cause is unknown but may relate to
an exaggeration of the bone loss that normally occurs during
pregnancy in patients with pre-existing low bone mass.
Clinical features
Osteoporosis does not cause symptoms until a fracture occurs.
Non-vertebral fractures are almost always caused by a traumatic
event, most usually a simple fall. The term ‘fragility fracture’ is
used to describe a fracture that occurs as the result of a fall
from standing height or less. These are typical of osteoporosis.
It is important to remember that the majority of people who
suffer a fragility fracture do not have osteoporosis; some have
normal bone density but most have osteopenia (Fig. 24.57
and p. 988). The clinical signs of fracture are pain, local
tenderness and deformity. In hip fracture, the patient is (with
rare exceptions) unable to weight-bear and has a shortened and
externally rotated limb on the affected side. The presentation
of vertebral fractures is variable. Some patients present with
acute severe back pain. This may radiate to the anterior chest
or abdominal wall and be mistaken for a myocardial infarction,
aortic dissection or intra-abdominal pathology (p. 176). In
others the presentation is with height loss and kyphosis in the
absence of pain or with chronic back pain. Sometimes the
presentation of osteoporosis is with radiological osteopenia or
as a vertebral deformity on an X-ray that has been performed for
other reasons.
1046 • RHEUMATOLOGY AND BONE DISEASE
24.69 Risk factors for osteoporosis
Genetics
• Single-gene disorders:
•
Polygenic inheritance:
LRP5 mutations
Common variants in many
Oestrogen receptor
mutations
pathways
Endocrine disease
• Hypogonadism
•
Hyperparathyroidism
• Hyperthyroidism
Inflammatory disease
•
Cushing’s syndrome
• Inflammatory bowel disease
• Ankylosing spondylitis
•
Rheumatoid arthritis
Drugs
• Glucocorticoids
•
Aromatase inhibitors
• Gonadotrophin-releasing
•
Thiazolidinediones
hormone (GnRH) agonists
•
Anticonvulsants
• Levothyroxine
•
Alcohol intake >3 U/day
over-replacement
•
Heparin
Gastrointestinal disease
• Malabsorption
•
Chronic liver disease
Lung disease
• Chronic obstructive pulmonary
•
Cystic fibrosis
disease
Miscellaneous
• Myeloma
•
Systemic mastocytosis
• Homocystinuria
•
Immobilisation
• Anorexia nervosa*
•
Body mass index <18
• Highly trained athletes*
•
Heavy smoking
• HIV infection
•
Autoantibodies to
• Gaucher’s disease
osteoprotegerin (OPG)
*Hypogonadism also plays a role in osteoporosis associated with these
conditions.
Investigations
The most important investigation is DXA at the lumbar spine and
hip (see Fig. 24.9, p. 990). This should be considered in patients
age over 50 who have already suffered a fragility fracture, and in
those with clinical risk factors (Box 24.70) when a fracture risk
assessment tool (p. 1060) has returned an elevated value. The
risk at which DXA should be performed remains a subject of
debate but a 1 0-year risk of over 1 0% has been suggested, since
there is evidence of benefit from treatment at this level. Other
indications for DXA are in patients under 50 years who have very
strong risk factors, such as premature menopause or high-dose
glucocorticoids. Figure 24.58 provides a suggested algorithm
for the investigation of patients with suspected osteoporosis.
A history should be taken to identify any predisposing causes,
such as early menopause, excessive alcohol intake, smoking and
glucocorticoid therapy. Signs of endocrine disease, neoplasia and
inflammatory disease should be sought on clinical examination. A
falls history should be taken and a ‘get up and go’ test performed,
especially in older patients (p. 1303). Screening for secondary
causes of osteoporosis should be performed, as summarised
in Box 24.71 .
Management
The aim of treatment is to reduce the risk of fracture and this
can be achieved by a combination of approaches.
24.70 Indications for dual X-ray
absorptiometry (DXA)
• Low-trauma fracture, age >50 years
• Clinical risk factors and 1 0-year fracture risk >10%
• Glucocorticoid therapy (>7.5 mg prednisolone daily for >3 months)
• Assessment of response of osteoporosis to treatment
• Assessment of progression of osteopenia to osteoporosis
• Age <50 years and very strong risk factors for osteoporosis
□
□
□
Normal BMD
Osteopenia
Osteoporosis
18%
Fig. 24.57 Relation between bone mineral density (BMD) and fractures. [A] The relative risk of fracture increases exponentially as BMD falls (blue
line), and is 14-fold higher in people with a T-score of <-3.5 compared with those with normal BMD. In absolute terms, however, more fractures occur in
people with normal BMD or osteopenia (red line), j¥] The proportions of fractures that occur in people with normal BMD, osteopenia and osteoporosis.
Diseases of bone • 1047
Age > 50
Low-trauma
fracture
r
Normal
Age >50
Fracture
risk >10%
4
DXA spine
and hip
4
T
Osteopenia
4^
Correct
modifiable
risk factors
T
Reassess
at a later
date
Age <50
Very strong
risk factors
0*.oporosis
Screen for
secondary
causes
Correct
modifiable
risk factors
+ give drug
treatment
Fig. 24.58 Algorithm for the investigation of patients with suspected
osteoporosis. Fracture risk is assessed using FRAX or QFracture (see
‘Further information’, p. 1060).
24.71 Investigations in osteoporosis
Investigation
Secondary cause of
osteoporosis
Urea, creatinine and electrolytes
Chronic kidney disease
Liver function tests and albumin
Chronic liver disease
Full blood count, erythrocyte
sedimentation rate
Inflammatory disease
Myeloma
Tissue transglutaminase antibodies
Coeliac disease
Serum calcium and phosphate
Primary hyperparathyroidism
Serum 25(0H)D and alkaline
phosphatase
Vitamin D deficiency
Osteomalacia
Serum parathyroid hormone
Primary hyperparathyroidism
Thyroid function tests
Hyperthyroidism
Serum protein electrophoresis
Myeloma
Monoclonal gammopathy of
uncertain significance
Urinary Bence Jones protein
Myeloma
Testosterone and gonadotrophins
Male hypogonadism
Oestrogen and gonadotrophins
Female hypogonadism1
Bone biopsy
Unexplained early-onset
osteoporosis2
Renal disease
Multiple possible causes of
low bone mass
^nly required for unexplained osteoporosis in young women who are
amenorrhoeic. 2Seldom required.
Non-pharmacological interventions
Advice on smoking cessation, moderation of alcohol intake,
adequate dietary calcium intake and exercise should be given.
Those with recurrent falls or unsteadiness on a ‘get up and go’
test should be referred to a multidisciplinary falls prevention team
Bisphosphonate
given orally or
intravenously
Osteoclast inhibition
increases bone density
and mineralisation
Bisphosphonate
binds avidly to
bone surface
Bisphosphonate
released within
osteoclast, causing
cell death
Osteoclasts resorb
bone containing
bisphosphonate
Fig. 24.59 Mechanism of action of bisphosphonates.
(p. 1308). Hip protectors can reduce the risk of hip fracture in
selected patients but adherence is often poor.
Pharmacological interventions
Several drug treatments are now available to reduce the risk of
fracture in osteoporosis. The dosages, mode of administration
and indications are summarised in Box 24.72. More detail on
the individual drugs is provided below.
Bisphosphonates Bisphosphonates are the first-line treatment
for osteoporosis. These are a class of drugs with a central core
of P-C-P atoms, to which various side-chains are attached.
Following administration, they target bone surfaces and are
ingested by osteoclasts during the process of bone resorption.
The bisphosphonate is released within the osteoclasts and
impairs bone resorption. This in turn causes an increase in bone
density but this is principally due to increased mineralisation
of bone, rather than an increase in bone mass (Fig. 24.59).
Bisphosphonates reduce the risk of fracture in patients with
osteoporosis but do not completely prevent fractures occurring.
Oral bisphosphonates are typically given for a period of
5 years, at which point the need for continued therapy should
be evaluated, with a repeat DXA if possible. If patients have
remained free of fractures after 5 years and if BMD levels have
increased and no longer remain in the osteoporotic range, it is
usual to instigate a 5-year spell off therapy. Treatment may be
continued for up to 10 years in patients whose BMD levels remain
in the osteoporotic range after 5 years. A change in treatment
should be considered in patients who have lost BMD despite
oral bisphosphonates (more than 4%). Most commonly, this
will be a switch to parenteral zoledronic acid but teriparatide
(TPTD) can also be considered in those with severe spinal
osteoporosis. With intravenous zoledronic acid, 3 years of therapy
is equivalent to 6 years in terms of fracture risk reduction and
many experts recommend periods of 3 years on and 3 years
off treatment to reduce the risk of over-suppression of bone
turnover.
Oral bisphosphonates are poorly absorbed from the
gastrointestinal tract and should be taken on an empty stomach
1048 • RHEUMATOLOGY AND BONE DISEASE
24.72 Drug treatments for osteoporosis
Drug
Regimen
Postmenopausal
osteoporosis
Glucocorticoid
osteoporosis
Male osteoporosis
Alendronic acid
70 mg/week orally
y
y
y
Risedronate
35 mg/week orally
y
y
y
Ibandronate
150 mg/monthly orally
3 mg/3-monthly IV
y
y
y
Zoledronic acid
5 mg annually IV
y
y
y
Denosumab
60 mg 6-monthly SC
y
-
y
Calcium/vitamin D
Calcium 500-1000 mg daily
Vitamin D 400-800 IU orally
y
y
y
Teriparatide
20 jxg/day SC
y
y
y
Abaloparatide
80 pig/day SC
y
-
-
Hormone replacement therapy
Various preparations
y
-
-
Raloxifene
60 mg/day orally
y
-
-
Tibolone
1.25 mg/day orally
y
-
-
(IV = intravenous; SC = subcutaneous)
i
Common
• Upper gastrointestinal intolerance (oral)
• Acute phase response (intravenous)
Less common
• Atrial fibrillation (intravenous zoledronic acid)
• Hypocalcaemia (intravenous bisphosphonates)
• Atypical subtrochanteric fractures
Rare
• Uveitis
• Osteonecrosis of the jaw
• Oesophageal ulceration
with plain water; no food should be eaten for 30-45 minutes
after administration. They are contraindicated in patients with
oesophageal stricture or achalasia, since tablets may stick in
the oesophagus, causing ulceration and perforation. Upper
gastrointestinal upset occurs in about 5% of cases. Oral
bisphosphonates can be used in patients with gastro-oesophageal
reflux disease but may cause worsening of symptoms. The
most common adverse effect with intravenous bisphosphonates
is a transient influenza-like illness typified by fever, malaise,
anorexia and generalised aches, which occurs 24-48 hours
after administration. This is self-limiting but can be treated with
paracetamol or NSAIDs if necessary. It predominantly occurs
after the first exposure and tolerance develops thereafter. Other
adverse effects are shown in Box 24.73. Osteonecrosis of the
jaw is characterised by the presence of necrotic bone in the
mandible or maxilla, typically occurring after tooth extraction
when the socket fails to heal. This complication is very rare in
osteoporosis but patients receiving bisphosphonates should
be advised to pay attention to good oral hygiene. There is no
evidence that temporarily stopping bisphosphonates for tooth
extraction alters the risk of osteonecrosis of the jaw. Atypical
subtrochanteric fractures have been described in patients who
have received long-term bisphosphonates and appear to be the
result of over-suppression of normal bone remodelling. In the vast
majority, the benefits of bisphosphonate therapy far outweigh the
risks but it is important for treatment to be targeted to patients
with low BMD who are most likely to benefit.
Denosumab Denosumab is a monoclonal antibody that inhibits
bone resorption by neutralising the effects of RANKL (see Fig.
24.2, p. 985). It is administered by subcutaneous injection of
60 mg every 6 months in the treatment of osteoporosis and
has similar efficacy to zoledronic acid. One potential adverse
effect is hypocalcaemia but this can be mitigated by calcium
and vitamin D supplements. Denosumab may rarely cause
osteonecrosis of the jaw and atypical subtrochanteric fractures.
If it is stopped, there is a rebound increase in bone turnover
that can be associated with a greater risk of fracture and even
hypercalcaemia. Because of this, many experts advise giving a
bisphosphonate following cessation of denosumab.
Calcium and vitamin D Combined calcium and vitamin D
supplements have limited efficacy in the prevention of osteoporotic
fractures when given alone but are widely used as an adjunct
to other treatments. A typical daily dosage is 1000 mg calcium
and 800 IU vitamin D. Calcium and vitamin D supplements have
efficacy in preventing fragility fractures in elderly or institutionalised
patients who are at high risk of deficiency (Box 24.74). Vitamin D
supplements alone do not prevent fractures in osteoporosis but
there is evidence that the response to bisphosphonates is blunted
in patients with vitamin D deficiency. If the patient’s dietary calcium
is sufficient, stand-alone vitamin D supplements (800 IU daily)
can be prescribed as an adjunct to anti-osteoporosis therapies.
Teriparatide Teriparatide (TPTD) is the 1 -34 fragment of human
PTH. It is an effective treatment for osteoporosis, which works by
stimulating new bone formation. Although TPTD also stimulates
bone resorption, the increase in bone formation is greater, resulting
in increased bone density, particularly at sites rich in trabecular
bone such as the spine. It is given by a self-administered
subcutaneous injection in a dose of 20 jig daily for 2 years.
At the end of this period, bisphosphonate therapy or another
24.73 Adverse effects of bisphosphonates
Diseases of bone • 1049
£
inhibitor of bone resorption should be administered to maintain
the increase in BMD. TPTD and oral bisphosphonates should
not be given in combination, however, since the bisphosphonate
blunts the anabolic effect. The efficacy of TPTD for prevention
of non-vertebral fractures is similar to that of bisphosphonates
but it is superior to oral bisphosphonates in preventing vertebral
fractures. The most common adverse effects are headache,
muscle cramps and dizziness. Mild hypercalcaemia may occur but
it is usually asymptomatic and does not require discontinuation
of treatment. Monitoring of serum calcium is not required during
TPTD treatment.
Abaloparatide Abaloparatide is the 1 -34 fragment of PTH-related
protein. It works in a similar way to TPTD to stimulate bone
formation. It is given as a self-administered injection of 80 jig
daily for 18 months. At the end of this period an inhibitor of bone
resorption should be given to maintain the increase in bone mass.
Efficacy has been demonstrated for the prevention of vertebral
fractures with effects similar to those of TPTD. Adverse effects
are similar to those of TPTD.
Hormone replacement therapy Cyclical HRT with oestrogen
and progestogen prevents post-menopausal bone loss and
reduces the risk of vertebral and non-vertebral fractures in post¬
menopausal women. It is primarily indicated for the prevention
of osteoporosis in women with an early menopause (p. 655)
and for treatment of women with osteoporosis in their early
fifties who have troublesome menopausal symptoms. It is not
recommended above the age of 60 because the risk of an
increased risk of breast cancer, cardiovascular disease and
venous thromboembolic disease.
Raloxifene Raloxifene is a selective oestrogen receptor modulator
(SERM) that acts as a partial agonist at oestrogen receptors in
bone and liver, but as an antagonist in breast and endometrium.
It is effective in reducing the risk of vertebral fractures but does
not influence the risk of non-vertebral fracture and is seldom
used. Adverse effects include muscle cramps, worsening of
hot flushes and an increased risk of venous thromboembolic
disease. Bazedoxifene is a related SERM that has similar effects
to raloxifene.
Tibolone Tibolone has partial agonist activity at oestrogen,
progestogen and androgen receptors. It has been shown to
prevent vertebral and non-vertebral fractures in post-menopausal
osteoporosis. Treatment is associated with a slightly increased
risk of stroke but a reduced risk of breast cancer.
Other drugs Romosozumab is antibody directed against sclerostin,
which is under development for the treatment of osteoporosis.
It increases bone formation, inhibits bone resorption and
increases BMD. When given subcutaneously in a dose of 210 mg
monthly, it reduces the risk of vertebral fractures in patients with
postmenopausal osteoporosis. Calcitriol (1 ,25(OH)2D3), the active
metabolite of vitamin D, is licensed for treatment of osteoporosis
but it is seldom used because the data on fracture prevention
are less robust than for other agents.
Surgery
Orthopaedic surgery with internal fixation is frequently required
to reduce and stabilise osteoporotic fractures. Patients with
intracapsular fracture of the femoral neck generally need hemi¬
arthroplasty or total hip replacement in view of the high risk of
avascular necrosis.
Vertebroplasty is sometimes used in the treatment of painful
vertebral compression fractures. It involves injecting methyl
methacrylate (MMA) into the affected vertebral body under
sedation and local anaesthesia. While randomised trials have
shown that vertebroplasty provides no better pain relief than
a sham procedure, it is still widely used, particularly in North
America. Kyphoplasty is used under similar circumstances, but in
this case a needle is introduced into the affected vertebral body
and a balloon is inflated, which is then filled with MMA. It has
similar efficacy to vertebroplasty but adverse effects are more
common. Adverse effects with both procedures include spinal
cord compression due to leakage of MMA and fat embolism.
Osteomalacia, rickets and
vitamin D deficiency
Osteomalacia and rickets are characterised by defective
mineralisation of bone. The most common cause is vitamin D
deficiency, but both conditions can also occur as the result of
inherited defects in renal phosphate excretion, and inherited
defects in the vitamin D receptor and in the pathways responsible
for vitamin D activation. Other causes are summarised in Box
24.75 and are discussed in more detail below. The term
osteomalacia refers to the syndrome when it occurs in adults
and rickets is the equivalent syndrome in children. The disease
remains prevalent in frail older people who have a poor diet and
limited sunlight exposure, and in some Muslim women.
Vitamin D deficiency
Vitamin D deficiency is defined to exist when serum 25(OH)D
concentrations are below 25 nmol/L (10 ng/mL). People with
vitamin D levels in the range 25-50 nmol/L (10-20 ng/mL) are
classified as having vitamin D insufficiency, whereas those with
25(OH)D levels above 50 nmol/L (20 ng/mL) are classified as
having normal vitamin D status. In the elderly, a more appropriate
normal threshold may be 75 nmol/L (30 ng/mL) or more, though
there is some debate on the issue and evidence is not conclusive.
The likelihood of developing vitamin D deficiency is strongly
related to sunlight exposure. It is common in northern latitudes
(or southern latitudes in the southern hemisphere) and shows
seasonal variation. Vitamin D deficiency is also common in women
who, for cultural reasons, cover their skin and face. Vitamin D
24.74 Osteoporosis in old age
• Bone loss: due to increased bone turnover, with an age-related
defect switch in differentiation of bone marrow stromal cells to form
adipocytes as opposed to osteoblasts.
• Fractures due to osteoporosis: common cause of morbidity and
mortality, although fracture healing is not delayed by age.
• Recurrent fractures: those who suffer a fragility fracture are at
increased risk of further fracture, so should be investigated for
osteoporosis and treated if this is confirmed.
• Falls: risk factors for falls (such as visual and neuromuscular
impairments) are independent risk factors for hip fracture in elderly
individuals, so intervention to prevent falls is as important as
treatment of osteoporosis (p. 1308).
• Intravenous zoledronic acid: reduces mortality and subsequent
fracture in selected elderly patients with hip fractures.
• Calcium and vitamin D: reduce the risk of fractures in those who
are housebound or living in care homes.
1050 • RHEUMATOLOGY AND BONE DISEASE
24.75 Causes of osteomalacia and rickets
Cause
Predisposing factor
Mechanism
Vitamin D deficiency
Classical
Gastrointestinal disease
Lack of sunlight exposure and poor diet
Malabsorption
Reduced cholecalciferol synthesis in the skin/low
levels of vitamin D in the diet
Malabsorption of dietary vitamin D and calcium
Failure of 1,25 vitamin D synthesis
Chronic renal failure
Vitamin D-resistant rickets type 1 (autosomal
recessive)
Hyperphosphataemia and kidney damage
Loss-of-function mutations in renal
25(0H)D 1 a-hydroxylase enzyme
Impaired conversion of 25(0H)D3 to 1,25(0H)2D3
Impaired conversion of 25(0H)D3 to 1,25(0H)2D3
Vitamin D receptor defects
Vitamin D-resistant rickets type II (autosomal
recessive)
Loss-of-function mutations in vitamin D
receptor
Impaired response to 1,25(0H)2D3
Defects in phosphate and pyrophosphate metabolism
Hypophosphataemic rickets (X-linked dominant) Mutations in PHEX
Autosomal dominant hypophosphataemic rickets Mutation in FGF23
Autosomal recessive hypophosphataemic rickets Mutations in DMP1
Tumour-induced hypophosphataemic osteomalacia Ectopic production of FGF23 by tumour
Hypophosphatasia Mutations in ALPL, which encodes
alkaline phosphatase
Increased FGF23 production (mechanism unclear)
Mutant FGF23 is resistant to degradation
Increased production of FGF23
Local deficiency of DMP1 inhibits mineralisation
Over-production of FGF23
Inhibition of bone mineralisation due to
accumulation of pyrophosphate in bone
Iatrogenic and other causes
Bisphosphonate therapy
Aluminium
Fluoride
High-dose etidronate/pamidronate
Use of aluminium-containing phosphate
binders or aluminium in dialysis fluid
High fluoride in water
Drug-induced impairment of mineralisation
Aluminium-induced impairment of mineralisation
Inhibition of mineralisation by fluoride
(FGF23 = fibroblast growth factor 23)
Fig. 24.60 Seasonal changes in vitamin D concentrations. To convert
nmol/L to ng/mL, multiply by 2.5. Adapted from McDonald HM, Mavroeidi
A, Fraser WD, et al. Sunlight and dietary contributions to the seasonal
vitamin D status of cohorts of healthy postmenopausal women living at
northerly latitudes: a major cause for concern? Osteoporosis Int 201 1;
22:2461-2472.
deficiency is more common in the winter and spring, and less
common in summer and autumn (Fig. 24.60).
Pathogenesis
The source of vitamin D and pathways involved in regulating its
metabolism are shown in Figure 24.61 . In normal individuals,
vitamin D (also known as cholecalciferol) comes from two sources:
about 70% is made in the skin, where 7-dehydrocholesterol is
converted to cholecalciferol under the influence of ultraviolet
light, whereas the remaining 30% is derived from the diet. The
main dietary sources are oily fish and meat, although bread and
dairy products are fortified with vitamin D in some countries. On
entering the circulation, vitamin D is hydroxylated in the liver to
form 25(01-1) vitamin D and this is further hydroxylated in the
kidney to form 1 ,25(OH)2D, the biologically active metabolite.
The 1 ,25(OH)2D primarily acts on the gut to increase intestinal
calcium absorption but also acts on the skeleton to stimulate bone
remodelling. Synthesis of 1 ,25(OH)2D is regulated by a negative
feedback loop orchestrated by the parathyroid glands. When
vitamin D levels fall - as the result of lower sunlight exposure
or dietary lack - production of 1 ,25(OH)2D is reduced, causing
a reduction in calcium absorption from the gut. This causes a
transient fall in serum calcium, which is detected by calcium¬
sensing receptors on the parathyroid chief cells; this increases
PTH secretion, which restores calcium levels to normal. Vitamin
D deficiency is, therefore, usually characterised by a low level
of 25(OH)D and a raised level of PTH. Sometimes, low 25(OH)
D levels may be observed in the presence of a normal PTH
concentration. This is of uncertain clinical significance but might
be due to variations in levels of vitamin D-binding protein. Serum
concentrations of vitamin D are under genetic control and are
associated with variants close to the GC gene, which encodes
vitamin D-binding protein; the DHCR7 gene, which encodes
7-dehydrocholesterol reductase, responsible for catalysing
conversion of 7-DHC to 25(OH)D; the CYP2R1 gene, which
encodes vitamin D-25-hydroxylase, responsible for hydroxylation
of vitamin D in the liver; and the CYP24A1 gene, which encodes
vitamin D-24-hydroxylase, responsible for converting 25(OH)D
to the inactive metabolite 24,25(OH)2D.
Diseases of bone • 1051
Sunlight
Parathyroid
chief cell
Calcium-sensing
receptor
J Ca2+
;:^SCca2+
Ca2+
PTH/
secretory
granules
PTH
25(OH)D
(inactive)
Renal tubules
Parathyroids
-ve feedback \
Serum
calciumT
Fig. 24.61 Vitamin D metabolism. Vitamin D is produced in the skin from 7-dehydrocholesterol (7-DHC) by ultraviolet B (UVB) light. The
7-dehydrocholesterol reductase enzyme, which is encoded by the DHCR7 gene, opposes the effect of UVB by converting 7-DHC to cholesterol. The vitamin
D then undergoes hydroxylation steps in the liver and kidney to form the active metabolite 1,25(0H)2D, which regulates calcium homeostasis by stimulating
calcium absorption from the diet and bone resorption. See text for details.
Clinical features
Vitamin D deficiency does not cause symptoms and the diagnosis
is made as the result of biochemical testing. Low circulating
concentrations of vitamin D have been associated with a wide
range of diseases, including most types of cancer, diabetes,
multiple sclerosis and chronic inflammatory diseases. These
associations are unlikely to be causal but most probably arise
as the result of reduced sunlight exposure and poor diet in
people who are ill. If vitamin D deficiency is prolonged and
severe, then osteomalacia and rickets may occur, as discussed
below. The consequences of biochemical vitamin D deficiency
and insufficiency on bone health and general health are unclear.
Investigations
The diagnosis can be made by measurement of serum 25(OH)D. In
patients with low 25(OH)D, measurements of PTH, serum calcium,
phosphate and ALP should also be considered. Low levels of
25(OH)D in the absence of other abnormalities is unlikely to be of
any clinical significance and may be due to low levels of vitamin
D-binding protein. If low 25(OH)D levels are combined with raised
levels of PTH , this is of more significance since it indicates secondary
hyperparathyroidism. Serum ALP, calcium and phosphate levels
are normal in uncomplicated vitamin D deficiency.
Management
The clinical benefit of treating biochemical vitamin D deficiency
is uncertain. Vitamin D supplements should be considered in
patients who have low 25(OH)D levels and raised levels of PTH. In
most patients, cholecalciferol in a dose of 800 IU daily should be
sufficient to correct the deficiency. The benefit of treating seasonal
vitamin D deficiency or vitamin D insufficiency is uncertain. There
is some evidence that response to bisphosphonate treatment
of osteoporosis is impaired in patients with vitamin D deficiency
and this is another indication for supplements. In patients who
are receiving intravenous bisphosphonates and denosumab
for osteoporosis, vitamin D deficiency should be corrected by
supplementation to reduce the risk of hypocalcaemia. In this
case, it is customary to give higher doses of vitamin D, such
as 20000-25000 IU once a week for 4 weeks or to give lower
doses over a more prolonged period.
Osteomalacia and rickets
Severe and prolonged vitamin D deficiency can result in the
occurrence of osteomalacia in adults and rickets in children.
Improvements in nutrition mean that these are now relatively
uncommon conditions in developed countries but they remain
prevalent in elderly housebound individuals, some Muslim
women who wear a veil (hijab) that covers a large amount of
exposed skin, and people with malabsorption.
Pathogenesis
Osteomalacia and rickets occur as the result of chronic secondary
hyperparathyroidism, which invariably accompanies severe and
long-standing vitamin D deficiency. The sustained elevation
in PTH levels maintains normal levels of serum calcium by
increasing bone resorption, which eventually causes progressive
demineralisation of the skeleton. Phosphate that is released during
the process of bone resorption is lost through increased renal
excretion, resulting in hypophosphataemia. The raised levels of
PTH stimulate osteoblast activity and cause new bone formation
1052 • RHEUMATOLOGY AND BONE DISEASE
but the matrix is not mineralised properly because of deficiency
of calcium and phosphate. The under-mineralised bone is soft,
mechanically weak and subject to fractures, particularly stress
fractures. Normal levels of serum calcium tend to be maintained
until a very advanced stage, when hypocalcaemia may occur.
Clinical features
Vitamin D deficiency in children causes delayed development, muscle
hypotonia, craniotabes (small unossified areas in membranous
bones of the skull that yield to finger pressure with a cracking
feeling), bossing of the frontal and parietal bones and delayed
anterior fontanelle closure, enlargement of epiphyses at the lower
end of the radius, and swelling of the rib costochondral junctions
(‘rickety rosary’). Osteomalacia in adults can present with fractures
and low BMD, mimicking osteoporosis. Other symptoms include
bone pain and general malaise. Proximal muscle weakness is
prominent and the patient may walk with a waddling gait and
struggle to climb stairs or stand up from a chair. There may be
bone and muscle tenderness on pressure, and focal bone pain
can be due to fissure fractures of the ribs and pelvis.
Investigations
The diagnosis can usually be made by measurement of serum
25(OH)D, PTH, calcium, phosphate and ALP. Typically, serum
ALP levels are raised, 25(OH)D levels are undetectable and
PTH is markedly elevated. Serum phosphate levels tend to be
low but serum calcium is usually normal, unless the disease
is advanced. X-rays often show osteopenia or vertebral crush
fractures and, with more advanced disease, focal radiolucent
areas (pseudofractures or Looser’s zones) may be seen in
ribs, pelvis and long bones (Fig. 24.62A). In children, there is
Fig. 24.62 Osteomalacia. [A] X-ray of the pelvis showing
pseudofractures affecting the inferior and superior pubic rami on the left
side (arrows). Healing pseudofractures with callus formation are also
visible at the inferior and superior pubic rami on the right side (arrows).
[1] Photomicrograph of bone biopsy from an osteomalacic patient
showing thick osteoid seams (stained light blue, arrows) that cover
almost all of the bone surface. Calcified bone is stained dark blue.
thickening and widening of the epiphyseal plate. A radionuclide
bone scan may show multiple hot spots in the ribs and pelvis
at the site of fractures and the appearance may be mistaken
for metastases. Where there is doubt, the diagnosis can be
confirmed by bone biopsy, which shows the pathognomonic
features of increased thickness and extent of osteoid seams
(Fig. 24.62B).
Management
Osteomalacia and rickets respond promptly to treatment with
vitamin D. A wide variety of doses can be used. Treatment
with between 10000 and 25 000 IU daily for 2-4 weeks is
associated with rapid clinical improvement, an elevation in
serum 25(OH)D and a reduction in PTH. Serum ALP levels
sometimes rise initially as mineralisation of bone increases but
eventually fall to within the reference range as the bone disease
heals. Subsequently, the dose of vitamin D can usually be
reduced to a maintenance level of 800-1600 IU daily (10-20 jig),
except in patients with malabsorption, who may require higher
doses.
Vitamin D-resistant rickets
This is a genetically determined condition that presents in
childhood with rickets that is resistant to therapy with vitamin
D in standard dosages.
Pathogenesis
Type I vitamin D-resistant rickets (VDRR) is caused by inactivating
mutations in the 25-hydroxyvitamin D 1 a-hydroxylase (CYP27B1)
enzyme, which converts 25(OH)D to the active metabolite
1 ,25(OH)2D3. Type II VDRR is caused by inactivating mutations
in the vitamin D receptor, which impair its ability to activate gene
transcription. Both are recessive disorders and consanguinity
is common.
Clinical features
These are as described above for infantile rickets. The diagnosis
is usually first suspected when the patient fails to respond to
vitamin D supplementation.
Investigations
The biochemical features of type I VDRR are similar to those
of ordinary vitamin D deficiency, except that levels of 25(OH)D
are normal but 1 ,25(OH)2D is low. In type II VDRR, 25(OH)D is
normal but PTH and 1,25(OH)2D3 values are raised.
Management
Type I VDRR responds fully to treatment with the active vitamin
D metabolites 1 a-hydroxyvitamin D (1-2 jig daily, orally) or
1 ,25-dihydroxyvitamin D (0.25-1 .5 jig daily, orally). Calcium
supplements are not necessary unless there is dietary deficiency.
Type II VDRR sometimes responds partially to very high doses
of active vitamin D metabolites, which can activate the mutant
receptor, although additional calcium and phosphate supplements
are also necessary.
Hereditary hypophosphataemic rickets
This group of disorders are caused by inherited defects in renal
tubular phosphate reabsorption. The most common is X-linked
hypophosphataemic rickets (XLH), but autosomal dominant and
autosomal recessive forms also occur (Box 24.75).
Diseases of bone • 1053
Pathophysiology
All forms of hereditary hypophosphataemic rickets are associated
with raised circulating concentrations of the phosphate-regulating
hormone fibroblast growth factor 23 (FGF23). This hormone
is produced by osteocytes (see Fig 24.3, p. 986) and enters
the circulation, where it is normally inactivated by proteolytic
cleavage. Production of FGF23 by osteocytes is under tonic
inhibition by DMP1 and PPIEX. In XLH, the inhibitory effect on
FGF23 production is lost due to mutations in PHEX and a similar
situation occurs in autosomal recessive hypophosphataemic
rickets (ARHR1) due to loss-of-function mutations in DMP1 .
Mutations in the ENPP1 gene, which encodes a phosphatase
responsible for degradation of pyrophosphate, can also cause
a recessive form of hypophosphataemic rickets (ARHR2). In
autosomal dominant hypophosphataemic rickets (ADHR), the
FGF23 protein carries mutations that prevent FGF23 being
degraded, thereby causing accumulation of intact FGF23 hormone
in the circulation. In all three diseases, the elevation in FGF23
results in osteomalacia and rickets by causing phosphaturia by
up-regulation of sodium-dependent phosphate transporters in
the renal tubules, and also by inhibiting conversion of 25(OH)D
to 1 ,25(OH)2D by the kidney, which in turn causes reduced
calcium and phosphate absorption from the gut.
Clinical features
The presentation is with symptoms and signs of rickets during
childhood that do not respond to vitamin D supplementation.
In adults, hypophosphataemic rickets may be accompanied
by dental abscesses, and by bone and joint pain due to the
development of an enthesopathy.
Investigations
The diagnosis can be confirmed by the finding of low serum
phosphate levels and a reduction in tubular reabsorption of
phosphate. Serum levels of vitamin D are normal and PTH is
normal or slightly elevated. Serum concentrations of FGF23
are markedly elevated. The causal mutation can be defined by
genetic testing.
Management
The aim of treatment is to ameliorate symptoms, restore
normal growth and maintain serum phosphate levels within the
reference range. Traditionally, treatment has been with phosphate
supplements (1-4 g daily) and 1 -a-hydroxyvitamin D (1-2 jig
daily) or 1 ,25-dihydroxyvitamin D (0.5-1 .5 jig daily) with the
aim of promoting intestinal calcium and phosphate absorption.
Levels of calcium and phosphate, as well as renal function,
should be monitored regularly and the doses of phosphate
and vitamin D metabolites carefully titrated to maintain serum
phosphate within the normal range but avoid hypercalcaemia.
Recently, a neutralising antibody to FGF23 has been developed
that can reverse the biochemical abnormalities in hereditary
hypophosphataemic rickets and it is likely that this will be a
future treatment option.
| Tumour-induced osteomalacia
This is a rare syndrome caused by over-production of
FGF23 by mesenchymal tumours. The presentation is with
severe osteomalacia and hypophosphataemia in an adult
patient with no obvious predisposing risk factor for vitamin D
deficiency. Biochemical findings are as described for hereditary
hypophosphataemic rickets. The underlying tumour can sometimes
be identified by whole-body MRI or CT. Medical management is
with phosphate supplements and active vitamin D metabolites
but the treatment of choice is surgical resection of the primary
tumour, which is curative.
Hypophosphatasia
Hypophosphatasia is an autosomal recessive disorder caused
by loss-of-function mutations in the TNALP gene, which result
in accumulation of pyrophosphate and inhibition of bone
mineralisation. Chondrocalcinosis may also occur. The typical
presentation is with severe intractable rickets during infancy,
sometimes in association with seizures. Investigations show low
or undetectable levels of serum ALP but normal levels of calcium,
phosphate, PTH and vitamin D metabolites. Urinary excretion of
pyridoxal 5' phosphate and phosphoethanolamine (substrates for
ALP) is increased. Until recently, this condition was fatal during
childhood but remarkable therapeutic responses have been
obtained with recombinant ALP therapy (asfotase alfa), which
is curative. Heterozygous carriers of mutation in TNALP may
present in adulthood with osteoporosis, fractures and low ALP
values. The best mode of treatment for these patients remains to
be determined, except that bisphosphonates should be avoided
since they may exacerbate the mineralisation defect.
Other causes of osteomalacia
These are summarised in Box 24.75. Osteomalacia may occur
as a component of renal osteodystrophy in patients with chronic
kidney disease. The mechanism is reduced conversion of
25(OH)D into the active metabolite 1 ,25(OH)2D by the failing kidney
(p. 418). Aluminium intoxication is now rare due to reduced use of
aluminium-containing phosphate binders and removal of aluminium
from the water supplies used in dialysis. If aluminium intoxication
is suspected, the diagnosis can be confirmed by demonstration of
aluminium at the calcification front in a bone biopsy. Osteomalacia
due to bisphosphonates has mostly been described in patients
with Paget’s disease who are receiving etidronate and high-dose
pamidronate. It is usually asymptomatic and healing occurs
when treatment is stopped. Excessive fluoride intake causes
osteomalacia due to direct inhibition of mineralisation and is
common in parts of the world where there is a high fluoride
content in drinking water. The condition reverses when fluoride
intake is reduced.
Paget’s disease of bone
Paget’s disease of bone (PDB) is characterised by focal areas
of increased and disorganised bone remodelling involving one or
more skeletal sites. The disease is common in the UK, affecting
about 1 % of those aged above 55, and in other countries in
Europe. It is rare in Scandinavia, the Indian subcontinent and
the rest of Asia. The prevalence doubles each decade from the
age of 50 onwards and affects up to 8% of the UK population
by the age of 85.
Pathophysiology
The primary abnormality is increased osteoclastic bone resorption,
accompanied by marrow fibrosis, increased vascularity of bone
and increased, but disorganised, bone formation. Osteoclasts
in PDB are greater in number and unusually large, containing
characteristic nuclear inclusion bodies. Genetic factors are
important and mutations in the SQSTM1 gene are a common
1054 • RHEUMATOLOGY AND BONE DISEASE
Fig. 24.63 Paget’s disease. [A] 99mTc-labelled bisphosphonate scintigraphy from a patient with Paget’s disease, illustrating the intense tracer uptake and
deformity of the affected femur. [§] The typical radiographic features with expansion of the femur, alternating areas of osteosclerosis and radiolucency of
the trochanter, and pseudofractures breaching the bone cortex (arrows).
cause of classical PDB. The presence of nuclear inclusion bodies
in osteoclasts has fuelled speculation that PDB might be caused
by a slow virus infection but this is unproven. Biomechanical
factors may influence which bones are affected, as PDB often
starts at sites of muscle insertions into bone and, in some
cases, localises to bones or limbs that have been subjected
to repetitive trauma or overuse. Involvement of subchondral
bone can compromise the joint and predispose to OA. The
prevalence of PDB has fallen in many countries over recent
decades, suggesting that environmental factors play a role, but
the identity of these triggers remains unclear.
Clinical features
The axial skeleton is predominantly affected and common sites
of involvement are the pelvis, femur, tibia, lumbar spine, skull
and scapula. The most common presentation is with bone pain
localised to an affected site but bone deformity, deafness and
pathological fractures may also be presenting features. Many
patients are asymptomatic and the diagnosis is frequently made
on the basis of an X-ray or blood test performed for another
reason. Clinical signs include bone deformity and expansion,
and increased warmth over an affected bone. Neurological
problems, such as deafness, cranial nerve defects, nerve root
pain, spinal cord compression and spinal stenosis, may occur
due to enlargement of affected bones and encroachment on the
spinal cord and nerve foramina. Surprisingly, deafness seldom
results from compression of the auditory nerve but is conductive,
due to osteosclerosis of the temporal bone. The increased
vascularity of Pagetic bone can rarely precipitate high-output
cardiac failure in elderly patients with limited cardiac reserve.
Osteosarcoma is an unusual but serious complication that
presents with increasing pain and swelling of an affected site.
Investigations
The characteristic features are an isolated elevation in ALP and
bone expansion on X-rays, with alternating areas of radiolucency
and osteosclerosis (Fig. 24.63B). Levels of ALP can be normal if
only a single bone is affected. The best way of identifying affected
sites is a radionuclide bone scan, which shows increased uptake
24.76 Medical management of Paget’s disease
Drug
Route of
administration Dose
Etidronate
Oral
400 mg daily for 3-6 months
Tiludronate
Oral
400 mg daily for 3-6 months
Risedronate
Oral
30 mg daily for 2 months
Pamidronate
IV
1-3x60 mg infusions
Zoledronic acid
IV
1 x5 mg infusion
Calcitonin
SC
100-200 III 3 times weekly
for 2-3 months
in affected bones (Fig. 24.63A). If the bone scan is positive,
X-rays should be taken to confirm the diagnosis. Bone biopsy
is not usually required but may help to exclude osteosclerotic
metastases in cases of diagnostic uncertainty.
Management
The main indication for treatment with inhibitors of bone resorption
is bone pain, which is thought to be due to increased metabolic
activity (Box 24.76). Patients should be carefully assessed to
determine the cause of the pain since it can be difficult to
differentiate the pain caused by increased metabolic activity of
PDB from that caused by complications such as bone deformity,
nerve compression symptoms and OA. The bisphosphonates
pamidronate, risedronate and zoledronic acid are highly effective at
suppressing the elevations in bone turnover that are characteristic
of PDB and also improve bone pain that is caused by increased
metabolic activity. If there is doubt about whether the pain is
due to PDB, it can be worthwhile giving a therapeutic trial of
bisphosphonate to determine whether the symptoms improve. A
positive response indicates that the pain was due to increased
metabolic activity. There is no evidence as yet to suggest that
bisphosphonates prevent the development of complications in
PDB. Repeated courses of bisphosphonates can be given if
symptoms recur.
Diseases of bone • 1055
Fig. 24.64 Complex regional pain syndrome (osteodystrophy).
99mTc-labelled bisphosphonate scintigraphy showing increased uptake in
femoral condyle.
Other bone diseases
Ijtomplex regional pain syndrome type 1
Complex regional pain syndrome (CRPS) type 1 is characterised
by gradual onset of pain, swelling and local tenderness, usually
affecting a limb extremity. It may be triggered by fracture but
can also occur in association with soft tissue injury, pregnancy
and intercurrent illness or can develop spontaneously. The
cause is unknown but abnormalities of the sympathetic nervous
system are thought to play a pathogenic role. The affected limb
is swollen and tender, and there may be evidence of regional
autonomic dysfunction, with abnormal sweating and changes in
skin colour and temperature. The diagnosis is primarily clinical,
based on the features shown in Box 34.12 (p. 1349). Support
for the diagnosis can be obtained with MRI, which shows bone
marrow oedema, or radionuclide bone scan, which shows a
local increase in tracer uptake (Fig. 24.64). X-rays show localised
osteoporosis. Haematology, biochemistry and immunology
are normal.
The aims of treatment are to control pain and encourage
mobilisation. Analgesics, NSAIDs, antineuropathic agents,
calcitonin, glucocorticoids, (3-adrenoceptor antagonists
((3-blockers), sympathectomy and bisphosphonates have all
been tried but none is particularly effective. Although some cases
resolve with time, many individuals have persistent symptoms
and fail to regain normal function.
Osteonecrosis
Osteonecrosis describes death of bone due to impairment of its
blood supply. The most commonly affected sites are the femoral
head, humeral head and femoral condyles. In some cases, the
condition occurs as the result of direct trauma that interrupts
the blood supply to the affected bone. This is the reason for
osteonecrosis of the femoral head in patients with subtrochanteric
fractures of the femoral neck, and in patients with thrombophilia
and haemoglobinopathies, such as sickle cell disease. Other
important predisposing factors include high-dose glucocorticoid
treatment, alcohol excess, SLE, HIV and radiotherapy, but in many
of these conditions the pathophysiology is poorly understood. The
presentation is with pain localised to the affected site, which is
exacerbated by weight-bearing. The diagnosis can be confirmed
by MRI, which shows evidence of subchondral necrotic bone
and bone marrow oedema. X-rays are normal in the early stages
but later may show evidence of osteosclerosis and deformity of
the affected bone. There is no specific treatment. Management
should focus on controlling pain and encouraging mobilisation
(p. 1000). Symptoms often improve spontaneously with time
but joint replacement may be required in patients who have
persisting pain in association with significant structural damage
to the affected joint.
Scheuermann’s osteochondritis
This disorder predominantly affects adolescent boys, who develop
a dorsal kyphosis in association with irregular radiographic
ossification of the vertebral end plates. It has a strong genetic
component and may be inherited in an autosomal dominant
manner. Most patients are asymptomatic but back pain,
aggravated by exercise and relieved by rest, may occur. Excessive
exercise and heavy manual labour before epiphyseal fusion has
occurred may aggravate symptoms. Management consists of
advice to avoid excessive activity and provision of protective
postural exercises. Rarely, corrective surgery may be required if
there is severe deformity. Scheuermann’s disease can sometimes
present for the first time in adulthood, when it can be confused
with osteoporotic vertebral fractures. It can be differentiated from
osteoporosis by the characteristic X-ray changes, which show
mild wedge deformity of 3-4 adjacent vertebrae, irregularity of
the vertebral end plates, and normal BMD on DXA examination.
Polyostotic fibrous dysplasia
This is an acquired systemic disorder that mainly affects the
skeleton and is caused by somatic mutations in the GNAS1
gene. The characteristic presentation is with bone pain and
pathological fractures. Associated features include endocrine
dysfunction, especially precocious puberty, and cafe-au-lait skin
pigmentation (McCune-Albright syndrome). The diagnosis can
usually be made by imaging, which shows focal, predominantly
osteolytic lesions with bone expansion on X-rays (Fig. 24.65),
and focal increased uptake on bone scan. The condition can
resemble Paget’s disease of bone but the earlier age of onset
and pattern of involvement are usually distinctive. Very rarely,
malignant change can occur and should be suspected if there
is a sudden increase in pain and swelling. Management is
symptomatic. Intravenous bisphosphonates are often used in
an attempt to control pain but the evidence base for their use
is weak. Orthopaedic surgery may be required for treatment
of fracture and deformity. Endocrine manifestations, such as
precocious puberty (p. 654), may require specific treatment.
Osteogenesis imperfecta
Osteogenesis imperfecta (01) is the name given to a group of
disorders characterised by severe osteoporosis and multiple
fractures in infancy and childhood. Most cases are caused by
mutations in the COL1A1 and COL1A2 genes, which encode
the proteins that make type I collagen. These result in reduced
collagen production (in mild 01) or in formation of abnormal
collagen chains that are rapidly degraded (in severe 01). Mutations
1056 • RHEUMATOLOGY AND BONE DISEASE
Fig. 24.65 McCune-Albright syndrome. X-ray of tibia in a patient with
McCune-Albright syndrome showing expansile osteolytic lesion.
in several other genes have been described that can cause 01,
some of which affect post-translational modification of collagen
and others that affect bone formation. Many patients have no
family history. Some of these have new mutations whereas
others may have recessive forms of the disease. The Sillence
classification is commonly used to grade severity. This varies
from neonatal lethal 01 (type II), through very severe 01 with
multiple fractures in infancy and childhood (types III and IV), to
mild (type I), in which affected patients typically have blue sclerae.
The diagnosis of 01 is usually obvious clinically, based on the
presentation with multiple low-trauma fractures during infancy. The
disease can be mistaken for non-accidental injury in childhood
and for osteoporosis in adulthood; in such cases, genetic testing
can be of diagnostic value. Treatment is multidisciplinary, involving
surgical reduction and fixation of fractures and correction of limb
deformities, and physiotherapy and occupational therapy for
rehabilitation of patients with bone deformity. Bisphosphonates
are widely used in the treatment of 01, especially intravenous
pamidronate in children, but there is limited evidence for efficacy
in fracture prevention.
Osteopetrosis
Osteopetrosis is a rare group of inherited diseases caused by
failure of osteoclast function. Presentation is highly variable,
ranging from a lethal disorder that presents with bone marrow
failure in infancy to a milder and sometimes asymptomatic form
that presents in adulthood. Severe osteopetrosis is inherited in an
autosomal recessive manner and presents with failure to thrive,
delayed dentition, cranial nerve palsies (due to absent cranial
foramina), blindness, anaemia and recurrent infections due to
bone marrow failure. The adult-onset type (Albers-Schonberg
disease) shows autosomal dominant inheritance and presents
with bone pain, cranial nerve palsies, osteomyelitis, OA or
fracture, or is sometimes detected as an incidental radiographic
finding. The responsible mutations affect either the genes that
regulate osteoclast differentiation (RANK, RANKL), causing
‘osteoclast-poor’ osteopetrosis, or the genes involved in bone
resorption, causing ‘osteoclast-rich’ osteopetrosis. These include
mutations in the TCIRG1 gene, which encodes a component of
the osteoclast proton pump, and mutations in the CLCN7 gene,
which encodes the osteoclast chloride pump. Management is
difficult. I FN-y treatment can improve blood counts and reduce
frequency of infections, but in severe cases haematopoietic stem
cell transplantation is required to provide a source of osteoclasts
that resorb bone normally.
Sclerosing bone dysplasias
These are rare diseases characterised by osteosclerosis
and increased bone formation. Van Buchem’s disease and
sclerosteosis are recessive disorders caused by loss-of-fu notion
mutations in the SOST gene, which normally suppresses bone
formation (see Fig. 24.3, p. 986). The resulting lack of sclerostin
causes increased bone formation and bone overgrowth, leading
to enlargement of the cranium and jaw, tall stature and cranial
nerve palsies. There is no effective treatment. High bone mass
syndrome is a benign disorder caused by mutations in the LRP4
or LRP5 gene, which is characterised by unusually high bone
density. The mutations render the LRP receptors resistant to the
inhibitory effects of SOST. Most patients are asymptomatic but
bone overgrowth in the palate (torus palatinus) and enlargement
of the mandible can occur in later life. Treatment is not usually
required. Camurati-Engelmann disease is an autosomal dominant
condition caused by gain of function in the TGFB1 gene. It
presents with bone pain, muscle weakness and osteosclerosis
mainly affecting the diaphysis of long bones. Glucocorticoids can
help the bone pain, although usually analgesics are also required.
Bone and joint tumours
Primary tumours of bones and joints are rare, have a peak
incidence in childhood and adolescence, and can be benign or
malignant (Box 24.77). Paget’s disease of bone (p. 1 053) accounts
for most cases of osteosarcoma occurring above the age of 40.
Osteosarcoma
This is a rare tumour with an incidence of 0.6-0.85 per 1 00 000
population. It is the most common primary bone tumour. Most
24.77 Primary tumours of the musculoskeletal
system
Cell type
Benign
Malignant
Osteoblast
Osteoid osteoma
Osteosarcoma
Chondrocyte
Chondroma
Osteochondroma
Chondrosarcoma
Fibroblast
Fibroma
Fibrosarcoma
Bone marrow cell
Eosinophilic granuloma
Ewing’s sarcoma
Endothelial cell
Flaemangioma
Angiosarcoma
Osteoclast precursor
Giant cell tumour
Malignant giant
cell tumour
Rheumatological involvement in other diseases • 1057
patients present under the age of 30 but osteosarcoma also
occurs in the elderly in association with Paget’s disease. The
presentation is with local pain and swelling. X-rays show expansion
of the bone with a surrounding soft tissue mass, often containing
islands of calcification. If the diagnosis is being considered,
MRI or CT should be performed to determine the extent of
tumour. Patients suspected of having osteosarcoma should
be referred to a specialist team for biopsy. Treatment depends
on histological type but generally involves surgical removal of
the tumour, followed by chemotherapy and radiotherapy. The
prognosis is normally good in cases that present in childhood
and adolescence, but poor in elderly patients with osteosarcoma
related to Paget’s disease of bone.
Chondrosarcoma
This is the second most common primary bone tumour.
Presentation is as described for osteosarcoma. The treatment
of choice is surgical resection since chondrosarcomas are
relatively resistant to chemotherapy and radiotherapy. The
prognosis is good for low-grade tumours but poor for anaplastic
tumours.
Ewing’s sarcoma
This is the third most common sarcoma, which presents almost
exclusively under the age of 40. Presentation is as described
for osteosarcoma. Treatment is by local excision and surgical
resection. The prognosis is excellent for patients who present
before metastasis has occurred.
| Metastatic bone disease
Metastatic bone disease may present in a variety of ways: with
localised or generalised progressive bone pain, generalised
regional pain, symptoms of spinal cord compression, or acute
pain due to pathological fracture. Systemic features, such as
weight loss and anorexia, and symptoms referable to the primary
tumour are often present. The tumours that most commonly
metastasise to bone are myeloma and those of bronchus,
breast, prostate, kidney and thyroid. Management is discussed
in Chapter 33.
Rheumatological involvement
in other diseases
Many systemic diseases can affect the locomotor system, and
many drugs may cause adverse locomotor effects (Box 24.78).
The most common examples are described here. Bone disease
in sarcoidosis is described on page 608, haemophilia on page
972 and sickle-cell anaemia on page 952.
| Malignant disease
Malignant disease can cause a variety of non-metastatic
musculoskeletal problems (Box 24.79). One of the most striking is
hypertrophic pulmonary osteoarthropathy (HPOA), characterised
by clubbing and painful swelling of the limbs, periosteal new bone
formation and arthralgia/arthritis. The most common causes
are bronchial carcinoma and mesothelioma (pp. 598 and 618).
Bone scans show increased periosteal uptake before new bone
is apparent on X-ray. The course follows that of the underlying
malignancy and HPOA resolves if this is cured.
^9 24.78 Drug-induced effects on the
musculoskeletal system
Musculoskeletal problem
Principal drug
Secondary gout
Thiazides, furosemide, alcohol
Osteoporosis
Glucocorticoids, heparin, glitazones,
aromatase inhibitors, GnRH agonists
Osteomalacia
Anticonvulsants, etidronate and
pamidronate (high-dose)
Osteonecrosis
Glucocorticoids, alcohol
Drug-induced lupus
syndrome
Procainamide, hydralazine, isoniazid,
chlorpromazine
Arthralgias, arthritis
Glucocorticoid withdrawal,
glibenclamide, methyldopa, ciclosporin,
isoniazid, barbiturates
Myalgia
Glucocorticoid withdrawal, L-tryptophan,
fibrates, statins
Myopathy
Glucocorticoids, chloroquine
Myositis, myasthenia
Penicillamine, statins
Cramps
Glucocorticoids, ACTH, diuretics,
carbenoxolone
Vasculitis
Amphetamines, thiazides
(ACTH = adrenocorticotropic hormone; GnRH = gonadotrophin-releasing
hormone)
i
• Polyarthritis
• Dermatomyositis and polymyositis
• Hypophosphataemic osteomalacia
• Hypertrophic osteoarthropathy
• Vasculitis, connective tissue disease
• Raynaud’s syndrome
• Polymyalgia rheumatica-like syndrome
^Endocrine disease
Hypothyroidism (p. 639) may present with carpal tunnel syndrome
or, rarely, with painful, symmetrical proximal myopathy and muscle
hypertrophy. Both resolve with levothyroxine replacement. Primary
hyperparathyroidism (p. 663) is associated with osteoporosis and
also predisposes to calcium pyrophosphate dihydrate deposition
disease and to calcific periarthritis, especially in patients with
renal disease.
Diabetes mellitus (Ch. 20) commonly causes diabetic
cheiroarthropathy, characterised by tightening of skin and
periarticular structures, causing flexion deformities of the fingers
that may be painful. Diabetic osteopathy presents as forefoot
pain with radiographic progression from osteopenia to complete
osteolysis of the phalanges and metatarsals. Diabetes also
predisposes to osteoporosis, fragility fractures, adhesive capsulitis,
Dupuytren’s contracture, septic arthritis and Charcot’s joints.
Acromegaly (p. 685) can be associated with mechanical
back pain, with normal or excessive movement; carpal tunnel
syndrome; and Raynaud’s syndrome and an arthropathy (50%).
The arthropathy mainly affects the large joints and has clinical
similarities to OA but with a normal or increased range of
movement. X-rays may show widening of joint spaces, squaring
of bone ends, generalised osteopenia and tufting of terminal
phalanges. It does not improve with treatment of the acromegaly.
24.79 Rheumatological manifestations of malignancy
1058 • RHEUMATOLOGY AND BONE DISEASE
Haematological disease
Haemochromatosis (p. 895) is complicated by an arthropathy in
about 50% of cases. It typically presents between the ages of 40
and 50, and may predate other features of the disease. The small
joints of the hands and wrists are typically affected but the hips,
shoulders and knees may also be involved. The X-ray changes
resemble OA but cysts are often multiple and prominent, with little
osteophyte formation. Involvement of the radiocarpal and MCP
joints may occur, which is unusual in primary OA, and about 30%
have calcium pyrophosphate dihydrate deposition disease and/
or pseudogout. Treatment of the haemochromatosis does not
influence the arthropathy, and management is as described for
OA. Haemophilia (p. 972) can be complicated by haemarthrosis,
which, if recurrent, can result in the development of secondary
OA. Sickle-cell disease (p. 952) may be associated with bone
pain, osteonecrosis and osteomyelitis. Thalassaemia (p. 953)
may be complicated by bone deformity, especially affecting the
craniofacial bones, and by osteoporosis.
Neurological disease
Neurological disease may result in rapidly destructive arthritis
of joints, first described by Charcot in association with syphilis.
The cause is incompletely understood but may involve repetitive
trauma as the result of sensory loss and altered blood flow
secondary to impaired sympathetic nervous system control.
The main predisposing diseases and sites of involvement are:
• diabetic neuropathy (hindfoot)
• syringomyelia (shoulder, elbow, wrist)
• leprosy (hands, feet)
• tabes dorsalis (knees, spine).
The presentation is with subacute or chronic monoarthritis.
Pain can occur, especially at the onset, but once the joint is
severely deranged, pain is often minimal and signs become
disproportionately greater than symptoms. The joint is often
grossly swollen, with effusion, crepitus, marked instability
and deformity, but usually no increased warmth. X-rays show
disorganisation of normal joint architecture and often multiple
loose bodies (Fig. 24.66), and either no (atrophic) or gross
Fig. 24.66 Wrist X-ray showing a neuropathic (Charcot) joint in a
patient with syringomyelia. Note the disorganised architecture with
complete loss of the proximal carpal row, bony fragments and soft tissue
swelling.
(hypertrophic) new bone formation. Management principally
involves orthoses and occasionally arthrodesis.
Miscellaneous conditions
Anterior tibial compartment syndrome
This is characterised by severe pain in the front of the lower leg,
aggravated by exercise and relieved by rest. Symptoms result
from fascial compression of the muscles in the anterior tibial
compartment and may be associated with foot drop. Treatment
is by surgical decompression.
Carpal tunnel syndrome
This is a common nerve entrapment syndrome caused by
compression of the median nerve at the wrist. It presents with
numbness, tingling and pain in a median nerve distribution (p.
1139). The most common causes are hypothyroidism, diabetes
mellitus, RA, obesity and pregnancy, especially in the third
trimester. In some patients, no underlying cause may be identified.
Carpal tunnel syndrome often responds to treatment of the
underlying condition but other options include local glucocorticoid
injections and surgical decompression.
Diffuse idiopathic skeletal hyperostosis
Diffuse idiopathic skeletal hyperostosis (DISH) is a common
disorder, affecting 10% of men and 8% of women over the
age of 65, and is associated with obesity, hypertension and
type 2 diabetes mellitus. It is characterised by florid new bone
formation along the anterolateral aspect of at least four contiguous
vertebral bodies (Fig. 24.67). DISH is distinguished from lumbar
spondylosis by the absence of disc space narrowing and marginal
vertebral body sclerosis, and from ankylosing spondylitis by the
absence of sacroiliitis or apophyseal joint fusion. It is usually an
Fig. 24.67 Diffuse idiopathic skeletal hyperostosis (DISH).
Anteroposterior X-ray of the thoracic spine showing right-sided, flowing
new bone joining more than four contiguous vertebrae. The disc spaces
are preserved.
Miscellaneous conditions • 1059
asymptomatic radiographic finding but can cause back pain or
pain at peripheral sites, such as the heel, in association with
calcaneal spur formation.
|j)upuytren’s contracture
Dupuytren’s contracture results from fibrosis and contracture of
the superficial palmar fascia of the hands. The patient is unable
to extend the fingers fully and there is puckering of the skin with
palpable nodules. The ring and little fingers are usually the first
and worst affected. Dupuytren’s contracture is usually painless but
causes problems due to limitation of hand function and snagging
of the curled fingers in pockets. It is age-related, usually bilateral
and more common in men. There is a strong genetic component
and sometimes may be familial, with dominant inheritance. The
condition can be associated with plantar fibromatosis, Peyronie’s
disease, alcohol misuse and chronic vibration injury. It is very
slowly progressive. Often no treatment is required but it can be
treated medically by local injections of collagenase or surgically
by fasciotomy if symptoms are troublesome.
Hypermobility syndromes
Hypermobility is characterised by increased joint laxity and joint
pain. Causes include Marfan’s syndrome, resulting from mutations
in the FBN1 gene (p. 508); osteogenesis imperfecta (p. 1055); and
Ehlers-Danlos syndrome types 1,11 and IV, caused by mutations
in the COL3A1 , COL5A1 and COL5A2 genes (p. 970).
The term hypermobile Ehlers-Danlos syndrome (hEDS), which is
also known as EDS type III, is used to describe a polygenic form of
hypermobility. Many patients with this condition have hypermobile
joints but do not have symptoms, whereas in others a range of
symptoms can occur, including chronic joint and ligamentous pain,
fibromyalgia-like symptoms, recurrent dislocations, easy bruising,
abdominal symptoms, mitral valve prolapse (p. 520) and postural
tachycardia syndrome, in which there is dizziness, hypotension
and an increased heart rate on standing. The diagnosis of EDS
type III is clinical and can be made when the modified Beighton
score is 4 or above in the presence of arthralgia in four or more
joints (Box 24.80). There is no specific treatment, apart from the
general principles listed on page 1 000, but some patients become
very disabled as the result of their symptoms and are difficult
to manage.
| Inclusion body myositis
Inclusion body myositis is the most frequent primary myopathy
in middle age and after. It is characterised by slowly progressive
i
24.80 Modified Beighton score for joint hypermobility
Clinical test
Score
Extend little finger >90°
1 point each side
Bring thumb back parallel to/touching forearm
1 point each side
Extend elbow >10°
1 point each side
Extend knee > 1 0°
1 point each side
Touch floor with flat of hands, legs straight
1 point
Hypermobile = a score of 6 or more points out of a possible 9
for epidemiological studies, or 4 or more points (with arthralgia in
four or more joints) for a clinical diagnosis of the benign
joint hypermobility syndrome
muscle weakness and atrophy, with pathological changes of
inflammation, degeneration and mitochondrial abnormality
in affected muscle fibres. Inclusion body myositis typically
presents with distal muscle weakness. In time, muscles atrophy.
Investigation is the same as for polymyositis (p. 1039). There is
typically a slightly elevated creatine kinase and myopathic changes
on EMG. Muscle biopsy shows abnormal fibres containing
rimmed vacuoles and filamentous inclusions in the nucleus
and cytoplasm. Therapeutic response to glucocorticoids and
immunosuppressants is notably poor. There is anecdotal report
of efficacy with IVIg but trial evidence is lacking.
Periodic fever syndromes
These are a group of rare inherited disorders that present with
intermittent attacks of fever, rash, arthralgia and myalgia. They
are discussed in more detail on page 81 .
Pigmented villonodular synovitis
Pigmented villonodular synovitis is an uncommon proliferative
disorder of synovium, which typically affects young adults. It
is caused by a somatic chromosomal translocation in synovial
cells that places the CSF1 gene downstream of the COL6A3
gene promoter. The result is local over-production of M-CSF,
which causes accumulation of macrophages in the joint. The
presentation is with joint swelling, limitation of movement
and local discomfort. The diagnosis can be confirmed by
MRI or synovial biopsy. Treatment is by surgical or radiation
synovectomy.
| Scoliosis
Scoliosis is characterised by an abnormal lateral curvature of the
spine of greater than 10°. It typically presents during childhood or
adolescence but usually persists into adulthood, when it can be
associated with back pain, deformity and secondary OA. In about
20% of cases, scoliosis is secondary to a neuromuscular disorder,
such as muscular dystrophy, cerebral palsy or neurofibromatosis.
It may also occur in association with connective tissue disorders,
such as Marfan’s syndrome. The term idiopathic scoliosis is used
to described the remaining cases where there is no obvious
cause. In fact, there is strong evidence from twin studies that
idiopathic scoliosis is genetically mediated. The diagnosis can
usually be made clinically by physical examination, which shows
the characteristic spinal deformity. Spinal X-rays can be used to
confirm the diagnosis and assess severity. External bracing and/
or surgical intervention are often performed in adolescents with
severe deformities to correct deformity or prevent progression
but the evidence base is poor. In adulthood, treatment is
symptomatic in nature with analgesics, NSAID or antineuropathic
medications.
Spondylolysis
Spondylolysis describes a break in the integrity of the neural arch.
The principal cause is an acquired defect in the pars interarticularis
due to a fracture, mainly seen in gymnasts, dancers and runners,
in whom it is an important cause of back pain. Spondylolisthesis
describes the condition in which a defect causes slippage of a
vertebra on the one below. This may be congenital, post-traumatic
or degenerative. Rarely, it can result from metastatic destruction
of the posterior elements. Uncomplicated spondylolysis does not
cause symptoms but spondylolisthesis can lead to low back pain
1060 • RHEUMATOLOGY AND BONE DISEASE
aggravated by standing and walking. Occasionally, symptoms of
nerve root or spinal compression may occur. The diagnosis can
be made on lateral X-rays of the lumbar spine but MRI may be
required if there is neurological involvement. Advice on posture
and muscle-strengthening exercises is required in mild cases.
Surgical fusion is indicated for severe and recurrent low back
pain. Surgical decompression is mandatory prior to fusion in
patients with significant lumbar stenosis or symptoms of cauda
equina compression.
ISynovitis-acne-pustulosis-hyperostosis-
osteitis syndrome
The synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO)
syndrome is a disorder characterised by bone pain and swelling
due to a sterile osteomyelitis and hyperostosis predominantly
targeting the clavicles and bones of the anterior chest wall. SAPHO
syndrome is thought to be part of a spectrum of autoinflammatory
bone diseases that includes chronic recurrent (sterile) multifocal
osteomyelitis in children and adolescents. Other features include
a pustulotic rash affecting the palms and soles of the feet,
sacroiliitis and synovitis of peripheral joints. It most commonly
presents in children and young or middle-aged adults. Various
treatments have been used, including glucocorticoids, DMARDs,
bisphosphonates, anakinra and TNF blockers, with most success
arising from biologic use. The cause is unknown but has been
suggested to be an autoimmune process triggered by a bacterial
or viral pathogen.
| Trigger finger
This occurs as the result of stenosing tenosynovitis in the
flexor tendon sheath, with intermittent locking of the finger
in flexion. It can arise spontaneously or in association with
inflammatory diseases such as RA. Symptoms usually respond
to local glucocorticoid injections but surgical decompression is
occasionally required.
Further information
Journal articles
Campion EW. Calcium pyrophosphate deposition disease. N Engl J
Med 2016; 374:2575-2578.
Compston J. Osteoporosis: advances in risk assessment and
management. Clin Med (Lond) 2016; 16(Suppl 6): si 21 -si 24.
Gossec L, Smolen JS, Ramiro S, et al. European League Against
Rheumatism (EULAR) recommendations for the management of
psoriatic arthritis with pharmacological therapies: 201 5 update. Ann
Rheum Dis 2016; 75:499-510.
Mukhtyar C, Flossman O, Hellmich B, et al. Outcomes from studies of
antineutrophil cytoplasm antibody associated vasculitis: a systematic
review by the European League Against Rheumatism systemic
vasculitis task force. Ann Rheum Dis 2008; 67:1004-1010.
Ralston SH. Paget’s disease of bone. N Engl J Med 2013; 368:644-650.
Scott DL, Woolf F, Huizinga TW. Rheumatoid arthritis. Lancet 201 0;
376:1094-1108.
Taurog JD, Avneesh C, Colbert RA. Ankylosing spondylitis and axial
spondyloarthritis. N Engl J Med 2016; 374:2563-2567.
Teng MWL, Bowman EP, McElwee JJ, et al. IL-12 and IL-23
cytokines: from discovery to targeted therapies for immune-
mediated inflammatory diseases. Nat Med 2015; 21:719-729.
Zhang W, Doherty M, Bardin T, et al. EULAR recommendations for
gout. Part II: Management. Ann Rheum Dis 2006; 65:1312-1324.
Websites
4s-dawn.com/DAS28 Calculator for this measure of activity in
rheumatoid arthritis.
asas-group.org Repository of resources to aid assessment of
spondyloarthritis.
basdai.com/BASDAI.php BASDAI calculator for assessing ankylosing
spondylitis.
omim.org Online Mendelian Inheritance in Man (OMIM): genetic
diseases.
shef.ac.uk/FRAX/ and qfracture.org/ Fracture risk assessment tools.
sign.ac.uk Scottish Intercollegiate Guidelines Network 142 -
Management of osteoporosis and the prevention of fragility fractures.
thefreelibrary.com Information on drug-induced myopathies.
vasculitis.org/ Vasculitis resources from the European Vasculitis
Society.
JP Leach
RJ Davenport
Neurology
Clinical examination of the nervous system 1062
Infections of the nervous system 1117
Functional anatomy and physiology 1 064
Functional anatomy of the nervous system 1 065
Localising lesions in the central nervous system 1071
Investigation of neurological disease 1072
Neuroimaging 1072
Neurophysiological testing 1 074
Presenting problems in neurological disease 1078
Headache and facial pain 1 080
Dizziness, blackouts and ‘funny turns’ 1080
Status epilepticus 1080
Coma 1 080
Delirium 1080
Amnesia 1080
Meningitis 1118
Parenchymal viral infections 1 1 21
Parenchymal bacterial infections 1 1 24
Diseases caused by bacterial toxins 1 1 25
Prion diseases 1 1 26
Intracranial mass lesions and raised intracranial pressure 1127
Raised intracranial pressure 1 1 27
Brain tumours 1 1 29
Paraneoplastic neurological disease 1 1 32
Hydrocephalus 1 1 32
Idiopathic intracranial hypertension 1 1 33
Head injury 1 1 33
Disorders of cerebellar function 1134
Weakness 1 081
Disorders of the spine and spinal cord 1134
Sensory disturbance 1 083
Cervical spondylosis 1 1 34
Abnormal movements 1 084
Lumbar spondylosis 1 1 35
Abnormal perception 1 086
Spinal cord compression 1 1 36
Altered balance and vertigo 1 086
Intrinsic diseases of the spinal cord 1 1 37
Abnormal gait 1 086
Abnormal speech and language 1 087
Disturbance of smell 1 088
Visual disturbance and ocular abnormalities 1088
Hearing disturbance 1 093
Bulbar symptoms - dysphagia and dysarthria 1093
Bladder, bowel and sexual disturbance 1093
Personality change 1094
Sleep disturbance 1 094
Psychiatric disorders 1 094
Diseases of peripheral nerves 1138
Entrapment neuropathy 1 1 39
Multifocal neuropathy 1 1 40
Polyneuropathy 1 1 40
Guillain— Barre syndrome 1 1 40
Chronic polyneuropathy 1140
Brachial plexopathy 1 1 41
Lumbosacral plexopathy 1 1 41
Spinal root lesions 1 1 41
Diseases of the neuromuscular junction 1141
Functional symptoms 1094
Headache syndromes 1095
Myasthenia gravis 1 1 41
Lambert-Eaton myasthenic syndrome 1143
Epilepsy 1097
Diseases of muscle 1143
Vestibular disorders 1104
Disorders of sleep 1105
Excessive daytime sleepiness (hypersomnolence) 1 1 05
Parasomnias 1105
Muscular dystrophies 1 1 43
Inherited metabolic myopathies 1144
Acquired myopathies 1144
Neuro-inflammatory diseases 1106
Paraneoplastic neurological disorders 1110
Neurodegenerative diseases 1111
Movement disorders 1112
Ataxias 1115
Tremor disorders 1115
Dystonia 1116
Hemifacial spasm 1116
Motor neuron disease 1116
Spinal muscular atrophy 1117
1062 • NEUROLOGY
Clinical examination of the nervous system
4 Cranial nerves
5 Optic fundi
Papilloedema
Optic atrophy
Cupping of disc
(glaucoma)
Hypertensive changes
Signs of diabetes
A Right 12th nerve palsy:
wasting of right side of tongue
A 7th nerve palsy: drooping
mouth and flattening of
nasolabial skin fold
A 3rd nerve palsy: one eye
points ‘down and out’
3 Neck and skull
Skull size and shape
Neck stiffness and Kernig’s test
Carotid bruit
0
2 Back
Scoliosis
Operative scars
Evidence of spina bifida occulta
Winging of scapula
A Winging of right scapula
(muscular dystrophy)
1 Stance and gait
Posture
Romberg’s test
Arm swing
Pattern of gait
Tandem (heel-toe) gait
Observation/general
• General appearance
• Mood (e.g. anxious, depressed)
• Facial expression (or lack thereof)
• Handedness
• Nutritional status
• Blood pressure
AHaemorrhagic papilloedema
6 Motor
Wasting, fasciculation
Abnormal posture
Abnormal movements
Tone (including clonus)
Strength
Coordination
Tendon reflexes
Abdominal reflexes
Plantar reflexes
Awasting of right thenar
eminence due to cervical rib
7
8
7 Sensory
Pin-prick, temperature
Joint position, vibration
Two-point discrimination
8 Higher cerebral function
Orientation
Memory
Speech and language
Localised cortical functions
Insets (winging of scapula, 12th nerve palsy, wasting of thenar eminence) Courtesy of Dr R.E. Cull, Western General Hospital, Edinburgh.
Clinical examination of the nervous system • 1063
i Examination of gait and posture
Procedure
Abnormality
Disease
Rising from
Difficulty rising
Proximal muscle weakness
chair
or joint disorders
Gait initiation
Difficulty starting to walk,
Cerebrovascular disease or
frozen
parkinsonism
Posture
Stooped
Parkinsonism
Retropulsion/
anteropulsion
Postural instability
Parkinsonism
Arms during
Reduced arm swing
Parkinsonism or upper motor
walking
neuron lesion
Enhanced tremor
Parkinsonism
Dystonic posturing
Dystonia
Gait pattern
Circumduction (stiff leg moves
Hemiparesis, typically after
outwards in ‘circular’ manner)
stroke
‘Slapping’, high-stepping due
L5 radiculopathy or common
to foot drop
peroneal nerve lesion
Narrow-based, short strides,
freezing in doorways
Parkinsonism
Stiff-legged, scissors gait
Spastic paraparesis (multiple
sclerosis, vascular disease,
spinal cord lesions)
Wide-based, unsteady, unable
to perform tandem gait
Cerebellar lesion
Waddling gait
Myopathies with proximal
weakness
4 Examination of cranial nerves
Nerve
Name
Tests
1
Olfactory
Ask patient about sense of smell (examine only if
change is reported)
II
Optic
Visual acuity and colour vision
Visual fields
Pupillary responses
Ophthalmoscopy
III
Oculomotor
Eyelids (ptosis)
Pupil size, symmetry, reactions
Eye movements
IV
Trochlear
Eye movements (superior oblique muscle)
V
Trigeminal
Facial sensation
Corneal reflex
Muscles of mastication
VI
Abducens
Eye movements (lateral rectus muscle)
VII
Facial
Facial symmetry and movements
VIII
Vestibulocochlear
Otoscopy
Hearing
Tuning fork tests (Rinne and Weber)
IX
Glossopharyngeal
Swallowing
X
Vagus
Palatal elevation (uvula deviates to side opposite
lesion)
Swallowing
Cough (bovine)
Speech
XI
Accessory
Look for wasting of trapezius/sternocleidomastoid
Elevation of shoulders
Turning head to right and left
XII
Hypoglossal
Look for wasting/fasciculation
Tongue protrusion (deviates to side of lesion)
6 Root values of tendon reflexes
Reflex
Root value
Arm
Biceps jerk
C5
Supinator jerk
C6
Triceps jerk
C7
Finger jerk
C8
Leg
Knee jerk
L3/L4
Ankle jerk
SI
Motor
Motor cortex
(pre-central gyrus)
Sensory
ongue
Somatic cortex
(post-central gyrus)
Motor and sensory homunculi. The motor and sensory
homunculi illustrate the cortical areas serving each anatomical
area within the pre-central (motor) and post-central (sensory) gyri.
1064 • NEUROLOGY
The complexity of the brain differentiates us from other species,
and its interactions with the spinal cord and peripheral nerves
combine to allow us to perceive and react to the external world
while maintaining a stable internal environment. The cerebral
cortex provides a platform for processing information and forming
a response, and in doing so, both forms and is affected by our
personality and mental state.
Neurology has for too long been misperceived as a specialty in
which intricate clinical examination and numerous investigations
are required to diagnose obscure and untreatable conditions.
In fact, nervous system disorders are common, accounting for
around 10% of the UK’s general practice consultations, 20% of
acute medical admissions, and most chronic physical disability.
The development of specific, effective treatments has made
accurate diagnosis essential. Neurological management requires
knowledge of a range of common conditions, which can then
be applied to individual patients after careful history-taking,
with lesser contributions arising from targeted examination and
considered investigation.
Pathological and anatomical localisation of symptoms and
signs is important, but skill can be required to identify those
not associated with neurological disease, differentiating patients
requiring investigation and treatment from those who need
reassurance.
Initially, it is important to exclude conditions that constitute
neurological emergencies (Box 25.1). If the presentation is not
an emergency, time can be taken to reach a diagnosis. The
history should provide a hypothesis for the site and nature of the
potential pathology, which a focused examination may refine, and
direct appropriate further investigations. An informed discussion
with the patient and family regarding diagnosis, management
and prognosis may then take place.
As stroke has become a specific subspecialty in many centres,
it is described in a separate chapter, although it is clearly a
neurological condition. This chapter should be read with it, to
help clarify how the presentation, diagnosis and management
of stroke present their own challenges.
Functional anatomy and physiology
Cells of the nervous system
The nervous system comprises billions of specialised cells, forming
a spectacular network of connections, each human brain having
almost as many connections as there are grains of sand in the
whole world. In addition to neurons, there are three types of
glial cells. Astrocytes form the structural framework for neurons
25.1 Neurological emergencies
• Status epilepticus (p. 1080)
• Stroke (if thrombolysis available) (p. 1 1 58)
• Guillain— Barre syndrome (p. 1140)
• Myasthenia gravis (if bulbar and/or respiratory) (p. 1141)
• Spinal cord compression (p. 1136)
• Subarachnoid haemorrhage (p. 1160)
• Neuroleptic malignant syndrome (p. 1197)
Ependymal cell Oligodendrocyte
Astrocyte
Astrocyte foot processes
surround the brain capillary
Synapse (site of blood-brain barrier)
CSF
Neuron
Sensory cell
Spinal cord body in dorsal
grey matter root ganglion
Motor neuron
cell body in
anterior horn
Axon
Capillary
Capillary Tight
endothelial „ , , , , junction
cell Red blood
cell in capillary
Sensory
axon
Motor axon
Vas
nervorum
Node of Ranvier
Fig. 25.1 Cells of the nervous system. (CSF = cerebrospinal fluid)
Functional anatomy and physiology • 1065
and control their biochemical environment, their foot processes
adjoining small blood vessels and forming the blood-brain barrier
(Fig. 25.1). Oligodendrocytes are responsible for the formation
and maintenance of the myelin sheath, which surrounds axons
and is essential for maintaining the speed and consistency of
action potential propagation along axons. Peripheral nerves have
axons invested in myelin made by oligodendrocytes (Schwann
cells). Microglial cells derive from monocytes/macrophages and
play a role in fighting infection and removing damaged cells.
Ependymal cells line the cerebral ventricles.
I Generation and transmission
of the nervous impulse
The role of the central nervous system (CNS) is to generate
outputs in response to external stimuli and changes in internal
Fig. 25.2 Neurotransmission and neurotransmitters. (1) An action
potential arriving at the nerve terminal depolarises the membrane and
this opens voltage-gated calcium channels. (2) Entry of calcium causes
the fusion of synaptic vesicles containing neurotransmitters with the
pre-synaptic membrane and release of the neurotransmitter across
the synaptic cleft. (3) The neurotransmitter binds to receptors on the
post-synaptic membrane either (A) to open ligand-gated ion channels that,
by allowing ion entry, depolarise the membrane and initiate an action
potential (4), or (B) to bind to metabotropic receptors that activate an
effector enzyme (e.g. adenylyl cyclase) and thus modulate gene
transcription via the intracellular second messenger system, leading to
changes in synthesis of ion channels or modulating enzymes. (5)
Neurotransmitters are taken up at the pre-synaptic membrane and/or
metabolised. (cAMP = cyclic adenosine monophosphate; DNA =
deoxyribonucleic acid; mRNA = messenger ribonucleic acid)
conditions. The CNS has to maintain a delicate balance between
responsivity to external stimuli and remaining stoic enough to
remain stable in a rapidly changing environment. Each neuron
receives input by synaptic transmission from dendrites (branched
projections of other neurons), which sum to produce output in
the form of an action potential that is then conducted along the
axon, resulting in synaptic transmission to other neurons or, in
the motor system, to muscle cells. Summation of the inputs
causes net changes in the target neuron’s electrochemical
gradient, which, if large enough, will trigger an action potential.
Communication between cells is by synaptic transmission that
involves the release of neurotransmitters to interact with structures
on the target cell’s surface, including ion channels and other cell
surface receptors (Fig. 25.2). At least 20 different neurotransmitters
are known to act at different sites in the nervous system,
most of which are potentially amenable to pharmacological
manipulation.
Each neuronal cell body may receive synaptic input from
thousands of other neurons. The synapsing neuron terminals
are also subject to feedback regulation via receptor sites on the
pre-synaptic membrane, modifying the release of transmitter
across the synaptic cleft. In addition to such acute effects, some
neurotransmitters produce long-term modulation of metabolic
function or gene expression. This effect probably underlies more
complex processes such as long-term memory.
Functional anatomy of the nervous system
Major components of the nervous system and their inter¬
relationships are depicted in Figure 25.3.
1066 • NEUROLOGY
Cerebral hemispheres
The cerebral hemispheres coordinate the highest level of nervous
function, the anterior half dealing with executive (‘doing’) functions
and the posterior half constructing a perception of the environment.
Each cerebral hemisphere has four functionally specialised lobes
(Box 25.2 and Fig. 25.4), with some functions being distributed
asymmetrically (‘lateralised’), to produce cerebral dominance for
functions such as motor control, speech or memory. Cerebral
dominance aligns limb dominance with language function: in
right-handed individuals the left hemisphere is almost always
dominant, while around half of left-handers have a dominant
right hemisphere.
Frontal lobes are concerned with executive function, movement,
behaviour and planning. As well as the primary and supplementary
motor cortex, there are specialised areas for control of eye
movements, speech (Broca’s area) and micturition.
The parietal lobes integrate sensory perception. The primary
sensory cortex lies in the post-central gyrus of the parietal lobe.
Much of the remainder is devoted to ‘association’ cortex, which
processes and interprets input from the various sensory modalities.
The supramarginal and angular gyri of the dominant parietal
lobe form part of the language area (p. 1088). Close to these
are regions dealing with numerical function. The non-dominant
parietal lobe is concerned with spatial awareness and orientation.
The temporal lobes contain the primary auditory cortex and
primary vestibular cortex. On the inner medial sides lie the
olfactory and parahippocampal cortices, which are involved in
memory function. The temporal lobes also link intimately to the
limbic system, including the hippocampus and the amygdala,
which are involved in memory and emotional processing. The
dominant temporal lobe also participates in language functions,
particularly verbal comprehension (Wernicke’s area). Musical
processing occurs across both temporal lobes, rhythm on the
dominant side and melody/pitch on the non-dominant.
The occipital lobes are responsible for visual interpretation.
The contralateral visual hemifield is represented in each primary
visual cortex, with surrounding areas processing specific visual
submodalities such as colour, movement or depth, and the
analysis of more complex visual patterns such as faces.
Deep to the grey matter in the cortices, and the white matter
(composed of neuronal axons), are collections of cells known as the
basal ganglia that are concerned with motor control; the thalamus,
which is responsible for the level of attention to sensory perception;
the limbic system, concerned with emotion and memory; and the
hypothalamus, responsible for homeostasis, such as temperature
25.2 Cortical lobar functions
Effects of damage
Lobe
Function
Cognitive/behavioural
Associated physical signs
Positive phenomena
Frontal
Personality
Emotional control
Social behaviour
Contralateral motor control
Language
Micturition
Disinhibition
Lack of initiation
Antisocial behaviour
Impaired memory
Expressive dysphasia
Incontinence
Impaired smell
Contralateral hemiparesis
Frontal release signs1
Seizures - often nocturnal with
motor activity
Versive head movements
Parietal:
dominant
Language
Calculation
Dysphasia
Acalculia
Dyslexia
Apraxia3
Agnosia5
Contralateral hemisensory loss
Astereognosis2
Agraphaesthesia4
Contralateral homonymous
lower quadrantanopia
Asymmetry of optokinetic
nystagmus (OKN)
Focal sensory seizures
Parietal:
non-dominant
Spatial orientation
Constructional skills
Neglect of contralateral side
Spatial disorientation
Constructional apraxia
Dressing apraxia
Contralateral hemisensory loss
Astereognosis2
Agraphaesthesia4
Contralateral homonymous
lower quadrantanopia
Asymmetry of OKN
Focal sensory seizures
Temporal:
dominant
Auditory perception
Language
Verbal memory
Smell
Balance
Receptive aphasia
Dyslexia
Impaired verbal memory
Contralateral homonymous
upper quadrantanopia
Complex hallucinations (smell,
sound, vision, memory)
Temporal:
non-dominant
Auditory perception
Melody/pitch perception
Non-verbal memory
Smell
Balance
Impaired non-verbal memory
Impaired musical skills (tonal
perception)
Contralateral homonymous
upper quadrantanopia
Complex hallucinations (smell,
sound, vision, memory)
Occipital
Visual processing
Visual inattention
Visual loss
Visual agnosia
Homonymous hemianopia
(macular sparing)
Simple visual hallucinations
(e.g. phosphenes, zigzag lines)
^rasp reflex, palmomental response, pout response, inability to determine three-dimensional shape by touch, inability to perform complex movements in the presence of
normal motor, sensory and cerebellar function, inability to ‘read’ numbers or letters drawn on hand, with the eyes shut, inability to recognise familiar objects, e.g. faces.
Functional anatomy and physiology • 1067
Primary motor
cortex
Inferior frontal
gyrus
Superior
temporal gyrus
Central sulcus
Primary sensory
cortex
Supramarginal
gyrus
Angular gyrus
Face
Frontal lobe
Temporal lobe
Parietal lobe
Occipital lobe
Key
Fig. 25.4 Anatomy of the
cerebral cortex.
and appetite control. The cerebral ventricles contain cerebrospinal
fluid (CSF), which cushions the brain during cranial movement.
CSF is formed in the lateral ventricles and protects and
nourishes the CNS. CSF flows from third to fourth ventricles
and through foramina in the brainstem to dissipate over the
surface of the CNS, eventually being reabsorbed into the cerebral
venous system (see Fig. 25.44, p. 1132).
The brainstem
In addition to containing all the sensory and motor pathways
entering and leaving the hemispheres, the brainstem houses the
nuclei and projections of most cranial nerves, as well as other
important collections of neurons in the reticular formation (Fig.
25.5). Cranial nerve nuclei provide motor control to muscles of
the head (including face and eyes) and coordinate sensory input
from the special sense organs and the face, nose, mouth, larynx
and pharynx. They also relay autonomic messages, including
pupillary, salivary and lacrimal functions. The reticular formation
is mainly involved in control of conjugate eye movements, the
maintenance of balance and arousal, and cardiorespiratory control.
| The spinal cord
The spinal cord is the route for virtually all communication between
the extracranial structures and the CNS. Afferent and efferent
fibres are grouped in discrete bundles but collections of cells in
the grey matter are responsible for lower-order motor reflexes
and the primary processing of sensory information.
Reticular
system
Pyramidal
motor tract
Motor
tracts
Sensory
tracts
Fig. 25.5 Anatomy of the brainstem.
25
1068 • NEUROLOGY
Sensory peripheral nervous system
The sensory cell bodies of peripheral nerves are situated just
outside the spinal cord, in the dorsal root ganglia in the spinal
exit foramina, while the distal ends of their neurons utilise various
specialised endings for the conversion of external stimuli into
action potentials. Sensory nerves consist of a combination of
large, fast, myelinated axons (which carry information about joint
position sense and commands to muscles) and smaller, slower,
unmyelinated axons (which carry information about pain and
temperature, as well as autonomic function).
|Motor peripheral nervous system
The anterior horns of the spinal cord comprise cell bodies
of the lower motor neurons. To increase conduction speed,
peripheral motor nerve axons are wrapped in myelin produced
by Schwann cells. Motor neurons release acetylcholine across
the neuromuscular junction, which changes the muscle end-plate
potential and initiates muscle contraction.
| The autonomic system
The autonomic system regulates the cardiovascular and respiratory
systems, the smooth muscle of the gastrointestinal tract, and
many exocrine and endocrine glands throughout the body. The
autonomic system is controlled centrally by diffuse modulatory
systems in the brainstem, limbic system, hypothalamus and
frontal lobes, which are concerned with arousal and background
behavioural responses to threat. Autonomic output divides
functionally and pharmacologically into two divisions: the
parasympathetic and sympathetic systems.
| The motor system
A programme of movement formulated by the pre-motor cortex
is converted into a series of excitatory and inhibitory signals in
the motor cortex that are transmitted to the spinal cord in the
pyramidal tract (Fig. 25.6). This passes through the internal
capsule and the ventral brainstem before crossing (decussating)
in the medulla to enter the lateral columns of the spinal cord.
The pyramidal tract ‘upper motor neurons’ synapse with the
anterior horn cells of the spinal cord grey matter, which form
the lower motor neurons.
Any movement necessitates changes in posture and muscle
tone, sometimes in quite separate muscle groups to those
involved in the actual movement. The motor system consists of a
hierarchy of controls that maintain body posture and muscle tone,
on which any movement is superimposed. In the grey matter of
the spinal cord, the lowest order of the motor hierarchy controls
reflex responses to stretch. Muscle spindles sense lengthening
of the muscle; they provide the afferent side of the stretch
reflex and initiate a monosynaptic reflex leading to protective
or reactive muscle contraction. Inputs from the brainstem are
largely inhibitory. Polysynaptic connections in the spinal cord
grey matter control more complex reflex actions of flexion and
extension of the limbs that form the basic building blocks of
coordinated actions, but complete control requires input from
the extrapyramidal system and the cerebellum.
Lower motor neurons
Lower motor neurons in the anterior horn of the spinal cord
innervate a group of muscle fibres termed a ‘motor unit’. Loss of
lower motor neurons causes loss of contraction within this unit,
Fig. 25.6 The motor system. Neurons from the motor cortex descend as
the pyramidal tract in the internal capsule and cerebral peduncle to the
ventral brainstem, where most cross low in the medulla (A). In the spinal
cord the upper motor neurons form the corticospinal tract in the lateral
column before synapsing with the lower motor neurons in the anterior
horns. The activity in the motor cortex is modulated by influences from the
basal ganglia and cerebellum. Pathways descending from these structures
control posture and balance (B).
resulting in weakness and reduced muscle tone. Subsequently,
denervated muscle fibres atrophy, causing muscle wasting, and
depolarise spontaneously, causing ‘fibrillations’. Except in the
tongue, these are usually perceptible only on electromyography
(EMG; p. 1076). With the passage of time, neighbouring intact
neurons sprout to provide re-innervation, but the neuromuscular
junctions of the enlarged motor units are unstable and depolarise
spontaneously, causing fasciculations (large enough to be visible).
Fasciculations therefore imply chronic denervation with partial
re-innervation.
Upper motor neurons
Upper motor neurons have both inhibitory and excitatory influence
on the function of lower motor neurons in the anterior horn.
Lesions affecting the upper motor neuron result in increased
tone, most evident in the strongest muscle groups (i.e. the
extensors of the lower limbs and the flexors of the upper limbs).
The weakness of upper motor neuron lesions is conversely more
pronounced in the opposing muscle groups. Loss of inhibition
will also lead to brisk reflexes and enhanced reflex patterns of
movement, such as flexion withdrawal to noxious stimuli and
spasms of extension. The increased tone is more apparent
during rapid stretching (‘spastic catch’) but may quickly give
way with sustained tension (the ‘clasp-knife’ phenomenon). More
primitive reflexes are also released, manifest as extensor plantar
Cortical
pyramidal cells
Foot
Motor
cortex
Basal
ganglia
Cerebellum
Descending
©control of
posture and
balance
Spinal cord
Lateral
corticospinal
tract
Anterior
horn cells
Functional anatomy and physiology • 1069
responses. Spasticity may not be present until some weeks after
the onset of an upper motor neuron lesion.
| The extrapyramidal system
Circuits between the basal ganglia and the motor cortex
constitute the extrapyramidal system, which controls muscle
tone, body posture and the initiation of movement (see Fig.
25.6). Lesions of the extrapyramidal system produce an increase
in tone that, unlike spasticity, is continuous throughout the
range of movement at any speed of stretch (‘lead pipe’ rigidity).
Involuntary movements are also a feature of extrapyramidal lesions
(p. 1084), and tremor in combination with rigidity produces typical
‘cogwheel’ rigidity. Extrapyramidal lesions also cause slowed
and clumsy movements (bradykinesia), which characteristically
reduce in size with repetition, as well as postural instability,
which can precipitate falls.
The cerebellum
The cerebellum fine-tunes and coordinates movement initiated
by the motor cortex, including articulation of speech. It also
participates in the planning and learning of skilled movements
through reciprocal connections with the thalamus and cortex.
A lesion in a cerebellar hemisphere causes lack of coordination
on the same side of the body. Cerebellar dysfunction impairs
the smoothness of eye movements, causing nystagmus, and
renders speech dysarthric. In the limbs, the initial movement
is normal, but as the target is approached, the accuracy of
the movement deteriorates, producing an ‘intention tremor’.
The distances of targets are misjudged (dysmetria), resulting in
‘past-pointing’. The ability to produce rapid, accurate, regularly
alternating movements is also impaired (dysdiadochokinesis).
The central vermis of the cerebellum is concerned with the
coordination of gait and posture. Disorders of this area therefore
produce a characteristic ataxic gait (see below).
Vision
The neurological organisation of visual pathways is shown in
Figure 25.7. Fibres from ganglion cells in the retina pass to the
optic disc and then backwards through the lamina cribrosa to
the optic nerve. Nasal optic nerve fibres (subserving the temporal
visual field) cross at the chiasm but temporal fibres do not.
Hence, fibres in each optic tract and further posteriorly carry
representation of contralateral visual space. From the lateral
geniculate nucleus, lower fibres pass through the temporal lobes
on their way to the primary visual area in the occipital cortex,
while the upper fibres pass through the parietal lobe.
Normally, the eyes move conjugately (in the same direction at
the same speed), though horizontal convergence allows fusion
of images at different distances. The control of eye movements
begins in the cerebral hemispheres, particularly within the frontal
eye fields, and the pathway then descends to the brainstem with
input from the visual cortex, superior colliculus and cerebellum.
Horizontal and vertical gaze centres in the pons and mid-brain,
respectively, coordinate output to the ocular motor nerve nuclei
(3, 4 and 6), which are connected to each other by the medial
longitudinal fasciculus (MLF) (Fig. 25.8). The MLF is particularly
important in coordinating horizontal movements of the eyes.
The resulting signals to extraocular muscles are supplied
by the oculomotor (3rd), trochlear (4th) and abducens (6th)
cranial nerves.
The pupillary size is determined by a combination of
parasympathetic and sympathetic activity. Parasympathetic
fibres originate in the Edinger-Westphal subnucleus of the 3rd
nerve, and pass with the 3rd nerve to synapse in the ciliary
ganglion before supplying the constrictor pupillae of the iris.
Sympathetic fibres originate in the hypothalamus, pass down
the brainstem and cervical spinal cord to emerge at T1 , return
up to the eye in association with the internal carotid artery, and
supply the dilator pupillae.
Monocular
blindness
Bitemporal
hemianopia
Right
homonymous
hemianopia
Right superior
homonymous
quadrantanopia
Right inferior
homonymous
quadrantanopia
Right homonymous
hemianopia with
macular sparing
Visual field defects
L R
OO
o©
o©
> I
Visual fields
Retina
Optic nerve
Optic chiasm
Optic tract
Lateral geniculate body
Lower fibres in
temporal lobe
Upper fibres
in anterior
parietal lobe
Occipital cortex
. Optic
radiation
Fig. 25.7 Visual pathways and visual field defects. Schematic representation of eyes and brain in transverse section.
1070 • NEUROLOGY
Medial rectus Lateral rectus
Fig. 25.8 Control of conjugate eye movements. Downward projections
pass from the cortex to the pontine lateral gaze centre (A). The pontine
gaze centre projects to the 6th cranial nerve nucleus (B), which innervates
the ipsilateral lateral rectus and projects to the contralateral 3rd nerve
nucleus (and hence medial rectus) via the medial longitudinal fasciculus
(MLF). Tonic inputs from the vestibular apparatus (C) project to the
contralateral 6th nerve nucleus via the vestibular nuclei.
| Speech
Much of the cerebral cortex is involved in the process of
forming and interpreting communicating sounds, especially in
the dominant hemisphere (see Box 25.2). Decoding of speech
sounds (phonemes) is carried out in the upper part of the
posterior temporal lobe. The attribution of meaning, as well as
the formulation of the language required for the expression of
ideas and concepts, occurs predominantly in the lower parts
of the anterior parietal lobe (the angular and supramarginal gyri).
The temporal speech comprehension region is called Wernicke’s
area (Fig. 25.9). Other parts of the temporal lobe contribute to
verbal memory, where lexicons of meaningful words are ‘stored’.
Parts of the non-dominant parietal lobe appear to contribute
to non-verbal aspects of language in recognising meaningful
intonation patterns (prosody).
The frontal language area is in the posterior end of the dominant
inferior frontal gyrus known as Broca’s area. This receives input
from the temporal and parietal lobes via the arcuate fasciculus.
The motor commands generated in Broca’s area pass to the
cranial nerve nuclei in the pons and medulla, as well as to the
anterior horn cells in the spinal cord. Nerve impulses to the lips,
tongue, palate, pharynx, larynx and respiratory muscles result in
the series of ordered sounds comprising speech. The cerebellum
also plays an important role in coordinating speech, and lesions
of the cerebellum lead to dysarthria, where the problem lies in
motor articulation of speech.
| The somatosensory system
The body surface can be described by dermatomes, each
dermatome being an area of skin in which sensory nerves derive
from a single spinal nerve root (Fig. 25.10). Sensory information
ascends in two anatomically discrete systems (Fig. 25.11).
Fibres from proprioceptive organs and those mediating specific
Fig. 25.9 Areas of the cerebral cortex involved in the generation of
spoken language.
sensation (including vibration) enter the spinal cord at the posterior
horn and pass without synapsing into the ipsilateral posterior
columns. In contrast, fibres conveying pain and temperature
sensory information (nociceptive neurons) synapse with second-
order neurons that cross the midline in the spinal cord before
ascending in the contralateral anterolateral spinothalamic tract
to the brainstem.
The second-order neurons of the dorsal column sensory
system cross the midline in the upper medulla to ascend through
the brainstem. Here they lie just medial to the (already crossed)
spinothalamic pathway. Brainstem lesions can therefore cause
sensory loss affecting all modalities on the contralateral side of
the body. Distribution of facial sensory loss due to brainstem
lesions arises from the anatomy of the trigeminal fibres within
the brainstem. Fibres from the back of the face (near the ears)
descend within the brainstem to the upper part of the spinal
cord before synapsing, the second-order neurons crossing
the midline and then ascending with the spinothalamic fibres.
Fibres conveying sensation from more anterior areas of the face
descend a shorter distance in the brainstem. Thus, sensory
loss in the face from low brainstem lesions is in a ‘balaclava
helmet’ distribution, as the longer descending trigeminal fibres
are affected. Both dorsal column and spinothalamic tracts end
in the thalamus, relaying from there to the parietal cortex.
Pain
Pain is a complex perception that is only partly related to activity in
nociceptor neurons (p. 1338 and Fig. 34.2). Higher up, chronic and
severe pain interacts extensively with mood and can exacerbate
or be exacerbated by mood disorder, including depression and
anxiety. Modification of psychological and psychiatric sequelae
is a vital part of pain management (p. 1343).
Sphincter control
The sympathetic supply to the bladder arises from roots
T1 1-L2 to synapse in the inferior hypogastric plexus, while the
parasympathetic supply leaves from S2-4. In addition, a somatic
supply to the external (voluntary) sphincter arises from S2-4,
travelling via the pudendal nerves.
Functional anatomy and physiology • 1071
Fig. 25.10 The areas supplied by specific levels of the spinal cord. These are approximations and in practice there is much overlap. The clinical
utility of these dermatomes has diminished somewhat with the advent of good magnetic resonance imaging of the spinal cord but it remains important
to ascertain the presence of a ‘spinal level’ of sensation, to remember the supply of saddle area, and to note the cervical descent of some facial
spinothalamic pathways. [A] Anterior. [§] Posterior.
Storage of urine is maintained by inhibiting parasympathetic
activity and thus relaxing the detrusor muscle of the bladder wall.
Continence is also helped by simultaneous sympathetic- and
somatic-mediated tonic contraction of the urethral sphincters.
Voiding in adults is usually carried out under conscious control,
which triggers relaxation of tonic inhibition on the pontine
micturition centre from higher centres, leading to relaxation of the
pelvic floor muscles and external and internal urethral sphincters,
along with parasympathetic-mediated detrusor contraction.
Personality and mood
The physiology and pathology of mood disorders are discussed
elsewhere (Ch. 28) but it is important to remember that any
process affecting brain function may influence mood and affect.
Conversely, mood disorder may have a significant effect on
perception and function. It can be difficult to disentangle whether
psychological and psychiatric changes are the cause or the
effect of any neurological symptoms.
Sleep
The function of sleep is unknown but it is required for health.
Sleep is controlled by the reticular activating system in the
upper brainstem and diencephalon. It is composed of different
stages that can be visualised on electroencephalography (EEG).
As drowsiness occurs, normal EEG background alpha rhythm
disappears and activity becomes dominated by deepening
slow-wave activity. As sleep deepens and dreaming begins, the
limbs become flaccid, movements are ‘blocked’ and EEG signs
of rapid eye movements (REM) are superimposed on the slow
wave. REM sleep persists for a short spell before another slow-
wave spell starts, the cycle repeating several times throughout
the night. REM phases lengthen as sleep progresses. REM
sleep seems to be the most important part of the sleep cycle
for refreshing cognitive processes, and REM sleep deprivation
causes tiredness, irritability and impaired judgement.
Localising lesions in the central
nervous system
After taking a history and examining the patient, the clinician
should have an idea of the nature and site of any pathology
(see Box 25.10). Given the intricate anatomy of the brainstem,
this section will dwell on the possible localisation in more detail
(see Fig. 25.5).
Brainstem lesions typically present with symptoms due to
cranial nerve, cerebellar and upper motor neuron dysfunction
and are most commonly caused by vascular disease. Since
the anatomy of the brainstem is very precisely organised, it is
usually possible to localise the site of a lesion on the basis of
careful history and examination in order to determine exactly
1072 • NEUROLOGY
Fig. 25.1 1 The main somatic sensory pathways.
which tracts/nuclei are affected, usually invoking the fewest
number of lesions.
For example, in a patient presenting with sudden onset
of upper motor neuron features affecting the right face, arm
and leg in association with a left 3rd nerve palsy, the lesion
will be in the left cerebral peduncle in the brainstem and the
pathology is likely to have been a discrete stroke, as the onset
was sudden. This combination of symptoms and signs is known
as Weber’s syndrome, and is one of several well-described
brainstem syndromes, which are listed in Box 25.3. The effects
of individual cranial nerve deficits are discussed in the sections
on eye movements (p. 1088) and on facial weakness, sensory
loss in brainstem lesions, dysphonia and dysarthria, and bulbar
symptoms (pp. 1082, 1083, 1087 and 1093).
Investigation of neurological disease
Experienced clinicians make most neurological diagnoses on
history alone, with a lesser contribution from examination and
investigation. As investigations become more complex and more
easily available, it is tempting to adopt a ‘scan first, think later’
approach to neurological symptoms. The frequency of ‘false¬
positive’ results, the wide range of normality, and the negative
implications for patients (unnecessary expense, inconvenience,
discomfort and worry) necessitate a more thoughtful approach.
Investigation may include assessment of structure (imaging)
and function (neurophysiology). Neurophysiological testing has
become so complex that in some countries it constitutes a
separate specialty focusing on electroencephalography, evoked
potentials, nerve conduction studies and electromyography.
25.3 Major focal brainstem syndromes
Name of
syndrome
Site of lesions
Clinical features
Weber
Anterior cerebral
peduncle
(mid-brain)
Ipsilateral 3rd palsy
Contralateral upper motor
neuron 7th palsy
Contralateral hemiplegia
Claude
Cerebral peduncle
Involving red
nucleus
Ipsilateral 3rd palsy
Contralateral cerebellar signs
Parinaud
Dorsal mid-brain
(tectum)
Vertical gaze palsy
Convergence disorders
Convergence retraction
nystagmus
Pupillary and lid disorders
Millard-Gubler
Ponto-medullary
junction
Ipsilateral 6th palsy
Ipsilateral lower motor
neuron 7th palsy
Contralateral hemiplegia
Wallenberg
Lateral medulla
Ipsilateral 5th, 9th, 10th,
11th palsy
Ipsilateral Horner’s syndrome
Ipsilateral cerebellar signs
Contralateral spinothalamic
sensory loss
Vestibular disturbance
Neuroimaging
Neurological imaging has traditionally allowed only assessment of
structure but advances are allowing much more sophistication.
Imaging modalities can use X-rays (plain X-rays, computed
tomography (Cl), CT angiography, myelography and angiography),
magnetic resonance (MR imaging (MRI), MR angiography
(MRA)), ultrasound (Doppler imaging of blood vessels) and
nuclear medicine techniques (single photon emission computed
tomography (SPECT) and positron emission tomography (PET)).
The uses and limitations of each of these are shown in Box
25.4. Different sequences for analysing MRI signals can provide
helpful information for characterising tissues and pathologies
(Box 25.5).
Specialist MR techniques, such as functional MRI (fMRI), MR
spectroscopy or diffusion tensor imaging (DTI), can be used
to assess brain metabolism and chemical compositions. This
may be dynamic and can provide ‘maps’ of cortical function
to help plan lesionectomy and epilepsy surgery. Similarly, MR
spectroscopy can outline the chemical composition of specific
regions, providing notions of whether lesions are ischaemic,
neoplastic or inflammatory.
Some degenerative neurological conditions cause functional
rather than structural abnormalities that make metabolic and
neurochemical assessment increasingly useful. PET scanning
can display glucose metabolism in dementia and epilepsy.
SPECT scanning uses the lipid-soluble properties of radioactive
tracers to mark cerebral blood flow at the time of injection to
help in investigating seizures. Dopaminergic pathway tracers
can assess the integrity of the nigrostriatal pathway in patients
with possible parkinsonism.
Investigation of neurological disease • 1073
i
25.4 Imaging techniques for the nervous system
Technique Applications
Advantages
Disadvantages
Comments
X-ray/CT Plain X-rays, CT, CTA
Radiculography
Myelography
Intra-arterial angiography
Widely available
Relatively cheap
Relatively quick
Ionising radiation
Contrast reactions
Invasive (myelography and
angiography)
X-rays: used for fractures or
foreign bodies
CT: first line for stroke
Intra-arterial angiography: gold
standard for vascular lesions
MRI
Structural imaging
MRA
Functional MRI
MR spectroscopy
High-quality soft tissue
images, useful for posterior
fossa and temporal lobes
No ionising radiation
Non-invasive
Expensive
Less widely available
MRA images blood flow, not
vessel anatomy
Claustrophobic
Pacemakers are a contraindication
Contrast (gadolinium) reactions
Functional MR and spectroscopy:
mainly research tools
Ultrasound Doppler
Duplex scans
Cheap
Quick
Non-invasive
Operator-dependent
Poor anatomical definition
Screening tool to assess need for
carotid endarterectomy
Radioisotope Isotope brain scan
SPECT
PET
In vivo imaging of
functional anatomy (ligand
binding, blood flow)
Poor spatial resolution
Ionising radiation
Expensive
Not widely available
Isotope scans: obsolete
SPECT: useful in movement
disorders, epilepsy and dementias
PET: mainly research tool
(CT = computed tomography; CTA = computed tomographic angiography; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; PET = positron
emission tomography; SPECT = single photon emission computed tomography)
Head and orbit
Plain skull X-rays now have a very limited role in neurological
disease. CT or MRI is needed for intracranial imaging. CT
is good for demonstrating bone and calcification well. It will
also detect abnormalities of the brain and ventricles, such
as atrophy, tumours, cysts, abscesses, vascular lesions and
hydrocephalus. Diagnostic yield may be improved by the use
of intravenous contrast and thinner slicing but CT is not optimal
for lesions of meninges, cranial nerves or subtle parenchymal
changes.
MRI resolution is unaffected by bone and so is more useful
in posterior fossa disease. Its sensitivity for cortical and white
matter changes makes it the modality of choice in inflammatory
conditions such as multiple sclerosis and in the investigation
of epilepsy. Different MRI techniques can selectively suppress
1074 • NEUROLOGY
Fig. 25.12 Different techniques of imaging
the head and brain. {K\ Computed tomogram
showing complete middle cerebral artery infarct
(arrows). [§] Magnetic resonance image
showing widespread areas of high signal in
multiple sclerosis (arrows). [C] Single photon
emission computed tomography scan after
caudate infarct showing relative hypoperfusion
of overlying right cerebral cortex (arrows).
fDl Normal positron emission tomogram (PET
scan) of brain. A-C, Courtesy of Dr D. Collie.
D, Courtesy of Dr Ravi Jampana, Consultant
Neuroradiologist, Dept of Neuroradiology,
Institute of Neuroscience, Queen Elizabeth
University Hospital, Glasgow.
signal from fluid or fat, for example, and so increase sensitivity
for more subtle pathologies.
Examples of brain imaged by the various techniques are
shown in Figure 25.12.
Cervical, thoracic and lumbar spine
X-rays are useful for imaging bony structures and can show
destruction or damage to vertebrae, for example, but will provide
no information about non-bony tissues, such as intervertebral
discs, spinal cord and nerve roots. They have some usefulness
in dynamic imaging, e.g. flexion/extension of the spine, in
the assessment of instability. MRI has transformed spinal
investigation, as it can give information not only about vertebrae
and intervertebral discs but also about their effects on the spinal
cord and nerve roots. Myelography (usually with CT) is an invasive
technique requiring injection of contrast into the lumbar theca.
While outlining the nerve roots and spinal cord provides some
detail about abnormal structure, the accuracy and availability
of MRI have reduced the need for it. Myelography may still be
used where MRI is unavailable, contraindicated, or precluded
by a patient’s claustrophobia. Examples of the cervical spine
imaged by plain X-rays, myelography and MRI are shown in
Figure 25.13.
Blood vessels
Imaging of the extra- and intracranial blood vessels and
disturbance of arterial or venous blood flow is described on
page 1161.
Neurophysiological testing
| Electroencephalography
The electroencephalogram (EEG) detects electrical activity arising
in the cerebral cortex via electrodes placed on the scalp to record
the amplitude and frequency of the resulting waveforms. With
closed eyes, the normal background activity is 8-1 3 Hz (known
as alpha rhythm), most prominent occipitally and suppressed on
eye opening. Other frequency bands seen over different parts
of the brain in different circumstances are beta (faster than 13/
sec), theta (4-8/sec) and delta (slower than 4/sec). Normal
EEG patterns evolve with age and alertness; lower frequencies
predominate in the very young and during sleep.
In recent years, digital technology has allowed longer, cleaner
EEG recordings that can be analysed in a number of ways
and recorded alongside contemporaneous video of any clinical
‘event’. Meanwhile, the development of intracranial recording
allows more sensitive monitoring via surgically placed electrodes
in and around lesions to help increase the efficacy and safety
of epilepsy surgery.
Abnormal EEGs result from a number of conditions. Examples
include an increase in fast frequencies (beta) seen with sedating
drugs such as benzodiazepines, or marked focal slowing noted
over a structural lesion such as a tumour or an infarct. Improved
quality and accessibility of imaging have made EEG redundant in
lesion localisation, except in the specialist investigation of epilepsy
(p. 1100). EEG remains useful in progressive and continuous
disorders such as reduced consciousness (p. 194), encephalitis
Investigation of neurological disease • 1075
Fig. 25.13 Different techniques of imaging the cervical spine. [A] Lateral X-ray showing bilateral C6/7 facet dislocation. \W} Myelogram showing
widening of cervical cord due to astrocytoma (arrows). [C] Magnetic resonance image showing posterior epidural compression from adenocarcinomatous
metastasis to the posterior arch of T1 (arrows). A-C, Courtesy of Dr D. Collie.
0 (S'
Fig. 25.14 Electroencephalograms in epilepsy. 0 Generalised epileptic discharge, as seen in epilepsy syndromes such as childhood absence or
juvenile myoclonic epilepsy. [§] Focal sharp waves over the right parietal region (circled), with spread of discharge to cause a generalised tonic-clonic
seizure.
(p. 1121), and certain dementias such as Creutzfeldt-Jakob
disease (p. 1127).
Since sleep induces marked changes in cerebral activity, EEG
can be useful in diagnosis of sleep disturbances. In paroxysmal
disorders such as epilepsy, EEG is at its most useful when it
captures activity during one of the events in question. Over
50% of patients with epilepsy have a normal ‘routine’ EEG
but, conversely, the presence of epileptiform features does
not of itself make a diagnosis. Up to 5% of some normal
populations may demonstrate epileptiform discharges on EEG,
preventing its use as a screening test for epilepsy, most notably
in younger patients with a family history of epilepsy. In view
of this, the EEG should not be used where epilepsy is merely
‘possible’.
1076 • NEUROLOGY
Therefore the EEG in epilepsy is predominantly used for
classification and prognostication, but in some patients can
help localise the seat of epileptiform discharges when surgery is
being considered. During a seizure, high-voltage disturbances of
background activity (‘discharges’) are often noted. These may be
generalised, as in the 3 Hz ‘spike and wave’ of childhood absence
epilepsy, or more focal, as in localisation-related epilepsies (Fig.
25.14). Techniques such as hyperventilation or photic stimulation
can be used to increase the yield of epileptiform changes,
particularly in the generalised epilepsy syndromes. While some
argue that it is possible to detect ‘spikes’ and ‘sharp waves’ to
lend support to a clinical diagnosis, these are non-specific and
therefore not diagnostic, and can lead an unwary clinician to
err in ascribing other symptoms to epilepsy.
Nerve conduction studies
Electrical stimulation of a nerve causes an impulse to travel
both efferently and afferently along the underlying axons.
Nerve conduction studies (NCS) make use of this, recording
action potentials as they pass along peripheral nerves and
(with motor nerves) as they pass into the muscle belly. Digital
recording has enhanced sensitivity and reproducibility of these
tiny potentials. By measuring the time taken to traverse a known
distance, it is possible to calculate nerve conduction velocities
(NCVs). Healthy nerves at room temperature will conduct at a
speed of 40-50 m/sec. If the recorded potential is smaller than
expected, this provides evidence of a reduction in the overall
number of functioning axons. Significant slowing of conduction
velocity, in contrast, suggests impaired conduction due to
peripheral nerve demyelination. Such changes in NCS may be
diffuse (as in a hereditary demyelinating peripheral neuropathy,
p. 1138), focal (as in pressure palsies, p. 1139) or multifocal
(e.g. Guillain-Barre syndrome, p. 1140; mononeuritis multiplex,
p. 1140). The information gained can allow the disease responsible
for peripheral nerve dysfunction to be better deduced (see Box
25.84, p. 1139).
Stimulation of motor nerves allows for the recording of
compound muscle action potentials (CMAPs) over muscles (Fig.
25.15). These are around 500 times larger than sensory nerve
potentials, typically around 1-20 millivolts. Since a proportion of
stimulated impulses in motor nerves will ‘reflect’ back from the
anterior horn cell body (forming the ‘F’ wave), it is also possible
to obtain some information about the condition of nerve roots.
Repetitive nerve stimulation (RNS) at 3-15/sec provides
consistent CMAPs in healthy muscle. In myasthenia gravis
(p. 1 1 41), however, where there is partial blockage of acetylcholine
receptors, there is a diagnostic fall (decrement) in CMAP
amplitude. In contrast, an increasing CMAP with high-frequency
RNS is seen in Lambert-Eaton myasthenic syndrome (p. 1143).
| Electromyography
Electromyography (EMG) is usually performed alongside NCS and
involves needle recording of muscle electrical potential during
rest and contraction. At rest, muscle is electrically silent but loss
of nerve supply causes muscle membrane to become unstable,
manifest as fibrillations, positive sharp waves (‘spontaneous
activity’) or fasciculations. Motor unit action potentials are recorded
during muscle contraction. Axonal loss or destruction will result
in fewer motor units. Resultant sprouting of remaining units will
lead to increasing size of each individual unit on EMG. Myopathy,
in contrast, causes muscle fibre splitting, which results in a
large number of smaller units on EMG. Other abnormal activity,
such as myotonic discharges, may signify abnormal ion channel
conduction, as in myotonic dystrophy or myotonia congenita.
Specialised single-fibre electromyography (SFEMG) can be used
to investigate neuromuscular junction transmission. Measuring
‘jitter’ and ‘blocking’ can identify the effect of antibodies in
reducing the action of acetylcholine on the receptor.
| Evoked potentials
The cortical response to visual, auditory or electrical stimulation
can be measured on an EEG as an evoked potential (EP). If a
stimulus is provided - e.g. to the eye, the tiny EEG response
can be discerned when averaging 100-1000 repeated stimuli.
Assessing the latency (the time delay) and amplitude can give
Fig. 25.15 Motor nerve conduction tests.
Electrodes (R) on the muscle (abductor pollicis
here) record the compound muscle action
potential (CMAP) after stimulation at the median
nerve at the wrist (S^ and from the elbow (S2).
The velocity from elbow to wrist can be
determined if the distance between the two
stimulating electrodes (d) is known. A prolonged
H (L = latency) would be caused by dysfunction
distally in the median nerve (e.g. in carpal tunnel
syndrome). A prolonged L2 is caused by slow
nerve conduction (as in demyelinating
neuropathy). The F wave is a small delayed
response that appears when the electrical signal
travels backwards to the anterior horn cell,
sparking a second action potential in a minority
of fibres (see text). (NCV = nerve conduction
velocity)
Investigation of neurological disease • 1077
100
200
300
100
200
300
L
ms
R
ms
Fig. 25.16 Visual evoked potential (VEP) recording. The abnormality is
in the left hemisphere, with delay in latency and a reduction in signal of
the P100.
information about the integrity of the relevant pathway. MRI now
provides more information about CNS pathways, thus reducing
reliance on EPs. In practice, visual evoked potentials (VEPs) are
most commonly used to help differentiate CNS demyelination
from small-vessel white-matter changes (Fig. 25.16).
| Magnetic stimulation
Central conduction times can also be measured using
electromagnetic induction of action potentials in the cortex or
spinal cord by the local application of specialised coils. Again,
MRI has made this technique largely redundant, other than for
research.
Routine blood tests
Many systemic conditions that can affect the nervous system
can be identified by simple blood tests. Nutritional deficiencies,
metabolic disturbances, inflammatory conditions or infections
may all present or be associated with neurological symptoms,
and basic blood tests (full blood count, erythrocyte sedimentation
rate, C-reactive protein, biochemical screening) may provide
clues. Specific blood tests will be highlighted in the relevant
subsections of this chapter. Human immunodeficiency virus (HI V)
infection is increasingly recognised as a cause of neurological
disease and the clinician should have a low threshold for
checking this.
| Immunological tests
Recent developments have seen a host of new immune-mediated
conditions emerge in clinical neurology, with antibody targets
ranging from muscle and neuromuscular junction disturbance
(causing weakness and muscle pain) to specific neuronal ion
channels (causing cognitive decline, epilepsy and psychiatric
changes). The 21st century has seen the identification of many
causative antibodies (see Boxes 25.52 and 25.53, p. 1111)
and it is likely that further conditions will turn out to have an
immune basis.
Genetic testing
This evolving field represents a huge untapped area for
neurological exploration, particularly with the development of
genome-wide association study (GWAS) and whole-genome
sequencing. Relevant subsections will detail the increasing
numbers of inherited neurological conditions that can now be
diagnosed by DNA analysis (p. 56). These include diseases
caused by increased numbers of trinucleotide repeats, such
as Huntington’s disease (p. 1114); myotonic dystrophy
(p. 1143); and some types of spinocerebellar ataxia (p. 1115).
Mitochondrial DNA can also be sequenced to diagnose relevant
disorders (p. 1144).
Lumbar puncture
Lumbar puncture (LP) is the technique used to obtain both a
CSF sample and an indirect measure of intracranial pressure.
After local anaesthetic injection, a needle is inserted between
lumbar spinous processes (usually between L3 and L4) through
the dura and into the spinal canal. Intracranial pressure can be
deduced (if patients are lying on their side) and CSF removed
for analysis. CSF pressure measurement is important in the
diagnosis and monitoring of idiopathic intracranial hypertension
(p. 1133). In this condition, the LP itself is therapeutic.
CSF is normally clear and colourless, and the tests that are
usually performed include a naked eye examination of the CSF
and centrifugation to determine the colour of the supernatant
(yellow, or xanthochromic, some hours after subarachnoid
haemorrhage; p. 1160). Measurement of absorption of specific
light wavelengths helps quantify the amount of haem metabolites
in CSF. Routine analysis involves a cell count, as well as glucose
and protein concentrations.
CSF assessment is important in investigating infections
(meningitis or encephalitis), subarachnoid haemorrhage and
inflammatory conditions (multiple sclerosis, sarcoidosis and
cerebral lupus). Normal values and abnormalities found in specific
conditions are shown in Box 25.6.
More sophisticated analysis allows measurement of antibody
formation solely within the CNS (oligoclonal bands), genetic
analysis (e.g. polymerase chain reaction (PCR) for herpes simplex
or tuberculosis), immunological tests (paraneoplastic antibodies)
and cytology (to detect malignant cells).
If there is a cranial space-occupying lesion causing raised
intracranial pressure, LP presents a theoretical risk of downward
shift of intracerebral contents, a potentially fatal process known
as coning (p. 1128). Consequently, LP is contraindicated if
there is any clinical suggestion of raised intracranial pressure
(papilloedema), depressed level of consciousness, or focal
neurological signs suggesting a cerebral lesion, until imaging (by CT
or MRI) has excluded a space-occupying lesion or hydrocephalus.
When there is a risk of local haemorrhage (thrombocytopenia,
disseminated intravascular coagulation or anticoagulant treatment),
then caution should be exercised or specific measures should
be taken. LP can be safely performed in patients on antiplatelet
drugs or low-dose heparin, but may be unsafe in patients who
are fully anticoagulated due to the increased risk of epidural
haematoma.
About 30% of LPs are followed by a postural headache,
due to reduced CSF pressure. The frequency of headache
1078 • NEUROLOGY
25 6 How t0 interPret cerebrospinal fluid results
Normal
Subarachnoid
haemorrhage
Acute bacterial
meningitis
Viral meningitis
Tuberculous
meningitis
Multiple
sclerosis
Pressure
50-250 mm
of water
Increased
Normal/increased
Normal
Normal/increased
Normal
Colour
Clear
Blood-stained
Xanthochromic
Cloudy
Clear
Clear/cloudy
Clear
Red cell count
(x 1 06/L)
0-4
Raised
Normal
Normal
Normal
Normal
White cell count
(x106/L)
0-4
Normal/slightly
raised
1000-5000
polymorphs
10-2000
lymphocytes
50-5000 lymphocytes
0-50 lymphocytes
Glucose
>50-60% of
blood level
Normal
Decreased
Normal
Decreased
Normal
Protein
<0.45 g/L
Increased
Increased
Normal/increased
Increased
Normal/increased
Microbiology
Sterile
Sterile
Organisms on Gram
stain and/or culture
Sterile/virus
detected
Ziehl— Neelsen/auramine
stain or tuberculosis
culture positive
Sterile
Oligoclonal bands
Negative
Negative
Can be positive
Can be positive
Can be positive
Often positive
can be reduced by using smaller or atraumatic needles.
Rarer complications involve transient radicular pain, and
pain over the lumbar region during the procedure. Aseptic
technique renders secondary infections such as meningitis
extremely rare.
Biopsy
Biopsies of nervous tissue (peripheral nerve, muscle, meninges
or brain) are occasionally required for diagnosis.
Nerve biopsy can help in the investigation of peripheral
neuropathy. Usually, a distal sensory nerve (sural or radial) is
targeted. Histological examination can help identify underlying
causes, such as vasculitides or infiltrative disorders like amyloid.
Nerve biopsy should not be undertaken lightly since there is an
appreciable morbidity; it should be reserved for cases where
the diagnosis is in doubt after routine investigations and where
it will influence management.
Muscle biopsy is performed more frequently and is indicated for
the differentiation of myositis and myopathies. These conditions
can usually be distinguished by histological examination, and
enzyme histochemistry can be useful when mitochondrial diseases
and storage diseases are suspected. The quadriceps muscle
is most commonly biopsied but other muscles may also be
sampled if they are involved clinically. Although pain and infection
can follow the procedure, these are less of a problem than after
nerve biopsy.
Brain biopsy is required when imaging fails to clarify the
nature of intracerebral lesions, e.g. in unexplained degenerative
diseases such as unusual cases of dementia and in patients
with brain tumours. Most biopsies are performed stereotactically
through a burr hole in the skull, which lowers complication
rates. Nevertheless, haemorrhage, infection and death still occur
and brain biopsy should be considered only if a diagnosis is
otherwise elusive.
Biopsy of other organs can be useful in the diagnosis of
systemic disorders presenting as neurological problems, such
as tonsillar biopsy (diagnosis of prion diseases), or rectal or fat
biopsy (for assessment of amyloid).
Presenting problems in
neurological disease
While history is important in all medical specialties, it is especially
key in neurology, where many neurological diagnoses have no
confirmatory test. History-taking allows doctor and patient to get
to know one another; many neurological diseases follow chronic
paths and this may be the first of many such consultations. It
also allows the clinician to obtain information about the patient’s
affect, cognition and psychiatric state.
History-taking is a highly active process. While there are
generic templates (Box 25.7), each individual story will follow
its own course, and diagnostic considerations during the history
will guide further questioning.
It is important to be clear about what patients mean by certain
words. They may find it difficult to describe symptoms: for
instance, weakness may be called ‘numbness’, while there are
many possible interpretations of ‘dizziness’. These must be
clarified; even in emergency situations, a clear, accurate history is
the foundation of any management plan. While the story should
come primarily from the patient, input from eye-witnesses and
family members is crucial if the patient is unable to provide
details or if there has been loss of consciousness. This need
for corroboration and clarification means the telephone is as
important as any investigation.
The aim of the history is to address two key issues: where
is the lesion and what is the lesion (Box 25.8)? These should
remain uppermost in the doctor’s mind while the history is
being elicited. Some common combinations of symptoms may
suggest particular locations for a lesion (Box 25.10). Enquiry
about handedness is important; lateralisation of the dominant
hand helps designate the dominant hemisphere, which in turn
may help to localise any pathologies, or to plan rehabilitation or
treatment strategies in asymmetrical disorders such as stroke
or Parkinson’s disease.
Epidemiology must be borne in mind. How likely is it that this
particular patient has any specific condition under consideration?
Presenting problems in neurological disease • 1079
25.7 How to take a neurological history
Introduction
25.8 The key diagnostic questions
Where is the lesion?
• Age and sex
• Handedness
Presenting complaint
• Symptoms (clarify: see text)
• Overall pattern: intermittent or persistent?
• If intermittent, how often do symptoms occur and how long do they
last?
• Speed of onset: seconds, minutes, hours, days, weeks, months,
years, decades?
• Better, worse or the same over time?
• Associated symptoms (including non-neurological)
• Disability caused by symptoms
• Change in walking
• Difficulty with fine hand movements, e.g. writing, fastening buttons,
using cutlery
• Effect on work, family life and leisure
Background
• Previous neurological symptoms and whether similar to current
symptoms
• Previous medical history
• Domestic situation
• Driving licence status
• Medications (current and at time of symptom onset)
• Alcohol/smoking habits
• Recreational drug and other toxin exposure
• Family history and developmental history
• What are patient’s thoughts/fears/concerns?
• Is it neurological?
• If so, to which part of the nervous system does it localise?
Central versus peripheral
Sensory versus motor versus both
What is the lesion?
• Hereditary or congenital
• Acquired:
Traumatic
Infective
Neoplastic
Degenerative
Inflammatory or immune-mediated
Vascular
Functional
• Pupils: tend to be smaller, making fundoscopy more difficult.
• Limb tone: more difficult to assess because of poor relaxation and
concomitant joint disease.
• Ankle reflexes: may be absent.
• Gait assessment: more difficult because of concurrent
musculoskeletal disease and pre-existing neurological deficits.
• Sensory testing: especially difficult when there is cognitive
impairment.
• Vibration sense: may be reduced distally in the legs.
25.9 Neurological examination in old age
2510 How t0 ‘localise’ neurological disease
Combination of symptoms/signs
Probable site
Possible pathology
Other important information
Painless loss of hemilateral function
Cerebral cortex
Usually vascular, inflammatory or
Associated systemic symptoms
neoplastic
Tempo of evolution
Pyramidal weakness of all four limbs or
Spinal cord
Usually vascular, inflammatory or
Associated systemic symptoms
both legs, bladder signs, sensory loss
neoplastic
Tempo of evolution
Cranial nerve lesions, with limb pyramidal
Brainstem
Usually vascular or inflammatory
Associated systemic symptoms
signs or sensory loss ± sphincter
Mid-brain
Rarely neoplastic
Tempo of evolution
disturbance
Pons
Medulla
Visual loss + pyramidal signs and/or
Widespread cerebral lesions
Usually inflammatory
Tempo of evolution
cerebellar signs
Less commonly vasculitic
Weakness and/or sensory loss in a
Several peripheral nerves
Usually inflammatory or diabetic
Associated systemic symptoms
combination of individual peripheral nerves
(‘mononeuritis multiplex’)
Widespread LMN and UMN signs
Upper and lower motor
Motor neuron disease
Associated localised cervical
neurons
Cervical myeloradiculopathy
symptoms
Distal loss of sensation and/or weakness
Generalised peripheral nerves
See causes of neuropathy (p. 1138)
Associated systemic symptoms
(LMN/UMN = lower/upper motor neuron)
For example, a 20-year-old with right-sided headache and
tenderness will not have temporal arteritis, but this is an important
possibility if such symptoms present in a 78-year-old female.
Determining the evolution, speed of onset and progression of
a disease is important (Box 25.11). For example, if right-hand
weakness occurred overnight, it would suggest a stroke in an
older person or an acute entrapment neuropathy in a younger one.
Evolution over several days, however, might make demyelination
(multiple sclerosis) a possible diagnosis, or perhaps a subdural
haematoma if the weakness was preceded by a head injury in
an older person taking warfarin. Progression over weeks might
bring an intracranial mass lesion or motor neuron disease into
the differential. Slow progression over a year or so, with difficulty
in using the hand, could suggest a degenerative process such
1080 • NEUROLOGY
25.1 1 The evolution of symptoms
Onset Evolution Possible causes
Sudden (minutes Stable/improvement Vascular (stroke/transient
to hours) ischaemic attack (TIA))
Nerve entrapment
syndromes
Functional
Gradual
Progressive over
Demyelination
days
Infection
Gradual
Progressive over
weeks to months
Neoplastic/paraneoplastic
Gradual
Progressive over
Genetic
months to years
Degenerative
as Parkinson’s disease. The impact on day-to-day activities,
such as walking, climbing stairs and carrying out fine hand
movements, should also be established in order to gauge the
level of associated disability.
Estimates of the frequency and duration of specific events are
essential when taking details of a paroxysmal disorder such as
migraine and epilepsy. Vague terms such as ‘a lot’ or ‘sometimes’
are unhelpful, and it can assist the patient if choices are given
to estimate numbers, such as once a day, week or month.
Many neurological symptoms are not explained by disease.
Describing these as ‘functional’ is less pejorative and more
acceptable to patients than ‘psychogenic’ or ‘hysterical’.
Functional symptoms require considerable experience in diagnosis
and are frequently missed (p. 1094).
Headache and facial pain
Most headaches are chronic disorders but acute presentation of
headaches is an important aspect of emergency medical care.
Headache may be divided into primary (benign) or secondary, and
most patients, whether presenting in clinic or as emergencies,
have primary syndromes (see Box 1 0.1 0, p. 1 84). The emergency
clinical assessment of headaches is dealt with on page 185.
Ocular pain
Assuming that ocular disease (such as acute glaucoma) has
been excluded, ocular pain may be due to trigeminal autonomic
cephalalgias (TACs) or, rarely, inflammatory or infiltrative lesions
at the apex of the orbit or the cavernous sinus, when 3rd, 4th,
5th or 6th cranial nerve involvement is usually evident. Ocular
pain and headache are also discussed on page 1170.
^Facial pain
Pain in the face can be due to dental or temporomandibular
joint problems. Acute sinusitis is usually apparent from other
features of sinus congestion/infection and may cause localised
pain over the affected sinus, but is almost never the explanation
for persistent facial pain or headache.
Facial pain is not uncommon in migraine but some syndromes
can present solely with facial pain. The most common neurological
causes of facial pain are trigeminal neuralgia, herpes zoster
(shingles) and post-herpetic neuralgia, all characterised by their
extreme severity. In trigeminal neuralgia, the patient describes
bouts of brief (seconds), lancinating pain (‘electric shocks’), most
frequently felt in the second and third divisions of the nerve
and often triggered by talking or chewing. Facial shingles most
commonly affects the first (ophthalmic) division of the trigeminal
nerve, and pain usually precedes the rash. Post-herpetic neuralgia
may follow, typically a continuous burning pain throughout the
affected territory, with marked sensitivity to light touch (allodynia)
and resistance to treatment. Destructive lesions of the trigeminal
nerve usually cause numbness rather than pain.
Persistent idiopathic facial pain is most frequently seen in
middle-aged women, who report persistent pain, with no abnormal
signs or investigations, and is similar to other forms of idiopathic
chronic pain.
Dizziness, blackouts and ‘funny turns’
Acute onset of dizziness or blackouts will present to the acute
medical department. In neurological practice, it is common to
deal with patients presenting with a history of multiple events.
While detailed questioning will be dealt with in the relevant section
(p. 181), the neurologist will have to tease out the pattern of
each of the different attack types experienced by the patient to
be able to form a treatment and investigation plan, one of the
challenges of clinical neurology.
Status epilepticus
Status epilepticus is seizure activity not resolving spontaneously, or
recurrent seizure with no recovery of consciousness in between.
Persisting seizure activity has a recognised mortality and is a
medical emergency.
Diagnosis is usually clinical and can be made on the basis of
the description of prolonged rigidity and/or clonic movements
with loss of awareness. As seizure activity becomes prolonged,
movements may become more subtle. Cyanosis, pyrexia, acidosis
and sweating may occur, and complications include aspiration,
hypotension, cardiac arrhythmias and renal or hepatic failure.
In patients with pre-existing epilepsy, the most likely
cause is a fall in antiepileptic drug levels. In de novo status
epilepticus, it is essential to exclude precipitants such as infection
(meningitis, encephalitis), neoplasia and metabolic derangement
(hypoglycaemia, hyponatraemia or hypocalcaemia). Treatment
and investigation are outlined in Box 25.12.
Coma
Coma and loss of consciousness usually present to the acute
medical admissions department (p. 194). Clarification of cause
and prognosis may require specialist neurological input.
Delirium
Delirium describes cortical dysfunction and replaces the older
term ‘acute confusional state’. It has a range of primary causes,
and given its role in precipitating acute admission, it is covered
in detail on page 183.
Amnesia
Memory disturbance is a common symptom. In the absence of
significant functional impairment (e.g. inability to work, dyspraxias,
loss of daily function), many patients will prove to have benign
memory dysfunction related to age, mood or psychiatric disorders.
Presenting problems in neurological disease • 1081
25.12 Management of status epilepticus
Initial
• Ensure airway is patent; give oxygen to prevent cerebral hypoxia
• Check pulse, blood pressure, BM stix and respiratory rate
• Secure intravenous access
• Send blood for:
Glucose, urea and electrolytes, calcium and magnesium, liver
function, antiepileptic drug levels
Full blood count and coagulation screen
Storing a sample for future analysis (e.g. drug misuse)
• If seizures continue for >5 mins: give midazolam 10 mg bucally
or nasally or lorazepam 4 mg IV if access available or diazepam
10 mg rectally or IV if necessary; repeat once only after 15 mins
• Correct any metabolic trigger, e.g. hypoglycaemia
Ongoing
If seizures continue after 30 mins
• IV infusion (with cardiac monitoring) with one of:
Phenytoin: 15 mg/kg at 50 mg/min
Sodium valproate: 20-30 mg/kg IV at 40 mg/min
Phenobarbital: 10 mg/kg at 100 mg/min
• Cardiac monitor and pulse oximetry:
Monitor neurological condition, blood pressure, respiration; check
blood gases
If seizures still continue after 30-60 mins
• Transfer to intensive care:
Start treatment for refractory status with intubation, ventilation
and general anaesthesia using propofol or thiopental
EEG monitor
Once status controlled
• Commence longer-term antiepileptic medication with one of:
Sodium valproate 10 mg/kg IV over 3-5 mins, then 800—
2000 mg/day
Phenytoin: give loading dose (if not already used as above) of
15 mg/kg, infuse at <50 mg/min, then 300 mg/day
Carbamazepine 400 mg by nasogastric tube, then 400-
1200 mg/day
• Investigate cause
The increasing publicity given to dementia, combined with a
natural fear of losing one’s mind, has led to an increase in
patients presenting with memory loss but many will have benign
symptoms. Investigation and treatment of the dementias are
discussed elsewhere (p. 1191).
Temporary loss of memory may be due to a transient delirium
related to infection, the post-ictal period after seizure, or transient
global amnesia. These are usually distinguished on the basis of
the history. Transient amnesia resulting directly from a seizure
(transient epileptic amnesia) is a rare result of temporal lobe
epilepsy.
| Transient global amnesia
Transient global amnesia (TGA) predominantly affects middle-aged
people, with an abrupt, discrete loss of anterograde memory
function lasting up to a few hours. During the episode, patients are
unable to record new memories, resulting in repetitive questioning,
the hallmark of this condition. Consciousness is preserved and
patients may perform even complex motor acts normally. During
the attack there is retrograde amnesia for the events of the past
few days, weeks or years. After 4-6 hours, memory function
and behaviour return to normal but the patient has persistent,
complete amnesia for the duration of the attack itself. There are
no seizure markers and, unlike epileptic amnesia, transient global
amnesia recurs in only around 10-20% of cases. A vascular
aetiology is unlikely (TGA is not a risk factor for subsequent
vascular disease) and amnesia may be due to a benign process
similar to migraine, occurring in the hippocampus. TGA causes
no physical signs and, provided there is a typical history (which
requires a witness), no investigation is necessary and patients
may be reassured.
Persistent amnesia
Serious neurological disease must be excluded in patients with
persistent memory disturbance, although many will prove to
have benign symptoms. Symptoms corroborated by relatives
or colleagues are likely to be more significant than those noted
by the patient only. Where poor concentration is at the heart of
cognitive deterioration, it is more likely to be due to an underlying
mood disorder.
It is important to assess the timing of onset and to establish
which aspects of memory are affected. Complaints of getting lost
or of losing complex abilities are more pathological than word¬
finding difficulties. Disturbance of episodic or working memory
(previously called ‘short-term memory’) must be distinguished
from semantic memory (memory for concept-based knowledge
unrelated to specific experiences). Episodic memory is selectively
impaired in Korsakoff’s syndrome (often secondary to alcohol) or
bilateral temporal lobe damage. It can also be seen in conjunction
with other types of dementia. Progressive deterioration over
months suggests an underlying dementia, and a full medical
assessment must be performed to detect any underlying medical
problem.
It is important to identify and treat depression (p. 1185)
in patients with memory loss. Depression may present as a
‘pseudo-dementia’, with concentration and memory impairment as
dominant features, and this is often reversible with antidepressant
medication. Any patient with dementia (particularly of Alzheimer’s
type) may develop depression in the early stages of their illness,
however. Specific causes of progressive dementia, with their
investigation and treatment, are described elsewhere (p. 1191).
Weakness
The assessment of weakness requires the application of basic
anatomy, physiology and some pathology to the interpretation
of the history and clinical findings. Points to consider are shown
on Figure 25.17 and in Boxes 25.13 and 25.14. The pattern
and evolution of weakness and the clinical signs provide clues
to the site and nature of the lesion.
It is important to establish whether the patient has loss of
power rather than reduced sensation or generalised fatigue. Pain
may restrict movement and thus mimic weakness. Paradoxically,
sensory neglect (p. 1 083) may leave patients unaware of severe
weakness.
Patients with parkinsonism may complain of weakness;
extrapyramidal signs of rigidity (cogwheel or lead pipe) and
bradykinesia should be evident, and a resting tremor (usually
asymmetrical) may provide a further clue (p. 1112). Simple
observation of the patient walking into the consulting room
may be diagnostic, and is as important as formal strength
testing. Movement restricted by pain should be apparent, and
other features (contractures, wasting, fasciculations, abnormal
movements/postures) all provide diagnostic clues.
Weakness is a common symptom arising without an underlying
degenerative or destructive cause (functional symptom). Functional
1082 • NEUROLOGY
Fig. 25.17 Patterns of motor loss according
to the anatomical site of the lesion.
I f 25.13 Distinguishing signs in upper versus lower
motor neuron syndromes
Upper motor neuron
lesion
Lower motor neuron
lesion
Inspection
Normal (may be wasting
in chronic lesions)
Wasting, fasciculation
Tone
Increased with clonus
Normal or decreased,
no clonus
Pattern of
weakness
Preferentially affects
extensors in arms,
flexors in leg
Hemiparesis, paraparesis
or tetraparesis
Typically focal, in
distribution of nerve
root or peripheral
nerve, with associated
sensory changes
Deep tendon
reflexes
Increased
Decreased/absent
Plantar
response
Extensor (Babinski sign)
Flexor
weakness does not conform to typical organic patterns, and
the signs in Box 25.13 are absent. Clinical examination is often
variable (e.g. the patient can walk but appears to have no leg
movement when assessed on the couch), and strength may
appear to ‘give way’, with the patient able to achieve full power
for brief bursts, which does not occur in disease. Hoover’s sign
is useful to confirm functional weakness, and relies on eliciting
the normal phenomenon of simultaneous hip extension when
the contralateral hip flexes. In functional weakness, hip extension
weakness may be seen; this then returns to full strength when
contralateral hip flexion is tested. This sign may be demonstrated
to the patient in a non-confrontational manner, to show that the
potential limb power is intact.
■v9 25-14 How to assess weakness
Clinical finding
Likely level of lesion/diagnosis
Pattern and distribution
Isolated muscles
Both limbs on one side
(hemiparesis)
One limb
Both lower limbs (paraparesis)
Fatigability
Bizarre, fluctuating, not
following anatomical rules
Radiculopathy or mononeuropathy
Cerebral hemisphere, less likely cord
or brainstem
Neuronopathy, plexopathy, cord/brain
Spinal cord; look for a sensory level
Myasthenia gravis
Functional
Signs
Upper motor neuron
Lower motor neuron
Brain/spinal cord
Peripheral nervous system
Evolution of the weakness
Sudden and improving
Evolving over months or
years
Gradually worsening over
days or weeks
Stroke/mo no neuropathy
Meningioma, cervical spondylotic
myelopathy
Cerebral mass, demyelination
Associated symptoms
Absence of sensory
involvement
Motor neuron disease, myopathy,
myasthenia
| Facial weakness
Facial nerve palsy (Bell’s palsy)
One of the most common causes of facial weakness is Bell’s
palsy, a lower motor neuron lesion of the 7th (facial) nerve,
affecting all ages and both sexes. It is more common following
upper respiratory tract infections, during pregnancy, and in
patients with diabetes, immunosuppression and hypertension.
Presenting problems in neurological disease • 1083
The lesion is within the facial canal. Symptoms usually develop
subacutely over a few hours, with pain around the ear preceding
the unilateral facial weakness. Patients often describe the face as
‘numb’ but there is no objective sensory loss (except to taste, if the
chorda tympani is involved). Hyperacusis may occur if the nerve
to stapedius is involved and impairment of parasympathetic fibres
may cause diminished salivation and tear secretion. Examination
reveals an ipsilateral lower motor neuron facial nerve palsy (no
sparing of forehead muscles). Vesicles in the ear or on the palate
may indicate primary herpes zoster infection (p. 239). A clinical
search for signs of other causes of lower motor neuron facial
nerve weakness, such as parotid or scalp lesions, trauma or
skull base lesions, is justified.
Glucocorticoids improve recovery rates if started within
72 hours of onset but antiviral drugs are not effective. Artificial
tears applied regularly prevent corneal drying, and taping the
eye shut overnight helps prevent exposure keratitis and corneal
abrasion. Patients unable to close the eye should be referred
urgently to an ophthalmologist. About 80% of patients recover
spontaneously within 1 2 weeks. Plastic surgery may be considered
for the minority left with facial disfigurement after 12 months.
Recurrence is unusual and should prompt further investigation.
Aberrant re-innervation may occur during recovery, producing
unwanted facial movements, such as eye closure when the
mouth is moved (synkinesis) or ‘crocodile tears’ (tearing during
salivation).
Unlike Bell’s palsy, lesions with an upper motor neuron origin
may spare the upper face. Cortical lesions may cause a facial
weakness either in isolation or with associated hemiparesis and
speech difficulties.
Sensory disturbance
Sensory symptoms are common and frequently benign. Patients
often find sensory symptoms difficult to describe and sensory
examination is difficult for both doctor and patient. While
neurological disease can cause sensory symptoms, systemic
disorders can also be responsible. Tingling in both hands and
around the mouth can occur as the result of hyperventilation
(p. 558) or hypocalcaemia (p. 662). When there is dysfunction
of the relevant cerebral cortex, the patient’s perception of the
wholeness or actual presence of the relevant part of the body
may be distorted.
Numbness and paraesthesia
The history may give the best clues to localisation and pathology.
Certain common patterns are recognised: in migraine, the aura
may consist of spreading tingling or paraesthesia, followed by
numbness evolving over 20-30 minutes over one half of the body,
often splitting the tongue. Sensory loss caused by a stroke or
transient ischaemic attack (TIA) occurs much more rapidly and
is typically negative (numbness) rather than positive (tingling).
Rarely, unpleasant paraesthesia of sensory epilepsy spreads
within seconds. The sensory alteration of inflammatory spinal
cord lesions often ascends from one or both lower limbs to a
distinct level on the trunk over hours to days. Psychogenic sensory
change can occur as a manifestation of anxiety or as part of a
conversion disorder (p. 1202). In such cases, the distribution
usually neither conforms to a known anatomical pattern nor fits
with any organic disease. Care must be taken in diagnosing
non-organic sensory problems; a careful history and examination
will ensure there is no other objective neurological deficit.
Sensory neurological examination needs to be undertaken and
interpreted with care because the findings depend, by definition,
on subjective reports. The reported distribution of sensory loss
can be useful, however, when combined with the coexisting
deficits of motor and/or cranial nerve function (Fig. 25.18).
Sensory loss in peripheral nerve lesions
Here the symptoms are usually of sensory loss and paraesthesia.
Single nerve lesions cause disturbance in the sensory distribution
of the nerve, whereas in diffuse neuropathies the longest neurons
are affected first, giving a characteristic ‘glove and stocking’
distribution. If smaller nerve fibres are preferentially affected (e.g.
in diabetic neuropathy), temperature and pin-prick (pain) are
reduced, whilst vibration sense and proprioception (modalities
served by the larger, well-myelinated, sensory nerves) may be
relatively spared. In contrast, vibration and proprioception are
particularly affected if the neuropathy is demyelinating in character
(p. 1138), producing symptoms of tightness and swelling with
impairment of proprioception and vibration sensation.
Sensory loss in nerve root lesions
These typically present with pain as a prominent feature, either
within the spine or in the limb plexuses. Pain is often felt in the
myotome rather than the dermatome. The nerve root involved
may be deduced from the dermatomal pattern of sensory loss
(p. 1071), although overlap may lead to this being smaller than
expected.
Sensory loss in spinal cord lesions
Transverse lesions of the spinal cord produce loss of all sensory
modalities below that segmental level, although the clinical level
may only be manifest 2-3 segments lower than the anatomical
site of the lesion. Very often, there is a band of paraesthesia or
hyperaesthesia at the top of the area of sensory loss. Clinical
examination may reveal dissociated sensory loss, i.e. different
patterns in the spinothalamic and dorsal columnar pathways.
If the transverse lesion is vascular due to anterior spinal artery
thrombosis, the spinothalamic pathways may be affected while
the posterior one-third of the spinal cord (the dorsal column
modalities) may be spared.
Lesions damaging one side of the spinal cord will produce loss
of spinothalamic modalities (pain and temperature) on the opposite
side, and of dorsal column modalities (joint position and vibration
sense) on the same side of the body - the Brown-Sequard
syndrome (p. 1084).
Lesions in the centre of the spinal cord (such as syringomyelia:
see Box 25.83 and Fig. 25.51, pp. 1138 and 1139) spare the
dorsal columns but involve the spinothalamic fibres crossing
the cord from both sides over the length of the lesion. There is
no sensory loss in segments above and below the lesion; this
is described as ‘suspended’ sensory loss. There is sometimes
reflex loss at the level of the lesion if afferent fibres of the reflex
arc are affected.
An isolated lesion of the dorsal columns is not uncommon
in multiple sclerosis. This produces a characteristic unpleasant,
tight feeling over the limb(s) involved and, while there is no loss
of pin-prick or temperature sensation, the associated loss of
proprioception may severely limit function of the affected limb(s).
Sensory loss in brainstem lesions
Lesions in the brainstem can be associated with sensory loss but
the distribution depends on the site of the lesion. A lesion limited
to the trigeminal nucleus or its sensory projections will cause
1084 • NEUROLOGY
(Brown-Sequard)
Fig. 25.18 Patterns of sensory loss. [A] Generalised peripheral neuropathy. [§] Sensory roots: some common examples. [C] Single dorsal column lesion
(proprioception and some touch loss). [jj] Transverse thoracic spinal cord lesion. [E] Unilateral cord lesion (Brown-Sequard): ipsilateral dorsal column (and
motor) deficit and contralateral spinothalamic deficit. {¥} Central cord lesion: ‘cape’ distribution of spinothalamic loss. [G] Mid-brainstem lesion: ipsilateral
facial sensory loss and contralateral loss on body below the vertex. \W\ Hemisphere (thalamic) lesion: contralateral loss on one side of face and body.
ipsilateral facial sensory disturbance. For example, pain resembling
trigeminal neuralgia can be seen in patients with multiple sclerosis.
The anatomy of the trigeminal connections means that lesions in
the medulla or spinal cord can give rise to ‘balaclava’ patterns of
sensory loss (p. 1070). Sensory pathways running up from the
spinal cord can also be damaged in the brainstem, resulting in
simultaneous sensory loss in arm(s) and/or leg(s).
Sensory loss in hemispheric lesions
The temporal, parietal and occipital lobes receive sensory
information regarding the various modalities of touch, vision,
hearing and balance (see Box 25.2, p. 1066). The initial points of
entry into the cortex are the respective primary cortical areas (see
Fig. 25.4, p. 1067). Damage to any of these primary areas will
result in reduction or loss of the ability to perceive that particular
modality: ‘negative’ symptomatology. Abnormal excitation of
these areas can result in a false perception (‘positive’ symptoms),
the most common of which is migrainous visual aura (flashing
lights or teichopsia).
Cortical lesions are more likely to cause a mixed motor and
sensory loss. Substantial lesions of the parietal cortex (as in large
strokes) can cause severe loss of proprioception and may even
abolish conscious awareness of the existence of the affected
limb(s), known as neglect; this can be difficult to distinguish
from paralysis. Pathways are so tightly packed in the thalamus
that even small lacunar strokes can cause isolated contralateral
hemisensory loss.
Neuropathic pain
Neuropathic pain is a positive neurological symptom caused
by dysfunction of the pain perception apparatus, in contrast to
nociceptive pain, which is secondary to pathological processes
such as inflammation. Neuropathic pain has distinctive features
and typically provokes a very unpleasant, persistent, burning
sensation. There is often increased sensitivity to touch, so that
light brushing of the affected area causes exquisite pain (allodynia).
Painful stimuli are felt as though they arise from a larger area
than that touched, and spontaneous bursts of pain may also
occur. Pain may be elicited by other modalities (allodynia) and
is considerably affected by emotional influences. The most
common causes of neuropathic pain are diabetic neuropathies,
trigeminal and post-herpetic neuralgias, and trauma to a peripheral
nerve. Treatment of these syndromes can be difficult. Drugs
that modulate various parts of the nociceptive system, such as
gabapentin, carbamazepine or tricyclic antidepressants, may
help. Localised treatment (topical treatment or nerve blocks)
sometimes succeeds but may increase the sensory deficit and
worsen the situation. Electrical stimulation has occasionally proved
successful. For further information, see page 1347.
Abnormal movements
Disorders of movement lead to either extra, unwanted movement
(hyperkinetic disorders) or too little movement (hypokinetic
disorders) (Box 25.15). In either case, the lesion often localises to
the basal ganglia, although some tremors are related to cerebellar
or brainstem disturbance. Functional movement disorders are
common and may mimic all of the organic syndromes below.
The most important hypokinetic disorder is Parkinson’s disease
(p. 1112). Parkinsonism is a clinical description of a collection
of symptoms, including tremor, bradykinesia and rigidity. While
the history is always important, observation is clearly vital; much
Presenting problems in neurological disease • 1085
of the skill in diagnosing movement disorders lies in pattern
recognition. Once it is established whether the problem is hypo- or
hyperkinetic, the next task is to categorise the movements further,
accepting that there is often overlap. Videoing the movements
(with the patient’s consent), so that they can be shown to a
movement disorder expert, may provide a quick diagnosis in
cases of uncertainty.
iJYemor
Tremor is caused by alternating agonist/antagonist muscle
contractions and produces a rhythmical oscillation of the body
25.15
Movement disorders
Description
Features
Examples
Hypokinetic disorders
Parkinsonism
Akinesia
Idiopathic Parkinson’s
Rigidity
disease
Tremor
Other degenerative
Loss of postural reflexes
syndromes
Other features depending
Drug-induced
on cause
(See Box 25.54)
Catatonia
Mutism
Usually psychiatric; if
Sustained posturing and
neurological, is most
waxy flexibility
commonly of vascular
origin
Hyperkinetic disorders
Tremor
Rhythmical oscillation of
Essential tremor
body part (see Box 25.16)
Parkinson’s disease
Drug-induced
Chorea
Jerky, brief, involuntary
Huntington’s disease
movements
Drug-induced
Tics
Stereotyped, repetitive
movements, briefly
suppressible
Tourette’s syndrome
Myoclonus
Shock-like muscle jerks
Epilepsy
Hypnic jerks (p. 1086)
Focal cortical disease
Dystonia
Sustained muscle
Genetic
contraction causing
Generalised dystonic
abnormal postures ±
syndromes
tremor
Focal dystonias in
adults (e.g. torticollis)
Others
Various
Paroxysmal hyperkinetic
dyskinesias
Hemifacial spasm
Tardive syndromes
part affected. In the assessment of tremor, the position, body
part affected, frequency and amplitude should be considered,
as these provide diagnostic clues (Box 25.16).
Other hyperkinetic syndromes
Non-rhythmic involuntary movements include chorea, athetosis,
ballism, dystonia, myoclonus and tics. They are categorised by
clinical appearance, and coexistence and overlap are common,
such as in choreoathetosis.
Chorea
Chorea refers to jerky, brief, purposeless involuntary movements,
appearing fidgety and affecting different areas. They suggest
disease in the caudate nucleus (as in Huntington’s disease,
p. 1114) and are a common complication of levodopa treatment
for Parkinson’s disease. Other causes are shown in Box 25.17.
25.17 Causes of chorea
Hereditary
• Huntington’s disease (HD) and
• Dentato-rubro-pallidoluysian
HD-like syndromes
atrophy
• Wilson’s disease
• Benign hereditary chorea
• Neuroacanthocytosis
• Paroxysmal dyskinesias
Cerebral birth injury (including kernicterus)
Cerebral trauma
Drugs
• Levodopa (long-term with
• Antiepileptics
Parkinson’s disease)
• Oral contraceptive
• Antipsychotics
Metabolic
• Disorders affecting thyroid,
• Pregnancy
parathyroid, glucose, sodium,
calcium and magnesium
balance
Autoimmune
• Post-streptococcal
• Autoimmune encephalitis
(Sydenham’s chorea)
• Systemic lupus erythematosus
• Antiphospholipid antibody
syndrome
Structural lesions of basal ganglia (usually caudate)
• Vascular
• Brain tumour
• Demyelination
25.16 Causes and characteristics of tremors
Body part affected
Position
Frequency
Amplitude
Character
Physiological
Both arms > legs
Posture, movement
High
Small (fine)
Enhanced by anxiety,
emotion, drugs, toxins
Parkinsonism
Unilateral or asymmetrical
Arm > leg, chin, never head
Rest
Postural and re-emergent
may occur
Low (3-4 Hz)
Moderate
Typically pill-rolling, thumb
and index finger, other
features of parkinsonism
Essential tremor
Bilateral arms, head
Movement
High (8-10 Hz)
Low to moderate
Family history; 50%
respond to alcohol
Dystonic
Head, arms, legs
Posture
Variable
Variable
Other features of dystonia,
often jerky tremors
Functional
Any
Any
Variable
Variable
Distractible
1086 • NEUROLOGY
Athetosis
Slower, writhing movement of the limbs are often combined with
chorea and have similar causes.
Ballism
This more dramatic form of chorea causes often violent flinging
movements of one limb (monoballism) or one side of the body
(hemiballism). The lesion localises to the contralateral subthalamic
nucleus and the most common cause is stroke.
Dystonia
Sustained involuntary muscle contraction causes abnormal
postures or movement. It may be generalised (usually in childhood-
onset genetic syndromes) or, more commonly, focal/segmental
(such as in torticollis, when the head is twisted repeatedly to one
side). Some dystonias occur only with specific tasks, such as
writer’s cramp or other occupational ‘cramps’. Dystonic tremor
is associated, and is asymmetrical and of large amplitude.
Myoclonus
Myoclonus consists of brief, isolated, random jerks of muscle
groups. This is physiological at the onset of sleep (hypnic jerks).
Similarly, a myoclonic jerk is a component of the normal startle
response, which may be exaggerated in some rare (mostly
genetic) disorders. Myoclonus may occur in disorders of the
cerebral cortex, such as some forms of epilepsy. Alternatively,
myoclonus can arise from subcortical structures or, more rarely,
from segments of the spinal cord.
Tics
Tics are stereotyped repetitive movements, such as blinking,
winking, head shaking or shoulder shrugging. Unlike dyskinesias,
the patient may be able to suppress them, although only for a
short time. Isolated tics are common in childhood and usually
disappear. Tourette’s syndrome is defined by the presence of
multiple motor and vocal tics that may evolve over time; it is
frequently associated with psychiatric disease, including obsessive
compulsions, depression, self-harm or attention deficit disorder.
Tics may also occur in Huntington’s and Wilson’s diseases, or
after streptococcal infection.
Abnormal perception
The parietal lobes are involved in the higher processing and
integration of primary sensory information. This takes place in
areas referred to as ‘association’ cortex, damage to which gives
rise to sensory (including visual) inattention, disorders of spatial
perception, and disruption of spatially orientated behaviour,
leading to apraxia. Apraxia is the inability to perform complex,
organised activity in the presence of normal basic motor, sensory
and cerebellar function (after weakness, numbness and ataxia
have been excluded as causes). Examples of complex motor
activities include dressing, using cutlery and geographical
orientation. Other abnormalities that can result from damage
to the association cortex involve difficulty reading (dyslexia) or
writing (dysgraphia), or the inability to recognise familiar objects
(agnosia). The results of damage to particular lobes of the brain
are given in Box 25.2 (p. 1066).
Altered balance and vertigo
Balance is a complicated dynamic process that requires ongoing
modification of both axial and limb muscles to compensate for the
effects of gravity and alterations in body position and load (and
hence centre of gravity) in order to prevent a person from falling.
This requires input from a variety of sensory modalities (visual,
vestibular and proprioceptive), processing by the cerebellum and
brainstem, and output via a number of descending pathways
(e.g. vestibulospinal, rubrospinal and reticulospinal tracts).
Disorders of balance can therefore arise from any part of this
process. Disordered input (loss of vision, vestibular disorders or
lack of joint position sense), processing (damage to vestibular
nuclei or cerebellum) or motor function (spinal cord lesions, leg
weakness of any cause) can all impair balance. The patient
may complain of different symptoms, depending on the location
of the lesion. For example, loss of joint position sense or
cerebellar function may result in a sensation of unsteadiness,
while damage to the vestibular nuclei or labyrinth may result in
an illusion of movement, such as vertigo (see below). A careful
history is vital. Since vision can often compensate for lack of
joint position sense, patients with peripheral neuropathies or
dorsal column loss will often find their problem more noticeable
in the dark.
Examination of such patients may yield physical signs that
again depend on the site of the lesion. Sensory abnormalities
may be manifest as altered visual acuities or visual fields, possibly
with abnormalities on fundoscopy, altered eye movements
(including nystagmus, p. 1090), impaired vestibular function (p.
1104) or lack of joint position sense. Disturbance of cerebellar
function may be manifest as nystagmus, dysarthria or ataxia, or
difficulty with gait (unsteadiness or inability to perform tandem
gait; see below). Leg weakness, if present, will be detectable
on examination of the limbs.
Vertigo
Vertigo is defined as an abnormal perception of movement of
the environment or self, and occurs because of conflicting visual,
proprioceptive and vestibular information about a person’s position
in space. Vertigo commonly arises from imbalance of vestibular
input and is within the experience of most people, since this is the
‘dizziness’ that occurs after someone has spun round vigorously
and then stops. Bilateral labyrinthine dysfunction often causes
some unsteadiness. Labyrinthine vertigo usually lasts days at
a time, though it may recur, while vertigo arising from central
(brainstem) disorders is often persistent and accompanied by
other brainstem signs. Benign paroxysmal positional vertigo
(p. 1104) lasts a few seconds on head movement. A careful
history will reveal the likely cause in most patients.
Abnormal gait
Many neurological disorders can affect gait. Observing patients
as they walk into the consulting room can be very informative,
although formal examination is also important. Neurogenic gait
disorders need to be distinguished from those due to skeletal
abnormalities, usually characterised by pain producing an antalgic
gait, or limp. Gait alteration incompatible with any anatomical or
physiological deficit may be due to functional disorders.
Pyramidal gait
Upper motor neuron lesions cause characteristic extension of
the affected leg. The resultant tendency for the toes to strike
the ground on walking requires the leg to swing outwards
at the hip (circumduction). Nevertheless, a shoe on the affected
side worn down at the toes may provide evidence of this type of
Presenting problems in neurological disease • 1087
gait. In hemiplegia, the asymmetry between affected and normal
sides is obvious on walking, but in paraparesis both lower limbs
swing slowly from the hips in extension and are dragged stiffly
over the ground - described as ‘walking in mud’.
Foot drop
In normal walking, the heel is the first part of the foot to hit the
ground. A lower motor neuron lesion affecting the leg will cause
weakness of ankle dorsiflexion, resulting in a less controlled
descent of the foot, which makes a slapping noise as it hits the
ground. In severe cases, the foot will have to be lifted higher at
the knee to allow room for the inadequately dorsiflexed foot to
swing through, resulting in a high-stepping gait.
Myopathic gait
During walking, alternating transfer of the body’s weight through
each leg requires adequate hip abduction. In proximal muscle
weakness, usually caused by muscle disease, the hips are
not properly fixed by these muscles and trunk movements are
exaggerated, producing a rolling or waddling gait.
Ataxic gait
An ataxic gait can result from lesions in the cerebellum, vestibular
apparatus or peripheral nerves. Patients with lesions of the central
portion of the cerebellum (the vermis) walk with a characteristic
broad-based gait ‘as if drunk’ (cerebellar function is particularly
sensitive to alcohol). Patients with acute vestibular disturbances
walk similarly but the accompanying vertigo is characteristic.
Inability to walk heel to toe may be the only sign of less severe
cerebellar dysfunction.
Proprioceptive defects can also cause an ataxic gait. The
impairment of joint position sense makes walking unreliable,
especially in poor light. The feet tend to be placed on the ground
with greater emphasis, presumably to enhance proprioceptive
input, resulting in a ‘stamping’ gait.
Apraxic gait
In an apraxic gait, power, cerebellar function and proprioception
are normal on examination of the legs. The patient may be able
to carry out complex motor tasks (e.g. bicycling motion) while
recumbent and yet cannot formulate the motor act of walking.
In this higher cerebral dysfunction, the feet appear stuck to
the floor and the patient cannot walk. Gait apraxia is a sign of
diffuse bilateral hemisphere disease (such as normal pressure
hydrocephalus) or diffuse frontal lobe disease.
Marche a petits pas
This gait is characterised by small, slow steps and marked
instability. It differs from the festination found in Parkinson’s
disease (see below), in that it lacks increasing pace and freezing.
The usual cause is small-vessel cerebrovascular disease and
there may be accompanying bilateral upper motor neuron signs.
Extrapyramidal gait
The rigidity and bradykinesia of basal ganglia dysfunction
(p. 1112) lead to a stooped posture and characteristic gait
difficulties, with problems initiating walking and controlling the
pace of the gait. Patients may become stuck while trying to start
walking or when walking through doorways (‘freezing’). The centre
of gravity will be moved forwards to aid propulsion, which, with
poor axial control, can lead to an accelerating pace of shuffling
and difficulty stopping. This produces the festinant gait: initial
stuttering steps that quickly increase in frequency while decreasing
in length.
Abnormal speech and language
Speech disturbance may be isolated to disruption of sound output
(dysarthria) or may involve language disturbance (dysphasia).
Dysphonia (reduction in the sound/volume) is usually due to
mechanical laryngeal disruption, whereas dysarthria is more
typically neurological in origin. Dysphasia is always neurological
and localises to the dominant cerebral hemisphere (usually
left, regardless of handedness). Combinations of speech and
swallowing problems are explained below (p. 1093).
Dysphonia
Dysphonia describes hoarse or whispered speech. The most
common cause is laryngitis, but dysphonia can also result from
a lesion of the 10th cranial nerve or disease of the vocal cords,
including laryngeal dystonia. Parkinsonism may cause hypophonia
with marked reduction in speech volume, often in association
with dysarthria, making speech difficult to understand.
| Dysarthria
Dysarthria is characterised by poorly articulated or slurred speech
and can occur in association with lesions of the cerebellum,
brainstem and lower cranial nerves, as well as in myasthenia
or myopathic disease. Language function is not affected. The
quality of the speech tends to differ, depending on the cause, but
25.18 Causes of dysarthria
Type
Site
Characteristics
Associated features
Myopathic
Muscles of speech
Indistinct, poor articulation
Weakness of face, tongue and neck
Myasthenic
Motor end plate
Indistinct with fatigue and dysphonia
Fluctuating severity
Ptosis, diplopia, facial and neck weakness
Bulbar
Brainstem
Indistinct, slurred, often nasal
Dysphagia, diplopia, ataxia
‘Scanning’
Cerebellum
Slurred, impaired timing and cadence,
‘sing-song’
Ataxia of limbs and gait, tremor of head/limbs
Nystagmus
Spastic (‘pseudo-bulbar’)
Pyramidal tracts
Indistinct, nasal tone, mumbling
Poor rapid tongue movements, increased reflexes
and jaw jerk
Parkinsonian
Basal ganglia
Indistinct, rapid, stammering, quiet
Tremor, rigidity, slow shuffling gait
Dystonic
Basal ganglia
Strained, slow, high-pitched
Dystonia, athetosis
1088 • NEUROLOGY
it can be very difficult to distinguish the different types clinically
(Box 25.18). Dysarthria is discussed further in the section on
bulbar symptoms (p. 1093).
Dysphasia
Dysphasia (or aphasia) is a disorder of the language content of
speech. It can occur with lesions over a wide area of the dominant
hemisphere (Fig. 25.19). Dysphasia may be categorised according
to whether the speech output is fluent or non-fluent. Fluent
aphasias, also called receptive aphasias, are impairments related
mostly to the input or reception of language, with difficulties either
in auditory verbal comprehension or in the repetition of words,
phrases or sentences spoken by others. Speech is easy and
fluent but there are difficulties related to the output of language as
well, such as paraphasia (either substitution of similar-sounding
non-words, or incorrect words) and neologisms (non-existent
words). Examples include Wernicke’s aphasia (which localises
to the superior posterior temporal lobe), transcortical sensory
aphasia, conduction aphasia and anomic aphasia.
Non-fluent aphasias, also called expressive aphasias, are
difficulties in articulating, but in most cases there is relatively
good auditory verbal comprehension. Examples include Broca’s
aphasia (associated with pathologies in the inferior frontal region),
transcortical motor aphasia and global aphasia.
‘Pure’ aphasias are selective impairments in reading, writing
or the recognition of words. These disorders may be quite
selective. For example, a person is able to read but not write,
or is able to write but not read. Examples include pure alexia,
agraphia and pure word deafness.
Dysphasia (a focal symptom) is frequently misinterpreted as
disorientation (which is non-focal) and it is important always
to consider dysphasia as an alternative explanation for the
apparently ‘confused’ patient. Dysphasia can be misheard/
misspelt as dysphagia, and for this reason some prefer to use
‘aphasia’ to avoid confusion.
Central
sulcus
Fig. 25.19 Classification of cortical speech problems. (1) Wernicke’s
aphasia: fluent dysphasia with poor comprehension and poor repetition.
(2) Conduction aphasia: fluent aphasia with good comprehension
and poor repetition. (3) Broca’s aphasia: non-fluent aphasia with good
comprehension and poor repetition. (4) Transcortical sensory aphasia:
fluent aphasia with poor comprehension and good repetition. (5)
Transcortical motor aphasia: non-fluent aphasia with good comprehension
and good repetition. Large lesions affecting all of regions 1-5 cause global
aphasia.
Disturbance of smell
Symptomatic olfactory loss is most commonly due to local
causes (nasal obstruction) but may follow head injury. Hyposmia
may predate motor symptoms in Parkinson’s disease by many
years, although it is rarely noticed by the patient. Frontal lobe
lesions are a rare cause. Positive olfactory symptoms may arise
in Alzheimer’s disease or epilepsy.
Visual disturbance and
ocular abnormalities
Disturbances of vision may be due to primary ocular disease or
to disorders of the central connections and visual cortex. Visual
symptoms are usually negative (loss of vision) but sometimes
positive, most commonly in migraine. Eye movements may be
disturbed, giving rise to double vision (diplopia) or blurred vision.
Loss of vision is also discussed on page 1170.
| Visual loss
Visual loss can occur as the result of lesions in any areas between
the retina and the visual cortex. Patterns of visual field loss are
explained by the anatomy of the visual pathways (see Fig. 25.7,
p. 1069). Associated clinical manifestations are described in
Box 25.19. Visual symptoms affecting one eye only are due to
lesions anterior to the optic chiasm.
Transient visual loss is quite common and sudden-onset visual
loss lasting less than 1 5 minutes is likely to have a vascular origin.
It may be difficult to know whether the visual loss was monocular
(carotid circulation) or binocular (vertebrobasilar circulation), and
it is important to ask if the patient tried closing each eye in turn
to see whether the symptom affected one eye or both. Visual
field testing is an important part of the examination, either at
the bedside or formally with perimetry. Field defects become
more symmetrical (congruous), the closer the lesion comes to
the visual cortex.
Migrainous visual symptoms are very common and, when
associated with typical headache and other migraine features,
rarely pose a diagnostic challenge. They may occur in isolation,
however, making distinction from TIA difficult, but TIAs typically
cause negative (blindness) symptoms, whereas migraine causes
positive phenomena (see below). TIAs often last for a shorter
time (a few minutes), compared to the 10-60-minute duration
of migraine aura, and have an abrupt onset and end, unlike the
gradual evolution of a migraine aura.
|Positive visual phenomena
The most common cause is migraine; patients may describe
silvery zigzag lines (fortification spectra) or flashing coloured
lights (teichopsia), usually preceding the headache. Simple
flashes of light (phosphenes) may indicate damage to the retina
(e.g. detachment) or to the primary visual cortex. Formed visual
hallucinations may be caused by drugs or may be due to epilepsy
or ‘release phenomena’ in a blind visual field (Charles Bonnet
syndrome).
Double vision
Diplopia arises from misalignment of the eyes, meaning that the
image is not projected to the same points on the two retinas.
At its most subtle it may be reported as blurred rather than
Presenting problems in neurological disease • 1089
25.19 Clinical manifestations of visual field loss
Site of lesion
Common causes
Complaint
Visual field loss
Associated physical signs
Retina/optic disc
Vascular disease
(including vasculitis)
Glaucoma
Inflammation
Partial/complete visual loss
depending on site, involving
one or both eyes
Altitudinal field defect
Arcuate scotoma
Reduced acuity
Visual distortion (macula)
Abnormal retinal appearance
Optic nerve
Optic neuritis
Sarcoidosis
Tumour
Leber’s hereditary optic
neuropathy
Partial/complete loss of
vision in one eye
Often painful
Central vision particularly
affected
Central or paracentral
scotoma
Monocular blindness
Reduced acuity
Reduced colour vision
Relative afferent pupillary defect
Optic atrophy (late)
Optic chiasm
Pituitary tumour
Craniopharyngioma
Sarcoidosis
May be none
Rarely, diplopia (‘hemifield
slide’)
Bitemporal hemianopia
Pituitary function abnormalities
Optic tract
Tumour
Inflammatory disease
Disturbed vision to one side
of midline
Incongruous contralateral
homonymous hemianopia
Temporal lobe
Stroke
Tumour
Inflammatory disease
Disturbed vision to one side
of midline
Contralateral homonymous
upper quadrantanopia
Memory/language disorders
Parietal lobe
Stroke
Tumour
Inflammatory disease
Disturbed vision to one side
of midline
Bumping into things
Contralateral homonymous
lower quadrantanopia
Contralateral sensory disturbance
Asymmetry of optokinetic nystagmus
Occipital lobe
Stroke
Tumour
Inflammatory disease
Disturbed vision to one side
of midline
Difficulty reading
Bumping into things
Homonymous hemianopia
(may be macula-sparing)
Damage to other structures supplied
by posterior cerebral circulation
25.20 Common causes of damage to cranial nerves 3, 4 and 6
Site
Common pathology
Nerve(s) involved
Associated features
Brainstem
Infarction
3 (mid-brain)
Contralateral pyramidal signs
Haemorrhage
Demyelination
Intrinsic tumour
6 (ponto-medullary junction)
Ipsilateral lower motor neuron facial palsy
Other brainstem/cerebellar signs
Intrameningeal
Meningitis (infective/malignant)
3, 4 and/or 6
Meningism, features of primary disease course
Raised intracranial pressure
6
3 (uncal herniation)
Papilloedema
Features of space-occupying lesion
Aneurysms
3 (posterior communicating artery)
6 (basilar artery)
Pain
Features of subarachnoid haemorrhage
Cerebello-pontine angle tumour
6
8, 7, 5 nerve lesions (order of likelihood)
Ipsilateral cerebellar signs
Trauma
3, 4 and/or 6
Other features of trauma
Cavernous
sinus
Infection/thrombosis
Carotid artery aneurysm
Caroticocavernous fistula
3, 4 and/or 6
May be 5th nerve involvement also
Pupil may be fixed, mid-position
(Sympathetic plexus on carotid may also be
affected)
Superior
orbital fissure
Tumour (e.g. sphenoid wing meningioma)
Granuloma
3, 4 and/or 6
May be proptosis, chemosis
Orbit
Vascular (e.g. diabetes, vasculitis)
Infections
Tumour
Granuloma
Trauma
3, 4 and/or 6
Pain
Pupil often spared in vascular 3rd nerve palsy
double vision. Monocular diplopia indicates ocular disease, while
binocular diplopia suggests a neurological cause. Closing either
eye in turn will abort binocular diplopia. Once the presence
of binocular diplopia is confirmed, it should be established
whether the diplopia is maximal in any particular direction of
gaze, whether the images are separated horizontally or vertically,
and whether there are any associated symptoms or signs, such
as ptosis or pupillary disturbance.
Binocular diplopia may result from central disorders or
from disturbance of the ocular motor nerves, muscles or the
1090 • NEUROLOGY
Cranial nerve palsy
Direction of gaze
Primary position
Right 3rd nerve palsy
N.B. Pupil dilated; ptosis
Right 4th nerve palsy
(more evident on
downgaze)
No obvious squint
Right eye turns down
and out
Right eye turns slightly up
Right 6th nerve palsy
Unable to abduct right eye
Squint worse
Right eye turns medially
Direction of gaze
Unable to adduct right eye
Squint worse
Right eye elevates more as
it moves medially
Able to adduct right eye
No obvious squint
Fig. 25.20 Examination findings in 3rd, 4th and 6th nerve palsy. Diplopia tends to be more obvious on lateral gaze compared to primary position.
neuromuscular junction (see Fig. 25.8, p. 1070). The pattern
of double vision, along with any associated features, usually
allows the clinician to infer which nerves/muscles are affected,
while the mode of onset and other features (e.g. fatigability in
myasthenia) provide further clues to the cause.
The causes of ocular motor nerve palsies are listed in Box
25.20. Examination findings are illustrated in Figure 25.20.
Nystagmus
Nystagmus describes a repetitive to-and-fro movement of the
eyes. In central lesions, the slow drifts are the primary abnormal
movement, each followed by fast (corrective) phases. Nystagmus
occurs because the control systems of the eyes are defective,
causing them to drift off target; corrections then become
necessary to return fixation to the object of interest, causing
nystagmus. The direction of the fast phase is usually designated
as the direction of the nystagmus because it is easier to see.
Nystagmus may be horizontal, vertical or torsional, and usually
involves both eyes synchronously. It may be a physiological
phenomenon in response to sustained vestibular stimulation
or movement of the visual world (optokinetic nystagmus).
There are many causes of pathological nystagmus, the most
common sites of lesions being the vestibular system, brainstem
and cerebellum.
The brainstem and the cerebellum are involved in maintaining
eccentric positions of gaze. Lesions will therefore allow the eyes
to drift back in towards primary position, producing nystagmus
with fast component beats in the direction of gaze (gaze-evoked
nystagmus). This is the most common type of ‘central’ nystagmus;
it is most commonly bidirectional and not usually accompanied
by vertigo. Other signs of brainstem dysfunction may be evident.
Brainstem disease may also cause vertical nystagmus.
Unilateral cerebellar lesions may result in gaze-evoked
nystagmus when looking in the direction of the lesion, where
the fast phases are directed towards the side of the lesion.
Cerebellar hemisphere lesions also cause ‘ocular dysmetria’,
an overshoot of target-directed, fast eye movements (saccades)
resembling ‘past-pointing’ in limbs.
In vestibular lesions, damage to one of the horizontal canals
or its connections will allow the tonic output from the healthy
contralateral side to cause the eyes to drift towards the side of
the lesion. This elicits recurrent compensatory fast movements
away from the side of the lesion, manifest as unidirectional
horizontal nystagmus. Vertical and torsional components can
be seen with damage to other parts of the vestibular apparatus.
The nystagmus of peripheral labyrinthine lesions is accompanied
by vertigo and usually by nausea, vomiting and unsteadiness,
but as the CNS habituates, the nystagmus disappears (fatigues)
quite quickly. Central vestibular nystagmus is more persistent.
Nystagmus also occurs as a consequence of drug toxicity
and nutritional deficiency (e.g. thiamin). The severity is variable,
and it may or may not result in visual degradation, though it may
be associated with a sensation of movement of the visual world
(oscillopsia). Nystagmus may occur as a congenital phenomenon,
in which case both phases are equal and ‘pendular’, rather than
having alternating fast and slow components.
| Ptosis
Various disorders may cause drooping of the eyelids (ptosis)
and these are listed in Box 25.21 and shown on Figure 25.21 .
Abnormal pupillary responses
Abnormal pupillary responses may arise from lesions at
several points between the retina and brainstem. Lesions of
the oculomotor nerve, ciliary ganglion and sympathetic supply
produce characteristic ipsilateral disorders of pupillary function.
‘Afferent’ defects result from damage to an optic nerve, impairing
the direct response of a pupil to light, although leaving the
consensual response from stimulation of the normal eye intact.
Structural damage to the iris itself can also result in pupillary
abnormalities. Causes are given in Box 25.22. An example is
shown in Figure 25.22.
| Papilloedema
There are several causes of swelling of the optic disc but the
term ‘papilloedema’ is reserved for swelling secondary to raised
intracranial pressure, when obstructed axoplasmic flow from
retinal ganglion cells results in swollen nerve fibres, which in turn
cause capillary and venous congestion, producing papilloedema.
Presenting problems in neurological disease • 1091
25.21 Common causes of ptosis
Mechanism
Causes
Associated clinical features
3rd nerve palsy
Isolated palsy (see Box 25.20)
Central/supranuclear lesion
Ptosis is usually complete
Extraocular muscle palsy (eye ‘down and out’)
Depending on site of lesion, other cranial nerve palsies (e.g. 4, 5 and 6)
or contralateral upper motor neuron signs
Sympathetic lesion
(Horner’s syndrome:
see Fig. 25.22)
Central (hypothalamus/brainstem)
Peripheral (lung apex, carotid artery pathology)
Idiopathic
Ptosis is partial
Lack of sweating on affected side
Depending on site of lesion, brainstem signs, signs of apical lung/brachial
plexus disease, or ipsilateral carotid artery stroke
Myopathic
Myasthenia gravis
Dystrophia myotonica
Extraocular muscle palsies
Usually bilateral
More widespread muscle weakness, with fatigability in myasthenia
Progressive external ophthalmoplegia
Other characteristic features of individual causes
Other
Functional ptosis
Pseudo-ptosis (e.g. blepharospasm)
Local orbital/lid disease
Age-related levator dehiscence
Resistance to eye opening
Eyebrows depressed rather than raised
May be local orbital abnormality
Neurological causes of unilateral ptosis
r
Diplopia worse
on upgaze
?3rd nerve
paralysis
Check for dilated
pupil and other
signs of 3rd nerve
paralysis
T
3rd nerve
paralysis
T
Her |
T
T
Larger pupil
Smaller pupil
Diplopia
Diplopia
Increasing
accommodation
Normal pupil
T
Normal pupil
Horner’s
syndrome
Fatigable
weakness
Myasthenia
excluded
i
Consider
*
myasthenia
Family history
gravis
Consider
mitochondrial
disorder,
e.g. CPEO
Fig. 25.21 Differential diagnosis of unilateral ptosis. (CPEO = chronic progressive external ophthalmoplegia)
Fig. 25.22 Right-sided Horner’s syndrome due to paravertebral
metastasis at T1. There is ipsilateral partial ptosis and a small pupil.
The earliest sign is the cessation of venous pulsation seen at
the disc, progression causing the disc margins to become red
(hyperaemic). Disc margins become indistinct and haemorrhages
may occur in the retina (Fig. 25.23). Lack of papilloedema never
excludes raised intracranial pressure. Other causes of optic disc
swelling are listed in Box 25.23. Some normal variations of disc
appearance (e.g. optic nerve drusen, p. 1178) can mimic disc
swelling. Optic disc swelling is also discussed on page 1171.
Optic atrophy
Loss of nerve fibres causes the optic disc to appear pale, as
the choroid becomes visible (Fig. 25.24). A pale disc (optic
1092 • NEUROLOGY
25.22 Pupillary disorders
Disorder
Cause
Ophthalmological features
Associated features
3rd nerve palsy
See Box 25.21
Dilated pupil (especially with external
compression)
Extraocular muscle palsy (eye is typically
‘down and out’)
Complete ptosis
Other features of 3rd nerve palsy (see
Box 25.21)
Horner’s syndrome
(see Fig. 25.22)
Lesion to sympathetic
supply
Small pupil
Partial ptosis
Iris heterochromia (if congenital)
Ipsilateral failure of sweating
(anhidrosis)
Holmes-Adie syndrome
(tonic pupil)
Lesion of ciliary ganglion
(usually idiopathic)
Dilated pupil
Light-near dissociation (accommodate but do
not react to light)
Vermiform movement of iris during contraction
Disturbance of accommodation
Generalised areflexia
Argyll Robertson pupil
Dorsal mid-brain lesion
(syphilis or diabetes)
Small, irregular pupils
Light-near dissociation
Other features of tabes dorsalis
(P- 1125)
Local pupillary damage
Trauma/inflammatory
disease
Irregular pupils, often with adhesions to lens
(synechiae)
Variable degree of reactivity
Other features of trauma/underlying
inflammatory disease (e.g. cataract,
blindness etc.)
Relative afferent pupillary
defect (Marcus Gunn pupil)
Damage to optic nerve
Pupils symmetrical - swinging torch test
reveals dilatation in abnormal eye
Decreased visual acuity/colour vision
Central scotoma
Optic disc swelling or pallor
Choroid
CSF
Optic
nerve
Central retinal vein
Meningeal sheath
Swollen
optic disc
-Choroid Increased
Venous CSF pressure
Optic
nerve
Axonal transport
block
Swollen axons
Fig. 25.23 Mechanism of optic disc oedema (papilloedema). jj] Normal. [|J Disc oedema (e.g. due to cerebral tumour). [C] Fundus photograph of
the left eye showing optic disc oedema with a small haemorrhage on the nasal side of the disc. (CSF = cerebrospinal fluid) C, Courtesy of Dr B. Cullen.
25.23 Common causes of optic disc swelling
Raised intracranial pressure (papilloedema)
• Cerebral mass lesion (tumour,
abscess)
• Obstructive hydrocephalus
• Idiopathic intracranial
hypertension
Obstruction of ocular venous drainage
• Central retinal vein occlusion
• Cavernous sinus thrombosis
Systemic disorders affecting retinal vessels
• Hypertension
• Vasculitis
• Hypercapnia
Optic nerve damage
• Demyelination (optic neuritis/
papillitis)
• Leber’s hereditary optic
neuropathy
• Anterior ischaemic optic
neuropathy
• Toxins (e.g. methanol)
• Infiltration of optic disc
• Sarcoidosis
• Glioma
• Lymphoma
Fig. 25.24 Fundus photograph of the left eye of a patient with
familial optic atrophy. Note the marked pallor of the optic disc.
Presenting problems in neurological disease • 1093
atrophy) follows optic nerve damage; causes include previous
optic neuritis or ischaemic damage, long-standing papilloedema,
optic nerve compression, trauma and degenerative conditions
(e.g. Friedreich’s ataxia, p. 1116).
Hearing disturbance
Each cochlear organ has bilateral cortical representation, so
unilateral hearing loss is a result of peripheral organ damage.
Bilateral hearing dysfunction is usual and is most commonly due
to age-related degeneration or noise damage, although infection
and drugs (particularly diuretics and aminoglycoside antibiotics)
can be a primary cause. Prominent deafness may suggest a
mitochondrial disorder (see Box 25.93, p. 1144).
Bulbar symptoms - dysphagia
and dysarthria
Swallowing is a complex activity involving the coordinated
action of lips, tongue, soft palate, pharynx and larynx, which
are innervated by cranial nerves 7, 9, 10, 1 1 and 12. Structural
causes of dysphagia are considered on page 778. Neurological
mechanisms are vulnerable to damage at different points, resulting
in dysphagia that is usually accompanied by dysarthria. Tempo
is again crucial: acute onset of dysphagia may occur as a result
of brainstem stroke or a rapidly developing neuropathy, such
as Guillain-Barre syndrome or diphtheria. Intermittent fatigable
muscle weakness (including dysphagia) would suggest myasthenia
gravis. Dysphagia developing over weeks or months may be
seen in motor neuron disease, basal meningitis and inflammatory
brainstem disease. More slowly developing dysphagia suggests
a myopathy or possibly a brainstem or skull-base tumour.
Pathologies affecting lower cranial nerves (9, 10, 11 and
12) frequently manifest bilaterally, producing dysphagia and
dysarthria. The term ‘bulbar palsy’ is used to describe lower
motor neuron lesions, either within the medulla or outside the
brainstem. The tongue may be wasted and fasciculating, and
palatal movement is reduced.
Upper motor neuron innervation of swallowing is bilateral, so
persistent dysphagia is unusual with a unilateral upper motor
lesion (the exception being in the acute stages of, for example,
a hemispheric stroke). Widespread lesions above the medulla
I! 25.24 Causes of pseudobulbar and bulbar palsy
Type
Pseudobulbar
Bulbar
Genetic
-
Kennedy’s disease (X-linked
bulbospinal neuronopathy)
Vascular
Bilateral hemisphere
(lacunar) infarction
Medullary infarction (see
Box 25.3, p. 1072)
Degenerative
Motor neuron
disease (p. 1116)
Motor neuron disease
Syringobulbia
Inflammatory/
infective
Multiple sclerosis
(p. 1106)
Cerebral vasculitis
Myasthenia (p. 1140)
Guillain-Barre syndrome
(p. 1140)
Poliomyelitis (p. 1123)
Lyme disease (p. 255)
Vasculitis
Neoplastic
High brainstem
tumours
Brainstem glioma
Malignant meningitis
will cause upper motor neuron bulbar paralysis, known as
‘pseudobulbar palsy’. Here the tongue is small and contracted,
and moves slowly; the jaw jerk is brisk, and there may be
associated emotional variability. Causes of these are shown
in Box 25.24.
Bladder, bowel and sexual disturbance
While isolated disturbances of bladder, bowel and sexual function
are rarely the sole presenting features of neurological disease, they
are common complications of many chronic disorders such as
multiple sclerosis, stroke and dementia, and are frequently found
post head injury. Abnormalities in these functions considerably
reduce quality of life for patients. Incontinence and its management
are discussed elsewhere (pp. 397, 835 and 1309).
Bladder dysfunction
The anatomy and physiology involved in controlling bladder
functions are discussed on page 386 but it is worth emphasising
the role of the pontine micturition centre, which is itself under
higher control via inputs from the pre-frontal cortex, mid-brain
and hypothalamus.
In the absence of conscious control (e.g. in coma or dementia),
distension of the bladder to near capacity evokes reflex detrusor
contraction (analogous to the muscle stretch reflex), and reciprocal
changes in sympathetic activation and relaxation of the distal
sphincter result in coordinated bladder emptying.
Damage to the lower motor neuron pathways (the pelvic and
pudendal nerves) produces a flaccid bladder and sphincter with
overflow incontinence, often accompanied by loss of pudendal
sensation. Such damage may be due to disease of the conus
medullaris or sacral nerve roots, either within the dura (as in
inflammatory or carcinomatous meningitis) or as they pass
through the sacrum (trauma or malignancy), or due to damage
to the nerves themselves in the pelvis (infection, haematoma,
trauma or malignancy).
Damage to the pons or spinal cord results in an ‘upper motor
neuron’ pattern of bladder dysfunction due to uncontrolled
over-activity of the parasympathetic supply. The bladder is small
and highly sensitive to being stretched. This results in frequency,
urgency and urge incontinence. Loss of the coordinating control
of the pontine micturition centre will also result in the phenomenon
of detrusor-sphincter dyssynergia, in which detrusor contraction
and sphincter relaxation are not coordinated; the spastic
bladder will often try to empty against a closed sphincter. This
manifests as both urgency and an inability to pass urine, which
is distressing and painful. The resultant incomplete bladder
emptying predisposes to urinary infection, and the prolonged
high intravesical pressure may result in obstructive uropathy and
renal failure; post-micturition bladder ultrasound may confirm
incomplete bladder emptying. More severe lesions of the spinal
cord, as in spinal cord compression or trauma, can result in
painless urinary retention as bladder sensation, normally carried
in the lateral spinothalamic tracts, will be disrupted.
Damage to the frontal lobes gives rise to loss of awareness
of bladder fullness and consequent incontinence. Coexisting
cognitive impairment may result in inappropriate micturition.
These features may be seen in hydrocephalus, frontal tumours,
dementia and bifrontal subdural haematomas.
When a patient presents with bladder symptoms, it is important
to localise the lesion on the basis of history and examination,
remembering that most bladder problems are not neurological
1094 • NEUROLOGY
25.25 Neurogenic bladder: clinical features and treatment
Type
Site of lesion
Result
Treatment
Atonic (lower motor neuron)
Sacral segments of cord
(conus medullaris)
Sacral roots and nerves
Loss of detrusor contraction
Difficulty initiating micturition
Bladder distension with overflow
Intermittent self-catheterisation
In-dwelling catheterisation
Hypertonic (upper motor neuron)
Pyramidal tract in spinal cord
or brainstem
Urgency with urge incontinence
Bladder sphincter incoordination (dyssynergia)
Incomplete bladder emptying
Anticholinergics:
Solifenacin
Tolterodine
Imipramine
Intermittent self-catheterisation
Cortical
Post-central
Pre-central
Frontal
Loss of awareness of bladder fullness
Difficulty initiating micturition
Inappropriate micturition
Loss of social control
Intermittent or in-dwelling
catheterisation
unless there are overt neurological signs. Clinical features and
management are summarised in Box 25.25.
Rectal dysfunction
The rectum has an excitatory cholinergic input from the
parasympathetic sacral outflow, and inhibitory sympathetic supply
similar to the bladder. Continence depends largely on skeletal
muscle contraction in the puborectalis and pelvic floor muscles
supplied by the pudendal nerves, as well as the internal and
external anal sphincters. Damage to the autonomic components
usually causes constipation (a common early symptom in
Parkinson’s disease) but diabetic neuropathy can be associated
with diarrhoea. Lesions affecting the conus medullaris, the
somatic S2-4 roots and the pudendal nerves may cause faecal
incontinence.
Erectile failure and ejaculatory failure
These related functions are under autonomic control via
the pelvic nerves (parasympathetic, S2-4) and hypogastric
nerves (sympathetic, LI -2). Descending influences from the
cerebrum are important for erection but it can occur as a reflex
phenomenon in response to genital stimulation. Erection is largely
parasympathetic and may be impaired by a number of drugs,
including anticholinergic, antihypertensive and antidepressant
agents. Sympathetic activity is important for ejaculation and
may be inhibited by a-adrenoceptor antagonists (a-blockers).
For further information on erectile dysfunction, see page 440.
Personality change
While this is often due to psychiatric illness, neurological
conditions that alter the function of the frontal lobes can cause
personality change and mood disorder (see Box 25.2, p. 1066).
Personality change due to a frontal lobe disorder may occur as
the result of structural damage due to stroke, trauma, tumour
or hydrocephalus. The nature of any change may help localise
the lesion.
Patients with mesial frontal lesions become increasingly
withdrawn, unresponsive and mute (abulic), often in association
with urinary incontinence, gait apraxia and an increase in tone
known as gegenhalten, in which the patient varies the resistance
to movement in proportion to the force exerted by the examiner.
Patients with lesions of the dorsolateral pre-frontal cortex
develop a dysexecutive syndrome, which involves difficulties with
speech, motor planning and organisation. Those with orbitofrontal
lesions of the frontal lobes, in contrast, become disinhibited,
displaying grandiosity or irresponsible behaviour. Memory is
substantially intact but frontal release signs may emerge, such
as a grasp reflex, palmomental response or pout. Proximity to
the olfactory bulb and tracts means that inferior frontal lobe
tumours may be associated with anosmia.
Disturbance to the cortical areas responsible for speech
or memory can result in changes that may be interpreted as
changes in personality.
Sleep disturbance
Disturbances of sleep are common and are not usually due to
neurological disease. Patients may complain of insomnia (difficulty
sleeping), excessive daytime sleepiness, disturbed behaviour
during night-time sleep, parasomnia (sleep walking and talking,
or night terrors) or disturbing subjective experiences during
sleep and/or its onset (nightmares, hypnagogic hallucinations,
sleep paralysis). A careful history (from bed partner as well as
patient) usually allows specific causes of sleep disturbance
to be identified and these are discussed in more detail
on page 1105.
Psychiatric disorders
Psychiatric disorders are described in Chapter 28 but may cause
or result from neurological problems. Care is needed in their
identification, as effective management will help the underlying
neurological illness.
Functional symptoms
Many patients presenting with neurological symptoms do not
have a defined neurological disease and are best described
as having functional symptoms (p. 1187). Some of these are
psychogenic (or conversion) disorders. Such patients often
have symptoms affecting multiple systems and an impressively
long list of consultations and negative tests from other medical
specialties when they present. Considering the possibility of a
functional origin may save the patient some further anxiety and
further investigation (which will be unnecessary, expensive,
possibly invasive, and inconvenient).
Headache syndromes • 1095
25.26 Clinical features suggestive
of functional disorder
Weakness and sensory change predominate among patients
with functional neurological disorders but pain or loss of
consciousness can also occur. Associated symptoms, such as
tiredness, lethargy, poor concentration, bowel upset (irritable
bowel syndrome) and gynaecological complaints, are common.
A functional cause should always be considered, as it can allow
for more rapid diagnosis and minimise investigation. Some clinical
features may hint at a functional origin for symptoms (Box 25.26).
It is the clinician’s (rewarding, albeit sometimes challenging) job
to elicit the context of the patient’s symptoms in a sensitive and
non-judgemental manner. Whatever the cause of the illness, it
is important to acknowledge that mood and sleep disturbance
will exacerbate neurological symptoms, thus increasing disability.
The best practitioners have the skill to carry the patient with
them when describing the patterns of behaviour contributing
to worsening symptoms.
Assessment to detect an underlying or exacerbating mood
disorder is vital in all patients, ensuring that depression and
anxiety are managed to minimise their secondary effects on
neurological symptoms.
Headache syndromes
Acute management of headache is dealt with on page 1 84 but
management of chronic, complex, or refractory headaches may
require specialist input. Headaches may be classified as primary
or secondary, depending on the underlying cause (see Box
10.10, p. 184). Secondary headache may be due to structural,
infective, inflammatory or vascular conditions, discussed later in
this chapter. Primary headache syndromes are described here.
|Jension-type headache
This is the most common type of headache and is experienced
to some degree by the majority of the population.
Pathophysiology
Tension-type headache is incompletely understood, and some
consider that it is simply a milder version of migraine; certainly,
the original notion that it is due primarily to muscle tension
(hence the unsatisfactory name) has long since been dismissed.
Anxiety about the headache itself may lead to continuation of
symptoms, and patients may become convinced of a serious
underlying condition.
Clinical features
The pain of tension headache is characterised as ‘dull’, ‘tight’
or like a ‘pressure’, and there may be a sensation of a band
round the head or pressure at the vertex. It is of constant
character and generalised, but often radiates forwards from
the occipital region. It may be episodic or persistent, although
the severity may vary, and there is no associated vomiting or
photophobia. Tension-type headache is rarely disabling and
patients appear well. The pain often progresses throughout the
day. Tenderness may be present over the skull vault or in the
occiput but is easily distinguished from the triggered pains of
trigeminal neuralgia and the exquisite tenderness of temporal
arteritis. Analgesics may be taken with chronic regularity, despite
little effect, and may perpetuate the symptoms (see ‘Medication
overuse headache’ below).
Management
Most benefit is derived from a careful assessment, followed by
discussion of likely precipitants and reassurance that the prognosis
is good. The concept of medication overuse headache needs
careful explanation. An important therapeutic step is to allow
patients to realise that their problem has been taken seriously
and rigorously assessed. Physiotherapy (with muscle relaxation
and stress management) may help and low-dose amitriptyline can
provide benefit. Investigation is rarely required. The reassurance
value of brain imaging needs careful assessment: the pick-up rate
of structural abnormalities is exceedingly low, and significantly
outweighed by the likelihood of identifying an incidental and
irrelevant finding (e.g. an arachnoid cyst, Chiari I malformation or
vascular abnormality). The value of such ‘reassurance’ is usually
over-estimated by doctors and patients alike.
| Migraine
Migraine usually appears before middle age, or occasionally in
later life; it affects about 20% of females and 6% of males at
some point in life. Migraine is usually readily identifiable from
the history, although unusual variants can cause uncertainty.
Pathophysiology
The cause of migraine is unknown but there is increasing evidence
that the aura (see below) is due to dysfunction of ion channels
causing a spreading front of cortical depolarisation (excitation)
followed by hyperpolarisation (depression of activity). This process
(the ‘spreading depression of Leao’) spreads over the cortex at a
rate of about 3 mm/min, corresponding to the aura’s symptomatic
spread. The headache phase is associated with vasodilatation of
extracranial vessels and may be relayed by hypothalamic activity.
Activation of the trigeminovascular system is probably important.
A genetic contribution is implied by the frequently positive family
history, and similar phenomena occurring in disorders such as
CADASIL (p. 1 052) or mitochondrial disease (p. 1 1 44). The female
preponderance and the frequency of migraine attacks at certain
points in the menstrual cycle also suggest hormonal influences.
Oestrogen-containing oral contraception sometimes exacerbates
migraine and increases the very small risk of stroke in patients
who suffer from migraine with aura. Doctors and patients often
over-estimate the role of dietary precipitants such as cheese,
chocolate or red wine. When psychological factors contribute,
the migraine attack often occurs after a period of stress, being
more likely on Friday evening at the end of the working week
or at the beginning of a holiday.
Clinical features
Some patients report a prodrome of malaise, irritability or
behavioural change for some hours or days. Around 20% of
• Inconsistent examination findings (e.g. Hoover’s sign, p. 1082)
• Situational provocation of events (e.g. in medical settings)
• Associated mental health disorders:
Anxiety
Depression
• Lack of anatomical coherence to neurological symptoms
• Florid or bizarre descriptions of individual symptoms
• History of multiple other systemic symptoms inadequately explained
by disease (asthma/breathlessness, fatigue, pain, gastrointestinal
symptoms)
1096 • NEUROLOGY
patients experience an aura and are said to have migraine with
aura (previously known as classical migraine). The aura may
manifest as almost any neurological symptom but is most often
visual, consisting of fortification spectra, which are usually positive
phenomena such as shimmering, silvery zigzag lines marching
across the visual fields for up to 40 minutes, sometimes leaving a
trail of temporary visual field loss (scotoma). Sensory symptoms
characteristically spreading over 20-30 minutes, from one part
of the body to another, are more common than motor ones,
and language function can be affected, leading to similarities
with TIA/stroke. Isolated aura may occur (i.e. the neurological
symptoms are not followed by headache).
The 80% of patients with characteristic headache but no
‘aura’ are said to have migraine without aura (previously called
‘common’ migraine).
Migraine headache is usually severe and throbbing, with
photophobia, phonophobia and vomiting lasting from 4 to
72 hours. Movement makes the pain worse and patients prefer
to lie in a quiet, dark room.
In a small number of patients the aura may persist, leaving more
permanent neurological disturbance. This persistent migrainous
aura may occur with or without evidence of brain infarction.
Management
Avoidance of identified triggers or exacerbating factors (such
as the combined contraceptive pill) may prevent attacks.
Treatment of an acute attack consists of simple analgesia with
aspirin, paracetamol or non-steroidal anti-inflammatory agents.
Nausea may require an antiemetic such as metoclopramide or
domperidone. Severe attacks can be aborted by one of the
‘triptans’ (e.g. sumatriptan), which are potent 5-hydroxytryptamine
(5-HT, serotonin) agonists. These can be administered via the
oral, subcutaneous or nasal route. Caution is needed with
ergotamine preparations because they may lead to dependence.
Overuse of any analgesia, including triptans, may contribute to
medication overuse headache.
If attacks are frequent (more than two per month), prophylaxis
should be considered. Many drugs can be chosen but the
most frequently used are vasoactive drugs ((3-blockers),
antidepressants (amitriptyline, dosulepin) and antiepileptic
drugs (valproate, topiramate). Women with aura should avoid
oestrogen treatment for either oral contraception or hormone
replacement, although the increased risk of ischaemic stroke is
minimal.
|Medication overuse headache
With increasing availability of over-the-counter medication,
headache syndromes perpetuated by analgesia intake are
becoming much more common. Medication overuse headache
(MOH) can complicate any headache syndrome but is especially
common with migraine and chronic tension-type headache. The
most frequent culprits are compound analgesics (particularly
codeine and other opiate-containing preparations) and triptans,
and MOH is usually associated with use on more than 1 0-1 5 days
per month.
Management is by withdrawal of the responsible analgesics.
Patients should be warned that the initial effect will be to
exacerbate the headache, and migraine prophylactics may be
helpful in reducing the rebound headaches. Relapse rates are
high, and patients often need help and support in withdrawing
from analgesia; a careful explanation of this paradoxical concept
is vital.
Cluster headache
Cluster headaches (also known as migrainous neuralgia) are
much less common than migraine. Unusually for headache
syndromes, there is a significant male predominance and onset
is usually in the third decade.
Pathophysiology
The cause is unknown but this type of headache differs from
migraine in many ways, suggesting a different pathophysiological
basis. Although uncommon, it is the most common of the
trigeminal autonomic cephalalgia syndromes. Functional imaging
studies have suggested abnormal hypothalamic activity. Patients
are more often smokers with a higher than average alcohol
consumption.
Clinical features
Cluster headache is strikingly periodic, featuring runs of identical
headaches beginning at the same time for weeks at a stretch
(the ‘cluster’). Patients may experience either one or several
attacks within a 24-hour period, and typically are awoken from
sleep by symptoms (‘alarm clock headache’). Cluster headache
causes severe, unilateral periorbital pain with autonomic features,
such as ipsilateral tearing, nasal congestion and conjunctival
injection (occasionally with the other features of a Horner’s
syndrome). The pain, though severe, is characteristically brief
(30-90 minutes). In contrast to the behaviour of those with
migraine, patients are highly agitated during the headache phase.
The cluster period is typically a few weeks, followed by remission
for months to years, but a small proportion do not experience
remission.
Management
Acute attacks can usually be halted by subcutaneous injections
of sumatriptan or inhalation of 100% oxygen. The brevity of
the attack probably prevents other migraine therapies from
being effective. Migraine prophylaxis is often ineffective too but
attacks can be prevented in some patients by verapamil, sodium
valproate, or short courses of oral glucocorticoids. Patients with
severe debilitating clusters can be helped with lithium therapy,
although this requires monitoring (p. 1200).
| Trigeminal neuralgia
This is characterised by unilateral lancinating facial pain, most
commonly involving the second and/or third divisions of the
trigeminal nerve territory, usually in patients over the age of
50 years.
Pathophysiology
For most, trigeminal neuralgia remains an idiopathic condition
but there is a suggestion that it may be due to an irritative
lesion involving the trigeminal root zone, in some cases an
aberrant loop of artery. Other compressive lesions, usually
benign, are occasionally found. Trigeminal neuralgia associated
with multiple sclerosis may result from a plaque of demyelination
in the brainstem.
Clinical features
The pain is repetitive, severe and very brief (seconds or less). It
may be triggered by touch, a cold wind or eating. Physical signs
are usually absent, although the spasms may make the patient
wince and sit silently (tic douloureux). There is a tendency for
the condition to remit and relapse over many years. Rarely, there
Epilepsy • 1097
may be combined features of trigeminal neuralgia and cluster
headache (‘cluster-tic’).
Management
The pain often responds to carbamazepine. It is wise to start with
a low dose and increase gradually, according to effect. In patients
who cannot tolerate carbamazepine, oxcarbazepine, gabapentin,
pregabalin, amitriptyline or glucocorticoids may be effective
alternatives, but if medication is ineffective or poorly tolerated,
surgical treatment should be considered. Decompression of
the vascular loop encroaching on the trigeminal root is said
to have a 90% success rate. Otherwise, localised injection of
alcohol or phenol into a peripheral branch of the nerve may
be effective.
Headaches associated with specific activities
These usually affect men in their thirties and forties. Patients
develop a sudden, severe headache with exertion, including sexual
activity. There is usually no vomiting or neck stiffness, and the
headache lasts less than 1 0-1 5 minutes, though a less severe
dullness may persist for some hours. Subarachnoid haemorrhage
needs to be excluded by CT and/or CSF examination (see
Fig. 26.14, p. 1162) after a first event. The pathogenesis of
these headaches is unknown. Although frightening, attacks
are usually brief and patients may need only reassurance and
simple analgesia for the residual headache. The syndrome
may recur, and prevention may be necessary with propranolol
or indometacin.
Other headache syndromes
A number of rare headache syndromes produce pains about
the eye similar to cluster headaches (Box 25.27). These include
chronic paroxysmal hemicrania and SUNCT (short-lasting
unilateral neuralgiform headaches with conjunctival injection
and tearing). The recognition of these syndromes is useful
because they often respond to specific treatments such as
indometacin.
Epilepsy
A seizure can be defined as the occurrence of signs and/or
symptoms due to abnormal, excessive or synchronous neuronal
activity in the brain. The lifetime risk of an isolated seizure is
about 5%, although incidence is highest at the extremes of
age. Epilepsy is the tendency to have unprovoked seizures.
While the prevalence of active epilepsy in European countries
is about 0.5%, the figure in developing countries may be higher
because of parasitic illnesses such as cysticercosis (p. 298). A
recent change in definition allows the diagnosis of epilepsy to
be made after a single seizure with a high risk of recurrence
(e.g. a single seizure in the presence of a cortical lesion).
Such changes may lead to an observed increase in epilepsy
incidence.
Historical terms such as ‘grand mal’ (implying tonic-clonic
seizures) and ‘petit mal’ (intended originally to mean ‘absence
seizures’ but commonly misused to describe ‘anything other
than grand mal’) have been superseded. Subsequent revisions,
including terms such as ‘complex partial’ and ‘simple partial’,
have been imprecise and carry little information about underlying
pathology, treatment or prognosis. The modern equivalents for
these terms will be given below, but it is preferable to adhere to
the 2010 iteration of the International League Against Epilepsy’s
classification (Box 25.28).
Pathophysiology
To function normally, the brain must maintain a continual balance
between excitation and inhibition, remaining responsive to the
environment while avoiding continued unrestrained spontaneous
activity. The inhibitory transmitter gamma-aminobutyric acid
(GABA) is particularly important, acting on ion channels to enhance
chloride inflow and reducing the chances of action potential
formation. Excitatory amino acids (glutamate and aspartate)
allow influx of sodium and calcium, producing the opposite
effect. It is likely that many seizures result from an imbalance
25.27 Benign paroxysmal headaches
Type
Character of pain
Duration
Location
Comment
Ice pick
Stabbing
Very brief (split-second)
Variable, usually
temporoparietal
Benign, more common in
migraine
Ice cream
Sharp, severe
30-1 20 secs
Bitemporal/occipital
Obvious trigger by cold stimuli
Exertional/sexual activity
Bursting, thunderclap
Severe for mins, then
less severe for hours
Generalised
Subarachnoid haemorrhage
needs to be excluded
Cough
Bursting
Secs to mins
Occipital or generalised
Intracranial pathology needs to
be excluded (especially
craniocervical junction)
Cluster headache
(migrainous neuralgia)
Severe unilateral, with ptosis,
tearing, conjunctival injection,
unilateral nasal congestion
30-90 mins 1-3 times
per day
Periorbital
Usually in men, occurring in
clusters over weeks/months
Chronic paroxysmal
hemicrania
Severe unilateral with cluster
headache-like autonomic
features (see above)
5-20 mins, frequently
through day
Periorbital/temporal
Usually in women, responds to
indometacin
SUNCT*
Severe, sharp, triggered by
touch or neck movements
1 5-1 20 secs,
repetitive through day
Periorbital
May respond to carbamazepine
*Short-lasting, unilateral, neuralgiform headache with conjunctival injection, tearing, rhinorrhoea and forehead sweating.
1098 • NEUROLOGY
n 25.28 Classification of seizures (2010 International
League Against Epilepsy classification)
Generalised seizures
• Tonic-clonic (in any
• Myoclonic:
combination)
Myoclonic
• Absence:
Myoclonic-atonic
Typical
Myoclonic-tonic
Atypical
• Clonic
Absence with special
• Tonic
features
• Atonic
• Myoclonic absence
• Eyelid myoclonia
Focal seizures
• Without impairment of consciousness or awareness (was ‘simple
partial’):
Focal motor
Focal sensory
• With impairment of consciousness or awareness (was ‘complex
partial’)
• Evolving to a bilateral, convulsive seizure (was ‘secondarily
generalised seizure’):
Tonic
Clonic
Tonic-clonic
Unknown
• Epileptic spasms
between this excitation and inhibition. Intracellular recordings
during seizures demonstrate a paroxysmal depolarisation shift
in neuronal membrane potential, an upshift in internal potential
predisposing to recurrent action potentials. In vivo, epileptic
cortex shows repetitive discharges involving large groups
of neurons.
Focal epilepsy
Seizures may be related to a localised disturbance in the
cortex, becoming manifest in the first instance as focal seizures.
Any disturbance of cortical architecture and function can
precipitate this, whether focal infection, tumour, hamartoma
or trauma-related scarring. If focal seizures remain localised,
the symptoms experienced depend on which cortical area
is affected. If areas in the temporal lobes become involved,
then awareness of the environment becomes impaired but
without associated tonic-clonic movements. When both
hemispheres become involved, the seizure becomes generalised
(Fig. 25.25).
Generalised epilepsies
The new terminology is genetic generalised epilepsies (GGEs)
(previously idiopathic generalised epilepsies) to reflect their
likely cause. These seizures are generalised at onset, abnormal
activity probably originating in the central mechanisms controlling
cortical activation (Fig. 25.25) and spreading rapidly. This group
constitutes around 30% of all epilepsy and is likely to reflect
widespread disturbance of structure or function. GGEs almost
always become apparent before the age of 35.
Seizure activity is usually apparent on EEG as spike and wave
discharges (see Fig. 25.14, p. 1075). Other generalised seizures
may involve merely brief loss of awareness (absence seizures),
single jerks (myoclonus) or loss of tone (atonic seizures), as
detailed in Box 25.28.
Focal seizure Primary generalised
± secondary generalisation seizure
Fig. 25.25 The pathophysiological classification of seizures. [Ap
focal seizure originates from a paroxysmal discharge in a focal area of the
cerebral cortex (often the temporal lobe); the seizure may subsequently
spread to the rest of the brain (secondary generalisation) via diencephalic
activating pathways. [B] In genetic generalised epilepsies (GGEs) the
abnormal electrical discharges originate from the diencephalic activating
system and spread simultaneously to all areas of the cortex.
25.29 Trigger factors for seizures
• Sleep deprivation
• Missed doses of antiepileptic drugs in treated patients
• Alcohol (particularly withdrawal)
• Recreational drug misuse
• Physical and mental exhaustion
• Flickering lights, including TV and computer screens (generalised
epilepsy syndromes only)
• Intercurrent infections and metabolic disturbances
• Uncommon: loud noises, music, reading, hot baths
Clinical features
Seizure type and epilepsy type
Patients can experience more than one type of seizure attack, and
it is important to document each attack type and the patient’s
age at its onset, along with its frequency, duration and typical
features. Any triggers should be identified (Box 25.29). The type
of seizure, other clinical features and investigations can then be
used to determine the epilepsy syndrome, as discussed below.
Where there is doubt about the type, this is best stated and
a full classification should be deferred until the evolution of the
clinical features clarifies the picture.
To classify seizure type, the clinician should ask firstly whether
there is a focal onset, and secondly whether the seizures conform
to one of the recognised patterns (see Box 25.28). Epilepsy that
starts in patients beyond their mid-thirties will almost invariably
reflect a focal cerebral event. Where activity remains focal, the
classification will be obvious. With generalised tonic-clonic
seizures, a focal onset will be heralded by positive neurological
symptoms and signs corresponding to the normal function of
that area. Occipital onset causes visual changes (lights and
blobs of colour), temporal lobe onset causes false recognition
(deja vu), sensory strip involvement causes sensory alteration
(burning, tingling), and motor strip involvement causes jerking.
Alternatively, patients report a previous local cortical insult,
and it may be reasonably (but not invariably) inferred that this
is the seat of epileptogenesis.
Epilepsy • 1099
Focal seizures
The classification of focal seizures is shown in Box 25.28. They are
caused by localised cortical activity with retained awareness. The
localisation of such symptoms is described above. A spreading
pattern of seizure may occur, the abnormal sensation spreading
much faster (in seconds) than a migrainous focal sensory attack.
Awareness may become impaired if spread occurs to the
temporal lobes (previously ‘complex partial seizure’). Patients stop
and stare blankly, often blinking repetitively, making smacking
movements of their lips or displaying other automatisms, such
as picking at their clothes. After a few minutes consciousness
returns but the patient may be muddled and feel drowsy for
a period of up to an hour. The age of onset, preceding aura,
longer duration and post-ictal symptoms usually make these easy
to differentiate from childhood absence seizures (see below).
Seizures arising from the anterior parts of the frontal lobe may
produce bizarre behaviour patterns, including limb posturing, sleep
walking or even frenetic, ill-directed motor activity with incoherent
screaming. Video EEG may be necessary to differentiate these
from psychogenic attacks (which are more common) but
abruptness of onset, stereotyped nature, relative brevity and
nocturnal preponderance may indicate a frontal origin. Causes
of focal seizures are given in Box 25.30.
Generalised seizures
Tonic-clonic seizures An initial ‘aura’ may be experienced by the
patient, depending on the cortical area from which the seizure
i
25.30 Causes of focal seizures
Idiopathic
• Benign Rolandic epilepsy of
• Benign occipital epilepsy of
childhood
childhood
Focal structural lesions
von Hippel— Lindau disease
(p. 1132)
Neurofibromatosis (p. 1131)
Cerebral migration
abnormalities
Genetic
• Tuberous sclerosis (p. 1264)
• Autosomal dominant nocturnal
frontal lobe epilepsy
• Autosomal dominant partial
epilepsy with auditory features
(ADPEAF)
Infantile hemiplegia
Dysembryonic
• Cortical dysgenesis • Sturge-Weber syndrome
Mesial temporal sclerosis (associated with febrile convulsions)
Cerebrovascular disease (Ch. 26)
• Intracerebral haemorrhage • Arteriovenous malformation
• Cerebral infarction • Cavernous haemangioma
Tumours (primary and secondary) (p. 1129)
Trauma (including neurosurgery)
Infective (p. 1117)
• Cerebral abscess (pyogenic)
• Toxoplasmosis
• Cysticercosis
• Tuberculoma
Inflammatory
• Autoimmune encephalopathies
(e.g. anti-voltage-gated
potassium channel antibodies,
anti-NMDA receptor
antibodies, anti-glycine
receptor antibodies)
Subdural empyema
Encephalitis
Human immunodeficiency
virus (HIV)
Sarcoidosis
Vasculitis
originates (as above). The patient then becomes rigid (tonic) and
unconscious, falling heavily if standing (‘like a log’) and risking facial
injury. During this phase, breathing stops and central cyanosis
may occur. As cortical discharges reduce in frequency, jerking
(clonic) movements emerge for 2 minutes at most. Afterwards,
there is a flaccid state of deep coma, which can persist for
some minutes, and on regaining awareness the patient may
be confused, disorientated and/or amnesic. During the attack,
urinary incontinence and tongue-biting may occur. A severely
bitten, bleeding tongue after an attack of loss of consciousness
is pathognomonic of a generalised seizure but less marked
lingual injury can occur in syncope. Subsequently, the patient
usually feels unwell and sleepy, with headache and myalgia.
Witnesses are usually frightened by the event, often believe the
person to be dying, and may struggle to give a clear account of
the episode. Some may not describe the tonic or clonic phase
and may not mention cyanosis or tongue-biting. In less typical
episodes, post-ictal delirium, or sequelae such as headache or
myalgia, may be the main pointers to the diagnosis. Causes of
generalised tonic-clonic seizures are listed in Box 25.31 .
Absence seizures Absence seizures (previously ‘petit mal’) always
start in childhood. The attacks are rarely mistaken for focal
seizures because of their brevity. They can occur so frequently
(20-30 times a day) that they are mistaken for daydreaming or
poor concentration in school.
Myoclonic seizures These are typically brief, jerking movements,
predominating in the arms. In epilepsy, they are more marked
25.31 Causes of generalised tonic-clonic seizures
Generalisation from focal seizures
• See Box 25.30
Genetic
• Inborn errors of metabolism
(p. 1144)
• Storage diseases
Cerebral birth injury
Hydrocephalus
Cerebral anoxia
Drugs
• Antibiotics: penicillin, isoniazid,
metronidazole
• Antimalarials: chloroquine,
mefloquine
• Ciclosporin
• Amphetamines (withdrawal)
Alcohol (especially withdrawal)
Toxins
• Organophosphates (sarin)
Metabolic disease
• Hypocalcaemia
• Hyponatraemia
• Hypomagnesaemia
Infective
• Post-infectious encephalopathy
Inflammatory
• Multiple sclerosis (uncommon;
(p. 1106)
Diffuse degenerative diseases
• Alzheimer’s disease
(uncommonly; p. 1992)
Phakomatoses (e.g. tuberous
sclerosis, p. 1264)
Cardiac anti-arrhythmics:
lidocaine, disopyramide
Psychotropic agents:
phenothiazines, tricyclic
antidepressants, lithium
Heavy metals (lead, tin)
Hypoglycaemia
Renal failure
Liver failure
Meningitis (p. 1118)
Systemic lupus erythematosus
(p. 1034)
Creutzfeldt— Jakob disease
(rarely; p. 1127)
1100 • NEUROLOGY
in the morning or on awakening from sleep, and tend to be
provoked by fatigue, alcohol, or sleep deprivation.
Atonic seizures These are seizures involving brief loss of muscle
tone, usually resulting in heavy falls with or without loss of
consciousness. They occur only in the context of epilepsy
syndromes that involve other forms of seizure.
Tonic seizures These are associated with a generalised increase in
tone and an associated loss of awareness. They are usually seen
as part of an epilepsy syndrome and are unlikely to be isolated.
Clonic seizures Clonic seizures are similar to tonic-clonic seizures.
The clinical manifestations are similar but there is no preceding
tonic phase.
Seizures of uncertain generalised or focal nature
Epileptic spasms While these are highlighted in the classification
system, they are unusual in adult practice and occur mainly in
infancy. They signify widespread cortical disturbance and take
the form of marked contractions of the axial musculature, lasting
a fraction of a second but recurring in clusters of 5-50, often
on awakening.
Epilepsy syndromes
Many patients with epilepsy fall into specific patterns, depending
on seizure type(s), age of onset and treatment responsiveness: the
so-called electroclinical syndromes (Box 25.32). It is anticipated
that genetic testing will ultimately demonstrate similarities in
molecular pathophysiology.
Box 25.33 highlights the more common epilepsy syndromes,
which are largely of early onset and are sensitive to sleep
deprivation, hyperventilation, alcohol and photic stimulation.
Epilepsies that do not fit into any of these diagnostic categories
can be delineated firstly on the basis of the presence or absence
of a known structural or metabolic condition (presumed cause),
and then on the basis of the primary mode of seizure onset
(generalised versus focal).
| Investigations
Single seizure
All patients with transient loss of consciousness should have a
12-lead ECG. Where seizure is suspected or definite, patients
should have cranial imaging with either MRI or CT, although
the yield is low unless focal signs are present. EEG may help
to assess prognosis once a firm diagnosis has been made.
The recurrence rate after a first seizure is approximately 40%
and most recurrent attacks occur within a month or two of the
first. Further seizures are less likely if an identified trigger can
be avoided (see Box 25.29).
Other investigations for infective, toxic and metabolic causes
(Box 25.34) may be appropriate. An EEG performed immediately
after a seizure may be more helpful in showing focal features
than if performed after a delay.
i
Adolescence to adulthood
• Juvenile absence epilepsy (JAE)
• Juvenile myoclonic epilepsy (JME)
• Epilepsy with generalised tonic-clonic seizures alone
• Progressive myoclonus epilepsies (PMEs)
• Autosomal dominant epilepsy with auditory features (ADEAF)
• Other familial temporal lobe epilepsies
Less specific age relationship
• Familial focal epilepsy with variable foci (childhood to adult)
• Reflex epilepsies
Distinctive constellations
• Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE
with HS)
• Rasmussen’s syndrome
• Gelastic (from the Greek word for laughter) seizures with
hypothalamic hamartoma
• Hemiconvulsion— hemiplegia— epilepsy
Epilepsies with structural-metabolic causes
• Malformations of cortical development (hemimegalencephaly,
heterotopias etc.)
• Neurocutaneous syndromes (tuberous sclerosis complex,
Sturge-Weber etc.)
• Tumour
• Infection
• Trauma
• Angioma
• Perinatal insults
• Stroke etc.
Epilepsies of unknown cause
Conditions with epileptic seizures not needing long-term
treatment
• Benign neonatal seizures (BNS)
• Febrile seizures (FS)
25.32 Electroclinical epilepsy syndromes
25.33 Common generalised epilepsy syndromes
Syndrome
Age of onset
Type of seizure
EEG features
Treatment
Prognosis
Childhood absence
epilepsy
4-8 years
Frequent brief absences
3/sec spike and wave
Ethosuximide
Sodium valproate
Levetiracetam
40% develop GTCS, 80%
remit in adulthood
Juvenile absence
epilepsy
1 0-1 5 years
Less frequent absences
than childhood absence
Poly-spike and wave
Sodium valproate
Levetiracetam
80% develop GTCS, 80%
seizure-free in adulthood
Juvenile myoclonic
epilepsy
1 5-20 years
GTCS, absences,
morning myoclonus
Poly-spike and wave,
photosensitivity
Sodium valproate
Levetiracetam
90% remit with AEDs but
relapse if AED withdrawn
GTCS on awakening
1 0-25 years
GTCS, sometimes
myoclonus
Spike and wave on
waking and sleep onset
Sodium valproate
Levetiracetam
65% controlled with AEDs
but relapse off treatment
(AED = antiepileptic drug; GTCS = generalised tonic-clonic seizure)
Epilepsy • 1101
25.34 Investigation of epilepsy
From where is the epilepsy arising?
• Standard EEG • EEG with special electrodes
• Sleep EEG (foramen ovale, subdural)
What is the cause of the epilepsy?
Structural lesion?
• CT
Metabolic disorder?
• Urea and electrolytes
• Liver function tests
MRI
Blood glucose
Serum calcium, magnesium
Serology for syphilis, HIV,
collagen disease
CSF examination
Videotelemetry
Inflammatory or infective disorder?
• Full blood count, erythrocyte «
sedimentation rate, C-reactive
protein «
• Chest X-ray
Are the attacks truly epileptic?
• Ambulatory EEG «
(CSF = cerebrospinal fluid; CT = computed tomography; EEG =
electroencephalography; HIV = human immunodeficiency virus; MRI = magnetic
resonance imaging)
25.35 Indications for brain imaging in epilepsy
• Epilepsy starting after the age of 16 years
• Seizures having focal features clinically
• Electroencephalogram showing a focal seizure source
• Control of seizures difficult or deteriorating
Epilepsy
The same investigations are required in a patient with epilepsy
(Box 25.34). The EEG may help to establish the type of epilepsy
and guide therapy. Investigations should be revisited if the
epilepsy is intractable to treatment.
Inter-ictal EEG is abnormal in only about 50% of patients with
recurrent seizures, so it cannot be used to exclude epilepsy. The
sensitivity can be increased to about 85% by prolonging recording
time and including a period of natural or drug-induced sleep,
but this does not replace a well-taken history. Ambulatory EEG
recording or video EEG monitoring may help with differentiation of
epilepsy from other disorders if attacks are sufficiently frequent.
Indications for imaging are summarised in Box 25.35. Imaging
cannot establish a diagnosis of epilepsy but identifies any structural
cause. It is not required if a confident diagnosis of a recognised
GGE syndrome (e.g. juvenile myoclonic epilepsy) is made. While
CT excludes a major structural cause of epilepsy, MRI is required
to demonstrate subtle changes such as hippocampal sclerosis,
which may direct or inform surgical intervention.
| Management
It is important to explain the nature and cause of seizures to
patients and their relatives, and to instruct relatives in the first aid
management of seizures (Box 25.36). Many people with epilepsy
feel stigmatised and may become unnecessarily isolated from
work and social life. It is important to emphasise that epilepsy is
a common disorder that affects 0.5-1 % of the population, and
that full control of seizures can be expected in approximately
70% of patients (Box 25.37).
25.36 How to administer first aid for seizures
• Move the person away from danger (fire, water, machinery,
furniture)
• After convulsions cease, turn the person into the ‘recovery’ position
(semi-prone)
• Ensure the airway is clear but do NOT insert anything in the mouth
(tongue-biting occurs at seizure onset and cannot be prevented by
observers)
• If convulsions continue for more than 5 mins or recur without the
person regaining consciousness, summon urgent medical attention
• Do not leave the person alone until fully recovered (drowsiness and
delirium can persist for up to 1 hr)
25.37 Epilepsy: outcome after 20 years
• 50% are seizure-free, without drugs, for the previous 5 years
• 20% are seizure-free for the previous 5 years but continue to take
medication
• 30% continue to have seizures in spite of antiepileptic therapy
Immediate care
Little can or needs to be done for a person during a convulsive
seizure except for first aid and common-sense manoeuvres to
limit damage or secondary complications (see Box 25.36). Advice
should be given that on no account should anything be inserted
into the patient’s mouth. The management of status epilepticus
is described on page 1080.
Lifestyle advice
Patients should be advised to avoid activities where they might
place themselves or others at risk if they have a seizure. This
applies at work, at home and at leisure. At home, only shallow
baths (or showers) should be taken. Prolonged cycle journeys
should be discouraged until reasonable freedom from seizures
has been achieved. Activities involving prolonged proximity to
water (swimming, fishing or boating) should always be carried
out in the company of someone who is aware of the risks and
the potential need for rescue measures. Driving regulations
vary between countries and the patient should be made aware
of these (Box 25.38). Certain occupations, such as firefighter
or airline pilot, are not open to those with a previous or active
diagnosis of epilepsy; further information is available from epilepsy
support organisations.
The risk of harm from epilepsy should be discussed around the
time of diagnosis. This should be done with care and sensitivity,
and with the aim of motivating the patient to adapt habits and
lifestyle to optimise epilepsy control and minimise risks of serious
complications.
Antiepileptic drugs
Antiepileptic drugs (AEDs) should be considered where risk of
seizure recurrence is high. A diagnosis of two or more seizures
is justification enough but a prolonged inter-seizure interval may
deter some patients and physicians. Treatment decisions should
always be shared with the patient, to enhance adherence. A
wide range of drugs is available. These agents either increase
inhibitory neurotransmission in the brain or alter neuronal sodium
channels to prevent abnormally rapid transmission of impulses. In
the majority of patients, full control is achieved with a single drug.
Dose regimens should be kept as simple as possible. Guidelines
1102 • NEUROLOGY
25.38 UK driving regulations
i
• Start with one first-line drug (see Box 25.40)
• Start at a low dose; gradually increase dose until effective control of
seizures is achieved or side-effects develop
• Optimise adherence (use minimum number of doses per day)
• If first drug fails (seizures continue or side-effects develop), start
second first-line drug, followed if possible by gradual withdrawal of
first
• If second drug fails (seizures continue or side-effects develop), start
second-line drug in combination with the preferred baseline drug at
maximum tolerated dose (beware interactions)
• If this combination fails (seizures continue or side-effects develop),
replace second-line drug with alternative second-line drug
• If this combination fails, check adherence and reconsider diagnosis
(Are events seizures? Occult lesion? Treatment adherence/alcohol/
drugs confounding response?)
• Consider alternative, non-drug treatments (e.g. epilepsy surgery,
vagal nerve stimulation)
• Use minimum number of drugs in combination at any one time
*See Scottish Intercollegiate Guidelines Network SIGN 143 - Diagnosis and
management of epilepsy in adults (May 2015).
are listed in Box 25.39. For focal epilepsies, one large study
suggests that lamotrigine is the best-tolerated monotherapy,
which, alongside its favourable adverse-effect profile and relative
lack of pharmacokinetic interactions, makes it a good first-line
drug, although caution must be exercised with oral contraceptive
use. Unclassified or genetic generalised epilepsies respond best
to valproate, although pregnancy-related problems mean that
valproate should not be used in women of reproductive age
unless the benefits outweigh the risks. The initial choice should
be an established first-line drug (Box 25.40), with more recently
introduced drugs as second choice.
Monitoring therapy
Some practitioners confuse epilepsy care with serum level
monitoring. The newer drugs have much more predictable
25.40 Guidelines for choice of antiepileptic drug
Epilepsy type
First-line
Second-line
Third-line
Focal onset
and/or
secondary
GTCS
Lamotrigine
Carbamazepine
Levetiracetam
Sodium
valproate
Topiramate
Zonisamide
Lacosamide
Clobazam
Gabapentin
Oxcarbazepine
Phenobarbital
Phenytoin
Pregabalin
Primidone
Tiagabine
GTCS2
Sodium
valproate
Levetiracetam
Lamotrigine
Topiramate
Zonisamide
Carbamazepine
Phenytoin
Primidone
Phenobarbital
Acetazolamide
Absence2
Ethosuximide
Sodium
valproate
Lamotrigine
Clonazepam
Myoclonic2
Sodium
valproate
Levetiracetam
Clonazepam
Lamotrigine
Phenobarbital
^ee Scottish Intercollegiate Guidelines Network SIGN 143 - Diagnosis and
management of epilepsy in adults (May 2015). 2Genetic generalised epilepsies.
N.B. Use as few drugs as possible at the lowest possible dose.
(GTCS = generalised tonic-clonic seizure)
pharmacokinetics than the older ones and the only indication
for measuring serum levels is if there is doubt about adherence.
Blood levels need to be interpreted carefully and dose changes
made to treat the patient rather than to bring a serum level into
the ‘therapeutic range’. Some centres advocate serum level
monitoring during pregnancy (notably with lamotrigine) but the
evidence of benefit for this is not strong.
Epilepsy surgery
Some patients with drug-resistant epilepsy benefit from surgical
resection of epileptogenic brain tissue. Less invasive treatments,
including vagal nerve stimulation or deep brain stimulation, may
also be helpful in some patients. All those who continue to
experience seizures despite appropriate drug treatment should
be considered for surgical treatment. Planning such interventions
requires intensive specialist assessment and investigation to
identify the site of seizure onset and the dispensability of any
target areas for resection, i.e. whether the area of brain involved is
necessary for a critical function such as vision or motor function.
Withdrawing antiepileptic therapy
Withdrawal of medication may be considered after a patient
has been seizure-free for more than 2 years. Childhood-onset
epilepsy, particularly classical absence seizures, carries the
best prognosis for successful drug withdrawal. Other epilepsy
syndromes, such as juvenile myoclonic epilepsy, have a marked
tendency to recur after drug withdrawal.
Focal epilepsies that begin in adult life are also likely to recur,
especially if there is an identified structural lesion. Overall, the
recurrence rate after drug withdrawal depends on the individual’s
epilepsy history. An individualised estimate may be gained from
the SIGN guideline tables (see ‘Further information’, p. 1146).
Patients should be advised of the risks of recurrence, to
allow them to decide whether or not they wish to withdraw.
If undertaken, withdrawal should be done slowly, reducing
the drug dose gradually over weeks or months. Withdrawal
The physician’s prime duty is to ensure the patient is aware of the
legal obligation to inform the driving authority
Private use
Single seizure
• Cease driving for 6 months; a longer period may be required if risk
of recurrence is high
Epilepsy (i.e. more than one seizure over the age of 5 years)
• Cease driving immediately
• Licence restored when patient is seizure-free for 1 year, or an initial
sleep seizure is followed by exclusively sleep seizures for 1 year, or
mixed awake and sleep seizures are followed by 3 years of
exclusively sleep seizures
• Licence will require renewal every 3 years thereafter until patient is
seizure-free for 10 years
Withdrawal of antiepileptic drugs
• Cease driving during withdrawal period and for 6 months thereafter
Vocational drivers (heavy goods and public service vehicles)
• No licence permitted if any seizure has occurred after the age of
5 years until patient is off medication and seizure-free for more
than 10 years, and has no potentially epileptogenic brain lesion
25.39 Guidelines for antiepileptic drug therapy
Epilepsy • 1103
may necessitate precautions around driving or occupation (see
Box 25.38).
Contraception
Some AEDs induce hepatic enzymes that metabolise synthetic
hormones, increasing the risk of contraceptive failure. This is
most marked with carbamazepine, phenytoin and barbiturates,
but clinically significant effects can be seen with lamotrigine and
topiramate. If the AED cannot be changed, this can be overcome
by giving higher-dose preparations of the oral contraceptive.
Sodium valproate and levetiracetam have no interaction with
hormonal contraception.
Pregnancy and reproduction
Epilepsy presents specific management problems during
pregnancy (Box 25.41). There is usually concern about
teratogenesis associated with AEDs. It is important to recognise
proportionate risks: background risk of severe fetal malformation
in the general population is around 2-3%, while the AED most
associated with teratogenesis is sodium valproate, which, at high
dose, increases the risk to around 6-7%. Long-term observational
studies show that most of the commonly used AEDs can be
given safely in pregnancy.
Pre-conception treatment with folic acid (5 mg daily), along with
use of the smallest effective doses of as few AEDs as possible,
may reduce the risk of fetal abnormalities. The risks of abrupt
AED withdrawal to the mother should be stressed.
Seizures may become more frequent during pregnancy,
particularly if pharmacokinetic changes decrease serum levels
of AEDs (see Box 25.41).
Menstrual irregularities and reduced fertility are more
common in women with epilepsy, and are also increased by
sodium valproate. Patients with epilepsy are at greater risk of
osteoporosis, apparently independently of the drug used. Some
centres advocate vitamin D supplementation in any patient with
epilepsy but the higher female risk of osteoporosis makes this
most important in women. Oral contraception can interact with
individual AEDs (Box 25.41).
25.41 Epilepsy in pregnancy
• Provision of pre-conception counselling is best practice: start
folic acid (5 mg daily for 2 months) before conception to reduce the
risk of fetal malformations.
• Fetal malformation: risk is minimised if a single drug is used.
Carbamazepine and lamotrigine have the lowest incidence of
major fetal malformations.
The risk with sodium valproate is higher but should be carefully
balanced against its benefits.
Levetiracetam may be safe but avoid other newer drugs if
possible.
• Learning difficulties in children: IQ may be lower when children
are exposed to valproate in utero, so its use should always be
considered carefully.
• Haemorrhagic disease of the newborn: enzyme-inducing
antiepileptic drugs increase risk. Give oral vitamin K (20 mg daily) to
the mother during the last month of pregnancy and IM vitamin K
(1 mg) to the infant at birth.
• Increased frequency of seizures: where breakthrough seizures
occur, monitor antiepileptic drug levels and adjust the dose regimen
accordingly.
• Pharmacokinetic effects of pregnancy: carbamazepine levels
may fall in the third trimester. Lamotrigine and levetiracetam levels
may fall early in pregnancy. Some advocate monitoring of levels.
(fx
• Incidence and prevalence: late-onset epilepsy is very common
and the annual incidence in those over 60 years is rising.
• Fits and faints: the features that usually differentiate these may be
less definitive than in younger patients.
• Non-convulsive status epilepticus: can present as delirium in the
elderly.
• Cerebrovascular disease: the underlying cause of seizures in
30-50% of patients over the age of 50 years. A seizure may occur
with an overt stroke or with occult vascular disease.
• Antiepileptic drug regimens: keep as simple as possible and take
care to avoid interactions with other drugs being prescribed.
• Carbamazepine-induced hyponatraemia: increases significantly
with age; this is particularly important in patients on diuretics or
those with heart failure.
• Withdrawal of antiepileptic therapy: drug withdrawal should be
attempted only where benefits exceed risk of harm from seizures.
25.42 Epilepsy in old age
25.43 Epilepsy in adolescence
• Effect on school/education: seizures, antiepileptic drugs (AEDs)
and psychological complications of epilepsy may hamper education.
Fear may make some educational institutions unduly restrictive.
• Effect on family relationships: parents may adopt a protective
role, which can lead to epilepsy (and AEDs) becoming a point of
assertion and rebellion.
• Effect on career choice: epilepsy may exclude or restrict
employment in the emergency services and armed forces.
• Alcohol: may affect sleep pattern; excess may be associated with
poor AED adherence.
• Illicit drugs: may affect seizure threshold and be associated with
poor AED adherence.
• Sleep disturbance: may be worsened by social activities and
computer games.
• Oral contraception: interactions with AED can occur. Use may not
always be disclosed to parents.
Prognosis
The outcome of newly diagnosed epilepsy is generally good.
Overall, generalised epilepsies and generalised seizures are more
readily controlled than focal seizures. The presence of a structural
lesion reduces the chances of freedom from seizures. The overall
prognosis for epilepsy is shown in Box 25.37. The particular
problems that epilepsy poses in the elderly and in adolescents
are summarised in Boxes 25.42 and 25.43, respectively.
Status epilepticus
Presentation and management are described on page 1080.
While generalised status epilepticus is most easily recognised,
non-convulsive status may be less dramatic and less easily
diagnosed. It may cause only altered awareness, delirium or
wandering with automatisms. In an intensive care unit setting,
EEG monitoring is essential to ensure that diagnosis and treatment
are optimised.
I Non-epileptic attack disorder
(‘dissociative attacks’)
The difficulty with nomenclature is discussed on page 1097.
Patients may present with attacks that resemble epileptic
seizures but are caused by psychological phenomena and
1104 • NEUROLOGY
have no abnormal EEG discharges. Such attacks may be very
prolonged, sometimes mimicking status epilepticus. Epileptic
and non-epileptic attacks may coexist and time and effort are
needed to clarify the relative contribution of each, allowing more
accurate and comprehensive treatment.
Non-epileptic attack disorder (NEAD) may be accompanied
by dramatic flailing of the limbs and arching of the back, with
side-to-side head movements and vocalising. Cyanosis and
severe biting of the tongue are rare but incontinence can
occur. Distress and crying are common following non-epileptic
attacks. The distinction between epileptic attacks originating in
the frontal lobes and non-epileptic attacks may be especially
difficult, and may require videotelemetry with prolonged EEG
recordings. Non-epileptic attacks are three times more common
in women than in men and have been linked with a history of
past or ongoing life trauma. They are not necessarily associated
with formal psychiatric illness. Patients and carers may need
reassurance that hospital admission is not required for every
attack. Prevention requires psychotherapeutic interventions
rather than drug therapy (p. 1202).
Vestibular disorders
Vertigo is the typical symptom caused by vestibular dysfunction,
and most patients with vertigo have acute vestibular failure,
benign paroxysmal positional vertigo or Meniere’s disease.
Central (brain) causes of vertigo are rare by comparison, with
the exception of migraine (p. 1095).
Acute vestibular failure
Although commonly called ‘labyrinthitis’ or ‘vestibular neuronitis’,
acute vestibular failure is a more accurate term, as most cases
are idiopathic. It usually presents as isolated severe vertigo with
vomiting and unsteadiness. It begins abruptly, often on waking,
and many patients are initially bed-bound. The vertigo settles
0
Fig. 25.26 The Hallpike manoeuvre for diagnosis of benign paroxysmal
look at the examiner as their head is swung briskly backwards through 120°
FBI Perform next with the left ear down. The examiner looks for nystagmus (u
or B only and is torsional, the fast phase beating towards the lower ear. Its or
patient is returned to the upright position, transient nystagmus may occur in t
on repeat testing.
within a few days, though head movement may continue to
provoke transient symptoms (positional vertigo) for some time.
During the acute attack, nystagmus (p. 1090) will be present
for a few days.
Cinnarizine, prochlorperazine or betahistine provide symptomatic
relief but should not be used long-term, as this may delay
recovery. A small proportion of patients fail to recover fully and
complain of ongoing imbalance and dysequilibrium rather than
vertigo; vestibular rehabilitation by a physiotherapist may help.
Benign paroxysmal positional vertigo
Benign paroxysmal positional vertigo (BPPV) is due to the presence
of otolithic debris from the saccule or utricle affecting the free
flow of endolymph in the semicircular canals (cupulolithiasis). It
may follow minor head injury but typically is spontaneous. The
history is diagnostic, with transient (seconds) vertigo precipitated
by movement (typically, rolling over in bed or getting into or
out of bed). Although it is benign, and usually self-limiting after
weeks or months, patients are often alarmed by the symptoms.
The diagnosis can be confirmed by the ‘Hallpike manoeuvre’
to demonstrate positional nystagmus (Fig. 25.26). Treatment
comprises explanation and reassurance, along with positioning
procedures designed to return otolithic debris from the semicircular
canal to saccule or utricle (such as the Epley manoeuvre) and/or
to re-educate the brain to cope with the inappropriate signals
from the labyrinth (such as Cawthorne-Cooksey exercises: see
‘Further information’, p. 1146).
Meniere’s disease
This is due to an abnormality of the endolymph that causes
episodes of vertigo accompanied by tinnitus and fullness in the
ear, each attack typically lasting a few hours. Over the years,
patients may develop progressive deafness (typically low-tone on
audiometry). Examination is typically normal in between attacks.
The diagnosis is clinical, supported by abnormal audiometry.
Meniere’s disease is idiopathic but a similar syndrome may
H
positional vertigo (BPPV). Patients are asked to keep their eyes open and
:o overhang the edge of the couch. [A] Perform first with the right ear down,
sually accompanied by vertigo). In BPPV, the nystagmus typically occurs in A
set is usually delayed a few seconds and it lasts 10-20 seconds. As the
le opposite direction. Both nystagmus and vertigo typically decrease (fatigue)
Disorders of sleep • 1105
be caused by middle ear trauma or infection. Imaging may be
indicated to exclude other focal brainstem or cerebellopontine
angle pathology but will be normal in Meniere’s disease.
Management includes a low-salt diet, vestibular sedatives for acute
attacks (e.g. cinnarizine or prochlorperazine), and occasionally
surgery to increase endolymphatic drainage from the vestibular
system. Migraine may also cause episodic vertigo, and can
be confused with Meniere’s disease, although usually other
migrainous features will appear in the history.
Disorders of sleep
Sleep disturbances include too much sleep (hypersomnolence or
excessive daytime sleepiness), insufficient or poor-quality sleep
(insomnia), and abnormal behaviour during sleep (parasomnias).
Insomnia is usually caused by psychological or psychiatric
disorders, shift work and other environmental causes, pain
and so on, and will not be discussed further. Many symptoms
and disorders may affect sleep and sleep quality (e.g. pain,
depression/anxiety, parkinsonism).
Excessive daytime sleepiness
(hypersomnolence)
There are primary and secondary causes (Box 25.44). The most
common causes are impaired sleep due to lifestyle issues or
sleep-disordered breathing (p. 622). Sleepiness may be measured
using the Epworth Sleepiness Score (see Box 17.86, p. 623).
Most causes will be identified by a detailed history from the
patient and their bed partner, and a 2-week sleep diary.
Narcolepsy
This has a prevalence of about 1 in 2000, with peak onset in
adolescence and early middle age. The key symptom is sudden,
irresistible ‘sleep attacks’, often in inappropriate circumstances
such as while eating or talking. Other characteristic features
help distinguish this from excessive daytime sleepiness (Box
25.45). Symptoms may be due to loss of hypocretin-secreting
hypothalamic neurons. Diagnosis requires sleep study with
sleep latency testing (demonstrating rapid onset of REM sleep).
Narcolepsy may respond to stimulants such as modafinil but
more severe cases may require sodium oxybate, dexamfetamine,
methylphenidate or selective serotonin reuptake inhibitor (SSRIs).
Cataplexy can be debilitating and can respond to sodium oxybate
or to antidepressants, such as clomipramine or venlafaxine.
25.44 Causes of hypersomnolence
Primary causes
• Narcolepsy
• Idiopathic hypersomnolence
• Brain injury
Secondary causes (due to poor-quality sleep)
• Obstructive sleep apnoea
• Depression/anxiety
• Pain
• Medication
• Restless legs/periodic limb
• Environmental factors (noise,
movements of sleep
• Parkinsonism and other
temperature etc.)
neurodegenerative diseases
i
Sleep attacks
• Brief, frequent and unlike normal somnolence
Cataplexy
• Sudden loss of muscle tone triggered by surprise, laughter, strong
emotion etc.
Hypnagogic or hypnopompic hallucinations
• Frightening hallucinations experienced during sleep onset or waking
due to intrusion of REM sleep during wakefulness (can occur in
normal people)
Sleep paralysis
• Brief paralysis on waking (can occur in normal people)
Parasomnias
Parasomnias are abnormal motor behaviours that occur around
sleep. They may arise in either REM or non-REM sleep, with
characteristic features and timing. Non-REM parasomnias tend to
occur early in sleep. Parasomnias should be distinguished from
other motor disturbances (such as periodic limb movements,
hypnic jerks or sleep talking) and sleep-onset epileptic seizures
(p. 1101). History from a sleeping partner or other witness is
essential.
Non-REM parasomnias
These are due to incomplete arousal from non-REM sleep and
manifest as night terrors, sleep walking and confusional arousals
(sleep drunkenness). They typically occur within an hour or two
of sleep onset, and are common in children and usually of no
pathological significance. Rarely, they persist into adulthood and
may become increasingly complex, including dressing, moving
objects, eating, drinking or even acts of violence. Patients have
little or no recollection of the episodes, even though they appear
‘awake’. The episodes may be triggered by alcohol or unfamiliar
sleeping situations, and can be familial. Treatment is usually not
required but clonazepam can be used.
REM sleep behaviour disorder
In REM sleep behaviour disorder (RBD), patients ‘act out’ their
dreams during REM sleep, due to failure of the usual muscle
atonia. Sleep partners provide typical histories of patients
‘fighting’ or ‘struggling’ in their sleep, sometimes causing injury
to themselves or to their partner. They are easily roused from this
state, with recollection of their dream, unlike in non-REM states.
RBD is more common in men and may be an early symptom
of neurodegenerative diseases such as alpha synucleinopathies
(p. 1111), perhaps preceding more typical symptoms of these
conditions by years. Polysomnography will confirm absence of
atonia during REM sleep. Clonazepam is the most successful
treatment.
Restless legs syndrome
Restless legs syndrome (RLS) is common, with a prevalence of
up to 10%, but many patients never seek medical attention. It
is characterised by unpleasant leg (rarely, arm) sensations that
are eased by movement (motor restlessness); the diagnosis is
25.45 Narcolepsy symptoms
1106 • NEUROLOGY
i
clinical (Box 25.46). It has a strong familial tendency and can
present with daytime somnolence due to poor sleep. It is usually
idiopathic but may be associated with iron deficiency, pregnancy,
peripheral neuropathy, Parkinson’s disease or uraemia. It should
be distinguished from akathisia, the daytime motor restlessness
that is an adverse effect of antipsychotic drugs. Treatment, if
required, is with dopaminergic drugs (dopamine agonists or
levodopa, p. 1113) or benzodiazepines.
Periodic limb movements in sleep
Unlike RLS, periodic limb movements in sleep (PLMS) only occur
during sleep and cause repetitive flexion movements of the limbs,
usually in the early (non-REM) stages of sleep. Although patients
are unaware of the symptoms, they may disrupt sleep quality
and often disturb partners. The pathological significance of PLMS
is uncertain and it often occurs in normal health. There is an
overlap with RLS. Treatment is most successful with clonazepam
or dopaminergic drugs.
Neuro-inflammatory diseases
| Multiple sclerosis
Multiple sclerosis (MS) is an important cause of long-term
disability in adults, especially in the UK, where the prevalence
is approximately 120 per 100000. The annual incidence is around
7 per 100000, while the lifetime risk of developing MS is about
1 in 400. The incidence of MS is higher in Northern Europeans
and the disease is about twice as common in females.
Pathophysiology
There is evidence that both genetic and environmental factors play
a causative role. The prevalence of MS is low near the equator
and increases in the temperate zones of both hemispheres.
People retain the risk of developing the disease in the zone in
which they grew up, indicating that environmental exposures
during growth and development are important. Prevalence
also correlates with environmental factors, such as sunlight
exposure, vitamin D (a controversial association) and exposure
to Epstein-Barr virus (EBV), although causative mechanisms
remain unclear. Genetic factors are also relevant; the risk of
familial occurrence in MS is 15%, with highest risk in first-degree
relatives (age-adjusted risk 4-5% for siblings and 2-3% for
parents or offspring). Monozygotic twins have a concordance
rate of 30%. The genes that predispose to MS are incompletely
defined but inheritance appears to be polygenic, with influences
from genes for human leucocyte antigen (HLA) typing, interleukin
receptors, CLEC16A (C-type lectin domain family 16 member
A) and CD226 genes. An immune hypothesis is supported by
increased levels of activated T lymphocytes in the CSF and
increased immunoglobulin synthesis within the CNS.
Initial CNS inflammation in MS involves entry of activated T
lymphocytes across the blood-brain barrier. These recognise
myelin-derived antigens on the surface of the nervous system’s
antigen-presenting cells, the microglia, and undergo clonal
proliferation. The resulting inflammatory cascade releases cytokines
and initiates destruction of the oligodendrocyte-myelin unit by
macrophages. Histologically, the resultant lesion is a plaque of
inflammatory demyelination, most commonly in the periventricular
regions of the brain, the optic nerves and the subpial regions
of the spinal cord (Fig. 25.27). This begins as a circumscribed
area of disintegration of the myelin sheath, accompanied by
infiltration by activated lymphocytes and macrophages, often
with conspicuous perivascular inflammation. After the acute
attack, gliosis follows, leaving a shrunken scar.
Much of the initial acute clinical deficit is caused by the effect
of inflammatory cytokines on transmission of the nervous impulse
rather than structural disruption of myelin, and may explain the
rapid recovery of some deficits and probably the acute benefit
from glucocorticoids. In the long term, accumulating myelin
loss reduces the efficiency of impulse propagation or causes
complete conduction block, contributing to sustained impairment
of CNS functions. Inflammatory mediators released during the
acute attack (particularly nitric oxide) probably also initiate axonal
damage, which is a feature of the latter stages of the disease. In
established MS there is progressive axonal loss, probably due to
the successive damage from acute attacks and the subsequent
loss of neurotrophic factors from oligodendrocytes. This axonal
loss may account for the phase of the disease characterised by
progressive and persistent disability (Fig. 25.28).
Clinical features
The diagnosis of MS requires the demonstration of otherwise
unexplained CNS lesions separated in time and space (Box
25.47); traditionally, this meant two or more clinical relapses
affecting different parts of the nervous system, and the first ever
episode was labelled ‘clinically isolated syndrome’ (CIS). Recent
changes to diagnostic criteria mean that MS may be diagnosed
after an isolated episode (i.e. at the CIS stage), provided that
certain criteria are met (Box 25.47) The peak age of onset of
MS is the fourth decade; onset before puberty or after the age
of 60 years is rare. Symptoms and signs of MS usually evolve
over days or weeks, resolving over weeks or months. Rarely, a
more rapid stroke-like presentation may occur. About 85-90% of
patients have an initial relapsing and remitting clinical course with
variable intervening recovery, although the majority will eventually
enter a secondary progressive phase. Most of the rest follow a
slowly progressive clinical course (so-called primary progressive
MS), while rare patients have a fulminant variety leading to
early death (see Fig. 25.28). Frequent relapses with incomplete
recovery indicate a poor prognosis. Some milder cases have
an interval of years or even decades between attacks, while
in others (particularly if optic neuritis is the initial manifestation)
there is no recurrence of disease.
There are a number of clinical symptoms and syndromes
suggestive of MS, occurring either at presentation or during the
course of the illness (Box 25.48). The physical signs observed
in MS are determined by the anatomical site of demyelination.
Combined spinal cord and brainstem signs are common, although
evidence of previous optic neuritis may be found in the form of
an afferent pupillary deficit. Significant intellectual impairment
25.46 Diagnostic criteria for restless legs syndrome
A need to move the legs, usually accompanied or caused by
uncomfortable, unpleasant sensations in the legs, with the following
features:
• only present or worse during periods of rest or inactivity such as
lying or sitting
• partially or totally relieved by movement such as walking or
stretching, at least as long as the activity continues
• generally worse or occurs only in the evening or night.
Neuro-inflammatory diseases • 1107
Fig. 25.27 Multiple sclerosis. [A] Photomicrograph from demyelinating
plaque, showing perivascular cuffing of blood vessel by lymphocytes.
[81 Brain magnetic resonance imaging in multiple sclerosis. Multiple
high-signal lesions (arrows) seen particularly in the paraventricular region
on T2 image. [C] In T1 image with gadolinium enhancement, recent
lesions (A arrows) show enhancement, suggesting active inflammation
(enhancement persists for 4 weeks); older lesions (B arrows) show no
enhancement but low signal, suggesting gliosis.
^9 25.47 The Macdonald criteria for the diagnosis of
multiple sclerosis (2011)
Clinical presentation2
Additional evidence required for
diagnosis of MS
Two or more attacks with
either objective clinical
evidence of at least 2
lesions
or
Objective clinical evidence
of 1 attack with reasonable
evidence (on clinical history)
of at least 1 prior attack
None
Two or more attacks with
objective clinical evidence
of 1 lesion
Dissemination in ‘space’ demonstrated
by magnetic resonance imaging (MRI)
> 1 lesion in at least 2 of the
MS-typical regions3 (multiple lesions in
different sites)
or
Await further clinical attack at different
anatomical site
One attack with objective
clinical evidence of > 2
lesions
Dissemination in ‘time’ demonstrated
by evolving MRI showing combined
enhancing (new) and non-enhancing
(old) lesions
or
New T2 or enhancing lesion on repeat
MRI
or
Await further (second) clinical attack at
different anatomical site
One attack with clinical
evidence of only 1 lesion
(clinically isolated
syndrome)
Dissemination in ‘space’ demonstrated
by > 1 T2 lesion in at least 2
MS-typical regions
or
Dissemination in ‘time’, demonstrated
by simultaneous enhancing and
non-enhancing lesions
or
New T2 or enhancing lesions on
repeat MRI
or
Await further (second) clinical attack
Insidious neurological
progression suggestive of
MS
1 year of progression plus 2 of the
following:
Evidence for dissemination in space
with > 1 T2 lesions in MS-typical
regions
Evidence for dissemination in space
based on > 2 lesions in the spinal
cord
Positive cerebrospinal fluid
(evidence of oligoclonal band and/or
elevated immunoglobulin G index)
If the clinical presentation in the left-hand column is associated with the
features in the right-hand column, the diagnosis is MS. If there is incomplete
association, the diagnosis is ‘possible MS’. 2Assumes other possible causes for
central nervous system inflammation (e.g. sarcoidosis, systemic lupus
erythematosus) have been excluded. 3MS-typical regions = periventricular,
juxtacortical, infratentorial, spinal cord.
From Potman CH, Reingold SC, Branwell B, et al. Diagnostic criteria for multiple
sclerosis. Ann Neurol 201 1; 69:292-302.
1108 • NEUROLOGY
Fig. 25.28 The progression of disability in
fulminant, relapsing-remitting and progressive
multiple sclerosis. Courtesy of Prof. D.A.S.
Compston.
25.48 Clinical features of multiple sclerosis
Common presentations of multiple sclerosis
• Optic neuritis
• Relapsing/remitting sensory symptoms
• Subacute painless spinal cord lesion
• Acute brainstem syndrome
• Subacute loss of function of upper limb (dorsal column deficit)
• 6th cranial nerve palsy
Other symptoms and syndromes suggestive of central nervous
system demyelination
• Afferent pupillary defect and optic atrophy (previous optic neuritis)
• Lhermitte’s symptom (tingling in spine or limbs on neck flexion)
• Progressive non-compressive paraparesis
• Partial Brown-Sequard syndrome (p. 1 083)
• Internuclear ophthalmoplegia with ataxia
• Postural (‘rubral’, ‘Holmes’) tremor
• Trigeminal neuralgia (p. 1096) under the age of 50
• Recurrent facial palsy
appears only late in the disease, when loss of frontal lobe
functions and impairment of memory are common.
The prognosis for patients with MS is difficult to predict with
confidence, especially early in the disease. Those with relapsing
and remitting MS experience, on average, 1-2 relapses every
2 years, although this may decline with time. Approximately 5%
of patients die within 5 years of disease onset, and slightly more
have very good long-term outcome with little or no disability.
Prognosis is good for patients with optic neuritis and only sensory
relapses. Overall, about one-third of patients are disabled to
the point of needing help with walking after 10 years, and this
proportion rises to about half after 1 5 years. It would appear
likely (though this is as yet unproven) that disease-modifying
drugs will have an effect on long-term disability.
Investigations
There is no single diagnostic test that is definitive for MS and
the results of investigation need to be combined with the clinical
picture in order to make a diagnosis; MRI is the most important
investigation (Fig. 25.29). MS mimics should be excluded (see
below). Following the first clinical event (CIS), investigations may
help prognosis by confirming the disseminated nature of the
disease. MRI is the most sensitive technique for imaging lesions in
Exclude other structural disease
and identify plaques of demyelination
Image area of clinical involvement
(magnetic resonance imaging, myelography)
Demonstrate other sites of involvement
Imaging (MRI)
Visual evoked potentials
Other evoked potentials
Demonstrate inflammatory nature of lesion(s)
Cerebrospinal fluid examination
Cell count
Protein electrophoresis (oligoclonal bands)
Exclude other conditions
Chest X-ray
Serum angiotensin-converting enzyme
Serum vitamin B12
Antinuclear antibodies
Antiphospholipid antibodies
Fig. 25.29 Investigations in a patient suspected of having multiple
sclerosis.
brain and spinal cord (Fig. 25.30) and for excluding other causes
that have provoked the neurological deficit. However, the MRI
appearances in MS may be confused with those of small-vessel
disease or cerebral vasculitis, and these diagnoses should be
considered and excluded. Evoked potentials (visual, auditory or
somatosensory) may detect clinically silent lesions but are rarely
used nowadays with the advent of MRI.
The CSF may show a lymphocytic pleocytosis in the acute
phase and unique (i.e. absent from the serum) oligoclonal bands
of IgG in 70-90% of patients between attacks. Oligoclonal bands
are not specific for MS and denote only intrathecal inflammation,
provided they are unique for the CSF. These can appear in
other disorders, which should be excluded by examination and
investigation. It is important to exclude other potentially treatable
conditions, such as infection, vitamin B12 deficiency and spinal
cord compression.
Neuro-inflammatory diseases • 1109
Fig. 25.30 Multiple sclerosis: demyelinating lesion in cervical spinal
cord, high-signal T2 images (arrows). [A] Sagittal plane. [§] Axial plane.
Management
The management of MS involves four different strands: treatment
of the acute episode, prevention of future relapses, treatment
of complications, and management of the patient’s disability.
The acute episode
In a disabling exacerbation of MS, pulses of high-dose
glucocorticoid, given either intravenously or orally over 3-5 days,
will shorten the duration of the acute episode. Prolonged
administration of glucocorticoids does not alter the long-term
outcome and is associated with severe adverse effects; it should
therefore be avoided. Pulses of glucocorticoids can be given
up to three times in a year but use should be restricted to
those individuals with significant function-threatening deficits.
Prophylaxis to prevent glucocorticoid-induced osteoporosis
(p. 1045) should be considered in patients requiring multiple
courses of glucocorticoids.
Disease-modifying treatment
Until the 1990s, there were no effective disease-modifying
treatments (DMTs) for MS; azathioprine showed some promise
but this was offset by adverse effects and the drug was rarely
used. The introduction of, initially, beta- interferons and glatiramer
acetate paved the way for a new and exciting era of DMTs, which
is still evolving. All reduce annual relapse rates and the number
and size of lesions on MRI, and some may reduce disability.
They are not indicated for treatment of early or pre-clinical MS.
25.49 Disease-modifying treatments
in multiple sclerosis
Route of
Treatment administration/dosing Comment
Moderate efficacy for less severe cases: average relapse rate
reduction 30-50%
Interferon-
Alternate-day or weekly
In widespread use for
beta
intramuscular or
subcutaneous injection
reducing relapse rate
Glatiramer
Alternate-day
Similar efficacy to
acetate
subcutaneous injection
interferon -beta
Teriflunomide
Daily oral
May cause diarrhoea,
alopecia, hepatotoxicity
Highly teratogenic
Dimethyl
Daily oral
May cause flushing and
fumarate
gastrointestinal
disturbance
Risk of PML
Fingolimod
Daily oral
Superior efficacy to
interferon -beta in
randomised trials
Cardiac conduction
defects, especially with
first dose
High efficacy for severe cases: average relapse rate reduction
>50%
Alemtuzumab
Intravenous infusion over
May precipitate
two courses separated
autoimmune reactions,
by 12 months; 5-day
infusion initially, second
course 3 days
e.g. thyroid disease, UP
Natalizumab
4-weekly intravenous
Recently introduced;
infusion
may be more effective
than interferon -beta and
glatiramer acetate
Risk of PML
(UP = idiopathic thrombocytopenic purpura; PML = progressive multifocal
leucoencephalopathy)
These drugs - available orally, as regular subcutaneous injections
or as pulsed intravenous treatments - may be divided into two
groups (Box 25.49). All DMTs have strict licensing criteria and are
associated with a range of adverse effects, some occasionally
fatal, especially the more effective drugs. Careful selection and
counselling of patients are necessary and these drugs should be
supervised by teams experienced in their use, as recommended
in national guidelines.
Clinical trials suggest that DMT options for primary and
secondary progressive MS will be available in coming years.
Clinical trials involving stem cells are ongoing.
Special diets, including gluten-free regimens or linoleic acid
supplements, and hyperbaric oxygen therapy are popular with
patients but their efficacy has not been demonstrated.
Treatment of symptoms, complications and disability
Treatments for the complications of MS are summarised in Box
25.50. It is important to provide patients with a careful explanation
of the nature of the disease and its outcome. When and if
disability occurs, patients and their relatives need appropriate
support. Specialist nurses working in a multidisciplinary team
of health-care professionals are of great value in managing the
chronic phase of the disease. Periods of physiotherapy and
occupational therapy may improve functional capacity in those
who become disabled, and guidance can be provided on the
1110 • NEUROLOGY
KM 25.50 Treatment of complications in multiple
sclerosis
Spasticity
• Physiotherapy
• Tizanidine
• Baclofen (usually oral)
• Intrathecal baclofen
• Dantrolene
• Local (intramuscular) injection
• Gabapentin
of botulinum toxin
• Sativex
• Chemical neuronectomy
Dysaesthesia
• Carbamazepine
• Phenytoin
• Gabapentin
• Amitriptyline
Bladder symptoms
• See Box 25.25 (p. 1094)
Fatigue
• Amantadine
• Amitriptyline
• Modafinil
Erectile dysfunction
• Sildenafil 50-100 mg/day
• Tadalafil
25.51 Multiple sclerosis in pregnancy
• Counselling: provision of pre-conception counselling is best
practice.
• Relapse risk: endocrine effects on the immune system ensure that
relapse risk drops during pregnancy.
• Disease-modifying drugs: risk of teratogenicity means that all
disease-modifying drugs should ideally be stopped 6-8 weeks
before conception and recommenced after breastfeeding has
stopped.
• Post-partum relapse rate: rebound of immune system activity
means that the highest risk of relapse is in the first year after
delivery.
provision of aids at home, reducing handicap. Bladder care is
particularly important. Urgency and frequency can be treated
pharmacologically (see Box 25.25, p. 1094) but this may lead
to a degree of retention with an attendant risk of infection.
Urinary retention can be managed initially by intermittent urinary
catheterisation (performed by the patient, if possible) but an
in-dwelling catheter may become necessary. Sexual dysfunction is
a frequent source of distress. Sildenafil or tadalafil helps impotence
in men, and skilled counselling and prosthetic aids may be
beneficial. Pregnancy does not increase the risk of progression
of MS but relapses may occur post-partum (Box 25.51).
Acute disseminated encephalomyelitis
This is an acute monophasic demyelinating condition in which
areas of perivenous demyelination are widely disseminated
throughout the brain and spinal cord. The illness may arise
spontaneously but often occurs a week or so after a viral infection,
especially measles or chickenpox, or following vaccination,
suggesting that it is immunologically mediated.
Clinical features
Headache, vomiting, pyrexia, delirium and meningism may be
presenting features, often with focal or multifocal brain and spinal
cord signs. Seizures or coma may occur. A minority of patients
who recover have further episodes.
Investigations
MRI shows multiple high-signal areas in a pattern similar to that of
MS, although often with large confluent areas of abnormality. CSF
may be normal or show an increase in protein and lymphocytes
(occasional ly > 1 00 xIO6 cel Is/L). Oligoclonal bands may be found
in the acute episode but, in contrast to MS, do not persist
beyond clinical recovery. The clinical picture may be very similar
to a first relapse of MS.
Management
The prognosis for acute disseminated encephalomyelitis is
generally good, although occasionally it may be fatal (probably
less than 10%). Treatment with high-dose intravenous
methylprednisolone, using the same regimen as for a relapse
of MS, is recommended.
| Transverse myelitis
Transverse myelitis is an acute, usually monophasic, demyelinating
disorder affecting the spinal cord. It is usually thought to be
post-infectious in origin. It occurs at any age and presents with
a subacute paraparesis with a sensory level, accompanied
by severe pain in the neck or back at the onset. MRI should
distinguish this from an external lesion affecting the spinal
cord. CSF examination shows cellular pleocytosis, often with
polymorphs at the onset. Oligoclonal bands are usually absent.
Treatment is with high-dose intravenous methylprednisolone.
The outcome is variable: one-third have static deficit, one-third
go on to develop MS and one-third recover with no subsequent
relapse. Some clinical features may suggest a higher risk of MS
after transverse myelitis.
|Neuromyelitis optica
Neuromyelitis optica (previously Devic’s disease) is the occurrence
of transverse myelitis and bilateral optic neuritis. The disease has
been recognised for many years, particularly in Asia. The majority
of cases are associated with an antibody to a neuronal membrane
channel, aquaporin 4. If changes are seen on brain MRI (this
is variable), they are typically high-signal lesions restricted to
periventricular regions. Spinal MRI scans show lesions that are
typically longer than three spinal segments (unlike the shorter
lesions of MS). Clinical deficits tend to recover less well than
in MS, and the disease may be more aggressive with more
frequent relapses. Treatment with glucocorticoids, azathioprine
or cyclophosphamide, and/or plasmapheresis seems to be more
effective than in MS.
Paraneoplastic neurological disorders
Neurological disease may occur with systemic malignant tumours
in the absence of cerebral metastases. It is now recognised
that, in the majority of these cases, antigen production in the
body of the tumour leads to development of antibodies to
parts of the CNS. Paraneoplastic conditions are increasingly
recognised and the number of antibodies identified is also growing
(Boxes 25.52 and 25.53). These syndromes are particularly
associated with small-cell carcinoma of lung, ovarian tumours
and lymphomas. Autoantibodies are found in the serum and/or
CSF, and biopsy will show a lymphocytic infiltrate of the neural
tissue affected.
Neurodegenerative diseases • 1111
25.52 Paraneoplastic disorders of the central nervous system
Clinical presentation
Associated tumour
Antibodies demonstrated
Limbic encephalitis
SCLC
Anti-Hu, anti-CV2, PCA-2, anti-VGKC, anti-Mai , anti-amphiphysin, anti-Ri,
ANNA-3, anti-VGCC, anti-Zic4, anti-GluRI/2, anti-GABAR
Testicular, breast
Anti-Ma2, anti-GluR1/2
Thymoma
Anti-VGKC, anti-CV2, anti-GluR1/2
Ovarian/testicular teratoma
Anti-NMDAR
Myelopathy
SCLC, thymoma, others
Anti-CV2, anti-amphiphysin, anti-aquaporin
Motor neuron disease
SCLC, others
Anti-Hu
Stiff person syndrome
Breast, SCLC, thymoma, others
Anti-amphiphysin, anti-Ri, anti-GAD, anti-GlyR
Cerebellar degeneration
Breast, ovarian, others
Anti-Yo, anti-Mai, anti-Ri
SCLC, others
Anti-Hu, anti-CV2, PCA-2, ANNA-3, anti-amphiphysin, anti-VGCC, anti-Ri,
anti-Zic4, anti-GAD
Lymphoma
Anti-Tr, anti-mGluRI
Multifocal encephalomyelitis
SCLC, thymoma
Anti-Hu, anti-CV2, anti-VGKC, anti-Mai, anti-amphiphysin, anti-Ri, ANNA-3
Opsoclonus-myoclonus
Breast, ovarian
Anti-Ri, anti-Yo, anti-amphiphysin
SCLC
Anti Hu, anti-Ri, anti-CV2, anti-amphiphysin, anti-VGCC
Neuroblastoma
Anti-Hu
Testicular
Anti-Mai /2, anti-CV2
Extrapyramidal encephalitis
SCLC, thymoma, testicular
Anti-CV2, anti-Hu, anti-VGKC, anti-Ma
Optic neuritis
SCLC
Anti-CV2, anti-aquaporin
Retinal degeneration
SCLC
Anti-recoverin
(ANNA = anti-neuronal nucleolar antibody; GABAR = GABA receptor; GAD = glutamic acid decarboxylase; GluR = glutamate receptor; GlyR = glycine receptor; NMDAR =
/V-methyl-D-aspartate receptor; PCA =
Purkinje cell antibody; SCLC = small-cell lung cancer; VGCC = voltage-gated calcium channel; VGKC = voltage-gated potassium
channel)
25.53 Paraneoplastic disorders of the peripheral nervous system
Clinical presentation
Associated tumour
Antibodies demonstrated
Neuromyotonia
Thymoma, SCLC, others
Anti-VGKC
Myasthenia gravis
Thymoma
Anti-Achr, anti-MuSK
Sensorimotor polyneuropathy
Lymphoma, SCLC, others
Anti-Hu, anti-CV2, ANNA-3, anti-Mai , anti-amphiphysin
Lambert-Eaton syndrome
SCLC
Anti-VGCC
Motor neuropathy
Lymphoma, SCLC, others
Anti-Hu, anti-Yo, anti-CV2
Sensory neuropathy
Lymphoma, SCLC, others
Anti-Hu, anti-Yo, anti-CV2
Polymyositis/dermatomyositis
Lung, breast
Anti-Jol
(MuSK = muscle-specific kinase; for other abbreviations, see Box 25.52)
Clinical features
Clinical presentations are summarised in Boxes 25.52 and 25.53.
In most instances, the neurological condition progresses quite
rapidly over a few months, preceding the malignant disease
in around half of cases. The range of clinical patterns is so
wide that paraneoplastic disease should be considered in the
diagnosis of any unusual progressive neurological syndrome.
The paraneoplastic disorders of the peripheral nervous system
particularly affect the synaptic cleft (p. 1065).
Investigations and management
The presence of characteristic autoantibodies in the context of
a suspicious clinical picture may be diagnostic. The causative
tumour may be very small and therefore CT of the chest or
abdomen or PET scanning may be necessary to find it. These
investigations should be pursued only when paraneoplastic
disease has been proven, rather than when it is suspected. The
CSF often shows an increased protein and lymphocyte count
with oligoclonal bands.
Treatment is directed at the primary tumour. Occasionally,
successful therapy of the tumour is associated with improvement
of the paraneoplastic syndrome. Some improvement may occur
following administration of intravenous immunoglobulin.
Neurodegenerative diseases
While MS is the most common cause of disability in young
people in the UK, vascular and neurodegenerative diseases are
increasingly important in later life. The neurodegenerative diseases
are united in having a pathological process that leads to specific
neuronal death, causing relentlessly progressive symptoms, with
1112 • NEUROLOGY
incidence rising with age. The causes are not yet known, although
genetic influences are important. Alzheimer’s disease (p. 1192)
and Parkinson’s disease are the most common.
Movement disorders
Movement disorders present with a wide range of symptoms.
They may be genetic or acquired, and the most important is
Parkinson’s disease. Most movement disorders are categorised
clinically, with few confirmatory investigations available other
than for those with a known gene abnormality.
|Jdiopathic Parkinson’s disease
Parkinsonism is a clinical syndrome characterised primarily by
bradykinesia (p. 1084), with associated increased tone (rigidity),
tremor and loss of postural reflexes. There are many causes (Box
25.54) but the most common is Parkinson’s disease (PD). PD
has an annual incidence of about 18/100000 in the UK and a
prevalence of about 1 80/1 00 000. Age has a critical influence on
incidence and prevalence, the latter rising to 300-500/1 00 000
after 80 years of age. Average age of onset is about 60 years
and fewer than 5% of patients present under the age of 40.
Genetic factors are increasingly recognised and several single
genes causing parkinsonism have been identified, although they
account for a very small proportion of cases overall. Having
a first-degree relative with PD confers a 2-3 times increased
risk of developing the disorder. It is progressive and incurable,
with a variable prognosis. While motor symptoms are the most
common presenting features, non-motor symptoms (particularly
cognitive impairment, depression and anxiety) become increasingly
prominent as the disease progresses, and significantly reduce
quality of life.
Pathophysiology
Although mutations in several genes have been identified in a
few cases, in most patients the cause remains unknown. The
discovery that methyl-phenyl-tetrahydropyridine (MPTP) caused
severe parkinsonism in young drug users suggested that PD might
■
I
Idiopathic Parkinson’s disease (at least 80% of parkinsonism)
Cerebrovascular disease
Drugs and toxins
• Antipsychotic drugs (older and
‘atypical’)
• Metoclopramide,
prochlorperazine
• Tetrabenazine
Other degenerative diseases
• Dementia with Lewy bodies
• Progressive supranuclear palsy
• Multiple system atrophy
Genetic
• Huntington’s disease
• Fragile X tremor ataxia
syndrome
• Dopa-responsive dystonia
Anoxic brain injury
(MPTP = methyl-phenyl-tetrahydropyridine)
be due to an environmental toxin but none has been convincingly
identified. The pathological hallmarks of PD are depletion of the
pigmented dopaminergic neurons in the substantia nigra and the
presence of a-synuclein and other protein inclusions in nigral
cells (Lewy bodies; Fig. 25.31). It is thought that environmental
or genetic factors alter the a-synuclein protein, rendering it toxic
and leading to Lewy body formation within the nigral cells. Lewy
bodies are also found in the basal ganglia, brainstem and cortex,
and increase with disease progression. PD is recognised as a
synucleinopathy alongside multiple system atrophy and dementia
with Lewy bodies. The loss of dopaminergic neurotransmission
is responsible for many of the clinical features.
Clinical features
Non-motor symptoms, including reduction in sense of smell
(hyposmia), anxiety/depression, constipation and REM sleep
behavioural disturbance (RBD), may precede the development of
typical motor features by many years but patients rarely present
at this stage. The motor symptoms are almost always initially
asymmetrical. The hallmark is bradykinesia, leading to classic
symptoms such as increasingly small handwriting (‘micrographia’),
difficulty tying shoelaces or buttoning clothes, and difficulty rolling
over in bed. Tremor is an early feature but may not be present
in at least 20% of people with PD. It is typically a unilateral rest
tremor (p. 1085) affecting limbs, jaw and chin but not the head. In
some patients, tremor remains the dominant symptom for many
years. Rigidity causes stiffness and a flexed posture. Although
postural righting reflexes are impaired early on in the disease,
falls tend not to occur until later. As the disease advances,
speech becomes softer and indistinct. There are a number of
abnormalities on neurological examination (Box 25.55).
Although features are initially unilateral, gradual bilateral
involvement evolves with time. Cognition is spared in early
disease; if impaired, it should trigger consideration of alternative
diagnoses, such as dementia with Lewy bodies.
Non-motor symptoms
While non-motor symptoms may precede the onset of more
typical symptoms by many years, for most patients these
features become increasingly common and disabling as PD
progresses. Cognitive impairment, including dementia, is the
symptom most likely to impair quality of life for patients and their
carers. Estimates of dementia frequency range from 30% to 80%,
depending on definitions and length of follow-up. Other distressing
Fig. 25.31 Parkinson’s disease. High power (x400) view of substantia
nigra of a patient with Parkinson’s disease showing classical Lewy body
(haematoxylin and eosin). Courtesy of Dr J. Xuereb.
25.54 Causes of parkinsonism
• Sodium valproate
• Lithium
• Manganese
• MPTP
• Corticobasal degeneration
• Alzheimer’s disease
• Spinocerebellar ataxias
(particularly SCA 3)
• Wilson’s disease
Neurodegenerative diseases • 1113
i
General
• Expressionless face
(hypomimia)
• Soft, rapid, indistinct speech
(dysphonia)
Gait
• Slow to start walking (failure
of gait ignition)
• Rapid, short stride length,
tendency to shorten
(festi nation)
Tremor
Resting (3-4 Hz, moderate amplitude): most common
• Asymmetric, usually first in arm/hand (‘pill rolling’)
• May affect legs, jaw and chin but not head
• Intermittent, present at rest, often briefly abolished by movement of
limb, exacerbated by walking
Postural (6-8 Hz, moderate amplitude)
• Present immediately on stretching out arms
Re-emergent tremor (3-4 Hz, moderate amplitude)
• Initially no tremor on stretching arms out, rest tremor re-emerges
after a few seconds
Rigidity
• Cogwheel type, mostly upper limbs (due to tremor superimposed on
rigidity)
• Lead pipe type
Akinesia (fundamental feature)
• Slowness of movement
• Fatiguing and decrease in size of repetitive movements
Normal findings (if abnormal, consider other causes)
• Power, deep tendon reflexes, plantar responses
• Eye movements
• Sensory and cerebellar examination
non-motor symptoms include neuropsychiatric features (anxiety,
depression, apathy, hallucinosis/psychosis), sleep disturbance
and hypersomnolence, fatigue, pain, sphincter disturbance and
constipation, sexual problems (erectile failure, loss of libido or
hypersexuality), drooling and weight loss.
Investigations
The diagnosis is clinical. Structural imaging (CT or MRI) is
usually normal for age and thus rarely helpful, although it may
support a suspected vascular cause of parkinsonism. Functional
dopaminergic imaging (SPECT or PET) is abnormal, even in the
early stages (Fig. 25.32), but does not differentiate between the
different forms of degenerative parkinsonism (see Box 25.54)
and so is not specific for PD. In younger patients, specific
investigations may be appropriate (e.g. exclusion of Huntington’s
or Wilson’s diseases). Some patients with family histories may
wish to consider genetic testing, although the role of genetic
counselling is uncertain at present.
Management
Drug therapy
Drug treatment for PD remains symptomatic rather than curative,
and there is no evidence that any of the currently available drugs
Fig. 25.32 Imaging in Parkinson’s disease. [A] Single photon emission
computed tomography (SPECT) in Parkinson’s disease showing reduced
dopamine activity in the basal ganglia. \B} Normal.
are neuroprotective. Levodopa (LD) remains the most effective
treatment available but other agents include dopamine agonists,
anticholinergics, inhibitors of monoamine oxidase (MAOI)-B and
catechol-O-methyl-transferase (COMT), and amantadine. Debate
continues about when and what treatment should be started. In
general, most specialists recommend initiating treatment when
symptoms are impacting on everyday life although some favour
treatment as soon as the diagnosis is made. Whether it is best to
start with LD, a dopamine agonist or MAOI-B remains unclear but
most accept that the most effective, best-tolerated and cheapest
drug is LD. Many motor symptoms, such as tremor, freezing,
falling, head-drop and abnormal flexion, are quite resistant to
treatment. Some non-motor symptoms, such as anxiety or
depression, may respond to drug or non-drug treatments. In the
UK, rivastigmine is licensed for use in PD-associated dementia,
although its effect is modest. Many other non-motor symptoms
are resistant to treatment. Drugs for PD should not be stopped
abruptly, as this can precipitate malignant hyperthermia.
Levodopa Levodopa is the precursor to dopamine. When
administered orally, more than 90% is decarboxylated to dopamine
peripherally in the gastrointestinal tract and blood vessels, and only
a small proportion reaches the brain. This peripheral conversion
is responsible for the high frequency of adverse effects. To
avoid this, LD is combined with a dopa decarboxylase inhibitor
(DDI); the inhibitor does not cross the blood-brain barrier, thus
avoiding unwanted decarboxylation-blocking in the brain. Two
DDIs, carbidopa and benserazide, are available as combination
preparations with LD (Sinemet and Madopar, respectively).
LD is most effective for relieving akinesia and rigidity; tremor
response is often less satisfactory and it has no effect on many
motor (posture, freezing) and non-motor symptoms. Failure of
akinesia/rigidity to respond to LD (1000 mg/day) should prompt
reconsideration of the diagnosis. Although controlled-release
versions of LD exist, these are usually best reserved for use
overnight, as their variable bioavailability makes them difficult to
use throughout the day. Madopar is also available as a dispersible
tablet for more rapid-onset effect.
Adverse effects include postural hypotension, nausea and
vomiting, which may be offset by domperidone. LD may
exacerbate or trigger hallucinations, and abnormal LD-seeking
behaviour (dopamine dysregulation syndrome), in which the
patient takes excessive doses of LD, may occur uncommonly.
As PD progresses, the response to LD becomes less
predictable in many patients, leading to motor fluctuations. This
end-of-dose deterioration is due to progressive loss of dopamine
storage capacity by dwindling numbers of striatonigral neurons.
25.55 Physical signs in Parkinson’s disease
• Flexed (stooped) posture
• Impaired postural reflexes
• Reduction of arm swing
• Impaired balance on
turning
1114 • NEUROLOGY
LD-induced involuntary movements (dyskinesia) may occur
as a peak-dose phenomenon or as a biphasic phenomenon
(occurring during both the build-up and wearing-off phases).
More complex fluctuations present as sudden, unpredictable
changes in response, in which periods of parkinsonism (‘off
phases) alternate with improved mobility but with dyskinesias (‘on’
phases). Motor complication management is difficult; wearing-off
effects may respond to increased dose or frequency of LD or
the addition of a COMT inhibitor (see below). More complex
fluctuations may be improved by the addition of dopamine
agonists (including continuous infusion of apomorphine), use of
intraintestinal LD via a percutaneous endoscopic jejunostomy,
or deep brain stimulator implantation.
Dopamine receptor agonists Originally introduced in the hope of
delaying the initiation of LD and thus delaying motor complications,
several dopamine agonists are available, and may be delivered
orally, transdermally or subcutaneously (Box 25.56).
The ergot-derived agonists are no longer recommended
because of rare but serious fibrotic effects. With the exception
of apomorphine, all the agonists are considerably less effective
than LD in relieving parkinsonism, have more adverse effects
(nausea, vomiting, disorientation and hallucinations, impulse
control disorders) and are more expensive. Their role in the
management of PD (monotherapy or adjunctive) remains uncertain,
and evidence suggests that their usefulness as initial monotherapy
is short-lasting.
MAOI-B inhibitors Monoamine oxidase type B facilitates breakdown
of excess dopamine in the synapse. Two inhibitors are used in
PD: selegiline and rasagiline. The effects of both are modest,
although usually well tolerated. Neither is neuroprotective, despite
initial hopes.
COMT inhibitors Catechol-O-methyl-transferase (along with dopa
decarboxylase) is involved in peripheral breakdown of LD. Two
inhibitors are available: entacapone and tolcapone (which also
inhibits central COMT). Entacapone has a modest effect and
is most useful for early wearing-off. It is available either as a
single tablet taken with each LD/DDI dose, or as a combination
tablet with LD and DDL The more potent tolcapone is less used
because of rare but serious hepatotoxicity.
Amantadine This has a mild, usually short-lived effect on
bradykinesia and is rarely used unless patients are unable to
tolerate other drugs. It is more commonly employed as a treatment
for LD-induced dyskinesias, although again benefit is modest and
short-lived. Adverse effects include livedo reticularis, peripheral
oedema, delirium and other anticholinergic effects.
Anticholinergic drugs These were the main treatment for PD
prior to the introduction of LD. Their role now is limited by
i
25.56 Dopamine agonists
Ergot-derived
• Bromocriptine
•
Pergolide
• Lisuride
•
Cabergoline
Non-ergot-derived
• Ropinirole
•
Rotigotine (transdermal patch)
• Pramipexole
•
Apomorphine (subcutaneous)
*0ral unless otherwise stated.
lack of efficacy (apart from an effect on tremor sometimes)
and adverse effects, including dry mouth, blurred vision,
constipation, urinary retention, delirium and hallucinosis, as
well as long-term concerns regarding cognitive impairment.
Several anticholinergics are available, including trihexyphenidyl
(benzhexol) and orphenadrine.
Surgery
Destructive neurosurgery was commonly used before the
introduction of LD. In the last 20 years, stereotactic surgery has
emerged and most commonly involves deep brain stimulation
(DBS), rather than the destructive approach of previous eras.
Various targets have been identified, including the thalamus (only
effective for tremor), globus pallidus and subthalamic nucleus.
DBS is usually reserved for individuals with medically refractory
tremor or motor fluctuations, and careful patient selection is vital
to success. Intracranial delivery of fetal grafts or specific growth
factors remains experimental.
Physiotherapy, occupational therapy and speech therapy
Patients at all stages of PD benefit from physiotherapy, which
helps reduce rigidity and corrects abnormal posture. Occupational
therapists can provide equipment to help overcome functional
limitations, such as rails for stairs and the toilet, and bathing
equipment. Speech therapy can help where dysarthria and
dysphonia interfere with communication, and advice may also
be provided to those with dysphagia. As with many complex
neurological disorders, patients with PD should ideally be
managed by a multidisciplinary team, including PD specialist
nurses.
Other parkinsonian syndromes
Cerebrovascular disease and drug-induced parkinsonism are
the most common alternative causes of parkinsonism (see Box
25.54). There are several degenerative conditions that cause
parkinsonism, including multiple system atrophy, progressive
supranuclear palsy and corticobasal degeneration. They typically
have a more rapid progression than PD and tend to be resistant
to treatment with LD. They are defined pathologically and
identification during life is difficult. There are other conditions
that may rarely manifest as parkinsonism, including Huntington’s
and Wilson’s diseases.
Multiple system atrophy
Multiple system atrophy (MSA) is characterised by parkinsonism,
autonomic failure and cerebellar symptoms, with either
parkinsonism (MSA-P) or cerebellar features (MSA-C)
predominating. It is much less common than PD, with a prevalence
of about 4/100 000. Although early distinction between PD
and MSA-P may be difficult, early falls, postural instability and
lack of response to LD are clues. The pathological hallmark is
a-synuclein-containing glial cytoplasmic inclusions found in the
basal ganglia, cerebellum and motor cortex. Management is
symptomatic and the prognosis is less good than for PD, with
mean survival from symptom onset of fewer than 1 0 years and
early disability. Cognition is usually unaffected.
Progressive supranuclear palsy
Progressive supranuclear palsy (PSP) presents with symmetrical
parkinsonism, cognitive impairment, early falls and bulbar
symptoms. The characteristic eye movement disorder, with
slowed vertical saccades leading to impairment of up- and down-
gaze, may take years to emerge. PSP has different pathological
Neurodegenerative diseases • 1115
features, being associated with abnormal accumulation of tau (t)
proteins and degeneration of the substantia nigra, subthalamic
nucleus and mid-brain. It is therefore a tauopathy rather than
synucleinopathy. The prevalence is about 5/1 00 000, with average
survival similar to that in MSA. There is no treatment, and the
parkinsonism usually does not respond to LD.
Corticobasal degeneration
Corticobasal degeneration (CBD) is less common than MSA
or PSP, and the clinical manifestations are variable, including
parkinsonism, dystonia, myoclonus and ‘alien limb’ phenomenon,
whereby a limb (usually upper) moves about or interferes with the
other limb without apparent conscious control. Cortical symptoms,
including dementia and especially apraxia, are common and
may be the only features in some cases. A number of other
diseases may present with a corticobasal syndrome, including
other dementias. CBD is a tauopathy with widespread deposition
throughout the brain, and has similar survival rates to MSA
and PSP.
Wilson’s disease
This is an autosomal recessive disorder resulting from mutation in
the ATP7B gene, causing a defect of copper metabolism (p. 896).
It is a treatable cause of various movement disorders, including
tremor, dystonia, parkinsonism and ataxia; psychiatric symptoms
may also occur. Wilson’s disease should always be excluded
in patients under the age of 50 presenting with any movement
disorder.
Huntington’s disease
Huntington’s disease (HD) is an autosomal dominant disorder,
presenting in adults usually but occasionally in children. It is due
to expansion of a trinucleotide CAG repeat in the Huntingtin gene
on chromosome 4 (p. 43). The disease frequently demonstrates
the phenomenon of anticipation, in which there is a younger
age at onset as the disease is passed through generations,
due to progressive expansion of the repeat. The prevalence is
about 4-8/1 00 000.
Clinical features
HD typically presents with a progressive behavioural disturbance,
abnormal movements (usually chorea), and cognitive impairment
leading to dementia. Onset under 18 years is rare but patients
may then present with parkinsonism rather than chorea (the
‘Westphal variant’). There is always a family history, although
this may be concealed.
Investigations and management
The diagnosis is confirmed by genetic testing; pre-symptomatic
testing for other family members is available but must be preceded
by appropriate counselling (p. 59). Brain imaging may show
caudate atrophy but is not a reliable test. There are a number
of HD mimics.
Management is symptomatic. The chorea may respond to
neuroleptics such as risperidone or sulpiride, or tetrabenazine.
Depression and anxiety are common and may be helped by
medication.
Ataxias
The ataxias are a heterogeneous group of inherited and acquired
disorders, presenting either with pure ataxia or in association with
other neurological and non-neurological features. The differential
i
Structural
• Brain tumour • Brain abscess
Toxic
• Drugs: lithium, phenytoin, amiodarone, toluene, 5-fluorouracil,
cytosine arabinoside
• Alcohol
• Heavy metals/chemicals: mercury, lead, thallium
Infection/post-infectious
• HIV
•
Whipple’s disease
• Varicella zoster
•
Miller Fisher syndrome
(p. 1140)
Degenerative
• Multiple system atrophy
•
Idiopathic (or sporadic)
• Sporadic Creutzfeldt— Jakob
late-onset cerebellar ataxia
disease
Inflammatory/immune-mediated
• Multiple sclerosis
•
Paraneoplastic ataxia
• Gluten ataxia (coeliac disease)
Metabolic
•
Hashimoto encephalopathy
• Vitamin B^ or E deficiency
• Hypothyroidism
•
Hypoparathyroidism
Vascular
• Stroke (ischaemic or
•
Vascular malformations
haemorrhagic)
•
Superficial siderosis
is wide (Boxes 25.57 and 25.58), and diagnosis is guided by age
of onset, evolution and clinical features. A significant proportion
of cases remain idiopathic despite investigation.
The hereditary ataxias are a group of inherited disorders
in which degenerative changes occur to varying extents in
the cerebellum, brainstem, pyramidal tracts, spinocerebellar
tracts and optic and peripheral nerves, and influence the clinical
manifestations. Onset ranges from infancy to adulthood, with
recessive, sex-linked or dominant inheritance (see Box 25.58).
While the genetic abnormality has been identified for some,
allowing diagnostic testing, this is not currently the case for
many of the hereditary ataxias.
Tremor disorders
Tremor (p. 1085) is a feature of many disorders but the most
important clinical syndromes are PD, essential tremor, drug-
induced tremors (Box 25.59) and functional (psychogenic) tremors.
Essential tremor
This has a prevalence of about 300/1 00 000 and may display a
dominant pattern of inheritance, although no genes have thus
far been identified. It may present at any age with a bilateral arm
tremor (8-10 Hz), rarely at rest but typical with movement. The
head and voice may be involved. The tremor improves in about
50% of patients with small amounts of alcohol. There are no
specific tests and essential tremor should be distinguished from
other tremor syndromes, including dystonic tremor. Beta-blockers
and primidone are sometimes helpful, and DBS of the thalamus
is an effective treatment for severe cases.
25.57 Causes of acquired ataxia
1116 • NEUROLOGY
25.58 Inherited ataxias
Inheritance pattern
Age of onset
Clinical features
Autosomal dominant
Episodic ataxias
Spinocerebellar ataxias (SCAs)
Dentato-rubro-pallidoluysian
atrophy (DRPLA)
Childhood and early
adulthood
Childhood to middle age
Childhood to middle age
Brief episodes of ataxia, sometimes induced by stress or startle. May develop
progressive ataxia
Over 30 subtypes identified thus far. Progressive ataxia, sometimes associated with
other features, including retinitis pigmentosa, pyramidal tract abnormalities,
peripheral neuropathy and cognitive deficits
Children present with myoclonic epilepsy and progressive ataxia. Adults have
progressive ataxia with psychiatric features, dementia and choreoathetosis
Autosomal recessive
Friedreich’s ataxia
Ataxia telangiectasia
Abetalipoproteinaemia
Hereditary ataxia with vitamin E
deficiency
Others
Childhood/adolescence
(late onset possible)
Childhood
Childhood
<20 years
Usually young onset
Ataxia, nystagmus, dysarthria, spasticity, areflexia, proprioceptive impairment,
diabetes mellitus, optic atrophy, cardiac abnormalities. Usually chair-bound
Progressive ataxia, athetosis, telangiectasia on conjunctivae, impaired DNA repair,
immune deficiency, tendency to malignancies
Steatorrhoea, sensorimotor neuropathy, retinitis pigmentosa, malabsorption of
vitamins A, D, E and K
Similar to Friedreich’s ataxia, visual loss or retinitis pigmentosa, chorea
Numerous, with genes identified only in some
X-linked
Fragile X tremor ataxia syndrome
Adrenoleukodystrophy
>50 years
Childhood to adult
Tremor, ataxia, parkinsonism, autonomic failure, cognitive impairment and dementia
Impaired adrenal and cognitive function, sometimes spastic paraparesis
Mitochondrial disease
Various
Ataxia features in several mitochondrial diseases, including Kearns-Sayre
syndrome, MELAS, MERRF, Leigh’s syndrome (p. 49)
(MELAS = mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF = myoclonic epilepsy with ragged red fibres)
25.59 Drug-induced tremor (usually postural)
• (3-agonists (e.g. salbutamol)
• Tricyclic antidepressants
• Theophylline
• Recreational drugs (e.g.
• Sodium valproate
amphetamines)
• Thyroxine
• Alcohol
• Lithium
• Caffeine
*Drugs causing parkinsonism and associated tremor are listed in Box 25.54.
Dystonia
Dystonia is characterised by a focal increase in tone affecting
muscles in the limbs or trunk. It may be a feature of a number
of neurological conditions (PD, Wilson’s disease), or occur
secondary to brain damage (trauma, stroke) or drugs (tardive
syndromes). Dystonia also occurs as a primary disorder. With
childhood onset the cause is usually genetic and dystonia is
generalised, but adult onset is usually focal; examples include
a twisted neck (torticollis), repetitive blinking (blepharospasm) or
tremor. Task-specific symptoms (e.g. writer’s cramp, musician’s
dystonia) are often dystonic. Treatment is difficult but botulinum
toxin injections or DBS may be useful.
Hemifacial spasm
This usually presents after middle age with intermittent twitching
around one eye, spreading ipsilaterally to other facial muscles.
The spasms are exacerbated by talking, eating and stress.
Hemifacial spasm is usually idiopathic, similar to trigeminal
neuralgia; it has been suggested that it may be due to an aberrant
arterial loop irritating the 7th nerve just outside the pons. It may,
however, be symptomatic and secondary to structural lesions.
Drug treatment is not effective but injections of botulinum toxin
into affected muscles help, although these usually have to be
repeated every 3 months or so. In refractory cases, microvascular
decompression may be considered.
Motor neuron disease
Motor neuron disease (MND) is a neurodegenerative condition
caused by loss of upper and lower motor neurons in the spinal
cord, cranial nerve nuclei and motor cortex. Annual incidence is
about 2/100000, with a prevalence of about 7/100000. Most
cases are sporadic but 10% of cases are familial. Abnormalities
in the superoxide dismutase (SOD1) gene account for about
20% of such cases, and an expanded repeat sequence in the
C9orf72 gene on chromosome 9 is associated with MND and
frontotemporal dementia. The most common form of MND (Fig.
25.33) is amyotrophic lateral sclerosis (ALS), and many use the
terms MND and ALS interchangeably. ALS is characterised by
a combination of upper and lower motor neuron signs; there
are rarer, pure lower (progressive muscular atrophy) or upper
(progressive lateral sclerosis) motor neuron variants of MND. The
average age of onset is 65, with 10% presenting before 45 years.
Clinical features
Diagnosis can be difficult and is often delayed. MND typically
presents focal ly, either with limb onset (e.g. foot drop or loss of
manual dexterity) or with bulbar symptoms (dysarthria, swallowing
difficulty); respiratory onset is rare but type II respiratory failure
is a common terminal event. Sensory, autonomic and visual
symptoms do not occur, although cramp is common (Box
25.60). Examination reveals a combination of lower and upper
Infections of the nervous system • 1117
Motor neuron disease
{ i r~ i
Progressive
Primary
Progressive
Amyotrophic
muscular atrophy
lateral sclerosis
bulbar palsy
lateral sclerosis
i i i — r
Predominantly LMN
Weakness and wasting of
distal limb muscles initially
Fasciculation
Tendon reflexes may be
present
Predominantly UMN
Spasticity-few lower
motor neuron signs
Gradual progression
Predominantly cranial nerves
Early involvement of tongue,
palate and pharyngeal muscles
Dysarthria/dysphagia
Wasting and fasciculation
of tongue
Pyramidal signs may
be present
Mixed LMN and UMN
Distal and proximal muscle
wasting and weakness
Fasciculation
Spasticity, exaggerated
reflexes, extensor plantars
Bulbar and pseudobulbar
palsy follow eventually
Pyramidal tract features
may predominate
Fig. 25.33 Patterns of involvement in motor neuron disease. (LMN = lower motor neuron; UMN = upper motor neuron)
i
Onset
• Usually after the age of 50 years
• Very uncommon before the age of 30 years
• Affects males more commonly than females
Symptoms
• Limb muscle weakness, cramps, occasionally fasciculation
• Disturbance of speech/swallowing (dysarthria/dysphagia)
• Cognitive and behavioural features common (similar to
frontotemporal dementia)
Signs
• Wasting and fasciculation of muscles
• Weakness of muscles of limbs, tongue, face and palate
• Pyramidal tract involvement, causing spasticity, exaggerated tendon
reflexes, extensor plantar responses
• External ocular muscles and sphincters usually remain intact
• No objective sensory deficit
• Evidence of cognitive impairment with frontotemporal dominance
Course
• Symptoms often begin focally in one part and spread gradually but
relentlessly to become widespread
motor neuron signs (e.g. brisk reflexes in wasted, fasciculating
muscles) without sensory involvement (Fig. 25.33). Cognitive
impairment is under-recognised in MND: up to 50% will have
a mainly executive impairment on formal testing, and around
10% develop a frontotemporal dementia (FTD). About 10% of
patients presenting with FTD will develop ALS within a few years
of dementia onset. Even with treatment, MND is relentlessly
progressive, but median survival is improved with specialist
follow-up offering non-invasive ventilation, feeding measures
and access to pharmacological treatment.
Investigations
Clinical features are often typical but alternative diagnoses should
be excluded. Exclusion of treatable causes, such as immune-
mediated multifocal motor neuropathy with conduction block
(p. 1140) and cervical myeloradiculopathy, is essential. Blood
tests are usually normal, other than a mildly raised creatine kinase.
Sensory and motor nerve conduction studies are normal but there
may be reduction in amplitude of motor action potentials due
to axonal loss. EMG will usually confirm the typical features of
widespread denervation and re- in nervation. Spinal fluid analysis is
not usually necessary. Genetic testing is increasing in importance,
with mutations found in SOD1 , FUS, TARDBP and C9orf72 that
may help predict risk and phenotype of disease in those with
a family history of MND.
Management
Patients should be managed within a multidisciplinary service,
including physiotherapists, speech and occupational therapists,
dietitians, ventilatory and feeding support, and palliative care
teams, with neurological and respiratory input. Riluzole, a
glutamate release antagonist, is licensed for ALS but has only
a modest effect, prolonging median survival by about 2-3 months.
Non-invasive ventilation significantly prolongs survival and
improves or maintains quality of life in people with ALS. Survival
and some measures of quality of life are significantly improved
in the subgroup of people with better baseline bulbar function
but not in those with severe bulbar impairment. Feeding by
percutaneous gastrostomy may improve quality of life and prolong
survival, even when done at a late stage. Rapid access to
palliative care teams is essential for patients as they enter the
terminal stages of MND.
Spinal muscular atrophy
This is a group of genetically determined disorders affecting spinal
and cranial lower motor neurons, characterised by proximal and
distal wasting, fasciculation and weakness of muscles. Involvement
is usually symmetrical but occasional localised forms occur. With
the exception of the infantile form, progression is slow and the
prognosis better than for MND.
Infections of the nervous system
The clinical features of nervous system infections depend on the
location of the infection (the meninges or the parenchyma of the
brain and spinal cord), the causative organism (virus, bacterium,
25.60 Clinical features of motor neuron disease
1118 • NEUROLOGY
25.62 Causes of meningitis
Infective
Bacteria (see Box 25.63)
Viruses
• Enteroviruses (echo,
•
Epstein— Barr
Coxsackie, polio)
•
HIV
• Mumps
•
Lymphocytic choriomeningitis
• Influenza
•
Mollaret’s meningitis (herpes
• Herpes simplex
• Varicella zoster
simplex virus type 2)
Protozoa and parasites
• Cysticerci
•
Amoeba
Fungi
• Cryptococcus neoformans
•
Blastomyces
• Candida
•
Coccidioides
• Histoplasma
•
Sporothrix
Non-infective (‘sterile’)
Malignant disease
• Breast cancer
•
Leukaemia
• Bronchial cancer
•
Lymphoma
Inflammatory disease (may be recurrent)
• Sarcoidosis
• Systemic lupus erythematosus
•
Behget’s disease
25.61 Infections of the nervous system
Bacterial infections
• Meningitis
• Suppurative encephalitis
• Brain abscess
• Paravertebral (epidural)
abscess
• Tuberculosis (p. 588)
Viral infections
• Neurosyphilis
• Leprosy (Hansen’s disease)
(peripheral nerves)*
• Diphtheria (peripheral nerves)*
• Tetanus (motor cells)
• Meningitis
• Poliomyelitis
• Encephalitis
• Subacute sclerosing
• Transverse myelitis
panencephalitis (late sequel)
• Progressive multifocal
• Rabies
leucoencephalopathy
• HIV infection (Ch. 12)
Prion diseases
• Creutzfeldt-Jakob disease
• Kuru
Protozoal infections
• Malaria*
• Trypanosomiasis*
• Toxoplasmosis (in
• Amoebic abscess*
immune-suppressed)*
Helminthic infections
• Schistosomiasis (spinal cord)*
• Hydatid disease*
• Cysticercosis*
• Strongyloidiasis*
Fungal infections
• Candida meningitis or brain
• Cryptococcal meningitis
abscess
*These infections are discussed in Chapter 1 1 .
fungus or parasite), and whether the infection is acute or chronic.
The major infections of the nervous system are listed in Box
25.61 . The frequency of these varies geographically. Helminthic
infections, such as cysticercosis and hydatid disease, and
protozoal infections are described in Chapter 1 1 .
Meningitis
Acute infection of the meninges presents with a characteristic
combination of pyrexia, headache and meningism. Meningism
consists of headache, photophobia and stiffness of the neck,
often accompanied by other signs of meningeal irritation, including
Kernig’s sign (extension at the knee with the hip joint flexed
causes spasm in the hamstring muscles) and Brudzinski’s sign
(passive flexion of the neck causes flexion of the hips and knees).
Meningism is not specific to meningitis and can occur in patients
with subarachnoid haemorrhage. The severity of clinical features
varies with the causative organism, as does the presence of other
features such as a rash. Abnormalities in the CSF (see Box 25.6,
p. 1078) are important in distinguishing the cause of meningitis.
Causes of meningitis are listed in Box 25.62.
Viral meningitis
Viruses are the most common cause of meningitis, usually
resulting in a benign and self-limiting illness requiring no specific
therapy. It is much less serious than bacterial meningitis unless
there is associated encephalitis. A number of viruses can cause
meningitis (see Box 25.62), the most common being enteroviruses.
Where specific immunisation is not employed, the mumps virus
is a common cause.
Clinical features
Viral meningitis occurs mainly in children or young adults, with
acute onset of headache and irritability and the rapid development
of meningism. The headache is usually the most severe feature.
There may be a high pyrexia but focal neurological signs are rare.
Investigations
The diagnosis is made by lumbar puncture. CSF usually contains
an excess of lymphocytes. While glucose and protein levels are
commonly normal, the latter may be raised. It is important to
verify that the patient has not received antibiotics (for whatever
cause) prior to the lumbar puncture, as CSF lymphocytosis can
also be found in partially treated bacterial meningitis.
Management
There is no specific treatment and the condition is usually benign
and self-limiting. The patient should be treated symptomatically
in a quiet environment. Recovery usually occurs within days,
although a lymphocytic pleocytosis may persist in the CSF.
Meningitis may also occur as a complication of a systemic viral
infection such as mumps, measles, infectious mononucleosis,
herpes zoster and hepatitis. Whatever the virus, complete recovery
without specific therapy is the rule.
Bacterial meningitis
Many bacteria can cause meningitis but geographical patterns
vary, as does age-related sensitivity (Box 25.63). In the ‘meningitis
belt’ of sub-Saharan Africa, drought and dust storms are often
associated with meningococcal outbreaks (Harmattan meningitis).
Bacterial meningitis is usually part of a bacteraemic illness,
although direct spread from an adjacent focus of infection in
the ear, skull fracture or sinus can be causative. Antibiotics have
rendered this less common but mortality and morbidity remain
Infections of the nervous system • 1119
25.63
Bacterial causes of meningitis
Age of onset
Common
Less common
Neonate
Gram-negative bacilli
(Escherichia coii, Proteus)
Group B streptococci
Listeria monocytogenes
Pre-school
child
Haemophilus influenzae
Neisseria meningitidis
(subtypes B, C, Y, W)
Streptococcus
pneumoniae
Mycobacterium
tuberculosis
Older child
and adult
N. meningitidis (subtypes
B, C, Y, W)
Strep, pneumoniae
L. monocytogenes
M. tuberculosis
Staphylococcus aureus
(skull fracture)
H. influenzae
significant. An important factor in determining prognosis is early
diagnosis and the prompt initiation of appropriate therapy. The
meningococcus and other common causes of meningitis are
normal commensals of the upper respiratory tract. New and
potentially pathogenic strains are acquired by the air-borne route
but close contact is necessary. Epidemics of meningococcal
meningitis occur, particularly in cramped living conditions
or where the climate is hot and dry. The organism invades
through the nasopharynx, producing sepsis and leading to
meningitis.
Pathophysiology
The meningococcus (Neisseria meningitidis) is now the most
common cause of bacterial meningitis in Western Europe after
Streptococcus pneumoniae, while in the USA Haemophilus
influenzae remains common. In India, H. influenzae B and
Strep, pneumoniae are probably the most common causes of
bacterial meningitis, especially in children. Streptococcus suis
is a rare zoonotic cause of meningitis associated with porcine
contact. Infection stimulates an immune response, causing the
pia-arachnoid membrane to become congested and infiltrated
with inflammatory cells. Pus then forms in layers, which may
later organise to form adhesions. These may obstruct the free
flow of CSF, leading to hydrocephalus, or they may damage
the cranial nerves at the base of the brain. Hearing loss is a
frequent complication. The CSF pressure rises rapidly, the protein
content increases, and there is a cellular reaction that varies in
type and severity according to the nature of the inflammation
and the causative organism. An obliterative endarteritis of the
leptomeningeal arteries passing through the meningeal exudate
may produce secondary cerebral infarction. Pneumococcal
meningitis is often associated with a very purulent CSF and a
high mortality, especially in older adults.
Clinical features
Headache, drowsiness, fever and neck stiffness are the usual
presenting features. In severe bacterial meningitis the patient may
be comatose, later developing focal neurological signs. Ninety
per cent of patients with meningococcal meningitis will have
two of the following: fever, neck stiffness, altered consciousness
and rash. When accompanied by sepsis, presenting signs may
evolve rapidly, with abrupt onset of obtundation due to cerebral
oedema. Complications of meningococcal sepsis are listed in
Box 25.64. Chronic meningococcaemia is a rare condition in
which the patient can be unwell for weeks or even months
i
25.64 Complications of meningococcal sepsis
• Meningitis
• Renal failure
• Rash (morbilliform, petechial
• Peripheral gangrene
or purpuric)
• Arthritis (septic or reactive)
• Shock
• Pericarditis (septic or reactive)
• Intravascular coagulation
Resuscitate and stabilise patient
Initial tests
(blood culture and polymerase
chain reaction, throat swab)
Empirical antibiotics (Box 25.65)
Transfer to critical care facility
Drowsy, focal signs?
(possible mass lesion, hydrocephalus
or cerebral oedema)
N0
Yes
No other
Computed
contraindication
tomography
to lumbar puncture
brain
No mass lesion,
hydrocephalus
or other
contraindication
to lumbar
puncture seen
Lumbar
puncture
Fig. 25.34 The investigation of meningitis.
with recurrent fever, sweating, joint pains and transient rash.
It usually occurs in the middle-aged and elderly, and in those
who have previously had a splenectomy. In pneumococcal
and Haemophilus infections there may be an accompanying
otitis media. Pneumococcal meningitis may be associated with
pneumonia and occurs especially in older patients and alcoholics,
as well as those with hyposplenism. Listeria monocytogenes
is an increasing cause of meningitis and rhombencephalitis
(brainstem encephalitis) in the immunosuppressed, people with
diabetes, alcoholics and pregnant women (p. 259). It can also
cause meningitis in neonates.
Investigations
Lumbar puncture is mandatory unless there are contraindications
(p. 1077). If the patient is drowsy and has focal neurological
signs or seizures, is immunosuppressed, has undergone recent
neurosurgery or has suffered a head injury, it is wise to obtain a
CT to exclude a mass lesion (such as a cerebral abscess) before
lumbar puncture because of the risk of coning. This should not,
however, delay treatment of presumed meningitis. If lumbar
puncture is deferred or omitted, it is essential to take blood
cultures and to start empirical treatment (Fig. 25.34). Lumbar
1120 • NEUROLOGY
puncture will help differentiate the causative organism: in bacterial
meningitis the CSF is cloudy (turbid) due to the presence of
many neutrophils (often >1 000 xIO6 cells/L), the protein content
is significantly elevated and the glucose reduced. Gram film and
culture may allow identification of the organism. Blood cultures
may be positive. PCR techniques can be used on both blood
and CSF to identify bacterial DNA. These methods are useful in
detecting meningococcal infection and in typing the organism.
Management
There is an untreated mortality rate of around 80%, so action
must be swift. In suspected bacterial meningitis the patient should
be given parenteral benzylpenicillin immediately (intravenous is
preferable) and prompt hospital admission should be arranged.
25.65 Treatment of pyogenic meningitis
of unknown cause
1. Adults aged 18-50 years with or without a typical
meningococcal rash
• Cefotaxime 2 g IV 4 times daily or
• Ceftriaxone 2 g IV twice daily
2. Patients in whom penicillin-resistant pneumococcal infection
is suspected, or in areas with a significant incidence of penicillin
resistance in the community
As for (1) but add:
• Vancomycin 1 g IV twice daily or
• Rifampicin 600 mg IV twice daily
3. Adults aged >50 years and those in whom Listeria
monocytogenes infection is suspected (brainstem signs,
immunosuppression, diabetic, alcoholic)
As for (1) but add:
• Ampicillin 2 g IV 6 times daily or
• Co-trimoxazole 5 mg/kg IV daily in two divided doses
4. Patients with a clear history of anaphylaxis to (3-lactams
• Chloramphenicol 25 mg/kg IV 4 times daily plus
• Vancomycin 1 g IV twice daily
5. Adjunctive treatment (see text)
• Dexamethasone 0.15 mg/kg 4 times daily for 2-4 days
The only contraindication is a history of penicillin anaphylaxis.
Recommended empirical therapies are outlined in Box 25.65, and
the preferred antibiotic when the organism is known after CSF
examination is stipulated in Box 25.66. Adjunctive glucocorticoid
therapy is useful in reducing hearing loss and neurological
sequelae in both children and adults in developed countries
where the incidence of penicillin resistance is low, but its role
where there are high rates of resistance or in countries where
there are high rates of untreated HIV is unclear.
In meningococcal disease, mortality is doubled if the patient
presents with features of sepsis rather than meningitis. Individuals
likely to require intensive care facilities and expertise include
those with cardiac, respiratory or renal involvement, and those
with CNS depression prejudicing the airway. Early endotracheal
intubation and mechanical ventilation protect the airway and
may prevent the development of the acute respiratory distress
syndrome (ARDS, p. 198). Adverse prognostic features include
hypotensive shock, a rapidly developing rash, a haemorrhagic
diathesis, multisystem failure and age over 60 years.
Prevention of meningococcal infection
Close contacts of patients with meningococcal infection (Box
25.67) should be given 2 days of oral rifampicin. In adults, a
single dose of ciprofloxacin is an alternative. If not treated with
ceftriaxone, the index case should be given similar treatment to
clear infection from the nasopharynx before hospital discharge.
Vaccines are available for most meningococcal subgroups but
not group B, which is one of the most common serogroups
isolated in many countries.
| Tuberculous meningitis
Tuberculous meningitis is now uncommon in developed countries
except in immunocompromised individuals, although it is still seen
in those born in endemic areas and in developing countries. It is
seen more frequently as a secondary infection in patients with
the acquired immunodeficiency syndrome (AIDS).
Pathophysiology
Tuberculous meningitis most commonly occurs shortly after a
primary infection in childhood or as part of miliary tuberculosis
(p. 588). The usual local source of infection is a caseous focus in
25.66 Chemotherapy of bacterial meningitis when the cause is known
Pathogen Regimen of choice Alternative agents
Neisseria meningitidis
Benzylpenicillin 2.4 g IV 6 times daily for
5-7 days
Cefuroxime, ampicillin
Chloramphenicol*
Streptococcus pneumoniae (sensitive to
(3-lactams, MIC <1 mg/L)
Cefotaxime 2 g IV 4 times daily or
Ceftriaxone 2 g IV twice daily for 10-14 days
Chloramphenicol*
Strep, pneumoniae (resistant to (3-lactams)
As for sensitive strains but add:
Vancomycin 1 g IV twice daily or
Rifampicin 600 mg IV twice daily
Vancomycin plus rifampicin*
Moxifloxacin
Gatifloxacin
Haemophilus influenzae
Cefotaxime 2 g IV 4 times daily or
Ceftriaxone 2 g IV twice daily for 10-14 days
Chloramphenicol*
Listeria monocytogenes
Ampicillin 2 g IV 6 times daily plus
Gentamicin 5 mg/kg IV daily
Ampicillin 2 g IV 4-hourly plus
Co-trimoxazole 50 mg/kg daily in two divided doses
Streptococcus suis
Cefotaxime 2 g IV 4 times daily or
Ceftriaxone 2 g IV twice daily for 10-14 days
Chloramphenicol*
*For patients with a history of anaphylaxis to (3-lactam antibiotics.
(MIC = minimum inhibitory concentration)
Infections of the nervous system • 1121
25.67 Chemoprophylaxis following
meningococcal exposure
the meninges or brain substance adjacent to the CSF pathway.
The brain is covered by a greenish, gelatinous exudate, especially
around the base, and numerous scattered tubercles are found
on the meninges.
Clinical features
The clinical features and staging criteria are listed in Box 25.68.
Onset is much slower than in other bacterial meningitis - over
2-8 weeks. If untreated, tuberculous meningitis is fatal in a few
weeks but complete recovery is usual if treatment is started
at stage I (Box 25.68). When treatment is initiated later, the
rate of death or serious neurological deficit may be as high
as 30%.
Investigations
Lumbar puncture should be performed if the diagnosis is
suspected. The CSF is under increased pressure. It is usually
clear but, when allowed to stand, a fine clot (‘spider web’) may
form. The fluid contains up to 500x1 06 cells/L, predominantly
lymphocytes, but can contain neutrophils. There is a rise in
protein and a marked fall in glucose. The tubercle bacillus may
be detected in a smear of the centrifuged deposit from the
CSF but a negative result does not exclude the diagnosis. The
CSF should be cultured but, as this result will not be known
for up to 6 weeks, treatment must be started without waiting
for confirmation. Brain imaging may show hydrocephalus, brisk
meningeal enhancement on enhanced CT or MRI, and/or an
intracranial tuberculoma.
Management
As soon as the diagnosis is made or strongly suspected,
chemotherapy should be started using one of the regimens
that include pyrazinamide, described on page 592. The use of
glucocorticoids in addition to antituberculous therapy has been
controversial. Recent evidence suggests that it improves mortality,
especially if given early, but not focal neurological damage.
Surgical ventricular drainage may be needed if obstructive
hydrocephalus develops. Skilled nursing is essential during the
acute phase of the illness, and adequate hydration and nutrition
must be maintained.
Other forms of meningitis
Fungal meningitis (especially cryptococcosis; p. 302) usually
occurs in patients who are immunosuppressed and is a recognised
complication of HIV infection (p. 321). The CSF findings are similar
to those of tuberculous meningitis, but the diagnosis can be
confirmed by microscopy or specific serological tests.
In some areas, meningitis may be caused by spirochaetes
(leptospirosis, Lyme disease and syphilis; pp. 257, 255 and 337),
rickettsiae (typhus fever; p. 270) or protozoa (amoebiasis; p. 286).
Meningitis can also be due to non-infective pathologies. This is
seen in recurrent aseptic meningitis resulting from systemic lupus
erythematosus (SLE), Behget’s disease or sarcoidosis, as well
as a condition of previously unknown origin known as Mollaret’s
syndrome, in which the recurrent meningitis is associated with
epithelioid cells in the spinal fluid (‘Mollaret’ cells). Recent evidence
suggests that this condition may be due to herpes simplex virus
type 2 and is therefore infective after all. Meningitis can also be
caused by direct invasion of the meninges by neoplastic cells
(‘malignant meningitis’; see Box 25.62).
Parenchymal viral infections
Infection of the substance of the nervous system will produce
symptoms of focal dysfunction (deficits and/or seizures) with
general signs of infection, depending on the acuteness of the
infection and the type of organism.
Viral encephalitis
A range of viruses can cause encephalitis but only a minority
of patients report recent systemic viral infection. In Europe,
the most serious cause of viral encephalitis is herpes simplex
(p. 247), which probably reaches the brain via the olfactory nerves.
Varicella zoster is also an important cause. The development of
effective therapy for some forms of encephalitis has increased
the importance of clinical diagnosis and virological examination
of the CSF. In some parts of the world, viruses transmitted by
mosquitoes and ticks (arboviruses) are an important cause of
encephalitis. The epidemiology of some of these infections is
changing. Japanese encephalitis (p. 249) has spread relentlessly
across Asia to Australia, and there have been outbreaks of West
Nile encephalitis in Romania, Israel and New York. Zika virus has
Close contacts warranting chemoprophylaxis
• Household contacts (including persons who ate or slept in the same
dwelling as the patient during the 7 days prior to disease onset)
• Child-care and nursery-school contacts
• Persons having contact with patient’s oral secretions during the
7 days prior to disease onset:
Kissing
Sharing of toothbrushes
Sharing of eating utensils
Mouth-to-mouth resuscitation
Unprotected contact during endotracheal intubation
• Aircraft contacts for persons seated next to the patient for >8 hrs
Persons at low risk in whom chemoprophylaxis is
not recommended
• Casual contact (e.g. at school or work) without direct exposure to
patient’s oral secretions
• Indirect contact only (contact with a high-risk contact and not a
case)
• Health-care worker without direct exposure to patient’s oral
secretions
25.68 Clinical features and staging of
tuberculous meningitis
Symptoms
• Headache
• Vomiting
• Low-grade fever
• Lassitude
Signs
• Meningism (may be absent) • Depression of conscious level
• Oculomotor palsies • Focal hemisphere signs
• Papilloedema
Staging of severity
• Stage I (early): non-specific symptoms and signs without alteration
of consciousness
• Stage II (intermediate): altered consciousness without coma or
delirium plus minor focal neurological signs
• Stage III (advanced): stupor or coma, severe neurological deficits,
seizures or abnormal movements
• Depression
• Delirium
• Behaviour changes
1122 • NEUROLOGY
mutated in the last decades and become a more significant global
health problem. HIV may cause encephalitis with a subacute or
chronic presentation but occasionally has an acute presentation
with seroconversion.
Pathophysiology
The infection provokes an inflammatory response that involves
the cortex, white matter, basal ganglia and brainstem. The
distribution of lesions varies with the type of virus. For example,
in herpes simplex encephalitis, the temporal lobes are usually
primarily affected, whereas cytomegalovirus can involve the
areas adjacent to the ventricles (ventriculitis). Inclusion bodies
may be present in the neurons and glial cells, and there is an
infiltration of polymorphonuclear cells in the perivascular space.
There is neuronal degeneration and diffuse glial proliferation,
often associated with cerebral oedema.
Clinical features
Viral encephalitis presents with acute onset of headache, fever,
focal neurological signs (aphasia and/or hemiplegia, visual field
defects) and seizures. Disturbance of consciousness ranging from
drowsiness to deep coma supervenes early and may advance
dramatically. Meningism occurs in many patients. Rabies presents
a distinct clinical picture and is described below.
Investigations
Imaging by CT scan may show low-density lesions in the temporal
lobes but MRI is more sensitive in detecting early abnormalities.
Lumbar puncture should be performed once imaging has excluded
a mass lesion. The CSF usually contains excess lymphocytes but
polymorphonuclear cells may predominate in the early stages.
The CSF may be normal in up to 10% of cases. Some viruses,
including the West Nile virus, may cause a sustained neutrophilic
CSF. The protein content may be elevated but the glucose is
normal. The EEG is usually abnormal in the early stages, especially
in herpes simplex encephalitis, with characteristic periodic slow-
wave activity in the temporal lobes. Virological investigations of
the CSF, including PCR, may reveal the causative organism but
treatment initiation should not await this.
Management
Optimum treatment for herpes simplex encephalitis (aciclovir
10 mg/kg IV 3 times daily for 2-3 weeks) has reduced mortality
from 70% to around 10%. This should be given early to all
patients suspected of having viral encephalitis.
Some survivors will have residual epilepsy or cognitive
impairment. For details of post-infectious encephalomyelitis,
see page 1110. Antiepileptic treatment may be required
(p. 1101) and raised intracranial pressure may indicate the need
for dexamethasone.
Brainstem encephalitis
This presents with ataxia, dysarthria, diplopia or other cranial
nerve palsies. The CSF is lymphocytic, with a normal glucose.
The causative agent is presumed to be viral. However, Listeria
monocytogenes may cause a similar syndrome with meningitis (and
often a polymorphonuclear CSF pleocytosis) and requires specific
treatment with ampicillin (500 mg 4 times daily; see Box 25.66).
Rabies
Rabies is caused by a rhabdovirus that infects the central nervous
tissue and salivary glands of a wide range of mammals. It is
usually conveyed by saliva through bites or licks on abrasions
or on intact mucous membranes. Humans are most frequently
infected from dogs and bats. In Europe, the maintenance host is
the fox. The incubation period varies in humans from a minimum
of 9 days to many months but is usually between 4 and 8 weeks.
Severe bites, especially if on the head or neck, are associated
with shorter incubation periods. Human rabies is a rare disease,
even in endemic areas. However, because it is usually fatal,
major efforts are directed at limiting its spread and preventing
its importation into uninfected countries, such as the UK.
Clinical features
At the onset there may be fever, and paraesthesia at the site
of the bite. A prodromal period of 1-10 days, during which the
patient becomes increasingly anxious, leads to the characteristic
‘hydrophobia’. Although the patient is thirsty, attempts at drinking
provoke violent contractions of the diaphragm and other inspiratory
muscles. Delusions and hallucinations may develop, accompanied
by spitting, biting and mania, with lucid intervals in which the
patient is markedly anxious. Cranial nerve lesions develop and
terminal hyperpyrexia is common. Death ensues, usually within
a week of the onset of symptoms.
Investigations
During life, the diagnosis is usually made on clinical grounds
but rapid immunofluorescent techniques can detect antigen in
corneal impression smears or skin biopsies.
Management
Established disease
Only a few patients with established rabies have survived. All
received some post-exposure prophylaxis (see below) and
needed intensive care facilities to control cardiac and respiratory
failure. Otherwise, only palliative treatment is possible once
symptoms have appeared. The patient should be heavily sedated
with diazepam, supplemented by chlorpromazine if needed.
Nutrition and fluids should be given intravenously or through
a gastrostomy.
Pre-exposure prophylaxis
Pre-exposure prophylaxis is required by those who handle
potentially infected animals professionally, work with rabies virus
in laboratories or live at special risk in rabies-endemic areas.
Protection is afforded by intradermal injections of human diploid
cell strain vaccine, or two intramuscular injections given 4 weeks
apart, followed by yearly boosters.
Post-exposure prophylaxis
The wounds should be thoroughly cleaned, preferably with a
quaternary ammonium detergent or soap; damaged tissues
should be excised and the wound left unsutured. Rabies can
usually be prevented if treatment is started within a day or two
of biting. Delayed treatment may still be of value. For maximum
protection, hyperimmune serum and vaccine are required.
The safest antirabies antiserum is human rabies immunoglobulin.
The dose is 20 lU/kg body weight; half is infiltrated around the
bite and half is given intramuscularly at a different site from
the vaccine. Hyperimmune animal serum may be used but
hypersensitivity reactions, including anaphylaxis, are common.
The safest vaccine, free of complications, is human diploid
cell strain vaccine; 1 .0 mL is given intramuscularly on days 0, 3,
7, 14, 30 and 90. In developing countries, where human rabies
globulin may not be obtainable, 0.1 mL of vaccine may be given
Infections of the nervous system • 1123
intradermally into eight sites on day 1 , with single boosters on
days 7 and 28. Where human products are not available and
when risk of rabies is slight (licks on the skin, or minor bites
of covered arms or legs), it may be justifiable to delay starting
treatment while observing the biting animal or awaiting examination
of its brain, rather than use the older vaccine.
Poliomyelitis
Pathophysiology
Disease is caused by one of three polioviruses, which constitute
a subgroup of the enteroviruses. Poliomyelitis has become much
less common in developed countries following the widespread
use of oral vaccines but is still a problem in the developing
world, especially parts of Africa. Infection usually occurs through
the nasopharynx.
The virus causes a lymphocytic meningitis and infects the
grey matter of the spinal cord, brainstem and cortex. There is
a particular propensity to damage anterior horn cells, especially
in the lumbar segments.
Clinical features
The incubation period is 7-14 days. Figure 25.35 illustrates the
various features of the infection. Many patients recover fully after
the initial phase of a few days of mild fever and headache. In
other individuals, after a week of well-being, there is a recurrence
of pyrexia, headache and meningism. Weakness may start later
in one muscle group and can progress to widespread paresis.
Respiratory failure may supervene if intercostal muscles are
paralysed or the medullary motor nuclei are involved. Epidemics
vary widely in terms of the incidence of non-paralytic cases
and in mortality rate. Death occurs from respiratory paralysis.
Muscle weakness is maximal at the end of the first week and
gradual recovery may then take place over several months.
Muscles showing no signs of recovery after a month will probably
Fig. 25.35 Poliomyelitis. Possible consequences of infection.
not regain useful function. Second attacks are very rare but
occasionally patients show late deterioration in muscle bulk and
power many years after the initial infection (this is termed the
‘post-polio syndrome’).
Investigations
The CSF shows a lymphocytic pleocytosis, a rise in protein and
a normal sugar content. Poliomyelitis virus may be cultured from
CSF and stool.
Management
Established disease
In the early stages, bed rest is imperative because exercise
appears to worsen the paralysis or precipitate it. At the onset of
respiratory difficulties, a tracheostomy and ventilation are required.
Subsequent treatment is by physiotherapy and orthopaedic
measures.
Prophylaxis
Prevention of poliomyelitis is by immunisation with live (Sabin)
vaccine. In developed countries where polio is now very rare, the
live vaccine has been replaced by the killed vaccine in childhood
immunisation schedules.
Herpes zoster (shingles)
Herpes zoster is the result of reactivation of the varicella zoster
virus that has lain dormant in a nerve root ganglion following
chickenpox earlier in life. Reactivation may be spontaneous
(as usually occurs in the middle-aged or elderly) or due to
immunosuppression (as in patients with diabetes, malignant
disease or AIDS). Full details are given on page 239.
Subacute sclerosing panencephalitis
This is a rare, chronic, progressive and eventually fatal
complication of measles, presumably a result of an inability of
the nervous system to eradicate the virus. It occurs in children
and adolescents, usually many years after the primary virus
infection. There is generalised neurological deterioration and
onset is insidious, with intellectual deterioration, apathy and
clumsiness, followed by myoclonic jerks, rigidity and dementia.
The CSF may show a mild lymphocytic pleocytosis and the
EEG demonstrates characteristic periodic bursts of triphasic
waves. Although there is persistent measles-specific IgG in
serum and CSF, antiviral therapy is ineffective and death ensues
within a few years.
Progressive multifocal leucoencephalopathy
This was originally described as a rare complication of lymphoma,
leukaemia or carcinomatosis but has become more frequent as
a feature of AIDS (p. 31 9) or secondary to immunosuppression,
e.g. following organ transplantation or use of disease-modifying
drugs for MS. It is an infection of oligodendrocytes by human
polyomavirus JC, causing widespread demyelination of the
white matter of the cerebral hemispheres. Clinical signs include
dementia, hemiparesis and aphasia, which progress rapidly,
usually leading to death within weeks or months. Areas of
low density in the white matter are seen on CT but MRI is
more sensitive, showing diffuse high signal in the cerebral white
matter on T2-weighted images. The only treatment available is
restoration of the immune response (by treating AIDS or reversing
immunosuppression).
1124 • NEUROLOGY
Parenchymal bacterial infections
| Cerebral abscess
Bacteria may enter the cerebral substance through penetrating
injury, by direct spread from paranasal sinuses or the middle ear,
or secondary to sepsis. Untreated congenital heart disease is a
recognised risk factor. The site of abscess formation and the likely
causative organism are both related to the source of infection
(Box 25.69). Initial infection leads to local suppuration followed
by loculation of pus within a surrounding wall of gliosis, which in
a chronic abscess may form a tough capsule. Haematogenous
spread may lead to multiple abscesses.
Clinical features
A cerebral abscess may present acutely with fever, headache,
meningism and drowsiness, but more commonly presents over
days or weeks as a cerebral mass lesion with little or no evidence
of infection. Seizures, raised intracranial pressure and focal
hemisphere signs occur alone or in combination. Distinction
from a cerebral tumour may be impossible on clinical grounds.
Investigations
Lumbar puncture is potentially hazardous in the presence of
raised intracranial pressure and CT should always precede it.
CT reveals single or multiple low-density areas, which show ring
enhancement with contrast and surrounding cerebral oedema
(Fig. 25.36). There may be an elevated white blood cell count
and ESR in patients with active local infection. The possibility
of cerebral toxoplasmosis or tuberculous disease secondary to
HIV infection (p. 320) should always be considered.
Management and prognosis
Antimicrobial therapy is indicated once the diagnosis is made. The
likely source of infection should guide the choice of antibiotic (see
Box 25.69). In neurosurgical patients, the addition of vancomycin
should be considered. Surgical drainage by burr-hole aspiration
or excision may be necessary, especially where the presence of
a capsule may lead to a persistent focus of infection. Epilepsy
frequently develops and is often resistant to treatment.
Despite advances in therapy, mortality remains 10-20% and
may partly relate to delay in diagnosis and treatment.
Fig. 25.36 Right temporal cerebral abscess (arrows),
with surrounding oedema and midline shift to the left.
[A~| Unenhanced computed tomography (CT) image. [§] Contrast-
enhanced CT image.
25.69 Aetiology and treatment of bacterial cerebral abscess
Site of abscess
Source of infection
Likely organisms
Recommended treatment
Frontal lobe
Paranasal sinuses
Teeth
Streptococci
Anaerobes
Cefotaxime 2-3 g IV 4 times daily plus
Metronidazole 500 mg IV 3 times daily
Temporal lobe
Middle ear
Streptococci
Enterobacteriaceae
Ampicillin 2-3 g IV 3 times daily plus
Metronidazole 500 mg IV 3 times daily plus either
Cerebellum
Sphenoid sinus
Mastoid/middle ear
Pseudomonas spp.
Anaerobes
Ceftazidime 2 g IV 3 times daily or
Gentamicin* 5 mg/kg IV daily
Any site
Penetrating trauma
Staphylococci
Flucloxacillin 2-3 g IV 4 times daily or
Cefuroxime 1 .5 g IV 3 times daily
Multiple
Metastatic and
cryptogenic
Streptococci
Anaerobes
Benzylpenicillin 1.8-2. 4 g IV 4 times daily if endocarditis or cyanotic heart
disease
Otherwise cefotaxime 2-3 g IV 4 times daily plus
Metronidazole 500 mg IV 3 times daily
*Monitor gentamicin levels.
Infections of the nervous system • 1125
| Subdural empyema
This is a rare complication of frontal sinusitis, osteomyelitis of
the skull vault or middle ear disease. A collection of pus in the
subdural space spreads over the surface of the hemisphere,
causing underlying cortical oedema or thrombophlebitis. Patients
present with severe pain in the face or head and pyrexia, often
with a history of preceding paranasal sinus or ear infection. The
patient then becomes drowsy, with seizures and focal signs
such as a progressive hemiparesis.
The diagnosis rests on a strong clinical suspicion in patients
with a local focus of infection. Careful assessment with contrast-
enhanced CT or MRI may show a subdural collection with
underlying cerebral oedema. Management requires aspiration of
pus via a burr hole and appropriate parenteral antibiotics. Any
local source of infection must be treated to prevent re-infection.
Spinal epidural abscess
The characteristic clinical features are pain in a root distribution
and progressive transverse spinal cord syndrome with paraparesis,
sensory impairment and sphincter dysfunction. Features of the
primary focus of infection may be less obvious and thus can be
overlooked. The resurgence of resistant staphylococcal infection
and intravenous drug misuse has contributed to a recent marked
rise in incidence.
X-ray changes occur late, if present, so MRI or myelography
should precede urgent neurosurgical intervention. Decompressive
laminectomy with abscess drainage relieves the pressure on the
dura. Organisms may be grown from the pus or blood. Surgery,
together with appropriate antibiotics, may prevent complete and
irreversible paraplegia.
|J.yme disease
Infection with Borrelia burgdorferi can cause numerous neurological
problems, including polyradiculopathy, meningitis, encephalitis
and mononeuritis multiplex (p. 255).
Neurosyphilis
Neurosyphilis may present as an acute or chronic process and
may involve the meninges, blood vessels and/or parenchyma of
the brain and spinal cord. The decade to 2008 saw a 10-fold
increase in the incidence of syphilis, mostly as a result of
misguided relaxation of safe sex measures with the advent
of effective antiretroviral treatments for AIDS. Paralleled future
increases in neurosyphilis are inevitable. The clinical manifestations
are diverse and early diagnosis and treatment are essential.
Clinical features
The clinical and pathological features of the three most common
presentations are summarised in Box 25.70. Neurological
examination reveals signs indicative of the anatomical localisation
of lesions. Delusions of grandeur suggest general paresis of
the insane, but more commonly there is simply progressive
dementia. Small and irregular pupils that react to convergence
but not light, as described by Argyll Robertson (see Box 25.22,
p. 1092), may accompany any neurosyphilitic syndrome but
most commonly tabes dorsalis.
Investigations
Routine screening for syphilis is warranted in many neurological
patients. Treponemal antibodies (p. 338) are positive in the serum
in most patients, but CSF examination is essential if neurological
25.70 Clinical and pathological features of
neurosyphilis
Type and interval
from primary
infection
Pathology
Clinical features
Meningovascular
(5 years)*
Endarteritis
obliterans
Meningeal exudate
Granuloma (gumma)
Stroke
Cranial nerve palsies
Seizures/mass lesion
General paralysis
of the insane
(5-1 5 years)*
Degeneration in
cerebral cortex/
cerebral atrophy
Thickened meninges
Dementia
Tremor
Bilateral upper motor
signs
Tabes dorsalis
(5-20 years)*
Degeneration of
sensory neurons
Wasting of dorsal
columns
Optic atrophy
Lightning pains
Sensory ataxia
Visual failure
Abdominal crises
Incontinence
Trophic changes
Any of the above
Argyll Robertson
pupils (p. 1092)
involvement is suspected. Active disease is suggested by an
elevated cell count, usually lymphocytic, and the protein content
may be elevated to 0.5-1 .0 g/L with an increased gamma
globulin fraction. Serological tests in CSF are usually positive
but progressive disease can occur with negative CSF serology.
Management
The injection of procaine benzylpenicillin (procaine penicillin)
and probenecid for 1 7 days is essential in the treatment of
neurosyphilis of all types (p. 338). Further courses of penicillin
must be given if symptoms are not relieved, if the condition
continues to advance or if the CSF continues to show signs of
active disease. The cell count returns to normal within 3 months
of completion of treatment, but the elevated protein takes longer
to subside and some serological tests may never revert to normal.
Evidence of clinical progression at any time is an indication for
renewed treatment.
Diseases caused by bacterial toxins
|Jetanus
This disease results from infection with Clostridium tetani, a
commensal in the gut of humans and domestic animals that is
found in soil. Infection enters the body through wounds, which may
be trivial. It is rare in the UK, occurring mostly in gardeners and
farmers, but a recent increase has been seen in intravenous drug
misusers. By contrast, the disease is common in many developing
countries, where dust contains spores derived from animal and
human excreta. Unhygienic practices soon after birth may lead
to infection of the umbilical stump or site of circumcision, causing
tetanus neonatorum. Tetanus is still one of the major killers of adults,
children and neonates in developing countries, where the mortality
rate can be nearly 1 00% in the newborn and around 40% in others.
In circumstances unfavourable to growth of the organism,
spores are formed and these may remain dormant for years in the
soil. Spores germinate and bacilli multiply only in the anaerobic
conditions that occur in areas of tissue necrosis or if the oxygen
tension is lowered by the presence of other organisms, particularly
if aerobic. The bacilli remain localised but produce an exotoxin
with an affinity for motor nerve endings and motor nerve cells.
1126 • NEUROLOGY
The anterior horn cells are affected after the exotoxin has
passed into the blood stream and their involvement results in
rigidity and convulsions. Symptoms first appear from 2 days to
several weeks after injury: the shorter the incubation period, the
more severe the attack and the worse the prognosis.
Clinical features
By far the most important early symptom is trismus - spasm of
the masseter muscles, which causes difficulty in opening the
mouth and in masticating; hence the name ‘lockjaw’. Lockjaw
in tetanus is painless, unlike the spasm of the masseters due to
dental abscess, septic throat or other causes. Conditions that can
mimic tetanus include hysteria and phenothiazine overdosage,
or overdose in intravenous drug misusers.
In tetanus, the tonic rigidity spreads to involve the muscles
of the face, neck and trunk. Contraction of the frontalis and
the muscles at the angles of the mouth leads to the so-called
‘risus sardonicus’. There is rigidity of the muscles at the neck
and trunk of varying degree. The back is usually slightly arched
(‘opisthotonus’) and there is a board-like abdominal wall.
In the more severe cases, violent spasms lasting for a few
seconds to 3-4 minutes occur spontaneously, or may be induced
by stimuli such as movement or noise. These episodes are painful
and exhausting, and suggest a grave outlook, especially if they
appear soon after the onset of symptoms. They gradually increase
in frequency and severity for about 1 week and the patient may
die from exhaustion, asphyxia or aspiration pneumonia. In less
severe illness, periods of spasm may not commence until a week
or so after the first sign of rigidity, and in very mild infections
they may never appear. Autonomic involvement may cause
cardiovascular complications, such as hypertension. Rarely, the
only manifestation of the disease may be ‘local tetanus’ - stiffness
or spasm of the muscles near the infected wound - and the
prognosis is good if treatment is commenced at this stage.
Investigations
The diagnosis is made on clinical grounds. It is rarely possible
to isolate the infecting organism from the original locus of entry.
Management
Established disease
Management of established disease should begin as soon as
possible, as shown in Box 25.71.
25.71 Treatment of tetanus
Neutralise absorbed toxin
• Give IV injection of 3000 IU of human tetanus antitoxin
Prevent further toxin production
• Debride wound
• Give benzylpenicillin 600 mg IV 4 times daily (metronidazole if
patient is allergic to penicillin)
Control spasms
• Nurse in a quiet room
• Avoid unnecessary stimuli
• Give IV diazepam
• If spasms continue, paralyse patient and ventilate
General measures
• Maintain hydration and nutrition
• Treat secondary infections
Prevention
Tetanus can be prevented by immunisation and prompt treatment
of contaminated wounds by debridement and antibiotics. In
patients with a contaminated wound, the immediate danger of
tetanus can be greatly reduced by the injection of 1 200 mg of
penicillin followed by a 7-day course of oral penicillin. For those
allergic to penicillin, erythromycin should be used. When the risk
of tetanus is judged to be present, an intramuscular injection of
250 IU of human tetanus antitoxin should be given, along with
toxoid, which should be repeated 1 month and 6 months later.
For those already immunised, only a booster dose of toxoid is
required.
Botulism
Botulism is caused by the neurotoxins of Clostridium botulinum,
which are extremely potent and cause disease after ingestion
of even picogram amounts. Its classical form is an acute onset
of bilateral cranial neuropathies associated with symmetric
descending weakness.
Anaerobic conditions are necessary for the organism’s growth.
It may contaminate and thrive in many foodstuffs, where sealing
and preserving provide the requisite conditions. Contaminated
honey has been implicated in infant botulism, in which the
organism colonises the gastrointestinal tract. Wound botulism
is a growing problem in injection drug-users.
The toxin causes predominantly bulbar and ocular palsies
(difficulty in swallowing, blurred or double vision, ptosis),
progressing to limb weakness and respiratory paralysis. Criteria
for the clinical diagnosis are shown in Box 25.72.
25.72 US Centers for Disease Control (CDC) definition
of botulism
Three main syndromes
• Infantile
• Food-borne
• Wound infection
Clinical features
• Absence of fever
• Symmetrical neurological deficits
• Patient remains responsive
• Normal or slow heart rate and normal blood pressure
• No sensory deficits with the exception of blurred vision
Management includes assisted ventilation and general
supportive measures until the toxin eventually dissociates from
nerve endings 6-8 weeks following ingestion. A polyvalent
antitoxin is available for post-exposure prophylaxis and for the
treatment of suspected botulism. It specifically neutralises toxin
types A, B and E and is not effective against infantile botulism
(in which active growth of the organism allows continued toxin
production).
Prion diseases
Prions are unique amongst infectious agents in that they are
devoid of any nucleic acid. They appear to be transmitted by
acquisition of a normal mammalian protein (prion protein, PrPc)
that is in an abnormal conformation (PrPsc, containing an excess
of beta-sheet protein); the abnormal protein inhibits the 26S
Intracranial mass lesions and raised intracranial pressure • 1127
25.73 Prion diseases affecting humans
Disease
Mechanism
Creutzfeldt-Jakob disease
Sporadic
Familial
Variant
Unknown: spontaneous PrPc to PrPsc
conversion or somatic mutation
Genetic: mutations in the PrP gene
Dietary ingestion: infection from
bovine spongiform encephalopathy
Gerstmann-Straussler-
Scheinker disease
Genetic: mutations in the PrP gene
Fatal familial insomnia
Genetic: mutations in the PrP gene
Sporadic fatal insomnia
Genetic: spontaneous PrPc to PrPsc
conversion or somatic mutation
Kuru
Dietary: ingestion of affected human
brain
proteasome, which can degrade misfolded proteins, leading
to accumulation of the abnormally configured PrPsc protein
instead of normal PrPc. The result is accumulation of protein that
forms amyloid in the CNS, causing a transmissible spongiform
encephalopathy (TSE) across several species.
Human prion diseases (Box 25.73) are characterised by the
histopathological triad of cortical spongiform change, neuronal cell
loss and gliosis. Associated with these changes there is deposition
of amyloid, made up of an altered form of a normally occurring
protein, the prion protein. Prion proteins are not inactivated by
cooking or conventional sterilisation, and transmission is thought
to occur by consumption of infected CNS tissue or by inoculation
(e.g. via depth EEG electrodes, corneal grafts, cadaveric dura
mater grafts and pooled cadaveric growth hormone preparations).
The same diseases can occur in an inherited form, due to
mutations in the PrP gene.
The apparent transmission of bovine spongiform encephalopathy
(BSE) to humans was thought to be responsible for the emergence
of a new variant of CJD (vCJD) in the UK (see below). This
outbreak led to nationwide precautionary measures, such as
leucodepletion of all blood used for transfusion, and the mandatory
use of disposable surgical instruments wherever possible for
tonsillectomy, append icectomy and ophthalmological procedures.
Creutzfeldt-Jakob disease
Creutzfeldt-Jakob disease (CJD) is the best-characterised human
TSE. Some 10% of cases arise from a mutation in the gene
coding for the prion protein. The sporadic form is the most
common, occurring in middle-aged to elderly patients. Clinical
features usually involve a rapidly progressive dementia, with
myoclonus and a characteristic EEG pattern (repetitive slow-wave
complexes), although a number of other features, such as visual
disturbance or ataxia, may also be seen. These are particularly
common in CJD transmitted by inoculation (e.g. by infected dura
mater grafts). Death occurs after a mean of 4-6 months. There
is no effective treatment.
|Variant Creutzfeldt-Jakob disease
This type of CJD (vCJD) emerged in the late 1990s, affecting a
small number of patients in the UK. The causative agent appears
to be identical to that causing BSE in cows, and the disease may
have been a result of the epidemic of BSE in the UK a decade
Fig. 25.37 Magnetic resonance imaging in variant Creutzfeldt-Jakob
disease. Arrows indicate bilateral pulvinar hyperintensity.
earlier. Patients affected by vCJD are typically younger than those
with sporadic CJD and present with neuropsychiatric changes and
sensory symptoms in the limbs, followed by ataxia, dementia and
death. Progression is slightly slower than in patients with sporadic
CJD (mean time to death is over a year). Characteristic EEG
changes are not present, but MRI brain scans show characteristic
high-signal changes in the pulvinar thalami in a high proportion
of cases (Fig. 25.37). Brain histology is distinct, with very florid
plaques containing the prion proteins. Abnormal prion protein
has been identified in tonsil specimens from patients with vCJD,
leading to the suggestion that the disease could be transmitted
by reticulo-endothelial tissue (like TSEs in animals but unlike
sporadic CJD in humans). It was the emergence of this form of
the disorder that led to the changes in public health and farming
policy in the UK; while the incidence of vCJD has declined
dramatically, surveillance and research continue.
Intracranial mass lesions and raised
intracranial pressure
Many different types of mass lesion may arise within the intracranial
cavity (Box 25.74). In developing countries tuberculoma and
other infections are frequent causes, but in the West intracranial
haemorrhage and brain tumours are more common. The clinical
features depend on the site of the mass, its nature and its rate of
expansion. Symptoms and signs (see Box 25.75) are produced
by a number of mechanisms.
Raised intracranial pressure
Raised intracranial pressure (RICP) may be caused by mass
lesions, cerebral oedema, obstruction to CSF circulation leading
1128 • NEUROLOGY
25.74 Common causes of raised intracranial pressure
Mass lesions
• Intracranial haemorrhage (traumatic or spontaneous):
Extradural haematoma
Subdural haematoma
Intracerebral haemorrhage
• Cerebral tumour (particularly posterior fossa lesions or high-grade
gliomas: see Box 25.76)
• Infective:
Cerebral abscess
Tuberculoma
Cysticercosis (p. 298)
Hydatid cyst (p. 299)
• Colloid cyst (in ventricles)
Disturbance of cerebrospinal fluid circulation
• Obstructive (non-communicating) hydrocephalus: obstruction within
ventricular system
• Communicating hydrocephalus: site of obstruction outside
ventricular system
Obstruction to venous sinuses
• Cerebral venous thrombosis
• Trauma (depressed fractures overlying sinuses)
Diffuse brain oedema or swelling
• Meningo-encephalitis
• Trauma (diffuse head injury, near-drowning)
• Subarachnoid haemorrhage
• Metabolic (e.g. water intoxication)
• Idiopathic intracranial hypertension
to hydrocephalus, impaired CSF absorption and cerebral venous
obstruction (see Box 25.74).
Clinical features
In adults, intracranial pressure is less than 10-15 mmHg.
The features of RICP are listed in Box 25.75. The speed of
pressure increase influences presentation. If slow, compensatory
mechanisms may occur, including alteration in the volume of
fluid in CSF spaces and venous sinuses, minimising symptoms.
Rapid pressure increase (as in aggressive tumours) does not
permit these compensatory mechanisms to take place, leading
to early symptoms, including sudden death. Papilloedema is
not always present, either because the pressure rise has been
too rapid or because of anatomical anomalies of the meningeal
sheath of the optic nerve.
A false localising sign is one in which the pathology is remote
from the site of the expected lesion; in RICP, the 6th cranial nerve
(unilateral or bilateral) is most commonly affected but the 3rd,
5th and 7th nerves may also be involved. Sixth nerve palsies are
thought to be due either to stretching of the long slender nerve
or to compression against the petrous temporal bone ridge.
Transtentorial herniation of the uncus may compress the ipsilateral
3rd nerve and usually involves the pupillary fibres first, causing a
dilated pupil; however, a false localising contralateral 3rd nerve
palsy may also occur, perhaps due to extrinsic compression by
the tentorial margin. Vomiting, coma, bradycardia and arterial
hypertension are later features of RICP.
The rise in intracranial pressure from a mass lesion may
cause displacement of the brain. Downward displacement of
the medial temporal lobe (uncus) through the tentorium due to
25.75 Clinical features of intracranial mass lesions
Presentation
Features
Seizures
Focal onset ± generalised spread
Focal symptoms
Progressive loss of function
Weakness
Numbness
Dysphasia
Cranial neuropathy
False localising signs
Unilateral/bilateral 6th nerve palsies
Contralateral 3rd nerve (usually
pupil first)
Raised intracranial pressure
(usually aggressive tumours
causing vasogenic oedema or
obstructive hydrocephalus)
Headache worse on lying/straining
Vomiting
Diplopia (6th nerve involvement)
Papilloedema
Bradycardia, raised blood pressure
Impaired conscious level
Stroke/TIA-like symptoms
Acute haemorrhage into tumour
Paroxysmal ‘tumour attacks’
Cognitive/behavioural change
Usually frontal mass lesions
Endocrine abnormalities
Pituitary tumours
Incidental finding
Asymptomatic but identified on
imaging (meningiomas commonly)
(TIA = transient ischaemic attack)
3rd nerve
deformed
Cerebral
tumour
Fig. 25.38 Cerebral tumour displacing medial temporal lobe and
causing pressure on the mid-brain and 3rd cranial nerve.
a large hemisphere mass may cause ‘temporal coning’ (Fig.
25.38). This may stretch the 3rd and/or 6th cranial nerves or
cause pressure on the contralateral cerebral peduncle (giving
rise to ipsilateral upper motor neuron signs), and is usually
accompanied by progressive coma. Downward movement of the
cerebellar tonsils through the foramen magnum may compress
the medulla - ‘tonsillar coning’ (Fig. 25.39). This may result in
brainstem haemorrhage and/or acute obstruction of the CSF
pathways. As coning progresses, coma and death occur unless
the condition is rapidly treated.
Management
Primary management of RICP should be targeted at relieving the
cause (e.g. surgical decompression of mass lesion, glucocorticoids
to reduce vasogenic oedema or shunt procedure to relieve
hydrocephalus). Supportive treatment includes maintenance of
Intracranial mass lesions and raised intracranial pressure • 1129
Fig. 25.39 Tonsillar cone. Downward displacement of the cerebellar
tonsils below the level of the foramen magnum.
fluid balance, blood pressure control, head elevation, and use
of diuretics such as mannitol. Intensive care support may be
needed (p. 208).
Brain tumours
Primary brain tumours are a heterogeneous collection of
neoplasms arising from the brain tissue or meninges, and vary
from benign to highly malignant. Primary malignant brain tumours
(Box 25.76) are rare, accounting for 1% of all adult tumours
but a higher proportion in children. The most common benign
brain tumour is a meningioma. Primary brain tumours do not
metastasise due to the absence of lymphatic drainage in the
brain. There are rare pathological subtypes, however, such as
medulloblastoma, which do have a propensity to metastasise;
the reasons for this are not clear. Most cerebral tumours are
sporadic but may be associated with genetic syndromes such
as neurofibromatosis or tuberous sclerosis. Brain tumours are
not classified by the usual TNM system but by the World Health
Organisation (WHO) grading I— IV; this is based on histology (e.g.
nuclear pleomorphism, presence of mitoses and presence of
necrosis), with grade I the most benign and grade IV the most
malignant. Gliomas account for 60% of brain tumours, with the
aggressive glioblastoma multiforme (WHO grade IV) the most
common glioma, followed by meningiomas (20%) and pituitary
tumours (10%). Although the lower-grade gliomas (I and II) may
be very indolent, with prognosis measured in terms of many
years, these may transform to higher-grade disease at any time,
with a resultant sharp decline in life expectancy.
Most malignant brain tumours are due to metastases, with
intracranial metastases complicating about 20% of extracranial
malignancies. The rate is higher with primaries in the bronchus,
breast and gastrointestinal tract (Fig. 25.40). Metastases usually
occur in the white matter of the cerebral or cerebellar hemispheres
but there are diffuse leptomeningeal types.
Clinical features
The presentation is variable and usually influenced by the rate
of growth. High-grade disease (WHO grades III and IV) tends to
present with a short (weeks) history of mass effect (headache,
nausea secondary to RICP), while more indolent tumours can
present with slowly progressive focal neurological deficits,
depending on their location (see Box 25.75); generalised or
focal seizures are common in either. Headache, if present,
is usually accompanied by focal deficits or seizures, and
25.76 Primary brain tumours
Histological type
Common site
Age
Malignant
Glioma
Cerebral hemisphere
Adulthood
(astrocytoma)
Cerebellum
Childhood/adulthood
Brainstem
Childhood/young
adulthood
Oligodendroglioma
Cerebral hemisphere
Adulthood
Medulloblastoma
Posterior fossa
Childhood
Ependymoma
Posterior fossa
Childhood/adolescence
Cerebral lymphoma
Cerebral hemisphere
Adulthood
Benign
Meningioma
Cortical dura
Adulthood (often
Parasagittal
Sphenoid ridge
Suprasellar
Olfactory groove
incidental finding)
Neurofibroma
Acoustic neuroma
Adulthood
Craniopharyngioma
Suprasellar
Childhood/adolescence
Pituitary adenoma
Pituitary fossa
Adulthood
Colloid cyst
Third ventricle
Any age
Pineal tumours
Ouadrigeminal
Childhood (teratomas)
cistern
Young adulthood
(germ cell)
Fig. 25.40 Contrast-enhanced computed tomogram of the head
showing a large metastasis within the left hemisphere (large arrow).
There is surrounding cerebral oedema, and a smaller metastasis (small
arrow) within the wall of the right lateral ventricle. The primary lesion was
a lung carcinoma.
isolated stable headache is almost never due to intracranial
tumour.
The size of the primary tumour is of far less prognostic
significance than its location within the brain. Tumours within
the brainstem will result in early neurological deficits, while those
in the frontal region may be quite large before symptoms occur.
1130 • NEUROLOGY
Fig. 25.41 Magnetic resonance image showing a meningioma in the
frontal lobe (arrow A) with associated oedema (arrow B).
Investigations
Diagnosis is by neuroimaging (Figs 25.41 and 25.42) and
pathological grading following biopsy or resection where possible.
The more malignant tumours are more likely to demonstrate
contrast enhancement on imaging. If the tumour appears
metastatic, further investigation to find the primary is required.
Management
Brain tumours are treated with a combination of surgery,
radiotherapy and chemotherapy, depending on the type of
tumour and the patient. Advancing age is the most powerful
negative prognostic factor in CNS tumours, so best supportive
care (including glucocorticoid therapy) may be most appropriate in
older patients with metastases or high-grade disease. Treatment
may not always be indicated in low-grade gliomas and watchful
waiting may be appropriate, although a more aggressive approach
is increasingly favoured.
Dexamethasone given orally (or intravenously where RICP is
acutely or severely raised) may reduce the vasogenic oedema
typically associated with metastases and high-grade gliomas.
Prolactin- or growth hormone-secreting pituitary adenomas
(p. 683) may respond well to treatment with dopamine agonists
(such as bromocriptine, cabergoline or quinagolide); in this
situation, imaging and hormone levels may be all that is required
to establish a formal diagnosis, precluding the need for surgery.
Surgical
The mainstay of primary treatment is surgery, either resection
(full or partial debulking) or biopsy, depending on the site and
likely radiological diagnosis. Clearly, if a tumour occurs in
an area of brain that is highly important for normal function
(e.g. motor strip), then biopsy may be the only safe surgical
intervention but, in general, maximal safe resection is the optimal
surgical management. Meningiomas and acoustic neuromas
offer the best prospects for complete removal and thus cure.
Some meningiomas can recur, however, particularly those of
Fig. 25.42 Magnetic resonance image of an acoustic neuroma
(arrows) in the posterior fossa compressing the brainstem. Axial
image. [§] Coronal image.
the sphenoid ridge, when partial excision is often all that is
possible. Thereafter, post-operative surveillance may be required,
as radiotherapy is effective at preventing further growth of
residual tumour. Pituitary adenomas may be removed by a
trans-sphenoidal route, avoiding the need for a craniotomy.
Unfortunately, gliomas, which account for the majority of brain
tumours, cannot be completely excised, since infiltration spreads
well beyond the apparent radiological boundaries of the intracranial
mass. Recurrence is therefore the rule, even if the mass of
the tumour is apparently removed completely; partial excision
(‘debulking’) may be useful in alleviating symptoms caused by
RICP, but although there is increasing evidence that the degree
of surgical excision may have a positive influence on survival,
this has not yet been convincingly demonstrated.
Radiotherapy and chemotherapy
In the majority of primary CNS tumours, radiation and
chemotherapy are used to control disease and extend survival
rather than for cure. Meningioma and pituitary adenoma offer the
Intracranial mass lesions and raised intracranial pressure • 1131
best chance of life-long remission. The gliomas are incurable;
high-grade, WHO grade IV disease still carries a median survival of
just over 1 year. In this situation, patient and family should always
be involved in decisions regarding treatment. The diagnosis, and
often the symptoms, are devastating, and support from palliative
care and social work is crucial at an early stage. In WHO grade
III disease, prognosis is a little better (2-4 years), and in rarer,
more indolent tumours very prolonged survival is possible.
Advances have been made recently in terms of therapeutic
outcome. Standard care for WHO grade IV glioblastoma
multiforme is now combination radiotherapy with temozolomide
chemotherapy; although this improves median survival of the
population from only 12 to 14.5 months, up to 25% of patients
survive for more than 2 years (compared to approximately 1 0%
with radiotherapy alone). Ten percept will survive more than
5 years with temozolomide (virtually unheard of with radiotherapy
alone). Benefits are more likely in well-debulked patients who
are younger and fitter. Implantation of chemotherapy gives a
small survival benefit.
Understanding of the molecular biology of brain tumours has
allowed the use of biomarkers to guide therapy and prognostic
discussions. In patients with methylation of the promoter region of
the MGMT (methyl guanine methyl transferase) gene (about 30%
of the population), 2-year survival is almost 50%. MGMT reduces
the cytotoxicity of temozolomide and this mutation also reduces
the enzyme’s activity, rendering the tumour more sensitive to
chemotherapy. In grade II and III gliomas, the presence of the loss
of heterozygosity (LOH) 1 p19q chromosomal abnormality confers
chemosensitivity and thus improves prognosis. The presence
of a rare mutation in the IDH-1 (isocitrate dehydrogenase) gene
confers a more favourable prognosis in patients with glioblastoma.
There is a small group of highly malignant grade IV tumours that
can be cured with aggressive therapy. Medulloblastomas have a
good chance of long-term remission with maximal surgery followed
by irradiation of the whole brain and spine; younger patients
may also benefit from concomitant and adjuvant chemotherapy.
Older patients do not tolerate this, however.
Once tumours relapse, chemotherapy response rates are low
and survival is short in high-grade disease. In the more uncommon
low-grade tumours, repeated courses of chemotherapy can
result in much more prolonged survival.
In metastatic disease, radiotherapy offers a modest improvement
in survival but with costs in terms of quality of life; treatment
therefore needs careful discussion with the patient. Benefits
may be superior in breast cancer but there is little to separate
other pathologies. Occasional chemosensitive cancers, such as
small-cell lung cancer, may benefit from systemic chemotherapy
but intracerebral metastases represent a late stage of disease
and have a short prognosis.
Prognosis
The WHO histological grading system is a powerful predictor
of prognosis in primary CNS tumours, though it does not yet
take account of individual biomarkers. For each tumour type
and grade, advancing age and deteriorating functional status
are the next most important negative prognostic features. The
overall 5-year survival rate of about 1 4% in adults masks a wide
variation that depends on tumour type.
Acoustic neuroma
This is a benign tumour of Schwann cells of the 8th cranial nerve,
which may arise in isolation or as part of neurofibromatosis type
2 (see below). When sporadic, acoustic neuroma occurs after
the third decade and is more frequent in females. The tumour
commonly arises near the nerve’s entry point into the medulla
or in the internal auditory meatus, usually on the vestibular
division. Acoustic neuromas account for 80-90% of tumours
at the cerebellopontine angle.
Clinical features
Acoustic neuroma typically presents with unilateral progressive
hearing loss, sometimes with tinnitus. Vertigo is an unusual
symptom, as slow growth allows compensatory brainstem
mechanisms to develop. In some cases, progressive enlargement
leads to distortion of the brainstem and/or cerebellar peduncle,
causing ataxia and/or cerebellar signs in the limbs. Distortion of the
fourth ventricle and cerebral aqueduct may cause hydrocephalus
(see below), which may be the presenting feature. Facial weakness
is unusual at presentation but facial palsy may follow surgical
removal of the tumour. The tumour may be identified incidentally
on cranial imaging.
Investigations
MRI is the investigation of choice (see Fig. 25.42).
Management
Surgery is the treatment of choice. If the tumour can be completely
removed, the prognosis is excellent, although deafness is a
common complication of surgery. Stereotactic radiosurgery
(radiotherapy) may be appropriate for some lesions.
Neurofibromatosis
Neurofibromatosis encompasses two clinically and genetically
separate conditions, with an autosomal dominant pattern of
inheritance. The more common neurofibromatosis type 1 (NF1) is
caused by mutations in the NF1 gene on chromosome 1 7, half of
which are new mutations. NF1 is characterised by neurofibromas
(benign peripheral nerve sheath tumours) and skin involvement
(Fig. 25.43), and may affect numerous systems (Box 25.77).
Fig. 25.43 A cafe au lait spot (arrow A) and subcutaneous nodules
(arrows B) on the forearm of a patient with neurofibromatosis type 1.
1132 • NEUROLOGY
25.77 Neurofibromatosis types 1 and 2:
clinical features
Neurofibromatosis 1
Neurofibromatosis 2
Skin
Cutaneous/subcutaneous
neurofibromas
Angiomas
Cafe au lait patches (>6)
Axillary/groin freckling
Hypopigmented patches
Much less commonly
affected than in NF1
Cafe au lait patches (usually
<6)
Cutaneous schwannomas:
plaque lesions
Subcutaneous schwannomas
Eyes
Lisch nodules (iris fibromas)
Glaucoma
Congenital ptosis
Cataracts
Retinal hamartoma
Optic nerve meningioma
Nervous system
Plexiform neurofibromas
Malignant peripheral nerve sheath
tumours
Aqueduct stenosis
Slight tonsillar descent
Cognitive impairment
Epilepsy
Vestibular schwannomas
Cranial nerve schwannomas
(not 1 and 2)
Spinal schwannomas
Peripheral nerve
schwannomas
Cranial meningiomas
Spinal meningiomas
Spinal/brainstem
ependymomas
Spinal/cranial astrocytoma
Bone
Scoliosis
Osteoporosis
Pseudoarthrosis
Cardiorespiratory systems
Pulmonary stenosis
Hypertension
Renal artery stenosis
Compression from neurofibroma
causing restrictive lung defect
Gastrointestinal system
Gastrointestinal stromal tumour
(GIST)
Duodenal/ampullary neuro¬
endocrine tumour
Neurofibromatosis type 2 (NF2) is caused by mutations of the NF2
gene on chromosome 22, and is characterised by schwannomas
(benign peripheral nerve sheath tumours comprising Schwann
cells only) with little skin involvement; the clinical manifestations
are more restricted to the eye and nervous system (Box 25.77).
Malignant change may occur in NF1 neurofibromas but is rare
in NF2 schwannomas. The prevalence of NF1 and NF2 is about
20-50 per 100000 and 1.5 per 100000, respectively.
Von Hippel-Lindau disease
This rare autosomal dominant disease is caused by mutations
of the VHL tumour suppressor gene on chromosome 3. It
promotes development of tumours affecting the kidney, adrenal
gland, CNS, eye, inner ear, epididymis and pancreas, which
may undergo malignant change. Benign haemangiomas and
haemangioblastomas affect about 80% of patients, and are
mostly cerebellar and retinal.
Paraneoplastic neurological disease
Paraneoplastic neurological syndromes often present before
the underlying tumour declares itself and cause considerable
disability. They are discussed in full on page 1110.
Hydrocephalus
Hydrocephalus is the excessive accumulation of CSF within the
brain, and may be caused either by increased CSF production, by
reduced CSF absorption, or by obstruction of the circulation (Fig.
25.44). Symptoms range from none to sudden death, depending
on the speed at which and degree to which hydrocephalus
develops. The causes are listed in Box 25.78. The terms
‘communicating’ and ‘non-communicating’ (also known as
obstructive) hydrocephalus refer to blockage either outside or
within the ventricular system, respectively (Fig. 25.45).
|Normal pressure hydrocephalus
Normal pressure hydrocephalus (NPH) is a controversial entity,
said to involve intermittent rises in CSF pressure, particularly at
night. It is described in old age as being associated with a triad
of gait apraxia, dementia and urinary incontinence.
Fig. 25.44 The circulation of cerebrospinal fluid (CSF). (1) CSF is
synthesised in the choroid plexus of the ventricles and flows from the
lateral and third ventricles through the aqueduct to the fourth ventricle. (2)
At the foramina of Luschka and Magendie it exits the brain, flowing over
the hemispheres (3) and down around the spinal cord and roots in the
subarachnoid space. (4) It is then absorbed into the dural venous sinuses
via the arachnoid villi.
i
25.78 Causes of hydrocephalus
Congenital malformations
• Aqueduct stenosis
•
Vein of Galen aneurysms
• Chiari malformations
•
Congenital central nervous
• Dandy-Walker syndrome
system infections
• Benign intracranial cysts
•
Craniofacial anomalies
Acquired causes
• Mass lesions (especially those
•
Haematoma
in the posterior fossa)
•
Absorption blockages due to:
• Tumour
Inflammation (e.g.
• Colloid cyst of third ventricle
meningitis, sarcoidosis)
• Abscess
Intracranial haemorrhage
Intracranial mass lesions and raised intracranial pressure • 1133
Fig. 25.45 Magnetic resonance image of hydrocephalus due to
aqueduct stenosis. [A] Axial T2-weighted image (cerebrospinal fluid
appears white): note the dilated lateral ventricles. [§] Sagittal T1 -weighted
image (cerebrospinal fluid appears black): note the dilated ventricles (top
arrow) and narrowed aqueduct (bottom arrow).
Management
Diversion of the CSF by means of a shunt placed between the
ventricular system and the peritoneal cavity or right atrium may
result in rapid relief of symptoms in obstructive hydrocephalus.
The outcome of shunting in NPH is much less predictable and,
until a good response can be predicted, the management of
individual cases will remain uncertain.
Idiopathic intracranial hypertension
This usually occurs in obese young women. The annual incidence
is about 3 per 1 00000. RICP occurs in the absence of a structural
lesion, hydrocephalus or other identifiable cause. The aetiology
is uncertain but there is an association with obesity in females,
perhaps inducing a defect of CSF reabsorption by the arachnoid
villi. A number of drugs may be associated, including tetracycline,
vitamin A and retinoid derivatives.
Clinical features
The usual presentation is with headache, sometimes accompanied
by diplopia and visual disturbance (most commonly, transient
obscurations of vision associated with changes in posture).
Clinical examination reveals papilloedema but little else. False
localising cranial nerve palsies (usually of the 6th nerve) may
be present. It is important to record visual fields accurately for
future monitoring.
Investigations
Brain imaging is required to exclude a structural or other
cause (e.g. cerebral venous sinus thrombosis, p. 1162). The
ventricles are typically normal in size or small (‘slit’ ventricles). The
diagnosis may be confirmed by lumbar puncture, which shows
raised normal CSF constituents at increased pressure (usually
>30 cmPI20 CSF).
Management
Management can be difficult and there is no evidence to support
any specific treatment. Weight loss in overweight patients may
be helpful if it can be achieved. Acetazolamide or topiramate
may help to lower intracranial pressure, the latter perhaps aiding
weight loss in some patients. Repeated lumbar puncture is an
effective treatment for headache but may be technically difficult
in obese individuals and is often poorly tolerated. Patients failing
to respond, in whom chronic papilloedema threatens vision, may
require optic nerve sheath fenestration or a lumbo-peritoneal
shunt.
Head injury
Diagnosis of head trauma is usually clear - either from the history
or from signs of external trauma to the head. Brain injury is more
likely with skull fracture but can occur without. Individual cranial
nerves may be damaged in fractures of the facial bones or skull
base. Intracranial effects can be substantial and take several
forms: extradural haematoma (collection of blood between the
skull and dura); subdural haematoma (collection of blood between
the dura and the surface of the brain); intracerebral haematoma;
or diffuse axonal injury.
Whatever pathology occurs, the resultant RICP may lead to
coning (see Figs 25.38 and 25.39). Haematomas are identified
by CT and management is by surgical drainage, usually via a
burr hole. Penetrating skull fractures lead to increased infection
risk. Long-term sequelae include headache, cognitive decline and
depression, all contributing to significant social, work, personality
and family difficulties.
Subdural haematoma may occur spontaneously, particularly in
patients on anticoagulants, in old age, and with alcohol misuse.
There may or may not be a history of trauma. Patients present with
subacute impairment of brain function, both globally (obtundation
and coma) and focally (hemiparesis, seizures). Headache may
not be present. The diagnosis should always be considered in
those who present with reduced conscious level.
Beyond the immediate consequences of brain injury, there
is increasing suspicion of long-term consequences, including
dementia, postulated after either single (moderate or severe)
injuries or even after multiple mild injuries, such as in boxers.
If substantiated, this would encourage more effort to go into
prevention of repeated brain injury in sporting contexts.
1134 • NEUROLOGY
Disorders of cerebellar function
Cerebellar dysfunction can manifest as incoordination of limb
function, gait ataxia (p. 1087), speech or eye movements. Acute
dysfunction may be caused by alcohol or prescription drugs
(especially the sodium channel-blocking antiepileptic drugs
phenytoin and carbamazepine).
Inflammatory changes in the cerebellum may cause symptoms
in the aftermath of some infections (especially herpes zoster) or
as a paraneoplastic phenomenon. The hereditary spinocerebellar
ataxias are described on page 1115; they manifest as progressive
ataxias in middle and old age, often with other neurological
features that aid specific diagnosis.
Disorders of the spine and spinal cord
The spinal cord and spinal roots may be affected by intrinsic
disease or by disorders of the surrounding meninges and bones.
The clinical presentation of these conditions depends on the
anatomical level at which the cord or roots are affected, as well
as the nature of the pathological process involved. It is important
to recognise when the spinal cord is at risk of compression
(p. 1136) so that urgent action can be taken.
Cervical spondylosis
Cervical spondylosis is the result of osteoarthritis in the cervical
spine. It is characterised by degeneration of the intervertebral
discs and osteophyte formation. Such ‘wear and tear’ is extremely
common and radiological changes are frequently found in
asymptomatic individuals over the age of 50. Spondylosis may
be associated with neurological dysfunction. In order of frequency,
the C5/6, C6/7 and C4/5 vertebral levels affect C6, C7 and C5
roots, respectively (Fig. 25.46).
Cervical radiculopathy
Acute onset of compression of a nerve root occurs when a disc
prolapses laterally. More gradual onset may be due to osteophytic
encroachment of the intervertebral foramina.
Clinical features
The patient complains of pain in the neck that may radiate in the
distribution of the affected nerve root. The neck is held rigidly
and neck movements may exacerbate pain. Paraesthesia and
sensory loss may be found in the affected segment and there
may be lower motor neuron signs, including weakness, wasting
and reflex impairment (Fig. 25.47).
Investigations
Where there is no trauma, imaging should not be carried out for
isolated cervical pain. MRI is the investigation of choice in those
with radicular symptoms. X-rays offer limited benefit, except in
excluding destructive lesions, and electrophysiological studies
rarely add to clinical examination with MRI.
Management
Conservative treatment with analgesics and physiotherapy results
in resolution of symptoms in the great majority of patients, but
a few require surgery in the form of discectomy or radicular
decompression.
Cervical myelopathy
Dorsomedial herniation of a disc and the development of
transverse bony bars or posterior osteophytes may result in
pressure on the spinal cord or the anterior spinal artery, which
supplies the anterior two-thirds of the cord (see Fig. 25.46).
Fig. 25.46 Magnetic resonance image showing cervical cord
compression (arrow) in cervical spondylosis.
Root
Sensory loss
(see Fig 25.10,
p. 1071)
Muscle weakness Biceps, deltoid and
spinati
Brachioradialis
Triceps, fingers and
wrist extensors
Reflex loss @ Biceps
Supinator
Triceps
Fig. 25.47 Findings in cervical nerve root compression.
Disorders of the spine and spinal cord • 1135
Clinical features
The onset is usually insidious and painless but acute deterioration
may occur after trauma, especially hyperextension injury. Upper
motor neuron signs develop in the limbs, with spasticity of the
legs usually appearing before the arms are involved. Sensory loss
in the upper limbs is common, producing tingling, numbness and
proprioception loss in the hands, with progressive clumsiness.
Sensory manifestations in the legs are much less common.
Neurological deficit usually progresses gradually and disturbance
of micturition is a very late feature.
Investigations
MRI (see Fig. 25.46) (or rarely myelography) will direct surgical
intervention. The former provides information on the state of the
spinal cord at the level of compression.
Management
Surgical procedures, including laminectomy and anterior
discectomy, may arrest progression of disability but neurological
improvement is not the rule. The decision as to whether surgery
should be undertaken may be difficult. Manual manipulation of
the cervical spine is of no proven benefit and may precipitate
acute neurological deterioration.
Prognosis
The prognosis of cervical myelopathy is variable. In many patients,
the condition stabilises or even improves without intervention. If
progression results in sphincter dysfunction or pyramidal signs,
surgical decompression should be considered.
Lumbar spondylosis
This term covers degenerative disc disease and osteoarthritic
change in the lumbar spine. Pain in the distribution of the lumbar
or sacral roots (‘sciatica’) is almost always due to disc protrusion
but can be a feature of other rare but important disorders,
including spinal tumour, malignant disease in the pelvis and
tuberculosis of the vertebral bodies.
Lumbar disc herniation
While acute lumbar disc herniation is often precipitated by
trauma (usually lifting heavy weights while the spine is flexed),
genetic factors may also be important. The nucleus pulposus
may bulge or rupture through the annulus fibrosus, giving rise
to pressure on nerve endings in the spinal ligaments, changes
in the vertebral joints or pressure on nerve roots.
Pathophysiology
The altered mechanics of the lumbar spine result in loss of lumbar
lordosis and there may be spasm of the paraspinal musculature.
Root pressure is suggested by limitation of flexion of the hip on
the affected side if the straight leg is raised (Lasegue’s sign). If
the third or fourth lumbar root is involved, Lasegue’s sign may be
negative, but pain in the back may be induced by hyperextension
of the hip (femoral nerve stretch test). The roots most frequently
affected are SI , L5 and L4; the signs of root pressure at these
levels are summarised in Figure 25.48.
Clinical features
The onset may be sudden or gradual. Alternatively, repeated
episodes of low back pain may precede sciatica by months or
years. Constant aching pain is felt in the lumbar region and may
radiate to the buttock, thigh, calf and foot. Pain is exacerbated
by coughing or straining but may be relieved by lying flat.
Investigations
MRI is the investigation of choice if available, since soft tissues
are well imaged. Plain X-rays of the lumbar spine are of little value
in the diagnosis of disc disease, although they may demonstrate
conditions affecting the vertebral body. CT can provide helpful
images of the disc protrusion and/or narrowing of exit foramina.
Management
Some 90% of patients with sciatica recover following conservative
treatment with analgesia and early mobilisation; bed rest does
not help recovery. The patient should be instructed in back-
strengthening exercises and advised to avoid physical manoeuvres
likely to strain the lumbar spine. Injections of local anaesthetic or
glucocorticoids may be useful adjunctive treatment if symptoms
are due to ligamentous injury or joint dysfunction. Surgery may
have to be considered if there is no response to conservative
treatment or if progressive neurological deficits develop. Central
disc prolapse with bilateral symptoms and signs and disturbance
of sphincter function requires urgent surgical decompression.
Lumbar canal stenosis
This occurs with a congenitally narrowed lumbar spinal canal,
exacerbated by the degenerative changes that commonly occur
with age.
Pathophysiology
The symptoms of spinal stenosis are thought to be due to local
vascular compromise secondary to the canal stenosis, rendering
Disc level
Root
Sensory loss
(see Fig 25.10,
p. 1071)
Muscle weakness
Reflex loss f|
L4/L5
L5/S1
Knee extension
Knee
L5
Ankle dorsiflexion
Ankle inversion
None
SI
Plantar flexion
Ankle
Fig. 25.48 Findings in lumbar nerve root compression.
1136 • NEUROLOGY
the nerve roots ischaemic and intolerant of the increased demand
that occurs on exercise.
Clinical features
Patients, who are usually elderly, develop exercise-induced
weakness and paraesthesia in the legs (‘spinal claudication’).
These symptoms progress with continued exertion, often to the
point that the patient can no longer walk, but are quickly relieved
by a short period of rest. Physical examination at rest shows
preservation of peripheral pulses with absent ankle reflexes.
Weakness or sensory loss may only be apparent if the patient
is examined immediately after exercise.
Investigations
The investigation of first choice is MRI, but contraindications
(body habitus, metallic implants) may make CT or myelography
necessary.
Management
Lumbar laminectomy may provide relief of symptoms and recovery
of normal exercise tolerance.
Spinal cord compression
Spinal cord compression is one of the more common neurological
emergencies encountered in clinical practice and the usual causes
are listed in Box 25.79. A space-occupying lesion within the
spinal canal may damage nerve tissue either directly by pressure
or indirectly by interference with blood supply. Oedema from
venous obstruction impairs neuronal function, and ischaemia
from arterial obstruction may lead to necrosis of the spinal
cord. The early stages of damage are reversible but severely
damaged neurons do not recover; hence the importance of early
diagnosis and treatment.
Clinical features
The onset of symptoms of spinal cord compression is usually
slow (over weeks) but can be acute as a result of trauma or
metastases (see Figs 25.46, 25.49 and 25.50), especially if
there is associated arterial occlusion. The symptoms are shown
in Box 25.80.
Pain and sensory symptoms occur early, while weakness and
sphincter dysfunction are usually late manifestations. The signs
vary according to the level of the cord compression and the
! 25.79 Causes of spinal cord compression
Site
Frequency
Causes
Vertebral
80%
Trauma (extradural)
Intervertebral disc prolapse
Metastatic carcinoma (e.g. breast,
prostate, bronchus)
Myeloma
Tuberculosis
Meninges
(intradural,
extramedullary)
15%
Tumours (e.g. meningioma,
neurofibroma, ependymoma,
metastasis, lymphoma, leukaemia)
Epidural abscess
Spinal cord
(intradural,
intramedullary)
5%
Tumours (e.g. glioma,
ependymoma, metastasis)
structures involved. There may be tenderness to percussion over
the spine if there is vertebral disease and this may be associated
with a local kyphosis. Involvement of the roots at the level of
the compression may cause dermatomal sensory impairment
and corresponding lower motor signs. Interruption of fibres in
the spinal cord causes sensory loss (p. 1083) and upper motor
neuron signs below the level of the lesion, and there is often
disturbance of sphincter function. The distribution of these signs
varies with the level of the lesion (Box 25.81).
The Brown-Sequard syndrome (see Fig. 25.1 8E, p. 1084)
results if damage is confined to one side of the cord; the findings
are explained by the anatomy of the sensory tracts (see Fig.
25.11, p. 1072). With compressive lesions, there is usually a
band of pain at the level of the lesion in the distribution of the
nerve roots subject to compression.
Investigations
Patients with a history of acute or subacute spinal cord syndrome
should be investigated urgently, as listed in Box 25.82. The
25.82 Investigation of acute spinal cord syndrome
• Magnetic resonance imaging • Chest X-ray
of spine or myelography • Cerebrospinal fluid
• Plain X-rays of spine • Serum vitamin B12
25.80 Symptoms of spinal cord compression
Pain
• Localised over the spine or in a root distribution, which may be
aggravated by coughing, sneezing or straining
Sensory
• Paraesthesia, numbness or cold sensations, especially in the lower
limbs, which spread proximally, often to a level on the trunk
Motor
• Weakness, heaviness or stiffness of the limbs, most commonly the
legs
Sphincters
• Urgency or hesitancy of micturition, leading eventually to urinary
retention
25.81 Signs of spinal cord compression
Cervical, above C5
• Upper motor neuron signs and sensory loss in all four limbs
• Diaphragm weakness (phrenic nerve)
Cervical, C5-T1
• Lower motor neuron signs and segmental sensory loss in the arms;
upper motor neuron signs in the legs
• Respiratory (intercostal) muscle weakness
Thoracic cord
• Spastic paraplegia with a sensory level on the trunk
• Weakness of legs, sacral loss of sensation and extensor plantar
responses
Cauda equina
• Spinal cord ends approximately at the T12/L1 spinal level and
spinal lesions below this level can cause lower motor neuron signs
only by affecting the cauda equina
Disorders of the spine and spinal cord • 1137
Fig. 25.49 Axial magnetic resonance image of thoracic spine.
A neurofibroma (N) is compressing the spinal cord (SC) and emerging
in a ‘dumbbell’ fashion through the vertebral foramen into the paraspinal
space.
Fig. 25.50 Computed tomographic myelogram of cervical spine at
the level of C2 showing bony erosion of vertebra by a metastasis
(arrow).
investigation of choice is MRI (Fig. 25.49), as it can define the
extent of compression and associated soft-tissue abnormality (Fig.
25.50). Plain X-rays may show bony destruction and soft-tissue
abnormalities. Routine investigations, including chest X-ray,
may provide evidence of systemic disease. If myelography
is performed, CSF should be taken for analysis; in cases of
complete spinal block, this shows a normal cell count with a very
elevated protein causing yellow discoloration of the fluid (Froin’s
syndrome). The risk of acute deterioration after myelography in
spinal cord compression means that the neurosurgeons should
be alerted before it is undertaken. Where a secondary tumour
is causing the compression, needle biopsy may be required to
establish a tissue diagnosis.
Management
Treatment and prognosis depend on the nature of the underlying
lesion. Benign tumours should be surgically excised, and a
good functional recovery can be expected unless a marked
neurological deficit has developed before diagnosis. Extradural
compression due to malignancy is the most common cause
of spinal cord compression in developed countries and has a
poor prognosis. Useful function can be regained if treatment,
such as radiotherapy, is initiated within 24 hours of the onset
of severe weakness or sphincter dysfunction; management
should involve close cooperation with both oncologists and
neurosurgeons.
Spinal cord compression due to tuberculosis is common in
some areas of the world and may require surgical treatment.
This should be followed by appropriate antituberculous
chemotherapy (p. 592) for an extended period. Traumatic lesions
of the vertebral column require specialised neurosurgical
treatment.
Intrinsic diseases of the spinal cord
There are many disorders that interfere with spinal cord function
due to non-compressive involvement of the spinal cord itself.
A list of these disorders is given in Box 25.83. The symptoms
and signs are generally similar to those that would occur with
extrinsic compression (see Boxes 25.80 and 25.81), although a
suspended sensory loss (see Fig. 25.1 8F, p. 1084) can occur only
with intrinsic disease such as syringomyelia. Urinary symptoms
usually occur earlier in the course of an intrinsic cord disorder
than with compressive disorders.
Investigation of intrinsic disease starts with imaging to exclude
a compressive lesion. MRI provides most information about
structural lesions, such as diastematomyelia, syringomyelia (Fig.
25.51) or intrinsic tumours. Non-specific signal change may be
seen in the spinal cord in inflammatory (see Fig. 25.30, p. 1109)
or infective conditions and metabolic disorders such as vitamin
B12 deficiency. Lumbar puncture or blood tests may be required
to make a specific diagnosis.
Fig. 25.51 Sagittal magnetic resonance image showing descent of
cerebellar tonsils and central syrinx. The MRI shows descent of the
cerebellar tonsils (top arrow), with a large central cord syrinx extending
down from the cervical cord (middle arrow) to the thoracic cord (bottom
arrow).
1138 • NEUROLOGY
25.83 Intrinsic diseases of the spinal cord
Type of disorder
Condition
Clinical features
Congenital
Diastematomyelia (spina bifida)
Features variably present at birth and deteriorate thereafter
LMN features, deformity and sensory loss of legs
Impaired sphincter function
Hairy patch or pit over low back
Incidence reduced by increased maternal intake of folic acid during pregnancy
Hereditary spastic paraplegia
Onset usually in adult life
Autosomal dominant inheritance usual
Slowly progressive UMN features affecting legs > arms
Little or no sensory loss
Infective/inflammatory
Transverse myelitis due to viruses (HZV),
schistosomiasis, HIV, MS, sarcoidosis
Weakness and sensory loss, often with pain, developing over hours to days
UMN features below lesion
Impaired sphincter function
Paraneoplastic
May predate tumour diagnosis
Vascular
Anterior spinal artery infarct due to
atherosclerosis, aortic dissection,
embolus
Abrupt onset
Anterior horn cell loss (LMN) at level of lesion
UMN features below it
Spinothalamic sensory loss below lesion but dorsal column sensation spared
Spinal AVM/dural fistula
Onset variable (acute to slowly progressive)
Variable LMN, UMN, sensory and sphincter disturbance
Symptoms and signs often not well localised to site of AVM
Neoplastic
Glioma, ependymoma
Weakness and sensory loss often with pain, developing over months to years
UMN features below lesion in cord; additional LMN features in conus
Impaired sphincter function
Metabolic
Vitamin B12 deficiency (subacute
combined degeneration)
Progressive spastic paraparesis with proprioception loss
Absent reflexes due to peripheral neuropathy
± Optic nerve and cerebral involvement (p. 715)
Copper deficiency
Excess dietary zinc
Nitrous oxide toxicity
Modifies vitamin B12 metabolism
Degenerative
Motor neuron disease
Relentlessly progressive LMN and UMN features, associated bulbar weakness
No sensory involvement (p. 1116)
Syringomyelia
Gradual onset over months or years, pain in cervical segments
Anterior horn cell loss (LMN) at level of lesion, UMN features below it
Suspended spinothalamic sensory loss at level of lesion, dorsal columns
preserved (see Figs 25.1 8F (p. 1084) and 25.51)
(AVM = arteriovenous malformation; HIV = human immunodeficiency virus; HZV =
motor neuron)
herpes zoster virus; LMN = lower motor neuron; MS = multiple sclerosis; UMN = upper
Diseases of peripheral nerves
Disorders of the peripheral nervous system are common and
may affect the motor, sensory or autonomic components, either
in isolation or in combination. The site of pathology may be
nerve root (radiculopathy), nerve plexus (plexopathy) or nerve
(neuropathy). Neuropathies may present as mononeuropathy
(single nerve affected), multiple mononeuropathies (‘mononeuritis
multiplex’) or a symmetrical polyneuropathy (Box 25.84).
Cranial nerves 3-1 2 share the same tissue characteristics as
peripheral nerves elsewhere and are subject to the same range
of diseases.
Pathophysiology
Damage may occur to the nerve cell body (axon) or the myelin
sheath (Schwann cell), leading to axonal or demyelinating
neuropathies. The distinction is important, as only demyelinating
neuropathies are usually susceptible to treatment. Making
the distinction requires neurophysiology (nerve conduction
studies and EMG, p. 1076). Neuropathies can occur in
association with many systemic diseases, toxins and drugs
(Box 25.85).
Clinical features
Motor nerve involvement produces features of a lower motor
neuron lesion (p. 1082). Symptoms and signs of sensory nerve
involvement depend on the type of sensory nerve involved
(p. 1083); small-fibre neuropathies are often painful. Autonomic
involvement may cause postural hypotension, disturbance of
sweating, cardiac rhythm and gastrointestinal, bladder and
sexual functions; isolated autonomic neuropathies are rare and
more commonly complicate other neuropathies.
Investigations
The investigations required reflect the wide spectrum of causes
(Box 25.86). Neurophysiological tests are key in discriminating
between demyelinating and axonal neuropathies, and in identifying
entrapment neuropathies. Most neuropathies are of the chronic
axonal type.
Diseases of peripheral nerves • 1139
i
Genetic
• Charcot-Marie-Tooth disease (CMT)
• Hereditary neuropathy with liability to pressure palsies
(HNPP)
• Hereditary sensory ± autonomic neuropathies
(HSN, HSAN)
• Familial amyloid polyneuropathy
• Hereditary neuralgic amyotrophy
Drugs
• Amiodarone
• Antibiotics (dapsone,
isoniazid, metronidazole,
ethambutol)
• Antiretrovirals
Toxins
• Alcohol
• Rarely: lead, arsenic,
• Nitrous oxide (recreational
mercury, organophosphates,
use)
solvents
Vitamin deficiencies
• Thiamin
• Vitamin B12
• Pyridoxine
• Vitamin E
Infections
• HIV
• Leprosy
• Brucellosis
Inflammatory
• Guillain— Barre syndrome
• Chronic inflammatory demyelinating polyradiculoneuropathy
• Vasculitis (polyarteritis nodosa, granulomatosis with polyangiitis (also
known as Wegener’s granulomatosis), rheumatoid arthritis, systemic
lupus erythematosus)
• Paraneoplastic (antibody-mediated)
Systemic medical conditions
• Diabetes • Sarcoidosis
• Renal failure
Malignant disease
• Infiltration
Others
• Paraproteinaemias • Critical illness polyneuropathy/
• Amyloidosis myopathy
• Chemotherapy
(cisplatin, vincristine,
thalidomide)
• Phenytoin
25.84 Causes of polyneuropathy
25.85 Common causes of axonal and demyelinating
chronic polyneuropathies
Axonal
• Diabetes mellitus
• Alcohol
• Uraemia
• Cirrhosis
• Amyloid
• Myxoedema
• Acromegaly
• Paraneoplasm
Demyelinating
• Chronic inflammatory demyelinating polyradiculoneuropathy
• Multifocal motor neuropathy
• Paraprotein-associated demyelinating neuropathy
• Charcot-Marie-Tooth disease type I and type X
• Drugs and toxins (see Box
25.84)
• Deficiency states (see Box
25.84)
• Hereditary factors
• Infection (see Box 25.84)
• Idiopathic factors
25.86 Investigation of peripheral neuropathy
Initial tests
• Glucose (fasting)
• Erythrocyte sedimentation rate,
C-reactive protein
• Full blood count
• Urea and electrolytes
• Liver function tests
If initial tests are negative
• Nerve conduction studies
• Vitamins E and A
• Genetic testing (see
Box 25.84)
Serum protein electrophoresis
Vitamin B12, folate
ANA, ANCA
Chest X-ray
HIV testing
Lyme serology (p. 256)
Serum angiotensin-converting
enzyme
Serum amyloid
(ANCA = antineutrophil cytoplasmic antibody; ANA = antineutrophil antibody)
Entrapment neuropathy
Focal compression or entrapment is the usual cause of a
mononeuropathy. Symptoms and signs of entrapment neuropathy
are listed in Box 25.87. Entrapment neuropathies may affect
anyone but diabetes, excess alcohol or toxins, or genetic
syndromes may be predisposing causes. Unless axonal loss
25.87 Symptoms and signs in common entrapment neuropathies
Nerve
Symptoms
Muscle weakness/
muscle-wasting
Area of sensory loss
Median (at wrist) (carpal tunnel
syndrome)
Pain and paraesthesia on palmar aspect of
hands and fingers, waking patient from
sleep. Pain may extend to arm and shoulder
Abductor pollicis brevis
Lateral palm and thumb,
index, middle and lateral
half fourth finger
Ulnar (at elbow)
Paraesthesia on medial border of hand,
wasting and weakness of hand muscles
All small hand muscles,
excluding abductor pollicis
brevis
Medial palm and little finger,
and medial half fourth finger
Radial
Weakness of extension of wrist and fingers,
often precipitated by sleeping in abnormal
posture, e.g. arm over back of chair
Wrist and finger extensors,
supinator
Dorsum of thumb
Common peroneal
Foot drop, trauma to head of fibula
Dorsiflexion and eversion of foot
Nil or dorsum of foot
Lateral cutaneous nerve of the
thigh (meralgia paraesthetica)
Tingling and dysaesthesia on lateral border
of thigh
Nil
Lateral border of thigh
1140 • NEUROLOGY
i
has occurred, entrapment neuropathies will recover, provided
the primary cause is removed, either by avoiding the precipitation
of activity or by surgical decompression.
Multifocal neuropathy
Multifocal neuropathy (mononeuritis multiplex) is characterised
by lesions of multiple nerve roots, peripheral nerves or cranial
nerves (Box 25.88). Vasculitis is a common cause, either as
part of a systemic disease or isolated to the nerves, or it may
arise on a background of a polyneuropathy (e.g. diabetes).
Multifocal motor neuropathy (MMN) with conduction block is
a rare pure motor neuropathy, typically affecting the arms; it is
associated with anti-GMI antibodies in about 50% and responds
to intravenous immunoglobulin.
Polyneuropathy
A polyneuropathy is typically associated with a ‘length-dependent’
pattern, occurring in the longest peripheral nerves first and
affecting the distal lower limbs before the upper limbs. Sensory
symptoms and signs develop in an ascending ‘glove and stocking’
distribution (p. 1083). In inflammatory demyelinating neuropathies,
the pathology may be more patchy, affecting the upper rather
than lower limbs.
Guillain— Barre syndrome
Guillain-Barre syndrome (GBS) is a heterogeneous group of
immune-mediated conditions with an incidence of 1-2/100000/
year. In Europe and North America, the most common variant is an
acute inflammatory demyelinating polyneuropathy (AIDP). Axonal
variants, either motor (acute motor axonal neuropathy, AMAN)
or sensorimotor (acute motor and sensory axonal neuropathy,
AMSAN), are more common in China and Japan, and account
for 10% of GBS in Western countries (often associated with
Campylobacter jejuni). The hallmark is an acute paralysis evolving
over days or weeks with loss of tendon reflexes. About two-
thirds of those with AIDP have a prior history of infection, and
an autoimmune response triggered by the preceding infection
causes demyelination. A number of GBS variants have been
described, associated with specific anti-ganglioside antibodies;
the best recognised is Miller Fisher syndrome, which involves
anti-GQI b antibodies.
Clinical features
Distal paraesthesia and pain precede muscle weakness that
ascends rapidly from lower to upper limbs and is more marked
proximally than distally. Facial and bulbar weakness commonly
develops, and respiratory weakness requiring ventilatory support
occurs in 20% of cases. Weakness progresses over a maximum
of 4 weeks (usually less). Rapid deterioration to respiratory failure
can develop within hours. Examination shows diffuse weakness
with loss of reflexes. Miller Fisher syndrome presents with internal
and external ophthalmoplegia, ataxia and areflexia.
Investigations
The CSF protein is raised, but may be normal in the first 10 days.
There is usually no increase in CSF white cell count (>10x106
cells/L suggests an alternative diagnosis). Electrophysiological
changes may emerge after a week or so, with conduction block
and multifocal motor slowing, sometimes most evident proximally
as delayed F waves (p. 1076). Antibodies to the ganglioside
GM1 are found in about 25%, usually the motor axonal form.
Other causes of an acute neuromuscular paralysis should be
excluded (e.g. poliomyelitis, botulism, diphtheria, spinal cord
syndromes or myasthenia), via the history and examination
rather than investigations.
Management
Active treatment with plasma exchange or intravenous
immunoglobulin therapy shortens the duration of ventilation
and improves prognosis. In severe GBS, both intravenous
immunoglobulin (Mg) and plasma exchange started within 2 weeks
of onset hasten recovery with similar rates of adverse effects but
IVIg treatment is significantly more likely to be completed than
plasma exchange. Overall, 80% of patients recover completely
within 3-6 months, 4% die and the remainder suffer residual
neurological disability, which can be severe. Adverse prognostic
features include older age, rapid deterioration to ventilation and
evidence of axonal loss on EMG. Supportive measures to prevent
pressure sores and deep venous thrombosis are essential.
Regular monitoring of respiratory function (vital capacity) is
needed in the acute phase, as respiratory failure may develop
with little warning.
Chronic polyneuropathy
The most common axonal and demyelinating causes of
polyneuropathy are shown in Box 25.85. A chronic symmetrical
axonal polyneuropathy, evolving over months or years, is the
most common form of chronic neuropathy. Diabetes mellitus
is the most common cause but in about 25-50% no cause
can be found.
Hereditary neuropathy
Charcot-Marie-Tooth disease (CMT) is an umbrella term for
the inherited neuropathies. The members of this group of
syndromes have different clinical and genetic features. The
most common CMT is the autosomal dominantly inherited
CMT type 1 , usually caused by a mutation in the PMP-22
gene. Common signs are distal wasting (‘inverted champagne
bottle’ legs), often with pes cavus, and predominantly
motor involvement. X-linked and recessively inherited forms
of CMT, causing demyelinating or axonal neuropathies,
also occur.
25.88 Causes of multifocal mononeuropathy
Axonal (defined on nerve conduction studies)
• Vasculitis (systemic or non-systemic)
• Diabetes mellitus
• Sarcoidosis
• Infection (HIV, hepatitis C, Lyme disease, leprosy, diphtheria)
Focal demyelination with/without conduction block
• Multifocal motor neuropathy
• Multiple compression neuropathies (usually in association with
underlying disease, such as diabetes or alcoholism)
• Multifocal acquired demyelinating sensory and motor neuropathy
(MADSAM)
• Hereditary neuropathy with a predisposition to pressure palsy
(autosomal dominant, peripheral myelin protein 22 gene)
• Lymphoma
Diseases of the neuromuscular junction • 1141
|j;hronic demyelinating polyneuropathy
The acquired chronic demyelinating neuropathies include chronic
inflammatory demyelinating peripheral neuropathy (CIDP),
multifocal motor neuropathy (see above) and paraprotein-
associated demyelinating neuropathy. CIDP typically presents
with relapsing or progressive motor and sensory changes,
evolving over more than 8 weeks (in distinction to the more
acute GBS). It is important to recognise, as it usually responds to
glucocorticoids, plasma exchange or intravenous immunoglobulin.
Some 1 0% of patients with acquired demyelinating polyneu¬
ropathy have an abnormal serum paraprotein, sometimes
associated with a lymphoprol iterative malignancy. They may also
demonstrate positive antibodies to myelin-associated glycoprotein
(anti-MAG antibodies).
Brachial plexopathy
Trauma usually damages either the upper or the lower parts
of the brachial plexus, according to the mechanics of the
injury. The clinical features depend on the anatomical site
of the damage (Box 25.89). Lower parts of the brachial
plexus are vulnerable to infiltration from breast or apical lung
tumours (Pancoast tumour, p. 600) or damage by therapeutic
irradiation. The lower plexus may also be compressed by a
cervical rib or fibrous band between C7 and the first rib at the
thoracic outlet.
Neuralgic amyotrophy (also known as brachial neuritis) presents
as an acute brachial plexopathy of probable inflammatory origin.
Severe shoulder pain precedes the appearance of a patchy upper
brachial plexus lesion, with motor and/or sensory involvement.
There is no specific treatment and recovery is often incomplete; it
may recur in about 25% and there is a rare autosomal dominant
hereditary form. The appearance of vesicles should indicate the
alternative diagnosis of motor zoster.
25.89 Physical signs in brachial plexus lesions
Site
Affected muscles
Sensory loss
Upper plexus
(Erb-Duchenne)
Biceps, deltoid, spinati,
rhomboids, brachioradialis
(triceps, serratus anterior)
Patch over deltoid
Lower plexus
(Dejerine— Klumpke)
All small hand muscles,
claw hand (ulnar wrist
flexors)
Ulnar border of
hand/forearm
Thoracic outlet
syndrome
Small hand muscles,
ulnar forearm
Ulnar border of
hand/forearm/
upper arm
Lumbosacral plexopathy
Lumbosacral plexus lesions may be caused by neoplastic
infiltration or compression by retroperitoneal haematomas.
A small-vessel vasculopathy can produce a unilateral or
bilateral lumbar plexopathy in association with diabetes
mellitus (‘diabetic amyotrophy’) or an idiopathic form in non¬
diabetic patients. This presents with painful wasting of the
quadriceps with weakness of knee extension and an absent
knee reflex.
Spinal root lesions
Spinal root lesions (radiculopathy) are described above. Clinical
features include muscle weakness and wasting and dermatomal
sensory and reflex loss, which reflect the pattern of the roots
involved. Pain in the muscles innervated by the affected roots
may be prominent.
Diseases of the
neuromuscular junction
Myasthenia gravis
This is the most common cause of acutely evolving, fatigable
weakness and preferentially affects ocular, facial and bulbar
muscles.
Pathophysiology
Myasthenia gravis is an autoimmune disease, most commonly
(80% of cases) caused by antibodies to acetylcholine receptors
in the post-junctional membrane of the neuromuscular junction.
The resultant blockage of neuromuscular transmission and
complement-mediated inflammatory response reduces the
number of acetylcholine receptors and damages the end plate
(Fig. 25.52). Other antibodies can produce a similar clinical
picture, most notably autoantibodies to muscle-specific kinase
(MuSK), which is involved in the regulation and maintenance of
acetylcholine receptors.
About 1 5% of patients (mainly those with late onset) have
a thymoma, most of the remainder displaying thymic follicular
hyperplasia. Myasthenic patients are more likely to have associated
organ-specific autoimmune diseases. Triggers are not always
evident but some drugs (e.g. penicillamine) can precipitate an
antibody-mediated myasthenic syndrome that may persist after
drug withdrawal. Other drugs, especially aminoglycosides and
quinolones, may exacerbate the neuromuscular blockade and
should be avoided in patients with myasthenia.
Clinical features
Myasthenia gravis usually presents between the ages of 15
and 50 years and there is a female preponderance in younger
patients. In older patients, males are more commonly affected.
It tends to run a relapsing and remitting course.
The most evident symptom is fatigable muscle weakness;
movement is initially strong but rapidly weakens as muscle use
continues. Worsening of symptoms towards the end of the day
or following exercise is characteristic. There are no sensory signs
or signs of involvement of the CNS, although weakness of the
oculomotor muscles may mimic a central eye movement disorder.
The first symptoms are usually intermittent ptosis or diplopia but
weakness of chewing, swallowing, speaking or limb movement
also occurs. Resting of the eyelids (looking downwards) may be
followed by increased reflex elevation with up-gaze (so-called
Cogan’s lid twitch sign). Any limb muscle may be affected, most
commonly those of the shoulder girdle; the patient is unable to
undertake tasks above shoulder level, such as combing the hair,
without frequent rests. Respiratory muscles may be involved and
respiratory failure is an avoidable cause of death. Aspiration may
occur if the cough is ineffectual. Ventilatory support is required
where weakness is severe or of abrupt onset.
1142 • NEUROLOGY
membrane potential change
Fig. 25.52 Myasthenia gravis and Lambert-Eaton myasthenic syndrome (LEMS). In myasthenia there are antibodies to the acetylcholine receptors
on the post-synaptic membrane, which block conduction across the neuromuscular junction (NMJ). Myasthenic symptoms can be transiently improved by
inhibition of acetylcholinesterase (e.g. with Tensilon - edrophonium bromide), which normally removes the acetylcholine. A cell-mediated immune response
produces simplification of the post-synaptic membrane, further impairing the ‘safety factor’ of neuromuscular conduction. In LEMS, antibodies to the
pre-synaptic voltage calcium channels impair release of acetylcholine from the motor nerve ending; calcium is required for the acetylcholine-containing
vesicle to fuse with the pre-synaptic membrane for release into the NMJ.
Investigations
Intravenous injection of the short-acting anticholinesterase
edrophonium bromide (the Tensilon test) is less widely used
than before. Improvement in muscle function occurs within
30 seconds and usually persists for 2-3 minutes but the test is
not entirely specific or sensitive. Cover with intravenous atropine is
necessary to avoid bradycardia. Planning assessment beforehand
(e.g. speech or limb movements) allows some objectivity in
gauging the effect.
Repetitive stimulation during nerve conduction studies may
show a characteristic decremental response (p. 1076) if the
muscle has been clinically affected. Anti-MuSK antibodies are
more common in acetylcholine receptor antibody-negative patients
with prominent bulbar involvement. All patients should have
a thoracic CT to exclude thymoma, especially those without
anti-acetylcholine receptor antibodies. Screening for associated
autoimmune disorders, particularly thyroid disease, is important.
Management
The goals of treatment are to maximise the activity of acetylcholine
at remaining receptors in the neuromuscular junctions and to
limit or abolish the immunological attack on motor end plates.
The duration of action of acetylcholine is prolonged by inhibiting
acetylcholinesterase. The most commonly used anticholinesterase
drug is pyridostigmine. Muscarinic side-effects, including diarrhoea
and colic, may be controlled by propantheline. Overdosage
of anticholinesterase drugs may cause a ‘cholinergic crisis’
due to depolarisation block of motor end plates, with muscle
25.90 Immunological treatment of myasthenia
Acute treatments
Intravenous immunoglobulin
• Lowers production of antibodies and rapidly reduces
weakness
Plasma exchange
• Removing antibody from the blood may produce marked
improvement; this is usually brief, so is normally reserved for
myasthenic crisis or for pre-operative preparation
Long-term treatments
Glucocorticoid treatment
• Improvement is commonly preceded by marked exacerbation
of myasthenic symptoms, so treatment should be initiated in
hospital
• Usually necessary to continue treatment for months or years, risking
adverse effects
Pharmacological immunosuppression treatment
• Azathioprine 2.5 mg/kg daily reduces the necessary dosage of
glucocorticoids and may allow their withdrawal. Effect on clinical
features may be delayed for months
• Mycophenolate mofetil: less commonly used
Thymectomy
• Should be considered in any antibody-positive patient under
45 years with symptoms not confined to extraocular muscles,
unless the disease has been established for more than
7 years
• Likely to be required for thymoma
Diseases of muscle • 1143
fasciculation, paralysis, pallor, sweating, excessive salivation and
small pupils. This may be distinguished from severe weakness
due to exacerbation of myasthenia (‘myasthenic crisis’) by the
clinical features and, if necessary, by the injection of a small
dose of edrophonium.
Immunological treatment of myasthenia is outlined in Box
25.90. Thymectomy may improve overall prognosis but awaits
clinical trial confirmation. Prognosis is variable and remissions
may occur spontaneously. When myasthenia is entirely ocular,
prognosis is excellent and disability slight. Young female patients
with generalised disease may benefit from thymectomy, while
older patients are less likely to have a remission despite treatment.
Rapid progression of the disease more than 5 years after onset
is uncommon.
Lambert-Eaton myasthenic syndrome
Other rarer conditions can present with muscle weakness due
to impaired transmission across the neuromuscular junction.
The most common of these is the Lambert-Eaton myasthenic
syndrome (LEMS), which can occur as an inflammatory or
paraneoplastic phenomenon. Antibodies to pre-synaptic voltage¬
gated calcium channels (see Fig. 25.52) impair transmitter release.
Patients may have autonomic dysfunction (e.g. dry mouth)
in addition to muscle weakness but the cardinal clinical sign
is absence of tendon reflexes, which return after sustained
contraction of the relevant muscle. The condition is associated
with underlying malignancy in a high percentage of cases and
investigation must be directed towards identifying any neoplasm.
Diagnosis is made electrophysiologically on the presence of
post-tetanic potentiation of motor response to nerve stimulation at
a frequency of 20-50/sec. Treatment is with 3,4-diaminopyridine,
or pyridostigmine and immunosuppression.
Diseases of muscle
Muscle disease, either hereditary or acquired, is rare. Most
typically, it presents with a proximal symmetrical weakness.
Diagnosis is dependent on recognition of clinical clues, such as
cardiorespiratory involvement, evolution, family history, exposure to
drugs, the presence of contractures, myotonia and other systemic
features, and on investigation findings, most importantly EMG
and muscle biopsy. Hereditary syndromes include the muscular
dystrophies, muscle channelopathies, metabolic myopathies
(including mitochondrial diseases) and congenital myopathies.
Muscular dystrophies
These are inherited disorders with progressive muscle destruction
and may be associated with cardiac and/or respiratory involvement
and sometimes non-myopathic features (Box 25.91). Myotonic
dystrophy is the most common, with a prevalence of about
12/100000.
Clinical features
The pattern of the clinical features is defined by the specific
syndromes. Onset is often in childhood, although some patients,
especially those with myotonic dystrophy, may present as
adults. Wasting and weakness are usually symmetrical, without
fasciculation or sensory loss, and tendon reflexes are usually
preserved until a late stage. Weakness is usually proximal, except
in myotonic dystrophy type 1 , when it is distal.
Investigations
The diagnosis can be confirmed by specific molecular genetic
testing, supplemented with EMG and muscle biopsy if necessary.
Creatine kinase is markedly elevated in the dystrophinopathies
25.91 The muscular dystrophies
Type
Genetics
Age of onset
Muscles affected
Other features
Myotonic dystrophy
(DM1)
Autosomal dominant; expanded
triplet repeat chromosome 1 9q
Any
Face (including ptosis),
sternomastoids, distal limb,
generalised later
Myotonia, cognitive impairment,
cardiac conduction abnormalities,
lens opacities, frontal balding,
hypogonadism
Proximal myotonic
myopathy (PR0MM;
DM2)
Autosomal dominant; quadruplet
repeat expansion in Zn finger
protein 9 gene chromosome 3q
8-50 years
Proximal, especially thigh,
sometimes muscle
hypertrophy
As for DM1 but cognition not
affected
Muscle pain
Duchenne
X-linked; deletions in dystrophin
gene Xp21
<5 years
Proximal and limb girdle
Cardiomyopathy and respiratory
failure
Becker
X-linked; deletions in dystrophin
gene Xp21
Childhood/early
adulthood
Proximal and limb girdle
Cardiomyopathy common but
respiratory failure uncommon
Limb girdle
Many mutations on different
chromosomes
Childhood/early
adulthood
Limb girdle
Very variable depending on
genetic subtype, some involve
cardiac and respiratory systems
Facioscapulohumeral
(FSH)
Autosomal dominant; tandem
repeat deletion chromosome 4q35
7-30 years
Face and upper limb girdle,
distal lower limb weakness
Pain in shoulder girdle common,
deafness
Cardiorespiratory involvement rare
Oculopharyngeal
Autosomal dominant and
recessive; triplet repeat expansion
in PABP2 gene chromosome 14q
30-60 years
Ptosis, external
ophthalmoplegia, dysphagia,
tongue weakness
Mild lower limb weakness
Emery-Dreifuss
X-linked recessive; mutations in
emerin gene
4-5 years
Humero-peroneal, proximal
limb girdle later
Contractures develop early
Cardiac involvement leads to
sudden death
1144 • NEUROLOGY
(Duchenne and Becker) but is normal or moderately elevated
in the other dystrophies. Screening for an associated cardiac
abnormality (cardiomyopathy or dysrhythmia) is important.
Management
There is no specific therapy for most of these conditions but
physiotherapy and occupational therapy help patients cope
with their disability. Glucocorticoids can be used in Duchenne
muscular dystrophy but side-effects should be anticipated and
avoided by dose modification. Ataluren is a compound given by
infusion to affected individuals that may ‘override’ the stop sign in
Duchenne, theoretically leading to normalisation of muscle proteins
and potentially reducing or arresting functional deteriorations.
Treatment of associated cardiac failure or arrhythmia (with
pacemaker insertion if necessary) may be required; similarly,
management of respiratory complications (including nocturnal
hypoventilation) can improve quality of life. Improvements in
non-invasive ventilation have led to significant improvements in
survival for patients with Duchenne muscular dystrophy. Genetic
counselling is important.
Inherited metabolic myopathies
There are a large number of rare inherited disorders that interfere
with the biochemical pathways that maintain the energy supply
(adenosine triphosphate, ATP) to muscles. These are mostly
recessively inherited deficiencies in the enzymes necessary for
glycogen or fatty acid ((3-oxidation) metabolism (Box 25.92). They
typically present with muscle weakness and pain.
|Mitochondrial disorders
Mitochondrial diseases are discussed on page 49. Mitochondria
are present in all tissues and dysfunction causes widespread
effects on vision (optic atrophy, retinitis pigmentosa, cataracts),
hearing (sensorineural deafness) and the endocrine, cardiovascular,
gastrointestinal and renal systems. Any combination of these
should raise the suspicion of a mitochondrial disorder, especially
if there is evidence of maternal transmission.
25.92 Inherited disorders of muscle metabolism
Disease Clinical features Diagnosis
Carbohydrate (glycogen) metabolism
Myophosphorylase
Exercise-induced
Creatine kinase
deficiency
myalgia, stiffness,
(CK) elevated
(McArdle’s disease):
weakness (with ‘second
Muscle biopsy
autosomal recessive
wind’ phenomenon),
myoglobinuria
Enzyme assay
Acid maltase
Infantile form: death
CK elevated
deficiency (Pompe’s
within 2 years
Blood lymphocyte
disease): autosomal
Childhood: death in
analysis for
recessive
twenties or thirties
glycogen granules
Adult: progressive
Muscle biopsy
proximal myopathy with
respiratory failure
Enzyme assay
Lipid metabolism (|3-oxidation)
Carnitine-palmitoyl
Myalgia after exercise,
CK normal
transferase (CPT)
myoglobinuria,
between attacks
deficiency
weakness
Urinary organic
acids
Enzyme assays
Muscle biopsy
25.93 Mitochondrial syndromes
Syndrome
Clinical features
Myoclonic epilepsy with
ragged red fibres
(MERRF)
Myoclonic epilepsy, cerebellar ataxia,
dementia, sensorineural deafness ±
peripheral neuropathy, optic atrophy
and multiple lipomas
Mitochondrial myopathy,
encephalopathy, lactic
acidosis and stroke-like
episodes (MELAS)
Episodic encephalopathy, stroke-like
episodes often preceded by
migraine-like headache, nausea and
vomiting
Chronic progressive
external ophthalmoplegia
(CPEO)
Progressive ptosis and external
oculomotor palsy, proximal myopathy ±
deafness, ataxia and cardiac
conduction defects
Kearns-Sayre syndrome
Like CPEO but early age of onset
(<20 years), heart block, pigmentary
retinopathy
Mitochondrial
neurogastrointestinal
encephalomyopathy
(MNGIE)
Progressive ptosis, external oculomotor
palsy, gastrointestinal dysmotility (often
pseudo-obstruction), diffuse
leucoencephalopathy, thin body habitus,
peripheral neuropathy and myopathy
Neuropathy, ataxia and
retinitis pigmentosa
(NARP)
Weakness, ataxia and progressive loss
of vision, along with dementia, seizures
and proximal weakness
Mitochondrial dysfunction can be caused by alterations in either
mitochondrial DNA or genes encoding for oxidative processes.
Genetic abnormalities or mutations in mitochondrial DNA may
affect single individuals and single tissues (most commonly
muscle). Thus, patients with exercise intolerance, myalgia and
sometimes recurrent myoglobinuria may have isolated pathogenic
mutations in genes encoding for oxidation pathways.
Inherited disorders of the oxidative pathways of the respiratory
chain in mitochondria cause a group of disorders, either restricted
to the muscle or associated with non-myopathic features (Box
25.93). Many of these mitochondrial disorders are inherited
via the mitochondrial genome, down the maternal line (p. 49).
Diagnosis is based on clinical appearances, supported by muscle
biopsy appearance (usually with ‘ragged red’ and/or cytochrome
oxidase-negative fibres), and specific mutations either on blood
or, more reliably, muscle testing. Mutations may be due either to
point mutations or to deletions of mitochondrial DNA.
A disorder called Leber hereditary optic neuropathy (LHON) is
characterised by acute or subacute loss of vision, most frequently
in males, due to bilateral optic atrophy. Three point mutations
account for more than 90% of LHON cases.
Channelopathies
Inherited abnormalities of the sodium, calcium and chloride
ion channels in striated muscle produce various syndromes of
familial periodic paralysis, myotonia and malignant hyperthermia,
which may be recognised by their clinical characteristics and
potassium abnormalities (Box 25.94). Genetic testing is available.
Acquired myopathies
These include the inflammatory myopathies, or myopathy
associated with a range of metabolic and endocrine disorders
or drug and toxin exposure (Fig. 25.53).
Diseases of muscle • 1145
25.94 Muscle channelopathies
Channel
Muscle disease
Gene and inheritance
Clinical features
Sodium
Paramyotonia congenita
SCN4A (1 7q35)
Autosomal dominant
Cold-evoked myotonia with episodic weakness provoked by
exercise and cold
Potassium-aggravated
myotonia
SCN4A
Pure myotonia without weakness provoked by potassium
Hyperkalaemic periodic
paralysis
SCN4A
Autosomal dominant
Brief (mins to hours), frequent episodes of weakness provoked
by rest, cold, potassium, fasting, pregnancy, stress
Less common than hypokalaemic periodic paralysis
Hypokalaemic periodic
paralysis
SCN4A
Autosomal dominant
(one-third new mutations)
Longer (hours to days) episodic weakness triggered by rest,
carbohydrate loading, cold
Chloride
Myotonia congenita:
Thomsen’s disease
Becker’s disease
CLCN1
Autosomal dominant
CLCN1
Autosomal recessive
Myotonia usually mild, little weakness
Myotonia often severe, transient weakness
Calcium
Hypokalaemic periodic
paralysis
CACNA1S
Autosomal dominant
Episodic weakness triggered by carbohydrate meal
Malignant hyperthermia
CACNA1S, CACNL2A
Autosomal dominant
Hyperpyrexia due to excess muscle activity, precipitated by
drugs, usually anaesthetic agents; most common cause of
death during general anaesthetic
Potassium
Andersen-Tawil syndrome
KCNJ2
Autosomal dominant
Similar to hypokalaemic periodic paralysis, associated with
cardiac and non-myopathic features (skeletal and facial)
Ryanodine receptor
Malignant hyperthermia
RYR1 (1 9q1 3)
As malignant hyperthermia above
Central core and multicore
disease
RYR1
Mostly autosomal dominant
Present in infancy with mild progressive weakness
Inflammatory
Endocrine/metabolic
• Polymyositis • Hypothyroidism • Hypokalaemia (liquorice, diuretic and purgative abuse)
• Dermatomyositis • Hyperthyroidism • Hypercalcaemia (disseminated bony metastases)
• Alcohol (chronic and acute syndromes)
• Amphetamines/cocaine/heroin
• Vitamin E
• Organophosphates
• Snake venoms
• Glucocorticoids
• Statins
• Amiodarone
• p-blockers
• Opiates
• Chloroquine
• Ciclosporin
• Vincristine
• Clofibrate
• Zidovudine
• Carcinomatous neuromyopathy
• Dermatomyositis
Fig. 25.53 Causes of acquired proximal myopathy.
1146 • NEUROLOGY
Further information
Journal articles
Scolding N, Barnes D, Cader S, et al. Association of British
Neurologists: revised (201 5) guidelines for prescribing disease¬
modifying treatments in multiple sclerosis. Pract Neurol 2015;
0:1-7.
Websites
aneuroa.org/ American Neurological Association.
brainandspine.org.uk and dizziness-and-baiance.com/disorders
Diagnosing benign paroxysmal positional vertigo.
epilepsydiagnosis.org International League Against Epilepsy: free
access to videos of different seizure types and clinical summaries of
the epilepsies.
headinjurysymptoms.org Symptoms and management of mild and
moderate head injury.
ihs-classification.org/en/ International Headache Society: full access to
3rd edition of International Classification of Headache Disorders.
neurosymptoms.org Advice on managing functional neurological
symptoms.
ninds.nih.gov National Institute of Neurological Disorders and Stroke.
sign.ac.uk Scottish Intercollegiate Guidelines network: SIGN 107
Diagnosis and management of headache in adults; SIGN 1 10 Early
management of patients with a head injury; SIGN 1 13 Diagnosis
and pharmacological management of Parkinson’s disease; SIGN
143 Diagnosis and management of epilepsy in adults.
wfneurology.org World Federation of Neurology.
Stroke medicine
Clinical examination in stroke disease 1148
Stroke 1153
Functional anatomy and physiology 1150
Investigations 1151
Presenting problems 152
Weakness 1 1 52
Speech disturbance 1 1 52
Visual deficit 1 1 52
Visuo-spatial dysfunction 1 1 52
Ataxia 1 1 53
Pathophysiology 1 1 53
Clinical features 1 1 55
Investigations 1 1 57
Management 1 1 58
Subarachnoid haemorrhage 1160
Clinical features 1 1 61
Investigations 1 1 61
Management 1 1 62
Headache 1 1 53
Cerebral venous disease 1162
Seizure 1 1 53
Clinical features 1 1 62
Coma 1 1 53
Investigations and management 1 1 62
1148 • STROKE MEDICINE
Clinical examination in stroke disease
5 Cranial nerve function
Neck stiffness/pain
Visual fields
Nerve palsy, e.g. 3rd, 6th,
7th or 12th _
A Visual field defect
4 Higher cerebral function
Speech and language
Attention and neglect
Abbreviated mental test
3 Blood pressure and cardiac
auscultation
A Mitral stenosis
2 Pulse
Rate and rhythm
AAtrial fibrillation
1 General appearance
Conscious level
Posture: leaning to one side?
Facial symmetry
A Left facial (7th nerve) palsy
6 Motor system
Muscle bulk
Abnormal posture or movements
Tone
Strength, including pronator drift
Co-ordination
Tendon reflexes
Plantar reflexes
7 Sensory system
Touch sensation
Cortical sensory function:
sensory inattention or neglect
Joint position sense
A Extensor plantar reflex
8 Gait
Able to weight-bear?
Ataxic
Hemiparetic gait pattern
£ 'N
*
A Hemiparetic posture
Clinical examination in stroke disease • 1149
General examination
Skin
• Xanthelasma
• Rash (arteritis, splinter haemorrhages)
• Colour change (limb ischaemia, deep vein
thrombosis)
• Pressure injury
Eyes
• Arcus senilis
• Diabetic retinopathy
• Hypertensive retinopathy
• Retinal emboli
Cardiovascular system
• Heart rhythm (?atrial fibrillation)
• Blood pressure (high or low)
• Carotid bruit
• Jugular venous pulse (raised in heart
failure, low in hypovolaemia)
• Murmurs (source of embolism)
• Peripheral pulses and bruits (?generalised
arteriopathy)
Respiratory system
• Signs of pulmonary oedema or infection
• Oxygen saturation
Abdomen
• Palpable bladder (urinary retention)
Locomotor system
• Injuries sustained during collapse
• Comorbidities that influence recovery, e.g.
osteoarthritis
Rapid assessment of suspected stroke
Rosier scale
Can be used by emergency staff to indicate probability of a stroke in acute presentations:
Unilateral facial weakness
+1
Loss of consciousness
-1
Unilateral grip weakness
+1
Seizure
-1
Unilateral arm weakness
+1
Unilateral leg weakness
+1
Speech loss
+1
Visual field defect
+1
Total (-2 to +6); score of >0 indicates stroke is possible cause
Exclusion of hypoglycaemia
• Bedside blood glucose testing with BMstix
Language deficit
• History and examination may indicate a language deficit
• Check comprehension (‘lift your arms, close your eyes’) to identify a receptive dysphasia
• Ask patient to name people/objects (e.g. nurse, watch, pen) to identify a nominal dysphasia
• Check articulation (ask patient to repeat phrases after you) for dysarthria
Motor deficit
Subtle pyramidal signs:
• Check for pronator drift: ask patient to hold out arms and maintain their position with eyes
closed (see opposite)
• Check for clumsiness of fine finger movements
Sensory and visual inattention
• Establish that sensation/visual field is intact on testing one side at a time
• Retest sensation/visual fields on simultaneous testing of both sides; the affected side will no
longer be felt/seen
• Perform clock drawing test (see below)
Truncal ataxia
• Check if patient can sit up or stand without support
Clock drawing test [A] An image drawn by a
doctor. [§] An image drawn by a patient with
left-sided neglect.
1150 • STROKE MEDICINE
Cerebrovascular disease is the third most common cause of
death in high-income countries after cancers and ischaemic
heart disease, and the most common cause of severe physical
disability. It includes a range of disorders of the central
nervous system (Fig. 26.1). Stroke is the most common
clinical manifestation of cerebrovascular disease and results
in episodes of brain dysfunction due to focal ischaemia or
haemorrhage. Subarachnoid haemorrhage (SAH) and cerebral
venous thrombosis (CVT) will be discussed separately, since
their pathophysiology, clinical manifestations and management
are distinct from those of stroke. Vascular dementia is described
on page 1191.
Functional anatomy and physiology
The main arterial supply of the brain comes from the internal
carotid arteries, which supply the anterior brain through the
anterior and middle cerebral arteries, and the vertebral and basilar
arteries (vertebrobasilar system), which provide the posterior
circulation to the posterior cerebral arteries. The anterior and
middle cerebral arteries supply the frontal and parietal lobes,
while the posterior cerebral artery supplies the occipital lobe. The
vertebral and basilar arteries perfuse the brainstem, mid-brain
and cerebellum (Fig. 26.2). The functions of each of these
Vascular system
Pathology
Site of lesion
Clinical
classification
r
Arterial
Stroke
(acute, focal brain dysfunction due to vascular disease)
1
Venous
(>99%)
Infarct
(85%)
Anterior (carotid) circulation
(65%)
Total anterior
circulation
stroke (TACS)
(15%)
Partial anterior
circulation
stroke (PACS)
(30%)
“I
Lacunar stroke
(LACS)
(20%)
- 1
Posterior
(vertebrobasilar
circulation)
(20%)
Posterior
circulation
stroke (POCS)
(20%)
— I
Flaemorrhage
(15%)
i
Brain Subarachnoid
parenchyma space
(10%) (5%)
Intracerebral Subarachnoid
haemorrhage haemorrhage
(10%) (5%)
(<1%)
Infarct
(often develops
secondary
haemorrhage)
I
Venous
system
Central venous
thrombosis
(<1%)
Common
pathophysiology
• Embolism • Thrombosis
(cardiac, major vessels) in situ
• Thrombosis in situ
• Thrombosis
• Embolism
(cardiac)
Fig. 26.1 A classification of stroke disease.
• Vascular
degeneration
• Aneurysm
• Arteriovenous
malformation
• Aneurysm
• Arteriovenous
malformation
• Vascular
degeneration
• Thrombosis
in situ
Anterior
communicating
artery (ACoA)
Internal carotid
arteries (ICA)
Basilar artery (BA)
0
Vertebral
arteries (VA)
Anterior cerebral
artery (ACA)
Middle cerebral
artery (MCA)
Posterior
communicating
artery (PCoA)
Posterior cerebral
artery (PCA)
Anterior (carotid)
circulation
Fig. 26.2 Arterial circulation of the brain. [A] Horizontal view. ]§ Lateral view.
Investigations • 1151
areas of the brain are described on page 1064. Communicating
arteries provide connections between the anterior and posterior
circulations and between left and right hemispheres, creating
protective anastomotic connections that form the circle of Willis.
In health, regulatory mechanisms maintain a constant cerebral
blood flow across a wide range of arterial blood pressures to
meet the high resting metabolic activity of brain tissue; cerebral
blood vessels dilate when systemic blood pressure is lowered
and constrict when it is raised. This autoregulatory mechanism
can be disrupted after stroke. The venous collecting system is
formed by a collection of sinuses over the surface of the brain,
which drain into the jugular veins (Fig. 26.3).
Investigations
A range of investigations may be required to answer specific
questions about brain structure and function and about the
function of the vascular system.
Fig. 26.3 Venous circulation of the brain.
Neuroimaging
Computed tomography (CT) scanning is the mainstay of
emergency stroke imaging. It allows the rapid identification
of intracerebral bleeding and stroke ‘mimics’ (i.e. pathologies
other than stroke that have similar presentations), such as
tumours. Magnetic resonance imaging (MRI) is used when there
is diagnostic uncertainty or delayed presentation, and when
more information on brain structure and function is required
(Fig. 26.4). Contraindications to MRI include cardiac pacemakers
and claustrophobia on entering the scanner. CT angiography
(CTA) and CT perfusion are now being used to characterise
the cerebral circulation and areas of ischaemia better (p. 1072).
Vascular imaging
Various techniques are used to obtain images of extracranial
and intracranial blood vessels (Fig. 26.5). The least invasive is
ultrasound (Doppler or duplex scanning), which is used to image
the carotid and the vertebral arteries in the neck. In skilled hands,
reliable information can be provided about the degree of arterial
stenosis and the presence of ulcerated plaques. Blood flow in the
intracerebral vessels can be examined using transcranial Doppler.
While the anatomical resolution is limited, it is improving and many
centres no longer require formal angiography before proceeding
to carotid endarterectomy (see below). Blood flow can also be
detected by specialised sequences in MR angiography (MRA)
or CTA but the anatomical resolution is still not as good as that
of intra-arterial angiography, which outlines blood vessels by the
injection of radio-opaque contrast intravenously or intra-arterially.
The X-ray images obtained can be enhanced by the use of
computer-assisted digital subtraction or spiral CT. Because
of the significant risk of complications, intra-arterial contrast
angiography is reserved for use when non-invasive methods
have provided a contradictory picture or incomplete information,
or when it is necessary to image the intracranial circulation in
detail, e.g. to delineate a saccular aneurysm, an arteriovenous
malformation or vasculitis.
Blood tests
These identify underlying causes of cerebrovascular disease, e.g.
blood glucose (diabetes mellitus), triglycerides and cholesterol
(hyperlipidaemia) or full blood count (polycythaemia). Erythrocyte
0
26
Fig. 26.4 Acute stroke seen on
computed tomography (CT) scan with
corresponding magnetic resonance
imaging (MRI) appearance. [A] CT may
show no evidence of early infarction. J] A
corresponding image seen on MRI diffusion
weighted imaging (DWI) with changes of
infarction in the middle cerebral artery (MCA)
territory (arrows). A and B, Courtesy of Dr A.
Farrell and Prof. J. Ward law.
1152 • STROKE MEDICINE
Fig. 26.5 Different techniques for imaging blood vessels. [A] Doppler scan showing 80% stenosis of the internal carotid artery (arrow).
[§] Three-dimensional reconstruction of CT angiogram showing stenosis at the carotid bifurcation (arrow). [C] MR angiogram showing giant aneurysm at
the middle cerebral artery bifurcation (arrow). [6] Intra-arterial angiography showing arteriovenous malformation (arrow). A-D, Courtesy of Dr D. Collie.
sedimentation rate (ESR) and immunological tests, such as
antineutrophil cytoplasmic antibodies (ANCAs, p. 992), may
be required when vasculitis is suspected. Genetic testing
for rarer inherited conditions, such as CADASIL (cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leucoencephalopathy), may be indicated.
Lumbar puncture
Lumbar puncture (p. 1077) is reserved for investigation of SAH.
| Cardiovascular investigations
Electrocardiography (ECG; p. 448), including ECG monitoring
and echocardiography (p. 451), may reveal abnormalities that
may cause cardiac embolism in stroke.
Presenting problems
Most vascular lesions develop suddenly within a matter of minutes
or hours, and so should be considered in the differential diagnosis
of patients with any acute neurological presentation.
Weakness
Unilateral weakness is the classical presentation of stroke and,
much more rarely, of CVT. The weakness is sudden, progresses
rapidly and follows a hemiplegic pattern (see Fig. 25.17, p. 1082).
There is rarely any associated abnormal movement. Reflexes
are initially reduced but then become increased with a spastic
pattern of increased tone (see Box 25.14, p. 1082). Upper motor
neuron weakness of the face (7th cranial nerve) is often present.
Speech disturbance
Dysphasia and dysarthria are the most common presentations of
disturbed speech in stroke (p. 1087). Dysphasia indicates damage
to the dominant frontal or parietal lobe (see Box 25.2, p. 1066),
while dysarthria is a non-localising feature that reflects weakness
or incoordination of the face, pharynx, lips, tongue or palate.
Visual deficit
Visual loss can be due to unilateral optic ischaemia (called
amaurosis fugax if transient), caused by disturbance of blood
flow in the internal carotid artery and ophthalmic artery, leading
to monocular blindness. Ischaemia of the occipital cortex or
post-chiasmic nerve tracts results in a contralateral hemianopia
(p. 1088).
Visuo-spatial dysfunction
Damage to the non-dominant cortex often results in contralateral
visuo-spatial dysfunction, e.g. sensory or visual neglect and
apraxia (inability to perform complex tasks despite normal
motor, sensory and cerebellar function; p. 1086), sometimes
misdiagnosed as delirium.
Stroke • 1153
Ataxia
Stroke causing damage to the cerebellum and its connections can
present as an acute ataxia (p. 1 086) and there may be associated
brainstem features such as diplopia (p. 1 088) and vertigo (p. 1 086).
The differential diagnosis includes vestibular disorders (p. 1 1 04).
Headache
Sudden severe headache is the cardinal symptom of SAH but
also occurs in intracerebral haemorrhage. Although headache is
common in acute ischaemic stroke, it is rarely a dominant feature
(p. 1080). Headache also occurs in cerebral venous disease.
Seizure
Seizure is unusual in acute stroke but may be generalised or
focal (especially in cerebral venous disease).
Coma
Coma is uncommon, though it may occur with a brainstem event.
If present in the first 24 hours, it usually indicates a subarachnoid
or intracerebral haemorrhage (see Box 10.26, p. 194).
Stroke
Stroke is a common medical emergency. The incidence rises
steeply with age, and in many lower- and middle-income countries
it is rising in association with less healthy lifestyles. About 20%
of stroke patients die within a month of the event and at least
half of those who survive are left with physical disability.
Pathophysiology
Of the 180-300 patients per 100 000 population presenting
annually with a stroke, 85% sustain a cerebral infarction due
to inadequate blood flow to part of the brain, and most of the
remainder have an intracerebral haemorrhage (see Fig. 26.1).
Ijterebral infarction
Cerebral infarction is mostly caused by thromboembolic disease
secondary to atherosclerosis in the major extracranial arteries
(carotid artery and aortic arch). About 20% of infarctions are
due to embolism from the heart, and a further 20% are due to
thrombosis in situ caused by intrinsic disease of small perforating
vessels (lenticulostriate arteries), producing so-called lacunar
infarctions. The risk factors for ischaemic stroke reflect the risk
factors for the underlying vascular disease (Box 26.1). About 5%
are due to rare causes, including vasculitis (p. 1040), endocarditis
(p. 527) and cerebral venous disease (see below). Cerebral
infarction takes some hours to complete, even though the patient’s
deficit may be maximal shortly after the vascular occlusion. After
the occlusion of a cerebral artery, infarction may be forestalled
by the opening of anastomotic channels from other arterial
territories that restore perfusion to its territory. Similarly, reduction
in perfusion pressure leads to compensatory homeostatic changes
to maintain tissue oxygenation (Fig. 26.6). These compensatory
changes can sometimes prevent occlusion of even a carotid
artery from having any clinically apparent effect.
i
Fixed risk factors
• Age
• Gender (male > female except
at extremes of age)
• Race (Afro-Caribbean > Asian
> European)
• Previous vascular event:
Myocardial infarction
Stroke
Peripheral vascular disease
Modifiable risk factors
• Blood pressure
• Cigarette smoking
• Hyperlipidaemia
• Diabetes mellitus
• Heart disease:
Atrial fibrillation
Congestive cardiac failure
Infective endocarditis
Fig. 26.6 Homeostatic responses to falling perfusion pressure in the
brain following arterial occlusion. Vasodilatation initially maintains
cerebral blood flow (A), but after maximal vasodilatation further falls in
perfusion pressure lead to a decline in blood flow. An increase in tissue
oxygen extraction, however, maintains the cerebral metabolic rate for
oxygen (B). Still further falls in perfusion, and therefore blood flow, cannot
be compensated; cerebral oxygen availability falls and symptoms appear,
then infarction (C).
However, if and when these homeostatic mechanisms fail, the
process of ischaemia starts, and ultimately leads to infarction
unless the vascular supply is restored. As the cerebral blood flow
declines, different neuronal functions fail at various thresholds
(Fig. 26.7). Once blood flow falls below the threshold for the
maintenance of electrical activity, neurological deficit develops.
At this level of blood flow, neurons are still viable; if blood flow
increases again, function returns and the patient will have had a
26.1 Risk factors for stroke
• Heredity
• Sickle cell disease
• High fibrinogen
• Excessive alcohol intake
• Oestrogen-containing drugs:
Oral contraceptive pill
Hormone replacement
therapy
• Polycythaemia
1154 • STROKE MEDICINE
transient ischaemic attack (TIA). However, if blood flow falls further,
a level is reached at which irreversible cell death starts. Hypoxia
leads to an inadequate supply of adenosine triphosphate (ATP),
which leads to failure of membrane pumps, thereby allowing influx
of sodium and water into cells (cytotoxic oedema) and release
Cerebral blood flow
mL/100 g/min
50
40
30
Increased oxygen
extraction
20
10
0
Failure of
electrical function
Symptoms
Failure of ionic pumps
Potassium efflux
Sodium influx
Cell death
Fig. 26.7 Thresholds of cerebral ischaemia. Symptoms of cerebral
ischaemia appear when the blood flow has fallen to less than half of
normal and energy supply is insufficient to sustain neuronal electrical
function. Full recovery can occur if this level of flow is returned to normal
but not if it is sustained. Further blood flow reduction below the next
threshold causes failure of cell ionic pumps and starts the ischaemic
cascade, leading to cell death.
of the excitatory neurotransmitter glutamate into the extracellular
fluid. Glutamate opens membrane channels, allowing influx of
calcium and more sodium into the neurons. Calcium activates
intracellular enzymes that complete the destructive process. The
release of inflammatory mediators by microglia and astrocytes
causes death of all cell types in the area of maximum ischaemia.
The infarction process is worsened by anaerobic production of
lactic acid (Fig. 26.8) and consequent fall in tissue pH. There
have been attempts to develop neuroprotective drugs to slow
down the processes leading to irreversible cell death but so far
these have proved disappointing.
The final outcome of occlusion of a cerebral blood vessel
thus depends on the competence of circulatory homeostatic
mechanisms, the metabolic demand, and the severity and duration
of the reduction in blood flow. Higher brain temperature, e.g.
in fever, and higher blood glucose have both been associated
with a greater volume of infarction for a given reduction in
cerebral blood flow. Subsequent restoration of blood flow may
cause haemorrhage into the infarcted area (‘haemorrhagic
transformation’). This is particularly likely in patients given
antithrombotic or thrombolytic drugs, and in patients with larger
infarcts.
Radiologically, a cerebral infarct can be seen as a lesion
that comprises a mixture of dead brain tissue that is already
undergoing autolysis, and tissue that is ischaemic and swollen
but recoverable (the ‘ischaemic penumbra’). The infarct swells
with time and is at its maximal size a couple of days after stroke
onset. At this stage, it may be big enough to exert mass effect
both clinically and radiologically; sometimes, decompressive
craniectomy is required (see below). After a few weeks, the
oedema subsides and the infarcted area is replaced by a sharply
defined fluid-filled cavity.
|jntracerebral haemorrhage
Intracerebral haemorrhage causes about 10% of acute stroke
events but is more common in low-income countries. It
usually results from rupture of a blood vessel within the brain
parenchyma but may also occur in a patient with SAH (see
Fig. 26.8 The process of neuronal
ischaemia and infarction. (1) Reduction of
blood flow reduces supply of oxygen and hence
adenosine triphosphate (ATP). FT is produced by
anaerobic metabolism of available glucose. (2)
Energy-dependent membrane ionic pumps fail,
leading to cytotoxic oedema and membrane
depolarisation, allowing calcium entry and
releasing glutamate. (3) Calcium enters cells via
glutamate-gated channels and (4) activates
destructive intracellular enzymes (5), destroying
intracellular organelles and cell membrane, with
release of free radicals. Free fatty acid release
activates pro-coagulant pathways that
exacerbate local ischaemia. (6) Glial cells take
up FT, can no longer take up extracellular
glutamate and also suffer cell death, leading to
liquefactive necrosis of whole arterial territory.
(AMPA = a-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor; NMDA =
/V-methyl-D-aspartate; NO = nitric oxide)
Stroke • 1155
below) if the artery ruptures into the brain substance as well as
the subarachnoid space. Haemorrhage frequently occurs into
an area of brain infarction and, if the volume of haemorrhage is
large, it may be difficult to distinguish from primary intracerebral
haemorrhage both clinically and radiologically (Fig. 26.9). The
risk factors and underlying causes of intracerebral haemorrhage
are listed in Box 26.2. Explosive entry of blood into the brain
parenchyma causes immediate cessation of function in that
area as neurons are disrupted and white-matter fibre tracts
are split apart. The haemorrhage itself may expand over the
first minutes or hours, or it may be associated with a rim of
cerebral oedema, which, along with the haematoma, acts like
a mass lesion to cause progression of the neurological deficit.
If big enough, this can cause shift of the intracranial contents,
producing transtentorial coning and sometimes rapid death
(p. 1127). If the patient survives, the haematoma is gradually
absorbed, leaving a haemosiderin-lined slit in the brain
parenchyma.
Clinical features
Both acute stroke and transient ischaemic attack (TIA) are
characterised by a rapid-onset, focal deficit of brain function and
can be considered as a spectrum of symptoms from transient
(TIA) to persistent (stroke). The typical presentation occurs over
minutes, affects an identifiable area of brain and is ‘negative’ in
character (i.e. abrupt loss of function without positive features
BS 26.2 Causes of intracerebral haemorrhage and
associated risk factors
Disease
Risk factors
Complex small-vessel disease
with disruption of vessel wall
Age
Hypertension
High cholesterol
Amyloid angiopathy
Familial (rare)
Age
Impaired blood clotting
Anticoagulant therapy
Blood dyscrasia
Thrombolytic therapy
Vascular anomaly
Arteriovenous malformation
Cavernous haemangioma
Substance misuse
Alcohol
Amphetamines
Cocaine
such as abnormal movement). Provided there is a clear history
of this, the chance of a brain lesion being anything other than
vascular is 5% or less (Box 26.3). If symptoms progress over
hours or days, other diagnoses must be excluded. Delirium and
memory or balance disturbance are more often due to stroke
mimics. Transient symptoms, e.g. syncope, amnesia, delirium
and dizziness, do not reflect focal cerebral dysfunction but are
often mistakenly attributed to TIA (see Fig. 10.3, p. 182, and Box
26.4). Campaigns to raise public awareness of the emergency
nature of stroke exploit the fact that weakness of the face or
arm, or disturbance of speech is the most common presentation.
The clinical presentation of stroke depends on which arterial
territory is involved and the size of the lesion (see Fig. 26.1). These
will both have a bearing on management, such as suitability for
carotid endarterectomy. The neurological deficit can be identified
i
26.3 Differential diagnosis of stroke and transient
ischaemic attack
‘Structural’ stroke mimics
• Primary cerebral tumours
•
Demyelination
• Metastatic cerebral tumours
•
Peripheral nerve lesions
• Extradural or subdural
(vascular or compressive)
haematoma
•
Cerebral abscess
‘Functional’ stroke mimics
• Todd’s paresis (after epileptic
•
Focal seizures
seizure)
•
Meniere’s disease or other
• Hypoglycaemia
vestibular disorder
• Migrainous aura (with or
•
Conversion disorder (p. 1 202)
without headache)
•
Encephalitis
26.4 Characteristic features of stroke and non-stroke
syndromes (‘stroke mimics’)
Feature
Stroke
Stroke mimics
Symptom onset
Sudden (minutes)
Often slower onset
Symptom
progression
Rapidly reaches
maximum severity
Often gradual onset
Severity of deficit
Unequivocal
May be variable/uncertain
Pattern of deficit
Hemispheric
pattern
May be non-specific with
delirium, memory loss,
balance disturbance
Loss of
consciousness
Uncommon
More common
Fig. 26.9 CT scans showing intracerebral
haemorrhage. [A] Basal ganglia
haemorrhage with intraventricular extension.
fin Small cortical haemorrhage. A and B,
Courtesy of Dr A. Farrell and Prof. J.
Wardlaw.
26
1156 • STROKE MEDICINE
from the patient’s history and (if it is persistent) the neurological
examination. The presence of a unilateral motor deficit, a higher
cerebral function deficit such as aphasia or neglect, or a visual
field defect usually places the lesion in the cerebral hemisphere.
Ataxia, diplopia, vertigo and/or bilateral weakness usually indicate
a lesion in the brainstem or cerebellum. Different combinations
of these deficits define several stroke syndromes (Fig. 26.10),
which reflect the site and size of the lesion and may provide
clues to the underlying pathology.
Reduced conscious level usually indicates a large-volume lesion
in the cerebral hemisphere but may result from a lesion in the
brainstem or complications such as obstructive hydrocephalus,
hypoxia or severe systemic infection. The combination of severe
headache and vomiting at the onset of the focal deficit is
suggestive of intracerebral haemorrhage.
General examination may provide clues to the cause and
identify important comorbidities and complications.
Several terms have been used to classify strokes, often based
on the duration and evolution of symptoms:
• Transient ischaemic attack (TIA) describes a stroke in
which symptoms resolve within 24 hours - an arbitrary
cut-off that has little value in practice, apart from perhaps
indicating that underlying cerebral haemorrhage or
extensive cerebral infarction is extremely unlikely. The term
Clinical syndrome
Common symptoms
Common cause
Combination of:
Middle cerebral artery
occlusion
Hemiparesis
(Embolism from heart
Higher cerebral dysfunction
(e.g. aphasia)
or major vessels)
Hemisensory loss
Homonymous hemianopia
(damage to optic radiations)
Isolated motor loss (e.g. leg only,
Occlusion of a branch
arm only, face)
of the middle cerebral
artery or anterior
Isolated higher cerebral
dysfunction (e.g. aphasia,
cerebral artery
neglect)
(Embolism from heart
or major vessels)
Mixture of higher cerebral
dysfunction and motor loss
(e.g. aphasia with right
hemiparesis)
Pure motor stroke - affects
Thrombotic occlusion
two limbs
of small perforating
arteries
Pure sensory stroke
(Thrombosis in situ)
Sensory-motor stroke
No higher cerebral dysfunction
or hemianopia
Homonymous hemianopia
Occlusion in vertebral,
(damage to visual cortex)
basilar or posterior
cerebral artery territory
Cerebellar syndrome
(Cardiac embolism or
Cranial nerve syndromes
thrombosis in situ)
CT scan features
Total anterior circulation
syndrome (TACS)
Higher
cerebral
functions
Partial anterior circulation
syndrome (PACS)
Higher
cerebral
functions
Lacunar syndrome (LACS)
Higher
cerebral
functions
Posterior circulation
stroke (POCS)
(lateral view)
Fig. 26.10 Clinical and radiological features of the stroke syndromes. The top three diagrams show coronal sections of the brain and the bottom one
shows a sagittal section. The anatomical locations of cerebral functions are shown with the nerve tracts in green. A motor (or sensory) deficit (shown by
the areas shaded red) can occur with damage to the relevant cortex (PACS), nerve tracts (LACS) or both (TACS). The corresponding CT scans show
horizontal slices at the level of the lesion, highlighted by the arrows.
Stroke • 1157
TIA traditionally also includes patients with amaurosis
fugax, usually due to a vascular occlusion in the retina.
• Stroke describes those events in which symptoms last
more than 24 hours. The differential diagnosis of patients
with symptoms lasting a few minutes or hours is similar to
those with persisting symptoms (see Box 26.3). The term
‘minor stroke’ is sometimes used to refer to symptoms
lasting over 24 hours but not causing significant disability.
• Progressing stroke (or stroke in evolution) describes a
stroke in which the focal neurological deficit worsens
after the patient first presents. Such worsening may be
due to increasing volume of infarction, haemorrhagic
transformation or increasing cerebral oedema.
• Completed stroke describes a stroke in which the focal
deficit persists and is not progressing.
When assessing a patient within hours of symptom onset, it
is not possible to distinguish stroke from TIA unless symptoms
have already resolved. In clinical practice, it is important to
distinguish those patients with strokes who have persisting focal
neurological symptoms when seen from those whose symptoms
have already resolved.
Investigations
Investigation of acute stroke aims to confirm the vascular nature
of a lesion, distinguish infarction from haemorrhage and identify
the underlying vascular disease and risk factors (Box 26.5).
Risk factor analysis
Initial investigation includes a range of simple blood tests to detect
common vascular risk factors and markers of rarer causes, along
with an ECG and brain imaging. Where there is uncertainty about
the nature of the stroke, further investigations are indicated.
This especially applies to younger patients, who are less likely
to have atherosclerotic disease (Box 26.6).
i
Diagnostic question Investigation
Is it a vascular lesion? CT/MRI
Is it ischaemic or haemorrhagic? CT/MRI
Is it a subarachnoid CT/lumbar puncture
haemorrhage?
Is there any cardiac source of ECG
embolism? Holter monitoring
Echocardiogram
Duplex ultrasound of carotids
MRA
CTA
Contrast angiography
What are the risk factors? Full blood count
Cholesterol
Blood glucose
Is there an unusual cause? ESR
Serum protein electrophoresis
Clotting/thrombophilia screen
(CT = computed tomography; CTA = computed tomographic angiography; ECG =
electrocardiogram; ESR = erythrocyte sedimentation rate; MRA = magnetic
resonance angiography; MRI = magnetic resonance imaging)
Neuroimaging
Brain imaging with either CT or MRI should be performed in all
patients with acute stroke. Exceptions are where results would
not influence management, such as in the advanced stage of
a terminal illness. CT remains the most practical and widely
available method of imaging the brain. It will usually exclude
non-stroke lesions, including subdural haematomas and brain
tumours, and will demonstrate intracerebral haemorrhage within
minutes of stroke onset (see Fig. 26.9). However, especially
within the first few hours after symptom onset, CT changes in
cerebral infarction may be completely absent or only very subtle.
Changes often develop over time (see Fig. 26.13) but small
cerebral infarcts may never show up on CT scans. For some
purposes, a CT scan performed within 24 hours is adequate
26.6 Causes and investigation of acute stroke in
young patients
Cause
Investigation
Cerebral infarct
Cardiac embolism
Echocardiography (including
transoesophageal)
Premature atherosclerosis
Serum lipids
Arterial dissection
MRI
CTA
Reversible cerebral
MRI
vasoconstriction syndromes
CTA
Thrombophilia
Protein C, protein S
Antithrombin III
Factor V Leiden, prothrombin
Homocystinuria (p. 369)
Urinary amino acids
Methionine loading test
Antiphospholipid antibody
Anticardiolipin antibodies/lupus
syndrome (p. 977)
anticoagulant
Systemic lupus erythematosus
ANA
Vasculitis (e.g. primary angiitis of
ESR
the central nervous system)
CRP
ANCA
CADASIL
MRI brain
CARASIL
Genetic analysis
Skin biopsy
Mitochondrial cytopathy
Serum lactate
White cell mitochondrial DNA
Muscle biopsy
Mitochondrial molecular genetics
Fabry’s disease
Alpha-galactosidase levels
Sickle cell disease
Sickle cell studies
Neurovascular syphilis
Syphilis serology
Primary intracerebral haemorrhage
AVM
MRI/MRA
Drug misuse
Drug screen (amphetamine,
cocaine)
Coagulopathy
PT and APTT
Platelet count
Subarachnoid haemorrhage
Saccular (‘berry’) aneurysm
MRI/MRA
AVM
MRI/MRA
Vertebral dissection
MRI/MRA
(ANA = antinuclear antibody; ANCA =
antineutrophil cytoplasmic antibody; APTT
= activated partial thromboplastin time; AVM = arteriovenous malformation;
CADASIL/CARASIL = cerebral autosomal dominant/recessive arteriopathy with
subcortical infarcts and leucoencephalopathy; CRP = C-reactive protein;
CTA = computed tomographic angiography; ESR = erythrocyte sedimentation
rate; MRA = magnetic resonance angiography; MRI = magnetic resonance
imaging; PT = prothrombin time)
26.5 Investigation of a patient with an acute stroke
What is the underlying vascular
disease?
1158 • STROKE MEDICINE
Clinical diagnosis of stroke
(Box 26.4)
I
Neuroimaging
*
26.7 Indications for immediate CT/MRI in
acute stroke
Patient on anticoagulants or with abnormal coagulation
Consideration for reperfusion (thrombolysis) or immediate
anticoagulation
Deteriorating conscious level or rapidly progressing deficits
Suspected cerebellar haematoma, to exclude hydrocephalus
but there are certain circumstances in which an immediate CT
scan is essential (Box 26.7). Even in the absence of changes
suggesting infarction, abnormal perfusion of brain tissue can
be imaged with CT after injection of contrast media (i.e. CT
perfusion scanning). This can be useful in guiding immediate
treatment of ischaemic stroke.
MRI is not as widely available as CT and scanning times are
longer. However, MRI diffusion weighted imaging (DWI) can
detect ischaemia earlier than CT, and other MRI sequences can
also be used to demonstrate abnormal perfusion (see Fig. 26.4).
MRI is more sensitive than CT in detecting strokes affecting the
brainstem and cerebellum, and, unlike CT, can reliably distinguish
haemorrhagic from ischaemic stroke even several weeks after
the onset. CT and MRI may reveal clues as to the nature of the
arterial lesion. For example, there may be a small, deep lacunar
infarct indicating small-vessel disease, or a more peripheral infarct
suggesting an extracranial source of embolism (see Fig. 26.10). In
a haemorrhagic lesion, the location might indicate the presence
of an underlying vascular malformation, saccular aneurysm or
amyloid angiopathy. More recently, CTA is being used to show
vessel occlusion suitable for clot retrieval (see later).
| Vascular imaging
Many ischaemic strokes are caused by atherosclerotic
thromboembolic disease of the major extracranial vessels.
Detection of extracranial vascular disease can help establish
why the patient has had an ischaemic stroke and, in selected
patients, may lead on to specific treatments, including carotid
endarterectomy to reduce the risk of further stroke (see below).
The presence or absence of a carotid bruit is not a reliable
indicator of the degree of carotid stenosis. Extracranial arterial
disease can be non-invasively identified with duplex ultrasound,
MRA or CTA (see Fig. 26.5), or occasionally by intra-arterial
contrast radiography as above.
| Cardiac investigations
Approximately 20% of ischaemic strokes are due to embolism
from the heart. The most common causes are atrial fibrillation,
prosthetic heart valves, other valvular abnormalities and recent
myocardial infarction. These may be identified by clinical
examination and ECG, but a transthoracic or transoesophageal
echocardiogram is also required to confirm the presence of a
clinically apparent cardiac source or to identify an unsuspected
source such as endocarditis, atrial myxoma, intracardiac thrombus
or patent foramen ovale. Such findings may lead on to specific
cardiac treatment.
Management
Management (Fig. 26.11) is aimed at identifying the cause,
minimising the volume of brain that is irreversibly damaged,
preventing complications (Fig. 26.12), reducing the patient’s
Ischaemic stroke Haemorrhagic stroke
\
Eligible for urgent
Reverse coagulation
reperfusion therapy?
abnormality
r
1
l
Yes (20%)
I
No (80%)
1
▼
Intravenous thrombolysis
(NNT 9-20)* and/or
Mechanical thrombectomy
Aspirin
(NNT 80)
(NNT 8-10)*
I
r
Acute stroke unit care (NNT 20)
j
Identify cause and plan secondary prevention
Fig. 26.11 Emergency management of stroke. ^Varies with patient
selection and delay in treatment. (NNT = number needed to treat to avoid
one death or long-term disability)
disability and handicap through rehabilitation, and reducing the
risk of recurrent stroke or other vascular events. With TIA there
is no persisting brain damage and disability, so the priority is to
reduce the risk of further vascular events.
Supportive care
Rapid admission of patients to a specialised stroke unit facilitates
coordinated care from a specialised multidisciplinary team, and
has been shown to reduce both mortality and residual disability
amongst survivors. For every 1 000 patients managed in a stroke
unit, an extra 50 will avoid death or long-term disability, compared
to those managed in general wards. Consideration of a patient’s
rehabilitation needs should commence at the same time as
acute medical management. Dysphagia is common and can
be detected by an early bedside test of swallowing. This allows
hydration, feeding and medication to be given safely, if necessary
by nasogastric tube or intravenously. In the acute phase, a
checklist may be useful (Box 26.8) to ensure that all the factors
that might influence outcome have been addressed. In recent
years, many services have developed hyperacute stroke units
(HASUs) to ensure that patients are given immediate access
to these interventions, as well as urgent medical treatments.
The patient’s neurological deficits may worsen during the first
few hours or days after their onset. This may be due to extension
of the area of infarction, haemorrhage transformation of an
infarction, or the development of oedema with consequent mass
effect. It is important to distinguish these patients from those who
Stroke • 1159
Prevention
Maintain cerebral oxygenation
Avoid metabolic disturbance
Maintain positive attitude and
provide information
Avoid traction injury
Shoulder/arm supports
Physiotherapy
Nurse semi-erect
Avoid aspiration (nil by mouth,
nasogastric tube, possible
gastrostomy)
Appropriate aperients and diet
Avoid catheterisation if possible
Use penile sheath
Frequent turning
Monitor pressure areas
Avoid urine damage to skin
Early mobilisation
Heparin (for high-risk patients only)
Treatment
Anticonvulsants
Antidepressants
Physiotherapy
Local glucocorticoid
injections
Antibiotics
Physiotherapy
Appropriate aperients
Antibiotics
Nursing care
Pressure-relieving mattress
Anticoagulation (exclude
haemorrhage first)
26 8 How t0 mana9e a Patient with acute stroke
Airway
Blood glucose
• Perform bedside screen and keep patient nil by mouth if swallowing
• Check blood glucose and treat when levels are >1 1 .1 mmol/L
unsafe or aspiration occurs
(200 mg/dL) (by insulin infusion or glucose/potassium/insulin
Breathing
(GKI)
• Monitor closely to avoid hypoglycaemia
Temperature
• If pyrexic, investigate and treat underlying cause
• Control with antipyretics, as raised brain temperature may increase
infarct volume
Pressure areas
• Check respiratory rate and give oxygen if saturation <95%
Circulation
• Check peripheral perfusion, pulse and blood pressure, and treat
abnormalities with fluid replacement, anti-arrhythmics and inotropic
drugs as appropriate
Hydration
• If signs of dehydration, give fluids parenterally or by nasogastric tube
• Reduce risk of skin breakdown:
Treat infection
Nutrition
• Assess nutritional status and provide supplements if needed
• If dysphagia persists for >48 hrs, start feeding via nasogastric tube
Medication
Maintain nutrition
Provide pressure-relieving mattress
Turn immobile patients regularly
Incontinence
• Check for constipation and urinary retention; treat these
appropriately
• If dysphagic, consider other routes for essential medications
Blood pressure
• Avoid urinary catheterisation unless patient is in acute urinary retention
• Unless there is heart or renal failure, evidence of hypertensive
or incontinence is threatening pressure areas
encephalopathy or aortic dissection, do not lower blood pressure
abruptly in first week as it may reduce cerebral perfusion. Blood
pressure often returns towards patient’s normal level within days
Mobilisation
• Avoid bed rest
are deteriorating as a result of complications such as hypoxia,
sepsis, epileptic seizures or metabolic abnormalities that may be
reversed more easily. Patients with cerebellar haematomas or
infarcts with mass effect may develop obstructive hydrocephalus
and some will benefit from insertion of a ventricular drain and/or
decompressive surgery (see Fig. 26.1 1). Some patients with large
haematomas or infarction with massive oedema in the cerebral
hemispheres may benefit from anti-oedema agents, such as
mannitol or artificial ventilation. Surgical decompression to reduce
intracranial pressure should be considered in appropriate patients.
I Reperfusion (thrombolysis
and thrombectomy)
Rapid reperfusion in ischaemic stroke can reduce the extent of
brain damage. Intravenous thrombolysis with recombinant tissue
1160 • STROKE MEDICINE
(fx
• Increased risk: older age and previous stroke increase the risk of
stroke in the presence of atrial fibrillation, and bleeding risk with
anticoagulation.
• Falls risk: elderly patients are more prone to falls, including head
injuries, which increase bleeding risk.
• Monitoring of therapy: fine adjustments to daily dose of warfarin
may be more difficult, as may monitoring of therapy.
• Impact of comorbidities: the presence of conditions such as
chronic renal impairment, diabetes or heart failure may affect the
risk:benefit ratio, and decisions to use anticoagulation must be
weighed carefully. Decision aids have been developed to assist (see
‘Further information’).
plasminogen activator (rt-PA) increases the risk of haemorrhagic
transformation of the cerebral infarct with potentially fatal
results. The main contraindications are bleeding risk (recent
haemorrhage, anticoagulant therapy) and delay to treatment;
the earlier treatment is given, the greater the benefit. However,
if given within 4.5 hours of symptom onset to carefully selected
patients, the haemorrhagic risk is offset by an improved overall
outcome. Recently mechanical clot retrieval (thrombectomy) in
patients with a large-vessel occlusion can greatly improve the
chances of avoiding disability (see Fig. 26.1 1).
Aspirin
In the absence of contraindications, aspirin (300 mg daily) should
be started immediately after an ischaemic stroke unless rt-PA
has been given, in which case it should be withheld for at least
24 hours. Aspirin reduces the risk of early recurrence and has
a small but clinically worthwhile effect on long-term outcome
(see Fig. 26.11); it may be given by rectal suppository or by
nasogastric tube in dysphagic patients.
Heparin
Anticoagulation with heparin has been widely used to treat acute
ischaemic stroke in the past. While it reduces the risk of early
ischaemic recurrence and venous thromboembolism, it increases
the risk of both intracranial and extracranial haemorrhage.
Furthermore, routine use of heparin does not result in better
long-term outcomes, and therefore it should not be used in the
routine management of acute stroke. It is unclear whether heparin
might provide benefit in selected patients, such as those with
recent myocardial infarction, arterial dissection or progressing
strokes. Intracranial haemorrhage must be excluded on brain
imaging before considering anticoagulation.
Coagulation abnormalities
In those with intracerebral haemorrhage, coagulation abnormalities
should be reversed as quickly as possible to reduce the likelihood
of the haematoma enlarging. This most commonly arises in those
on warfarin therapy. There is no evidence that clotting factors
are useful in the absence of a clotting defect.
| Management of risk factors
The approaches used are summarised in Figure 26.13. The
average risk of a further stroke is 5-1 0% within the first week of
a stroke or TIA, perhaps 1 5% in the first year and 5% per year
thereafter. The risks are not substantially different for intracerebral
haemorrhage. The potential gain from good secondary prevention
can be expressed as the number needed to treat (NNT) to avoid
a recurrent stroke. Patients with ischaemic events should be put
on long-term antiplatelet drugs (NNT 100) and statins (NNT 60)
to lower cholesterol. For patients in atrial fibrillation, the risk can
be reduced substantially (NNT 15) by using oral anticoagulation
with warfarin to achieve an international normalised ratio (INR) of
2-3. The newer direct oral anticoagulants (such as dabigatran,
rivaroxaban and apixaban) are now widely used, offering improved
safety and effectiveness at increased drug cost. The risk of
recurrence after both ischaemic and haemorrhagic strokes can
be reduced by blood pressure reduction, even for those with
relatively normal blood pressures (NNT 50).
Carotid endarterectomy and angioplasty
A small proportion of patients with a carotid territory ischaemic
stroke or TIA will have more than 50% stenosis of the carotid
artery on the side of the brain lesion. Such patients have a greater
than average risk of stroke recurrence. For those without major
residual disability, removal of the stenosis has been shown to
reduce the overall risk of recurrence (NNT 15), although the
operation itself carries about a 5% risk of stroke. Surgery is
most effective in patients with more severe stenoses (70-99%)
and when it is performed within the first couple of weeks after
the TIA or ischaemic stroke. Carotid angioplasty and stenting
are technically feasible but have not been shown to be as
effective as endarterectomy for the majority of eligible patients.
Endarterectomy of asymptomatic carotid stenosis has been
shown to reduce the subsequent risk of stroke but the small
absolute benefit does not justify its routine use.
Unusual causes
A minority of strokes are caused by arterial dissection of the
carotid (carotid dissection) or vertebral artery (vertebral artery
dissection). The presenting history often includes minor injury and
face or neck pain. After confirmation on angiography (MRA or
CTA), treatment is with either antiplatelet drugs or anticoagulation.
Reversible vasoconstriction syndromes require good physiological
control (particularly blood pressure).
Subarachnoid haemorrhage
Subarachnoid haemorrhage (SAH) is less common than ischaemic
stroke or intracerebral haemorrhage (see Fig. 26.1) and affects
about 6/100000 of the population. Women are affected more
commonly than men and the condition usually presents before
the age of 65. The immediate mortality of aneurysmal SAH is
about 30%; survivors have a recurrence (or rebleed) rate of about
40% in the first 4 weeks and 3% annually thereafter.
Some 85% of cases of SAH are caused by saccular or ‘berry’
aneurysms arising from the bifurcation of cerebral arteries (see
Fig. 26.2), particularly in the region of the circle of Willis. The most
common sites are in the anterior communicating artery (30%),
posterior communicating artery (25%) or middle cerebral artery
(20%). There is an increased risk in first-degree relatives of those
with saccular aneurysms, and in patients with polycystic kidney
disease (p. 405) and congenital connective tissue defects such as
Ehlers-Danlos syndrome (p. 970). In about 10% of cases, SAHs
are non-aneurysmal haemorrhages (so-called peri-mesencephalic
haemorrhages), which have a very characteristic appearance on
CT and a benign outcome in terms of mortality and recurrence.
26.9 Anticoagulation in old age
Subarachnoid haemorrhage • 1161
Fig. 26.13 Strategies for secondary prevention of stroke. (1) Lower blood pressure with caution in patients with postural hypotension, renal
impairment or bilateral carotid stenosis. (2) Other statins can be used as an alternative to simvastatin in patients on warfarin or digoxin. (3) Warfarin and
aspirin have been used in combination in patients with prosthetic heart valves. (4) The combination of aspirin and clopidogrel is indicated only in patients
with unstable angina or those with a temporary high risk of recurrence (e.g. carotid stenosis). (ACE = angiotensin-converting enzyme; BP = blood pressure;
CT = computed tomography; ECG = electrocardiogram; MRI = magnetic resonance imaging; TIA = transient ischaemic attack; U&Es = urea and
electrolytes)
Around 5% of SAHs are due to arteriovenous malformations and
vertebral artery dissection.
Clinical features
SAH typically presents with a sudden, severe, ‘thunderclap’
headache (often occipital), which lasts for hours or even days,
often accompanied by vomiting, raised blood pressure and neck
stiffness or pain. It commonly occurs on physical exertion, straining
and sexual excitement. There may be loss of consciousness at
the onset, so SAH should be considered if a patient is found
comatose. About 1 patient in 8 with a sudden severe headache
has SAH and, in view of this, all who present in this way require
investigation to exclude it (Fig. 26.14).
On examination, the patient is usually distressed and
irritable, with photophobia. There may be neck stiffness due to
subarachnoid blood but this may take some hours to develop.
Focal hemisphere signs, such as hemiparesis or aphasia, may be
present at onset if there is an associated intracerebral haematoma.
A third nerve palsy may be present due to local pressure from
an aneurysm of the posterior communicating artery, but this is
rare. Fundoscopy may reveal a subhyaloid haemorrhage, which
represents blood tracking along the subarachnoid space around
the optic nerve.
Investigations
CT brain scanning and lumbar puncture are required. The
diagnosis of SAH can be made by CT but a negative result
does not completely exclude it, since small amounts of blood
in the subarachnoid space cannot be detected by CT (see Fig.
26.14). Lumbar puncture should be performed 12 hours after
symptom onset if possible, to allow detection of xanthochromia
(p. 1 077). If either of these tests is positive, cerebral angiography
(see Fig. 26.5) is required to determine the optimal approach to
prevent recurrent bleeding.
1162 • STROKE MEDICINE
26.10 Causes of cerebral venous thrombosis
Predisposing systemic causes
• Dehydration
• Thrombophilia (p. 922)
• Pregnancy
• Hypotension
• Behget’s disease (p. 1043)
• Oral contraceptive use
Local causes
• Paranasal sinusitis
• Facial skin infection
• Meningitis, subdural empyema
• Otitis media, mastoiditis
• Penetrating head and eye
• Skull fracture
wounds
26.1 1 Clinical features of cerebral venous thrombosis
Cavernous sinus thrombosis
• Proptosis, ptosis, headache, external and internal ophthalmoplegia,
papilloedema, reduced sensation in trigeminal first division
• Often bilateral, patient ill and febrile
Superior sagittal sinus thrombosis
• Headache, papilloedema, seizures
• Clinical features may resemble idiopathic intracranial hypertension
(p. 1133)
• May involve veins of both hemispheres, causing advancing motor
and sensory focal deficits
Transverse sinus thrombosis
• Hemiparesis, seizures, papilloedema
• May spread to jugular foramen and involve cranial nerves 9, 10
and 11
Refer to
neurosurgeons
Resuscitate
Nimodipine 60 mg
Fig. 26.14 Investigation of subarachnoid haemorrhage. (CSF =
cerebrospinal fluid; CT = computed tomography)
Management
Nimodipine (30-60 mg IV for 5-1 4 days, followed by 360 mg orally
for a further 7 days) is usually given to prevent delayed ischaemia
in the acute phase. Insertion of platinum coils into an aneurysm (via
an endovascular procedure) or surgical clipping of the aneurysm
neck reduces the risk of both early and late recurrence. Coiling
is associated with fewer perioperative complications and better
outcomes than surgery; where feasible, it is now the procedure
of first choice. Arteriovenous malformations can be managed
either by surgical removal, by ligation of the blood vessels that
feed or drain the lesion, or by injection of material to occlude
the fistula or draining veins. Treatment may also be needed for
complications of SAH, which include obstructive hydrocephalus
(that may require drainage via a shunt), delayed cerebral ischaemia
due to vasospasm (which may be treated with vasodilators),
hyponatraemia (best managed by fluid restriction) and systemic
complications associated with immobility, such as chest infection
and venous thrombosis.
Cerebral venous disease
Thrombosis of the cerebral veins and venous sinuses (cerebral
venous thrombosis) is much less common than arterial thrombosis.
However, it has been recognised with increasing frequency in
recent years, as access to non-invasive imaging of the venous
sinuses using MR venography has increased. The main causes
are listed in Box 26.10.
Clinical features
Cerebral venous sinus thrombosis usually presents with
symptoms of raised intracranial pressure, seizures and focal
neurological symptoms. The clinical features vary according to
the sinus involved (Box 26.11 and see Fig. 26.3). Cortical vein
thrombosis presents with focal cortical deficits such as aphasia
and hemiparesis (depending on the area affected), and epilepsy
(focal or generalised). The deficit can increase if spreading
thrombophlebitis occurs.
Investigations and management
MR venography demonstrates a filling defect in the affected
vessel. Anticoagulation, initially with heparin followed by warfarin,
is beneficial, even in the presence of venous haemorrhage. In
selected patients, endovascular thrombolysis has been advocated.
Management of underlying causes and complications, such as
persistently raised intracranial pressure, is important.
About 10% of cerebral venous sinus thrombosis,
particularly cavernous sinus thrombosis, is associated with
infection (most commonly Staphylococcus aureus), needing
antibiotic treatment. Otherwise, the treatment of choice is
anticoagulation.
Further information
Websites
eso-stroke.org European Stroke Organisation guidelines.
nhs.uk/actfast FAST (face, arms, speech, time) campaign to raise
public awareness of the emergency nature of stroke.
nice.org.uk/guidance National Institute for Health and Care Excellence
CGI 80 ‘Tools and resources’ includes a patient decision aid - Atrial
fibrillation: medicines to help reduce your risk of a stroke - what are
the options?
rcplondon.ac.uk/resources/stroke-guidelines Royal College of
Physicians of London clinical guideline.
stroke.cochrane.org Systematic reviews of stroke treatments.
stroketraining.org Stroke Training and Awareness Resources.
Emergency CT
Negative
(<10% of subarachnoid
haemorrhage)
Shows
subarachnoid
haemorrhage
CSF
Blood/xanthochromia (after
Traumatic lumbar 12h0Urs)
punctures
do not cause
xanthochromia in
that specimen
▼ ▼
If CT and CSF at
12 hours are negative
the patient has not
had a subarachnoid
haemorrhage
Medical
Functional anatomy and physiology 1164
Investigation of visual disorders 1168
Perimetry 1168
Imaging 1168
Visual electrophysiology 1 1 69
Presenting problems in ophthalmic disease 1169
Watery/dry eye 1 1 70
Pruritus 1 1 70
Pain/headache 1 1 70
Photophobia/glare 1170
Photopsia 1 1 70
Blurred vision 1170
Loss of vision 1 1 70
Distortion of vision 1 1 71
Eyelid retraction 1171
Optic disc swelling 1 1 71
Proptosis 1171
ophthalmology
Specialist ophthalmological conditions 1171
Ocular inflammation 1171
Infectious conditions 1173
Cataract 1 1 74
Diabetic eye disease 1 1 74
Retinal vascular occlusion 1177
Age-related macular degeneration 1 1 78
1164 • MEDICAL OPHTHALMOLOGY
The ability to see is an important aspect of everyday life. Although
rarely a cause of mortality, visual impairment can have a profoundly
negative impact on socioeconomic status.
Globally, although refractive errors and cataract remain the
main causes of visual impairment, significant progress has
occurred in prevention and treatment. Public health measures
have reduced diseases of poor hygiene and unclean water,
such as trachoma and onchocerciasis, and greater access
to surgery has reduced the burden of untreated cataract and
glaucoma. However, conditions associated with longevity, such
as age-related macular degeneration, diabetic retinopathy and
retinal vein occlusion, for which scientific advances have led to
effective but expensive therapies requiring frequent and long-term
attendance, are increasing in frequency.
Traditionally, ophthalmology relied on other specialties to
undertake extraocular investigation and treatment. Medical
ophthalmology bypasses that co-dependence, allowing
patients with visual disorders to receive overarching care within
ophthalmology. As such, it requires a good grounding in medicine,
particularly dermatology, diabetes and endocrinology, infectious
diseases, medical genetics, neurology, rheumatology and stroke
medicine.
Medical ophthalmology presents a challenge for a medical
textbook, as it overlaps with almost all other specialties,
but particularly neurology. In this book neuro-ophthalmology is
covered in Chapter 25. This chapter concentrates mainly on
intraocular inflammation, which was the prime drive to create
the specialty, and conditions that require intravitreal injection
therapy. It does not therefore represent the totality of the medical
ophthalmologist’s workload. Ophthalmological conditions that
are usually managed within non-ophthalmological specialties
are discussed in the corresponding chapters, although for ease
of reference the more common ophthalmic features of non-
ophthalmological conditions are listed throughout this chapter
(haematological disease in Box 27.1 , diabetes and endocrine disease
in Box 27.2, cardiovascular disease in Box 27.3, respiratory disease
in Box 27.4, rheumatological/musculoskeletal disease in Box 27.5,
gastrointestinal disease in Box 27.6 and skin disease in Box 27.7).
Functional anatomy and physiology
Visual pathways, innervation of the eye and the control of eye
movement are discussed in Chapter 25.
Orbit
The orbit is the fat-filled cavity in which the eye is suspended.
It is shaped like a hollow square pyramid, its base the orbital
rim. The orbital periosteum (‘periorbita’) is continuous with the
periosteal layer of cranial dura mater. The dura and arachnoid
form the optic nerve sheath, its subarachnoid space containing
cerebrospinal fluid in continuity with the third ventricle.
Eyelid/orbital septum/conjunctiva
In primary gaze, the eyelids just cover the superior and inferior
cornea. The eyelids contain the orbital septum and the tarsal plate.
Within the tarsal plates, modified sebaceous (Meibomian)
glands produce an oily surfactant to slow tear evaporation.
The conjunctiva, a mucous membrane, lines the posterior
surface of the eyelid, adhering only to the tarsal plates and the
scleral/corneal junction. The accessory lacrimal glands provide
basal tear production; mucus produced by goblet cells stabilises
the tear film by lowering surface tension.
27.1 Ophthalmic features of haematological disease
Condition
Ophthalmic findings
Severe anaemia of any cause
(retinopathy of anaemia)
Flame haemorrhages
Cotton wool spots
Roth spots
Pre-retinal haemorrhage
Megaloblastic anaemia
Optic neuropathy
Sickle cell anaemia
Conjunctival vasculopathy
Peripheral retinal
neovascularisation
Thalassaemia
Desferrioxamine-associated
pigmentary retinopathy
Leukaemia (leukaemic retinopathy)
Pseudohypopyon
Flame haemorrhages
Roth spots
Retinal oedema
Retinal vein occlusion
Lymphoma
Non-Hodgkin lymphoma
Central nervous system lymphoma
Lacrimal gland infiltration
Posterior uveitis (atypical
choroiditis)
Myeloproliferative disorders
Hyperviscosity
Cerebral venous thrombosis
Retinal vein occlusion
Papilloedema
Paraproteinaemias
Waldenstrom’s macroglobulinaemia
Multiple myeloma
Retinal vein engorgement/
occlusion
Thrombophilia
Cerebral venous thrombosis
Papilloedema
Lacrimal gland/lacrimal drainage
The lacrimal gland lies within the periorbita of the anterolateral
roof of the orbit. Its secretions (tears) wash away surface irritants
and convey emotion. Excess tears drain, via canaliculi in the lids,
into the lacrimal sac, nasolacrimal duct and inferior nasal meatus.
Extraocular muscles
The extraocular muscles (Fig. 27.1) consist of four recti, two
obliques and one levator. The recti originate from a circular
condensation of periorbita, the annulus of Zinn, which encircles
the superior orbital fissure and the optic canal. They extend
forwards to insert into the anterior sclera.
The levator palpebrae superioris originates above the optic
canal and inserts into the tarsal plate and overlying skin of
the upper eyelid. The superior tarsal muscle (Muller’s muscle)
originates from the inferior aspect of the levator and also inserts
into the tarsal plate.
The superior oblique originates superonasal to the recti, and runs
along the roof of the orbit, its tendon passing horizontally through
the trochlea at the orbital rim to insert into the anterior sclera.
The inferior oblique originates from the floor of the anterior
orbit, just posterior to the lacrimal sac. It turns horizontally,
passing beneath the inferior rectus, to insert into the inferior
anterior sclera.
B Eye
The optic vesicle develops from the diencephalon. The eye
is therefore contiguous with the brain. This is reflected in the
three- layer structure of the eye:
Functional anatomy and physiology • 1165
27.2 Ophthalmic features of diabetes and other
endocrine disease
Condition
Ophthalmic findings
Diabetes
Proliferative retinopathy
Macular oedema
Small pupils (autonomic neuropathy)
Cataract (including ‘snowflake’ cataract)
Thyrotoxicosis (any cause)
Eyelid retraction
Graves’ disease (TSH
receptor antibody-positive)
Exposure keratopathy
Conjunctival and periorbital oedema
Restrictive ocular motility
Proptosis
Optic neuropathy
Parathyroid disease
Band keratopathy
Corneal calcium deposition
Phaeochromocytoma
Hypertensive retinopathy
Cotton wool spots
Flame haemorrhages
Optic disc oedema with or without
macular oedema
Cushing’s syndrome
Posterior subcapsular cataract
Diabetic retinopathy
Central serous retinopathy
Thyroid carcinoma
Horner’s syndrome with absent
unilateral facial sweating
(TSH = thyroid stimulating hormone)
27.3 Ophthalmic features of cardiovascular disease
Condition
Ophthalmic findings
Arteriosclerosis
Arteriovenous nipping
Retinal vein occlusion, caused by
arteriovenous nipping
Retinal artery macroaneurysm
Ischaemic optic neuropathy
Pupil-sparing third and/or sixth nerve
palsy, caused by infarction of the
vasa nervosum
Hypertension
Hypertensive retinopathy
Cotton wool spots
Flame haemorrhages
Optic disc oedema, with or without
macular oedema
Infective endocarditis
Flame haemorrhages
Roth spots
Endophthalmitis, caused by
haematogenous spread of infection
Drugs
Vortex keratopathy (corneal epithelial
deposits), caused by amiodarone
(also seen in Fabry’s disease, p. 370)
Bilateral optic neuropathy, caused by
amiodarone
Thromboembolic
disorders (including
thromboembolus
from atrial fibrillation)
Retinal artery occlusion, caused by
artery-to-artery embolism
Homonymous hemianopia, caused by
embolic stroke (p. 1088)
• the sclera/cornea, a fibrous outer layer analogous to the
meningeal dura
• the choroid, ciliary body and iris (together known as the uveal
tract), a vascular middle layer analogous to the pia-arachnoid
• the retina, an inner layer analogous to white matter.
| 27.4 Ophthalmic features of respiratory disease
Condition
Ophthalmic findings
Chronic obstructive
pulmonary disease
(p. 573)
Optic disc oedema (type 2 respiratory
failure)
Cystic fibrosis (p. 580)
Diabetic retinopathy
Tuberculosis (p. 588)
Anterior uveitis
Choroidal granuloma
Serpiginous choroiditis
Peripheral retinal arteritis
Optic neuropathy, visual loss and
disturbance of colour vision (adverse
effects of ethambutol and isoniazid)
Sarcoidosis (p. 608)
Anterior uveitis (granulomatosis)
Mutton fat keratitic precipitates
Iris nodules
Choroidal granuloma
Panuveitis
Multifocal choroiditis
Retinal periphlebitis
Sicca syndrome, caused by lacrimal gland
infiltration
Exposure keratopathy, caused by corneal
exposure secondary to facial nerve palsy
Optic neuropathy, caused by optic disc
oedema secondary to meningeal infiltration
Lung cancer (p. 928)
Horner’s syndrome (p. 1091)
Cancer-associated retinopathy
Orbicularis oculi muscle
(palpebral portion)
Levator palpebrae superioris
Inferior rectus
Inferior oblique
Fig. 27.1 The extraocular musculature (right eye). Adapted from
Batterbury M, Bowling B, Murphy C. Ophthalmology. An illustrated colour
text, 3rd edn. Churchill Livingstone, Elsevier Ltd; 2009.
The major structures of the eye are shown in Figure 27.2.
During embryogenesis, overlying ectoderm sinks into the
neuroectoderm of the optic vesicle to form the lens vesicle,
thus inducing the optic vesicle to form the two-layered optic
cup. The inner and outer layers form the neurosensory retina
and the retinal pigment epithelium, respectively. The intervening
space is continuous with the third ventricle of the diencephalon,
1166 • MEDICAL OPHTHALMOLOGY
27.5 Ophthalmic features of rheumatological/
musculoskeletal disease
Rheumatoid arthritis
• Keratoconjunctivitis sicca
• Peripheral ulcerative keratitis
(‘corneal melt’)
• Painless episcleritis
• Scleritis and scleromalacia
Seronegative spondyloarthropathies
• Conjunctivitis (chlamydia-
• Anterior uveitis
associated reactive arthritis)
Connective tissue diseases
Dermatomyositis
• Periorbital oedema with violaceous eyelid rash
Sjogren’s syndrome
• Dry eyes
Treatment effects
• Bull’s eye maculopathy
• Viral retinitis
(hydroxychloroquine)
(immunosuppression)
Systemic vasculitides
Giant cell arteritis
• Central/branch retinal artery
• Ischaemic optic neuropathy
occlusion
Behget’s disease
• Occlusive retinal vasculitis
• Anterior uveitis with
(posterior uveitis)
hypopyon
Granulomatosis with polyangiitis (Wegener’s)
• Scleritis with involvement of
• Retro-orbital inflammation
adjacent cornea (sclerokeratitis)
(see Fig. 25.49)
Polyarteritis nodosa
• Peripheral ulcerative keratitis
• Retinal arteritis
• Scleritis
Others/non-specific
• Necrotising scleritis/
• Retinal arteritis
sclerokeratitis/peripheral
• Pupil-sparing 3rd nerve
ulcerative keratitis
palsy
• Anterior ischaemic optic
• 6th nerve palsy
neuropathy
• Proptosis
• Extraocular myositis (painful
• Occipital lobe infarction
diplopia)
Diseases of bone
Paget’s disease, polyostotic fibrous dysplasia
• Optic neuropathy
Others/non-specific
• Anterior uveitis (adverse effect of bisphosphonates)
the cilia of the third ventricle continuing as cilia on the outer
neurosensory retina. Laterally, these cilia form the outer segments
of the photoreceptors.
Initially, the hyaloid artery supplies the lens and vitreous. In
its final form, the vitreous develops from the retina and the
hyaloid artery regresses, leaving only the central retinal artery
and its branches.
Mesenchyme forms the tarsal plates of the eyelid, the stroma
and the endothelium of the cornea, the sclera and the choroid.
Surface ectoderm, as well as forming the lens, forms the
epidermis of the eyelid, the conjunctiva, the epithelium of the
cornea and the lacrimal gland.
Sclera/cornea
The sclera lends shape to the eye and provides attachment
for the ocular musculature. It makes up five-sixths of the eyeball,
the other sixth being formed by transparent cornea.
i
27.6 Ophthalmic features of gastrointestinal disease
Malabsorption
• Corneal and conjunctival
keratin isation
Chronic pancreatitis
• Diabetic retinopathy
Inflammatory bowel disease
• Rod photoreceptor loss
• Episcleritis
• Non-necrotising scleritis
Large bowel tumours
• Anterior uveitis
• Atypical congenital retinal pigment epithelium hypertrophy (familial
adenomatous polyposis)
Inherited liver disease
• Kayser-Fleischer corneal
• Diabetic retinopathy
rings, sunflower cataracts
(Wilson’s disease)
(haemochromatosis)
27.7 Ophthalmic features of skin disease
Rosacea
• Posterior blepharitis • Keratitis
Acne vulgaris
• Dry eye (adverse effect of • Papilloedema (adverse effect
isotretinoin) of tetracycline)
Psoriasis
• Anterior uveitis
Eczema
• Atopic keratoconjunctivitis
Urticaria
• Angioedema
Bullous diseases
• Ocular cicatricial pemphigoid • Stevens-Johnson syndrome
Alopecia areata
• Eyebrow and eyelash loss
Cutaneous melanoma
• Melanoma-associated retinopathy
Skin tumours
• Eyelid tumours (basal cell carcinoma, squamous cell carcinoma,
keratoacanthoma, naevus, melanoma)
Skin infections
• Stye (eyelash folliculitis) • Chronic conjunctivitis
• Acute blepharoconjunctivitis (molluscum contagiosum)
(herpes simplex)
The limbus lies at the junction between the cornea and
sclera, and contains stem cells and Schlemm’s canal. The stem
cells allow continuous regeneration of the corneal epithelium.
Schlemm’s canal, with its overlying trabecular meshwork, drains
aqueous fluid from the anterior chamber into the external veins
of the episclera and conjunctiva.
The avascular cornea is nourished by diffusion from the anterior
chamber, limbal capillaries and oxygen dissolved in the tear
film. The cornea, assisted by the lens and the length of the eye,
determines the refractive ability of the eye.
Functional anatomy and physiology • 1167
Vitreous gel
.Optic nerve fibres
> .Ganglion cell
/ Amacrine cell
l / Bipolar cell
/Horizontal cell
.Cone
/Rod
/Pigment
/ epithelium
Limbus
Suspensory
ligaments
Cornea
Iris
Lens
Pupil
Anterior
chamber
(aqueous)
Ciliary body
Ciliary muscle
Conjunctiva
Extraocular muscle
Hyaloid
canal
Retinal
vessels
Optic
nerve
Sclera
Choroid
Retina
Fovea
Fig. 27.2 The main structures of the eye. The inset
shows the arrangement of the retinal cells. Inset adapted
from Douglas G, Nicol F, Robertson C (eds). Macleod’s
Clinical examination, 13th edn. Churchill Livingstone,
Elsevier Ltd; 2013.
The sclera is pierced posteriorly by the optic nerve at the
lamina cribrosa, a sieve-like conduit. Its outer layer, the episclera,
consists of loose connective tissue, separating it from Tenon’s
capsule, the soft-tissue socket of the eye.
Choroid, ciliary body and iris - the uveal tract
Posteriorly, the choroid acts as a conduit for branches of the
ophthalmic artery and veins. The choriocapillaris, a network of wide-
bore, fenestrated capillaries, abuts the retinal pigment epithelium.
The ciliary body forms the junction between the choroid and
the iris, and lies just inferior to the limbus. Anteriorly, its ciliary
processes produce aqueous (fluid) that circulates through the
pupil into the anterior chamber. Posteriorly, it constitutes the pars
plana and forms the attachments for the suspensory ligaments
of the lens. The ciliary muscle encircles the eye within the ciliary
body. Contraction of this muscle relaxes the suspensory ligaments
of the lens, bringing near objects into focus.
The iris bows gently forwards as it lies against the lens. It is
divided into a pupillary zone, containing the circumferential sphincter
pupillae muscle, and a ciliary zone, containing the dilator pupillae.
Retina
The retina consists of the neurosensory retina and the retinal
pigment epithelium. The two layers are adherent only adjacent
to the optic disc and at the edge of the pars plana.
Histologically, the centre of the retina is termed the macula
lutea, its yellowish appearance caused by the presence of the
xanthophylls (yellow pigments) lutein and zeaxanthin. At the centre
of the macula, the neurosensory retina dips to form the fovea.
The single-layered retinal pigment epithelium is highly
metabolically active and is essential for the maintenance and
survival of the overlying photoreceptors.
The neurosensory retina initiates the visual pathway. Its
photoreceptors synapse with radially arranged bipolar neurons,
which in turn synapse with circumferentially arranged optic nerve
ganglion cells.
‘Horizontal’ and amacrine cells within the plexiform layers
modulate neuronal activity between bipolar cells, photoreceptors
and the ganglion cells. At the fovea, a one-to-one relationship
between cones, bipolar neurons and ganglion cells leads to
the highest acuity. In the peripheral retina, many rods converge
on to a bipolar neuron, and many bipolar neurons converge
on to a ganglion cell, leading to lower acuity. In effect, the
peripheral retina conveys black-and-white sentinel vision,
alerting the brain to move the higher-acuity colour vision of the
fovea into gaze. Photoreceptors are specialised neurons that
cause neurotransmitters to be released in response to light
(‘phototransduction’). There are three types of photoreceptors:
namely, rods, cones and ganglion cells, the latter of which
independently respond to blue light, influencing circadian rhythms.
1168 • MEDICAL OPHTHALMOLOGY
Lens
The lens is a transparent flexible structure suspended between
the iris and the vitreous. Its flexibility enables objects over a
range of distances to be focused on the retina. It has a capsule,
a central nucleus and a peripheral cortex. It continues to grow
throughout life, becoming less flexible with age.
Vitreous
The vitreous gel is 99% water and 1 % collagen/hyaluronic acid.
The outer edge (cortex) of the vitreous condenses to form the
anterior and posterior hyaloid membranes. The base of the
vitreous strongly adheres to the ora serrata/pars plana and
the optic disc rim, where the internal limiting membrane of the
retina is thinnest. Lesser degrees of adhesion occur at the
parafoveal retina and along the retinal vessels.
Blood supply of the orbit/eye
The main blood supply of the orbit originates from the intracranial
internal carotid artery. The ophthalmic artery, the first branch of
the internal carotid artery, traverses the subarachnoid space to
enter the optic canal within the dural sheath of the optic nerve.
On leaving the optic canal, it emerges from the dural sheath to
course briefly along, and then over, the optic nerve and reach
the medial wall of the orbit.
Several arterial circles are formed. The major arterial circle of
the iris is formed within the ciliary body by anterior ciliary arteries
anastomosing with the posterior ciliary arteries. The pial branches
of the optic nerve and the short ciliary arteries join together, as
the circle of Zinn, to supply the intraocular optic nerve.
The infraorbital artery, a branch of the maxillary artery, also
contributes to the orbital blood supply, in particular the inferior
rectus, the inferior oblique and the lacrimal sac.
The orbit is drained by the superior and inferior ophthalmic
veins, which converge to drain through the superior orbital fissure
into the cavernous sinus.
Investigation of visual disorders
History is the key to diagnosing visual disorders, with examination
and investigations used to confirm or refute the expectations
formed by the history.
Perimetry
In the era before modern radiology, manual perimetry was utilised
as a non-invasive form of ‘neuroimaging’. Nowadays, perimetry
is largely automated and its main role lies in the monitoring of
glaucoma; it also has a lesser role in assessing neuro-ophthalmic
disorders. All methods of perimetry are subjective and rely on
patient cooperation and mental agility.
Amsler chart
The Amsler chart (Fig. 27.3) is the simplest method of documenting
the visual field, and is easy for both patient and clinician to understand
and perform. It can be used for all forms of visual field loss but is
best suited to follow up the central scotomata of macular disorders,
which are often too subtle for other methods of perimetry.
| Tangent/Goldmann kinetic perimetry
Manual perimetry methods, such as tangent screen and Goldmann
kinetic perimetry, appeal to the non-specialist, as they produce
easily interpretable contoured maps of the visual field.
Fig. 27.3 Amsler chart. The Amsler chart is a grid of 0.5 cm squares
with a dot in the centre. The subject is asked to fix on the central dot with
one eye and any distorted or missing lines are recorded.
The tangent screen is a piece of black cloth attached to a wall,
in front of which the operator introduces moving targets into the
patient’s field of view. It retains an important role in the positive
identification of functional peripheral field loss (tunnel vision) versus
pathological field loss (funnel vision), although the results are
somewhat operator-dependent. Goldmann perimetry is a mechanical
improvement on tangent screen perimetry, which utilises targets
of varying size and illumination. An automated version is available.
Automated threshold perimetry
Automated visual fields test the threshold of the eye’s ability to
see at various points within the visual field, forming complex
outputs that can be stored digitally. Internal quality assurance
mechanisms monitor stability of fixation, false positives due to
trigger-happy patients and false negatives due to performance
fatigue. Many patients need practice before accurate results
are obtained; first-time fields are rarely reliable and often show
spurious and misleading findings.
Most automated perimetry assesses only central vision. Few
neurological disorders start peripherally, the exception being
unilateral loss of peripheral field with disease of the anterior
pole of the occipital lobe. However, retinal pathology, such as
retinal detachment and retinitis pigmentosa, may be missed if
reliance is placed on automated perimetry rather than clinical
examination.
Visual field defects on perimetry that affect the whole of the
superior or inferior half of the visual field need to be differentiated
by confrontation into arcuate visual field defects, which affect
central field only, and altitudinal field defects, which affect both
central and peripheral vision. Arcuate visual fields defects localise
a lesion to the optic nerve head, whereas a lesion anywhere
along the optic nerve can cause an altitudinal defect.
Imaging
See Figure 27.4.
I Photography
Digital photography is utilised to document surface anatomy.
Colour images are ideal for lesions affecting the skin and cornea.
For the retina, however, red-free imaging brings additional benefits,
particularly for discriminating red haemorrhages or abnormal
new vessels from the red background of the retina.
Presenting problems in ophthalmic disease • 1169
Fig. 27.4 Ocular imaging. Uj Colour retinal photograph from a healthy subject. ijj] Red-free retinal photograph from a healthy subject. [C] Optical
coherence tomogram of a normal eye, showing the layers of the retina. In this image, the macula shows normal foveal indentation. D] Fundus
autofluorescence (FAF) of the right eye in a normal subject. Distribution of FAF intensity shows typical background signal with reduced signal at the optic disc
(absence of autofluorescent material) and retinal vessels (absorption). Intensity is markedly decreased over the fovea due to the absorption of the blue light by
yellow macular pigment. {E\ Fundal fluorescein angiogram of a normal adult retinfL @j] Ocular ultrasound image showing typical biconvex appearance of a
choroidal melanoma. A, B, C and F, Courtesy of Aberdeen Royal Infirmary. D, From Schmitz-Valckenberg S, Fleckenstein M, Hendrik PN, etal. Fundus
autofluorescence and progression of age-related macular degeneration. Survey Ophthalmol 2009; 54(1 ):96-1 17. E, From WitmerMT, Szilard K. Wide-Held
imaging of the retina. Survey Ophthalmol 2013; 58(2):143-154.
Optical coherence tomography
Optical coherence tomography is the optical equivalent of
ultrasound, using light rather than sound waves to create its
images. It is invaluable, not least for assessing the integrity of the
layers of the retina and detecting macular oedema of any cause.
Autofluorescence
The retinal pigment epithelium contains autofluorescent lipofuscin,
which can be excited by blue- and green-coloured light and
captured by digital imaging.
Increased autofluorescence occurs when there is abnormal
accumulation of lipofuscin, as seen with certain inherited retinal
dystrophies; excess retinal pigment epithelium metabolic activity,
such as at the edge of evolving atrophic macular degeneration;
or drug deposition, such as with hydoxychloroquine.
Fundus angiography
Fluorescein angiography is an invasive technique with risks including
local extravasation of dye at the site of intravenous injection and
anaphylaxis. Currently, its role is limited to the diagnosis of
retinal vasculitis, retinal and choroidal neovascularisation, and
capillary occlusion. Non-invasive angiography is now possible
using optical coherence tomography, but its applicability is
limited by small field of view and inability to demonstrate flow
or leakage.
Indocyanine angiography directly images the choroidal
circulation and is particularly useful in guiding laser treatment
for the choroidal polyps of polypoidal choroidal vasculopathy.
Ocular ultrasound
The main role of ultrasound is where the retina is obscured: for
instance, by cataract or vitreous haemorrhage. It also has an
important role in diagnosing choroidal melanoma, based on its
distinctive internal reflectivity.
Visual electrophysiology
Electrophysiology is used to localise disorders to the
photoreceptors (electroretinogram), the retinal ganglion cells
(pattern electroretinogram) or the optic pathways (visual
evoked potential). The site of photoreceptor involvement can
be further localised to specific regions of the retina (multifocal
electroretinogram) or the macula itself (pattern electroretinogram).
Electrophysiology requires cooperation, correction of refractive
errors and the ability to fixate. Voluntary suppression of the
electrical responses is possible by simply not focusing on the
target. Despite this, it remains the investigation of choice for
visual symptoms unexplained by clinical examination.
Presenting problems in
ophthalmic disease
Presenting problems that are ophthalmological manifestations
of predominantly neurological disease (e.g. ptosis, diplopia,
oscillopsia, nystagmus and pupillary abnormalities) are discussed
in Chapter 25.
1170 • MEDICAL OPHTHALMOLOGY
Watery/dry eye
The most common cause of a watery eye is a dry eye triggering
reflex lacrimation. Patients with dry eye may complain of a foreign
body or gritty sensation in the eye or intermittent visual blurring,
triggered by reduced blinking, as occurs when reading or when
concentrating on a distant object, such as the television.
Pruritus
Common causes of itch are an acute allergic response to either
airborne allergens or direct contact. A significant proportion of
people are allergic to topical chloramphenicol, a first-line treatment
for many minor ocular ailments.
Pain/headache
The key consideration in deciding whether or not ocular pain
and/or headache originates from the eye is whether there is a
ciliary flush (red eye) or no ciliary flush (white eye).
Red eye
The presence of a ciliary flush in the region of the limbus is
a key finding in intraocular causes of pain. The presence of
watering or watery discharge is not a discriminatory feature, and
over-reliance on this symptom often results in anterior uveitis
being misdiagnosed as viral conjunctivitis.
White eye
In the absence of a ciliary flush, ocular or periorbital pain is most
commonly caused by migraine.
Pain on eye movement is a cardinal feature of optic neuritis
and scleritis. In optic neuritis the eye is white, whereas in scleritis,
except for posterior scleritis, it is red.
Posterior scleritis, in which the visible sclera is white, should
be diagnosed only in the setting of positive signs such as disc
swelling and exudative retinal detachment, or with confirmation
by ocular ultrasound. A more common cause of severe ocular/
periocular pain, with associated photophobia and lacrimation,
is cluster headache (p. 1096), which is often misdiagnosed as
scleritis. Just like scleritis, cluster headache responds to oral
glucocorticoids, adding to the diagnostic confusion.
Intermittent, subacute angle closure glaucoma can cause
headache, but usually accompanying corneal oedema causes
haloes (a form of glare with rainbow colours), elicited by looking
at lights or blurring of vision.
Giant cell arteritis is an uncommon, but usually striking,
cause of headache, predominantly seen in the elderly.
Rarely, it presents with sudden painless visual loss in the
absence of raised inflammatory markers. Diagnosis can be
made by demonstrating choroidal shutdown on fluorescein
angiography.
Photophobia/glare
Excessive sensitivity to light, rather than fear of light, usually
indicates ciliary muscle spasm due to inflammation in the iris.
Common causes are corneal abrasion, acute anterior uveitis
and contact lens-related keratitis.
Occasionally, photophobia can be a symptom of congenital
retinal dystrophies, especially cone photoreceptor deficiency.
Photophobia may also be a feature of meningitis, usually with
accompanying neck stiffness and headache (meningism, p. 1118).
Glare is a common early feature of cataract, particularly
triggered by oncoming car headlights when driving at night. It
is a relatively common indication for surgery. It may also be an
issue where there is insufficient melanin in the retinal pigment
epithelium, e.g. in atrophic age-related macular degeneration, in
ocular albinism or following extensive pan-retinal laser therapy. If
surgery is not an option, or while surgery is awaited, the symptom
of glare may be reduced by wearing a broad-brimmed hat.
Photopsia
A flickering light sensation is indicative of photoreceptor activity,
either through traction, as in the setting of posterior vitreous
detachment, or inflammation, as in the setting of autoimmune
or paraneoplastic retinopathy. Rarely, photopsia is a symptom
of occipital lobe epilepsy, in which case there is usually an
accompanying homonymous hemianopia.
Blurred vision
Blurred vision describes the situation in which patients are able
to see what they are looking at, but what they are looking at is
out of focus. The most common cause of intermittent blurred
vision is dry eye; the most common cause of permanent blurred
vision is cataract. If blurred vision is worse in the morning and
eases as the day progresses, this suggests macular oedema.
Loss of vision
In visual loss, patients are no longer able to see all or part of
what they are looking at. Some symptoms associated with visual
loss require urgent ophthalmological assessment (Box 27.8).
27.8 Red flag symptoms in visual loss
Symptom Possible causes
Sudden onset
Retinal artery occlusion
Ischaemic optic neuropathy
Headache
Giant cell arteritis if age >55 years
Eye pain
Angle closure glaucoma
Keratitis
Scleritis
Anterior uveitis
Pain on eye movement
Optic neuritis
Scleritis
Distortion
Choroidal neovascular membrane:
Age-related macular degeneration
Pathological myopia
Posterior uveitis
Idiopathic
Macular hole
Epiretinal membrane
Worse in the morning
Macular oedema:
Diabetic macular oedema
Retinal vein occlusion
Uveitis
*The presence of any of these symptoms in a patient with visual loss requires
emergency referral to an ophthalmologist.
Specialist ophthalmological conditions • 1171
The most common cause of transient visual loss is the aura
of migraine, usually a positive phenomenon with the object of
regard seemingly hidden by something in the way, rather than a
negative phenomenon in which part or all of what is being looked
at is missing. With positive visual phenomena the obstruction is
often white or coloured, expanding across the visual field, or in
a constant position but shimmering.
Negative visual phenomena are a cardinal feature of ocular,
usually retinal, ischaemia, with complete absence of vision
(blackness) occupying part or all the visual field. Transient ocular
ischaemia is usually embolic in nature but is occasionally seen in
giant cell arteritis, where it suggests critical optic nerve ischaemia.
Permanent monocular negative visual phenomena usually indicate
previous optic nerve or retinal infarction. Tiny negative visual
phenomena may also be seen in capillary disorders such as
diabetic retinopathy, where patchy macular capillary occlusion may,
for instance, cause letters to be missing from words on reading.
Distortion of vision
Distortion is a cardinal symptom of disruption of foveal
photoreceptor alignment. The most common cause is choroidal
neovascularisation. Less commonly, it can be caused by epiretinal
membrane formation, where posterior hyaloid surface scarring
causes foveal traction.
Usually with distortion, objects are not only misshapen but
also smaller (micropsia), due to the photoreceptors being pulled
apart. Macropsia, where objects look bigger than normal, is
uncommon. It is sometimes seen in the ‘Alice in Wonderland’
syndrome, a paediatric variant of migraine where there is altered
visual perception of body images.
Eyelid retraction
Eyelid retraction is usually caused by inflammatory thyroid eye
disease or thyrotoxicosis (see pp. 631 and 645, and Fig. 18.8).
The first muscle to be affected in thyroid eye disease is the
inferior rectus. The enlarged muscle tethers the eye and restricts
upgaze. Compensatory increased innervation to the superior
rectus and the levator palpebrae superioris, as well as direct
inflammation, leads to eyelid retraction.
In thyrotoxicosis, increased sympathetic nervous activity
leads to bilateral eyelid retraction. This, however, resolves with
beta-blockade and treatment of thyrotoxicosis.
Rarely, bilateral eyelid retraction is a sign of dorsal mid¬
brain pathology (Collier’s sign), where it is accompanied by
a supranuclear upgaze palsy and convergence-retraction
nystagmus.
Optic disc swelling
Optic disc swelling can be a developmental variant of normal
(pseudopapilloedema) or caused by optic nerve pathology, or
reflect more widespread nerve fibre oedema as with retinal
vein occlusion. Neurological causes of optic disc swelling are
discussed in on page 1090.
Proptosis
Proptosis, particularly if bilateral and symmetrical, is often first
recognised when it is quite advanced. Accompanying eyelid
retraction is a typical feature of thyroid eye disease. By far the
most common cause is thyroid eye disease, when proptosis is
termed exophthalmos.
Proptosis is a sign of retro-orbital expansion and may be
intraconal or extraconal. When expansion is within the cone
of extraocular muscles, then movement forwards will be in
line with the visual axis. When outside, the eye is additionally
displaced to the side.
The primary clinical concern is whether vision is at risk due
to optic nerve compression or corneal exposure. In addition,
there may be double vision. In thyroid eye disease, diplopia
may be absent if the disease is symmetrical. Instead, restricted
ocular movements make patients move their head en bloc when
looking at objects deviating from the primary position of gaze.
To the patient, however, the overarching concern is often the
change in appearance.
Specialist ophthalmological conditions
Ocular inflammation
Inflammation can affect any part of the eye. In structures in
direct contact with the environment, particularly the cornea
and the conjunctiva, inflammation is most likely to be caused
by infection. In other structures, such as the uveal tract and
sclera, inflammation is more likely to be caused by autoimmune
conditions, although it may also be a manifestation of infection
or malignancy. Although the latter conditions may present with
indicative ocular signs, their presence is often appreciated only
retrospectively, after failure to respond to immunosuppression.
Most non-infective forms of ocular inflammation are idiopathic;
all are more common in the presence of other autoimmune
conditions. Some may be directly associated but asynchronous
in disease activity, such as the anterior uveitis of ankylosing
spondylitis (p. 1028). Others are direct manifestations of an
overarching, underlying, inflammatory condition such as the
keratoscleritis of granulomatosis with polyangiitis (formerly known
as Wegener’s granulomatosis).
| Sjogren’s syndrome
Sjogren’s syndrome is the archetypal autoimmune disease and
its secondary form is associated with a large number of other
autoimmune conditions (see Box 24.64, p. 1039). The cardinal
features are inflammation of the lacrimal gland, its conjunctival
accessory glands and the parotid gland, leading to hyposecretion
of tears and saliva. Involvement of the lacrimal gland alone causes
keratoconjunctivitis sicca, a syndrome of dry eyes and corneal
and conjunctival irritation. Keratoconjunctivitis sicca, however,
can also be caused by reduced function of the lacrimal glands
and/or lacrimal ducts from other causes.
Treatment of the ophthalmological manifestations of Sjogren’s
syndrome is symptomatic, and consists of supplementing
tear production with artificial tears (e.g. hypromellose) and
reducing tear loss by humidification and avoidance of dry
environments. If these measures are insufficient, tear drainage
may be reduced with surgical options such as punctal plugs and
punctal occlusion.
Peripheral ulcerative keratitis
Peripheral ulcerative keratitis (‘corneal melting’) is an autoimmune
disorder affecting the corneal limbus, where it may be
1172 • MEDICAL OPHTHALMOLOGY
I
27.9 Aetiology of uveitis
Idiopathic
• Anterior uveitis often associated with the HLA-B27 haplotype,
even in the absence of other manifestations
Primary ophthalmic conditions
• Trauma, including penetrating injury and ophthalmic surgery
• Fuchs’ heterochromic cyclitis
• Posner-Schlossman syndrome
Rheumatological
• H LA- B27 - assoc i ated (seronegative) spondyloarthropathies:
ankylosing spondylitis, psoriatic arthritis, reactive arthritis
• Juvenile idiopathic arthritis
Systemic vasculitides
• Behget’s disease • Granulomatosis with
• Polyarteritis nodosa polyangiitis (Wegener’s)
Systemic infections (only the more common causes are listed)
• Brucellosis • Lyme borreliosis
• Herpes virus infections • Syphilis
(cytomegalovirus, herpes • Toxoplasmosis
simplex virus, varicella • Tuberculosis
zoster virus) • Whipple’s disease
• Leptospirosis
Gastrointestinal conditions
• Inflammatory bowel disease (Crohn’s disease, ulcerative colitis)
Malignancy
• Primary central nervous system lymphoma (rare)
Systemic conditions of unknown cause
• Multiple sclerosis • Sarcoidosis
accompanied by adjacent scleritis. It may be directly associated
with inflammatory disorders in which immune complexes
are formed, particularly rheumatoid arthritis, systemic lupus
erythematosus and granulomatosis with polyangiitis. Pain and
redness are helpful indicators but may not always be present.
Systemic immunosuppression is always required but topical
glucocorticoids should be used cautiously due to the risk of
aggravating keratolysis (corneal thinning). Secondary infection
should be prevented with topical antibiotics and attention should
be paid to corneal hydration, through the use of artificial tears
and lubricants.
More common causes of peripheral corneal ulceration are
blepharitis and acne rosacea, causing ocular irritation rather
than frank pain. Hypersensitivity to staphylococcal exotoxin
leads to stromal infiltrate adjacent to, but sparing, the limbus
(marginal keratitis). Resolution of this self-limiting condition can
be assisted by the use of topical chloramphenicol, with or without
topical glucocorticoids. Prevention is through management of the
underlying condition, usually with ocular lid hygiene for simple
blepharitis and metronidazole gel for rosacea.
Scleritis
Scleritis is usually accompanied by severe pain, worse on eye
movement and often waking the patient through the night.
Diagnosis of anterior scleritis is usually straightforward, with
the eye showing diffuse or nodular erythema (although it may
have to be searched for under the eyelids). Posterior uveitis is
often accompanied by reduced vision and oedema of the retina,
choroid and extraocular muscles.
White patches of necrosis (pallor) within the erythema are an
ominous sign, indicative of systemic vasculitis. Non-necrotising
scleritis is commonly idiopathic but may be associated with
other autoimmune conditions, particularly rheumatoid arthritis
and inflammatory bowel disease. It is also common with herpes
zoster ophthalmicus, intraocular involvement being indicated by
the involvement of the lateral external nose (Hutchison’s sign).
Necrotising scleritis requires aggressive immunosuppression;
non-necrotising scleritis can occasionally be managed by topical
glucocorticoids or non-steroidal anti-inflammatory drugs (NSAIDs)
but usually requires oral glucocorticoids.
Some patients with recurrent episodes of scleritis, or in whom
inflammation is gradual and prolonged, may develop scleral
thinning (scleromalacia), revealing the underlying blue choroid.
Episcleritis
Episcleritis is a benign self-limiting condition of uncertain aetiology,
occasionally associated with other inflammatory disorders.
Sectoral redness of the episclera is usual, although nodules
can form. Often confused with scleritis, although usually less
symptomatic, the diagnostic topical application of phenylephrine
turns the inflamed episclera white but has no effect on the
redness of scleritis. Treatment is with cold artificial tears, although
occasionally topical NSAIDs or topical glucocorticoids are required.
Uveitis
Uveitis is an overarching term for inflammation anywhere in the
uveal tract, retina or vitreous. It may be classified according to
speed of onset, location, specific features, or aetiology (Box 27.9).
Syphilis can cause all forms of uveitis. Active tuberculosis may
present with an occlusive vasculitis or serpiginous (snake-like)
choroiditis emanating from the optic disc. Latent tuberculosis is a
particular concern because treatment of the uveitis with biologies
may induce active systemic infection. Furthermore, the most
commonly used biologic for uveitis - anti-tumour necrosis factor
therapy (e.g. adalimumab, infliximab) - may trigger demyelination.
The most common form of uveitis is anterior uveitis, which is
usually idiopathic but may be associated with other autoimmune
conditions, particularly HLA-B27-related spondyloarthropathies
(p. 1027); it is rarely caused directly by infection. Acutely, dilating
drops are used to prevent the inflamed iris from sticking to the
lens (posterior synechiae) and obstructing the outflow of aqueous
fluid, while a tapering dose of topical glucocorticoids, usually
over 4-6 weeks, mitigates the local signs and symptoms of the
self-resolving inflammation. Inadequate treatment can lead to
pupil block glaucoma and cataract. Posterior complications can
also develop, predominantly macular oedema, the main cause
of visual impairment in all forms of uveitis.
With intermediate uveitis, inflammation occurs at the pars
plana, with most symptoms, predominantly floaters, being a
result of inflammation of the vitreous base. Unlike anterior uveitis,
pure intermediate uveitis is not associated with iris inflammation;
instead, white blood cells are seen predominantly in the anterior
vitreous, with a lesser amount overspilling into the anterior
chamber. Treatment is challenging. Topical therapy is ineffective,
as it does not penetrate beyond the anterior chamber, but
symptoms of floaters are not often sufficient to justify systemic
immunosuppression. In some cases, vitritis (vitreous inflammation),
or more commonly macular oedema, may cause visual
impairment. Occasionally, retinal neovascular proliferation may
occur, either as an inflammatory response or as a direct result
Specialist ophthalmological conditions • 1173
of capillary occlusion. Intermediate uveitis may be associated
with demyelination, sarcoidosis and inflammatory bowel disease.
Posterior uveitis tends to present with visual impairment
secondary to macular oedema, vitritis or choroiditis. More chronic
forms also exist and these tend to present with photopsia, visual field
defects or distortion inducing choroidal neovascular membranes.
Infectious conditions
Conjunctivitis
Conjunctivitis is predominantly caused by bacteria or viruses,
and is usually self-limiting in 7-10 days. Bacterial conjunctivitis
is associated with a purulent discharge and viral conjunctivitis
with a watery discharge, the latter often being confused with the
photophobia and reflex lacrimation of anterior uveitis. Underlying
chlamydial infection should always be considered if there is a
persistent thick, mucopurulent discharge (p. 340).
Allergic conjunctivitis is also common, either as a component
of hay fever (allergic rhinitis, p. 622) or as an allergy to
chloramphenicol, which is commonly used to treat conjunctivitis.
Rarely, conjunctivitis may be associated with inflammatory
systemic mucus membrane disorders, such as ocular mucus
membrane (cicatricial) pemphigoid or Stevens-Johnson syndrome
(pp. 1 254 and 1 264). The secondary effects of loss of conjunctival
function can be devastating to the cornea. Other causes of
conjunctival scarring include trachoma (p. 273), chemical burns
and orbital radiotherapy.
Ijnfectious keratitis/corneal ulceration
Inflammation of the cornea should always raise concern about
underlying infection (Box 27.10). Central ulceration is always
more serious than peripheral, through involvement of the visual
axis. Cultures from corneal scraping or biopsy may be required,
although much infectious keratitis is treated empirically on the
basis of site, morphology and response to treatment.
In the West, the most common cause of infectious keratitis
is herpes simplex virus type 1 (occasionally type 2) (Fig. 27.5).
All layers of the cornea may be involved: the epithelium in the
form of dendritic ulceration; the stroma in the form of white
infiltrate and occasionally necrosis; and the endothelium in the
form of localised oedema and keratitic precipitates. Loss of
corneal sensation is common following herpes simplex keratitis,
and occasionally neurotrophic keratopathy may result. Epithelial
disease is self-limiting but treatment with topical or oral antivirals
reduces the risk of stromal involvement and scarring. Stromal and
endothelial disease requires additional topical glucocorticoids, but
only once any epithelial defect has healed. Herpes simplex keratitis
is analogous to herpes labialis; recurrences are therefore common
and, if frequent, may warrant long-term oral antivirals. Corneal
grafting may be required but the risk of recurrence remains.
Bacteria also cause infectious keratitis, especially following
corneal trauma or contact lens misuse. Other risk factors for
microbial keratitis include topical glucocorticoids and pre-existing
ocular surface disease. Bacterial keratitis has many causes,
some of which do not respond to chloramphenicol, so topical
quinolones are used as first-line agents. Rarely, the free-living
amoeba Acanthamoeba castellanii may be a cause of contact
lens-associated keratitis, presenting subacutely and leading to
corneal nerve infiltration, keratitis and accompanying scleritis.
Fungal keratitis is the most common cause of infectious keratitis
in developing countries, particularly if there has been corneal
trauma and contact with soil or plant matter. It is usually caused
by Fusarium. Fungal keratitis has no particular distinguishing
features and delayed diagnosis is common. If it is suspected,
cultures should be undertaken and antifungal treatment, which
is hampered by poor corneal penetration of antifungals, started
promptly. Corneal transplantation is often required.
Endophthalmitis
Endophthalmitis is infection of the anterior and posterior chambers
of the eye. It may be exogenous (e.g. from penetrating trauma
or following surgery) or, less commonly, endogenous, caused
by haematogenous spread of microorganisms within the blood,
which gain entry to the eye via the choroid and ciliary body.
The causes of endogenous endophthalmitis are therefore the
causes of bacteraemia and fungaemia (p. 225). Gram-positive
j 27.10 Common causes of infectious keratitis
Organism
Features/comments
Treatment
Viruses
Herpes simplex
Varicella zoster
Characteristic ‘dendritic’ ulcer is the most
common form, often recurrent
Herpes zoster ophthalmicus
Topical/systemic aciclovir
(with topical glucocorticoid for stromal keratitis once the
epithelium is healed)
Systemic aciclovir
Bacteria
Pseudomonas aeruginosa
Staphylococcus aureus
Coagulase-negative staphylococci
Propionibacterium spp.
Coagulase-negative staphylococci and
Propionibacterium spp. are members of the skin
flora, and must not be dismissed as contaminants
Topical fluoroquinolone with Gram-positive and Gram¬
negative cover (e.g. ofloxacin)
Subsequent treatment depends on sensitivity testing results
Fungi
Fusarium sp.
Aspergillus sp.
Candida sp.
Fusarium and Aspergillus keratitis are often
associated with soil and/or corneal trauma; may
also be contact lens-related
Candida causes post-keratoplasty keratitis
Options include topical natamycin (if available),
amphotericin B, voriconazole and other azoles (e.g.
econazole), and systemic fluconazole or voriconazole
Parasites
Acanthamoeba castellanii
(free-living amoeba)
Onchocerca volvulus (nematode)
Associated with poor contact lens hygiene
See page 292
Topical polyhexamethylene biguanide
1174 • MEDICAL OPHTHALMOLOGY
Fig. 27.5 Infective keratitis. [A] Herpes simplex dendritic ulcer stained with fluorescein. [§] Fusarium keratitis. An irregularly edged lesion suggests a
fungal cause but is not pathognomonic. A, Courtesy of McPherson Optometry, Aberdeen. B, From Macsai MS, Fontes BM. Rapid diagnosis in ophthalmology:
anterior segment. Elsevier Inc.; 2008. (Courtesy of the External Eye Disease and Cornea Section, Federal University of Sao Paulo, Brazil.)
#
Fig. 27.6 Focal chorioretinitis in clinically suspected endogenous
Candida endophthalmitis. This patient was an intravenous drug user and
improved with empirical oral fluconazole. From Ryan SJ (ed). Retina, 5th
edn. Saunders, Elsevier Inc.; 2013. (Case courtesy of Jeffrey K. Moore,
MD.)
bacteria are most common, followed by Gram-negative bacteria
and then fungi.
Clinical presentation is with visual blurring and/or visual loss,
which are usually unilateral. Ocular findings range from a few
deposits in the retina/choroid (chorioretinitis) to panendophthalmitis,
in which there is a severe inflammatory reaction in both the anterior
and posterior chambers. A specific appearance of the retina is
described for Candida endophthalmitis, which characteristically
causes creamy-white retinal or chorioretinal lesions (Fig. 27.6).
It is vitally important to sample the vitreous, as this may provide
the only opportunity to determine the most appropriate therapy.
Treatment is with systemic and/or intravitreal antibiotics
or antifungal agents, depending on the cause and severity.
Vitrectomy may also be required.
Cataract
Cataract is permanent opacity of the lens (Fig. 27.7). Globally,
untreated cataract is the most common cause of visual
impairment, although in countries where surgery is available,
age-related macular degeneration is a more common cause.
Fig. 27.7 Sunflower cataract and Kayser-Fleischer ring (arrow) in
Wilson’s disease. From Kaiser PK, Friedman NJ (eds). Massachusetts Eye
and Ear Infirmary Illustrated manual of ophthalmology, 4th edn. Saunders,
Elsevier Inc.; 2014.
The normal lens thickens and opacifies with age, and
cataract can be detected in more than half the population
over the age 65 (senile cataract). Many ocular and systemic
diseases can predispose to cataract formation, the most
common being uveitis and diabetes mellitus. Wilson’s disease
(hepatolenticular degeneration, p. 896) causes a characteristic
‘sunflower’ cataract. Excessive exposure to ultraviolet light,
ionising radiation and glucocorticoid therapy are also predisposing
factors.
The characteristic symptoms of cataract are progressive
loss of vision and glare. If these become serious enough to
require treatment, surgical intervention will be required, usually
in the form of ultrasonic phacoemulsification with intraocular
lens (IOL) implant.
Other common ophthalmological findings in old age are shown
in Box 27.1 1 .
Diabetic eye disease
Diabetic retinopathy
Diabetic retinopathy is one of the most common causes of visual
impairment in people of working age in developed countries. The
prevalence of diabetic retinopathy increases with the duration
of diabetes. Almost all individuals with type 1 diabetes, and
most of those with type 2 diabetes, will have some degree of
Specialist ophthalmological conditions • 1175
£
• Small pupils that dilate poorly with mydriatics: common
neurodegenerative finding, particularly with diabetes.
• Spurious findings on automated perimetry: decreasing manual
dexterity and cognitive function often render automated perimetry
findings unreliable.
• Lens opacities: cataract is ubiquitous but requires treatment only if
symptomatic.
• Drusen: common from mid-life onwards. Larger (soft) drusen are
more likely to herald age-related macular degeneration than smaller
(hard) drusen.
• Glaucoma: angle closure glaucoma is more common as the
increasing size of the lens shallows the anterior chamber. Once it is
identified, both eyes are always treated to prevent development/
recurrence. Chronic open angle glaucoma is more common in those
with a family history or ocular hypertension (isolated raised
intraocular pressure).
• Impaired upgaze: common. It is differentiated from progressive
supranuclear palsy (p. 1114) by the doll’s head manoeuvre, the full
range of vertical movement being retained in progressive
supranuclear palsy PSP.
• Ptosis: mechanical ptosis is common due to degenerative
disinsertion of the levator palpebrae superioris aponeurosis. A high
skin crease and preserved ability to elevate help differentiate it from
other causes (p. 1090).
• Late-onset presentation of congenital conditions: adult
pseudovitelliform macular ‘degeneration’ is an autosomal dominant
retinal dystrophy, which causes mild visual impairment.
Oculopharyngeal muscular dystrophy is an autosomal dominant
condition characterised by later-onset chronic progressive external
ophthalmoparesis and swallowing difficulties.
27.1 1 Common ophthalmological findings in old age
retinopathy after 20 years. Fortunately, most patients develop
only mild forms of retinopathy.
Pathogenesis
The underlying pathogenesis of diabetic retinopathy is local
vascular endothelial growth factor production initiated by
hyperglycaemia-induced capillary occlusion. This occlusion
stimulates increased production of retinal vascular endothelial
growth factor, which not only increases capillary permeability,
leading to retinal oedema, but also stimulates angiogenesis,
leading to new vessel formation.
Clinical features
The initial clinical feature of diabetic retinopathy, capillary occlusion,
is visible only on retinal angiography. Capillaries adjacent to the
occluded capillary form discrete swellings (microaneurysms), which
leak fluid and blood, causing oedema and retinal haemorrhages
(Fig. 27.8).
Clinically, microaneurysms appear as isolated red dots, the
capillaries being too small to visualise. At the edge of any leaking fluid,
lipids precipitate out to form exudate, like the tidemark of the sea.
In turn, capillaries with microaneurysms also occlude, their
microaneurysms turning white before disappearing entirely from
clinical view. As more and more capillaries occlude, larger patches
of retinal ischaemia form, leading to sufficient vascular endothelial
growth factor production to induce the growth of new vessels
at the border of diseased and undiseased retina.
Within patches of retinal ischaemia, diseased remnants of
partially perfused capillaries form intraretinal microvascular
abnormalities (IRMAs) and retinal veins develop multiple diffuse
swellings (venous beading). These signs are best seen on
fluorescein angiography.
S
Inherited conditions
< Stargardt’s disease: autosomal recessive macular dystrophy that
commonly presents in adolescence/early adulthood, causing
significant bilateral impairment of central vision.
Developmental anomalies
• Pathological myopia: due to elongated ocular axial length rather
than refractive index of cornea and lens. Increased risk of retinal
detachment and choroidal neovascular membrane formation.
• Optic disc drusen: come to prominence during adolescence and
usually first detected during routine examination. Often mistaken for
papilloedema, particularly in the setting of coincidental daily
headache.
• Amblyopia: occasionally detected after the age of 7 years,
particularly in the absence of pre-school screening, when it is
unlikely to respond to patching of the other eye.
< Keratoconus: presents with increasing astigmatism (distortion of
vision due to abnormal corneal topography). Hard contact lenses are
the mainstay of therapy. Further progression may be prevented
through ‘cross-linking’ surgery.
Deterioration of existing conditions
• Diabetic retinopathy: in type 1 diabetes, retinopathy usually first
presents at least 5 years after diagnosis, which often coincides with
adolescence. Puberty may accelerate progression. Greatest risk is
disengagement with diabetes care, including retinal screening,
significantly increasing later presentation with advanced
symptomatic retinopathy.
• Adult manifestations of retinopathy of prematurity: clinical
features depend on the type of treatment used in the neonatal
period and include retinal detachment, angle closure glaucoma,
severe myopia and cataract.
Sexual activity
• Chlamydia conjunctivitis: onset of sexual activity may lead to this
ocular condition, which is associated with reactive arthritis (p. 1031).
Untreated coexistent genital tract infection may cause infertility.
Transition to adult services
• Neurofibromatosis type 1 : see page 1131.
• Optic nerve astrocytoma/glioma: often develops in late childhood or
early adolescence.
Sports medicine
• Contact sports: eye protection is important for all, especially if
there is only one functional eye, e.g. with amblyopia.
27.13 Visual disorders and pregnancy
• Ocular inflammation: pregnancy appears to have a protective
effect on many inflammatory disorders, although not systemic lupus
erythematosus. Most patients can taper treatment during
pregnancy. Mycophenolate mofetil is teratogenic. Glucocorticoids
and tacrolimus appear safe. The use of biologies during pregnancy
should be based on a balance of risks, and professional guidelines
should be consulted.
• Diabetic retinopathy: may be accelerated during pregnancy
because the placenta is a potent source of angiogenic growth
factors. Retinal screening each trimester is recommended.
• HELLP/pre-eclampsia/eclampsia (p. 1 284): retinal features of
accelerated hypertension (p. 514) may be seen, including optic disc
oedema, flame haemorrhages and cotton wool spots. Occasionally,
exudative retinal detachments occur. Vasogenic oedema (posterior
reversible encephalopathy syndrome), affecting the posterior occipital
and parietal lobes, may cause cortical visual impairment. All features
tend to resolve with delivery or control of blood pressure.
27.12 Medical ophthalmology in adolescence
1176 • MEDICAL OPHTHALMOLOGY
Fig. 27.8 Diabetic retinopathy. [A] Colour photograph of severe background diabetic retinopathy: multiple blot haemorrhages indicative of capillary
occlusion; dot haemorrhages indistinguishable from microaneurysms or microaneurysmal bleeds; and cotton wool spots indicative of arteriolar occlusion.
[B] Red-free image shows the presence of extensive haemorrhages more clearly; the more haemorrhages, the greater the degree of likely capillary
occlusion. [C] Fluorescein angiogram now reveals extensive entrapment of fluorescein within multiple microaneurysms. [D] Colour photograph showing three
cardinal consequences of capillary occlusion: intra-retinal microvascular anomalies occurring within an area of capillary occlusion (top arrow); venous
reduplication (rare finding), with venous beading, extending from the reduplication towards the optic disc, occurring where capillaries are occluded either
side of the vein (middle arrow); and new vessel formation occurring at the border between the diseased and health retina (bottom arrow). [|] Red -free image
shows these features, particularly intra-retinal microvascular anomalies, more clearly. Note the relative pallor compared to the right-hand side of the image,
which is indicative of widespread capillary occlusion. Absolute pallor never occurs, as it is ‘masked’ by the highly vascularised choroid lying underneath.
A-E, Courtesy of Aberdeen Royal Infirmary.
New vessels and their glial tissue (like a cabbage leaf) grow
from retinal veins, through the overlying internal limiting membrane
into the vitreous, triggering local inflammation and contracting
scars. The vitreous is strongly adherent to the pars plana. It
pulls back on the new vessel, triggering further bleeding, growth,
inflammation and scarring. If the scarring is sufficient, then
tractional retinal detachment and complete blindness may occur.
Other retinal lesions, not unique to capillary occlusion, are also
seen in diabetic retinopathy. These include flame haemorrhages
and cotton wool spots (soft exudates). Flame haemorrhages
are horizontal streaky haemorrhages in the retinal nerve-fibre
layer. They are also seen in any severe anaemia, e.g. bacterial
endocarditis and leukaemia. Cotton wool spots are also situated
in the nerve-fibre layer and are usually most numerous nasal
to the optic disc, where the nerve fibres crowd together.
They are also seen in accelerated hypertension, after severe
hypoglycaemia and occasionally in giant cell arteritis. A cotton
wool spot combined with an enclosing flame haemorrhage is
termed a Roth spot. Roth spots have traditionally been associated
with endocarditis, although they may be seen with any cause
of a flame haemorrhage.
Management of proliferative diabetic retinopathy
If untreated, proliferative retinopathy eventually causes severe
visual impairment through recurrent vitreous haemorrhage and
retinal detachment. Pan-retinal laser photocoagulation therapy
is extremely effective at preserving vision, if applied before
complications set in.
Historically, laser therapy was used empirically to ablate the
retina extensively outside the macula. However, this caused
secondary optic atrophy and night blindness (nyctalopia),
which interfered with the ability to drive. Modern application of
laser is lighter, more tailored to the sites of underlying capillary
ischaemia and relatively free of side-effects, only occasionally
resulting in loss of the ability to drive. In the UK there is a
requirement to inform the driver licensing authority if retinopathy
is (or has been) present in both eyes, irrespective of treatment
history.
Intravitreal injections of anti-vascular endothelial growth
factor (e.g. ranibizumab, aflibercept, bevacizumab) also cause
temporary regression of proliferative retinopathy, whereas, after
pan-retinal laser therapy, background and proliferative types
of retinopathy regress permanently. If both eyes have been
treated with laser, patients can be safely discharged to a retinal
screening programme.
Management of diabetic macular oedema
Traditionally, oedema seen on slit-lamp biomicroscopy was
categorised according to three patterns of leakage elucidated
from fluorescein angiogram studies:
• focal leakage from microaneurysms
• diffuse leakage from diseased capillaries
• ischaemia (no leakage) from thrombosis of the perifoveal
capillaries.
Laser was applied, either directly on leaking microaneurysms
or empirically by placing a grid of burns on the affected macula,
to reduce leakage. The main aim was to treat oedema before
the fovea was affected, as laser therapy for oedema affecting
the fovea was never particularly effective.
Specialist ophthalmological conditions • 1177
However, retinal screening programmes have demonstrated that
extrafoveal macular oedema often resolves spontaneously, and the
introduction of intravitreal injection therapy, which rescues vision
in 50% of those treated regardless of the mechanism of oedema,
has led to a paradigm shift in management. Now, rather than laser
treatment of asymptomatic oedema that does not involve the
centre of the fovea, the emphasis has shifted to treating those who
are symptomatic from centre- involving foveal oedema (confirmed
on optical coherence tomography) with anti-vascular endothelial
growth factor injections. Although this method of treatment is more
effective, monthly injections may be required indefinitely.
Prevention
There is a clear relationship between glycaemic control and
the incidence of diabetic retinopathy. A combination of good
glycaemic and blood pressure control also slows the progression
of retinopathy.
When blood glucose is rapidly lowered in patients with type
1 diabetes, however, there can be a transient deterioration
of retinopathy, predominantly in the form of cotton wool spot
formation, but occasionally triggering new vessel formation. The
trigger is believed to be increased systemic insulin growth factor
release, which is most likely to occur with sudden correction
of eating disorders or reinstitution of insulin therapy in those
who miss out injections, often to induce weight loss. This often
occurs during hospitalisation for other reasons.
Although, ideally, any improvement in glycaemic control should
be gradual, in many circumstances this is hard to achieve,
particularly if the patient suddenly decides to comply with
treatment, leading to dramatic improvement in glycaemic control.
Screening
Systematic screening for asymptomatic proliferative retinopathy
has been shown to be cost-effective. It has led to the introduction
of population-based screening programmes in the UK and other
countries, where health care is funded centrally. There is little
evidence that screening asymptomatic patients for macular
oedema is cost-effective, although a by-product of screening is
that suspected macular oedema has become the most common
reason for referral from retinal screening to ophthalmology.
Although hand-held ophthalmoscopy has been shown to
have poor sensitivity compared to examination by slit-lamp
biomicroscopy or retinal photography, any form of screening is
better than none where resources are scarce. Currently, optical
coherence tomography is being added to the screening pathway
to reduce false-negative referrals for macular oedema.
Historically, annual screening has been advocated. However,
evidence now indicates that patients with repeated normal
screens, particularly those with type 2 diabetes, can be safely
screened every 2 years.
In pregnancy, the placenta is a source of angiogenic growth
factors. For this reason, although the risk of developing significant
retinopathy during pregnancy remains low, pregnant women
should be screened every trimester until the placenta is delivered.
I Other causes of visual loss in people
with diabetes
Around 50% of visual loss in people with type 2 diabetes results
from causes other than diabetic retinopathy. These include
cataract, age-related macular degeneration, retinal vein occlusion,
retinal arterial occlusion, non-arteritic ischaemic optic neuropathy
and glaucoma. Some of these conditions are to be expected
in this group, as they relate to cardiovascular risk factors (e.g.
hypertension, hyperlipidaemia and smoking), all of which are
prevalent in people with type 2 diabetes.
In diabetes, metabolic changes in the lens (which are not yet
fully elaborated) cause premature and/or accelerated cataract
formation. A rare type of ‘snowflake’ cataract occurs in young
patients with poorly controlled diabetes. This does not usually
affect vision but tends to make fundal examination difficult. The
indications for cataract surgery in diabetes are similar to those
in the non-diabetic population, but an additional indication in
diabetes is when adequate assessment of the fundus and/or
retinal laser therapy becomes impossible.
Retinal vascular occlusion
Retinal vein occlusion (thrombosis)
Retinal vein occlusion is an important vascular cause of visual
impairment, visual loss resulting from macular oedema or occasionally
from neovascularisation, both of which are managed in a similar
way to diabetic macular oedema or proliferative diabetic retinopathy.
Although pathogenesis of retinal vein occlusion is not fully
understood, the most common mechanism is believed to be
compression of a vein by an adjacent arteriosclerotic artery. Retinal
vessels are unusual in that, where the arteries and veins cross over
each other, they share a common outer layer (tunica adventitia). This
means that arteriosclerotic thickening of an artery leads directly to
compression of the adjacent vein (arteriovenous nipping).
A less common cause of retinal vein occlusion is inflammation
of the retinal vein (periphlebitis), also called retinal vasculitis (unlike
systemic vasculitis, the arterial system is not involved). Periphlebitis
should be suspected in younger patients and in patients with
no obvious risk factors for arteriosclerosis. Diagnosis is made
by fluorescein angiography and treatment is with systemic
immunosuppression, with or without adjunctive intravitreal therapy.
Retinal vein occlusion is associated with systemic hypertension
and may rarely result from hyperviscosity due to a myeloproliferative
disorder, multiple myeloma, Waldenstrom’s macroglobulinaemia
or leukaemia. Glaucoma is associated with retinal vein occlusion
but whether this is a direct cause or merely a comorbidity in
the elderly is not known.
Clinical presentation is with unilateral painless loss of central
vision (central retinal vein thrombosis) or an area of peripheral
vision (branch retinal vein thrombosis). Fundoscopic features
include flame haemorrhages, cotton wool spots, macular oedema
and a swollen optic disc (Fig. 27.9).
Fig. 27.9 Central retinal vein occlusion (thrombosis), showing flame
haemorrhages, cotton wool spots, macular oedema and a swollen
optic disc. Courtesy of Aberdeen Royal Infirmary.
1178 • MEDICAL OPHTHALMOLOGY
Fig. 27.10 Retinal artery occlusion. [JO Colour fundus photograph of central retinal artery occlusion, showing a classic cherry-red spot and a superior
optic disc haemorrhage, -jj] Superior branch retinal artery occlusion due an embolus at the disc branch retinal artery occlusion, showing a pale segment
of retina. A, From DukerJS, Waheed NK, Goldman DR. Handbook of retinal OCT. Saunders, Elsevier Inc.; 2014. B, From Bowling B. Kanski’s Clinical
ophthalmology, 8th edn. Elsevier Ltd; 2016.
The management of retinal vein occlusion is twofold: management
of the underlying aetiology and management of the consequences
of retinal vein occlusion. Where an underlying risk factor for
arteriosclerosis is clearly present (p. 484), then secondary prevention
measures should be commenced. However, the role of secondary
prevention of arteriosclerosis in isolated retinal vein occlusion,
although common practice by some, remains controversial.
Retinal artery occlusion
Retinal artery occlusion is usually an embolic phenomenon.
Common predisposing factors are therefore (predominantly
carotid) atherosclerosis valvular heart disease, arrhythmias and
infective endocarditis. The next most common cause is vasculitis,
mainly giant cell arteritis (p. 1042).
Retinal artery occlusion presents with painless unilateral visual
loss, the extent and location of which depend on whether
there is a central occlusion or a branch occlusion (peripheral
occlusions may be asymptomatic). Transient occlusion of the
internal carotid or ophthalmic artery causes transient visual loss,
or amaurosis fugax (p. 1152). The typical fundoscopic finding in
a central occlusion is a transiently pale retina with a ‘cherry-red’
spot at the macula, the appearance developing over an hour or
so after the occlusion (Fig. 27.10). In branch occlusions there is
no cherry-red spot and the retinal pallor is regional.
Age-related macular degeneration
Age-related macular degeneration is the most common cause
of visual impairment in the Western world. There are two basic
forms: atrophic (dry) and neovascular (wet). The underlying
mechanism is dysfunction of the retinal pigment epithelium, leading
to overlying photoreceptor death. Choroidal neovascularisation,
growing under and into the overlying retina, may occur, distorting
the anatomy of the photoreceptors and ending in scar formation.
Both forms are preceded by deposits under the retinal pigment
epithelium (‘drusen’), often followed by the development of focal
areas of macular hypo- and hyperpigmentation, where diseased
retinal pigment epithelial cells have precipitated their pigment
(age-related maculopathy).
The atrophic form presents with gradual onset of central visual
blurring, accompanied, to a lesser degree, by visual distortion.
Large (geographic), central patches of atrophy are seen with
areas of adjacent hyperpigmentation. In the neovascular form,
sudden onset of central distortion, progressing within weeks, is
the predominant symptom. Apart from age the main risk factor
appears to be smoking.
The advent of anti -vascular endothelial growth factor injectors
has led to effective therapy for the neovascular form, in many
but not all. Unfortunately, treatment is expensive and requires
considerable financial and staff resources to treat in timely
fashion; delayed treatment can lead to irreversible visual loss.
For whichever type, whether treatable or not, visual rehabilitation,
through the use of appropriate magnifiers, alteration in lighting
and specialised adaptation of everyday living objects, remains
important adjunctive therapy.
Further information
Websites
jrcptb.org.uk/specialties/medical-ophthalmology Flow to train in
medical ophthalmology in the UK.
ndrs-wp.scot.nhs.uk Scottish Diabetic Retinopathy Screening
Collaborative: aspects of screening for diabetic retinopathy,
including rationale, organisation, delivery and an on-line training
handbook.
rcophth.ac.uk/standards-publications-research/clinical-guidelines Royal
College of Ophthalmologists, London: as part of its role in
championing excellence, produces a range of pragmatic surgical
and medical guidelines.
sun.scot.nhs.uk Scottish Uveitis Network: standards of care, treatment
guidelines and information leaflets.
Medical psychiatry
Clinical examination 1180
The psychiatric interview 1181
The mental state examination 1181
Investigations in medical psychiatry 1183
Functional anatomy and physiology 1183
Biological factors 1 1 83
Psychological and behavioural factors 1183
Social and environmental factors 1 1 84
Presenting problems in psychiatric illness 1184
Delirium 1184
Alcohol misuse 1 1 84
Substance misuse 1184
Delusions and hallucinations 1 1 84
Low mood 1 1 85
Elevated mood 1 1 86
Anxiety 1 1 86
Psychological factors affecting medical conditions 1186
Medically unexplained somatic symptoms 1 1 87
Self-harm 1187
Disturbed and aggressive behaviour 1 1 88
Principles of management of psychiatric disorders 1189
Pharmacological treatments 1 1 90
Electroconvulsive therapy 1190
Other forms of electromagnetic stimulation 1190
Surgery 1 1 90
Psychological therapies 1 1 90
Social interventions 1 1 91
Psychiatric disorders 1191
Dementia 1191
Alcohol misuse and dependence 1194
Substance misuse disorder 1195
Schizophrenia 1196
Mood disorders 1 1 98
Anxiety disorders 1 200
Obsessive-compulsive disorder 1 201
Stress-related disorders 1 201
Somatoform disorders 1 202
Eating disorders 1 203
Personality disorders 1 204
Factitious disorders and malingering 1 205
Puerperal psychiatric disorders 1 206
Psychiatry and the law 1207
1180 • MEDICAL PSYCHIATRY
Psychiatric disorders have traditionally been considered as ‘mental’
rather than as ‘physical’ illnesses. This is because they manifest
with disordered functioning in the areas of emotion, perception,
thinking and memory, and formerly had no clearly biological
basis. However, as biochemical and structural abnormalities of
the brain are identified in an increasing number of psychiatric
disorders, and psychological and behavioural factors are identified
in many medical illnesses, the distinction between mental and
physical illness has become questionable.
The World Health Organisation (WHO) periodically publishes
its International Classification of Disease (ICD), which provides
definitions for every recognised clinical condition. The current
edition (ICD-10) comprises 22 chapters. The diagnoses listed
in Chapter V, ‘Mental and behavioural disorders’ (Box 28.1),
are used by psychiatrists around the world in everyday clinical
practice and it is these conditions that provide the focus for this
chapter.
Psychiatric disorders are among the most common of all
human illnesses. The WHO’s Global Burden of Disease study
found ‘Mental, neurological and substance misuse disorders’ to
be the leading cause of ‘Years lost to disability’ (YLDs), accounting
for 28.5% of global YLDs. As with most clinical conditions, the
prevalence of mental disorders varies with the setting. In the
general population, depression, anxiety disorders and adjustment
disorders are most common (>10%) and psychosis is rare
(<2%); in acute medical wards of general hospitals, organic
disorders such as delirium are very common, with prevalence
highest among sick, elderly patients; in specialist general
psychiatric services, psychoses are the most common disorders
(Box 28.2).
Clinical examination
As in other areas of medicine, the psychiatric assessment
comprises a structured clinical history and examination followed
by appropriate investigations. However, psychiatric assessment
differs from a standard medical assessment in the following
ways:
• There is greater emphasis on the history and relatively less
reliance on investigations.
• A large part of the clinical examination component is
conducted as the history is being taken rather than as a
discrete set of procedures afterwards.
28.1 World Health Organisation classification of
psychiatric disorders
Chapter V (F00-F99)
Mental and behavioural disorders
Examples
F00-F09
Organic mental disorders
Dementias
Delirium
Other mental disorders due to
brain damage or disease
FI 0— FI 9
Disorders due to psychoactive
substances: alcohol, opioids,
cannabinoids etc.
Intoxication
Harmful use
Dependence
Withdrawal
F20-F29
Schizophrenia and delusional
disorders
Schizophrenia
F30-F39
Mood [affective] disorders
Depression
Bipolar affective disorder
F40-F48
Neurotic, stress- related and
somatoform disorders
Phobias
Generalised anxiety disorder
Obsessive-compulsive disorder
Post-traumatic stress disorder
Adjustment disorders
Somatoform disorders
F50-F59
Behavioural syndromes associated
with physiological disturbances
Eating disorders: anorexia and
bulimia nervosa
Sexual dysfunction
F60-F69
Disorders of adult personality and
behaviour
Specific personality disorders
Trichotillomania
Gender identity disorders
F70-F79
Mental retardation
Mild, moderate, severe or
profound
F80-F89
Disorders of psychological
development
Autism
Asperger’s syndrome
F90-F98
Behavioural and emotional disorders
of childhood
Hyperkinetic disorders
Tic disorders
From WHO. International Classification of Disease, 10th edn (ICD-10).
i
28.2 Prevalence of psychiatric disorders by medical setting
General practice
Medical/surgical
Outpatients
Inpatients
General psychiatric services
Delirium
-
-
+++
-
Alcohol/substance abuse
++
++
+++
+++
Schizophrenia
-
-
-
+++
Bipolar affective disorder
-
-
-
+++
Depression
++
++
+++
+++
Anxiety disorders
++
++
++
+++
Adjustment disorders
++
++
+++
+
Somatoform disorders
+
+++
++
-
Personality disorders
+
+
+
+++
- ‘rare’ (<2%); + ‘uncommon’ (2-5%); ++ ‘common’ (5-10%); +++ ‘very common’ (>10%)
Clinical examination • 1181
• It commonly includes the interviewing of an informant,
usually a relative or friend who knows the patient,
especially when the illness affects the patient’s ability to
give an accurate history.
A full psychiatric history (Box 28.3) incorporating a detailed
mental state examination may take an hour or more because of
its complexity. A brief mental state examination, usually taking
no more than a few minutes (see below), should be part of the
assessment of all patients, not merely those deemed to have
psychiatric illnesses.
The psychiatric interview
The aims of the interview are to:
• establish a therapeutic relationship with the patient
• elicit the symptoms, history and background information
(Box 28.3)
• examine the mental state
• provide information, reassurance and advice.
28.3 How to structure a psychiatric interview
Presenting problem
Reason for referral
• Why the patient has been referred and by whom
Presenting complaints
• The patient should be asked to describe the main problems for
which help is requested and what they want the doctor to do
History of present illness
• The patient should be asked to describe the course of the illness
from when symptoms were first noticed
• The interviewer asks direct questions to determine the nature,
duration and severity of symptoms, and any associated factors
Background
Family history
• Description of parents and siblings, and a record of any mental
illness in relatives
Personal history
• Birth and early developmental history, major events in childhood,
education, occupational history, relationship(s), marriage, children,
current social circumstances
Previous medical and psychiatric history
• Previous health, accidents and operations
• Use of alcohol, tobacco and other drugs
• Direct questions may be needed concerning previous psychiatric
history since this may not be volunteered: ‘Have you ever been
treated for depression or nerves?’ or ‘Have you ever suffered a
nervous breakdown?’
Previous personality
• The patterns of behaviour and thinking that characterise a person,
including their relationships with other people and reactions to
stress (useful information may be obtained from an informant who
has known the patient well for many years)
The mental state examination
The mental state examination (MSE) is a systematic examination
of the patient’s thinking, emotion and behaviour. As with the
clinical examination in other areas of medicine, the aim is to elicit
objective clinical signs. While many aspects of the patient’s mental
state may be observed as the history is being taken, specific
enquiries about important features should always be made.
General appearance and behaviour
Any abnormalities of alertness or motor behaviour, such as
restlessness or retardation, should be noted. The level of
consciousness should be determined, especially in the assessment
of possible delirium.
Speech
Speed and fluency should be observed, including slow (retarded)
speech and word-finding difficulty. ‘Pressure of speech’ describes
rapid speech that is difficult to interrupt.
Mood
This can be judged by facial expression, posture and movements.
Patients should also be asked if they feel sad or depressed and
if they lack ability to experience pleasure (anhedonia). Are they
anxious, worried or tense? Is mood elevated with excess energy
and a reduced need for sleep, as in (hypo)mania?
Thoughts
The content of thought can be elicited by asking ‘What are
your main concerns?’. Is thinking negative, guilty or hopeless,
suggesting depression? Are there thoughts of self-harm? If so,
enquiry should be made about plans. Are patients excessively
worried about many things, suggesting anxiety? Do they think
that they are especially powerful, important or gifted (grandiose
thoughts), suggesting mania?
The form of thinking may also be abnormal. In schizophrenia,
patients may display loosened associations between ideas,
making it difficult to follow their train of thought. There may
also be abnormalities of thought possession, when patients
experience the intrusion of alien thoughts into their mind or the
broadcasting of their own thoughts to other people (p. 1196).
Abnormal beliefs
A delusion is a false belief, out of keeping with a patient’s cultural
background, which is held with conviction despite evidence to
the contrary (p. 1184).
Abnormal perceptions
Illusions are misperceptions of real stimuli. Hallucinations are
sensory perceptions that occur in the absence of external stimuli,
such as hearing voices when no one is present (p. 1184).
Cognitive function
Cognitive function has many components: memory, concentration,
visuospatial abilities, executive function and so on. In most cases,
a brief assessment of orientation (person, place and time - the
patent is asked their name, age, date of birth, what building they
are in, the current date and day of the week) and attention (‘serial
7s’ - the patient is asked to subtract 7 from 1 00 and then 7 from
the answer, and so on) is sufficient to exclude clinically significant
cognitive impairment. Where there is reason to suspect cognitive
impairment, however, a standardised screening tool should be
used. In delirium, cognitive impairment typically fluctuates over
time so may be missed by a single assessment.
The Montreal Cognitive Assessment (MoCA) is a useful
screening questionnaire that covers all the main domains of
cognitive function (Fig. 28.1). It is designed to be easy to use
and is freely available online in many different languages. Another
widely used screening test is the Mini-Mental State Examination
(MMSE), although this is subject to copyright, unlike the MoCA.
1182 • MEDICAL PSYCHIATRY
NAME:
Education: Date of birth:
Sex: DATE:
Read list of words, subject must
FACE
VELVET
CHURCH
DAISY
RED
repeat them. Do 2 trials, even if 1st trial is successful.
Do a recall after 5 minutes.
1st trial
No
points
2nd trial
ATTENTION
Read list of digits (1 digit/ sec.)
Subject has to repeat them in the forward order [ ] 2 18 5 4
Subject has to repeat them in the backward order [ ] 7 4 2
/2
Read list of letters. The subject must tap with his hand at each letter A. No points if > 2 errors
[ ] FBACM NAAJ KLBAFAKDEAAAJ AMOFAAB
/I
Serial 7 subtraction starting at 100
[ ] 93 [ ] 86 [ ] 79 [ ] 72 [ ] 65
4 or 5 correct subtractions: 3 pts, 2 or 3 correct: 2 pts, 1 correct: 1 pt, 0 correct: Opt
/3
LANGUAGE
Repeat: I only know that John is the one to help today. [ ]
The cat always hid under the couch when dogs were in the room. [ ]
/2
Fluency / Name maximum number of words in one minute that begin with the letter F
[ ]
_ (N > 1 1 words)
/I
ABSTRACTION
DELAYED RECALL
Similarity between e.g. banana - orange = fruit
[ ] train - bicycle [ ] watch - ruler
/2
Optional
Has to recall words
WITH NO CUE
Category cue
Multiple choice cue
FACE
[ ]
VELVET
[ ]
CHURCH
[ ]
DAISY
[ ]
RED
[ ]
Points for
UNCUED
recall only
/5
[ ] Date
[ ] Month
[ ] Year
[ ] Day
[ ] Place [ ] City
/6
© Z.Nasreddine MD
Administered by: _
www.mocatest.org
r
Normal >26/30 | TOTAL
Add 1 point if < 12 yr edu
/30
Fig. 28.1 Montreal Cognitive Assessment (MoCA). A widely used screening tool for cognitive impairment. ©Z. Nasreddine MD, www.mocatest.org.
Functional anatomy and physiology • 1183
The Addenbrooke’s Cognitive Examination - 3rd edition (ACE-Ill)
offers a more comprehensive assessment and brief training
courses for clinicians wishing to use it. These resources are
available online (see ‘Further information’).
Patients’ own understanding of their symptoms
Patients should be asked what they think their symptoms are
due to and whether they warrant treatment. The failure of a
patient to understand their own symptoms is referred to as
‘lack of insight’. Psychotic patients characteristically have lack
of insight and fail to accept that they are in need of treatment.
Investigations in medical psychiatry
In many areas of medicine, laboratory or radiological tests play
a central role in diagnosis. Such tests are often performed in
psychiatry but are typically used to exclude non-psychiatric illness
rather than to confirm a psychiatric diagnosis. For example, in a
patient presenting with symptoms of anxiety it may be appropriate
to check thyroid function to exclude thyrotoxicosis as a cause
of their symptoms. Specific investigations are recommended in
certain psychiatric conditions such as dementia, delirium and
substance misuse. These will be discussed later in this chapter.
Functional anatomy and physiology
Most psychiatric disorders result from a complex interplay between
psychological, social, environmental and genetic factors. Each
of these factors may play a role in predisposing to, precipitating
or perpetuating a disorder (Box 28.4).
Biological factors
Genetic
Genetic factors play a predisposing role in many psychiatric
disorders, including schizophrenia and bipolar affective disorder.
However, while some disorders, such as Huntington’s disease,
are due to mutations in a single gene, the genetic contribution to
most psychiatric disorders is polygenic in nature and mediated
by the combined effects of several genetic variants, each with
modest effects and modulated by environmental factors.
28.4 Classification of risk factors for
psychiatric disorders
Classification Examples
Predisposing
Established in utero or in childhood Genetic and epigenetic factors
Congenital defects
Increase susceptibility to psychiatric Disturbed family background
disorder
Operate throughout patient’s lifetime Chronic physical illness
Precipitating
Trigger an episode of illness Stressful life events
Determine its time of onset Acute physical illness
Misuse of alcohol or drugs
Perpetuating
Delay recovery from illness Lack of social support
Chronic physical illness
Brain structure and function
Brain structure is grossly normal in most psychiatric disorders,
although abnormalities may be observed in some conditions,
such as generalised atrophy in Alzheimer’s disease and enlarged
ventricles with a slight decrease in brain size in schizophrenia.
The functioning of the brain, however, is commonly altered due
to changes in neurotransmitters such as dopamine, noradrenaline
(norepinephrine) and 5-hydroxytryptamine (5-HT, serotonin).
Functional differences in specific areas of the brain are increasingly
being recognised using advanced imaging techniques. For
example, positron emission tomography (PET) studies of dopamine
ligand binding in schizophrenia has consistently demonstrated
increased dopamine synthesis in the striatum, even in untreated
patients, while a smaller body of PET evidence points towards
reductions in 5-HT transporter binding in the mid-brain and
amygdala in depression.
Pattern classification approaches to structural magnetic
resonance imaging (MRI) data can accurately predict the
development of schizophrenia in at-risk populations, and
generalised grey matter loss over time is a poor prognostic
guide. Increased anterior cingulate activity in depression is a
consistent predictor of good response to both antidepressants
and cognitive behaviour therapy. While these and other
imaging techniques show potential as diagnostic, prognostic
and therapeutic aids, they remain research tools at the
present time.
It is also increasingly clear that psychiatric disorders are
associated with disruptions in neuronal systems rather than single
sites. These can be characterised using diffusion tensor imaging
(DTI) of white-matter projection fibres and resting -state/task- based
functional MRI (fMRI) studies of inter-regional connectivity. For
example, DTI has shown reduced white-matter density in limbic
(‘emotional’) system tracts, such as the fornix and cingulum, in
many disorders. Resting-state fMRI studies consistently identify
‘default mode’, salience and executive control networks of
interconnected neuronal populations for certain mental activities.
These pathways are implicated in several psychiatric disorders
but, as yet, in non-specific ways.
Psychological and behavioural factors
Early environment
Early childhood adversity, such as emotional deprivation or
abuse, predisposes to most psychiatric disorders, such as
depression, eating disorders and personality disorders in
adulthood.
Personality
The relationship between personality and psychiatric disorder
can be difficult to assess because the development of psychiatric
disorder can impact on a patient’s personality. Some personality
types predispose the individual to develop a psychiatric disorder,
however; for example, an obsessional (‘anankastic’) personality
increases the risk of obsessive-compulsive disorder. A disordered
personality may also perpetuate a psychiatric disorder once it
is established, leading to a poorer prognosis.
Behaviour
A person’s behaviour may predispose to the development or
perpetuation of a disorder. Examples include excess alcohol
intake leading to dependence, dieting in anorexia or persistent
avoidance of the feared situation in phobia.
1184 • MEDICAL PSYCHIATRY
28.5 Substance misuse: additional
presenting problems
Complications arising from the route of use
Intravenous
• Local: abscesses, cellulitis, thrombosis
• Systemic: bacterial (endocarditis), viral (hepatitis, human
immunodeficiency virus (HI V))
Nasal ingestion
• Erosion of nasal septum, epistaxis
Smoking
• Oral, laryngeal and lung cancer
Inhalation
• Burns, chemical pneumonitis, rashes
Pressure to prescribe misused substance
• Manipulation, deceit and threats
• Factitious description of illness
• Malingering
Social and environmental factors
Social isolation
The lack of a close, confiding relationship predisposes to some
psychiatric disorders, such as depression. The reduced social
support resulting from having a psychiatric disorder may also
act to perpetuate it.
Stressors
Social and environmental stressors often play an important role in
precipitating psychiatric disorder in those who are predisposed,
such as trauma in post-traumatic stress disorder, losses (such as
bereavement) in depression, and events perceived as threatening
(such as potential loss of employment) in anxiety.
Presenting problems in
psychiatric illness
Delirium
Delirium is a medical disorder that is common in the elderly and
in patients in high-dependency and intensive care units. The
causes, assessment and management are described on page 209.
Alcohol misuse
Misuse of alcohol is a major problem worldwide. It presents in
a multitude of ways, which are discussed further on page 1 1 94
and in Box 28.22. In many cases, the link to alcohol is obvious;
in others, it may not be, since denial and concealment of alcohol
intake are common.
Clinical assessment
The patient should be asked to describe a typical week’s
drinking, quantified in terms of units of alcohol (1 unit contains
approximately 8 g alcohol and is the equivalent of half a pint of
beer, a single measure of spirits or a small glass of wine). The
history from the patient may need corroboration by the GP,
earlier medical records and family members.
Investigations
Abnormalities in routine biochemistry and haematology can
support the diagnosis of alcohol excess (such as the finding
of a raised mean cell volume (MCV) and/or raised y-glutamyl
transferase (GGT)), but such tests are abnormal in only half of
problem drinkers; consequently, normal results on these tests do
not exclude an alcohol problem. When abnormal, these measures
may be helpful in challenging denial and monitoring treatment
response. Transient elastography (also known as FibroScan) is an
ultrasound-based technique that measures fibrosis and steatosis.
It is used in specialist services to complement information derived
from tests of MCV and GGT.
Management
The prevention and management of alcohol-related problems
are discussed on page 1195.
Substance misuse
The misuse of drugs of all kinds is also widespread. As well as
the general headings listed for alcohol problems in Box 28.22
(p. 1194), there are two additional sets of problems associated
with drug misuse (Box 28.5):
• problems linked with the route of administration, such as
intravenous injection
• problems arising from pressure applied to doctors to
prescribe the misused substances.
Assessment and management are described on page 1195.
Delusions and hallucinations
Delusions and hallucinations are abnormal beliefs and perceptions
that have no rational basis. They are often due to psychiatric
illness but can be secondary to substance misuse, physical
illness or neurological disorders, such as epilepsy.
Delusions
A delusion is a false belief, out of keeping with a patient’s cultural
background, which is held with conviction despite evidence to
the contrary. It is common to classify delusions on the basis of
their content. They may be:
• persecutory - such as a conviction that others are out to
harm one
• hypochondriacal - such as an unfounded conviction that
one has cancer
• grandiose - such as a belief that one has special powers
or status
• nihilistic - such as ‘My head is missing’, ‘I have no body’
or ‘I am dead’.
Hallucinations
Hallucinations are defined as sensory perceptions occurring
without external stimuli. They can occur in any sensory modality
but most commonly are visual or auditory. Typical examples are
hearing voices when no one else is present, or seeing ‘visions’.
Hallucinations have the quality of ordinary perceptions and are
perceived as originating in the external world, not in the patient’s
own mind (when they are termed ‘pseudo-hallucinations’). Those
occurring when falling asleep (‘hypnagogic’) and on waking
(‘hypnopompic’) are a normal phenomenon and not pathological.
Hallucinations should be distinguished from illusions, which are
misperceptions of real external stimuli (such as mistaking a shrub
for a person in poor light).
Presenting problems in psychiatric illness • 1185
Clinical assessment
Careful and tactful enquiry is required because agitation, terror
or the fear of being thought ‘mad’ may make patients unable
or unwilling to volunteer or describe their abnormal beliefs or
perceptions. The nature of hallucinations can be important
diagnostically; for example, ‘running commentary’ voices that
discuss the patient are strongly associated with schizophrenia.
In general, auditory hallucinations suggest schizophrenia, while
hallucinations in other sensory modalities, especially vision but also
taste and smell, suggest an organic cause, such as substance
misuse, delirium or temporal lobe epilepsy.
Hallucinations and delusions often co-occur. If their content
is consistent with coexisting emotional symptoms, they are
described as ‘mood-congruent’. Thus, patients with severely
depressed mood may believe themselves responsible for
all the evils in the world, and hear voices saying, ‘You are
worthless. Go and kill yourself.’ In this case, the diagnosis of
depressive psychosis is made on the basis of the congruence
of different phenomena (mood, delusion and hallucination).
Incongruence between hallucinations, delusions and mood
suggests schizophrenia.
Investigations
The presence of hallucinations and/or delusions should not
automatically trigger a round of expensive investigations; rather,
careful clinical assessment of the nature, extent and time course
of the patient’s symptoms will generate a list of likely diagnoses,
and investigations can then be intelligently deployed to differentiate
between these. When hallucinations and/or delusions arise in
the context of disturbed consciousness and impaired cognition,
the diagnosis is usually an organic disorder, most commonly
delirium and/or dementia, and should be investigated accordingly
(pp. 184 and 1192).
Management
The management of hallucinations and/or delusions is primarily
the management of the underlying condition (such as delirium,
schizophrenia, mania or psychotic depression). Certain principles
apply, however, whatever the underlying cause.
Hallucinations and delusions can be very real to, and often
frightening for, the person who is experiencing them. Patients
will often seek reassurance from the doctor. The doctor should
acknowledge that these experiences are real for the patient while
avoiding being drawn into colluding with the patient’s false beliefs
or perceptions. Statements such as ‘Sometimes when we are
unwell our brain plays tricks on us’ can help to reassure a patient.
Where the patient lacks insight, however, a more neutral ‘We will
have to agree to disagree’ may be necessary to avoid conflict.
Antipsychotic medication can reduce psychotic symptoms, such
as hallucinations and delusion, and is often used in combination
with other sedating medication (such as a benzodiazepine) to
alleviate acute distress and reduce behavioural disturbance
(p. 1197).
Low mood
It is not uncommon for general hospital patients to report low
mood. It is important to differentiate an understandable, self-
limiting reaction to adversity (such as physical illness or bad news),
which is normal and requires support rather than ‘treatment’,
from a depressive disorder (p. 1198), which is characterised by
a more severe and persistent disturbance of mood and requires
specific treatment.
Clinical assessment
Depression is a relatively common illness, with a prevalence
of approximately 5% in the general population and 10-20%
in medical patients. It is important to note that depression has
physical as well as mental symptoms (Box 28.6). The diagnosis of
depression in the medically ill, who may have physical symptoms
of disease such as weight loss, fatigue, disturbed sleep, reduced
appetite and so on that overlap with the physical symptoms
of depression, relies on detection of the core psychological
symptoms of ‘anhedonia’ (inability to experience pleasure) and
the negative cognitive triad (see Box 28.17).
In some cases, depression may occur as a result of a direct
effect of a medical condition or its treatment on the brain, when
it is referred to as an ‘organic mood disorder’ (Box 28.7).
Investigations
When a patient appears to be low in mood, it is good practice
to ask them specifically about their mood. Do they feel low
(nausea, over-sedation, parkinsonism and so on can all cause
a patient to appear low in mood). If so, how long have they
been feeling low? Are they still able to enjoy things? To what do
they attribute their low mood? If the low mood is persistent, not
adequately explained by circumstances and/or associated with
anhedonia, the patient should be investigated for depression (p.
1199). Where a patient’s mood is extremely low, the clinician
should ask about suicide. Asking about suicide does not increase
the risk of it occurring, whereas failure to enquire denies the
opportunity to prevent it. The assessment of suicide risk is
described on page 1185.
28.6 Symptoms of depressive disorders
Psychological
• Depressed mood
•
Loss of interest
• Reduced self-esteem
•
Loss of enjoyment (anhedonia)
• Pessimism
• Guilt
•
Suicidal thinking
Somatic
• Reduced appetite
•
Loss of libido
• Weight change
•
Bowel disturbance
• Disturbed sleep
•
Motor retardation (slowing of
• Fatigue
activity)
28.7 Organic mood disorders
Neurological
Infections
• Cerebrovascular disease
• Infectious mononucleosis
• Cerebral tumour
• Herpes simplex
• Multiple sclerosis
• Brucellosis
• Parkinson’s disease
• Typhoid
• Huntington’s disease
• Toxoplasmosis
• Alzheimer’s disease
Connective tissue disease
• Epilepsy
• Systemic lupus erythematosus
Endocrine
Drugs
• Hypothyroidism
• Phenothiazines
• Hyperthyroidism
• Phenylbutazone
• Cushing’s syndrome
• Glucocorticoids, oral
• Addison’s disease
contraceptives
• Hyperparathyroidism
• Interferon
Malignant disease
*Diseases that may cause organic affective disorders by direct action on the brain.
1186 • MEDICAL PSYCHIATRY
28.9 Differential diagnosis of anxiety
• Normal response to threat
• Adjustment disorder
• Generalised anxiety disorder
• Panic disorder
• Phobic disorder
• Organic (medical) cause:
Hyperthyroidism
Paroxysmal arrhythmias
Phaeochromocytoma
Alcohol and benzodiazepine withdrawal
Hypoglycaemia
Temporal lobe epilepsy
Management
The management of depression is discussed on page 1199.
Where a patient’s low mood is an understandable reaction to
adversity, the clinical team can support the patient by minimising
uncertainty through open and effective clinical communication
and by addressing isolation (allowing access to visitors, telephone
and so on).
Elevated mood
Elevated mood is much less common than depressed mood,
and in medical settings is often secondary to drug or alcohol
misuse, an organic disorder or medical treatment. Where none
of these applies, the patient may be experiencing a manic (or, if
less severe, ‘hypomanic’) episode as part of a bipolar affective
disorder (p. 1199). Mania is the converse of depression. It may
manifest as infectious joviality, over-activity, lack of sleep and
appetite, undue optimism, over-talkativeness, irritability, and
recklessness in spending and sexual behaviour. When elated
mood is severe, psychotic symptoms are often evident, like
delusions of grandeur such as believing erroneously that one
is royalty.
Investigations
The first investigation for any medical patient presenting with
persistent and inexplicable elevated mood in the absence of a
history of bipolar affective disorder is a medication review. Mania
is a relatively common side-effect of certain classes of drug, such
as glucocorticoids, and is a rare side-effect of many other drugs.
Recreational, herbal and over-the-counter preparations should
also be considered. Second-line investigations include tests
for Cushing’s disease (p. 666), thyrotoxicosis (p. 635), syphilis
(p. 337) and encephalitis (p. 1121).
Management
The management of bipolar affective disorder is discussed on
page 1200. Management of organic mania involves identifying
and addressing the underlying cause. The management of
disturbed or aggressive behaviour is discussed on page 1188.
Anxiety
Anxiety may be transient, persistent, episodic or limited to specific
situations. The symptoms of anxiety are both psychological and
physical (Box 28.8). The differential diagnosis of anxiety is shown
in Box 28.9. Most anxiety is part of a transient adjustment to
28.8 Symptoms of anxiety disorder
Psychological
• Apprehension
•
Poor concentration
• Irritability
•
Fear of impending disaster
• Worry
•
Depersonalisation
Somatic
• Palpitations
•
Frequent desire to pass urine
• Fatigue
•
Chest pain
• Tremor
•
Initial insomnia
• Dizziness
•
Breathlessness
• Sweating
•
Headache
• Diarrhoea
stressful events: adjustment disorders (p. 1201). Other more
persistent forms of anxiety are described in detail on page 1200.
Investigations
Anxiety may occasionally be a manifestation of a medical condition
such as thyrotoxicosis (Box 28.9). Tests to exclude or confirm
these conditions should be considered, particularly if anxiety is
a new symptom that has arisen in the absence of an obvious
stressor.
Management
The management of specific anxiety disorders is discussed later
in this chapter (p. 1200). Benzodiazepines and related drugs,
while extremely effective in the short term, cause tolerance and
unpleasant or even dangerous withdrawal syndromes if used
for more than a few weeks.
Psychological factors affecting
medical conditions
Psychological factors may influence the presentation, management
and outcome of medical conditions. Specific factors are shown
in Box 28.10. The most common psychiatric diagnoses in the
medically ill are anxiety and depressive disorders. Often these
appear understandable as adjustments to illness and its treatment;
however, if the anxiety and depression are severe and persistent,
they may complicate the management of the medical condition
and active management is required. Anxiety may present as an
increase in somatic symptoms, such as breathlessness, tremor
or palpitations, or as the avoidance of medical treatment. It is
most common in those facing difficult or painful treatments,
deterioration of their illness or death. Depression may manifest
as increased physical symptoms, such as pain, fatigue and
disability, as well as with depressed mood and loss of interest
and pleasure. It is most common in patients who have suffered
28.10 Risk factors for psychological problems
associated with medical conditions
• Previous history of depression or anxiety
• Lack of social support
• New diagnosis of a serious medical condition
• Deterioration of, or failure of treatment for, a medical condition
• Unpleasant, disabling or disfiguring treatment
• Change in medical care, such as discharge from hospital
• Impending death
Presenting problems in psychiatric illness • 1187
actual or anticipated losses, such as receiving a terminal diagnosis
or undergoing disfiguring surgery.
Treatment is by psychological and/or pharmacological
therapies, as described on page 1189. Care is required when
prescribing psychotropic drugs to the medically ill in order to avoid
exacerbation of the medical condition and harmful interactions
with other prescribed drugs.
Medically unexplained somatic symptoms
Patients commonly present to doctors with physical symptoms.
While these symptoms may be an expression of a medical
condition, they often are not (see Fig. 28.6). They may then be
referred to as ‘medically unexplained symptoms’ (MUS), which
are very common in patients attending general medical outpatient
clinics. Almost any symptom can be medically unexplained.
They include:
• pain (including back, chest, abdominal, pelvic and
headache)
• fatigue
• fits, ‘funny turns’, dizziness and feelings of weakness.
Patients with MUS may receive a medical diagnosis of a
so-called ‘functional somatic syndrome’, such as irritable bowel
syndrome (Box 28.1 1), and may also merit a psychiatric diagnosis
on the basis of the same symptoms. The most frequent psychiatric
diagnoses associated with MUS are anxiety or depressive
disorders. When these are absent, a diagnosis of somatoform
disorder may be appropriate. Somatoform disorders are discussed
in more detail on page 1202.
28.11 Functional somatic syndromes
Medical specialty
Somatic syndromes
Gastroenterology
Irritable bowel syndrome, functional
dyspepsia
Gynaecology
Pre-menstrual syndrome, chronic pelvic pain
Rheumatology
Fibromyalgia
Cardiology
Atypical or non-cardiac chest pain
Respiratory medicine
Hyperventilation syndrome
Infectious diseases
Chronic (post-viral) fatigue syndrome
Neurology
Tension headache, non-epileptic attacks,
functional gait disorder
Dentistry
Temporomandibular joint dysfunction,
atypical facial pain
Ear, nose and throat
Globus syndrome
Allergy medicine
Multiple chemical sensitivity
Self-harm
Self-harm (SH) is a common reason for presentation to medical
services. The term ‘attempted suicide’ is potentially misleading,
as most of these patients are not trying to kill themselves.
Most cases of SH involve overdose, of either prescribed or
non-prescribed drugs (Ch. 7). Less common methods include
asphyxiation, drowning, hanging, jumping from a height or in
front of a moving vehicle, and the use of firearms. Methods that
carry a high chance of being fatal are more likely to be associated
with serious psychiatric disorder. Self-cutting is common and
often repetitive, but rarely leads to contact with medical services.
The incidence of SH varies over time and between countries.
In the UK, the lifetime prevalence of suicidal ideation is 15% and
that of acts of SH is 4%. SH is more common in women than
men, and in young adults than the elderly. (In contrast, completed
suicide is more common in men and the elderly; Box 28.12.)
There is a higher incidence of SH among lower socioeconomic
groups, particularly those living in crowded, socially deprived
urban areas. There is also an association with alcohol misuse,
child abuse, unemployment and recently broken relationships.
Clinical assessment
The main differential diagnosis is from accidental poisoning
and so-called ‘recreational’ overdose in drug users. It must be
remembered that SH is not a diagnosis but a presentation, and
may be associated with any psychiatric diagnosis, the most
common being adjustment disorder, substance and alcohol
misuse, depressive disorder and personality disorder. In many
cases, however, no psychiatric diagnosis can be made.
Management
A thorough psychiatric and social assessment should be
attempted in all cases (Fig. 28.2), although some patients will
discharge themselves before this can take place. The need
for psychiatric assessment should not delay urgent medical or
surgical treatment, though, and may need to be deferred until
the patient is well enough for interview. The purpose of the
psychiatric assessment is to:
• establish the short-term risk of suicide
• identify potentially treatable problems, whether medical,
psychiatric or social.
Topics to be covered when assessing a patient are listed in Box
28.13. The history should include events occurring immediately
i
• Psychiatric illness (depressive illness, schizophrenia)
• Older age
• Male sex
• Living alone
• Unemployment
• Recent bereavement, divorce or separation
• Chronic physical ill health
• Drug or alcohol misuse
• Suicide note written
• History of previous attempts (especially if a violent method was used)
i
Current attempt
• Patient’s account
• Degree of intent at the time: preparations, plans, precautions
against discovery, note
• Method used, particularly whether violent
• Degree of intent now
• Symptoms of psychiatric illness
Background
• Previous attempts and their outcome
• Family and personal history
• Social support
• Previous response to stress
• Extent of drug and alcohol misuse
28.12 Risk factors for suicide
28.13 Assessment of patients after self-harm
1188 • MEDICAL PSYCHIATRY
Patient admitted following
deliberate self-harm
Medical assessment to determine
need for urgent medical treatment
Fig. 28.2 Assessment of patients admitted following self-harm.
before and after the act, and especially any evidence of planning.
The nature and severity of any current psychiatric symptoms
must be assessed, along with the personal and social supports
available to the patient outside hospital.
Most SH patients have depressive and anxiety symptoms on
a background of chronic social and personal difficulties (often
complicated by use of alcohol or other substances), but no
psychiatric disorder. They do not usually require psychotropic
medication or specialised psychiatric treatment but may benefit
from personal support and practical advice from a GP, social
worker or community psychiatric nurse. Admission to a psychiatric
ward is necessary only for persons who display one or more
of the following:
• an acute psychiatric disorder
• high short-term risk of suicide
• need for temporary respite from intolerable
circumstances
• requirement for further assessment of their mental state.
Approximately 20% of SH patients make a repeat act during
the following year and 1-2% kill themselves. Factors associated
with suicide after an episode of SH are listed in Box 28.12.
Disturbed and aggressive behaviour
Disturbed and aggressive behaviour is common in general
hospitals, especially in emergency departments. Most behavioural
disturbance arises not from medical or psychiatric illness, but
from alcohol intoxication, reaction to the situation and personality
characteristics.
Clinical assessment
The key principles of management are, firstly, to establish control
of the situation rapidly and thereby ensure the safety of the patient
and others; and secondly, to try to determine the cause of the
disturbance in order to remedy it. Establishing control requires the
presence of an adequate number of trained staff, an appropriate
physical environment and sometimes sedation (Fig. 28.3). The
assistance of hospital security staff and sometimes the police
may be required. In all cases, the staff approach is important; a
calm, non-threatening manner expressing understanding of the
patient’s concerns is often all that is required to defuse potential
aggression (Box 28.14).
An attempt should be made to try to identify the factors that
are contributing to the disturbed behaviour. When the patient
is cooperative, these are best determined at interview. Other
sources of information about the patient include medical and
psychiatric records, and discussion with nursing staff, family
members and other informants, including the patient’s GP. The
following information should be sought:
• psychiatric, medical (especially neurological) and criminal
history
• current psychiatric and medical treatment
• alcohol and drug misuse
• recent stressors
• the time course and accompaniments of the current
episode in terms of mood, belief and behaviour.
Observation of the patient’s behaviour may also yield useful
clues. Do they appear to be responding to hallucinations? Are
they alert or variably drowsy and confused? Are there physical
features suggestive of drug or alcohol misuse or withdrawal?
Are there new injuries or old scars, especially on the head? Do
they smell of alcohol or solvents? Do they bear the marks of
drug injection? Are they unwashed and unkempt, suggesting a
gradual development of their condition?
Investigations
Depending on the results of clinical assessment, routine
biochemistry, haematology and analysis of blood or urine for
illicit drugs or alcohol may be required.
Management
Measures such as restraint and sedation may be required
in patients with acute behavioural disturbance in order to
Principles of management of psychiatric disorders • 1189
Fig. 28.3 Acute management of disturbed behaviour.
28.14 Psychiatric emergencies
• Intervene as necessary to reduce the risk of harm to the patient and
to others
• Adopt a calm, non-threatening approach
• Arrange availability of other staff and parenteral medication
• Consider diagnostic possibilities of drug intoxication, acute
psychosis and delirium
• Involve friends and relatives as appropriate
identify the cause and to protect the patient and other people
from harm. While this potentially raises legal issues, in most
countries, including the UK, common law confers on doctors
the right, and indeed the duty, to intervene against a patient’s
wishes if this is necessary. Sedation may be required and
(fv
• Organic psychiatric disorders: especially common, so cognitive
function should always be assessed; if impaired, an associated
medical condition or adverse drug effect should be suspected.
• Disturbed behaviour: delirium is the most common cause.
• Depression: common. Just because a person is old and frail does
not mean that depression is ‘to be expected’ and that it should not
be treated.
• Self-harm: associated with an increased risk of completed suicide.
• Medically unexplained symptoms: common and often associated
with depressive disorder.
• Loneliness, poverty and lack of social support: must be taken
into consideration in management decisions.
can be achieved with antipsychotic drugs (such as haloperidol)
and/or benzodiazepines (such as lorazepam or diazepam).
The choice of drug, dose, route and rate of administration
depends on the patient’s age, gender and physical health,
as well as the likely cause of the disturbed behaviour. The
benefits of sedation must always be balanced against the
potential risks. When prescribing benzodiazepines, consider
the risk of respiratory depression (particularly in patients with
lung disease) and encephalopathy (in those with liver disease).
When prescribing antipsychotic drugs for acute sedation, consider
the risk of acute dystonias (such as ‘oculogyric crisis’) and acute
arrhythmias (in patients with heart disease). Thus for a frail
elderly woman with emphysema and delirium, sedation may be
achieved with a low dose (0.5 mg) of oral haloperidol, while for
a strong young man with an acute psychotic episode, 1 0 mg or
more of intravenous diazepam and a similar dose of haloperidol
may be required. A parenterally administered anticholinergic
agent, such as procyclidine, should be available to treat
extrapyramidal effects from haloperidol if they arise. Flumazenil
(p. 142) can be used to reverse respiratory depression caused by
benzodiazepines.
If the initial assessment suggests that the patient has an acute
psychiatric disorder, then admission to a psychiatric facility may
be indicated. If a medical cause is more likely, psychiatric transfer
is usually inappropriate and the patient should be managed in a
medical setting, with whatever nursing and security support is
required. Where it is clear that there is no medical or psychiatric
illness, the person should be removed from the hospital, to
police custody if necessary.
Many countries, such as the UK, also have specific mental
health legislation that may be used to detain patients if
necessary.
Principles of management of
psychiatric disorders
The multifactorial origin of most psychiatric disorders means
that there are multiple potential targets for treatment. It is useful
to consider management strategies within a bio-psycho-social
framework. This can help to address the biological factors that
contribute to the illness with medication and other physical
treatments such as electroconvulsive therapy, while also
considering the potential role for psychological therapies and
changes to the patient’s social environment.
28.15 Medical psychiatry in old age
1190 • MEDICAL PSYCHIATRY
28.16 Classification of commonly used psychotropic drugs
Action
Main groups
Clinical use
Antipsychotic
Phenothiazines
Schizophrenia
Butyrophenones
Bipolar mania
Second-generation antipsychotics
Delirium
Antidepressant
Tricyclics and related drugs
1 Depression/anxiety
Serotonin and noradrenergic re-uptake inhibitors .
1 Obsessive-compulsive disorder
Monoamine oxidase inhibitors
Depression/anxiety
Mood-stabilising
Lithium
Treatment and prophylaxis of bipolar disorder
Valproate
Lamotrigine
Adjunctive therapy in depression
Anti-anxiety
Benzodiazepines j
Anxiety/insomnia (short term)
Alcohol withdrawal (short term)
(3-adrenoceptor antagonists
Anxiety (somatic symptoms)
Pharmacological treatments
These aim to relieve psychiatric disorder by modifying brain
function. The main biological treatments are psychotropic
drugs. These are widely used for various purposes; a pragmatic
classification is set out in Box 28.1 6. It should be noted that some
drugs have applications to more than one condition; for example,
antidepressants are also widely used in the treatment of anxiety
and chronic pain. The specific subgroups of psychotropic drugs
are discussed in the sections on the appropriate disorders below.
Electroconvulsive therapy
Electroconvulsive therapy (ECT) entails producing a convulsion
by the brief administration of a high-voltage direct-current
impulse to the head while the patient is anaesthetised and
paralysed by muscle relaxant. If properly administered, it is
remarkably safe, has few side-effects, and is of proven efficacy
for severe depressive illness. There may be headaches and
amnesia for events occurring a few hours before ECT (retrograde)
and after it (anterograde). Pronounced amnesia can occur
but is infrequent and difficult to distinguish from the effects of
severe depression.
Other forms of electromagnetic stimulation
Clinical trials of transcranial magnetic stimulation (TMS) and vagal
nerve stimulation (VNS) suggest they may have a limited role in
patients with depression refractory to conventional treatments.
Surgery
Surgery to the brain (psychosurgery) has a very limited place and
then only in the treatment of severe chronic psychiatric illness
resistant to other measures. Frontal lobotomies are never done
now, and pre-frontal leucotomies are very rare. Operations these
days usually target specific sub-regions and tracts of the brain.
Psychological therapies
These treatments are useful in many psychiatric disorders and
also in non-psychiatric conditions. They are based on talking with
patients, either individually or in groups. Sometimes discussion
HI 28.17 The negative cognitive triad associated
with depression
Cognitive error
Example
Negative view of self
1 am no good’
Negative view of current life experiences
’The world is an awful place’
Negative view of the future
’The future is hopeless’
is supplemented by ‘homework’ or tasks to complete between
treatment sessions. Psychological treatments take a number
of forms based on the duration and frequency of contact, the
specific techniques applied and their underlying theory.
General psychotherapy
General psychotherapy should be part of all medical treatment.
It involves empathic listening to the patient’s account of their
symptoms and associated fears and concerns, followed by the
sympathetic provision of accurate information that addresses
these.
Cognitive therapy
This therapy is based on the observation that some psychiatric
disorders are associated with systematic errors in the patient’s
conscious thinking, such as a tendency to interpret events in
a negative way or see them as unduly threatening. A triad of
‘cognitive errors’ has been described in depression (Box 28.17).
Cognitive therapy aims to help patients to identify such cognitive
errors and to learn how to challenge them. It is widely used for
depression, anxiety and eating and somatoform disorders, and
also increasingly in psychoses.
Behaviour therapy
This is a practically orientated form of treatment, in which patients
are assisted in changing unhelpful behaviour, such as helping
patients to implement carefully graded exposure to the feared
stimulus in phobias.
~J Cognitive behaviour therapy
Cognitive behaviour therapy (CBT) combines the methods of
behaviour therapy and cognitive therapy. It is the most widely
available and extensively researched psychological treatment.
Psychiatric disorders • 1191
Problem-solving therapy
This is a simplified brief form of CBT, which helps patients
actively tackle problems in a structured way (Box 28.18). It
can be delivered by non-psychiatric doctors and nurses after
appropriate training and is commonly used to help patients who
self-harm in response to a situational crisis.
Psychodynamic psychotherapy
This treatment, also known as ‘interpretive psychotherapy’,
was pioneered by Freud, Jung and Klein, among others. It
is based on the theory that early life experience generates
powerful but unconscious motivations. Psychotherapy aims
to help the patient to become aware of these unconscious
factors on the assumption that, once identified, their negative
effects are reduced. The relationship between therapist and
patient is used as a therapeutic tool to identify issues in patients’
relationships with others, particularly parents, which may be
replicated or transferred to their relationship with the therapist.
Explicit discussion of this relationship (transference) is the basis
for the treatment, which traditionally requires frequent sessions
over a period of months or even years.
i
• Define and list problems
• Choose one to work on
• List possible solutions
• Evaluate these and choose the best
• Try it out
• Evaluate the result
• Repeat until problems are resolved
Interpersonal psychotherapy
Interpersonal psychotherapy (IPT) is a specific form of brief
psychotherapy that focuses on patients’ current interpersonal
relationships and is an effective treatment for mild to moderate
depression.
Social interventions
Some adverse social factors, such as unemployment, may
not be readily amenable to intervention but others, such as
access to benefits and poor housing, may be. Patients can be
helped to address these problems themselves by being taught
problem-solving. Befrienders and day centres can reduce social
isolation, benefits advisers can ensure appropriate financial
assistance, and medical recommendations can be made to local
housing departments to help patients obtain more appropriate
accommodation.
Dementia is a clinical syndrome characterised by a loss of
previously acquired intellectual function in the absence of
impairment of arousal. It affects 5% of those over 65 and 20%
of those over 85. It is defined as a global impairment of cognitive
function and is typically progressive and non-reversible. There
are many subtypes (Box 28.19) but Alzheimer’s disease and
diffuse vascular dementia are the most common. Rarer causes
of dementia should be actively sought in younger patients and
those with short histories.
28.18 Stages of problem-solving therapy
28.19 Subtypes and causes of dementia
Type
Common
Less common
Rare
Vascular
Diffuse small-vessel disease
Amyloid angiopathy
Multiple emboli
Cerebral vasculitis
Systemic lupus erythematosus
Inherited
Alzheimer’s disease
Fronto-temporal dementia
Leukodystrophies
Huntington’s disease
Wilson’s disease
Dystrophia myotonica
Lewy body dementia
Progressive supranuclear palsy
Mitochondrial encephalopathies
Cortico-basal degeneration
Neoplastic
(P- mo)
Secondary deposits
Primary cerebral tumour
Paraneoplastic syndrome (limbic encephalitis)
Inflammatory
-
Multiple sclerosis
Sarcoidosis
Traumatic
Chronic subdural haematoma
Post- head injury
Punch-drunk syndrome
-
Hydrocephalus
(p. 1132)
Communicating/non-communicating
‘normal pressure’ hydrocephalus
-
Toxic/nutritional
Alcohol
Thiamin deficiency
Vitamin B12 deficiency
Anoxia/carbon monoxide poisoning
Heavy metal poisoning
Infective
Syphilis
HIV
Post-encephalitis
Whipple’s disease
Subacute sclerosing panencephalitis
Prion diseases
(p. 1126)
Sporadic Creutzfeldt-Jakob disease (CJD)
Variant CJD
Kuru
Gerstmann-Straussler-Scheinker disease
1192 • MEDICAL PSYCHIATRY
Pathogenesis
Dementia may be divided into ‘cortical’ and ‘subcortical’ types,
depending on the clinical features.
Clinical features
The usual presentation is with a disturbance of personality
or memory dysfunction. A careful history is essential and it
is important to interview both the patient and a close family
member. Simple bedside tests, such as the MoCA (p. 1182),
are useful in assessing the nature and severity of the cognitive
deficit, although a more intensive neuropsychological assessment
may sometimes be required, especially if there is diagnostic
uncertainty. It is important to exclude a focal brain lesion. This
is done by determining that there is cognitive disturbance in
more than one area. Mental state assessment is important
to seek evidence of depression, which may coexist with or
occasionally cause apparent cognitive impairment. Many of
the primary degenerative diseases that cause dementia have
characteristic features that may allow a specific diagnosis during
life. Creutzfeldt-Jakob disease, for example, is usually quickly
progressive (over months) and is associated with myoclonus. The
more slowly progressive dementias are more difficult to distinguish
during life, but fronto-temporal dementia typically presents with
signs of temporal or frontal lobe dysfunction, whereas Lewy body
dementia may present with visual hallucinations. The course may
also help to distinguish types of dementia. Gradual worsening
suggests Alzheimer’s disease, whereas stepwise deterioration
is typical of vascular dementia.
Investigations
The aim is to seek treatable causes and to estimate prognosis.
This is done using a standard set of investigations (Box 28.20).
Imaging of the brain can exclude potentially treatable structural
lesions, such as hydrocephalus, cerebral tumour or chronic
subdural haematoma, though the only abnormality usually seen
is that of generalised atrophy. An electroencephalogram (EEG)
may be helpful if Creutzfeldt-Jakob disease is suspected, as
characteristic abnormalities of generalised periodic sharp wave
pattern are usually observed. If the initial tests are negative, more
i
In most patients
• Imaging of head (computed tomography and/or magnetic resonance
imaging)
• Blood tests:
Full blood count, erythrocyte sedimentation rate
Urea and electrolytes, glucose
Calcium, liver function tests
Thyroid function tests
Vitamin B12
Syphilis serology
ANA, anti-dsDNA
• Chest X-ray
• Electroencephalography
In selected patients
• Lumbar puncture
• HIV serology
• Brain biopsy
(ANA = antinuclear antibody; anti-dsDNA = anti-double-stranded DNA)
invasive investigations, such as lumbar puncture or, very rarely,
brain biopsy, may be indicated.
Management
This is mainly directed at addressing treatable causes and
providing support for patients and carers. Tackling risk factors
may slow deterioration, e.g. effective management of hypertension
in vascular dementia, or abstinence and vitamin replacement in
toxic/nutritional dementias. Psychotropic drugs may have a role
in alleviating symptoms, such as disturbance of sleep, perception
or mood, but should be used with care because of an increased
mortality in patients who have been treated long-term with these
agents. Sedation is not a substitute for good care of patients
and carers or, in the later stages, attentive residential nursing
care. In the UK, incapacity and mental health legislation may
be required to manage patients’ financial and domestic affairs,
as well as to determine their safe placement. If the diagnosis is
Alzheimer-type dementia, cholinesterase inhibitors and memantine
may slow progression for a time.
Alzheimer’s disease
Alzheimer’s disease is the most common form of dementia. It
increases in prevalence with age and is rare in people under
45 years.
Pathogenesis
Genetic factors play an important role and about 1 5% of cases
are familial. These cases fall into two main groups: early-onset
disease with autosomal dominant inheritance and a later-onset
group where the inheritance is polygenic. Mutations in several
genes have been described but most are rare and/or of small
effect. The inheritance of one of the alleles of apolipoprotein e
(apo s4) is associated with an increased risk of developing the
disease (2-4 times higher in heterozygotes and 6-8 times higher
in homozygotes). Its presence is, however, neither necessary
nor sufficient for the development of the disease and so genetic
testing for ApoE4 is not clinically useful. The brain in Alzheimer’s
disease is macroscopically atrophic, particularly the cerebral cortex
and hippocampus. Histologically, the disease is characterised by
the presence of senile plaques and neurofibrillary tangles in the
cerebral cortex. Histochemical staining demonstrates significant
quantities of amyloid in the plaques (Fig. 28.4); these typically
stain positive for the protein ubiquitin, which normally is involved
in targeting unwanted or damaged proteins for degradation. This
has led to the suggestion that the disease may be due to defects
in the ability of neuronal cells to degrade unwanted proteins. Many
different neurotransmitter abnormalities have also been described.
In particular, there is impairment of cholinergic transmission,
although abnormalities of noradrenaline (norepinephrine), 5-HT,
glutamate and substance P have also been described.
Clinical features
The key clinical feature is impairment of the ability to remember
new information. Hence, patients present with gradual impairment
of memory, usually in association with disorders of other cortical
functions. Short- and long-term memory are both affected
but defects in the former are usually more obvious. Later in
the course of the disease, typical features include apraxia,
visuo-spatial impairment and aphasia. In the early stages of
the disease, patients may notice these problems, but as the
disease progresses it is common for patients to deny that there
is anything wrong (anosognosia). In this situation, patients are
28.20 Initial investigation of dementia
Psychiatric disorders • 1193
Fig. 28.4 Alzheimer’s disease. Section of neocortex stained with
polyclonal antibody against (3A4 peptide showing amyloid deposits in
plaques in brain substance (arrow A) and in blood-vessel walls (arrow B).
Courtesy of Dr J. Xuereb.
Fig. 28.5 Fronto-temporal dementia. [A] Lateral view of formalin-fixed
brain from a patient who died of Pick’s disease, showing gyral atrophy of
frontal and parietal lobes and a more severe degree of atrophy affecting
the anterior half of the temporal lobe (arrow). [§] High power (x 200) view
of hippocampal pyramidal layer, prepared with monoclonal anti-tau
antibody. Many neuronal cell bodies contain sharply circumscribed,
spherical cytoplasmic inclusion bodies (Pick bodies, arrows). A and B,
Courtesy of Dr J. Xuereb.
often brought to medical attention by their carers. Depression is
commonly present. Occasionally, patients become aggressive, and
the clinical features can be made acutely worse by intercurrent
physical disease.
Patients typically present with subjective memory loss,
sometimes getting lost in familiar locations. A history of progressive
memory loss and associated functional impairment, corroborated
by an informant, is the key to making the diagnosis. Cognitive
testing and neuroimaging can be helpful but in themselves are
not diagnostic.
Investigations
Investigation is aimed at excluding treatable causes of dementia
(see Box 28.19), as histological confirmation of the diagnosis
usually occurs only after death.
Management
Treatment with anticholinesterases, such as donepezil, rivastigmine
and galantamine, has been shown to be of some benefit at
slowing progression of cognitive impairment in the early stages
of the disease while post-synaptic cholinergic receptors are still
available. The A/-methyl-D-aspartate (NMDA) receptor antagonist
memantine slightly enhances learning and memory in early disease
and can also be useful in selected patients with more advanced
disease. Novel treatments are under development to block amyloid
plaque formation directly, by inhibiting the enzyme y-secretase.
Non-pharmacological approaches include the provision of a
familiar environment for the patient and support for the carers.
Many patients are depressed, and if this is confirmed, treatment
with antidepressant medication may be helpful.
Fronto-temporal dementia
Fronto-temporal dementia encompasses a number of different
syndromes characterised by behaviour abnormalities and
impairment of language. Symptoms usually occur before the age
of 60 and the prevalence has been estimated at 1 5 per 1 00 000
in the population aged between 45 and 65 years. The three
major clinical subtypes are behavioural-variant fronto-temporal
dementia, primary progressive aphasia and semantic dementia.
Pick’s disease is a common cause of the first two in particular.
Genetic factors play an important role and familial cases have
been described caused by mutations in several genes, including
MAPT, which encodes microtubule-associated protein tau, GRN,
TPD43, FUS, VCP and C9orf72. The causal mutations trigger
abnormal accumulation of tau and other proteins in brain tissue,
which are seen as cytoplasmic inclusion bodies on histological
examination (Fig. 28.5). It is of interest that many of the gene
mutations that cause fronto-temporal dementia are also associated
with amyotrophic lateral sclerosis (p. 1116), suggesting that these
disorders share a similar pathogenic basis in which neuronal
degeneration is caused by accumulation of abnormal proteins.
The clinical presentation may be with personality change due
to frontal lobe involvement or with language disturbance due to
temporal lobe involvement. In contrast to Alzheimer’s disease,
memory is relatively preserved in the early stages. There is no
specific treatment. Disinhibition and compulsive behaviours can
1194 • MEDICAL PSYCHIATRY
be helped by selective serotonin re-uptake inhibitors (SSRIs).
Although Alzheimer’s and fronto-temporal dementia share certain
symptoms, they cannot be treated with the same pharmacological
agents because the cholinergic systems are not affected in
the latter.
Lewy body dementia
This neurodegenerative disorder is clinically characterised by
dementia and signs of Parkinson’s disease. It is often inherited
and mutations in the a-synuclein and p-synuclein genes have
been identified in affected patients. These mutations result in
accumulation of abnormal protein aggregates in neurons that
contain the protein a-synuclein in association with other proteins,
including ubiquitin (see Fig. 25.31 , p. 1 1 12). The cognitive state
often fluctuates and there is a high incidence of visual hallucinations.
Affected individuals are particularly sensitive to the side-effects
of anti-parkinsonian medication and also to antipsychotic
drugs. There is no curative treatment but anticholinesterase
drugs can be helpful in slowing progression of cognitive
impairment.
Alcohol misuse and dependence
Alcohol consumption associated with social, psychological and
physical problems constitutes misuse. The criteria for alcohol
dependence, a more restricted term, are shown in Box 28.21.
Approximately one-quarter of male patients in general hospital
medical wards in the UK have a current or previous alcohol
problem.
Pathogenesis
Availability of alcohol and social patterns of use appear to
be the most important factors. Genetic factors predispose to
dependence. The majority of people who misuse alcohol do not
have an associated psychiatric disorder, but a few drink heavily
in an attempt to relieve anxiety or depression.
Clinical features
The modes of presentation of alcohol misuse and complications
are summarised below.
Social problems
Common features include absenteeism from work, unemployment,
marital tensions, child abuse, financial difficulties and problems
with the law, such as violence and traffic offences.
Low mood
Low mood is common since alcohol has a direct depressant
effect and heavy drinking creates numerous social problems.
Attempted and completed suicide are associated with alcohol
misuse.
Anxiety
People who are anxious may use alcohol as a means of relieving
anxiety in the short term and this can develop into dependence.
Conversely, alcohol withdrawal increases anxiety.
Alcohol withdrawal syndrome
The features are described in Box 28.22. Symptoms usually
become maximal about 2-3 days after the last drink and
can include seizures. The term ‘delirium tremens’ is used to
describe severe alcohol withdrawal syndrome characterised
by both delirium (characteristically, agitation and visual
hallucinations) and physiological hyper-arousal (tremor, sweating
and tachycardia). It has a significant mortality and morbidity
(Box 28.22).
Hallucinations
Hallucinations (characteristically visual but sometimes in other
modalities) are common in delirium tremens. Less common is
the phenomenon called ‘alcoholic hallucinosis’, where a patient
with alcohol dependence experiences auditory hallucination in
clear consciousness at a time when they are not withdrawing
from alcohol.
28.22 Presentation and consequences of chronic
alcohol misuse
Acute intoxication
• Emotional and behavioural disturbance
• Medical problems: hypoglycaemia, ketoacidosis, aspiration of vomit,
respiratory depression
• Accidents, injuries sustained in fights
Withdrawal phenomena
• Psychological symptoms: restlessness, anxiety, panic attacks
• Autonomic symptoms: tachycardia, sweating, pupil dilatation,
nausea, vomiting
• Delirium: agitation, hallucinations (classically ‘Lilliputian’), illusions,
delusions
• Seizures
Consequences of harmful use
Medical
• Neurological: peripheral neuropathy, cerebellar degeneration,
cerebral haemorrhage, dementia
• Hepatic: fatty change and cirrhosis, liver cancer
• Gastrointestinal: oesophagitis, gastritis, pancreatitis, oesophageal
cancer, Mallory— Weiss syndrome, malabsorption, oesophageal
varices
• Respiratory: pulmonary tuberculosis, pneumonia
• Skin: spider naevi, palmar erythema, Dupuytren’s contractures,
telangiectasias
• Cardiac: cardiomyopathy, hypertension
• Musculoskeletal: myopathy, fractures
• Endocrine and metabolic: pseudo-Cushing’s syndrome,
hypoglycaemia, gout
• Reproductive: hypogonadism, fetal alcohol syndrome,
infertility
Psychiatric and cerebral
• Depression
• Alcoholic hallucinosis
• Alcoholic ‘blackouts’
• Wernicke’s encephalopathy: nystagmus or ophthalmoplegia with
ataxia and delirium
• Korsakoff’s syndrome: short-term memory deficits leading to
confabulation
28.21 Criteria for alcohol dependence
• Narrowing of the drinking repertoire
• Priority of drinking over other activities (salience)
• Tolerance of effects of alcohol
• Repeated withdrawal symptoms
• Relief of withdrawal symptoms by further drinking
• Subjective compulsion to drink
• Reinstatement of drinking behaviour after abstinence
Psychiatric disorders • 1195
Wernicke-Korsakoff syndrome
This is a rare but important indirect complication of chronic
alcohol misuse. It is an organic brain disorder resulting from
damage to the mamillary bodies, dorsomedial nuclei of the
thalamus and adjacent areas of periventricular grey matter
caused by a deficiency of thiamin (vitamin B^. The syndrome
most commonly results from long-standing heavy drinking and
an inadequate diet but can also arise from malabsorption or even
protracted vomiting. Wernicke’s encephalopathy (nystagmus or
ophthalmoplegia with ataxia and delirium) often presents acutely
and, without prompt treatment (see below), can progress and
become irreversible. Korsakoff’s syndrome (severe short-term
memory deficits and confabulation) can develop chronically or
acutely (with Wernicke’s).
Alcohol-related brain damage
The term alcohol-related brain damage (ARBD) is often used as
a collective description of the many brain pathologies associated
with alcohol excess, which often coexist in the same patient.
Acute alcohol intoxication causes ataxia, slurred speech, emotional
incontinence and aggression. Very heavy drinkers may experience
periods of amnesia for events that occurred during bouts of
intoxication, termed ‘alcoholic blackouts’. Established alcohol
dependence may lead to ‘alcoholic dementia’, a global cognitive
impairment resembling Alzheimer’s disease, but which does
not progress and may even improve if the patient becomes
abstinent. Heavy alcohol use can damage the brain indirectly
through Wernicke-Korsakoff syndrome (see above), head injury,
hypoglycaemia and encephalopathy (p. 864).
Effects on other organs
These are protean and virtually any organ can be involved (Box
28.22). These effects are discussed in detail in other chapters
in this book.
Diagnosis
The diagnosis of alcohol excess may emerge while taking the
patient’s history, but many patients do not tell the truth about
their alcohol intake. Alcohol misuse may also present through
its effects on one or more aspects of the patient’s life, as listed
above. Alcohol dependence commonly presents with withdrawal
in those admitted to hospital, as they can no longer maintain
their high alcohol intake in this setting.
Management
For the person misusing alcohol, provision of clear information
from a doctor about the harmful effects of alcohol and safe
levels of consumption is often all that is needed. In more serious
cases, patients may have to be advised to alter leisure activities
or change jobs to help them to reduce their consumption.
Psychological treatment is used for people who have recurrent
relapses and is usually available at specialised centres. Support
to stop drinking is also provided by voluntary organisations, such
as Alcoholics Anonymous (AA) in the UK.
Alcohol withdrawal syndromes can be prevented, or treated
once established, with long-acting benzodiazepines. Large doses
may be required (such as diazepam 20 mg 4 times daily), tailed
off over a period of 5-7 days as symptoms subside. Prevention
of the Wernicke-Korsakoff syndrome requires the immediate use
of high doses of thiamin, which is initially given parenterally in
the form of Pabrinex (two vials 3 times daily for 48 hrs, longer if
symptoms persist) and then orally (100 mg 3 times daily). There
is no treatment for Wernicke-Korsakoff syndrome once it has
arisen. The risk of side-effects, such as respiratory depression
with benzodiazepines and anaphylaxis with Pabrinex, is small
when weighed against the potential benefits of treatment.
Acamprosate (666 mg 3 times daily) may help to maintain
abstinence by reducing the craving for alcohol. Disulfiram
(200-400 mg daily) can be given as a deterrent to patients
who have difficulty resisting the impulse to drink after becoming
abstinent. It blocks the metabolism of alcohol, causing
acetaldehyde to accumulate. When alcohol is consumed, an
unpleasant reaction follows, with headache, flushing and nausea.
Disulfiram is always an adjunct to other treatments, especially
supportive psychotherapy. Treatment with antidepressants may
be required if depression is severe or does not resolve with
abstinence. Antipsychotics, such as chlorpromazine (100 mg
3 times daily), are needed for alcoholic hallucinosis. Although
such treatment may be successful, there is a high relapse rate.
Prognosis
Between 80% and 90% of patients with established alcohol
dependence syndrome who embark on medically supervised
detoxification will successfully complete detoxification without
encountering significant complications. Sustaining abstinence
is more challenging than achieving it, however. Studies indicate
that 1 year after successful detoxification, only 20% of patients
will remain abstinent. This figure rises to approximately 30% for
patients who are engaged with alcohol services, and to over
40% if such specialist support is combined with supervised
disulfiram treatment.
Substance misuse disorder
Dependence on and misuse of both illegal and prescribed drugs
is a major problem worldwide. Drugs of misuse are described in
detail in Chapter 7. They can be grouped as follows.
Sedatives
These commonly give rise to physical dependence, the
manifestations of which are tolerance and a withdrawal syndrome.
Drugs include benzodiazepines, opiates (including morphine,
heroin, methadone and dihydrocodeine) and barbiturates (now
rarely prescribed). Overdosage with sedatives can be fatal,
primarily as a result of respiratory depression (Ch. 7). Withdrawal
from opiates is notoriously unpleasant, and withdrawal from
benzodiazepines and barbiturates can cause prolonged anxiety
and even hallucinations and/or seizures.
Intravenous opiate users are prone to bacterial infections,
hepatitis B (p. 873), hepatitis C (p. 877) and HIV infection
(Ch. 12) through needle contamination. Accidental overdose is
common, mainly because of the varied and uncertain potency
of illicit supplies of the drug. The withdrawal syndrome, which
can start within 12 hours of last use, presents with intense
craving, rhinorrhoea, lacrimation, yawning, perspiration, shivering,
piloerection, vomiting, diarrhoea and abdominal cramps.
Examination reveals tachycardia, hypertension, mydriasis and
facial flushing.
Stimulants
Stimulant drugs include amphetamines and cocaine. They are
less dangerous than the sedatives in overdose, although they
can cause cardiac and cerebrovascular problems through their
pressor effects. Physical dependence syndromes do not arise,
but withdrawal causes a rebound lowering in mood and can give
rise to an intense craving for further use, especially in any form
1196 • MEDICAL PSYCHIATRY
of drug with a rapid onset and offset of effect, such as crack
cocaine. Chronic ingestion can cause a paranoid psychosis
similar to schizophrenia. A ‘toxic psychosis’ (delirium) can occur
with high levels of consumption. Unpleasant tactile hallucinations
described as ‘like ants crawling under the skin’ (formication) may
be prominent in either acute intoxication or withdrawal.
Hallucinogens
The hallucinogens are a disparate group of drugs that cause
prominent sensory disturbances. They include cannabis,
ecstasy, lysergic acid diethylamide (LSD), Psilocybin (magic
mushrooms) and a variety of synthetic cannabinoids (as one of
the so-called ‘legal highs’ or ‘novel psychoactive substances’).
A toxic confusional state can occur after heavy cannabis
consumption. Acute psychotic episodes are well recognised,
especially in those with a family or personal history of psychosis,
and there is evidence that prolonged heavy use increases the
risk of developing schizophrenia. Paranoid psychoses have been
reported in association with ecstasy. A chronic psychosis has
also been documented after regular LSD use.
Organic solvents
Solvent inhalation (glue sniffing) is popular in some adolescent
groups. Solvents produce acute intoxication characterised by
euphoria, excitement, dizziness and a floating sensation. Further
inhalation leads to loss of consciousness; death can occur from
the direct toxic effect of the solvent, or from asphyxiation if the
substance is inhaled from a plastic bag.
Pathogenesis
Many of the causal factors for alcohol misuse also apply to
substance misuse. The main factors are the psychological and
behavioural vulnerabilities described above, cultural pressures,
particularly within a peer group, and availability of a drug. In the
case of some drugs such as opiates, medical over-prescribing
has increased their availability, but there has also been a relative
decline in the price of illegal drugs. Most drug users take a range
of drugs - so-called polydrug misuse.
Diagnosis
As with alcohol, the diagnosis either may be apparent from the
history and examination, or may be made only once the patient
presents with a complication. Drug screening of samples of urine
or blood can be valuable in confirming the diagnosis, especially
if the patient persists in denial.
Management
The first step is to determine whether patients wish to stop using
the drug. If they do not, they can still benefit from advice about
how to minimise harm from their habit, such as how to obtain
and use clean needles for those who inject. For those who are
physically dependent on sedative drugs, substitute prescribing
(using methadone, for example, in opiate dependence) may help
stabilise their lives sufficiently to allow a gradual reduction in
dosage until they reach abstinence. Some specialist units offer
inpatient detoxification. For details of the medical management of
overdose, see page 135. The drug lofexidine, a centrally acting
a-agonist, can be useful in treating the autonomic symptoms
of opiate withdrawal, as can clonidine, although this carries a
risk of hypotension and is best used by specialists. Long-acting
opiate antagonists, such as naltrexone, may also have a place,
again in specialist hands, in blocking the euphoriant effects of
the opiate, thereby reducing addiction.
In some cases, complete opiate withdrawal is not successful
and the patient functions better if maintained on regular doses
of oral methadone as an outpatient. This decision to prescribe
long-term methadone should be taken only by a specialist, and
carried out under long-term supervision at a specialist drug
treatment centre.
Substitute prescribing is neither necessary nor possible for the
hallucinogens and stimulants, but the principles of management
are the same as those that should accompany prescribing for
the sedatives. These include identifying problems associated with
the drug misuse that may serve to maintain it, and intervening
where possible. Intervention may be directed at physical illness,
psychiatric comorbidity, social problems or family disharmony.
Relapsing patients and those with complications should be
referred to specialist drug misuse services. Support can also
be provided by self-help groups and voluntary bodies, such as
Narcotics Anonymous (NA) in the UK.
Schizophrenia
Schizophrenia is characterised by delusions, hallucinations
and lack of insight. Acute schizophrenia may also present with
disturbed behaviour, disordered thinking, or with insidious social
withdrawal and other so-called negative symptoms and less
obvious delusions and hallucinations. Schizophrenia occurs
worldwide in all ethnic groups with a prevalence of about 0.5%.
It is more common in men (1.4 to 1). Children of an affected
parent have an approximate 10% risk of developing the illness,
but this rises to 50% if an identical twin is affected. The usual
age of onset is the mid-twenties but can be older, particularly
in women.
Pathogenesis
There is a strong genetic contribution, usually involving many
susceptibility genes, each of small effect, but 2-3% of cases
can be attributed to increased or decreased copies of genes
(so-called ‘copy number variations’, p. 44). Environmental risk
factors include a history of obstetric complications at the time of
the patient’s birth and urban upbringing. Brain imaging techniques
have identified subtle structural abnormalities in groups of people
with schizophrenia, including an overall decrease in brain size
(by about 3% on average), with a relatively greater reduction in
temporal lobe volume (5-1 0%). Episodes of acute schizophrenia
may be precipitated by social stress and also by cannabis, which
increases dopamine turnover. Consequently, schizophrenia
is now viewed as a neurodevelopmental disorder, caused by
abnormalities of brain development associated with genetic
predisposition and early environmental influences, but precipitated
by later triggers.
Clinical features
Acute schizophrenia should be suspected in any individual with
bizarre behaviour accompanied by delusions and hallucinations
that are not due to organic brain disease or substance misuse.
The characteristic clinical features are listed in Box 28.23.
Hallucinations are typically auditory but can occur in any sensory
modality. They commonly involve voices from outside the head
that talk to or about the person. Sometimes the voices repeat
the person’s thoughts. Patients may also describe ‘passivity of
thought’, experienced as disturbances in the normal privacy of
thinking, such as the delusional belief that their thoughts are
being ‘withdrawn’ from them and perhaps ‘broadcast’ to others,
and/or that alien thoughts are being ‘inserted’ into their mind.
Psychiatric disorders • 1197
28.23 Symptoms of schizophrenia
Other characteristic symptoms are delusions of control: believing
that one’s emotions, impulses or acts are controlled by others.
Another phenomenon is delusional perception, a delusion that
arises suddenly alongside a normal perception, such as ‘I saw the
moon and I immediately knew he was evil.’ Other, less common,
symptoms may occur, including thought disorder, as manifest by
incomprehensible speech, and abnormalities of movement, such
as those in which the patient can become immobile or adopt
awkward postures for prolonged periods (catatonia).
Diagnosis
The diagnosis is made primarily on clinical grounds but
investigations may be required to rule out organic brain disease.
The main differential diagnosis of schizophrenia (Box 28.24)
includes:
• Other functional psychoses, particularly psychotic
depression and mania, in which delusions and
hallucinations are congruent with a marked mood
disturbance (negative in depression and grandiose in
mania). Schizophrenia must also be differentiated from
specific delusional disorders that are not associated with
the other typical features of schizophrenia.
• Organic psychoses, including delirium, in which there is
impairment of consciousness and loss of orientation (not
found in schizophrenia), typically with visual hallucinations;
drug misuse, particularly in young people; and temporal
lobe epilepsy with psychotic symptoms, in which olfactory
and gustatory hallucinations may occur.
Many of those who experience acute schizophrenia go on to
develop a chronic state in which the acute, so-called positive
symptoms resolve, or at least do not dominate the clinical picture,
leaving so-called negative symptoms that include blunt affect,
apathy, social isolation, poverty of speech and poor self-care.
Patients with chronic schizophrenia may also manifest positive
symptoms, particularly when under stress, and it can be difficult
for those who do not know the patient to judge whether or not
these are signs of an acute relapse.
Investigations
As in dementia, investigations are focused on excluding a treatable
cause, such as a slow-growing brain tumour, temporal lobe
epilepsy, neurosyphilis or various autoimmune conditions. These
are required only in patients with neurological or other organic
symptoms or signs.
28.24 Differential diagnosis of schizophrenia
Alternative diagnosis
Distinguishing features
Other functional psychoses
Delusional disorders
Absence of specific features of
schizophrenia
Psychotic depression
Prominent depressive symptoms
Manic episode
Prominent manic symptoms
Schizoaffective disorder
Mood and schizophrenia symptoms
both prominent
Puerperal psychosis
Acute onset after childbirth
Organic disorders
Drug-induced psychosis
Evidence of drug or alcohol misuse
Side-effects of prescribed
Levodopa, methyldopa, glucocorticoids,
drugs
antimalarial drugs
Temporal lobe epilepsy
Other evidence of seizures
Delirium
Visual hallucinations, impaired
consciousness
Dementia
Age, established cognitive impairment
Huntington’s disease
Family history, choreiform movements,
dementia
Management
First-episode schizophrenia usually requires admission to hospital
because patients lack the insight that they are ill and are unwilling
to accept treatment. In some cases, they may be at risk of
harming themselves or others. Subsequent acute relapses and
chronic schizophrenia are now usually managed in the community.
Drug treatment
Antipsychotic agents are effective against the positive symptoms
of schizophrenia in the majority of cases. They take 2-4 weeks
to be maximally effective but have some beneficial effects shortly
after administration. Treatment is then ideally continued to prevent
relapse. In a patient with a first episode of schizophrenia this
will usually be for 1 or 2 years, but in patients with multiple
episodes treatment may be required for many years. The benefits
of prolonged treatment must be weighed against the adverse
effects, which include extrapyramidal side-effects (EPSE) like acute
dystonic reactions (which may require treatment with parenteral
anticholinergics), akathisia and parkinsonism. For long-term use,
antipsychotic agents are often given by slow-release (depot)
injections to improve adherence.
A number of antipsychotic agents are available (Box 28.25).
These may be divided into conventional (first-generation) drugs
such as chlorpromazine and haloperidol, and novel or second-
generation drugs such as olanzapine and clozapine. All work by
blocking D2 dopamine receptors in the brain. Patients who have
not responded to conventional drugs may respond to newer
agents, which are also less likely to produce unwanted EPSE but
do tend to cause greater weight gain and metabolic disturbances,
such as dyslipidaemia. Clozapine can be remarkably effective in
those who do not respond to other antipsychotics but can cause
agranulocytosis in about 1 % of patients in the first few months.
Prescription therefore requires regular monitoring of white blood
cell count, initially on a weekly basis, then fortnightly and monthly
thereafter. Clozapine should not be stopped suddenly because of
the likelihood of relapse. Adverse effects of antipsychotic drugs
are listed in Box 28.26. Two serious adverse effects deserve
special mention.
Neuroleptic malignant syndrome This is a rare but serious condition
characterised by fever, tremor and rigidity, autonomic instability
First-rank symptoms of acute schizophrenia
• A = Auditory hallucinations - second- or third-person/echo de la
pensee
• B = Broadcasting, insertion/withdrawal of thoughts
• C = Controlled feelings, impulses or acts (‘passivity’ experiences/
phenomena)
• D = Delusional perception (a particular experience is bizarrely
interpreted)
Symptoms of chronic schizophrenia (negative symptoms)
• Flattened (blunted) affect
• Apathy and loss of drive (avolition)
• Social isolation/withdrawal (autism)
• Poverty of speech (alogia)
• Poor self-care
1198 • MEDICAL PSYCHIATRY
28.25 Antipsychotic drugs
Group
Drug
Usual adult dose
Phenothiazines
Chlorpromazine
400-600 mg daily
Butyrophenones
Haloperidol
8-12 mg daily
Thioxanthenes
Flupentixol
decanoate
40 mg fortnightly
(depot injection)
Diphenylbutylpiperidines
Pimozide
8-1 0 mg daily
Substituted benzamides
Sulpiride
800-1200 mg daily
Dibenzodiazepines2
Clozapine
300-600 mg daily
Benzisoxazole2
Risperidone
4-6 mg daily
Thienobenzodiazepines2
Olanzapine
10-15 mg daily
Dibenzothiazepines2
Quetiapine
300-600 mg daily
Tower or higher doses may be required in some patients. 2Second-generation
antipsychotics.
i
Weight gain due to increased appetite
Effects due to dopamine blockade"
• Acute dystonia •
• Akathisia (motor restlessness) •
• Parkinsonism •
Effects due to cholinergic blockade
• Dry mouth •
• Blurred vision •
• Impotence
Hypersensitivity reactions
• Blood dyscrasias (neutropenia •
with clozapine) •
Ocular complications
• Corneal and lens opacities
(long-term use)
*Less severe with clozapine, quetiapine and olanzapine, possibly because of
strong 5-hydroxytrytamine-blocking effect and relatively weak dopamine blockade.
and delirium. Characteristic laboratory findings are an elevated
creatinine phosphokinase and leucocytosis. Antipsychotic
medication must be stopped immediately and supportive therapy
provided, often in an intensive care unit. Treatment includes
ensuring hydration and reducing hyperthermia. Dantrolene sodium
and bromocriptine may be helpful. Mortality is 20% untreated
and 5% with treatment.
Cardiac arrhythmias Antipsychotic medications cause prolongation
of the QTc interval, which may be associated with ventricular
tachycardia, torsades de pointes and sudden death. If this
occurs, treatment should be stopped, with careful electrocar¬
diographic monitoring and treatment of serious arrhythmias if
necessary (p. 479).
Psychological treatment
Psychological treatment, including general support for the
patient and family, is now seen as an essential component of
management. CBT may help patients to cope with symptoms.
There is evidence that personal and/or family education, when
given as part of an integrated treatment package, reduces the
rate of relapse.
Social treatment
After an acute episode of schizophrenia has been controlled by
drug therapy, social rehabilitation may be required. Recurrent
illness is likely to cause disruption to patients’ relationships and
their ability to manage their accommodation and occupation;
consequently, patients with schizophrenia often need help to
obtain housing and employment. A graded return to employment
and sometimes a period of supported accommodation are
required.
Patients with chronic schizophrenia have particular difficulties
and may need long-term, supervised accommodation. This now
tends to be in supported accommodation in the community.
Patients may also benefit from sheltered employment if they are
unable to participate effectively in the labour market. Ongoing
contact with a health worker allows monitoring for signs of
relapse, sometimes as part of a multidisciplinary team working to
agreed plans (the ‘care programme approach’). Partly because
of a tendency to inactivity, smoking and a poor diet, patients
with chronic schizophrenia are at increased risk of cardiovascular
disease, diabetes and stroke, and require proactive medical as
well as psychiatric care.
Prognosis
About one-third of those who develop an acute schizophrenic
episode have a good outcome. One-third develop chronic,
incapacitating schizophrenia, and the remainder largely
recover after each episode but suffer relapses. Most affected
patients cannot work or live independently. Schizophrenia is
associated with suicide and up to 10% of patients take their
own lives.
Mood disorders
Mood or affective disorders include:
• unipolar depression: one or more episodes of low mood
and associated symptoms
• bipolar disorder: episodes of elevated mood interspersed
with episodes of depression
• dysthymia: chronic low-grade depressed mood without
sufficient other symptoms to count as ‘clinically significant’
or ‘major’ depression.
Depression
Major depressive disorder has a prevalence of 5% in the general
population and approximately 10-20% in chronically ill medical
outpatients. It is a major cause of disability and suicide. If
comorbid with a medical condition, depression magnifies disability,
diminishes adherence to medical treatment and rehabilitation,
and may even shorten life expectancy.
Pathogenesis
There is a genetic predisposition to depression, especially
when of early onset. The genetic predisposition is mediated
by variants in a large number of genes and loci of small effect
rather than mutations in single genes. Adversity and emotional
deprivation early in life also predispose to depression. Depressive
episodes are often, but not always, triggered by stressful life
events (especially those that involve loss or imposed change),
including medical illnesses. Associated biological factors include
28.26 Adverse effects of antipsychotic drugs
Tardive dyskinesia
Gynaecomastia
Galactorrhoea
Constipation
Urinary retention
Cholestatic jaundice
Photosensitive dermatitis
Psychiatric disorders • 1199
hypofunction of monoamine neurotransmitter systems, including
5-HT and noradrenaline (norepinephrine), and abnormalities
of the hypothalamic-pituitary-adrenal (HPA) axis, which
results in elevated cortisol levels that do not suppress with
dexamethasone.
Diagnosis
The symptoms are listed in Box 28.6. Depression may be mild,
moderate or severe. It may also be recurrent or chronic. It can
be both a complication of a medical condition and a cause
of MUS (see below), so physical examination is essential; an
associated medical condition should always be considered,
particularly where there is no past history of depression and no
apparent psychological precipitant.
Investigations
Investigations are not usually required unless there are clinical
grounds for suspicion of an underlying medical disorder, such
as Cushing’s syndrome or hypothyroidism.
Management
Pharmacological and psychological treatments both work in
depression. In practice, the choice is determined by patient
preference and local availability. Severe depression complicated by
psychotic symptoms, dehydration or suicide risk may require ECT.
Drug treatment
Antidepressant drugs are effective in moderate and severe
depression, whether it is primary or secondary to a medical
illness. The most suitable drug for an individual patient will
depend on their previous response, likely side-effects, their
concurrent illnesses and potential drug interactions. Commonly
used antidepressants are shown in Box 28.27.
The different classes of antidepressant have similar efficacy and
about three-quarters of patients respond to treatment. Successful
treatment requires the patient to take an appropriate dose of
28.27 Antidepressant drugs
Group
Drug
Usual adult dose
Tricyclic
antidepressants
Amitriptyline
Imipramine
Dosulepin
Clomipramine
75-150 mg daily
75-150 mg daily
75-150 mg daily
75-150 mg daily
Selective serotonin
re-uptake inhibitors
(SSRIs)
Citalopram
Escitalopram
Fluoxetine
Sertraline
Paroxetine
20-40 mg daily
10-20 mg daily
20-60 mg daily
50-100 mg daily
20-50 mg daily
Monoamine oxidase
inhibitors
Phenelzine
Tranylcypromine
Moclobemide
45-90 mg daily
20-40 mg daily
300-600 mg daily
Noradrenaline
(norepinephrine)
re-uptake inhibitors
and SSRIs
Venlafaxine
Duloxetine
75-375 mg daily
60-120 mg daily
Noradrenaline and
specific serotonergic
inhibitor
Mirtazapine
15-45 mg daily
*Higher doses may be required in some patients: see guidelines.
an effective drug for an adequate period. For those who do not
respond, a proportion will do so if changed to another class
of antidepressant. The patient’s progress must be monitored
and, after recovery, treatment should be continued for at least
6-1 2 months to reduce the high risk of relapse. The dose should
then be tapered off over several weeks to avoid discontinuation
symptoms. The Scottish Intercollegiate Guidelines Network (SIGN)
and National Institute for Health and Clinical Excellence (NICE)
have published treatment guidelines.
Tricyclic antidepressants Tricyclic antidepressant (TCA) agents
inhibit re-uptake of the amines noradrenaline (norepinephrine) and
5-HT at synaptic clefts. The therapeutic effect is noticeable within
a week or two. Adverse effects, such as sedation, anticholinergic
effects, postural hypotension, lowering of the seizure threshold
and cardiotoxicity, can be troublesome during this period. TCAs
may be dangerous in overdose and should be used with caution
in people who have coexisting heart disease, glaucoma and
prostatism.
Selective serotonin re-uptake inhibitors Selective serotonin reuptake
inhibitors (SSRIs) are less cardiotoxic and less sedative than
TCAs, and have fewer anticholinergic effects. They are safer in
overdose but can still cause QTc prolongation, headache, nausea,
anorexia and sexual dysfunction. They can also interact with
other drugs increasing serotonin (5-HT), to produce ‘serotonin
syndrome’. This is a rare syndrome of neuromuscular hyperactivity,
autonomic hyperactivity and agitation, and potentially seizures,
hyperthermia, delirium and even death.
Noradrenaline (norepinephrine) re-uptake inhibitors These agents
inhibit noradrenaline uptake at the synaptic cleft but have additional
pharmacological effects. Venlafaxine and duloxetine also act as
serotonin re-uptake inhibitors, whereas mirtazapine also acts as
an antagonist at 5-HT2a, 5-HT2c and 5-HT3 receptors. These
drugs have similar efficacy to the agents listed above but a
different adverse-effect profile.
Monoamine oxidase inhibitors Monoamine oxidase inhibitors
(MAOIs) increase the availability of neurotransmitters at synaptic
clefts by inhibiting metabolism of noradrenaline (norepinephrine)
and 5-HT. They are now rarely prescribed in the UK, since they
can cause potentially dangerous interactions with drugs such as
amphetamines and certain anaesthetic agents, and with foods
rich in tyramine (such as cheese and red wine). This is due to
accumulation of amines in the systemic circulation, causing a
potentially fatal hypertensive crisis.
Psychological treatment
Both CBT and interpersonal therapy are as effective as
antidepressants for mild to moderate depression. Antidepressant
drugs are, however, preferred for severe depression. Drug and
psychological treatments can be used in combination.
Prognosis
Over 50% of people who have had one depressive episode and
over 90% of people who have had three or more episodes will
have another. The risk of suicide in an individual who has had
a depressive disorder is 10 times greater than in the general
population.
Bipolar disorder
Bipolar disorder is an episodic disturbance with interspersed
periods of depressed and elevated mood; the latter is known
1200 • MEDICAL PSYCHIATRY
as hypomania when mild or short-lived, or mania when severe
or chronic. The lifetime risk of developing bipolar disorder is
approximately 1-2%. Onset is usually in the twenties, and men
and women are equally affected.
Pathogenesis
Bipolar disorder is strongly heritable (approximately 70%). Relatives
of patients have an increased incidence of both bipolar and
unipolar affective disorder. A number of genetic variants of
small effect have been identified by genome- wide association
studies. Life events, such as physical illness, sleep deprivation
and medication, may also play a role in triggering episodes.
Diagnosis
The diagnosis is based on clear evidence of episodes of depression
and mania. Isolated episodes of hypomania or mania do occur but
they are usually preceded or followed by an episode of depression.
Psychotic symptoms may occur in both the depressive and the
manic phases, with delusions and hallucinations that are usually
in keeping with the mood disturbance. This is described as an
affective psychosis. Patients who present with symptoms of
both bipolar disorder and schizophrenia in equal measure may
be given a diagnosis of schizoaffective disorder.
Management
Depression should be treated as described above. If
antidepressants are prescribed, however, they should be
combined with a mood-stabilising drug (see below) to avoid
‘switching’ the patients into (hypo)mania. Manic episodes and
psychotic symptoms usually respond well to antipsychotic drugs
(see Box 28.25).
Prophylaxis to prevent recurrent episodes of depression and
mania with mood-stabilising agents is important. The main
drugs used are lithium and sodium valproate but lamotrigine,
olanzapine, quetiapine and risperidone are increasingly employed.
Caution must be exercised when stopping these drugs, as a
relapse may follow.
Lithium carbonate is the drug of first choice. It is also used for
acute mania, and in combination with a tricyclic as an adjuvant
treatment for resistant depression. It has a narrow therapeutic
range, so regular blood monitoring is required to maintain a
serum level of 0.5-1 .0 mmol/L. Toxic effects include nausea,
vomiting, tremor and convulsions. With long-term treatment,
weight gain, hypothyroidism, increased calcium and parathyroid
hormone (PTH), nephrogenic diabetes insipidus (p. 687) and
renal failure can occur. Thyroid and renal function should be
checked before treatment is started and regularly thereafter.
Lithium may be teratogenic and should not be prescribed during
the first trimester of pregnancy.
Anticonvulsants, such as sodium valproate and lamotrigine, and
the antipsychotic drug olanzapine can all be used as prophylaxis
in bipolar disorder, usually as a second-line alternative to lithium.
Valproate conveys a high risk of birth defects and should not
be used in women of child-bearing age. Olanzapine can cause
significant weight gain. (For a list of the adverse effects of
antipsychotic drugs, see Box 28.26.)
Prognosis
The relapse rate of bipolar disorder is high, although patients
may be perfectly well between episodes. After one episode, the
annual average risk of relapse is about 10-15%, which doubles
after more than three episodes. There is a substantially increased
lifetime risk of suicide of 5-10%.
Anxiety disorders
These are characterised by the emotion of anxiety, worrisome
thoughts, avoidance behaviours and the somatic symptoms of
autonomic arousal. Anxiety disorders are divided into three main
subtypes: phobic, paroxysmal (panic) and generalised (Box 28.28).
The nature and prominence of the somatic symptoms often lead
the patient to present initially to medical services. Anxiety may
be stress-related and phobic anxiety may follow an unpleasant
incident. Many patients with anxiety also have depression.
Clinical features
Phobic anxiety disorder
A phobia is an abnormal or excessive fear of a specific object
or situation, which leads to avoidance of it (such as excessive
fear of dying in an air crash, leading to avoidance of flying).
A generalised phobia of going out alone or being in crowded
places is called ‘agoraphobia’. Phobic responses can develop
to medical procedures such as venepuncture.
Panic disorder
Panic disorder describes repeated attacks of severe anxiety, which
are not restricted to any particular situation or circumstances.
Somatic symptoms, such as chest pain, palpitations and
paraesthesia in lips and fingers, are common. The symptoms
are in part due to involuntary over- breathing (hyperventilation).
Patients with panic attacks often fear that they are suffering
from a serious illness, such as a heart attack or stroke, and
seek emergency medical attention. Panic disorder may coexist
with agoraphobia.
Generalised anxiety disorder
This is a chronic anxiety state associated with uncontrollable
worry. The associated somatic symptoms of muscle tension
and bowel disturbance often lead to a medical presentation.
Diagnosis
The diagnosis is made on the basis of clinical history and typical
symptoms, as described above. Where a diagnosis of panic
disorder is suspected, it can be confirmed by asking the patient
to hyperventilate deliberately for 1-2 minutes and observing
whether the symptoms are reproduced. A finding of respiratory
alkalosis on arterial blood gas measurement is indicative of
chronic hyperventilation.
Management
Psychological treatment
Explanation and reassurance are essential, especially when
patients fear they have a serious medical condition. Specific
Classification of anxiety disorders
Phobic anxiety
disorder
Panic
disorder
Generalised
anxiety disorder
Occurrence
Situational
Paroxysmal
Persistent
Behaviour
Avoidance
Escape
Agitation
Cognitions
Fear of situation
Fear of
symptoms
Worry
Symptoms
On exposure
Episodic
Persistent
Psychiatric disorders • 1201
treatment may be needed. Treatments include relaxation, graded
exposure (desensitisation) to feared situations for phobic disorders,
and CBT.
Drug treatment
Antidepressants are the drugs of first choice (p. 1199). The
therapeutic dose is usually higher for anxiety disorders than
for depression and there is some evidence that, within their
respective classes, paroxetine (SSRI) and clomipramine (TCA)
have greatest efficacy against anxiety disorders. Early side-effects
of antidepressants can lead to a worsening of anxiety symptoms
in the first 2 weeks and patients should be warned of this.
Benzodiazepines are useful in the short term but regular
(>3 doses per week) long-term use carries a very high risk of
dependence. Regular prescriptions should therefore be limited
to 3 weeks; beyond that, prescriptions should be restricted
to occasional use as required, with periodic review to guard
against dose escalation. Short-acting benzodiazepines, such as
lorazepam, have a rapid onset and provide symptomatic relief for
up to 2 hours but have the greatest potential for dependence.
Longer-acting drugs, such as diazepam, can take an hour to
take effect when given orally but provide symptomatic relief for
up to 12 hours. A (3-blocker, such as propranolol, can help when
somatic symptoms are prominent.
Obsessive-compulsive disorder
Obsessive-compulsive disorder (OCD) is characterised by
‘obsessions’ - thoughts, images or impulses that are recurrent,
unwanted and usually anxiety- provoking, but recognised as one’s
own. In many cases, the obsessions give rise to ‘compulsions,
which are repeated acts performed to relieve the anxiety. Unlike
the anxiety disorders discussed above, which are more common
in women, OCD is equally common in men and women.
Clinical features
Common examples include thoughts of contamination, giving rise
to repeated and ritualised hand-washing, and thoughts of having
forgotten something, giving rise to time-consuming repeated
checking. The differential diagnoses include normal checking
behaviour and delusional beliefs about thought possession.
Diagnosis
The diagnosis is made on the basis of the typical history, as
described above.
Management
OCD usually responds to some degree to antidepressant
drugs (high-dose clomipramine or SSRI; see Box 28.27) and
to ‘exposure response prevention’ - a form of CBT in which
patients are encouraged to expose themselves to the feared
thought or situation without performing the anxiety-relieving
compulsions. Relapses are common, however, and the condition
often becomes chronic.
Stress-related disorders
Acute stress reaction
Following a stressful event, such as a serious medical diagnosis
or a major accident, some people develop a characteristic pattern
of symptoms: an initial state of ‘daze’ or bewilderment is followed
by altered activity (withdrawal or agitation), often with anxiety.
The symptoms are transient and usually resolve completely
within a few days. The lay media often describes this as ‘shock’.
Adjustment disorder
A more common psychological response to a major stressor is
a less severe but more prolonged emotional reaction.
Clinical features
The predominant symptom is usually depression and/or anxiety,
which is insufficiently persistent or intense to merit a diagnosis
of depressive or anxiety disorder. There may also be anger,
aggressive behaviour and associated excessive alcohol use.
Symptoms develop within a month of the onset of the stress,
and their duration and severity reflect the course of the underlying
stressor. Grief reactions following bereavement are a particular
type of adjustment disorder. They manifest as a brief period of
emotional numbing, followed by a period of distress lasting several
weeks, during which sorrow, tearfulness, sleep disturbance, a
sense of futility, anger and ‘bargaining’ are common. Perceptual
distortions may occur, including misinterpreting sounds as the
dead person’s voice or ‘seeing’ the dead person. ‘Pathological
grief describes a grief reaction that is abnormally intense or
persistent.
Diagnosis
The diagnosis is made on the basis of the typical history following
a stressful life event, as described above.
Management
Ongoing contact with and support from a doctor or another
person who can listen, reassure, explain and advise are often
all that is needed. Most patients do not require psychotropic
medication, although benzodiazepines reduce arousal in acute
stress reactions and can aid sleep in adjustment disorders.
Post-traumatic stress disorder
Post-traumatic stress disorder (PTSD) is a delayed and/or
protracted response to a stressful event of an exceptionally
threatening or catastrophic nature. Examples of such events
include natural disasters, terrorist activity, serious accidents and
witnessing violent deaths. PTSD may also sometimes occur after
distressing medical treatments or intensive care.
Clinical features
The development of PTSD is usually delayed from a few days to
several months between the traumatic event and the onset of
symptoms. Typical symptoms are recurrent intrusive memories
(flashbacks) of the trauma; sleep disturbance, especially
nightmares (usually of the traumatic event) from which the patient
awakes in a state of anxiety; symptoms of autonomic arousal
(anxiety, palpitations, enhanced startle); emotional blunting; and
avoidance of situations that evoke memories of the trauma.
Anxiety and depression are often associated and excessive use
of alcohol or drugs frequently complicates the clinical picture.
Diagnosis
The diagnosis is made on the basis of the typical clinical features
following a traumatic life event.
Management
In the immediate aftermath of a significant trauma, the main
aim is to provide support, direct advice and the opportunity
1202 • MEDICAL PSYCHIATRY
for emotional catharsis (debriefing may actually be harmful). In
established PTSD, structured psychological approaches (CBT,
eye movement desensitisation and reprocessing (EMDR), and
stress management) are effective. Antidepressant drugs are
moderately effective.
Prognosis
The condition runs a fluctuating course, with most patients
recovering within 2 years. In a small proportion, the symptoms
become chronic.
Somatoform disorders
The essential feature of these disorders is that the somatic
symptoms are not explained by a medical condition (medically
unexplained symptoms), nor better diagnosed as part of a
depressive or anxiety disorder. The derivation of the term
‘somatoform’ is ‘body-like’. Several syndromes are described
within this category; there is considerable overlap between
them, both in the underlying causes and in the clinical
presentation.
Pathogenesis
The cause of somatoform disorders is incompletely understood
but contributory factors include depression and anxiety, the
erroneous interpretation of somatic symptoms as evidence of
disease, excessive concern with physical illness and a tendency
to seek medical care. A family history or previous history of a
particular condition may have shaped the patient’s beliefs about
illness. Doctors may exacerbate the problem, either by dismissing
the complaints as non-existent or by over-emphasising and
investigating the possibility of disease.
Clinical features
Somatoform disorders can present in several different ways,
as described below.
Somatoform autonomic dysfunction
This describes somatic symptoms referable to bodily organs
that are largely under the control of the autonomic nervous
system. The most common examples involve the cardiovascular
system (‘cardiac neurosis’), respiratory system (‘psychogenic
hyperventilation’) and gut (‘psychogenic vomiting’ and ‘irritable
bowel syndrome’). Antidepressant drugs and CBT may be helpful.
Somatoform pain disorder
This describes severe, persistent pain that cannot be adequately
explained by a medical condition. Antidepressant drugs (especially
tricyclics and dual action drugs such as duloxetine) are helpful, as
are some of the anticonvulsant drugs, particularly carbamazepine,
gabapentin and pregabalin. CBT and multidisciplinary pain
management teams are also useful.
Chronic fatigue syndrome
Chronic fatigue syndrome (CFS) is characterised by excessive
fatigue after minimal physical or mental exertion, poor
concentration, dizziness, muscular aches and sleep disturbance.
This pattern of symptoms may follow a viral infection such as
infectious mononucleosis, influenza or hepatitis. Symptoms
overlap with those of depression and anxiety. There is good
evidence that many patients improve with carefully graded
exercise and with CBT, as long as the benefits of such treatment
are carefully explained.
28.29 Common presentations of dissociative
(conversion) disorder
• Gait disturbance • Non-epileptic seizures
• Loss of function in limbs • Sensory loss
• Aphonia • Blindness
Dissociative conversion disorders
Dissociative conversion disorders are characterised by a loss or
distortion of neurological functioning that is not fully explained
by organic disease. These may be psychological functions such
as memory (‘dissociative amnesia’), sensory functions such as
vision (‘dissociative blindness’), or motor functions (‘functional
gait disorder’) (Box 28.29). The cause is unknown but there is
an association with recent stress and with adverse childhood
experiences, including physical and sexual abuse. Organic disease
may precipitate dissociation and provide a model for symptoms.
For example, non-epileptic seizures often occur in those with
epilepsy. Treatment with CBT may be of benefit.
Somatisation disorder
This is defined as the occurrence of multiple medically unexplained
physical symptoms affecting several bodily systems. It is also
known as Briquet’s syndrome after the physician who first
described the presentation. Symptoms often start in early adult
life but somatisation disorder can arise later, usually following
an episode of physical illness. The disorder is much more
common in women. Patients may undergo a multitude of negative
investigations and unhelpful operations, particularly hysterectomy
and cholecystectomy. There is no proven treatment except to try
to ensure that unnecessary investigations and surgical procedures
are avoided to minimise iatrogenic harm.
Hypochondriacal disorder
Patients with this condition have a strong fear or belief that they
have a serious, often fatal, disease (such as cancer), and that
fear persists despite appropriate medical reassurance. They
are typically highly anxious and seek many medical opinions
and investigations in futile but repeated attempts to relieve
their fears.
Hypochondriacal disorder often resembles OCD, but in a
small proportion of cases the conviction that disease is present
reaches delusional intensity. The best-known example is that of
parasitic infestation (‘delusional parasitosis’), which leads patients
to consult dermatologists. Treatment with CBT can be helpful.
Patients who suffer delusions may benefit from antipsychotic
medication. The condition may become chronic.
Body dysmorphic disorder
This is defined as a preoccupation with bodily shape or
appearance, with the belief that one is disfigured in some way
(previously known as ‘dysmorphophobia’). People with this
condition may make inappropriate requests for cosmetic surgery.
Treatment with CBT or antidepressants may be helpful. The
belief in disfigurement may sometimes be delusional, in which
case antipsychotic drugs can help.
Management
The management of the various syndromes of medically
unexplained complaints described above is based on the
general principles outlined in Box 28.30 and discussed in more
detail below.
Psychiatric disorders • 1203
28.30 General management principles for medically
unexplained symptoms
Reassurance
Patients should be asked what they are most worried about.
Clearly, it may be unwise to state categorically that the patient
does not have any disease, as that is difficult to establish with
certainty. However, it can be emphasised that the probability
of having a disease is low and that doctors often see patients
with physical symptoms but no physical disease. If patients
repeatedly ask for reassurance about the same health concern
despite reassurance, they may have hypochondriasis.
Explanation
Patients need a positive explanation for their symptoms. It is
unhelpful to say that symptoms are psychological or ‘all in the
mind’. Rather, a term such as ‘functional’ (meaning that the
symptoms represent a reversible disturbance of bodily function)
may be more acceptable. When possible, it is useful to describe a
plausible physiological mechanism that is linked to psychological
factors such as stress and implies that the symptoms are
reversible. For example, in irritable bowel syndrome, psychological
stress results in increased activation of the autonomic nervous
system, which leads to constriction of smooth muscle in the gut
wall, which in turn causes pain and bowel disturbance.
Advice
This should focus on how to overcome factors perpetuating the
symptoms: for example, by resolving stressful social problems or
by practising relaxation. The doctor can offer to review progress, to
prescribe (for example) an antidepressant drug and, if appropriate,
to refer for physiotherapy or psychological treatments such as
CBT. The attitudes of relatives may need to be addressed if they
have adopted an over- protective role, unwittingly reinforcing the
patient’s disability.
Drug treatment
Antidepressant drugs are often helpful, even if the patient is
not depressed.
Psychological treatment
There is evidence for the effectiveness of CBT. Other psychological
treatments such as IPT may also have a role.
Rehabilitation
Where there is chronic disability, particularly in dissociative
(conversion) disorder, conventional physical rehabilitation may
be the best approach.
Shared care
Ongoing planned care is required for patients with chronic
intractable symptoms, especially those of somatisation disorder.
Review by the same specialist, interspersed with visits to the
same GP, is probably the best way to avoid unnecessary multiple
re-referral for investigation, to ensure that treatable aspects of the
patient’s problems, such as depression, are actively managed
and to prevent the GP from becoming demoralised.
Eating disorders
There are two well-defined eating disorders, anorexia nervosa
(AN) and bulimia nervosa (BN); they share some overlapping
features. Ninety per cent of people affected are female. There
is a much higher prevalence of abnormal eating behaviour in
the population that does not meet diagnostic criteria for AN or
BN but may attract a diagnostic label such as ‘binge eating
disorder’. In developed societies, obesity is arguably a much
greater problem but is usually considered to be more a disorder
of lifestyle or physiology than a psychiatric disorder.
Anorexia nervosa
The lifetime risk of anorexia nervosa for women living in Europe
is approximately 1-2% (for men it is <0.5%) with a peak age of
onset of 1 5-1 9 years. Predisposing factors include familiality (both
genetic and shared environmental factors appear to play a role)
and ‘neurotic’ personality traits. The illness is often precipitated
by weight loss, whether due to non-pathological dieting/increased
exercise or physical illness such as gastrointestinal disorders or
diabetes mellitus. Many sufferers do not engage with specialist
services and it is not uncommon for the first presentation to be with
a medical problem (Box 28.31 ) rather than to psychiatric services.
Clinical features
There is marked weight loss, arising from food avoidance, often
in combination with bingeing, purging, excessive exercise and/
or the use of diuretics and laxatives. Body image is profoundly
disturbed so that, despite emaciation, patients still feel overweight
and are terrified of weight gain. These preoccupations are
intense and pervasive, and the false beliefs may be held with a
conviction approaching the delusional. Anxiety and depressive
symptoms are common accompaniments. Downy hair (lanugo)
may develop on the back, forearms and cheeks. Extreme
starvation is associated with a wide range of physiological
and pathological bodily changes. All organ systems may be
affected, although the most serious problems are cardiac and
skeletal (Box 28.31).
Pathogenesis
The underlying cause is unclear but probably includes personality
(high neuroticism), genetic (twin studies indicate heritability of
0. 3-0.5) and environmental factors, including, in many societies,
the social pressure on women to be thin.
Diagnosis
Diagnostic criteria are shown in Box 28.32. Differential diagnosis
is from other causes of weight loss, including psychiatric disorders
such as depression, and medical conditions such as inflammatory
bowel disease, malabsorption, hypopituitarism and cancer,
although it is important to remember that AN can coexist with
any of these. The diagnosis is based on a pronounced fear of
fatness despite being thin, and on the absence of an adequate
alternative explanation for weight loss.
Management
The aims of management are to ensure patients’ physical well¬
being while helping them to gain weight by addressing the
• Take a full sympathetic history
• Exclude disease but avoid unnecessary investigation or referral
• Seek specific treatable psychiatric syndromes
• Demonstrate to patients that you believe their complaints
• Establish a collaborative relationship
• Give a positive explanation for the symptoms, including but not
over-emphasising psychological factors
• Encourage a return to normal functioning
1204 • MEDICAL PSYCHIATRY
i
beliefs and behaviours that maintain the low weight. Treatment
is usually given on an outpatient basis. Inpatient treatment
should be reserved for those at risk of death from medical
complications or from suicide. There is a limited evidence base
for CBT-based psychological treatments. Family behaviour
therapy (FBT) has efficacy among adolescent but not adult
patients. Psychotropic drugs are of no proven benefit in AN
but antidepressant medication may be indicated in those with
clear-cut comorbid depressive disorder.
Weight gain is best achieved in a collaborative fashion.
Compulsory admission and refeeding (including tube feeding)
are very occasionally resorted to when patients are at risk of
death and other measures have failed. While this may produce
a short-term improvement in weight, it rarely changes long-term
prognosis.
Prognosis
Two-thirds of patients with AN no longer meet diagnostic criteria
at 5-year follow-up. However, long-term follow-up studies suggest
that many sufferers continue to have a relatively low body mass
index (BMI), suggesting that the symptoms do not completely
resolve. Approximately 20% of patients develop a chronic,
intractable disorder. Long-term follow-up studies demonstrate
that minimum lifetime BMI is the strongest prognostic indicator
(BMI <1 1 .5 is associated with an standardised mortality ratio of
4-5). Other indicators of poor prognosis are comorbid BN and
atypical demographics (very early or relatively late onset, male
gender). Forty per cent of additional deaths are due to suicide,
the remainder being due to complications of starvation.
Bulimia nervosa
The prevalence of BN is difficult to determine with precision, as
only a small proportion of sufferers come to medical attention. It
is believed to be more common than AN, with a similar gender
ratio. Peak age of onset is slightly later than for AN, typically
late adolescence or early adult life.
Clinical features
Patients with BN are usually at or near normal weight (unlike in AN),
but display a morbid fear of fatness associated with disordered
eating behaviour. They recurrently embark on eating binges, often
followed by corrective measures such as self-induced vomiting.
Diagnosis
Diagnostic criteria are shown in Box 28.32. Physical signs of
repeated self-induced vomiting include pitted teeth (from gastric
acid), calluses on knuckles (‘Russell’s sign’) and parotid gland
enlargement. There are many associated physical complications,
including the dental and oesophageal consequences of repeated
vomiting, as well as electrolyte abnormalities, cardiac arrhythmias
and renal problems (see Box 28.31).
Investigations
Self-induced vomiting and/or abuse of laxatives and diuretics
can lead to clinically significant electrolyte disturbances, including
hypokalaemia leading to cardiac arrhythmias. Hence it is good
practice to measure urea and electrolytes and obtain an ECG
whenever these behaviours are prominent in any patient and
when BN is suspected in any medical inpatient. Repeated
vomiting can also give rise to Mallory-Weiss tears and even
oesophageal rupture; if symptoms are suggestive of these, an
endoscopy should be performed.
Management
Treatment of bulimia with CBT achieves both short-term and
long-term improvements. Guided self-help and IPT may also
be of value. There is also evidence for benefit from the SSRI
fluoxetine, but high doses of up to 60 mg daily may be required
for a prolonged period of up to 1 year; this appears to be
independent of the antidepressant effect.
Prognosis
Bulimia is not associated with increased mortality but a proportion
of sufferers go on to develop anorexia. At 10-year follow-up,
approximately 10% are still unwell, 20% have a subclinical degree
of bulimia, and the remainder have recovered.
Personality disorders
Personality refers to the set of characteristics and behavioural
traits that best describes an individual’s patterns of interaction
with the world. The intensity of particular traits varies from person
to person, although certain ones, such as shyness or irritability,
are displayed to some degree by most people. A personality
disorder (PD) is diagnosed when an individual’s personality causes
persistent and severe problems for the person or for others.
28.31 Medical consequences of eating disorders
Cardiac
• ECG abnormalities: T-wave inversion, ST depression and prolonged
QTc interval
• Arrhythmias, including profound sinus bradycardia and ventricular
tachycardia
Haematological
• Anaemia, thrombocytopenia and leucopenia
Endocrine
• Pubertal delay or arrest
• Growth retardation and short stature
• Amenorrhoea
• Sick euthyroid state
Metabolic
• Uraemia
• Renal calculi
• Osteoporosis
Gastrointestinal
• Constipation
• Abnormal liver function tests
28.32 Diagnostic criteria for eating disorders
Anorexia nervosa
• Weight loss of at least 15% of total body weight (or body mass
index < 1 7.5)
• Avoidance of high-calorie foods
• Distortion of body image so that patients regard themselves as fat
even when grossly underweight
• Amenorrhoea for at least 3 months
Bulimia nervosa
• Recurrent bouts of binge eating
• Lack of self-control over eating during binges
• Self-induced vomiting, purgation or dieting after binges
• Weight maintained within normal limits
Psychiatric disorders • 1205
Pathogenesis
Some PDs appear to have an inherited aspect (especially
schizotypal and paranoid subtypes) but most are more clearly
related to an unsatisfactory upbringing and adverse childhood
experiences.
Clinical features
PD can present in various ways. For example, anxiety may be so
pronounced that the individual rarely ventures into any situation
where they fear scrutiny. Dissocial traits, such as disregard for the
well-being of others and a lack of guilt concerning the adverse
effects of one’s actions on others, may occur. If pronounced, they
may lead to damage to others, to criminal acts or to successful
careers, such as in politics.
Diagnosis
It is possible to classify PD into several subtypes (such as
emotionally unstable, antisocial or dependent), depending on
the particular behavioural traits in question. A patient who
meets diagnostic criteria for one subtype may also meet criteria
for others. As allocation to one particular subtype gives little
guidance to management or prognosis, classification is of
limited value. Diagnosis requires a longitudinal perspective, with
clear evidence that the patient’s behavioural traits and pattern
of interaction with the world have been present throughout
their adult life, have been evident across a range of settings
and have caused repeated and persistent problems. It can
be difficult to achieve this during a single interview, and most
psychiatrists warn against making a diagnosis of personality
disorder until the patient has been seen several times and
corroborative accounts have been obtained. It is common
for PD to accompany other psychiatric conditions, making
treatment of the latter more difficult and therefore affecting their
prognosis.
Management
PDs usually persist throughout life and are not readily treated.
They typically become less extreme with age but can re-emerge in
the context of cognitive decline. Treatment options are limited but
there is some evidence that emotionally unstable PD may respond
to dialectical behavioural therapy (DBT). Anxious (avoidant) and
obsessional (anankastic) PD may benefit from prescription of
anxiolytic drugs, while paranoid/schizotypal PD may be improved
by treatment with low doses of antipsychotic agents.
The problematic and inflexible patterns of interaction that
characterise a PD are often apparent in the patient’s interaction
with health services and can present a challenge to both the service
and the patient. Clear clinical communication supported by robust
documentation can help to minimise any potential disruption.
Factitious disorder and malingering
Factitious disorder describes the repeated and deliberate production
of the signs or symptoms of disease to obtain medical care.
Pathogenesis
It is difficult to understand what motivates a person to act in this
way. Several theories have been proposed but the deception
that lies at the heart of the condition makes it impossible to
gather accurate data from which to draw reliable conclusions.
Clinical features
The disorder feigned is usually medical but can be a psychiatric
illness (for example false reports of hallucinations or symptoms
of depression). An example of a medical factitious disorder
is dipping of a thermometer into a hot drink to fake a fever.
Factitious disorder is uncommon and is important to distinguish
from somatoform disorders. A suggested diagnostic algorithm
is shown in Figure 28.6.
Fig. 28.6 Diagnosis of medically unexplained symptoms (MUS).
1206 • MEDICAL PSYCHIATRY
Munchausen’s syndrome
This refers to a severe chronic form of factitious disorder. Patients
characteristically travel widely, sometimes visiting several hospitals
in one day. Although the condition is rare, such patients are
memorable because they present so dramatically. The history
can be convincing enough to persuade doctors to undertake
investigations or initiate treatment, including exploratory surgery.
It may be possible to trace the patient’s history and show
that they have presented similarly elsewhere, often changing
name several times. Some emergency departments hold lists of
such patients.
Malingering
Malingering is a description of behaviour, not a psychiatric
diagnosis. It refers to the deliberate and conscious simulation
of signs of disease and disability for an identifiable gain (patients
have motives that are clear to them but which they initially conceal
from doctors). Examples include the avoidance of burdensome
responsibilities (such as work or court appearances) or the pursuit
of financial gain (fraudulent claims for benefits or compensation).
Malingering can be hard to detect at clinical assessment but is
suggested by evasion or inconsistency in the history.
Management
Management is by gentle but firm confrontation with clear evidence
of the fabrication of illness, together with an offer of psychological
support. Treatment is usually declined but recognition of the
condition may help to avoid further iatrogenic harm.
Puerperal psychiatric disorders
There are three important psychiatric presentations following
childbirth. When managing these conditions, it is important
always to consider both the mother and the baby, and their
relationship (Box 28.33).
Post-partum blues
This is characterised by irritability, labile mood and tearfulness.
About 80% of women are affected to some degree. Symptoms
begin soon after childbirth, typically peak on about the fourth
day and then resolve spontaneously within a few weeks. While
the aetiology of baby blues is not fully understood, it is likely to
be related to hormonal or physiological changes associated with
childbirth. No treatment is required, other than to reassure the
28.33 Psychiatric illness and pregnancy
• Psychiatric disorder and pregnancy: always consider effects on
mother, fetus and child.
• Bipolar disorder: women should have pre-conceptual advice
because there is a very high risk of relapse following delivery and
some mood stabilisers are teratogenic.
• Psychiatric treatments and pregnancy: always make an
individual assessment of the risks and benefits taking into
consideration effects on mother, fetus and child.
• Post-partum low mood (‘blues’): weeks 1-3; most cases are
transient.
• Persistent low mood and anhedonia: may indicate depressive
illness.
• Puerperal psychosis: progresses rapidly and is an indication for
psychiatric admission.
mother and to remain vigilant for development of post-partum
depression.
|Post-partum depression
This occurs in 10-15% of women, with onset typically within a
month of delivery (although women often suffer for some time
before presenting). It can usually be differentiated from post¬
partum blues by the duration and severity of the symptoms, in
particular anhedonia (loss of capacity for pleasure) and negative
thoughts. Risk factors include a previous history of depression,
a previous history of post-partum depression, antenatal
depression and antenatal anxiety. Unlike depression arising at
other times, post-partum depression is not more common in
lower socioeconomic groups; the prevalence is similar across
all social backgrounds. Diagnosis, explanation and reassurance
are important. The usual psychological and drug treatments
for depression should be considered (p. 1199) to minimise the
impact on the mother and child at what is a very important time
for both. A number of helpful guidelines are available to inform
prescribing decisions. The potential risks to both mother and
child should be considered and, if hospital admission is required,
it should ideally be to a mother and baby unit.
| Puerperal psychosis
This has its peak onset in the first 2 weeks after childbirth but
can arise several weeks later. It is a rare but serious complication
affecting approximately 1 in 500 women. There is a strong
association with a personal or familial history of bipolar disorder.
It usually takes the form of a manic or depressive psychosis but
with sudden onset and fluctuation in severity. Delirium is rare with
modern obstetric management but should still be considered
in the differential diagnosis. Suspiciousness, concealment and
impulsivity are common features of puerperal psychosis; hence
the risks to both mother and baby are considerable. The clinical
priority is to ensure the safety of both mother and baby and so
psychiatric admission, ideally to a psychiatric mother and baby
unit, is usually necessary. Pharmacological treatment reflects
the clinical picture; antipsychotic medication is almost always
indicated, augmented by antidepressants if the picture is of
psychotic depression and/or by mood stabilisers if the picture is
bipolar. Most women recover but the risk of recurrence following
subsequent deliveries is 50% and some women will progress
to psychotic episodes not associated with childbirth, usually
bipolar disorder.
| Psychiatric disorders during pregnancy
Pregnancy can affect the course of psychiatric illnesses and of
bipolar affective disorder in particular. Mood-stabilising drugs such
as lithium and valproate, which are prescribed for prophylaxis
in bipolar disorder (p. 1200), are teratogenic and should be
avoided whenever possible. Most guidelines recommend deferring
conception until mood-stabilising medication is not required,
or replacing the mood stabiliser with an antipsychotic such as
chlorpromazine. Furthermore, the immediate post-partum period
is associated with a dramatically increased risk of relapse in
bipolar disorder: studies report relapse rates of up to 60% in
the first 3 months after delivery in the absence of prophylactic
medication. When relapse occurs following childbirth, not only
are the stakes higher than at other times but also the onset of
illness is more rapid, the symptoms more severe and concealment
more pronounced. Post-partum relapse of bipolar affective
Further information • 1207
disorder requires urgent specialist treatment, usually comprising
admission to a psychiatric mother and baby unit. Ideally, women
with major mental disorders such as bipolar affective disorder
should be offered expert pre-conception advice to help them
make informed decisions about medication and other aspects
of their psychiatric care. A comprehensive post-partum risk
management plan should be agreed during pregnancy.
Psychiatry and the law
Medicine takes place in a legal framework, made up of legislation
(statute law) drafted by parliament or other governing bodies,
precedent built up from court judgements over time (case law),
and established tradition (common law). Psychiatry is similar to
other branches of medicine in the applicability of common and
case law but differs in that patients with psychiatric disorders can
also be subject to legislative requirements to remain in hospital
or to undergo treatments they refuse, such as the administration
of antipsychotic drugs to a patient with acute schizophrenia who
lacks insight and whose symptoms and/or behaviour pose a risk
to himself/herself or to others.
The UK has three different Mental Health Acts, covering England
and Wales, Scotland, and Northern Ireland, and all of these have
recently been revised. Other countries may have very different
provisions. It is important for practitioners to be familiar with the
relevant provisions that apply in their jurisdictions and are likely
to arise in the clinical settings in which they work.
All the countries that make up the UK have also introduced
Incapacity Acts in recent years, with detailed provisions covering
medical treatments for patients incapable of consenting, whether
this incapacity arises from physical or mental illness. In general,
the guiding principle in British law is that people should be free to
make their own decision about any proposed medical treatment,
except where their ability to make and/or communicate that
decision is demonstrably impaired (by mental illness or physical
incapacity). Any restrictions or compulsions applied should be
the minimum necessary, they should be applied only for as long
as is necessary, and there should be a benefit to the patient
that balances the restrictions imposed. There should also be
provisions for appeals and oversight.
Further information
Books and journal articles
Hofer H, Pozzi A, Joray M, et al. Safe refeeding management of
anorexia nervosa inpatients: an evidence-based protocol. Nutrition
2014; 30:524-30.
Steel RM. Factitious disorder (Munchausen’s syndrome). J R Coll
Physicians Edinb 2009; 39:343-7.
Taylor D, Meader N, Bird V, et al. Pharmacological interventions for
people with depression and chronic physical health problems:
systematic review and meta-analyses of safety and efficacy.
Br J Psychiatry 201 1 ; 1 98:1 79-88.
Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease
attributable to mental and substance use disorders: findings from
the Global Burden of Disease Study 2010. Lancet 2013; 382:
1575-86.
Websites
cebmh.com Centre for Evidence-based Mental Health.
dementia.ie/images/uploads/site-images/ACE-lll_Scoring_(UK)-pdf
Addenbrooke’s Cognitive Examination - 3rd edn (ACE-Ill):
administration and scoring guide.
mind.org.uk Information on depression.
mocatest.org Montreal Cognitive Assessment.
neurosymptoms.org A guide to medically unexplained neurological
symptoms.
niaaa.nih.gov/ Information on alcoholism.
nice.org.uk National Institute for Health and Care Excellence: treatment
guidelines for depression.
ocdaction.org.uk Useful information about obsessive-compulsive
disorder.
rcpsych.ac.uk/info/index.htm Royal College of Psychiatrists: mental
health information.
sign.ac.uk Scottish Intercollegiate Guidelines Network: treatment
guidelines for depression, including Guideline 127 - Management of
perinatal mood disorders.
who.int/mental_health/ World Health Organisation: mental health and
brain disorders.
www4.parinc.com/ Mini-Mental State Examination.
28
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SH Ibbotson
Dermatology
Clinical examination in skin disease 1210
Acne and rosacea 1 241
Functional anatomy and physiology 1212
Investigation of skin disease 1214
Presenting problems in skin disease 1216
Lumps and lesions 1216
Rash 1216
Blisters 1 21 8
Itch 1219
Photosensitivity 1 220
Leg ulcers 1 223
Abnormal pigmentation 1 224
Hair and nail abnormalities 1 224
Acute skin failure 1 224
Eczemas 1244
Psoriasis and other erythematous scaly eruptions 1 247
Lichenoid eruptions 1252
Urticaria 1252
Bullous diseases 1254
Toxic epidermal necrolysis 1 254
Immunobullous diseases 1255
Pigmentation disorders 1257
Decreased pigmentation 1 257
Increased pigmentation 1 258
Principles of management of skin disease 1225
General measures 1 225
Topical treatments 1 225
Phototherapy and photochemotherapy 1 227
Systemic therapies 1 227
Dermatological surgery 1228
Non-surgical treatments 1 228
Skin tumours 1229
Malignant tumours 1229
Benign skin lesions 1234
Common skin infections and infestations 1235
Bacterial infections 1 235
Viral infections 1 238
Fungal infections 1 239
Infestations 1 241
Hair disorders 1258
Nail disorders 1260
Skin disease in general medicine 1261
Conditions involving cutaneous vasculature 1 261
Connective tissue disease 1 262
Granulomatous disease 1 263
Porphyrias 1 263
Abnormal deposition disorders 1 264
Genetic disorders 1 264
Reactive disorders 1 264
Drug eruptions 1 265
1210 • DERMATOLOGY
Clinical examination in skin disease
8 Detailed morphology of individual lesions
Use a magnifying lens in good lighting to assist
Use correct terminology (see definitions throughout text)
A Palmoplantar pustulosis
A Magnifying lens image of
benign naevus
7 Overall description of
individual lesions
Discrete, grouped, confluent,
reticulate (lace-like), linear
6 Morphology of rash
Monomorphic or polymorphic
5 Involvement of axillae/groins
e.g. hidradenitis suppurativa
4 Nail involvement
A Psoriatic changes in nails
and peri-ungual involvement
3 Involvement of hands,
including nail folds and finger
webs
2 If symmetrical
| Extensor, e.g. psoriasis
Flexor, e.g. eczema
1 Distribution of rash
Symmetrical vs asymmetrical
Proximal vs distal vs facial
Localised vs widespread
The patient must be undressed, with
make-up and dressings removed,
and examined in good lighting.
Consider the following:
•Age
• General health
• Distress
• Scratching
9 Examination of scalp
Hair loss
Scalp changes
10 Involvement of face
Central
Hairline
Cheeks and nasal bridge:
‘butterfly’ distribution
Sparing of light-protected sites,
e.g. behind ears, under chin
11 Eye involvement
e.g. Conjunctivitis/blepharitis
in rosacea or eyelash loss in
alopecia areata
12 Oral and genital involvement
A Reticulate (lacy) network on
buccal mucosa in lichen
planus. May also be genital
involvement
13 Joint involvement
e.g. Psoriatic arthritis
A Arthritis, plaque psoriasis and
psoriatic nail dystrophy
14 General medical examination
Including lymph nodes and
other systems as indicated
Clinical examination in skin disease • 1211
It is tempting to examine the skin first. This is a mistake; take a history, then examine the skin and the rest of the patient.
1. Hi story- taking 2. Drug/allergy history 3. Examination of skin 4. Closer inspection 5. General examination
1 Onset and course
1 Exacerbating/relieving
factors
1 Past history of skin
disease, atopy or
autoimmune disease
1 Social history,
occupation, recreation
1 Psychological impact,
gauged by health-
related life quality
indices
Always take a detailed
drug and allergy
history
Include all systemic
and topical drugs,
and over-the-counter
preparations
1 Examine skin, hair,
nails and mucous
membranes
1 Is it a rash or a lesion?
1 Distribution and
morphology important
for rash
1 Use of a magnifying <
lens and/or
dermatoscope may be
invaluable
1 Site, size and detailed <
morphology of a lesion
are essential factors
to elicit
General examination,
incl. peripheral
lymph nodes, may be
indicated/important
Skin diseases may
have systemic features
(e.g. cardiovascular
disease in psoriasis);
many systemic
diseases have
dermatological
features (e.g. diabetes)
6. Define type of lesion using correct terminology
Helps in differential diagnosis and allows colleagues to visualise the process. Other definitions are provided in the chapter.
Macule/patch
Papule
Nodule
Plaque
Macule: circumscribed flat
area of colour change < 1 cm
diameter; patch: > 1 cm
Vesicle
Discrete elevation < 1 cm
diameter
Blisters/bullae
Like papule but deeper (into Raised area > 1 cm diameter
dermis or subcutaneous layer), with flat top
> 1 cm diameter
Pustule
Petechiae/purpura
Small (< 1 cm diameter) fluid-
filled blister
Large (> 1 cm diameter) fluid-
filled blister
Visible accumulation of pus
in blister
Petechiae: tiny macules due
to extravascular blood in
dermis; purpura: larger, may
be palpable
7. Score activity
Tools for objective assessment of disease severity (e.g. Psoriasis Area and Severity Index, PASI) are important
in assessing severity and treatment responses.
■ Four body parts are each scored
individually
(A) Each of the four body parts is scored:
Redness (erythema) 0-4
Thickness (induration) 0-4
Scaling (desquamation) 0-4
(B) The area of each involved
0
0%
1
<10%
2
10-29%
3
30-49%
4
50-69%
5
70-89%
6
90-100%
To find the PASI score, add together: (A) Sum for each part x (B) % of that part involved x (C) % weighting of that body part
Minimum = 0; maximum = 72
1212 • DERMATOLOGY
Diseases affecting the skin are common, and important because
the absence of normal skin function, as well as sometimes being
life-threatening, can severely impair quality of life. This may be
exacerbated by the fact that people with skin disease can suffer
the effects of stigma, often brought about by the ill-informed
understanding of others with respect to skin diseases, particularly
as regards visually disfiguring skin changes or the belief that
they are contagious.
Skin diseases affect all ages and there are more than 2000
different types and presentations. Assessment of the skin is
valuable in the management of anyone presenting with a medical
problem and, conversely, assessment of the other body systems
is important when managing primary skin diseases. This chapter
concentrates on common skin diseases and those that are
important components of general medical conditions. Skin
infections, including those related to the human immunodeficiency
virus (HIV), tuberculosis, leprosy (Hansen’s disease) and syphilis
are also discussed in Chapters 12, 17, 11 and 13, respectively.
Functional anatomy and physiology
The skin covers just under 2 m2 in the average adult. The
outer layer is the epidermis, a stratified squamous epithelium
consisting mainly of keratinocytes. The epidermis is attached
to, but separated from, the underlying dermis by the basement
membrane. The dermis is less cellular and supports blood vessels,
nerves and epidermal-derived appendages (hair follicles and sweat
glands). Below it is the subcutis, consisting of adipose tissue.
Epidermis
In most sites, the epidermis is only 0.1 -0.2 mm thick, except on
the palms or soles, where it can extend to several millimetres.
Keratinocytes make up approximately 90% of epidermal cells
(Fig. 29.1). The main proliferative compartment is the basal layer.
Keratinocytes synthesise a range of structural proteins, such
as keratins, loricrin and filaggrin (filament aggregating protein),
which play key roles in maintaining the skin’s barrier function.
Keratinocytes are also responsible for synthesis of vitamin D
under the influence of ultraviolet B (UVB) light (p. 1049). There
are more than 50 types of keratin and their expression varies by
body site, site within the epidermis and disease state. Mutations
of certain keratin genes can result in blistering disorders (p. 1254)
and ichthyosis (characterised by scale without major inflammation).
As keratinocytes migrate from the basal layer, they differentiate,
producing a variety of protein and lipid products. Keratinocytes
undergo apoptosis in the granular layer before losing their nuclei
and becoming the flattened corneocytes of the stratum corneum
(keratin layer). The epidermis is a site of lipid production, and the
ability of the stratum corneum to act as a hydrophobic barrier
is the result of its ‘bricks and mortar’ design; dead corneocytes
with highly cross-linked protein membranes (‘bricks’) lie within
a metabolically active lipid layer synthesised by keratinocytes
(‘mortar’). Terminal differentiation of keratinocytes relies on the
keratin filaments being aggregated and this is, in part, mediated
by filaggrin. Mutations of the filaggrin gene are found in icthyosis
vulgaris and in some patients with atopic eczema (p. 1245).
The skin is a barrier against physical stresses. Cell-to-cell
attachments must be able to transmit and dissipate stress,
a function performed by desmosomes. Diseases that affect
desmosomes, such as pemphigus (p. 1256), result in blistering
due to keratinocyte separation.
The remaining 10% of epidermal cells are:
• Langerhans’ cells: these are dendritic, bone marrow-
derived cells that circulate between the epidermis and
local lymph nodes. Their prime function is antigen
presentation to lymphocytes. Other dermal antigen-
presenting dendritic cells are also present.
• Melanocytes: these occur predominantly in the basal layer
and are of neural crest origin. They synthesise the pigment
melanin from tyrosine, package it in melanosomes and
transfer it to surrounding keratinocytes via their dendritic
processes.
• Merkel cells: these occur in the basal layer and are
thought to play a role in signal transduction of fine touch.
Their embryological derivation is unclear.
Basement membrane
The basement membrane (Fig. 29.1) is an anchor for the epidermis
and allows movement of cells and nutrients between dermis
and epidermis. The cell membrane of the epidermal basal cell
is attached to the basement membrane via hemi-desmosomes.
The lamina lucida lies immediately below the basal cell membrane
and is composed predominantly of laminin. Anchoring filaments
extend through the lamina lucida to attach to the lamina densa.
This electron-dense layer consists mostly of type IV collagen;
from it extend loops of type VII collagen, forming anchoring fibrils
that fasten the basement membrane to the dermis.
Dermis
The dermis is vascular and supports the epidermis structurally
and nutritionally. It varies in thickness from just over 1 mm on
the inner forearm to 4 mm on the back. Fibroblasts are the
predominant cells but others include mast cells, mononuclear
phagocytes, T lymphocytes, dendritic cells, neurons and
endothelial cells. The acellular part of the dermis consists
mainly of collagen I and III, elastin and reticulin, synthesised
by fibroblasts. Support is provided by an amorphous ground
substance (mostly glycosaminoglycans, hyaluronic acid and
dermatan sulphate), whose production and catabolism are
altered by hormonal changes and ultraviolet radiation (UVR).
Based on the pattern of collagen fibrils, the superficial dermis is
termed the ‘papillary dermis’, and the deeper, coarser part is the
‘reticular dermis’.
| Epidermal appendages
Hair follicles
There are 3-5 million hair follicles, epidermal invaginations that
develop during the second trimester. They occur throughout
the skin, with the exception of palms, soles and parts of the
genitalia (glabrous skin). The highest density of hair follicles is
on the scalp (500-1000/cm2). Newborns are covered with fine
‘lanugo’ hairs, which are usually non-pigmented and lack a central
medulla; these are subsequently replaced by vellus hair, which is
similar but more likely to be pigmented. By contrast, scalp hair
becomes terminal hair, which is thicker with a central medulla,
is usually pigmented and grows longer. At puberty, vellus hairs
in hormonally sensitive regions, such as the axillary and genital
areas, become terminal hairs.
Human hairs grow in a cycle with three phases: anagen
(active hair growth), catagen (transitional phase) and telogen
(resting phase). The duration of each phase varies by site. On
the scalp, anagen lasts several years, catagen a few days and
Functional anatomy and physiology • 1213
Basement membrane
Desmosome
(desmoglein-1 and 3,
desmoplakin)
Basal keratinocyte
Basal cell membrane
Lamina lucida
(laminin-1)
Lamina densa
(type IV collagen)
I Till-
Tonofilaments
(keratins 5 and 14)
Hemi-desmosome
/(BP230, type XVII collagen,
a6p4 integrin, plectin)
v Anchoring filament
(laminin 332)
Sublamina densa >
_ Anchoring fibrils
(collagen VII)
Stratum corneum
(keratin layer)
Granular layer
Prickle
cell layer
Basal layer
Hair shaft -
Dermis
Epidermis
Keratinocytes containing
keratins 1 and 10
Keratinocytes containing
keratins 5 and 14
Langerhans1
cell
Melanocyte
Epidermis
Eccrine sweat duct
Superficial vascular
plexus
Sebaceous gland
Hair sheath
Eccrine sweat gland
Deep vascular plexus
Hair matrix
Dermis
Dermal papilla
Subcutaneous
vessel
Subcutis
Fig. 29.1 Structure of normal skin.
telogen around 3 months. The length of hair at different sites
reflects the differing lengths of anagen.
Sebaceous glands
Sebaceous glands are epidermal downgrowths, usually associated
with hair follicles and composed of modified keratinocytes. The
cells of the sebaceous gland (sebocytes) produce a range of lipids,
discharging the contents into the duct around the hair follicle.
Sebum excretion is under hormonal control, with androgens
increasing it (as do progesterones, to a lesser degree) and
oestrogens reducing it. In animals, sebum is important for hair
waterproofing but its role in humans is unclear.
Sweat glands
Eccrine sweat glands develop in the second trimester and are
also epidermal invaginations found all over the body. Their coiled
ducts open directly on to the skin surface. They play a major role
in thermoregulation and, unusually, are innervated by cholinergic
fibres of the sympathetic nervous system. Eccrine glands of the
palms and soles are innervated differently and are activated in the
1214 • DERMATOLOGY
‘fight or flight’ response. Apocrine sweat glands are restricted to
the axillae and the mammary and genital areas, are connected
to hair follicles and are not involved in thermoregulation.
Nails
Fingernail growth commences at approximately 8 weeks of
gestation and is complete by 32 weeks. Toenails develop slightly
later. The anatomy of the nail apparatus is covered later in the
chapter (p. 1260).
Blood vessels and nerves
Human skin has a plentiful blood supply, arranged in superficial
and deep plexuses consisting of arterioles, arterial and venous
capillaries, and venules. The upper plexus in the papillary dermis
communicates with the lower plexus at the junction between
the dermis and the subcutis. Capillary loops arise from terminal
arterioles in the horizontal papillary plexus. Blood vessels are
supplied by sympathetic and parasympathetic nerves, with
the relative contributions of the pathways differing by site.
Sympathetic signals are important in mediating autonomic-induced
vasoconstriction. The blood supply of skin is far greater than that
required for normal skin physiology and reflects the importance
of skin in thermoregulation.
Functions of the skin
The skin has many functions, all of which can be affected by
disease (Box 29.1). Skin changes associated with ageing are
shown in Box 29.2.
Investigation of skin disease
| Magnifying glass
A hand-held or freestanding magnifying lens used under good
lighting conditions (ideally daylight) is valuable for examination
of the skin.
Wood’s light
Wood’s light is a long-wavelength UVA/short-wavelength
visible (violet) light source that can be used in various ways. In
hypopigmentation, such as in vitiligo, it can help in appreciating
the extent of disease. In pigmented conditions, such as melasma,
it can determine whether pigmentation is mainly epidermal
(sharp cut-off under Wood’s lamp) or mixed epidermal and
dermal (ill-defined cut-off). Wood’s lamp can also be used to
help with the diagnosis of some fungal infections because of
their characteristic fluorescence.
Dermatoscopy and diascopy
Dermatoscopy (also known as dermoscopy and epiluminescence
microscopy) is increasingly performed with hand-held
dermatoscopes. What makes dermatoscopy unique is the fact
that it allows visualisation through contact of a glass plate on
the instrument with a liquid film applied to the skin, or through
special optics to allow non-contact dermatoscopy, enabling
deeper structures to be seen without interference from reflection
and refraction of light in the epidermis.
Diascopy is simply pressing on the lesion with a glass slide. This
provides some of the effect of dermatoscopy, but is mainly used
to remove blood from vascular lesions to make the appearance
29.1 Functions of the skin
Function
Structure/cell involved
Protection against:
Chemicals, particles, desiccation
Ultraviolet radiation
Antigens, haptens
Microorganisms
Stratum corneum
Melanin produced by
melanocytes and transferred to
keratinocytes
Stratum corneum
hyperproliferation
Langerhans’ cells, lymphocytes,
mononuclear phagocytes, mast
cells, dermal dendritic cells
Stratum corneum, Langerhans’
cells, mononuclear phagocytes,
mast cells, dermal dendritic cells
Maintenance of fluid balance
Prevents loss of water,
electrolytes and macromolecules
Stratum corneum
Shock absorber
Strong, elastic and compliant
covering
Dermis and subcutaneous fat
Sensation
Specialised nerve endings
mediating pain and withdrawal
Itch leading to scratch and
removal of a parasite
Metabolism
Detoxification of xenobiotics,
retinoid metabolism,
isomerisation of urocanic acid
Predominantly keratinocytes
Temperature regulation
Eccrine sweat glands and blood
vessels
Protection, and fine
manipulation of small objects
Nails
Hormonal
Steroidogenesis, testosterone
synthesis and conversion to other
androgenic steroids
Conversion of thyroxine (T4) to
triiodothyronine (T3)
Conversion of
7-dehydrocholesterol to vitamin D
Hair follicles, sebaceous glands
Keratinocytes
Keratinocytes
Pheromonal
Importance unknown in humans
Apocrine sweat glands, possibly
sebaceous glands
Psychosocial, grooming and
sexual behaviour
Appearance, tactile quality of
skin, hair, nails
of the lesion clearer. Granulomatous skin diseases may have
a characteristic appearance under diascopy, such as in lupus
vulgaris (cutaneous tuberculosis), in which ‘apple jelly nodules’
are typically seen on diascopy.
| Skin biopsy
Skin biopsy is a mainstay investigation in dermatology and
can be used in a range of dermatological presentations. In the
most common scenario, a skin biopsy is undertaken in order
to obtain tissue on which to perform standard histopathology.
However, tissue may also be subjected to a variety of
staining and culture techniques, including immunostaining.
Histopathological examination of skin biopsies is especially
Investigation of skin disease • 1215
£
useful for tumour diagnosis. When a dermatologist or pathologist
with dermatopathology expertise is involved, it can also assist
in the diagnosis of inflammatory skin diseases. It is rare for
histopathology of a previously undiagnosed inflammatory skin
disease to provide a diagnosis on its own; clinico-pathological
correlation is critical. Most biopsies are stained with haematoxylin
and eosin but other stains may be useful in special situations, such
as for fungal hyphae, iron or mucin. Direct immunofluorescence
can also be undertaken on a fresh skin biopsy, allowing antigen
visualisation using fluorescein-labelled antibodies; this is especially
important in the diagnosis of autoimmune bullous disorders or
connective tissue disease, such as cutaneous lupus.
| Microbiology
Bacteriology
Bacterial swabs may identify a causative infective agent. However,
organisms identified from the skin surface may not be the cause
of the skin disease but instead may simply reflect colonisation
of skin that has already been damaged by a primary skin
disease.
Virology
A number of techniques, including immunofluorescence and
polymerase chain reaction (PCR), are available to diagnose
herpes simplex or herpes zoster viruses from vesicle fluid (p. 1 06).
Mycology
Scale, nail clippings (or scrapings of crumbly subungual
hyperkeratosis) and plucked hairs can be examined by light
microscopy. If potassium hydroxide and a simple light microscope
are available, this can be performed in any outpatient clinic.
Microbiology laboratories will also routinely undertake microscopy
and culture for fungi and yeasts.
Patch testing
Patch testing is the investigation of choice for delayed, cell-
mediated, type IV hypersensitivity, which clinically manifests
as dermatitis. Potential allergens (see Box 29.22, p. 1247) are
applied as patches to the back under occlusion for 48 hours, in
vehicles and at concentrations that minimise false-positive and
false-negative reactions. After 48 hours the patches are removed
and patch-test readings are undertaken at time points of up to
7 days after patch-test application, with the most typical time
point being at 96 hours. When interpreting patch test readings,
it is important to determine the clinical relevance of any allergic
reactions before giving avoidance advice.
Photopatch testing is similar to patch testing but investigates
delayed hypersensitivity to an agent (usually a sunscreen or a
non-steroidal anti-inflammatory drug (NSAID)) after the absorption
of UVR. It involves applying substances in duplicate and irradiating
one set with UVR (typically UVA, 5 J/cm2), readings then being
conducted in a similar manner to patch testing.
I Prick tests and specific immunoglobulin E
testing
Prick tests are used to investigate cutaneous type I (immediate)
hypersensitivity to various antigens such as pollen, house dust
mite or dander. The skin is pricked with commercially available
stylets through a dilution of the appropriate antigen solution
(p. 86). Alternatively, specific immunoglobulin E (IgE) levels
to antigens can be measured in serum. If challenge tests are
undertaken for patients with suspected allergy, these must be
performed under controlled conditions due to the potential risk
of triggering a severe reaction (p. 86).
Phototesting
Phototesting is extremely valuable in the assessment of suspected
photosensitivity. The mainstay investigation is monochromator
phototesting, which involves exposing the patient’s back to
increasing doses of irradiation using narrow wavebands across
the solar spectrum and then assessing responses, using the
minimal erythema dose (MED) at each waveband. This is the
dose required to cause just perceptible skin reddening and is
compared with values for the normal population. If a patient
has reduced MED (develops erythema at lower doses than
healthy subjects), this indicates abnormal photosensitivity. Thus,
monochromator phototesting can be used to determine whether
a patient is abnormally photosensitive, which wavebands are
involved and how sensitive the patient is (p. 1220). Provocation
testing can be performed with a broadband (usually UVA) source
to induce rash at a test site (most useful for polymorphic light
eruption) and can be helpful for diagnosis. Provocation testing to
a variety of light sources, including artificial compact fluorescent
lamps, may also be indicated, the latter being most relevant in
patients with severe photosensitivity.
Patients who are referred for phototherapy will also commonly
undergo an MED test, in which they are exposed to a series of
test doses of the light source that will be used therapeutically
(often narrowband UVB); the MED is determined 24 hours later
(or 72-96 hours for the psoralen-ultraviolet A (PUVA) minimal
phototoxic dose; p. 1227). This allows treatment regimens to
be individualised, based on a patient’s erythemal responses,
and may detect abnormal photosensitivity.
Blood tests
Although most patients presenting with a skin problem do not
need blood tests as part of their investigations, there are many
systemic diseases that can present with skin features and, indeed,
blood tests may also be indicated in the investigation of primary
skin disease. A wide range of possible investigations may be
required and some examples include haemoglobin, iron studies
and thyroid function tests in pruritus or hair loss; autoantibody
screening if lupus is suspected; porphyrin plasma scan for skin
fragility and hypertrichosis; and hepatitis screening in lichen
29.2 Skin changes in old age
• Chronological ageing: due to the intrinsic ageing process.
• Photo-ageing: due to cumulative ultraviolet radiation (UVR)
exposure and superimposed on intrinsic ageing.
• Typical changes: include atrophy, laxity, yellow discoloration,
wrinkling, dryness, irregular pigmentation, and thinning and greying
of hair.
• Causes: age-related alterations in structure and function of the
skin, cumulative effects of environmental insults, especially UVR and
smoking, cutaneous consequences of disease in other organ
systems.
• Consequences: reduction in immune and inflammatory responses,
reduction in absorption and clearance of topical medications,
reduced healing, increased susceptibility to irritants, dermatitis,
adverse drug effects (including topical glucocorticoid-induced
atrophy and purpura) and diseases such as skin cancer.
1216 • DERMATOLOGY
planus. These diverse examples emphasise the importance of
considering an underlying systemic disease when assessing a
patient with a dermatological presentation.
|jmaging
Imaging techniques are not typically required but X-rays,
ultrasound, magnetic resonance imaging (MRI) or computed
tomography (CT) may occasionally be indicated in specific
situations, such as in metastatic melanoma or in a patient
presenting with a diagnosis of cutaneous sarcoid.
Presenting problems in skin disease
The major presentations in dermatology are outlined below.
Detail of the underlying disorders is mostly provided in the
disease-specific sections further on in the chapter.
Lumps and lesions
The term lump or lesion is typically used to describe a papule
or nodule, although sometimes may refer to a macule or plaque
(p. 1 21 1). A new or changing lump is one of the key dermatology
presentations.
Clinical assessment
Detailed history-taking and examination are essential:
• Change: Is the lump new or has there been a change in a
pre-existing lesion? What is the nature of the change
- size, colour, shape or surface change? Has change
been rapid or slow? Are there other features - pain,
itch, inflammation, bleeding or ulceration (definition of
‘ulcer’: an area from which the epidermis and at least
the upper part of the dermis have been lost - see
Fig. 29.9, p. 1223)?
• Patient : What is the patient’s age? Are they fair-skinned
and freckled? Has there been much sun exposure? Have
they used sunbeds or lived in sunny climates? Have they
used photoprotection?
• Site: Is it on a sun-exposed or covered site? The scalp,
face, upper limbs and back in men, and face, hands and
lower legs in women, are the most chronically sun-
exposed sites.
• Are there other similar lesions? These might include actinic
keratoses (see Fig. 29.13, p. 1231) or basal cell
papillomas (see Fig. 29.17, p. 1234).
• Morphology: Tenderness, size, symmetry, regularity of
border, colour, surface characteristics and the presence
of features such as crust (definition: dried exudate of
blood or serous fluid - see Fig. 29.19, p. 1235), scale
(definition: a flake arising from the stratum corneum;
any condition with a thickened stratum corneum can
cause scaling - see Fig. 29.13, p. 1231) and ulceration
must be assessed. Stretching the skin and using a
magnifying lens can be helpful, such as for detecting the
raised, pearled edge of a basal cell carcinoma (see
Fig. 29.11, p. 1229).
• Dermatoscopy: This can be used to detect the presence
of abnormal vessels, such as in basal cell carcinoma or
the characteristic keratin cysts in basal cell papillomas. It is
invaluable for assessing pigmented and vascular lesions
(Fig. 29.2).
i
• Asymmetry
• Border irregular
• Colour irregular
• Diameter >0.5 cm
• Elevation irregular
(+ Loss of skin markings)
Is it a melanocytic naevus or a malignant melanoma?
This is a common clinical scenario and one that it is critical to
resolve correctly.
• The precise nature of the change should be determined
(as above). Listen to the patient and pay attention to
subtle changes, as people know their skin well.
• If the patient has other pigmented lesions, then these
should be examined too, as they may be informative. For
example, if the presenting lesion looks different from the
others, then suspicion of melanoma is increased;
conversely, if the patient has multiple basal cell papillomas,
this may be reassuring - although do not be falsely
reassured.
• Is there a positive family history of melanoma? A
suspicious naevus in a patient with a first-degree relative
with melanoma probably warrants excision.
The ABODE ‘rule’ is a guide to the characteristic features of
melanoma (Box 29.3 and see Figs 29.2 and 29.15), although
melanomas should ideally be diagnosed before the diameter is
greater than 0.5 cm. Loss of normal skin markings in a pigmented
lesion may be suggestive of melanoma. Conversely, normal
skin markings and fine hairs dispersed evenly over a lesion
are reassuring but do not exclude melanoma. The Glasgow
seven-point checklist is another useful guide:
• major features: change in size, shape and colour
• minor features: diameter >0.5 cm, inflammation, oozing,
bleeding, itch or altered sensation.
Patients with one major or one minor feature should be referred
for further evaluation.
Investigations and management
If a benign diagnosis, such as basal cell papilloma, is made
on clinical grounds, then the patient can be reassured and the
lesion either left or treated: for example, with cryotherapy. If there
are concerns about the diagnosis or malignancy is suspected
on clinical grounds, then skin biopsy in order to obtain a tissue
diagnosis is the usual approach. An incisional biopsy may be
indicated, although if the lesion is small, excision may be most
appropriate. If significant concern exists about the possibility of
malignant melanoma, initial excision with a 2 mm margin would
usually be undertaken prior to more definitive management once
histology was confirmed. Further management of a changed
lesion would, of course, depend on the histology of the diagnostic
biopsy.
Rash
A rash is the other common presentation in dermatology. The
main categories of scaly rashes are listed in Box 29.4. The most
common type of rash presentation is maculopapular. Diagnosis
can often be made on clinical grounds, although a biopsy may
be required.
29.3 ABCDE features of malignant melanoma
Presenting problems in skin disease • 1217
Fig. 29.2 Dermatoscopy.
{K\ A changing lesion. [8]
Dermatoscopy highlights the
abnormal pigment network and
other features suggestive of
melanoma. Excision biopsy
confirmed the diagnosis of
superficial spreading malignant
melanoma (Breslow thickness
0.8 mm), [g] Another changing
lesion. [jj] Dermatoscopy
highlights the vascular lacunae
of this benign angioma and the
patient was reassured.
29.4 Causes and clinical features of common scaly rashes
Diagnosis
Distribution
Morphology
Associated signs
Atopic eczema
(p. 1245)
Face and flexures
Poorly defined erythema, scaling
Vesicles
Lichenification if chronic
Shiny nails
Infra-orbital crease
‘Dirty neck’ (grey-brown discoloration)
Psoriasis
(p. 1247)
Extensor surfaces
Lower back
Well-defined
Erythematous plaques
Silvery scale
Nail pitting, onycholysis
Scalp involvement
Axillae and genital areas often affected
Joint involvement
Kobner phenomenon (p. 1252)
Pityriasis rosea
(p. 1251)
‘Fir tree’ pattern on trunk
Well-defined
Small, erythematous plaques
Collarette of scale
Herald patch
Drug eruption
(p. 1265)
Widespread
Macules and papules
Erythema and scale
Exfoliation
Possible mucosal involvement or erythroderma
Pityriasis versicolor
(p. 1240)
Upper trunk and shoulders
Hypo- and hyper-pigmented scaly patches
Lichen planus
(p. 1252)
Distal limbs
Flexural aspect of wrists
Lower back
Shiny, flat-topped, violaceous papules
Wickham’s striae
White, lacy network on buccal mucosa
Nail changes
Scarring alopecia
Kobner phenomenon
Tinea corporis
(p. 1240)
Asymmetrical
Often isolated lesions
Erythematous, often annular plaques
Peripheral scale (sometimes pustules)
Expansion with central clearing
Possible nail, scalp, groin involvement
Secondary syphilis
(p. 337)
Trunk and proximal limbs
Palms and soles
Red macules and papules, which become
‘gun-metal’ grey
History of chancre
Systemic symptoms, e.g. malaise and fever
1218 • DERMATOLOGY
Clinical assessment
Important aspects of the history include:
• Age at onset and duration of rash. Atopic eczema often
starts in early childhood and psoriasis between 15 and
40 years, and both may be chronic. Infective or drug-
induced rashes are more likely to be of short duration and
the latter to occur in relation to drug ingestion. Duration of
individual lesions is also important, as in urticaria, for
example.
• Body site at onset and distribution. Flexural sites are more
typically involved in atopic eczema, and extensor surfaces
and scalp in psoriasis. Symmetry is often indicative of
an endogenous disease, such as psoriasis, whereas
asymmetry is more common with exogenous causes, such
as contact dermatitis or infections like herpes zoster.
• Itch. Eczema is usually extremely itchy and psoriasis may
be less so.
• Preceding illness and systemic symptoms. Guttate
psoriasis may be precipitated by a p-haemolytic
streptococcal throat infection; almost all patients with
infectious mononucleosis (p. 241) treated with amoxicillin
will develop an erythematous maculopapular eruption; a
history of chancre at the site of inoculation may be elicited
in a presentation of secondary syphilis; malaise and
arthralgia are common in drug eruptions and
vasculitis.
The morphology of the rash and the characteristics of individual
lesions are important (Box 29.4).
Investigations and management
It is important to have a short differential diagnosis based
on clinical assessment in order to direct investigations. For
example, in psoriasis, no investigations may be needed and
initial management with patient counselling and topical therapies
may suffice. If the diagnosis is unclear, then a diagnostic skin
biopsy and other targeted investigations based on the clinical
picture may be required. An initial management plan should also
be implemented. For example, in a child presenting with a rash
that has features suggestive of impetigo, skin and nasal swabs
should be performed and, once these have been taken, topical
or systemic antibiotics should be introduced, depending on
clinical extent of disease, and management should be adjusted
accordingly, dependent on investigation findings and clinical
course. In contrast, if a patient presents with a maculopapular
rash shortly after introduction of a new drug, then drug withdrawal,
diagnostic biopsy, full blood count, including eosinophil count,
and liver and renal function tests, in parallel with topical emollients
and glucocorticoids, may be indicated.
Blisters
A blister is a fluid-filled collection in the skin. The term vesicle
is used for small lesions and bulla for larger lesions (p. 1211).
Blistering occurs due to loss of cell adhesion within the epidermis
or subepidermal region (see Fig. 29.1). The clinical presentation
depends on the site or level of blistering within the skin, which in
turn reflects the underlying cause (p. 1254). There are a limited
number of conditions that present with blisters (Box 29.5):
• Intact blisters are not often seen if the split is high in the
epidermis (below the stratum corneum), as the blister roof
is so fragile that it ruptures easily, leaving erosions
(definition: an area of skin denuded by complete or
partial loss of the epidermis). This occurs in pemphigus
foliaceus, staphylococcal scalded skin syndrome (see
Fig. 29.20, p. 1236) and bullous impetigo.
• If the split is lower in the epidermis, then intact flaccid
blisters and erosions may be seen, as occurs in
pemphigus vulgaris and toxic epidermal necrolysis (see
Fig. 29.41, p. 1254).
• If the split is subepidermal, then tense-roofed blisters are
seen. This occurs in bullous pemphigoid (see Fig. 29.42,
p. 1256), epidermolysis bullosa acquisita and porphyria
cutanea tarda (see Fig. 29.52, p. 1264).
• If there are foci of separation at different levels of the
epidermis, as in dermatitis (p. 1244), then multilocular
bullae made up of coalescing vesicles can occur.
29.5 Causes of acquired blisters
Localised
Generalised
Vesicular Herpes simplex
Eczema herpeticum*
Herpes zoster
Dermatitis herpetiformis
Impetigo
Acute eczema
Pompholyx
Bullous
Impetigo
Cellulitis
Stasis oedema
Acute eczema
Insect bites
Fixed drug eruption
Toxic epidermal necrolysis*
Erythema multiforme
Stevens-Johnson syndrome*
Bullous pemphigoid
Pemphigus*
Epidermolysis bullosa acquisita
Lupus erythematosus
Porphyria cutanea tarda
Pseudoporphyria
Drug eruptions
Usually with mucosal involvement too.
I
Exclude infection
Herpes simplex,
varicella zoster,
Staphylococcus aureus
Systematic approach to the
diagnosis of blistering diseases
T
Consider common
diseases in which
blisters are uncommon
Peripheral oedema,
cellulitis, allergic contact
dermatitis, other eczemas
Remember blisters
in drug eruptions
Fixed drug eruptions,
erythema multiforme,
vasculitis, TEN
— l
Think of
immunobullous causes
Bullous pemphigoid,
pemphigus, linear IgA
disease, bullous lupus
Fig. 29.3 A systematic approach to the diagnosis of blistering diseases. (TEN = toxic epidermal necrolysis)
Presenting problems in skin disease • 1219
Clinical assessment
Detailed history-taking and examination are critical. A history
of onset, progression, mucosal involvement, drugs and
systemic symptoms should be sought. Clinical assessment of
the distribution, extent and morphology of the rash should be
made. The Nikolsky sign is useful: sliding lateral pressure from
a finger on normal-looking epidermis can dislodge and detach
the epidermis in conditions with intra-epidermal defects, such
as pemphigus and toxic epidermal necrolysis. A systematic
approach to diagnosis is required (Fig. 29.3).
Investigations and management
Investigations and initial management will be guided by the clinical
presentation and differential diagnosis, and are described in more
detail under the specific diseases. For example, an initial approach
may include directed investigations, such as incisional diagnostic
skin biopsy for histology and direct immunofluorescence, indirect
immunofluorescence and other targeted blood tests or skin swabs.
Management should be based on the likely diagnosis and begin
in parallel with investigations, until the diagnosis is confirmed.
Itch
Itch describes the unpleasant sensation that leads to
scratching or rubbing.
The terms ‘itch’ and ‘pruritus’ are
29.6 Primary skin diseases causing pruritus
Generalised pruritus
• Scabies
• Urticarias
• Eczemas
• Xeroderma of old age
• Pre-bullous pemphigoid
• Psoriasis
Localised pruritus
• Eczemas
• Pediculosis
• Lichen planus
• Tinea infections
• Dermatitis herpetiformis
synonymous; however, ‘pruritus’ is often used when itch is
generalised. Itch can arise from primary cutaneous disease or
be secondary to systemic disease, which may cause itch by
central or peripheral mechanisms. Even when the mechanism
is peripheral, there are not always signs of primary skin
disease.
The nerve endings that signal itch are in the epidermis or near
the dermo-epidermal junction. The underlying mechanisms of
itch are not fully understood. Transmission is by unmyelinated
slow-conducting C fibres through the spinothalamic tract to
the thalamus and then the cortex. A5 fibres also seem to be
involved in transmitting signals to the spinal cord, and the
heat-sensitive transient receptor potential (TRP) channels 1-4
are important. There is an inhibitory relationship between pain
and itch. Scratching may relieve the symptom of itch after the
sensation has ceased and this is either by stimulation of ascending
sensory pathways that inhibit itch-transmitting neurons at the
spinal cord (Wall’s ‘gate’ mechanism), or by direct damage to
cutaneous sensory nerves.
The mechanisms of itch in most systemic diseases remain
unclear. The itch of kidney disease, for example, may be mediated
by circulating endogenous opioids. The clinical observation
that peritoneal dialysis helps reduce itch more frequently than
haemodialysis is consistent with this, with smaller molecules
generally being dialysed more readily if the peritoneal membrane
is used rather than a dialysis machine membrane.
Clinical assessment
It is important to determine whether skin changes are primary
(a process in the skin causing itch) or secondary (skin changes
caused by rubbing and scratching because of itch). This
requires a thorough history and examination, sometimes with
investigations, to exclude systemic disease. Many common
primary skin disorders are associated with itch (Box 29.6). If
itch is not connected with primary skin disease, other causes
should be considered (Box 29.7). These include liver diseases
(mainly cholestatic diseases, such as primary biliary cirrhosis),
malignancies (generalised itch may be the presenting feature
29.7 Secondary causes of pruritus
Medical condition Cause of pruritus Treatment*
Liver disease
Central opioid effect
Elevation in bile salts
may contribute
Naltrexone
Colestyramine
Rifampicin
Sedative antihistamines
UVB
Renal failure
Unknown; uraemia
UVB
contributes
Oral activated charcoal
Haematological
disease
Anaemia
Iron deficiency
Iron replacement
Polycythaemia
Unknown (often
rubra vera
Lymphoma i
aquagenic pruritus)
Laukaemia
Myeloma
Unknown
Endocrine disease
Diabetes mellitus
Increased infection
risk, e.g. candidiasis,
tinea
Treatment of infection
Medical condition
Cause of pruritus
Treatment*
Thyrotoxicosis
Hypothyroidism
Carcinoid syndrome
(P- 678)
Unknown
Unknown
5-HT-mediated
HIV infection
Infection, infestation
Eosinophilic folliculitis
Seborrhoeic
dermatitis
Unknown
Treatment of infection
Local corticosteroids,
UVB
Anti-pityrosporal
treatment
UVB
Malignancy
Unknown
Psychogenic
Unknown
Psychotherapy,
anxiolytics,
antidepressants
*ln addition to specific treatment of the primary condition and symptomatic treatments, such as emollients. (5-HT = 5 - hyd roxytry pta mine, serotonin; UVB = ultraviolet B)
1220 • DERMATOLOGY
29.8 Causes of pruritus in pregnancy
Diagnosis
Pregnancy, gestation and features
Treatment
Polymorphic eruption of
pregnancy (pruritic urticarial
papules and plaques, PUPP)
Typically first pregnancy and uncommonly recurs
3rd trimester, after delivery
Polymorphic urticated papules and plaques, start in striae
Chlorphenamine, emollients
Topical glucocorticoids
Acute cholestasis of
pregnancy (p. 1284)
3rd trimester and commonly recurs in subsequent pregnancies
Abnormal liver function tests
Increased fetal and maternal risk
Emollients
Chlorphenamine
Colestyramine
UVB
Early delivery
Pemphigoid gestationis
Any stage, often 2nd trimester and commonly recurs in subsequent pregnancies
Urticated erythema, blistering initially periumbilical
Characteristic histology and immunofluorescence
Topical or oral
glucocorticoids
Prurigo gestationis
2nd trimester
Excoriated papules
Emollients
Topical glucocorticoids
Chlorphenamine
UVB
Pruritic folliculitis
3rd trimester
Sterile pustules on trunk
Topical glucocorticoids
UVB
(UVB = ultraviolet B)
of lymphoma), haematological conditions (generalised itch in
chronic iron deficiency or water contact- provoked (aquagenic)
intense itch in polycythaemia), endocrine diseases (including
hypo- and hyperthyroidism), chronic kidney disease (in which
severity of itch is not always clearly associated with plasma
creatinine concentration) and psychogenic causes (such as in
‘delusions of infestation’). Itch is common in pregnancy and may
be due to one of the pregnancy-specific dermatoses. Making
a correct diagnosis is particularly important in pregnancy, as
some disorders can be associated with increased fetal risk
(Box 29.8).
Investigations and management
Investigations should be directed towards finding an underlying
cause and there will be a different approach for itch with rash, as
opposed to itch with no signs of primary skin disease (Fig. 29.4).
If there are no signs of primary skin disease, investigations should
be undertaken to exclude systemic disease or iatrogenic causes.
Psychogenic itch should be considered only if organic disease
has been ruled out. There are no consistently effective therapies
to suppress itch, and so establishing the underlying cause is
critical. If a clear-cut diagnosis cannot be made, non-specific
approaches can be used for symptom relief. These include
sedation, often with H1 receptor antihistamines, along with
emollients and counter-irritants (such as topical menthol-containing
preparations). UVB phototherapy is useful for generalised itch
due to a variety of causes but the only randomised controlled
study of efficacy is in chronic kidney disease. Other treatments
include low-dose tricyclic antidepressants (probably through
similar mechanisms to those involved when these drugs are used
for chronic pain) and opiate antagonists. If a psychogenic itch is
considered likely, antidepressants and/or cognitive behavioural
therapy may be effective. Itch of any cause can be severe and
its potentially major adverse effects on quality of life are not
always fully appreciated. Assessments of impact on quality of
life, such as Dermatology Life Quality Index (DLQI) scores, are
essential.
Primary
skin disease
Only secondary
changes of
excoriation due
to itch
Diagnose and manage
underlying skin disease
(Box 29.6)
Investigate for
underlying causes of itch
(Box 29.7)
Fig. 29.4 An overall approach to the investigation and management
of itch (pruritus).
Photosensitivity
Cutaneous photosensitivity is an abnormal response of the skin
to UVR or visible radiation. The sun is the natural source but
patients may also be exposed to artificial sources of UVR through
the use of sunbeds and/or phototherapy (p. 1227). Chronic
UVR exposure increases skin cancer risk and photo-ageing
(p. 1215). Acute exposure can induce erythema (redness) as a
normal response (Fig. 29.5). However, abnormal photosensitivity
occurs when a patient reacts to lower doses than would normally
cause a response, either with a heightened erythemal reaction
or the development of a rash. Photo-aggravated skin diseases
are exacerbated by sunlight but not caused by it. The main
photosensitive and photo-aggravated diseases are listed in
Box 29.9.
Presenting problems in skin disease • 1221
29.9 The photosensitivity and photo-aggravated diseases
Cause
Condition
Clinical features
Immunological (previously
known as idiopathic)
Polymorphic light eruption (PLE)
Chronic actinic dermatitis (CAD)
Solar urticaria
Actinic prurigo
Hydroa vacciniforme
Seasonal, itchy, papulovesicular rash on photo-exposed sites; face and back of
hands often spared. Often hours of UVR exposure needed to provoke; lasts a few
days; affects about 20% in Northern Europe, more common in young women
Chronic dermatitis on sun-exposed sites. Most common in elderly males.
Predominantly UVB, but also often UVA and visible light photosensitivity. Most also
have contact allergies
Immediate-onset urticaria on photo-exposed sites. Usually UVA and visible light
photosensitivity. Can occur at any age
Uncommon, presents in childhood. Often familial, with strong HLA association.
Some similarities to PLE, although scarring occurs
Rare childhood photodermatosis. Varioliform scarring
Drugs (variety of
mechanisms)
Phototoxicity
Pseudoporphyria
Photoallergy
Usually UVA (and visible light) photosensitivity
Most common. Exaggerated sunburn and exfoliation. Many drugs such as thiazides,
tetracyclines, fluoroquinolones, quinine, NSAIDs
NSAIDs, retinoids, tetracyclines, furosemide are examples
Usually to topical agents, particularly sunscreens and NSAIDs
Metabolic
Porphyrias
Pellagra
Mainly porphyria cutanea tarda and erythropoietic protoporphyria (p. 378).
Photo-exposed site dermatitis due to tryptophan deficiency (see Fig. 14.15, p. 378)
Photogenodermatoses
Xeroderma pigmentosum
Rare. Defect in DNA excision repair, abnormal photosensitivity, photo-ageing and
skin cancer. There may be neurological features
Photo-aggravation of
pre-existing conditions
Lupus erythematosus
Erythema multiforme
Rosacea
Can also be drug-induced (see Box 29.35, p. 1266)
p. 1264
p. 1243
(HLA = human leucocyte antigen; NSAID = non-steroidal anti-inflammatory drug; UVA/UVB = ultraviolet A/B; UVR = ultraviolet radiation)
Fig. 29.5 Sunburn. Acute exposure to ultraviolet radiation results in an
erythemal response that peaks 1 2-24 hours later. Sensitivity depends on
the individual’s constitutive skin phototype.
Sunlight consists mainly of visible light, and the UVR component
is divided into three wavebands (Fig. 29.6), according to the
Commission Internationale de I’Eclairage (CIE):
• UVC (200-280 nm), which is absorbed by ozone and does
not reach the Earth’s surface.
• UVB (280-315 nm), which constitutes less than 10% of
UVR exposure but is around 1 000-fold more potent than
UVA and so accounts for the erythemal ‘sunburning’
effects of sunlight.
• UVA (315-400 nm), which is the most abundant UVR
component reaching the Earth’s surface.
The arbitrary division between UVB and UVA regions is more
often considered to be at 320 nm by photobiologists, and the
UVA region can be further subdivided into UVA2 (320-340 nm)
and UVA1 (340-400 nm). UVA2 behaves biologically more like
UVB, and UVA1 can be used therapeutically for several skin
conditions, such as morphoea and eczema.
Patients with photosensitivity diseases can be abnormally
sensitive to UVB, UVA, visible light (over 400 nm) or, commonly,
a combination of wavebands. UVB is absorbed by window glass,
whereas UVA and visible light are transmitted through glass.
Clinical assessment
Taking a careful history is essential, as the patient may not have
the rash when assessed. Seasonal pattern and distribution of rash
are important. Key sites are the face (particularly nose, cheeks
and forehead), top of ears, neck (Fig. 29.7), bald scalp, back
of hands and forearms. Sparing is often seen under the chin
and nose, behind the ears, on the upper eyelids and the distal
digits - as we normally walk about with our eyes open and fingers
flexed! It can be misleading if there is covered site involvement.
Patients who are sensitive to UVA and visible light may be
affected through clothing. These patients commonly experience
perennial symptoms and may not be aware of the association
with daylight exposure. Other photosensitive conditions, such
as actinic prurigo or chronic actinic dermatitis, may also involve
covered sites. Sparing of habitually exposed sites, such as the
face and back of hands, occurs most commonly in polymorphic
light eruption (PLE) and is called the ‘hardening phenomenon’.
Importantly, some conditions, such as solar urticaria, develop
rapidly after sunlight exposure, whereas others, such as cutaneous
lupus, can take several days to evolve.
Investigations and management
If photosensitivity is suspected, the patient should be referred to
a specialist centre for monochromator phototesting (p. 1215),
if feasible. Other investigations will often include provocation,
1222 • DERMATOLOGY
Sunscreens
UVR absorbers
or reflectors
Behavioural avoidance, shelter, clothing
Wavelength 200 nm
Skin disorders
and the main
wavelengths
involved
290 nm
320 nm
400 nm
760 nm
Sunburn (erythema)
Pigmentation
Skin cancer
Skin ageing
l\/l OQt nhntni
Porphyria
IVIUoL [Jl IULLM
◄Mo:
Jcl 1 1 laLUoco
itivity
st drug photosens
Fig. 29.6 The electromagnetic spectrum. The action spectrum is not well defined for many conditions and, for some, is approximate and may vary
between patients. The action spectrum for non-melanoma skin cancer mirrors that for erythema. The action spectrum for melanoma is not known but
includes ultraviolet (UV) B. Photoprotection measures vary, depending on condition, although the mainstay always includes behavioural modification,
clothing cover and appropriate sunscreen choices. (UVR = ultraviolet radiation)
Fig. 29.7 Chronic actinic dermatitis. Note the sharp cut-off and sparing
behind the ear in the shadow cast by the earlobe (Wilkinson’s triangle).
patch or photopatch testing and screening for lupus and the
porphyrias (p. 1263). Rarely, investigations such as human
leucocyte antigen (HLA) typing in suspected actinic prurigo, or
DNA excision repair functional activity or genotyping in suspected
xeroderma pigmentosum, may be required.
Management depends on the cause. If there is a phototoxic
drug or chemical cause, this must be addressed: for instance,
by stopping the drug or treating the porphyria. Counselling in
regard to sun avoidance is essential: keeping out of direct sun
in the middle of the day, covering up with clothing, wearing hats
with a wide brim and careful use of high-factor sunscreens.
Paradoxically, in some conditions, particularly PLE and solar
urticaria, phototherapy can be used to induce ‘hardening’; the
mechanism of desensitisation is uncertain. Other approaches
may be necessary, depending on disease and severity, and
may include antihistamines (useful in two-thirds of patients with
solar urticaria) and systemic immunosuppression (sometimes
required in the immunological photodermatoses). Patients with
photosensitivity are at risk of vitamin D deficiency because of
reduced synthesis in the skin and should be advised to optimise
dietary vitamin D intake or take supplements (p. 1052).
Sunscreens
Sunscreens can be divided into two categories: chemical
sunscreens, which absorb specific wavelengths of UVR,
and physical sunscreens, which reflect UVR and the shorter
visible wavelengths (see Fig. 29.6). Sunscreens are now highly
sophisticated and most offer protection against UVB and most
UVA wavelengths. If a patient is abnormally photosensitive to the
longer wavelengths of UVA and the visible part of the spectrum
(for example, in cutaneous porphyrias and solar urticaria), then
conventional sunscreens are not beneficial and specific reflectant
sunscreens are required. Historically, these agents were less
cosmetically acceptable due to visible light reflection, but current
formulations, some of which are tinted, have reduced this problem.
Sunscreen protection levels are described by sun protection
factor (SPF). This is the ratio of the dose of UVR required to
produce skin erythema in the presence and absence of the
sunscreen. A sunscreen of SPF20 means that it would take 20
times as long for a person to develop sunburn in the presence
of the sunscreen, as compared to not using it. Therefore, SPF
is really a sunburn protection factor and is not a good guide to
how well a sunscreen will perform in protecting against other
reactions (such as skin pain in erythropoietic protoporphyria or
UVR-induced immunosuppression). SPF values are determined
under experimental conditions whereas, in practice, people tend
to use 25-33% of the amount of sunscreen required to achieve
Presenting problems in skin disease • 1223
the stated SPF. Patient counselling is therefore important with
regard to adequate application of sunscreen. All sunscreens
offer, at best, partial protection only and are no substitute for
modifying behaviour and covering up.
Leg ulcers
Leg ulcer is not a diagnosis, but a symptom of an underlying
disease in which there is complete loss of the epidermis, leaving
dermal layers exposed. Ulcers on the lower leg are frequently
caused by vascular disease but there are other causes, as
summarised in Box 29.10.
Clinical assessment
A detailed history of the onset and course of leg ulceration
and predisposing conditions should be elicited. The site and
surrounding skin should be assessed. Varicose veins are often
present, although not inevitably. Assessment of the venous and
arterial vasculature and neurological examination are critical.
The site of ulceration may also help to indicate the underlying
primary cause (Fig. 29.8). Full clinical examination is essential
as the ulcer may be arising in the context of systemic disease,
such as vasculitis.
Leg ulceration due to venous disease
Varicose veins, a history of deep venous thrombosis and obesity
are predisposing factors. Incompetent valves in the deep and
perforating veins of the lower leg result in retrograde flow of
blood to the superficial system, and a rise in capillary pressure
(‘venous hypertension’). Pericapillary fibrin cuffing occurs, leading
to impairment of local tissue oxygenation and homeostasis.
The first symptom in venous ulceration is often heaviness of the
legs, followed by oedema. Haemosiderin pigmentation, pallor and
firmness of surrounding skin, and sometimes venous/gravitational
eczema (p. 1247) subsequently develop. This progresses to
lipodermatosclerosis - firm induration due to fibrosis of the dermis
i
Venous hypertension
• Sometimes following deep vein thrombosis
Arterial disease
• Atherosclerosis • Buerger’s disease
• Vasculitis
Small-vessel disease
• Diabetes mellitus • Vasculitis
Haematological disorders
• Sickle-cell disease
• Cryoglobulinaemia
• Spherocytosis
• Polycythaemia
Neuropathy
• Diabetes mellitus
• Leprosy (Hansen’s disease)
Tumour
• Squamous cell carcinoma
• Malignant melanoma
• Basal cell carcinoma
• Kaposi’s sarcoma
Trauma
• Injury
• Factitious
• Myeloma
• Waldenstrom’s
macroglobulinaemia
• Immune complex disease
• Syphilis
29.10 Causes of leg ulceration
and subcutis, which may produce the well-known ‘inverted
champagne bottle’ appearance. Ulceration, often precipitated
by trauma or infection, follows. Venous ulcers typically occur on
the medial lower leg (Fig. 29.9).
Complications of venous leg ulceration include bacterial
colonisation and infection, and contact allergic dermatitis to topical
medicaments, dressings and bandages. Lipodermatosclerosis
may cause lymphoedema and hyperkeratosis; rarely, a squamous
cell carcinoma (SCC) may develop in a long-standing venous
ulcer (Marjolin’s ulcer).
Leg ulceration due to arterial disease
Deep, painful, punched-out ulcers on the lower leg, especially the
shin and foot and in the context of intermittent claudication, are
Anterior
Posterior
Venous | Vasculitis |j| Arterial | | Neuropathic
Fig. 29.8 Causes of lower limb ulceration. The main types of leg ulcer
tend to affect particular sites.
Fig. 29.9 A chronic venous ulcer on the medial lower leg, with
surrounding lipodermatosclerosis.
1224 • DERMATOLOGY
likely to be due to arterial disease. Risk factors include smoking,
hypertension, diabetes and hyperlipidaemia. The foot is cold and
dusky, and the skin atrophic and hairless. Peripheral pulses are
absent or reduced. A vascular surgical assessment should be
sought urgently (p. 502).
Leg ulceration due to vasculitis
Vasculitis can cause leg ulceration either directly through epidermal
necrosis due to damage to the underlying vasculature, or indirectly
due to neuropathy.
Leg ulceration due to neuropathy
The most common causes of neuropathic ulcers are diabetes
and leprosy. Microangiopathy also contributes to ulceration in
diabetes (p. 758). The ulcers occur over weight-bearing areas,
such as the heel. In the presence of neuropathy, protection of
skin from trauma is essential to prevent ulceration.
Investigations
Appropriate investigations include:
• Full blood count to detect anaemia and blood dyscrasias.
• Urea and electrolytes to assess renal function.
• Urinalysis for glycosuria.
• Bacterial swab if there is a purulent discharge, rapid
extension, cellulitis, lymphangitis or sepsis. This can guide
antibiotic therapy for secondary infection but pathogenic
bacteria are not always the same as those identified from
the ulcer surface.
• Doppler ultrasound to assess arterial circulation. An ankle
systolic pressure to brachial systolic pressure index (ABPI)
of below 0.8 suggests significant arterial disease and a
vascular surgery opinion should be sought. However,
arterial calcification, such as in diabetes, can produce a
spuriously high ABPI. Pulse oximetry may also be useful,
although ABPI is the preferred investigation if feasible.
Management
General advice on exercise, weight loss and smoking cessation
is important in all cases. Specific management depends on
making the correct diagnosis to identify the cause(s) of ulceration.
Underlying factors, such as diabetes or anaemia, must be treated.
Oedema must be reduced by leg elevation and, if there is no
arterial compromise, graduated compression bandaging from
toes to knees to enhance venous return and improve healing.
Compression bandaging is effective for individuals with an ABPI of
more than 0.8 but should be avoided if the ABPI is less than 0.8.
If the ulcer is purulent, weak potassium permanganate soaks
may help, and exudate and slough can be removed with normal
saline or clean water. Dressings do not themselves heal leg
ulcers, but can reduce discomfort and odour and, by reducing
colonisation by potential pathogens, may reduce the frequency of
secondary infection. A variety of dressings may be used, including
non-adherent and absorbent (alginates, hydrogels, hydrocolloids)
types. The frequency of dressing changes varies; heavily exudative
ulcers may need daily dressings, whereas changes once weekly
may suffice for drier ulcers. Occasionally, leeches may be used
topically for ulcers with heavy adherent exudate.
Surrounding eczema should be suppressed with a topical
glucocorticoid. Commonly, this is venous eczema, but there
should be a low threshold for referral for patch testing, as contact
allergy to topical applications is common (p. 1215). Systemic
antibiotics are indicated only if there is evidence of infection, as
opposed to colonisation. Various techniques of split-thickness
grafting (such as pinch and mince grafts) may hasten healing of
clean ulcers but do not reduce recurrence risk. Leg ulcers can
be very persistent. Symptomatic relief, including oral analgesics
and sometimes chronic pain management, is important. Once
the ulcer has healed, ongoing use of compression hosiery may
limit the risk of recurrence.
Abnormal pigmentation
Loss of skin pigmentation (depigmentation), reduction in
pigmentation (hypopigmentation) and increased pigment
(hyperpigmentation) are features of a variety of disorders. A
detailed history and examination, including use of a Wood’s light,
are required to establish the diagnosis. Investigations will depend
on the presentation. For example, microscopy of skin scrapings
should be undertaken if hypopigmentation is associated with
inflammation and scaling; screening for autoimmune disease
may be required if vitiligo is suspected; and investigation for
endocrine disease or the porphyrias may be appropriate in
hyperpigmentation. Further details of the specific conditions are
included on page 1257.
Hair and nail abnormalities
Many conditions affect the skin appendages, particularly hair and
nails. Conditions causing hair loss (alopecia) are listed in Box
29.30 (p. 1259). Nail changes may be a marker for systemic
disease (e.g. iron deficiency) or be a feature of certain skin
conditions (e.g. psoriasis).
Acute skin failure
Acute skin failure is a medical emergency. Several conditions
can cause widespread and acute failure of many skin functions
(see Box 29.1 , p. 1214), including thermoregulation, fluid balance
control and barrier to infection. Many of these conditions involve
widespread dilatation of the dermal vasculature and can provoke
high-output cardiac failure; they are also associated with increased
protein loss from the skin and often from the gut. Many lead to
acute skin failure by causing erythroderma (erythema affecting at
least 90% of the body surface area), although severe autoimmune
blistering diseases and the spectrum of Stevens-Johnson
syndrome/toxic epidermal necrolysis (TEN) disease can produce
acute skin failure without erythroderma (p. 1254).
Clinical assessment
Detailed history-taking and full examination are required. Particular
attention should be paid to drug history, chronology and history
of any preceding skin disease. Eczema, psoriasis, drug eruptions
and cutaneous T-cell lymphoma (Sezary’s syndrome, p. 1232) are
among the diseases that can either present with, or progress to,
erythroderma. Other causes include the psoriasis-like condition,
pityriasis rubra pilaris, and rare types of ichthyosis. Erythroderma
may occur at any age and is associated with severe morbidity and
significant mortality (see Fig. 29.35D, p. 1249). Older people are at
greatest risk, especially if they have comorbidities. Erythroderma
may appear suddenly or evolve slowly. In dark skin, the presence
of pigmentation may mask erythema, giving a purplish hue.
Erythrodermic patients are usually systemically unwell with
shivering and hypothermia, secondary to excess heat loss. They
may also be pyrexial, however, and unable to lose heat due to
damage to sweat gland function and sweat duct occlusion.
Principles of management of skin disease • 1225
Tachycardia and hypotension may be present because of volume
depletion. Peripheral oedema is common in erythroderma, owing
to low albumin and high-output cardiac failure. Lymph nodes
may be enlarged, either as a reaction to skin inflammation or,
rarely, due to lymphomatous infiltration.
Investigations and management
Investigations are required to establish the underlying cause and
to identify any systemic impact, such as hypoalbuminaemia and
electrolyte disturbances. Skin biopsy may be necessary if the
cause is unclear. Regardless of the cause, important aspects of
the management of erythroderma include supportive measures
to ensure adequate hydration, maintenance of core temperature
and adequate nutrition. Insensible fluid loss can be many litres
above normal losses. Protein may be lost directly from the skin
and through the gut because of the protein-losing enteropathy that
often accompanies conditions such as erythrodermic psoriasis.
To reduce the risks of infection, any intravenous cannulae should
be sited in peripheral veins, if possible. In the initial management
of acute erythroderma, urinary catheterisation is often required
(for patient comfort and accurate fluid balance monitoring) but
catheters should be removed as soon as possible. Frequent
application of a simple ointment emollient (such as white soft
paraffin/liquid paraffin mix) is usually appropriate.
Principles of management of
skin disease
General measures
General measures that apply in all skin diseases include
establishment of the correct diagnosis, removal of precipitating
or aggravating factors, use of safe, effective treatments and
consideration of the patient holistically, taking into account the
impact of the disease on quality of life and the person’s support
network. The psychological impact of chronic skin diseases
should not be under-estimated and it is important to remember
that psychiatric illness can also manifest as a skin disease, such
as in delusions of infestation or trichotillomania. Careful clinical
assessment, taking psychological factors into account, is essential
and any management strategy must include approaches to
address the psychological well-being of the patient.
Topical treatments
Topical treatments are first-line therapy for most skin diseases
and many can be treated effectively by topical therapies alone.
Selection of the appropriate active drug/ingredient and vehicle
is essential. Ointments are preferred to creams for dry skin
conditions, such as chronic eczemas, as they are more hydrating
and contain fewer preservatives than creams, and so allergy
risk is reduced. However, patients find creams easier to apply
and so adherence may be better. Gels and lotions can be
easier to use on hair-bearing sites. The molecular weight and
lipid-water coefficient of a drug determine its skin penetration,
with larger, water-soluble, polar molecules penetrating poorly.
In skin disease, if the stratum corneum is impaired - as in
eczema - increased drug absorption occurs. Occlusion under
dressings also increases absorption. Drugs can be used in
different potencies or concentrations, or in combination with
other active ingredients, and many are available in more than
one formulation. The properties of different vehicles are listed
in Box 29.1 1 . Overall, adherence to topical treatments can be
problematic, so it is essential for patients to know exactly what
is required of them and for regimens to be kept as simple as
possible. Emollients, topical glucocorticoids and other selected
key topical therapies that are widely used in a diverse range
of skin conditions are detailed below. For the more disease-
specific therapies, detailed descriptions are included in the
disease sections.
29.11
Characteristics of vehicles used in topical treatments
Vehicle
Definition
Use
Site
Cosmetic
acceptability
Risk of contact
sensitisation
Creams
Emulsions of oil and water
(aqueous cream)
Acute presentations
Cooling, soothing
Well absorbed
Mild emollients
All sites, including
mucous membranes
and flexures, but not
hair-bearing areas
Very good
Helps adherence
Significant, due
to preservatives,
antimicrobials and
often lanolin
Ointments
Greasy preparations
Insoluble in water (white soft
paraffin)
Soluble (emulsifying ointment)
Chronic dry skin conditions
Occlusive and emollient
Hydrating
Mildly anti-inflammatory
Avoid hair-bearing
areas and flexures
Moderate
Low
Lotions
Water-based
Liquid formulations
Often antiseptic and astringent
(potassium permanganate)
Cooling effect
Cleans the skin and
removes exudates
Large areas of the skin
and the scalp
Good, but can
sting if in an
alcoholic base
Rare
Gels
Thickened lotions
Hydrophilic and hydrophobic
bases
For specific sites
Hair-bearing areas and
the face
Good
Low
Pastes
Semi-solid preparations
consisting of finely powdered
solids suspended in an
ointment
Occlusive, protective
Hydrating
Circumscribed skin lesions,
(psoriasis, lichen simplex
chronicus)
Any area of skin
Often used in
medicated bandages
Moderate
Moderate
29
1226 • DERMATOLOGY
Emollients
These are mainstays in the treatment of eczema, psoriasis and
many other conditions, and are used to moisturise, lubricate,
protect and ‘soften’ skin. They are essentially vehicles without
active drug and are available in many formulations: creams,
ointments, gels and bath, shower and soap substitutes. White
soft paraffin is the most effective and is widely used.
|jopical glucocorticoids
Glucocorticoids are available in a variety of formulations, potencies
and strengths, most commonly as creams and ointments (Box
29.1 2). Selection of the correct product depends on the condition
being treated, body site and duration of expected use. Mild
topical glucocorticoids are used in delicate areas, such as the
face or genitals, and close supervision of glucocorticoid use at
these sites is required. In contrast, very potent glucocorticoids
may be required under occlusion for chronic resistant disease
such as nodular prurigo.
Adverse cutaneous effects of chronic glucocorticoid use include
atrophy (definition: an area of thin, translucent skin caused by
loss of epidermis, dermis or subcutaneous fat - Fig. 29.10),
striae (definition: linear, atrophic, pink, purple or white bands
caused by connective tissue changes - Fig. 29.10), petechiae
and purpura (definition: haemorrhagic macules or papules
caused by extravasated blood - see p. 1211) and telangiectasiae
(definition: visible dilatations of small cutaneous blood
vessels - see Fig. 29.1 1 A), increased risk of infection and systemic
absorption, causing Cushingoid features and suppression of the
hypothalamic-pituitary-adrenal axis. However, under-treatment
with glucocorticoids is more common than over-treatment
in routine clinical practice. In general, the lowest potency of
glucocorticoid should be used for the shortest period to gain
control of the disease; this can be achieved by initial use of a more
potent glucocorticoid, with reduction in potency or frequency of
application as control is gained. Tolerance or tachyphylaxis can
develop with chronic use, so intermittent courses of treatment are
advised. Caution is required with glucocorticoids in psoriasis, as
rebound, unstable or pustular psoriasis can occur with sudden
29.12 Potencies and strengths of commonly used
topical glucocorticoid preparations
Mild
• Hydrocortisone 0.5%, 1%, 2.5%
• Hydrocortisone 1% and fusidic acid 2% (Fucidin H)
Moderate
• Clobetasone butyrate 0.05% (Eumovate)
• Betamethasone valerate 0.025% (Betnovate-RD)
• Fluocinolone acetonide 0.00625% (Synalar 1 :4)
Potent
• Betamethasone valerate 0.1% (Betnovate)
• Betamethasone valerate 0.1% and clioquinol 3% (Betnovate-C)
• Fluocinolone acetonide 0.025% (Synalar)
• Hydrocortisone butyrate 0.1% (Locoid)
• Mometasone furoate 0.1% (Elocon)
Very potent
• Clobetasol propionate 0.05% (Dermovate)
*UK trade names are given in brackets.
Fig. 29.10 Striae and atrophy induced by excess prolonged potent
topical glucocorticoid use.
cessation of use. Nevertheless, glucocorticoids are invaluable
for many sites, particularly the flexures. Topical glucocorticoids
are often formulated in combination with antiseptics, antibiotics
or antifungals, and their controlled use may be appropriate in
infected eczema or flexural psoriasis. Intralesional injections of
glucocorticoids can be used in a variety of indications, including
nodular prurigo, keloid scar (definition of ‘scar’: replacement
of normal structures by fibrous tissue at the site of an injury,
although keloid scar describes a pathological process extending
beyond the site of injury), acne cysts and alopecia areata.
Anti-infective agents
Antiseptics should be considered before antibiotics, as they cover
a wide range of organisms and help to reduce the risk of antibiotic
resistance. Antibiotics can be used either for their anti -infective
properties (p. 1236) or for their anti-inflammatory properties
(pp. 1242 and 1244). Topical antiviral and antifungal agents are
also widely used for a range of mild skin infections (p. 1 239).
Calcineurin inhibitors
The topical calcineurin inhibitors, tacrolimus and pimecrolimus,
can be used to treat eczema and a variety of other conditions,
through local cutaneous immunosuppression (p. 1244).
| Immune response modifiers
Topical imiquimod was introduced for the treatment of anogenital
warts but can be used for a diverse range of other skin diseases,
including actinic keratosis, Bowen’s disease, basal cell carcinoma,
lentigo maligna, cutaneous lupus and common and planar
warts. Its mechanism of action is via stimulation of endogenous
Th2 immune responses and release of cytokines, including
interferon-gamma (IFN-y). It can cause significant inflammation,
requiring dose adjustments, but subclinical disease may respond
to treatment.
Dressings
A ‘wound’ covering is called a dressing. Box 29.13 shows the
indications for their use. The active agent, vehicle and ‘wound’
type should be considered. Wet lesions should be treated with
Principles of management of skin disease • 1227
i
• Protection
• Symptomatic relief from pain or itch
• Maintenance of direct application of topical treatment
• Possible improvement in healing time
• Reduction of exudate
• Reduction of odour
wet dressings. Paste bandages can be used in conjunction with
topical emollients and glucocorticoids to soothe and cool, ease
pruritus and scratching, and reduce inflammation. Dressings for
venous leg ulcers are described on page 1224.
Phototherapy and photochemotherapy
Ultraviolet radiation (UVR) treatments (most commonly,
narrowband ultraviolet B and psoralen-ultraviolet A (PUVA))
are used in the management of many different diseases. The
best evidence for their efficacy is in psoriasis, atopic eczema,
vitiligo and chronic urticaria, although there is also evidence
that UVB is helpful in treating generalised itch associated
with chronic kidney disease and a range of other diverse skin
conditions.
Psoralens are natural photosensitisers found in a number of
plants. They intercalate between the strands of DNA and, on
excitation with UVA, cross-link the DNA strands. Psoralens are
therefore prodrugs that are activated only in skin that is exposed
to UVA. Psoralens can also be applied topically in a bath before
irradiation with UVA (bath PUVA) or can be applied in creams or
gels for localised topical PUVA. PUVA is a more complex treatment
than UVB and has more adverse effects; in particular, cumulative
exposure to PUVA increases the risk of skin cancer, particularly
squamous cell carcinoma. Therefore, PUVA is generally used for
poor responders to UVB, or in diseases such as plaque-stage
cutaneous T-cell lymphoma or pityriasis rubra pilaris, where it
is the phototherapy of first choice. Phototherapy or PUVA may
be offered as a whole-body or localised treatment.
Longer-wavelength UVA1 (340-400 nm) is also used for
several conditions, particularly the fibrosing skin diseases such
as morphoea, where efficacy has been shown and there is a
lack of other well-proven therapies. The evidence base for its
place in the management of several diseases, such as eczema,
is not fully proven and availability of UVA1 is mainly through
centres of specialist expertise.
Systemic therapies
General information is provided here for drugs used in a range
of skin diseases; details of other drugs are provided in disease-
specific sections.
Antibiotics
Antibiotics are generally used for their anti-infective properties,
particularly for staphylococcal and streptococcal skin infections.
In these indications, the correct antibiotic should be selected,
based on bacterial sensitivity and patient factors. As examples,
oral flucloxacillin may be indicated for clinically infected eczema,
intravenous flucloxacillin for cellulitis, and clarithromycin for a
patient with a staphylococcal carbuncle who is penicillin-allergic.
Optimal therapeutic doses and courses must be chosen, based
on local antimicrobial prescribing guidelines. Several antibiotics,
such as tetracyclines, erythromycin and co-trimoxazole are used
predominantly for their anti-inflammatory effects in indications such
as acne vulgaris, bullous pemphigoid and pyoderma gangrenosum.
| Antihistamines
A range of H1 and H2 receptor antagonists are used in dermatology.
For diseases in which histamine in the skin is relevant (such as
urticaria), non-sedating antihistamines should be given: for
example, fexofenadine or cetirizine. For pruritic conditions such as
eczema, the sedating effect of antihistamines like hydroxyzine or
chlorphenamine is important. However, antihistamines are widely
used in older patients for the symptom of pruritus due to a variety
of causes such as xeroderma, metabolic impairment, malignancy
or concomitant drugs. Sedating antihistamines should be used
with caution in older patients, as they may increase the risk of
falls and accidents in the home, with disastrous consequences.
Careful choice of drug and dose is therefore essential. Leukotriene
receptor antagonists, such as montelukast, may be added to
antihistamine regimes.
Retinoids
Oral retinoids are used in a range of conditions, including acne,
psoriasis and other keratinisation disorders. They promote
differentiation of skin cells and have anti-inflammatory effects.
Isotretinoin (13-c/s-retinoic acid) is widely used for moderate
to severe acne (p. 1243). Acitretin can be effective in psoriasis
and other keratinisation disorders, such as ichthyosis, as can
alitretinoin (9-c/s- retinoic acid) in hand and foot eczema and
bexarotene in cutaneous T-cell lymphoma.
Adverse effects of retinoids include dryness of the skin and
mucous membranes, abnormalities in liver function or hepatitis,
increase in serum triglycerides (levels should be checked before
and during therapy) and mood disturbances. Alitretinoin and
bexarotene can cause hypothyroidism. Systemic retinoids are
teratogenic and must be prescribed along with a robust form
of contraception. Females must have a negative pregnancy
test before, during and after therapy, and pregnancy must be
avoided for 2 months after stopping isotretinoin and 2 years
after stopping acitretin.
Ijmmunosuppressants
Systemic glucocorticoids, particularly prednisolone, are
widely used in inflammatory skin diseases, such as eczema,
immunobullous disease and connective tissue disorders.
Methotrexate, azathioprine and mycophenolate mofetil are effective
in eczema and psoriasis either alone or as glucocorticoid-sparing
agents. Further details on the mechanism of action, adverse
effects and monitoring requirements for these agents are provided
on page 1004, although it is important to be aware that there
may be different approaches to treatment regimens and doses
between specialties for some drugs. For example, in dermatology,
methotrexate is used in a once-weekly regimen, with doses of
up to 25 mg per week, depending on the response (p. 1004).
Hydroxycarbamide is an alternative immunosuppressant to
methotrexate in psoriasis, but appears to be less effective and
the risk of myelosuppression is greater. Ciclosporin (p. 1005)
has a rapid onset of action and is effective in inducing clearance
of psoriasis and eczema. Monitoring of blood pressure and
renal function is required. Ciclosporin should be used only with
caution after phototherapy, particularly PUVA, because of the
29.13 Indications for dressings
1228 • DERMATOLOGY
increased risk of skin cancer. Long-term use of ciclosporin is not
advised. Dapsone is an immunomodulator and may be used in
diseases in which neutrophils are implicated, such as dermatitis
herpetiformis (p. 1256). Haemolysis, methaemoglobinaemia and
hypersensitivity can occur, and monitoring is required (pp. 123
and 269). Hydroxychloroquine is of particular value in cutaneous
lupus. More details on the mechanism of action, adverse effects
and monitoring requirements are provided on page 1005.
Biological therapies
Biological inhibitors of pro-inflammatory cytokines, including
tumour necrosis factor alpha (TNF-a) inhibitors, ustekinumab (an
antibody to the p40 component of interleukin (IL)-12 and IL-23),
guselkumab (an antibody to IL-23), secukinumab and ixekizumab
(antibodies to IL-1 7A) and brodalumab (an antibody to the IL-1 7
receptor) are effective treatments for psoriasis. Rituximab, which
causes depletion of B cells, may be used in pemphigus vulgaris.
More details on the dosages, mechanism of action and adverse
effects of these agents are provided on page 1006. Omalizumab,
a monoclonal antibody directed against immunoglobulin E (IgE),
was introduced for allergic asthma but may also have a role
in non-allergic diseases, such as treatment-resistant urticaria
(pp. 86 and 572). Intravenous immunoglobulin, pooled from
donor plasma, may be used in the treatment of dermatomyositis
(p. 1 039) and occasionally may be indicated in other dermatological
diseases.
Dermatological surgery
Most dermatological surgical procedures are performed under
local anaesthetic. Knowledge of local anatomy is essential,
particularly the locations of vessels and nerves. In certain sites,
such as the fingers, soles of the feet and nose, local cutaneous
nerve blocks are useful. Some sites are associated with particular
risks, such as keloidal scarring on the upper trunk of young
patients, unsightly scars over the scapulae, and poor healing
and risk of ulceration following procedures on the lower legs.
Excision biopsy
This involves surgical removal of the lesion followed by histological
examination. The most common indication is suspicion of
malignancy. The lesion and line of excision should be marked
out and the margin of excision decided before the procedure. It
is important to excise down to the appropriate anatomical plane.
Depending on body site, a range of procedures can minimise
the resulting defect. Healing by secondary intention may also
achieve good cosmetic results.
| Curettage
Curettage involves using a small, spoon-shaped implement
(curette), not only as a definitive treatment but also to obtain
histology. Curettage does not preserve tissue architecture very
well, however, and it may be difficult to distinguish between
dysplasia and invasive malignancy. It can be an effective treatment
for basal cell papillomas, actinic keratoses, intra-epidermal
carcinoma and superficial basal cell carcinoma.
| Shave excision
Shave excision using local anaesthetic may be used for simple
and effective treatment of raised superficial benign skin lesions
affecting epidermis and upper dermis, such as benign naevi
and skin tags.
Mohs’ micrographic surgery
Mohs’ micrographic surgery is employed to ensure adequate
tumour excision margins, while conserving unaffected tissue.
It is most commonly used for basal cell carcinoma (p. 1229).
Non-surgical treatments
Cryotherapy
Cryotherapy is a destructive treatment using liquid nitrogen
to cause cell-wall and membrane destruction and cell death.
Liquid nitrogen can be applied either with a cotton bud or,
more effectively, with a spray gun. A wide variety of conditions
can be treated but it is essential for the correct diagnosis to
be made first, if necessary by diagnostic biopsy. Cryotherapy
should not be used to treat melanocytic naevi. Benign lesions,
such as viral warts and basal cell papillomas, respond well,
and cryotherapy can also be effective for actinic keratoses,
Bowen’s disease or superficial non-melanoma skin cancer.
Malignant indications require more vigorous treatment, usually
with two cycles, and this is normally carried out in secondary
care. Considerable inflammation, blistering and pigmentary
change, particularly hypopigmentation, can occur. Caution is
required to avoid damage to tendons and nerves, especially
when using cryotherapy on digits.
| Laser therapy
Laser therapy involves treatment with monochromatic light. Skin
components (chromophores), such as haemoglobin and melanin,
absorb specific wavelengths of electromagnetic radiation, and
these wavelengths can therefore be used to destroy these
targets selectively and to treat certain skin disorders. Lasers
targeting haemoglobin are employed for vascular abnormalities,
such as spider naevi, telangiectasiae and port-wine stains, and
lasers targeting melanin can treat benign pigmentary disorders
or pigment in tattoos or drug-induced hyperpigmentation (for
example, secondary to minocycline). Melanin lasers can also be
used for hair removal if the hair is pigmented. Light delivery in
short pulses restricts damage to the treated site.
The carbon dioxide laser emits infrared light that is absorbed
by water in tissues and can therefore be used for destructive
purposes. The depth of effect can be controlled, such that
the carbon dioxide laser is widely employed for resurfacing
in photorejuvenation or acne scarring. Significant morbidity is
associated with this destructive laser, although this may be
minimised with fractionated regimens, and general anaesthesia
is usually required.
Photodynamic therapy
Photodynamic therapy (PDT) is widely used in dermatology,
predominantly for actinic keratoses, Bowen’s disease and
superficial basal cell carcinoma (p. 1229).
j Radiotherapy and grenz (Bucky) ray therapy
Radiotherapy can be employed for several skin conditions,
including non-melanoma skin cancer or lentigo maligna that is
not suitable for surgical treatment, but its use in dermatology
has declined. Scarring and poikiloderma can occur at treated
Skin tumours • 1229
sites, although these are minimised if fractionated regimens are
chosen. Superficial radiotherapy is now rarely employed to treat
benign dermatoses. Even more superficial ionising radiation
(grenz, or Bucky, rays) can be useful for localised dermatoses
that are having severe effects on quality of life, if conventional
treatments have been inadequate; for example, it may avoid the
need for systemic immunosuppression in a patient with severe
recalcitrant localised scalp psoriasis.
Skin tumours
Pathogenesis
Skin cancer is the most common malignancy in fair-skinned
populations. It is subdivided into non-melanoma skin cancer
(NMSC) and melanoma. NMSC is further subdivided into the
most common skin cancer, basal cell carcinoma (BCC), and
squamous cell carcinoma (SCC). The latter has precursor non-
invasive states of intra-epithelial carcinoma (Bowen’s disease,
BD) and dysplasia (actinic keratosis, AK). Melanoma is much
less common than NMSC, but because of its metastatic risk it
is the cause of most skin cancer deaths.
UVR is a complete carcinogen and is the main environmental
risk factor for skin cancer, which is much more common in
countries with high ambient sun exposure, such as Australia.
Skin cancer risk also increases if an individual migrates to such
a country when young, particularly if less than 10 years of age.
Epidemiological evidence supports a close link between chronic
UVR exposure and risk of SCC and AK, and a modest link
between sun exposure and BCC risk. Melanoma usually arises
on sites that are intermittently exposed to UVR, and episodes
of sunburn have been implicated as a risk factor for melanoma.
There is good evidence to show that sunbed exposure is also a
risk for both melanoma and NMSC, particularly when exposure
starts in adolescence and early adult life. Strategies to reduce
sun exposure are therefore important for skin cancer prevention,
with reliance mainly on behavioural modification, covering up and
judicious sunscreen use. Indeed, there is evidence to show that
sunscreen use reduces naevi development in children, and in
adults regular sunscreen use reduces the risk of AK and SCC
and is likely also to have preventative roles in melanoma and
BCC development.
There are identifiable genetic predispositions for some skin
cancers, such as in xeroderma pigmentosum, an autosomal
recessive condition caused by an inherited defect in DNA excision
repair (pp. 1221 and 1321), or basal cell naevus (Gorlin’s)
syndrome, an autosomal dominant disorder caused by loss-
of-function mutations affecting the PTCH1 tumour suppressor
genes, with consequent activation of the Hedgehog pathway
(p. 1321). Interestingly, the Hedgehog pathway is also almost
invariably activated in sporadic BCC, which usually contain somatic
mutations in PTCH1 and less commonly in the SMO gene, which
lies in the same signalling pathway. The genetics of SCC are
heterogeneous and less clearly defined, with several mutations
and pathways implicated, including TP53, CDKN2A/p16, NOTCH,
EGFR and the MAPK signalling pathways. Interestingly, many of
the mutations seen in SCC also occur in the pre-cancers AK and
BD. The genetics of melanoma are discussed on page 1232.
Cutaneous immune surveillance is also critical and
immunosuppressed organ transplant recipients have a greatly
increased risk of skin cancer, particularly SCC. Interestingly,
patients who have received high treatment numbers of PUVA
(more than 150), which is immunosuppressive, are also at
increased risk of skin cancer, particularly SCC.
Despite UVB being a complete carcinogen, there is no evidence
at present that UVB phototherapy significantly increases skin
cancer risk, although ongoing vigilance is required. Ionising
radiation, notably radiotherapy, thermal radiation and chemical
carcinogens, such as arsenic or coal tar, can increase NMSC risk,
particularly SCC. A role for oncogenic human papillomaviruses
in SCC development is also implicated, particularly in
immunosuppressed patients, where viral DNA is detected in
more than 80% of tumours. Chronic inflammation is a risk
factor for SCC, which may arise in chronic skin ulcers (p. 1223),
discoid lupus erythematosus or vulgaris, and the scarring genetic
skin disease dystrophic epidermolysis bullosa (see Box 29.25,
p. 1254), in which up to 50% of patients develop SCC.
Malignant tumours
Basal cell carcinoma
The incidence of NMSC has increased dramatically in recent
decades and basal cell carcinoma (BCC) accounts for more than
70% of cases. In Europe, the ratio of BCC to SCC is 4-5:1 in
immunocompetent patients. It is a malignant tumour that rarely
metastasises; it is thought to derive from immature pluripotent
epidermal cells and is composed of cells with similarities to
basal layer epidermis and appendages. Lesions typically occur
at sites of moderate sun exposure, particularly the face, and
are slow-growing. The incidence increases with age and males
are more commonly affected. Lesions may ulcerate and invade
locally; hence the term ‘rodent ulcer’.
Clinical features
Early BCCs usually present as pale, translucent papules or
nodules, with overlying superficial telangiectatic vessels (nodular
BCC). If untreated, they increase in size and ulcerate, to form
a crater with a rolled, pearled edge and ectatic vessels (Fig.
29.1 1). There may be some pigmentation or a cystic component.
A superficial multifocal type can occur, frequently on the trunk,
and may be large (up to 10 cm in diameter); often there are
multiple lesions. Superficial BCC usually presents as a red/
brown plaque or patch with a raised, thread-like edge, which is
Fig. 29.11 Basal cell carcinoma. {k\ A nodular BCC showing the
translucent nature of the tumour and the abnormal arborising vessels.
[W1 An ulcerated BCC showing the raised, rolled edge.
1230 • DERMATOLOGY
often best seen by stretching the skin; this helps to distinguish it
from Bowen’s disease. Less commonly, a morphoeic, infiltrative
BCC presents as a poorly defined, slowly enlarging, sclerotic
yellow/grey plaque.
Diagnosis and management
The diagnosis is often obvious clinically, based on the features
mentioned above, although a diagnostic confirmatory biopsy
may be required prior to definitive treatment. Management
depends on the characteristics of the tumour and on patient
factors, including comorbidities and patient wishes. Essentially,
treatment will be either surgical or, in some cases, medical
(Box 29.14). Surgical excision, ideally with a 4-5 mm margin,
is the treatment of choice, with a cure rate of approximately
95%. Curettage and cautery may also be effective for selected
lesions. Management of infiltrative morphoeic BCC and/or lesions
at difficult sites, such as around the eye, may require more
complex techniques such as Mohs’ micrographic surgery to
ensure adequate tumour excision margins, while conserving
unaffected tissue. This involves processing of frozen sections
of all margins in stages (usually on the same day) until all the
tumour is removed. The procedure is time-consuming (so can be
difficult for elderly, frail patients) and requires particular surgical
and pathology skills, but is associated with the highest long-term
cure rates, with 98-99% clear at 5-year follow-up.
If a surgical approach is used for management of BCC and
the primary tumour is not completely excised, re-excision may
29.14 Management of non-melanoma skin cancer
and pre-cancer
Basal cell carcinoma
• Excision results in the lowest recurrence rates
• Mohs’ micrographic surgery is effective for high-risk BCC
• Medical treatments are often appropriate for low-risk superficial
tumours in patients with comorbidities
• Cryotherapy and topical 5-fluorouracil can be used for
superficial BCC
• Topical photodynamic therapy and topical imiquimod are both
effective in superficial BCC
• BCC in patients with Gorlin’s syndrome should not be treated with
radiotherapy
• Hedgehog pathway inhibitors can induce clinical response in
patients with advanced inoperable BCC
Squamous cell carcinoma
• Excision is the treatment of choice for invasive SCC
• Most recurrences or metastases occur within 5 years
• Medical management is not usually considered for invasive SCC
Carcinoma in situ (Bowen’s disease)
• For single/few lesions on good healing sites, cryotherapy, curettage,
photodynamic therapy, topical imiquimod and 5-fluorouracil are
options
• For multiple lesions and/or poor healing sites such as the lower leg,
photodynamic therapy, where feasible, is the treatment of choice,
although topical 5-fluorouracil or imiquimod is an alternative
Actinic keratosis
• For single/few lesions on good healing sites, cryotherapy, curettage,
5-fluorouracil/salicylic acid and ingenol mebutate are options,
especially if hyperkeratotic
• For multiple lesions/field change, conventional or daylight
photodynamic therapy, topical 5-fluorouracil, imiquimod or
diclofenac in hyaluronic acid gel may be effective
be required, although follow-up may be appropriate as not
all tumours that are incompletely excised recur. However,
this is not recommended for tumours at high-risk sites or for
infiltrative morphoeic BCC, where complete excision is advisable.
Cryotherapy may be effective for BCC but can cause blistering
and scarring, so is best suited to small, superficial lesions at
low-risk sites.
Radiotherapy can be invaluable for large BCC lesions in frail
patients but is less commonly used because of the risk of scarring.
Medical therapies can be used to treat low-risk BCC,
particularly when surgery is not appropriate for a patient. Topical
immunomodulators, such as imiquimod, are effective for low-risk
BCC and may be particularly useful for patients who are not able
to attend a hospital clinic setting but are able to apply a topical
preparation at home over a 6-week period. Imiquimod usually
induces a prominent inflammatory reaction and patients should
be advised that dose adjustments may be required. Topical
5-fluorouracil can also be effective for low-risk small lesions of
superficial BCC, but is rarely used since it usually provokes an
intense inflammatory reaction. Intralesional interferon-alpha2b
has been used for BCC but multiple treatments and high cost
preclude its regular use.
PDT is an effective treatment for low-risk, predominantly
superficial BCC, as well as AK and BD. Usually, topical porphyrin
PDT is employed, which involves application of a porphyrin
prodrug to the lesion to be treated. The prodrug is taken up
and converted by the cell’s haem cycle to protoporphyrin IX,
a photosensitiser. This is photochemically activated by visible
(normally red) light, usually delivered by a light-emitting diode
(LED), in the presence of oxygen, causing the production of
reactive oxygen species, which cause destruction of treated
tissue. The photosensitiser is taken up preferentially by diseased
skin, and adverse effects in normal skin are minimised. PDT is
at least as effective as cryotherapy and surgery for superficial
BCC and may be preferred at sites of poor healing, such as
the lower leg, or where cosmetic outcome is important. PDT is
not as effective as surgery for long-term clearance of nodular
BCC but can be considered if surgery is not appropriate. Pain
during irradiation may occur during PDT, although adjustments
to the irradiation regime can reduce discomfort. PDT is usually
undertaken in the outpatient clinic setting and is well suited to
frail elderly patients who are not able to undertake treatment
with topical agents at home.
Rarely, advanced BCC may be locally invasive or even
metastasise. Major advances have been made in targeted
drug development, and Hedgehog pathway inhibitors, such as
vismodegib and sonidegib, can be used effectively for disease
control and palliation in this setting, although there may be
significant associated drug-induced toxicity.
Squamous cell carcinoma
Squamous cell carcinoma (SCC) is a malignancy that arises from
epidermal keratinocytes and is the second most common skin
cancer, occurring most frequently in elderly males and smokers.
There is a close association between cumulative UVR exposure
and SCC risk, with most SCC lesions occurring on chronically
sun-exposed sites in white populations and often arising at sites
of field -change carcinogenesis, with coexistent precursors of AK
and BD commonly evident. In the immunosuppressed patient
population, such as organ transplant recipients, SCC is the most
common skin cancer and its incidence is dramatically increased,
particularly in association with the duration of immunosuppression
Skin tumours • 1231
and the degree of sun exposure and damage accrued pre¬
transplant. The risk of SCC is also increased in HIV infection.
Furthermore, SCC arising in the immunosuppressed is more
likely to behave aggressively or to metastasise.
Clinical features
The tumours usually occur on chronically sun-exposed sites, such
as bald scalp, tops of ears, face and back of hands. The clinical
presentation may be diverse, ranging from rapid development of
a painful keratotic nodule in a pre-existing area of dysplasia (Fig.
29.12) to the de novo presentation of an erythematous, infiltrated,
often-warty nodule or plaque that may ulcerate. The clinical
appearance depends on histological grading; well -differentiated
tumours more often present as defined keratotic nodules (Fig.
29.12) , whereas poorly differentiated tumours tend to be ill
defined and infiltrative, and may ulcerate. SCC has metastatic
potential; some tumours, such as those on lips and ears and in
immunosuppressed patients, behave more aggressively and are
more likely to metastasise to draining lymph nodes.
Management
Early diagnosis is important and complete surgical excision
is the usual treatment of choice (see Box 29.14). Standard
excision with a 4-6 mm margin is advised and the cure rate is
approximately 90-95%. Mohs’ surgery is an option but is used
less frequently for SCC than for BCC. High-risk SCC should be
treated aggressively, with a wider margin of excision of at least
6 mm where feasible. This may include larger, thicker lesions,
tumours at sites where metastases are more likely, such as the
ear, lip or non-sun-exposed sites, and those occurring in the
immunosuppressed and/or with histology showing the tumour
to be poorly differentiated, with evidence of lymphatic, vascular
or perineural involvement or a high mitotic index. Such patients
and those with metastatic disease require management via a
multidisciplinary team. In patients who are at high risk for further
SCC, systemic retinoids may have a role in reducing the rate
of SCC development, but rapid appearance of tumours occurs
on drug cessation. Occasionally, curettage and cautery may
be appropriate if the tumour is small and low-risk and either
surgical excision is contraindicated or the patient is unwilling to
proceed. Radiotherapy may be indicated if surgical excision is
not feasible. Cryotherapy and topical non-surgical therapies are
not usually used in invasive SCC because of risk of recurrence
and metastasis.
Fig. 29.12 Squamous cell carcinoma. \k\ A centrally keratinous,
symmetrical, well-differentiated SCC. Clinically, this could be confused with
keratoacanthoma. [B An SCC arising from an area of epidermal dysplasia.
Actinic keratosis
Actinic keratoses (AK) are scaly, erythematous lesions arising
on chronically sun-exposed sites. Histology shows dysplasia,
although the diagnosis of typical AK is usually made on clinical
grounds (Fig. 29.13). They are common in fair-skinned people
who have had significant sun exposure, are often multiple and
increase with age. The prevalence is much higher in Australia than
in the UK and some surveys have shown a prevalence of more
than 50% in those over 40 years old. The rate of progression to
SCC is less than 0.1 % and spontaneous resolution is possible.
However, SCC can also arise de novo and without progression
from AK. Increase in size, ulceration, bleeding, pain or tenderness
can be indicative of transformation into SCC.
Management
Several treatments are available for AK (see Box 29.1 4). Emollients
and photoprotection, including high-factor sunscreens, may suffice
for mild disease. Single or low numbers of lesions of AK can be
effectively treated with cryotherapy. Hyperkeratotic lesions may
be treated with the antimetabolite 5-fluorouracil, combined with
salicylic acid, or may require curettage and cautery.
Multiple lesions require field -directed therapy; 5-fluorouracil is
widely used in this setting and is effective but topical imiquimod
is an alternative. Diclofenac in a hyaluronic acid gel base can
also be used topically for low-grade maintenance control of
AK, the rationale for its use being the over-expression of cyclo¬
oxygenase (COX)-2 in AK lesions. Topical ingenol mebutate can
also be used and has the advantage of a short treatment regime,
although severe inflammation may be induced. PDT is widely
used for field-change multiple AK, with high efficacy rates; it is
at least as effective as cryotherapy or 5-fluorouracil. The relative
selectivity of treatment allows subclinical disease to be treated,
while sparing normal skin. A regimen using daylight to activate
the photosensitiser is increasingly used worldwide for extensive
mild AK, with high efficacy rates, comparable to hospital-based
PDT but without the need for specialised equipment and allowing
patients to be treated at home.
Fig. 29.13 Actinic keratosis. Close-up of a hyperkeratotic AK on the ear.
1232 • DERMATOLOGY
Fig. 29.14 Intra-epidermal carcinoma (Bowen’s disease). The lower
leg is a common site and lesions are often treated non-surgically.
Bowen’s disease
Clinical features
Bowen’s disease (BD) is the name given to an intra-epidermal
carcinoma that usually presents as a slowly enlarging,
erythematous, scaly plaque on the lower legs of fair-skinned elderly
women (Fig. 29.14) but other sites can also be involved. It can be
confused with eczema or psoriasis, but is usually asymptomatic
and does not respond to topical glucocorticoids. It may also
be hard to distinguish from superficial BCC. Transformation into
SCC occurs in 3% or less.
Diagnosis
Incisional biopsy is usually undertaken to confirm the diagnosis.
This shows an intra-epidermal carcinoma with no invasion through
the basement membrane. Histology may also be obtained by
curettage but this does not allow distinction from invasive SCC
to be made, due to loss of tissue orientation and architecture.
Management
While curettage or excision may be appropriate in some
settings, non-surgical therapies are generally preferred (see
Box 29.14), especially on the lower legs. PDT, in particular,
may be advantageous for BD on the lower leg because of
relative selectivity of treatment and sparing of normal tissue,
thus reducing the risk of poor healing and ulceration at this
vulnerable site. Given the low risk of malignant transformation,
the option of no active treatment may also be appropriate for
some elderly frail patients.
| Cutaneous lymphomas
The most common form of cutaneous T-cell lymphoma is mycosis
fungoides (MF). This can persist for years in patch and plaque
stages, often resembling eczema or psoriasis. Only sometimes
does it progress through to nodules and finally a systemic stage,
Sezary’s syndrome. B-cell lymphomas, on the other hand, usually
present as nodules or plaque-like tumours. The diagnosis of
cutaneous T-cell lymphoma requires a high index of suspicion,
particularly in patients thought to have unusual recalcitrant forms
of eczema or psoriasis.
Treatment is symptomatic and there is no evidence that it alters
prognosis. In the early stages of cutaneous T-cell lymphoma,
systemic or local glucocorticoids may be indicated; alternatively,
narrowband UVB phototherapy (for patch-stage MF) or PUVA
(for plaque-stage MF) may be used. Once lesions have moved
beyond plaque stage, localised radiotherapy, electron beam
29.15 Classification of cutaneous
malignant melanoma
Melanoma without metastatic potential
• Melanoma in situ • Lentigo maligna
Melanoma with metastatic potential
• Superficial spreading • Acral lentiginous melanoma
melanoma • Subungual melanoma
• Nodular melanoma • Lentigo maligna melanoma
radiation, the synthetic retinoid bexarotene, interferon-alpha,
extracorporeal photopheresis and systemic anti-lymphoma
chemotherapy regimens may be needed. Management of
advanced disease invariably requires a multidisciplinary team
approach, with collaboration between dermatologists, pathologists
and haematological oncologists.
Melanoma
Melanoma is a malignant tumour of epidermal melanocytes.
While only 4% of skin cancers are melanomas, they account
for 80% of skin cancer deaths. There has been a steady rise
in the incidence of melanoma in fair-skinned populations over
recent decades, with the highest figures in Australasia. Primary
prevention and early detection are essential, as therapy for
advanced and metastatic disease remains unsatisfactory.
Pathophysiology
Risk factors for melanoma include fair skin, freckles, red hair,
number of naevi and sunlight exposure. The type of sunlight
exposure is under debate but intermittent exposure, such
as recreational time in the sun, sunburn and sunbed use, is
implicated. Patients with multiple atypical naevi (dysplastic naevus
syndrome) and fair-skinned people, often with variant alleles in
the melanocortin-1 gene, are at increased risk of melanoma. A
family history of melanoma increases the risk but a strong family
history is unusual. Rarely, autosomal dominant inheritance of
melanoma with incomplete penetrance can occur due to mutations
in CDKN2A, which encodes the pi 6 tumour suppressor protein.
In these patients, the lifetime risk of melanoma is more than
50%. Several other susceptibility genes and potential genetic
targets for therapeutic intervention in advanced disease have
also been identified.
Clinical features
Melanoma can occur at any age and site and in either sex,
but typically affects the leg in females and back in males. It
is rare before puberty. The classification of invasive malignant
melanoma is shown in Box 29.15. Early lesions may be in situ and
pre-invasive before becoming invasive melanoma with metastatic
potential. Any change in naevi or development of new lesions
should be assessed to exclude malignancy and, for this, the
dermatoscope is invaluable (see Fig. 29.2, p. 1217). Real-time
non-invasive imaging techniques are being investigated as tools
to assist in diagnosis but are largely experimental. If there is any
doubt, excision is advised.
Superficial spreading melanoma
Superficial spreading melanoma (SSM) is the most common
type in Caucasians. It usually presents as a slowly enlarging,
macular, pigmented lesion, with increasing irregularity in shape
and pigment; this superficial, radial growth phase can last for
Skin tumours • 1233
Fig. 29.15 Superficial spreading melanoma. [A] A superficial
spreading malignant melanoma with a palpable area indicative of vertical
growth phase (Breslow thickness 1 .3 mm). [§] A nodular malignant
melanoma arising de novo and with Breslow thickness of 3.5 mm.
approximately 2 years. Subsequently, the lesion may become
palpable and this is indicative of a vertical growth phase, with
dermal invasion; when this occurs, the tumour has the potential
to invade lymphatics and vessels and to become metastatic
(Fig. 29.15A). Approximately 50% of melanomas arise from a
pre-existing naevus.
Nodular melanoma
Nodular melanoma is most common in the fifth and sixth decades,
particularly in men and on the trunk (Fig. 29.15B). This may
account in part for the increased mortality rates from melanoma
in men, as these are tumours with greater metastatic risk. They
often present as a rapidly growing nodule that may bleed and
ulcerate. Nodular melanomas may be heavily pigmented, or
relatively amelanotic and erythematous, and be confused with
benign vascular lesions. A rim of pigmentation may, however,
be seen under the dermatoscope. Lesions may develop de novo
or from a pre-existing naevus or SSM.
Lentigo maligna melanoma
This arises from a prolonged pre-invasive phase termed lentigo
maligna. It occurs as a very slowly expanding, pigmented, macular
lesion, usually on photo-exposed head and neck sites of elderly
patients; histology shows in situ changes only. This phase may
last for several years before a nodule of invasive melanoma
develops in a proportion of cases (lentigo maligna melanoma).
Acral lentiginous or palmoplantar melanoma
This accounts for only approximately 10% of melanomas in
fair-skinned races and is more common in dark-skinned people,
in whom it is responsible for 50% of cases. This indicates that
UVR exposure may not be implicated in acral melanoma risk.
Subungual melanoma
This form of melanoma is rare. It may present as a painless,
proximally expanding streak of pigmentation arising from the
nail matrix, and progresses to nail dystrophy and involvement
of the adjacent nail fold (Hutchinson’s sign).
Diagnosis and management
The diagnosis is made by excision biopsy of a suspicious lesion.
The initial biopsy should include a 2 mm margin, followed up
where possible by wider excision if the diagnosis is confirmed.
Occasionally, radiotherapy or imiquimod may be used for lentigo
maligna, if surgery is not feasible. The Breslow thickness of the
tumour (the maximal depth from epidermal granular cell layer to
deepest tumour cells) is critical for management and prognosis.
The presence of ulceration may lead to under-estimation of the
Breslow thickness. The mitotic rate and the presence or absence
of any evidence of lymphovascular or perineural involvement
should also be ascertained. The clinical staging of melanoma
extent is essential, in order to establish whether disease is
primary and localised, or if there is nodal or metastatic spread.
Wide excision of melanoma with a low risk of metastasis
(stage 1 disease, Breslow thickness < 1 mm) with a 1 cm clear
margin is accepted practice. The margin of excision for more
advanced disease is controversial, although a 2-3 cm margin
for thicker tumours is generally advised as an attempt to reduce
risk of local recurrence. There is no evidence that more radical
surgery with 4-6 cm margins is beneficial. The majority of tumours
can be excised without the need for grafting. For tumours
with a Breslow thickness of 1 mm or more, a sentinel lymph
node biopsy should be considered. This is usually performed
at the time of wider excision and involves injection of radio-
labelled blue dye at the site of the primary melanoma, allowing
identification of the draining ‘sentinel’ node by radioscintigraphy;
this sentinel node is then removed and examined in detail by
histology, immunohistochemistry and/or PCR of melanocyte gene
products to look for tumour deposits. If the biopsy is positive,
local lymphadenectomy is usually offered. This procedure provides
additional prognostic information but there is no evidence that
it improves survival. Local recurrence of disease and palpable
local node involvement should be treated surgically. Localised
cutaneous metastases or in transit disease may be amenable
to palliation with electrochemotherapy if there is no evidence of
widespread metastatic disease.
Despite the major advances in treatment options for advanced
melanoma, the prognosis for metastatic disease remains poor
and treatment options are palliative. Genetic developments
have facilitated the introduction of tumour-targeted treatments
for advanced, unresectable and/or metastatic disease, such
as the B-Raf and c-Kit kinase inhibitors for patients expressing
these gene mutations, notably dabrafenib and vemurafenib,
with demonstrable clinical responses. Immunotherapy with
ipilimumab, which blocks T-cell activation by inhibiting CTLA-4,
alone or in combination with the programmed cell death (PD1)
pathway blockers nivolumab or pembrolizumab, provides clinically
meaningful improvements in quality of life and survival to patients
with advanced disease. Standard chemotherapy may also be
used in some cases of metastatic disease, although outcomes
are poor. Other biological and gene therapies and vaccines
are also being investigated. It is important for patients with
advanced melanoma to be managed through a multidisciplinary
team in order to optimise care and facilitate their inclusion in
clinical trials.
All patients should be advised regarding ongoing
photoprotection, with sensible behaviour in the sun, covering
up, wearing hats and high-factor sunscreen use. However,
evidence has shown that despite patients with melanoma being
advised to photoprotect, many follow this advice only for the first
year following diagnosis, thus emphasising the need for ongoing
reinforcement of guidance with regard to photoprotection. It
is also prudent to advise patients who are photoprotecting to
optimise oral vitamin D through diet and/or supplements.
Prognosis
Patients with a primary tumour of less than 1 mm Breslow
thickness have more than a 95% chance of disease-free survival
1234 • DERMATOLOGY
at 1 0 years, but this figure drops to approximately 50% for a
tumour of greater than 3.5 mm thickness. Survival rates fall to less
than 1 0% for those with advanced nodal or metastatic disease.
Benign skin lesions
In practice, it is often difficult to distinguish between skin cancer
and a benign lesion on clinical grounds; if there is any doubt,
biopsy and histology are required. Benign melanocytic naevi
and basal cell papillomas, in particular, can often be mistaken
for melanoma, even by dermatologists. Keratoacanthoma, while
benign, is also commonly considered to be invasive SCC on
clinical grounds.
Keratoacanthoma
This benign tumour has a striking clinical presentation of rapid
growth over weeks to months and subsequent spontaneous
resolution. It is thought to be associated with chronic sun exposure
and most commonly occurs on the central face. The classical
appearance is of an isolated dome-shaped nodule often of 5 cm
or more in diameter, with a central keratin plug (Fig. 29.16).
Clinically and histologically, the lesion often resembles SCC (see
Fig. 29.1 2A). Most are treated surgically, either by curettage
and cautery or by excision, to rule out SCC and to avoid the
unsightly scar after spontaneous resolution.
^Freckle
Histologically, a freckle (ephelis) consists of normal numbers of
melanocytes, but with focal increases in melanin in keratinocytes.
They are most common on sun-exposed sites in fair-skinned
individuals, particularly children and those with red hair, and
on the face. There is a familial tendency. Clinically, freckles are
brown macules that darken following UVR exposure.
Lentigo
A lentigo (plural lentigines) consists of increased numbers
of melanocytes along the basement membrane, but without
formation of the nests that occur in melanocytic naevi. These
lesions usually occur at sites of chronic sun exposure (see the
'//////////;/', 777TT7T
Fig. 29.16 Keratoacanthoma.
background skin changes in Fig. 29.1 2A), become more common
with age, and are often referred to as ‘liver spots’ or ‘age spots’.
They can vary in colour from light to very dark brown. Distinction
from melanoma is essential and histology may be required.
Haemangiomas
Benign vascular tumours or hamartomas are common and include
Campbell de Morgan spots (Fig. 29.17), which present as pink/
red papules on the upper half of the body. They can sometimes
be difficult to distinguish from melanocytic lesions, particularly
if they are thrombosed or occur on particular sites, such as
the lip or genitalia. The dermatoscope is helpful for this (see
Fig. 29.2, p. 1217).
Basal cell papilloma
Basal cell papillomas (also known as seborrhoeic warts or
keratoses) are common, benign epidermal tumours (Fig. 29.17).
They may be flat, raised, pedunculated or warty-surfaced, and
can appear to be ‘stuck on’. They occur in both sexes
and with increasing age, and are most common on the face
and trunk. The colour may vary from yellow to almost black and
the surface may seem ‘greasy’, with pinpoint keratin plugs
visible, particularly with a magnifying lens. If there is no doubt
about the diagnosis, they can be left alone or treated by
cryotherapy or curettage if they are cosmetically troublesome.
If there is a suspicion of melanoma, excision or diagnostic biopsy
should be undertaken.
Melanocytic naevi
Melanocytic naevi (moles) are localised benign clonal proliferations
of melanocytes. It is thought that they may arise as the result
of abnormalities in the normal migration of melanocytes during
development. It is quite normal to have 20-50, although,
interestingly, individuals with red hair have fewer. Genetic and
environmental factors are implicated. Monozygotic twins have
higher concordance in naevi numbers than dizygotic twins.
Individuals who have had greater sun exposure have higher
numbers of naevi. Most melanocytic naevi appear in childhood
and early adult life, or during pregnancy or oestrogen therapy. The
onset of a new mole is less common after the age of 25 years.
Congenital melanocytic naevi occur at or shortly after birth.
Fig. 29.17 Atypical basal cell papilloma. Note the neighbouring basal
cell papillomas and the coincidental benign angiomas (Campbell de
Morgan spots).
Common skin infections and infestations • 1235
Junctional Compound Intradermal
Fig. 29.18 Classification of melanocytic naevi. Classification is based
on microscopic location of the nests of naevus cells.
Clinical features
Acquired melanocytic naevi are classified according to the
microscopic location of the melanocyte nests (Fig. 29.18).
Junctional naevi are usually macular, circular or oval, and mid- to
dark brown. Compound and intradermal naevi are nodules
because of the dermal component, and may be hair-bearing.
Intradermal naevi are usually less pigmented than compound
naevi. Their surface may be smooth, cerebriform, hyperkeratotic
or papillomatous.
Some individuals have large numbers of naevi, often at unusual
sites, such as the scalp, palms or soles, and these may frequently
appear ‘atypical’ in terms of variability in pigmentation, size
and shape. Some may be very dark or pink and may show a
depigmented or inflamed halo. If these naevi are removed, then
‘dysplastic changes’ are often seen. Such naevi are known
to occur in some rare families with an inherited melanoma
predisposition. However, the significance of such changes in
non-familial cases is unclear and there is no consensus on
management and follow-up.
Although approximately 50% of melanomas arise in pre-existing
naevi, most naevi do not become malignant; although a changing
naevus must be taken seriously, most will not be melanomas.
Malignant change is most likely in large congenital melanocytic
naevi (risk may correlate with the size of the lesion) and possibly
in families who have been diagnosed as showing large numbers
of atypical naevi with a history of melanoma.
Diagnosis and management
Melanocytic naevi are normal and do not require excision, unless
malignancy is suspected or they become repeatedly inflamed
or traumatised. Advice on photoprotection is important for
fair-skinned individuals with multiple naevi.
Blue naevi
These are melanocytic naevi in which there is a proliferation of
spindled melanocytes relatively deep within the dermis. Light
scattering means that the pigment appears blue rather than
brown. They may be difficult to distinguish from nodular melanoma
and are therefore often excised.
|j)ermatofibroma
A dermatofibroma is a characteristically firm, often pigmented,
raised lesion, most commonly found on the lower legs. Its
aetiology is unclear, although a reactive process secondary to
insect bites or trauma is one hypothesis. There is frequently a
ring of pigment around the lesion and dimpling when the skin
is pinched, reflecting epidermal tethering.
Acrochordon
Acrochordons, or skin tags, are benign pedunculated lesions;
they are most common in skin flexures and usually have a
very characteristic clinical appearance. However, they may
sometimes be confused with melanocytic naevi. Treatment
is not required unless there is diagnostic doubt or they are
causing symptoms, such as irritation, or for cosmetic reasons.
Cryotherapy or snip or shave excision may be appropriate in
that situation.
| Lipoma
Lipomas are benign tumours of adipocytes that are
characteristically soft and lie more deeply in the skin than
epidermal tumours; they are usually diagnosed easily on
clinical grounds. A variant, angiolipoma, is typically painful.
Treatment is not required unless there is diagnostic doubt
or they are symptomatic or cosmetically troublesome, in
which case a diagnostic biopsy or surgical excision may
be required.
Common skin infections
and infestations
Bacterial infections
|jmpetigo
Impetigo is a common and highly contagious superficial
bacterial skin infection. There are two main presentations:
bullous impetigo, caused by a staphylococcal epidermolytic
toxin, and non-bullous impetigo (Fig. 29.19), which can be
caused by either Staphylococcus aureus or streptococci, or both
together. Staphylococcus spp. are the most common agents
in temperate climates, whereas streptococcal impetigo is more
often seen in hot, humid areas. All ages can be affected but
non-bullous disease particularly affects young children, often in
late summer. Outbreaks can arise in conditions of overcrowding
1236 • DERMATOLOGY
and poor hygiene or in institutions. A widespread form can occur
in neonates. Predisposing factors are minor skin abrasions and
the existence of other skin conditions, such as infestations or
eczema.
In non-bullous impetigo, a thin-walled vesicle develops; it rapidly
ruptures and is rarely seen intact. Dried exudate, forming golden
crusting, arises on an erythematous base. In bullous disease, the
toxins cleave desmoglein-1 , causing a superficial epidermal split
and the occurrence of intact blisters with clear to cloudy fluid,
which last for 2-3 days. The face, scalp and limbs are commonly
affected but other sites can also be involved, particularly if there
are predisposing factors such as eczema. Lesions may be single
or multiple and coalesce. Constitutional symptoms are uncommon.
A bacterial swab should be taken from blister fluid or an active
lesion before treatment commences. Around one-third of the
population is a nasal carrier of Staphylococcus, so swabs from
the nostrils should also be obtained.
In mild, localised disease, topical treatment with mupirocin or
fusidic acid is usually effective and limits the spread of infection.
The use of topical antiseptics and soap and water to remove
infected crusts is also helpful. Staphylococcal carriage should
be treated, with mupirocin topically to the nostrils, if swabs are
positive. In severe cases, an oral antibiotic, such as flucloxacillin
or clarithromycin, is indicated. If nephritogenic streptococci
are isolated then systemic antibiotics should be considered to
reduce the risk of streptococcal glomerulonephritis (p. 401).
Underlying disease, such as infestations, must be treated and
cross-infection minimised. Scarring does not occur but there
may be temporary dyspigmentation.
Staphylococcal scalded skin syndrome
Staphylococcal scalded skin syndrome (SSSS) is a potentially
serious exfoliating condition occurring predominantly in children,
particularly neonates (Fig. 29.20). It is caused by systemic
circulation of epidermolytic toxins from a Staph, aureus infection.
The same toxins are implicated in bullous impetigo, which is a
localised form of SSSS. The focus of infection may be minor skin
trauma, the umbilicus, urinary tract or nasopharynx. The child
presents with fever, irritability and skin tenderness. Erythema
usually begins in the groin and axillae, and around the mouth.
Blisters and superficial erosions develop over 1-2 days and can
rapidly involve large areas, with severe systemic upset. Bacterial
swabs should be obtained from possible primary sites of infection.
A skin snip should also be taken for urgent histology. This is a
sample of the superficial peeling skin removed by ‘snipping with
scissors’, without the need for local anaesthetic. It shows a split
beneath the stratum corneum, and differentiates SSSS from toxic
epidermal necrolysis, in which the whole epidermis is affected
(see Fig. 29.41, p. 1254). Systemic antibiotics and intensive
supportive measures should be commenced immediately.
Bacterial swabs from nostrils, axillae and groins should be
taken from family members to exclude staphylococcal carriage.
Although the acute presentation of SSSS is often severe, rapid
recovery and absence of scarring are usual, as the epidermal split
is superficial.
| Toxic shock syndrome
This condition is characterised by fever, desquamating rash,
circulatory collapse and multi-organ involvement (p. 252). It is
caused by staphylococcal toxins and early cases were thought
to arise with tampon use. Intensive supportive care and systemic
antibiotics are required.
Fig. 29.20 Staphylococcal scalded skin syndrome. [A] Extensive
erythema and superficial peeling of the skin. [§] The condition was rapidly
diagnosed by examination of a frozen section of skin snip. A, From Savin
JA, Dahl M, Hunter JAA. Clinical dermatology, 3rd edn. Oxford: Blackwell;
2002.
| Ecthyma
Ecthyma is caused by either staphylococci or streptococci, or
both together, and is characterised by adherent crusts overlying
ulceration. It occurs worldwide but is more common in the tropics.
In Europe, it occurs more frequently in children. Predisposing
factors include poor hygiene, malnutrition and underlying skin
disease, such as scabies. It is commonly seen in drug abusers,
and minor trauma can predispose to lesion development.
| Folliculitis, furuncles and carbuncles
Hair follicle inflammation can be superficial, involving just the
ostium of the follicle (folliculitis), or deep (furuncles and carbuncles).
Superficial folliculitis
The primary lesions are follicular pustules and erythema. Superficial
folliculitis is often infective, caused by Staph, aureus, but can also
be sterile and caused by physical (for example, traumatic epilation)
or chemical (for example, mineral oil) injury. Staphylococcal
folliculitis is most common in children and often occurs on
the scalp or limbs. Pustules usually resolve without scarring in
7-1 0 days but can become chronic. In older children and adults,
they may progress to a deeper form of folliculitis. The condition
Common skin infections and infestations • 1237
Fig. 29.21 Staphylococcal carbuncle.
is often self-limiting and may respond to irritant removal and
antiseptics. More severe cases may require topical or systemic
antibiotics and treatment of Staph, aureus carrier sites.
Deep folliculitis (furuncles and carbuncles)
A furuncle (boil) is an acute Staph, aureus infection of the hair
follicle, usually with necrosis. It is most common in young adults
and males. It is usually sporadic but epidemics occasionally occur.
Malnutrition, diabetes and HIV predispose, although most cases
arise in otherwise healthy people. Any body site can be involved
but neck, buttocks and anogenital areas are common. Infection
is often associated with chronic Staph, aureus carriage in the
nostrils and perineum, and may be due to resistant strains, such
as meticillin-resistant organisms (MRSA). Friction caused by tight
clothing may be contributory. Initially, an inflammatory follicular
nodule develops and becomes pustular, fluctuant and tender.
Crops of lesions sometimes occur. There may be fever and
mild constitutional upset. Lesions rupture over days to weeks,
discharge pus, become necrotic and leave a scar.
If a deep Staph, aureus infection of a group of contiguous
hair follicles occurs, this is termed a carbuncle and is associated
with intense deep inflammation (Fig. 29.21). This usually occurs
in middle-aged men, often with predisposing conditions such as
diabetes or immunosuppression. A carbuncle is an exquisitely
tender nodule, usually on the neck, shoulders or hips, associated
with severe constitutional symptoms. Discharge, necrosis and
scarring are usual. Bacterial swabs must be taken and treatment
is with anti-staphylococcal antibiotics, e.g. flucloxacillin, and
sometimes incision and drainage.
Other staphylococcal toxins may also be pathogenic. For
example, Panton-Valentine leukocidin-producing Staph, aureus
can cause recurrent abscesses (definition: localised collections
of pus in cavities) and may be difficult to eradicate.
Cellulitis and erysipelas
Cellulitis is inflammation of subcutaneous tissue, due to bacterial
infection (Fig. 29.22). In contrast, erysipelas is bacterial infection
of the dermis and upper subcutaneous tissue (Fig. 29.23),
although in practice it may be difficult to distinguish between
them. These conditions are most commonly caused by group
A streptococci but culture of swabs from affected sites is often
negative. There is frequently a source of organism entry, such
as an ear infection, varicose eczema/ulcer or tinea pedis, and
swabs should also be taken from these sites. Diabetes and
immunosuppression are predisposing factors. The patient usually
Fig. 29.22 Acute cellulitis of the leg. Note the chronic lymphoedema
and the haemorrhagic blistering. Blister fluid was positive for group G
streptococci.
Fig. 29.23 Erysipelas. Note the blistering and the crusted rash with
raised, erythematous edge. The yellow discoloration is due to topical iodine
treatment.
has malaise, fever and leucocytosis, and streptococcal serology
will often be positive. The face (erysipelas) and legs (cellulitis) are
most often affected and the site is hot, painful, erythematous and
oedematous. Blistering often occurs and may be haemorrhagic.
Regional lymphadenopathy is common. Erysipelas typically has a
well-defined edge due to its more superficial level of involvement,
whereas cellulitis is typically ill defined. Treatment is usually with
intravenous flucloxacillin, with clarithromycin, clindomycin and
vancomycin as alternatives for penicillin-allergic patients. Milder
cases may be treated with oral antibiotics. If cases are untreated,
sequelae include lymphoedema, cavernous sinus thrombosis,
sepsis and glomerulonephritis.
| Mycobacterial infections
Mycobacterium leprae infection may involve the skin and its
manifestations will be influenced by host immunity, patients
with high levels of immunity presenting with paucibacillary
1238 • DERMATOLOGY
tuberculoid leprosy and those with low immune resistance
developing multibacillary lepromatous leprosy. Hypopigmented or
erythematous patches, with associated altered or lost sensation,
or skin thickening, nodules and infiltration should raise suspicion
of a diagnosis of leprosy (p. 267).
The skin may also be an extrapulmonary site of involvement
in tuberculosis, usually due to infection with Mycobacterium
tuberculosis. Skin manifestations depend on the route of infection,
previous sensitisation and host immunity. There may be a
variety of cutaneous features, including the red-brown scarring
inflammatory plaques seen in lupus vulgaris due to direct skin
inoculation; scrofuloderma, which describes the skin changes
overlying lymph nodes or joints infected with tuberculosis; and
the reactive nodular and ulcerated changes seen in patients with
high levels of immune response, notably the tuberculids and
erythema induratum (Bazin’s disease). On diascopy, an ‘apple
jelly’ appearance is typically seen, indicating the granulomatous
nature of skin involvement. Granulomas evident on skin biopsy
should certainly raise suspicion of a diagnosis of mycobacterial
infection. Culture of organisms may be tricky but PCR can assist
with diagnosis. Patients should be thoroughly investigated for
signs of tuberculosis at pulmonary or other extrapulmonary sites
(p. 588). Reactivation of latent tuberculosis is a particular concern
for patients receiving treatment with immunosuppressants and
biological agents, particularly TNF-a antagonists for conditions
such as psoriasis. Vigilance is required in screening and workup of
such patients prior to consideration of these therapeutic agents.
Other mycobacterial skin infections may occur, such as
Mycobacterium marinum, typically seen in those who clean tropical
fish tanks. Sporotrichoid spread of granulomatous nodules from
the site of inoculation along lymphatics is typical; granulomatous
changes are seen on histology and resolution usually occurs
with a prolonged course of antibiotics such as doxycycline or
minocycline. Resolution may also take place spontaneously or
after destructive therapies, such as cryotherapy.
Leishmaniasis
This protozoan infection may be restricted to the skin or there
may be may be systemic features depending on the species,
which occur in different geographical areas (p. 281).
Necrotising soft tissue infections and anthrax
See pages 226 and 266, respectively.
Erythrasma
Erythrasma is a mild, chronic, localised, superficial skin infection
caused by Corynebacterium minutissimum, which is part of
the normal skin flora. Warmth and humidity predispose to this
infection, which usually occurs in flexures and toe clefts. It
is asymptomatic or mildly itchy and lesions are well defined,
red-brown and scaly. C. minutissimum has characteristic coral-
pink fluorescence under Wood’s light. Microscopy and culture
of skin scrapings can confirm the diagnosis but are not usually
needed if Wood’s light examination is positive. A topical azole
(clotrimazole or miconazole) or fusidic acid is usually effective.
Oral erythromycin can be used for extensive or resistant disease.
Antiseptics can be used to prevent disease recurrence.
Pitted keratolysis
This is another superficial skin infection caused by Corynebacterium
and Streptomyces spp., and possibly other organisms, producing
characteristic circular erosions (‘pits’) on the soles. It is usually
asymptomatic. The bacterium can be identified in skin scrapings
and typically occurs in association with hyperhidrosis, which must
be treated to prevent recurrence. Treatment is as for erythrasma.
Other bacterial skin infections
Syphilis and the non-venereal treponematoses are described
on pages 337 and 253. There has been a marked increase in
incidence of syphilis. Skin signs may be subtle; for example,
secondary syphilis may be misdiagnosed as pityriasis rosea.
Lesions on palms, soles and mucosae should raise suspicion.
Microscopic identification of the spirochaete may be possible
and syphilitic serology should be undertaken using enzyme
immunoassay or PCR-based techniques, depending on availability.
Lyme disease is described on page 255.
Viral infections
Herpesvirus infections
The cutaneous manifestations of the human herpesviruses
are described on page 247. Topical antivirals may suffice for
prophylaxis or treatment of mild viral disease, such as herpes
simplex cold sore virus infection. Systemic antivirals are indicated
for significant viral skin disease. For example, systemic aciclovir
should be prescribed for eczema herpeticum (see Fig. 11.14,
p. 247).
| Papillomaviruses and viral warts
Viral warts are extremely common and are caused by the DNA
human papillomavirus (HPV). There are over 90 subtypes, based
on DNA sequence analysis, causing different clinical presentations.
Transmission is by direct virus contact, in living or shed skin, and
is encouraged by trauma and moisture such as in swimming
pools. Genital warts are spread by sexual activity and show a
clear relationship with cervical and intra-epithelial cancers of
the genital area. HPV-16 and 18 appear to inactivate tumour
suppressor gene pathways and lead to squamous cell carcinoma
of the cervix or intra-epithelial carcinoma of the genital skin
(p. 242). Vaccinations are available against FIPV-16 and 18
and are recommended for adolescent females before they
become sexually active. The relationship between skin HPV
and skin cancer is unclear. Individuals who are systemically
immunosuppressed - after organ transplantation, for example
- have greatly increased risks of skin cancer and HPV infection
but a causal link is not certain.
Clinical features
Common warts are initially smooth, skin-coloured papules, which
become hyperkeratotic and ‘warty’. They are most common
on the hands (Fig. 29.24) but can occur on the face, genitalia
and limbs, and are often multiple. Plantar warts (verrucae)
have a slightly protruding rough surface and horny rim, and
are often painful on walking. Paring reveals capillary loops
that distinguish plantar warts from corns. Other varieties of
wart include:
• mosaic warts: mosaic- 1 ike sheets of warts
• plane warts: smooth, flat-topped papules, usually on the
face and backs of hands, which may be pigmented and
therefore misdiagnosed
• facial warts: often filiform
• genital warts: may be papillomatous and exuberant.
Common skin infections and infestations • 1239
Fig. 29.24 Viral wart on the finger. The capillary loops are evident
within the warty hyperkeratosis. Periungual sites are common and more
difficult to treat.
Management
Most viral warts resolve spontaneously, although this may take
years and active treatment is therefore often sought. However,
asymptomatic warts generally should not be treated. Viral warts
are particularly problematic and more recalcitrant to treatment
in immunosuppressed patients following organ transplantation.
Treatments are destructive. Salicylic acid or salicylic/lactic
acid combinations and regular wart paring for several months
are the most consistently effective treatments. For certain types
of warts, such as filiform facial warts, cryotherapy is generally
the treatment of choice, but for common hand and foot warts
salicylic acid wart paint should be used first. Cryotherapy is
usually the next step and is repeated 2-4-weekly. However,
caution is required, particularly on the hands, as over-vigorous
cryotherapy can lead to scarring, nail dystrophy and even tendon
rupture. Periungual and subungual warts can be problematic
and nail cutting and subsequent electrodessication may help.
Several other therapies have been used for recalcitrant warts,
including topical formaldehyde, podophyllotoxin, trichloroacetic
acid, cantharidin, topical or systemic retinoids, intralesional
bleomycin or interferon injections, and contact sensitisation with,
for example, diphencyprone. Imiquimod and PDT may also be
beneficial, particularly for multiple warts in immunosuppressed
patients, and laser therapy can have a role in some cases.
| Molluscum contagiosum
Molluscum contagiosum is caused by a DNA poxvirus skin
infection. It is most common in children over the age of 1 year,
particularly those with atopic dermatitis. It also occurs frequently
in immunosuppressed patients, including those with HIV (p. 306).
Lesions are dome-shaped, ‘umbilicated’, skin-coloured papules
with central punctum (Fig. 29.25). They are often multiple and
found at sites of apposition, such as the side of the chest and
the inner arm. Spontaneous resolution occurs but can take
months. Prior to resolution, they often become inflamed and
may leave small, atrophic scars. Destructive therapies may
be painful and risk scarring, and the decision not to treat is
often sensible. Gentle squeezing with forceps after bathing can
hasten resolution. Topical salicylic acid, podophyllin, cantharidin,
trichloroacetic acid, cryotherapy and curettage are alternatives.
Efficacy with imiquimod has also been reported.
Fig. 29.25 Molluscum contagiosum. Note the central umbilication,
Orf
Orf is a parapoxvirus skin infection and is an occupational
risk for those who work with sheep and goats. Inoculation of
virus, usually into finger skin, causes significant inflammation
and necrosis, which typically resolves within 2-6 weeks. No
specific treatment is required, unless there is secondary infection.
Erythema multiforme (p. 1 264) can be provoked by orf.
Other viral exanthems
See page 236.
Fungal infections
Fungal skin infections can be superficial (dermatophytes and yeasts)
or, less commonly, deep (chromomycosis or sporotrichosis);
the latter are seen more often in tropical climates or in the
immunocompromised. Dermatophyte infections (ringworm)
are extremely common and usually caused by fungi of the
Microsporum, Trichophyton and Epidermophyton species. The
fungi can originate from soil (geophilic) or animals (zoophilic), or be
confined to human skin (anthropophilic). Dermatophyte infections
usually present with skin (tinea corporis), scalp (tinea capitis),
groin (tinea cruris), foot (tinea pedis) and/or nail (onychomycosis)
involvement (Fig. 29.26).
Diagnosis
Skin scrapings, hair pluckings or nail clippings must be taken
from areas of disease activity - typically, the advancing lesion
edge for skin involvement, the crumbling dystrophic nail and
subungual hyperkeratosis for nail involvement, and plucked
hair from scalp or other affected hair-bearing sites - in order
to confirm the diagnosis by microscopy and culture (p. 1215).
Management
The azoles (ketoconazole, miconazole), triazoles (itraconazole,
fluconazole) and triallylamines (terbinafine) are used most widely
in fungal skin disease. Topical antifungals such as terbinafine or
miconazole may suffice, although systemic treatment (terbinafine,
itraconazole or griseofulvin) may be required for stubborn or
extensive disease and scalp or nail involvement. Indeed, prolonged
courses of systemic treatment may be needed for nail involvement.
The fungistatic agent griseofulvin, given orally, is usually used
for fungal infection of scalp or nails in children in the UK, as it
is the only drug licensed in children for this indication; outside
the UK, and in adults, terbinafine is usually the treatment of
1240 • DERMATOLOGY
Fig. 29.26 Dermatophyte infections.
[XI Trichophyton rubrum infection of the groin
(tinea cruris). \B\ Microsporum canis infection of
the scalp (tinea capitis).
choice. In addition to systemic antifungals, short courses of
systemic or topical glucocorticoid are often used in kerion on the
basis of reducing inflammation and possible hair loss. However,
glucocorticoid use is controversial, with no good evidence of
benefit.
| Tinea corporis
Tinea corporis should feature in the differential diagnosis of a
red, scaly rash (p. 1217). Typically, lesions are erythematous,
annular and scaly, with a well-defined edge and central clearing.
There may also be pustules at the active edge. Lesions are
usually asymmetrical and may be single or multiple. The degree
of inflammation is dependent on the organism involved and the
host immune response. Microsporum canis (from dogs) and
Trichophyton verrucosum (from cats) are common culprits.
Ill-advised use of topical glucocorticoids can modify the clinical
presentation and increase disease extension (tinea incognito).
|jmea cruris
This is extremely common worldwide and is usually caused
by Trichophyton rubrum. Itchy, erythematous plaques develop
in the groins and extend on to the thighs, with a raised active
edge (Fig. 29.26A).
| Tinea pedis
Tinea pedis or ‘athlete’s foot’ is the most common fungal infection
in the UK and USA, and is usually caused by anthropophilic
fungi, such as T. rubrum, T. interdigitale and Epidermophyton
floccosum. It typically presents as an itchy rash between the
toes, with peeling, fissuring and maceration. Involvement of one
sole or palm (tinea manuum) with fine scaling is characteristic
of T. rubrum infection. Vesiculation or blistering is more often
seen with T. mentagrophytes.
| Tinea capitis
This is a dermatophyte infection of scalp hair shafts and is most
common in children. It typically presents as an area of scalp
inflammation and scaling, often with pustules and partial hair loss
(Fig. 29.26B). Infection may be within the shaft (endothrix, most
commonly caused by T. tonsurans), causing patchy hair loss
with broken hairs at the surface (‘black dot’), little inflammation
and no fluorescence with Wood’s light. Infection outside the
hair shaft (ectothrix, most commonly caused by Microsporum
audouinii (anthropophilic)) shows minimal inflammation; M. canis
(from dogs and cats) infections are more inflammatory and can
be identified by green fluorescence with Wood’s light. Kerion is
a boggy, inflammatory area of tinea capitis, usually caused by
zoophilic fungi such as cattle ringworm (T. verrucosum).
Onychomycosis
This is a fungal infection of the nail plate and the species
involved are generally those that cause tinea capitis or tinea
pedis. Onychomycosis usually presents with yellow/brown nail
discoloration, crumbling, thickening and subungual hyperkeratosis.
Usually, some nails are spared, there is asymmetry and toenails
are more commonly involved.
Candidiasis
This is a superficial skin or mucosal infection caused by a yeast-like
fungus, Candida albicans (p. 300). Infections are usually not
serious, unless the patient is immunocompromised, in which
case deeper tissues can be involved (p. 316). The organism
has a predilection for warm, moist environments and typical
presentations are napkin candidiasis in babies, genital and perineal
candidiasis, intertrigo and oral candidiasis. The diagnosis can
be confirmed by microscopy and culture of skin swabs, and
treatment is with topical or systemic antifungals, such as azoles.
| Pityriasis versicolor
Pityriasis versicolor is a persistent, superficial skin condition caused
by various species of the commensal yeast Malassezia, most
commonly Malassezia globosa, but sometimes M. sympadialis
or M. furfur, It occurs in men and women and in different races.
It is found more frequently in warmer, humid climates, and is
usually more severe and persistent in the immunocompromised.
It is characterised by scaly, oval macules on the upper trunk,
usually hypopigmented but occasionally hyperpigmented.
Hypopigmentation is more obvious after sun exposure and
tanning. The diagnosis can be confirmed by microscopy of
skin scrapings, showing ‘spaghetti and meatballs’ hyphae.
Treatment with selenium sulphide or ketoconazole shampoos and
topical or systemic azole antifungal agents is usually effective,
although recurrence is common because these yeasts are
skin commensals, and maintenance topical therapy may be
required. Altered pigmentation can persist for months after
treatment.
Acne and rosacea • 1241
Infestations
Scabies
Scabies is caused by the mite Sarcoptes scabiei. It spreads in
households and environments where there is intimate personal
contact. The diagnosis is made by identifying the scabietic
burrow (definition: a linear or curvilinear papule, caused by a
burrowing scabies mite; p. 234 and Fig. 29.27) and visualising
the mite (by extracting with a needle or using a dermatoscope).
In small children, the palms and soles can be involved, with
pustules. Pruritus is prominent. The clinical features include
secondary eczematisation elsewhere on the body; the face and
scalp are rarely affected, except in infants. Involvement of the
genitals in males and of the nipples commonly occurs. Even
after successful treatment, itch can continue and occasionally
nodular lesions persist.
Topical treatment of the affected individual and all asymptomatic
family members/physical contacts is required to ensure
eradication. Two applications 1 week apart of an aqueous
solution of permethrin or malathion to the whole body, excluding
the head, are usually successful. If there is poor adherence,
immunosuppression or heavy infestation (crusted ‘Norwegian’
scabies), systemic treatment with a single oral dose of ivermectin
is sometimes appropriate.
Head lice
Infestation with the head louse, Pediculus humanus capitis, is
common. It is highly contagious and spread by direct head-to-
head contact. Scalp itch leads to scratching, secondary infection
Fig. 29.27 Scabies. jj Burrows evident on the palm of the hand. [§] A
mite still in its egg, seen on light microscopy of scrapings over a burrow.
Note that the mite has only six legs, unlike adult mites, which have eight.
and cervical lymphadenopathy. The diagnosis is confirmed by
identifying the living louse or nymph on the scalp or on a black
sheet of paper after careful fine-toothed combing of wet hair
following conditioner application. The empty egg cases (‘nits’) are
easily seen on the hair shaft (p. 1210) and are hard to dislodge.
Treatment is recommended for the affected individual and
any infected household/school contacts. Eradication in school
populations is difficult because of poor adherence and treatment
resistance. Topical treatment with dimeticone, permethrin, carbaryl
or, less often, malathion in lotion or aqueous formulations may be
effective and should be applied twice at an interval of 7-10 days.
Rotational treatments within a community may avoid resistance.
‘Wet-combing’ (physical removal of live lice by regular combing
of conditioned wet hair - ‘bug busting’) can suffice but may be
less effective than pharmacological treatments. Vaseline should
be applied to eyelashes/brows twice daily for at least a fortnight.
High -temperature washing of clothing and bedding is required.
Treatment resistance and recurrence can be problematic.
Body lice
These are similar to head lice but live on clothing, particularly in
seams, and feed on the skin. Poor hygiene and overcrowded
conditions predispose. Itch, excoriation (definition: a linear ulcer
or erosion resulting from scratching) and secondary infection
occur. Dry-cleaning and high-temperature washing or insecticide
treatment of clothes are required. Treatment options are as for
head lice. For heavy infestation, oral ivermectin may be indicated.
Pubic (crab) lice
Usually, these are sexually acquired and very itchy. Management
is as for head and body lice and whole-body treatment should
be undertaken. Pubic hair may need to be shaved. Sexual and
other close contacts should also be treated and patients should
also be screened for sexually transmitted diseases.
Acne and rosacea
Acne vulgaris
Acne is chronic inflammation of the pilosebaceous units. It is
extremely common, generally starts during puberty and has been
estimated to affect over 90% of adolescents. It is usually most
severe in the late teenage years but can persist into the thirties
and forties, particularly in females (Box 29.16).
• Epidemiology: acne vulgaris is most common between the ages of
12 and 20. It often begins around 10-13 years of age, lasts
5-10 years and usually resolves by age 20-25.
« Emotional effects: at all ages acne can have negative effects on
self-esteem, but it is especially important to assess how it affects
an adolescent. Depression and suicideal ideation may occur. The
consequences (whether acne is objectively severe or not) can be
devastating, leading to embarrassment, school avoidance, and
life-long effects on ability to form friendships, attract partners, and
acquire and keep employment.
• Treatment: effective treatments aim to improve the condition,
prevent worsening (including later scarring) and restore emotional
well-being and self-esteem.
29.16 Acne in adolescence
1242 • DERMATOLOGY
Occlusion of
pilosebaceous duct
Bacterial colonisation
of duct and release of
inflammatory mediators
Increased
sebum
secretion rate
Rupture of
obstructed
sebaceous
gland, with
release of
contents into
dermis
Sebaceous
gland
Hair follicle
Epidermis
i
Fig. 29.28 Pathogenesis of acne.
Pathogenesis
The key components are increased sebum production;
colonisation of pilosebaceous ducts by Propionibacterium acnes,
which in turn causes inflammation; and hypercornification and
occlusion of pilosebaceous ducts (Fig. 29.28). Severity of acne
is associated with sebum excretion rate, which increases at
puberty. Both androgens and progestogens increase sebum
excretion and oestrogens reduce it, but most patients with acne
have normal hormone profiles. There may be a positive family
history and there is high concordance in monozygotic twins,
indicating that genetic factors are important, but the candidate
genes are poorly defined.
Clinical features
Acne usually affects the face and often the trunk. Greasiness
of the skin may be obvious (seborrhoea). The hallmark is the
comedone (definition: open comedones (blackheads) are dilated
keratin-filled follicles, which appear as black papules due to the
keratin debris; closed comedones (whiteheads) usually have no
visible follicular opening and are caused by accumulation of sebum
and keratin deeper in the pilosebaceous ducts - Fig. 29.28).
Inflammatory papules, nodules and cysts occur and may arise
from comedones (Fig. 29.29). Scarring may follow deep-seated
or superficial acne and may be keloidal.
There are also distinct clinical variants:
Fig. 29.29 Cystic acne in a teenager. [A] Before treatment. \W\ After
prolonged systemic antibiotic treatment.
• Acne excoriee: self-inflicted excoriations due to compulsive
picking of pre-existing or imagined acne lesions. It usually
affects teenage girls, and underlying psychological
problems are common.
• Secondary acne : comedonal acne can be caused by
greasy cosmetics or occupational exposure to oils, tars or
chlorinated aromatic hydrocarbons. Predominantly pustular
acne can occur in patients using systemic or topical
glucocorticoids, oral contraceptives, anticonvulsants,
lithium or antineoplastic drugs, such as the epidermal
growth factor receptor (EGFR) inhibitors. Most patients
with acne do not have an underlying endocrine disorder
but acne is a common feature of polycystic ovary
syndrome (p. 658), which should be suspected if acne is
moderate to severe and associated with hirsutism and
menstrual irregularities. Virilisation should also raise
suspicion of an androgen-secreting tumour.
• Acne conglobata : characterised by comedones, nodules,
abscesses, sinuses (definition: cavities or channels that
permit the escape of pus or fluid) and cysts, usually with
marked scarring. It is rare, usually affecting adult males,
and most commonly occurs on trunk and upper limbs.
It may be associated with hidradenitis suppurativa (a
chronic, inflammatory disorder of apocrine glands,
predominantly affecting axillae and groins), scalp folliculitis
and pilonidal sinus.
• Acne fulminans: a rare but severe presentation of acne,
associated with fever, arthralgias and systemic
inflammation, with raised neutrophil count and plasma
viscosity. It is usually found on the trunk in adolescent
males. Costochondritis can occur.
Investigations
Investigations are not required in typical acne vulgaris. Secondary
causes and suspected underlying endocrine disease or virilisation
should be investigated (p. 657).
Management
Mild to moderate disease
Mild disease is usually managed with topical therapy (p. 1225).
If comedones predominate, then topical benzoyl peroxide or
retinoids should be used. Benzoyl peroxide has both anti-
comedogenic and antiseptic effects. It is an irritant, which
may contribute to the therapeutic response, but this can be
minimised by adjusting treatment regimes. Azelaic acid may
Acne and rosacea • 1243
also be used for mild acne and has both antimicrobial and
anti-comedogenic action. Topical retinoids, in particular all-trans
retinoic acid and adapalene, are widely employed for mild to
moderate comedonal acne vulgaris. Treatment should be initially
applied at low concentrations for short duration and increased as
tolerated. Patients with mild inflammatory acne should respond
to topical antibiotics, such as erythromycin or clindamycin, which
can be used in combination with other treatments.
For moderate inflammatory acne, a systemic tetracycline should
be used at adequate dose for 3-6 months in the first instance
(p. 1227; Fig. 29.29B). Oxytetracycline must be taken on an
empty stomach, in a dose of up to 1 .5 g a day. It has a good
safety profile, even with long-term use, but adherence may be a
challenge. Lymecycline is an alternative and is taken once daily,
with or without food, thereby improving adherence. Doxycycline is
another option but commonly causes photosensitivity. Minocycline
is used less frequently, as it can cause hyperpigmentation,
autoimmune hepatitis and drug-induced lupus, and monitoring is
required. If the patient fails to respond, then alternatives include
erythromycin or trimethoprim.
In women with acne, oestrogen-containing oral contraceptives
can be a useful adjunct, as they are associated with a small
reduction in sebum production. Combined oestrogen and anti¬
androgen (such as cyproterone acetate) contraceptives may
provide additional efficacy, particularly in women with acne
and hirsutism, as seen in polycystic ovary syndrome (p. 658).
Patients should be referred for consideration of isotretinoin
(1 3-c/s-retinoic acid) if there is a failure to respond adequately to
6 months of therapy with these combined systemic and topical
approaches (p. 1227).
Moderate to severe disease
Isotretinoin (1 3-c/s-retinoic acid) has revolutionised the treatment
of moderate to severe acne that has not responded adequately
to other therapies. It has multifactorial mechanisms of action,
with reduction in sebum excretion by over 90%, follicular
hypercornification, P. acnes colonisation and inflammation.
Oral isotretinoin is usually used at a dose of 0.5-1 mg/kg over
4 months. Sebum excretion typically returns to baseline within
a year after treatment cessation, although clinical benefit is
usually longer-lasting. Many patients will not require further
treatment, although a second or third course of isotretinoin
may be needed. A low-dose continuous or intermittent-dose
regimen may occasionally be considered for a longer duration in
patients who relapse after a higher-dose regimen, and may also
be beneficial for older females with persistent acne. Combination
with systemic glucocorticoid may be required in the short term for
severe acne, in order to minimise the risk of disease flare early
in the treatment course. Thorough screening and monitoring are
required, given the side-effect profile of isotretinoin, particularly
with respect to teratogenicity and possible mood disturbance
(p. 1227). Pregnancy must be avoided during treatment and for a
minimum of 2 months after drug cessation, and a strict pregnancy
prevention programme and regular pregnancy testing are required.
Depression and suicide have been reported in association with
isotretinoin, although a causal role has not been established.
However, pre-drug screening for depressive symptoms should
be undertaken and mood monitored during therapy.
Other treatments and physical measures
Intralesional injections of triamcinolone acetonide may be required
for inflamed acne nodules or cysts, which can also be incised
and drained, or excised under local anaesthetic. Scarring may
be prevented by adequate treatment of active acne. Keloid
scars may respond to intralesional glucocorticoid and/or silicone
dressings. Carbon dioxide laser, microdermabrasion, chemical
peeling or localised excision can also be considered for scarring.
UVB phototherapy or PDT can occasionally be used in patients
with inflammatory acne who are unable to use conventional
therapy, such as isotretinoin. There is no convincing evidence
to support a causal association between diet and acne. The
psychological impact of acne must not be under-estimated and
should be considered in management decisions (Box 29.16).
Rosacea
This chronic inflammatory condition affects the central face
and consists of flushing, erythema, papules, pustules and
telangiectasiae. The cause is unknown. Rosacea is distinct
from acne vulgaris; sebum excretion is normal and comedones
are absent. The relative contribution of Demodex mite and
cutaneous vasomotor instability to the pathogenesis of rosacea
remains poorly defined.
Clinical features
Rosacea most commonly affects fair-skinned, middle-aged
females and can be exacerbated by heat, sunlight and alcohol.
The convexities of nose, forehead, cheeks and chin are
typically involved (Fig. 29.30). The condition is heterogeneous
and intermittent flushing, followed by fixed erythema and
telangiectasiae, predominates in some; in others, papules and
pustules are prominent. Sebaceous gland hyperplasia and soft
tissue overgrowth of the nose (rhinophyma) can occur, particularly
in males. Conjunctivitis and blepharitis may also occur. Facial
lymphoedema can be an added complication.
Investigations
Usually, no investigations are required and the diagnosis is obvious
clinically. However, rosacea must be distinguished from acne
vulgaris, systemic lupus erythematosus, photosensitivity disorders
and seborrhoeic dermatitis (the latter may coexist with rosacea).
Fig. 29.30 Rosacea. Typical erythematous papulopustular rosacea
affecting the mid -face.
1244 • DERMATOLOGY
Management
Mild disease may respond to topical antimicrobials, such as
metronidazole or azelaic acid. Topical ivermectin may be beneficial
in some cases, supporting a contributory role of Demodex in
pathogenesis. Tetracycline or erythromycin for 3-6 months is
usually effective in inflammatory pustular disease resistant to
topical therapy (p. 1227). Relapse may require intermittent or
chronic antibiotic use. Erythema and telangiectasiae do not usually
respond well to antibiotics but vascular laser therapy may be
effective. Topical vasoconstrictors, such as the a2-adrenoceptor
agonist brimonidine, may be of benefit in some cases where
erythema and telangiectasiae predominate. Systemic isotretinoin
may be helpful in severe resistant disease and rhinophyma may
require laser therapy or surgery.
Eczemas
The term ‘eczema’ derives from the Greek word ‘to boil’ and
is synonymous with the other descriptive term, ‘dermatitis’.
Eczema describes a clinical and histological pattern, which can
be acute or chronic and has several causes. Acutely, epidermal
oedema (spongiosis) and intra-epidermal vesiculation (producing
multilocular blisters) predominate, whereas with chronicity there
is more epidermal thickening (acanthosis). Vasodilatation and
T-cell lymphocytic infiltration of the upper dermis also occur.
Clinical features
There are several patterns of eczema (Box 29.1 7) but the clinical
features are similar, irrespective of the cause (Box 29.18). Some
subtypes of eczema have specific distinguishing features and
these are discussed in more detail below.
Investigations
Bacterial and viral swabs for microscopy and culture are
important in suspected secondary infection. Bacterial swabs
29.17 Classification of eczema
Endogenous
• Atopic, seborrhoeic
Exogenous
• Irritant, allergic, photo-allergic, chronic actinic dermatitis
Characteristic patterns and morphology
• Asteatotic, discoid, gravitational, lichen simplex, pompholyx
29.18 The clinical morphology of eczema
Acute
• Erythema, oedema, usually typically ill defined
• Papules, vesicles and occasionally bullae
• Exudation, fissuring
• Scaling
Chronic
• May be as above but less oedema, vesiculation and exudate
• Lichenification: skin thickening with pronounced skin markings,
secondary to chronic rubbing and scratching
• Fissures (definition: slit-shaped deep ulcers), excoriations
• Dyspigmentation: hyper- and hypopigmentation can occur
are commonly positive, particularly for staphylococci, although
clinical assessment is required in order to ascertain whether
swab results are of clinical significance and whether antibiotic
treatment is required. Individuals with atopic eczema have an
increased susceptibility to herpes simplex virus (HSV) and are at
risk of developing a widespread infection, eczema herpeticum.
The presence of small, punched-out lesions on a background
of worsening eczema suggests the possibility of secondary HSV
infection. Skin scrapings to rule out secondary fungal infection
should also be considered. Total IgE and specific IgE tests and
skin prick tests are not routinely undertaken in atopic eczema as
they are not usually helpful, although they may occasionally be
indicated in some cases as directed by the history. Patch tests
should be performed if contact allergic dermatitis is suspected
(see Box 29.22 below). Skin biopsy is not usually required unless
there is diagnostic doubt.
Management
A general approach to the management of eczema includes
advice, education and support, required for patients with eczema
of any type (Fig. 29.31). Input from patient support groups,
such as the National Eczema Society in the UK, can be very
helpful. Intensive and prolonged treatments are often required
and chronic eczema can have a major and devastating adverse
impact on personal and family lives. Emollients and topical
glucocorticoids are mainstays of treatment for all eczema types,
in order to improve skin barrier function, limit transepidermal
water loss and reduce inflammation. Emollients can be used as
bath additives and soap substitutes, and applied directly to the
skin, often combined with antiseptics. Sedative antihistamines
are useful if sleep is interrupted but non-sedating antihistamines
are ineffective, as the itch of eczema is not primarily mediated
by histamine.
Ointments are preferred for chronic eczema, whereas cream- or
lotion-based treatment may be more appropriate for acute
eczema (see Box 29.11). Treatment is once to twice daily
(p. 1 225). Hydrocortisone (1 %) or clobetasone butyrate is generally
used on the face, with more potent glucocorticoids restricted to
trunk and limbs (see Box 29.1 2). A good strategy is to employ an
intensive regimen with more potent glucocorticoids initially and
then taper use according to response. A key principle is to use
the least potent glucocorticoid that is effective for the shortest
possible time. The patient should be given instructions on how
much to apply, using the fingertip unit for guidance (a strip of
glucocorticoid cream on distal phalanx pulp should cover two
palm-size areas). It is also important to monitor glucocorticoid
use and the easiest way to do this is ask how long it takes
to use a specific size of glucocorticoid tube. The side-effects
of topical glucocorticoid therapy need to be considered but
glucocorticoid phobia and under-treatment of eczema are often
more of a problem than over-treatment. Particular care should
be taken on certain sites, such as the face and flexures, and in
children and the elderly (see Box 29.2 and Fig. 29.10, p. 1226).
The clinical features of eczema influence the choice of topical
treatment. For example, appropriate treatment of acute exudative
eczema could be with potassium permanganate soaks, emollients
and topical glucocorticoids under wet wraps. Chronic eczema
may be best treated with a potent topical glucocorticoid in an
ointment formulation and occlusion with a paste bandage to
ease itching and scratching.
The topical calcineurin inhibitors tacrolimus and pimecrolimus
may be useful glucocorticoid-sparing agents for eczema, particularly
on the face; they cause local cutaneous immunosuppression.
Eczemas • 1245
Initial steps
Accurate diagnosis
Establishing severity and impact
Removal of triggers and treatable
causes, such as infection, and
allergens
Education and support
of patient and family
Psychological support
T
General treatment approach
Emollients, topical glucocorticoids,
topical calcineurin inhibitors,
sedating antihistamines
Consider bandages, wet wraps
T
Next steps
Narrowband UVB, PUVA/UVA1
(depending on availability,
patient age etc.)
I
r
1
1
▼
Inpatient admission
If feasible, for intensive
inpatient care
± Phototherapy
± Systemic treatment
▼
Immunosuppression
Prednisolone,
azathioprine,
ciclosporin,
methotrexate
▼
Systemic retinoids
Acitretin or
alitretinoin for
hand eczema
l
For severe resistant disease
Dupilumab
(Trials in progress with other
biologies and PDE inhibitors)
Initial burning and stinging may limit use but are usually transient
side-effects. Bacterial and viral skin infection risk may be increased
due to immunosuppression. Caution should be employed with sun
exposure and these agents should not be used in combination
with phototherapy because of their immunosuppressive effects.
Atopic eczema
This is the most common subtype of eczema. The prevalence
has increased dramatically since the early 1980s, and the disease
now affects at least 20% of schoolchildren and 5-10% of adults
in the UK.
Pathogenesis
Generalised prolonged hypersensitivity to common environmental
antigens, such as pollen and house-dust mite, is the hallmark
of atopy, in which there is a genetic predisposition to produce
excess IgE. Atopic individuals manifest one or more of a group of
diseases that includes asthma, hay fever, food and other allergies,
and atopic eczema. Genetic factors play an important role in all
of these conditions, supported by higher concordance of atopic
disease in monozygotic twins compared with dizygotic twins.
Filaggrin gene mutations increase the risk of developing atopic
eczema by more than threefold, emphasising the importance of
epidermal barrier impairment in this disease. Other genes are also
likely to be implicated, with many other susceptibility loci identified,
although these studies require further replication. Decreased skin
Fig. 29.31 General management
approaches: atopic eczema. (PDE =
phosphodiesterase; PUVA = psoralen-ultraviolet
A; UVA1 = ultraviolet A1 ; UVB = narrowband
ultraviolet B)
barrier function may also allow greater penetration of allergens
through the epidermis, and thus cause immune stimulation and
subsequent inflammation. The interaction between genes and
environment is important; it has been estimated that 60-80%
of individuals are genetically susceptible to the induction of
IgE-mediated sensitisation to environmental allergens such as
food and animal hair. Eczema is characterised by infiltration of Th2
cells, which are known to play a role in activating mast cells and
eosinophils, as well as stimulating IgE production by IgE-producing
B cells. The contributing roles of the microbiome are also being
explored. Thus, the pathogenesis of atopic eczema is complex
and multifactorial, involving an interplay of contributing factors.
Clinical features
Atopic eczema is extremely itchy and scratching accounts for
many of the signs (Fig. 29.32). Widespread cutaneous dryness
(also known as xeroderma or xerosis) is another feature. The
distribution and character of the rash vary with age (Box 29.1 9).
Complications are listed in Box 29.20.
Investigations
The diagnosis of atopic eczema is made using clinical criteria
(Box 29.21). Interestingly, while most patients with atopic eczema
have raised total IgE levels and IgE-specific antibodies, this is
not a prerequisite for the diagnosis, as a significant minority
have normal levels of IgE.
1246 • DERMATOLOGY
Fig. 29.32 Atopic eczema. [A] This patient had life-long chronic atopic
eczema and experienced a generalised flare of disease triggered by
infection. [SJ Lichenification of chronic flexural eczema secondary to
rubbing and scratching.
29.19 Atopic eczema: distribution and character
of rash
i
Itchy skin rash (or history of itch or rubbing from parent) and at least
three of the following:
• History of involvement of skin creases (or cheeks if <4 years)
• History of atopic disease (asthma, hay fever) (or in a first-degree
relative if <4 years)
• Dry skin (xeroderma)
• Visible flexural eczema (cheeks, forehead, outer limbs if <4 years)
• Onset in first 2 years of life
Management
The general principles of management are as described in
Figure 29.31 . Emollients and topical glucocorticoids, tar and
ichthammol paste bandages, or wet wraps in children, are
often required. Topical calcineurin inhibitors may be used as
glucocorticoid-sparing agents but should not be used in infected
eczema. Secondary infection should be treated but positive
skin swabs in isolation, without clinical evidence of infection,
do not necessarily require treatment with antibiotics, although
antiseptics would be appropriate. Sedating antihistamines may
help to break the itch/scratch cycle. Identification and avoidance
of allergens are important.
Phototherapy is generally the next step, if topical therapies are
insufficient (see Fig. 29.31). Narrowband UVB is usually the initial
phototherapy of choice and can also be used in children. PUVA
or UVA1 can also be chosen if UVB is ineffective, although mainly
in adults as PUVA is generally avoided in children. Localised
phototherapy may be used for eczema on hands and feet
and PUVA may be more effective in that situation. Systemic
immunosuppression with, for example, oral glucocorticoids,
intermittent ciclosporin, azathioprine or methotrexate may be
needed if the response to topical therapies and phototherapy is
inadequate. Systemic retinoids, such as acitretin or alitretinoin,
may be indicated: for example, in hand and foot eczema.
Encouraging early trial data are emerging to support the
use of dupilumab, which blocks IL-4Ra, and the anti-IL-13
agents lebrikizumab and tralokinumab in atopic eczema.
Phosphodiesterase 4 inhibitors are also being investigated.
Seborrhoeic eczema
This is an erythematous scaly rash affecting the scalp (dandruff),
central face, nasolabial folds, eyebrows, central chest and upper
back. It is associated with, and may be due to, overgrowth of
Malassezia yeasts. When severe, it may resemble psoriasis.
Severe or recalcitrant seborrhoeic eczema can be a marker of
immunodeficiency, including HIV infection (p. 314). Topical azoles,
such as ketoconazole shampoo and cream, often combined
with mild glucocorticoid, are mainstays. Treatment often needs
to be repeated due to disease recurrence.
Discoid eczema
Discoid eczema, which is also known as nummular eczema, is
common and characteristically consists of discrete, coin-shaped
eczematous lesions, which are often impetiginised and most
commonly occur on the limbs of men. It is an eczema type that
can be due to any chronic itchy condition, whether primarily of the
skin or secondary to an underlying disease. Initial management
should include topical antiseptics, in addition to emollients and
topical glucocorticoids. Judicious antibiotic use may also be
required for acute flares.
Babies and infants
• Often acute and facial involvement prominent
• Trunk involved but nappy area usually spared
Children
• Flexures: behind knees, antecubital fossae, wrists and ankles
Adults
• Face and trunk usually involved, limb involvement not restricted to
flexures
• Lichenification common
29.20 Complications of atopic eczema
Secondary infection
Bacterial
• Staphylococcus aureus most common
Viral
• Herpes simplex virus can cause a widespread severe eruption
- eczema herpeticum
• Papillomavirus and molluscum contagiosum are more common in
atopic eczema, especially if treated with topical glucocorticoids
Increased susceptibility to irritants
• Defective barrier function
Increased susceptibility to allergy
• Food allergy - mainly relevant in infants; eggs, cow’s milk protein,
nuts, fish, wheat and soya may cause an immediate reaction with
angioedema and/or urticaria rather than exacerbation of eczema
• Anaphylaxis in severe allergy
• Increased risk of sensitisation to type IV allergens because of
impaired barrier function
Impact on life and health
• Poor sleep, loss of schooling, behavioural difficulties, failure to
thrive in children
• Impact on sleep, work, relationships, hobbies, psychology and
quality of life in adults
29.21 Diagnostic criteria for atopic eczema
Psoriasis and other erythematous scaly eruptions • 1247
^9 29.22 Common type IV delayed hypersensitivity
allergens
Allergen
Source
Nickel
Jewellery, jean studs, bra clips,
watches
Dichromate
Cement, leather, matches
Rubber chemicals
Clothing, shoes, rubber gloves, tyres
Colophony
Sticking plaster, collodion, nail varnish
Paraphenylenediamine
Hair dye, clothing, tattoos
Balsam of Peru
Perfumes, citrus fruits, shower/bath
products
Neomycin, benzocaine
Topical medications
Parabens
Preservative in cosmetics and creams
Wool alcohols
Lanolin, cosmetics, creams
Epoxy resin
Resin adhesives, glues
Methyl- and chloromethyl-
isothiazolinone
Preservatives, with increasing
numbers of cases of allergy reported
| Irritant eczema
Detergents, alkalis, acids, solvents and abrasives are common
irritants. Strong irritants have acute effects, whereas weaker
irritants commonly cause chronic eczema, especially of the
hands, after prolonged exposure. Individual susceptibility varies
and the elderly, atopic and fair-skinned are predisposed. Irritant
eczema accounts for most occupational cases of eczema and is
a significant cause of time off work. Irritant avoidance, including
protective clothing (such as gloves), is essential. Emollients and
topical glucocorticoids are indicated.
Allergic contact eczema
This occurs due to a delayed hypersensitivity reaction following
contact with antigens or haptens. Previous allergen exposure
is required for sensitisation and the reaction is specific to the
allergen or closely related chemicals. Common allergens are
listed in Box 29.22.
Allergy persists indefinitely and eczema occurs at sites of
allergen contact and can secondarily spread beyond this. The
distribution of eczema can be very informative with regard to
possible culprits. There are many recognisable patterns of sites
of eczema involvement, such as earlobes, wrists and umbilicus
due to contact with nickel in earrings, watches and jeans studs;
hands and wrists due to rubber gloves; and upper eyelids due
to colophony from rubbing of the eyes in nail varnish wearers.
Oedema may also be a feature (Fig. 29.33). Allergen avoidance
is key and may involve a change of occupation, recreational
activities or hobbies. It is important to ensure that patients are
fully informed as to the nature and likely occurrence of allergens
and good detective work is required to scrutinise lifestyle and daily
activities. Treatment with emollients and topical glucocorticoids
helps but will not suffice if there is continued allergen exposure.
Asteatotic eczema
This occurs in dry skin and is common in the elderly. Low
humidity caused by central heating, over-washing, diuretics and
cholesterol-lowering drugs predispose. The most common site is
the lower legs, and a ‘crazy paving’ pattern of fine Assuring on
an erythematous background is seen. Emollients are a mainstay,
Fig. 29.33 Allergic contact eczema. This was caused by the application
of an antihistamine cream. The acute eczematous reaction and bilateral
periorbital oedema are typical.
in combination with topical glucocorticoids. Patients must be
advised to use caution with flammable emollients and to avoid
bathroom slippages related to emollients on floor and feet, and
this is particularly relevant for the elderly.
Gravitational eczema
Gravitational or stasis eczema occurs on the lower legs and is
often associated with signs of venous insufficiency: oedema, loss
of hair, induration, lipodermatosclerosis and ulceration. Emollients
should be used and topical glucocorticoids should be applied
to eczematous areas but not to ulcers. There is a high risk of
sensitisation to topical preservatives (such as chlorocresol),
antibiotics (such as neomycin) and bandages (such as rubber
additives). Oedema and ulceration are treated by leg elevation
and compression bandages (p. 1224).
| Lichen simplex
Lichenification of eczema occurs secondary to chronic rubbing
and scratching, and lichen simplex is a localised form. Common
sites include the neck, lower legs and anogenital region. Treatment
with emollients and very potent topical glucocorticoids may be
required, often impregnated in tape or with occlusion.
Pompholyx
Intensely itchy vesicles and bullae occur on the palms, palmar
surface and sides of the fingers and soles. Pompholyx may
have several causes, which include atopic eczema, irritant and
contact allergic dermatitis and fungal infection. The underlying
cause must be treated or removed.
Psoriasis and other erythematous
scaly eruptions
Psoriasis
Psoriasis is a chronic inflammatory, hyperprol iterative skin disease.
It is characterised by well-defined, erythematous scaly plaques,
1248 • DERMATOLOGY
particularly affecting extensor surfaces, scalp and nails, and
usually follows a relapsing and remitting course. Psoriasis affects
approximately 1 .5-3% of Caucasians but is less common in Asian,
South American and African populations. It occurs equally in both
sexes and at any age; although it is uncommon under the age
of 5 years, more than 50% of patients present before the age of
30 years. The age of onset follows a bimodal distribution, with
an early-onset type in the teenage or early adult years, often with
a family history of psoriasis, a more severe disease course and
strong HLA association. The later-onset type is typically seen
between 50 and 60 years, usually without a family history and
with a less severe disease course.
Pathogenesis
Both genetic and environmental factors are important. Twin studies
show concordance rates of 60-75% and 15-20% for psoriasis
arising in monozygotic and dizygotic twins, respectively. The
age at onset and severity of disease are often similar in familial
cases. If one parent has psoriasis, the chance of a child being
affected is about 15-20%; if both parents have the disease,
this rises to 50% and the risk is increased further if a sibling
also has the disease.
Variants of the HLA-C region within the major histocompatibility
complex (MHC) on chromosome 6 account for almost half of
the heritability of psoriasis. However, at least 70 other loci are
implicated, with susceptibility variants that lie within or close to
genes involved in regulating epidermal barrier function, antigen
presentation, cytokine production, notably IL-13 and IL-23,
T-cell differentiation (especially Th-1 and Th-17 subsets) and
nuclear factor kappa B (NFkB) signalling. Some of the loci that
predispose to psoriasis overlap with those implicated in Crohn’s
disease, ankylosing spondylitis and psoriatic arthritis.
Environmental triggers for psoriasis are shown in (Box 29.23).
Although the theory is controversial, stress may exacerbate
psoriasis in susceptible individuals and psoriasis is itself a cause
of psychological stress. Likewise, there is a higher incidence of
smoking and heavy alcohol consumption in patients with psoriasis
but it is unclear whether this is cause or effect. There is also an
association between psoriasis and metabolic syndrome (p. 730).
The histological changes of psoriasis are shown in Figure
29.34. The main features are:
• keratinocyte hyperproliferation and abnormal differentiation,
leading to retention of nuclei in the stratum corneum
• inflammation, with a T-cell (mainly activated Th-1 and
Th-17) lymphocytic infiltrate and release of cytokines and
adhesion molecules, such as interleukins (including IL-17
and IL-23), TNF-a, IFN-y and intercellular adhesion
molecule (ICAM)-I
• vascular changes, with tortuosity of dermal capillary loop
vessels and release of mediators, such as vascular
endothelial growth factor (VEGF).
The initiating event for psoriasis is unknown. Disordered cell
proliferation is a key feature; this was previously thought to be
the primary event but is now considered to be secondary to
inflammatory change. The transit time for keratinocyte migration,
from basal layer to shedding from stratum corneum, is shortened
from approximately 28 to 5 days, so that immature cells reach the
stratum corneum prematurely. Proliferation rate is also increased
in non-lesional skin but to a lesser extent. Similarly, even the
clinically unaffected nails of patients with psoriasis grow more
quickly than those of controls.
While immunological factors clearly play a key role in psoriasis,
the precise mechanisms of disease initiation and the sequence
of events that lead to psoriasis are not fully defined.
i
Trauma
• Lesions can appear at sites of skin trauma, such as scratches or
surgical wounds (Kobner isomorphic phenomenon)
Infection
• p-haemolytic streptococcal throat infections often precede guttate
psoriasis (see Fig. 29.35C)
• Severe psoriasis may be the initial presentation of HIV infection
Sunlight
• Psoriasis may occur or worsen after sun exposure, mainly due to
Kobnerisation at sites of sunburn or polymorphic light eruption
Drugs
• Antimalarials, p-adrenoceptor antagonists (p-blockers), lithium,
NSAIDs and TNF-a inhibitors can exacerbate psoriasis
• ‘Rebound’ flare of psoriasis may occur after withdrawal of systemic
glucocorticoids or potent topical glucocorticoids. Rebound psoriasis
is often unstable and may be pustular
Psychological factors
• Anxiety and stress may exacerbate psoriasis in predisposed
individuals
(NSAID = non-steroidal anti-inflammatory drug; TNF-a = tumour necrosis
factor alpha)
29.23 Exacerbating factors in psoriasis
Normal
Keratin
layer
Epidermis-
Dermis-
Psoriasis
Parakeratosis
Hyperkeratosis
Micro-abscess
Supra-papillary
plate thinning
Dilated and tortuous
capillary loops
Irregular thickening
of epidermis
Fig. 29.34 The histology of psoriasis.
Upper dermal
T-lymphocyte infiltrate
Psoriasis and other erythematous scaly eruptions • 1249
Fig. 29.35 Psoriasis. [A] Chronic plaque
psoriasis, most prominent on extensor
surfaces, [j] Nail involvement, with coarse
pitting and separation from the nail plate
(onycholysis). [C] Guttate psoriasis
following a streptococcal throat infection.
[Pi Erythrodermic psoriasis.
Clinical features
Psoriasis has several different presentations (Fig. 29.35).
Plaque psoriasis
This is the most common presentation and usually represents
more stable disease. The typical lesion is a raised, well-demarcated
erythematous plaque of variable size (Fig. 29.35A). In untreated
disease, silver/white scale is evident and more obvious on scraping
the surface, which reveals bleeding points (Auspitz sign). The
most common sites are the extensor surfaces, notably elbows
and knees, and the lower back. Others include:
• Scalp : involvement is seen in approximately 60% of
patients. Typically, easily palpable, erythematous scaly
plaques are evident within hair-bearing scalp and there is
clear demarcation at or beyond the hair margin. Occipital
involvement is common and difficult to treat. Less often,
fine diffuse scaling may be present and difficult to
distinguish from seborrhoeic dermatitis. Involvement of
other ‘seborrhoeic sites’, such as eyebrows, nasolabial
folds and the pre-sternal area, is not uncommon and again
may be confused with seborrhoeic dermatitis. Temporary
hair loss can occur but permanent loss is unusual.
• Nails: involvement is common, with ‘thimble pitting’,
onycholysis (separation of the nail from the nail bed,
Fig. 29.35B), subungual hyperkeratosis and periungual
involvement (p. 1210).
• Flexures: psoriasis of the natal cleft and submammary and
axillary folds is usually symmetrical, erythematous and
smooth, without scale.
• Palms: psoriasis of the palms can be difficult to distinguish
from eczema.
Guttate psoriasis
This is most common in children and adolescents and is often
the initial presentation (Fig. 29.35C). It may present shortly after
a streptococcal throat infection and evolves rapidly. Individual
lesions are droplet-shaped, small (usually less than 1 cm in
diameter), erythematous, scaly and numerous. An episode
of guttate psoriasis may clear spontaneously or with topical
treatment within a few months, but UVB phototherapy is often
required and is highly effective. Guttate psoriasis often heralds
the onset of plaque psoriasis in adulthood.
Erythrodermic psoriasis
Generalised erythrodermic psoriasis is a medical emergency
(Fig. 29.35D).
Pustular psoriasis
Pustular psoriasis may be generalised or localised. Generalised
pustular psoriasis is uncommon, unstable and life-threatening.
It will often emerge in the context of plaque disease and the
onset is usually sudden, with large numbers of small, sterile
pustules on an erythematous background, often merging into
sheets, with waves of new pustules in subsequent days. The
patient is usually febrile and systemically unwell, and this must be
dealt with as a medical emergency (p. 1224). Unstable pustular
psoriasis may be precipitated as a rebound phenomenon following
either topical or systemic glucocorticoid use in a patient with
psoriasis. Localised pustular psoriasis of the palms and soles
(palmoplantar pustulosis) is more common, chronic and closely
associated with smoking; small, sterile pustules and erythema
develop and resolve with pigmentation and scaling (p. 1210). A
localised form of sterile pustulosis of a few digits (acropustulosis)
can also occur. It is unclear whether these localised forms of
pustulosis are truly psoriatic.
Arthropathy
Between 5% and 10% of individuals with psoriasis develop
an inflammatory arthropathy, which can take on a number of
patterns (p. 1035). Joint involvement is more likely in patients
with psoriatic nail disease.
1250 • DERMATOLOGY
Investigations
Skin biopsy is not usually required but may be performed if
there is diagnostic doubt. An infection screen, particularly throat
swab and/or serology for recent streptococcal infection, may
be informative in guttate psoriasis. Assessment of impact on
life using the DLQI and disease extent using PASI (Psoriasis
Area and Severity Index, p. 1211) is essential. Due to the
association of psoriasis with metabolic syndrome, comorbidities
and cardiovascular risk factors should be assessed and managed
(p. 730). HIV testing should be considered in severe or recalcitrant
psoriasis.
Management
Counselling about diagnosis and management of skin involvement
and other comorbidities is paramount. Information and services
must be available for patients. Psoriasis can have a major impact
on all aspects of life and this must not be under-estimated.
Reassurance is also needed, as the condition is generally not
life-threatening. Advice regarding reduction in risk factors for
cardiovascular disease should be given (smoking cessation,
reduction of alcohol intake, adequate exercise and a normal
body mass index). Associated diseases, such as hypertension
and diabetes, should be treated.
Patients need to be involved in their own management, as the
disease is usually chronic and the benefit/risk profile of treatments
must be discussed and tailored to individuals. The endpoint for
treatment also needs to be discussed because complete disease
clearance may not be practical or appropriate and patients vary
considerably in their treatment requirements. Extent of disease
and impact on quality of life must be taken into account. Patient
adherence to topical and systemic therapies is essential and
dependent on the treatment practicalities.
The treatment approach generally follows a stepwise
progression, with treatment categories broadly summarised
(Fig. 29.36).
Topical treatments, including emollients, are the first-line
approach. Vitamin D receptor agonists, such as calcipotriol,
calcitriol and tacalcitol, are often used as first-line topical treatment.
The mechanism of action includes increased differentiation and
reduction of proliferation, reducing plaque scale and thickness.
Calcipotriol is most widely used and can be applied once to twice
daily; if less than 1 00 g of ointment is used each week, there
is no risk of hypercalcaemia. Vitamin D analogues can cause
irritation but this is often temporary. Topical glucocorticoids
may be required in the management of psoriasis, particularly at
flexural or facial sites, and may be alternated or combined with
vitamin D analogues. However, safe, appropriately supervised
and judicious use is necessary, with awareness of the potential
risk of rebound unstable or pustular psoriasis with glucocorticoid
over-use or sudden cessation. Dithranol and coal tar are effective
and, like vitamin D analogues, work by increasing differentiation
and inhibiting proliferation. Although often effective, they are messy
and time-consuming. Modified versions of Goeckerman’s regimen
(the combination of coal tar and UVB) are still used, but coal
tar has a characteristic odour and can be irritant. Short-contact
dithranol therapy at relatively high concentrations applied for
15-30 minutes can be used but causes brown staining of skin
and purple discoloration of light hair. In recent years, efforts
have been made to improve the tolerance of tar and dithranol
preparations, but at reduced efficacy. Overall, the use of tar and
dithranol has reduced in recent years but they can be highly
effective in selected patients.
Initial steps
Accurate diagnosis
Establishing severity and impact
Removal or treatment of triggers
Identification of comorbidities
(especially in severe disease)
Education, support,
psychological input
I
General treatment approach
Emollients, topical vitamin D
analogues, tars, dithranol, retinoids
± Topical glucocorticoids,
e.g. flexural sites
I
Next steps
Narrow-band UVB (or excimer laser,
if available, for localised disease),
PUVA
Inpatient admission
If feasible, for intensive
inpatient care
± Phototherapy/PUVA
± Systemic treatment
Systemic agents
Methotrexate,
ciclosporin,
acitretin (can add to
phototherapy or PUVA)
I
May consider
Fumaric acid esters/apremilast
-j-
For resistant disease
i
Biologies
Anti-TNF-a Anti-IL-12/23 Anti-IL-23 Anti-IL-17
Infliximab Ustekinumab Guselkumab Secukinumab
Etanercept Ixekizumab
Adalimumab Brodalumab
Fig. 29.36 General management approaches: psoriasis. (IL =
interleukin; PUVA = psoralen-ultraviolet A; TNF-a = tumour necrosis factor
alpha; UVB = ultraviolet B)
If topical treatment is insufficient, then UVB phototherapy or
PUVA should usually be the next step. If the patient continues
to have active disease or early recurrence, then the addition
of systemic retinoid such as acitretin to UVB or PUVA can be
effective. Alternatively, immunosuppressants, such as methotrexate
or ciclosporin, may be required. For difficult treatment-resistant
disease, fumaric acid esters, apremilast and biologies should
be considered (p. 1005 and Fig. 29.37).
The active component of fumaric acid ester therapy is dimethyl
fumarate and efficacy in psoriasis has been confirmed. Common
adverse effects are flushing and diarrhoea. Lymphopenia is
also expected at effective doses. Apremilast is indicated for
moderate to severe psoriasis resistant to standard measures.
Of the biological agents, the anti-TNF-a agents (etanercept,
infliximab, adalimumab or golimumab), ustekinumab (an inhibitor
Psoriasis and other erythematous scaly eruptions • 1251
Fig. 29.37 Developments in understanding of key pathways and drug targets in psoriasis. Other drug targets are also under development, such as
Janus kinase (JAK) inhibitors (tofacitinib and baricitinib) and sphingosine-1 -phosphate receptor (S1PR1) antagonists (ponesimod). This diagrammatic image
is illustrative of key pathways and drug targets but is not comprehensive. (AMP = adenosine monophosphate; cAMP = cyclic adenosine monophosphate;
GM-CSF = granulocyte macrophage colony-stimulating factor; IL = interleukin; TNF-a = tumour necrosis factor alpha)
of IL-12 and IL-23), guselkumab (an IL-23 inhibitor) and
secukinumab or ixekizumab (an IL-17 inhibitor) may all be
effective and this is a rapidly evolving field. More details of the
mechanisms of action and adverse effects of these agents are
provided on page 1006.
Individualised management is essential. For example, a patient
with localised plaque psoriasis on elbows, knees and sacrum
should respond to topical treatment only, whereas someone
with guttate psoriasis is likely to need phototherapy as a first-line
approach because of difficulties in topical drug application
in extensive disease. A patient with extensive chronic plaque
psoriasis and significant arthropathy would be better suited to
a systemic drug, such as methotrexate, than phototherapy,
which would be unlikely to improve joint symptoms. Thus, whilst
a stepwise general approach to management (see Fig. 29.36)
may offer guidance, the correct choice for any given patient
must be determined on an individual basis.
Pityriasis rosea
This is an acute, self-limiting exanthem that particularly affects
young adults and occurs worldwide, with a slight female
predominance. It usually presents in spring and summer, although
no infective agent has been identified and its aetiology is unknown.
It is characterised by the appearance of a ‘herald patch’, an oval
lesion (1-2 cm) with a central pinkish (salmon-coloured) centre,
a darker periphery and a characteristic collarette of scale. It is
followed 1-2 weeks later by a widespread papulosquamous
eruption, which is typically arranged in a symmetrical ‘fir tree’
pattern on the trunk. Individual lesions also have a collarette of
scale. An inverse variant with flexural involvement can occur.
Mucosal involvement is rare. There is a small risk of recurrence.
Symptomatic relief can be achieved with emollients and mild
topical glucocorticoids. Post-inflammatory hyperpigmentation
can supervene, particularly in darker skin types.
Pityriasis lichenoides chronica
This is rare but typically presents within the first three decades
of life. The aetiology is unclear but the condition is part of a
spectrum and remits spontaneously. The more acute variety
(pityriasis lichenoides et varioliformis acuta, PLEVA) presents as
crops of papules that rapidly evolve with central necrosis, each
attack lasting up to 3 months. The more chronic variety presents
as a persistent, widespread, scaly eruption. Characteristically,
lesions are brown papules with a mica-like scale (‘cornflake’).
The condition fluctuates but can persist for months or years.
Emollients, topical glucocorticoids and long-term oral erythromycin
can occasionally be helpful. UVB phototherapy or PUVA is usually
effective, although recurrences are high.
|j)rug eruptions
It is essential to consider a drug cause in anyone presenting with
an erythematous maculopapular or papulosquamous eruption, and
a careful drug history is critical (p. 1265). Exfoliation (‘peeling’) and
post-inflammatory hyper- or, less commonly, hypopigmentation
can occur.
Other causes
Secondary syphilis (p. 337), pityriasis versicolor (p. 1240) and
fungal infection with Tinea corporis (p. 1240) can all cause an
1252 • DERMATOLOGY
erythematous papulosquamous rash and must be considered in
the differential diagnosis of erythematous papulosquamous rashes.
Lichenoid eruptions
Lichen planus
Lichen planus occurs worldwide. It typically presents as a pruritic
rash; the mucosae, hair and nails may also be involved.
Pathogenesis
The disease probably has an autoimmune basis since there is
an association with inflammatory bowel disease, primary biliary
cirrhosis, autoimmune hepatitis, hepatitis B and C, alopecia
areata, myasthenia gravis (p. 1141) and thymoma. There are
also similarities with graft-versus-host disease (GVHD, p. 937).
Lichen planus can occasionally occur in families and possible HL4
associations have been reported but there is no clear inheritance
pattern. On skin biopsy, characteristic histological changes include
hyperkeratosis, basal cell degeneration and a heavy, band-like
T-lymphocyte infiltrate in the papillary dermis, with affinity for the
epidermis (epidermotropism). The dermo-epidermal junction has
a ‘sawtooth’ appearance.
Clinical features
Lichen planus occurs in both sexes and at any age, although
usually between 30 and 60 years. It generally presents on the
distal limbs, most commonly on the flexural aspects of the wrists
and forearms (Fig. 29.38), and on the lower back. It is intensely
itchy and lesions are violaceous, shiny, flat-topped, polygonal
papules, with a characteristic fine lacy, white network on the
surface (Wickham’s striae). New lesions may appear at sites of
skin trauma (Kobner phenomenon) and the rash may become
generalised. Individual lesions may last for many months and can
become hypertrophic and modified by scratching, particularly
on the lower legs. The eruption usually remits over months but
can become chronic, particularly with hypertrophic disease.
Post-inflammatory pigmentary change is common, particularly
in darker skin types. Mucous membrane involvement occurs in
30-70% of patients, usually as a network of white, lacy striae on
the buccal mucosae (p. 1210) and tongue. These oral changes
are often asymptomatic and should be sought on examination.
Genital and other mucosal surfaces can also be affected (pp. 334
and 336). Nail involvement occurs in about 10% and can range
from longitudinal ridging to a destructive nail dystrophy, scarring
(pterygium) and nail loss (p. 1261). Scalp involvement usually
Fig. 29.38 Lichen planus. Violaceous papules on the flexural aspect of
forearm, arising at a site of minor linear trauma (Kobner phenomenon).
presents as an inflammatory scarring alopecia, often with tufting
of residual hairs. The classical presentation of lichen planus is
unmistakable, but less common atypical variants, which include
annular, atrophic, actinic, linear, bullous, follicular, pigmented and
ulcerative types, can be a diagnostic challenge.
Investigations
A skin biopsy should be performed if there is diagnostic doubt.
A careful drug history must be taken, as, although the classical
presentation of lichen planus is usually ‘idiopathic’, the main
differential is a drug-induced lichenoid reaction (see below).
Other differential diagnoses include psoriasis, pityriasis rosea,
pityriasis lichenoides chronica and secondary syphilis. Screening
for underlying disease, such as hepatitis, must be considered.
Management
The condition is usually self-limiting, although rarely it may
persist for years, particularly oral lichen planus. Treatment is
symptomatic and potent local glucocorticoids (topical, with
occlusion or by injection for hypertrophic disease, or as oral
rinse for oral involvement) may help the intense itch; short
courses of systemic glucocorticoids are sometimes required
for extensive disease. UVB, PUVA or UVA1 can be beneficial
and, for recalcitrant disease, retinoids or immunosuppressants,
such as ciclosporin or methotrexate, may be needed. A low but
significant risk of malignant transformation exists with persistent
oral and genital disease, so active treatment, surveillance and
smoking cessation are important.
Drug-induced lichenoid eruptions
Drug-induced lichenoid reactions that are clinically and
histologically difficult to distinguish from idiopathic lichen planus are
important to identify. The likely culprits are gold, quinine, proton
pump inhibitors, sulphonamides, penicillamine, antimalarials,
antituberculous drugs, thiazide diuretics, (3-blockers, angiotensin¬
converting enzyme (ACE) inhibitors, NSAIDs, sulphonylureas,
lithium and dyes in colour developers (see Box 29.35, p. 1266).
Graft-versus-host disease
In the acute stage of graft-versus-host disease (GVHD, p. 937),
there is a distinctive dermatitis associated with hepatitis. After
about 3 months, chronic GVHD can present with a lichenoid
eruption on the palms, soles, face and upper trunk. Progressive
sclerodermatous skin thickening, associated with pigmentary
changes, may lead to contractures and limited mobility.
Urticaria
Urticaria (‘hives’) is caused by localised dermal oedema
secondary to a temporary increase in capillary permeability. If
oedema involves subcutaneous or submucosal layers, the term
angioedema is used.
Clinical features
Acute urticaria may be associated with angioedema of the lips,
face, tongue, throat and, rarely, wheezing, abdominal pain,
headaches and even anaphylaxis (p. 75). Urticaria present for
less than 6 weeks is considered to be acute, and chronic if it
continues for more than 6 weeks. Individual weals (definition:
evanescent discrete areas of dermal oedema, often centrally
white due to masking of local blood supply by fluid; weals can
Urticaria • 1253
be papules, macules, patches and plaques - Fig. 29.39) last for
less than 24 hours; if they persist, urticarial vasculitis needs to
be considered. Clarification of the duration of urticaria can be
achieved by drawing around the weal and re-assessing 24 hours
later. History-taking should probe for possible causes, including
medications (Box 29.24). Physical triggers can also be assessed
in challenge testing, such as eliciting dermographism or pressure
testing. Enquiry about family history and medication, particularly
ACE inhibitors, is important in angioedema. Examination may
be unremarkable or weals may be evident (Fig. 29.39). The skin
should be stroked firmly with an orange stick in order to ascertain
whether dermographism is present or not.
Mast cell degranulation and release of histamine and other
vasoactive mediators is the basis of urticaria (Fig. 29.40). Chronic
spontaneous urticaria (previously called ‘chronic idiopathic’ or
‘chronic ordinary’ urticaria) is the most common chronic urticaria
and has an autoimmune pathogenesis in some cases.
Fig. 29.39 Urticaria. Erythema, reflecting dilated dermal vessels, and
oedema (with upper dermal oedema obscuring the erythema centrally) are
evident. Note the absence of epidermal changes.
Investigations
Investigations should be guided by the history and possible
causes but are often negative, particularly in acute urticaria.
Some or all of the following may be appropriate:
• Full blood count eosinophilia in parasitic infection or drug
cause.
• Erythrocyte sedimentation rate (ESR) or plasma viscosity:
elevated in vasculitis.
• Urea and electrolytes, thyroid and liver function tests, iron
studies: may reveal an underlying systemic disorder.
• Total IgE and specific IgE to possible allergens: shellfish,
peanut, house-dust mite. Particularly relevant if there is
angioedema.
• Autoantibodies, particularly antinuclear factor: positive in
systemic lupus erythematosus (SLE) and often positive in
urticarial vasculitis. Other autoimmune diseases, such as
i
Acute and chronic urticaria
• Autoimmune: due to antibodies that cross-link the IgE receptor on
mast cells
• Allergens in foods and inhalants
• Contact allergens: latex, animal saliva
• Drugs: see Box 29.35 (p. 1266)
• Physical stimuli: heat, cold, pressure, sun, sweat, water
• Infections: intestinal parasites, hepatitis
• Others: SLE, pregnancy, thyroid disease
• Idiopathic: chronic spontaneous urticaria and angioedema
Urticarial vasculitis
• Hepatitis B, SLE, idiopathic
(IgE = immunoglobulin E; SLE = systemic lupus erythematosus)
29.24 Causes of urticaria
Morphine
Codeine
Benzoic acid
Key
□=□ High-affinity IgE receptor (FceRI)
^ Antigen
r
x
igE
Autoantibody to FceRI and IgE
Histamine
Inflammatory mediators
• prostaglandins
• leukotrienes
• chemotactic cytokines
for eosinophils and
neutrophils
Heparin
5-hydroxytryptamine
Proteases
Fig. 29.40 Pathogenesis of urticaria. Mast cell degranulation occurs in a variety of ways. (1) Type I hypersensitivity causes degranulation. (2)
Spontaneous mast cell degranulation in chronic urticaria. (3) Chemical mast cell degranulation. (4) Autoimmunity, with IgE antibodies directed against IgE
receptors or IgE itself. Histamine and the leukotrienes are especially relevant mediators in urticaria. Heparin release is probably not a major factor in
urticaria but plays a role in the osteoporosis that can occur in systemic mastocytosis. (IgE = immunoglobulin E; NSAID = non-steroidal anti-inflammatory
drug)
1254 • DERMATOLOGY
rheumatoid arthritis and autoimmune hepatitis or thyroid
disease, may be associated.
• Complement C3 and C4 levels : if these are low due to
complement consumption, C1 esterase inhibitor activity
should be measured.
• Infection screen: hepatitis screen and HIV may be
indicated.
• Skin biopsy: if urticarial vasculitis is suspected.
• Challenge tests: to confirm physical urticarias, such as
dermographism, pressure, heat, cold.
Management
Removal or treatment of any trigger is essential, although this
may not be identified in the majority of cases. Urticaria may be
precipitated by aspirin, NSAIDs, codeine and opioids, and it is
advisable to suggest alternatives such as paracetamol. In chronic
urticaria, non-sedating antihistamines, such as fexofenadine,
loratadine or cetirizine, are usually beneficial. If there is lack of
response after 2 weeks, an alternative non-sedating antihistamine
should be used and an H2-blocker, such as cimetidine or
ranitidine, can be added. Mast cell stabilisers or leukotriene
receptor antagonists, such as montelukast, can be used for
more recalcitrant disease. For chronic urticaria, narrowband
UVB phototherapy is valuable and has proven efficacy. Systemic
glucocorticoids are widely prescribed for urticaria but are not
indicated in the majority of cases. If systemic glucocorticoids
are used, efficacy may be seen only at relatively high doses and
they are appropriate only for occasional short courses in the
acute setting, usually in association with angioedema. Patients
with a history of life-threatening anaphylaxis, as in peanut or
wasp sting allergy, should carry a self-administered adrenaline
(epinephrine) injection kit. The management of anaphylaxis and
hereditary angioedema is discussed on pages 76 and 87. The
IgE monoclonal antibody omalizumab may be effective in patients
with severe recalcitrant urticaria.
Bullous diseases
Blistering can occur at any level in the skin and there are a
variety of different presentations, depending on the underlying
defect and level of involvement. Knowledge of the molecular
basis of many blistering disorders has advanced considerably
through understanding of the basic processes of cell adhesion
and studies of rare genetic blistering disorders, particularly
epidermolysis bullosa (Box 29.25). This section concentrates on
primary blistering skin diseases.
29.25 Classification of epidermolysis bullosa
Type
Mode of
inheritance
Level of
blister
Abnormality
Simple
Autosomal
dominant
Epidermal
basal cell
Keratins 5
and 14
Junctional
Autosomal
recessive
Lamina lucida
Laminin-5 and
a6(34 integrin
Dystrophic
Autosomal
dominant and
recessive
Dermis below
lamina densa
Collagen VII
*See Figure 29.1 (p. 1213).
Toxic epidermal necrolysis
Toxic epidermal necrolysis (TEN) is a medical emergency, as the
extensive mucocutaneous blistering is associated with a high
mortality rate. It is usually drug-induced (see Box 29.35, p. 1266),
with anticonvulsants, sulphonamides, sulphonylureas, NSAIDs,
allopurinol and antiretroviral therapy often implicated. Usually
1-4 weeks after drug commencement, the patient becomes
systemically unwell and often pyrexial. Erythema and blistering
develop, initially on the trunk but rapidly involving all skin; an
early warning sign is cutaneous pain. Sheets of blisters coalesce
and denude, and the underlying skin is painful and erythematous
(Fig. 29.41). Gentle lateral pressure on stroking the skin results
in epidermal detachment (Nikolsky sign), demonstrating the
severity of skin fragility. Mucous membrane involvement and
blistering are usual. Blistering of skin and mucosae may be
haemorrhagic. A disease severity score (Box 29.26) is used to
predict outcome. The main differential diagnosis is staphylococcal
scalded skin syndrome (p. 1236), although the diagnosis is
usually obvious in an adult patient with a culprit drug. There is
often overlap with Stevens-Johnson syndrome and targetoid
lesions, especially on palms and soles, may be evident. Skin
Fig. 29.41 Toxic epidermal necrolysis. Note the extensive erythema,
oedema and epidermal loss secondary to carbamazepine.
29.26 Disease severity score for toxic epidermal
necrolysis: SCORTEN
Factor
• Age >40 years
• Heart rate >120 beats/min
• Cancer or haematological malignancy
• Involved body surface area >10%
• Blood urea >10 mmol/L (28 mg/dL)
• Serum bicarbonate <20 mmol/L
• Blood glucose >14 mmol/L (252 mg/dL)
Mortality rates
• 0-1 factor present = 3%
• 2 factors = 1 2%
• 3 factors = 35%
• 4 factors = 58%
• > 5 factors = 90%
From Bastuji-Garin S, Fouchard N, Bertocchi M, et al. SCORTEN: a severity-of-
iiiness score for toxic epidermal necrolysis. J Invest Dermatol 2000;
115:149-153.
Bullous diseases • 1255
snip may allow early diagnosis. If there is diagnostic doubt, then
full-thickness skin biopsy should be undertaken for histology and
direct immunofluorescence in order to exclude immunobullous
or other diagnoses.
Identification and discontinuation of the causative drug are
essential. Sepsis and multi-organ failure are major risks. Intensive
care in a dedicated dermatology ward or intensive care or burns
unit is of paramount importance. Treatment is supportive, with
regular sterile dressings and emollients, careful attention to
fluid balance and treatment of infection if it develops. Urethral
and ocular involvement is common and must be looked for
and treated symptomatically. Ocular and urethral scarring can
be problematic in survivors. There is no conclusive evidence
that intravenous immunoglobulins, systemic glucocorticoids or
ciclosporin improve outcomes and survival.
Immunobullous diseases
There are various subtypes of immunobullous disease that affect
patients of different ages and have clinical characteristics (Box
29.27). The key investigation is an elliptical biopsy taken from
the edge of a recent blister (Box 29.28). The sample is halved:
one half is put in formalin for subsequent histology, while the
other is sent fresh for direct immunofluorescence. Serum should
also be sent for indirect immunofluorescence in suspected
immunobullous disease (p. 1215).
Bullous pemphigoid
Bullous pemphigoid (BP) is the most common immunobullous
disease and occurs worldwide. It is a disease of the elderly,
with an average age of onset of 65 years; males and females
are equally affected.
Pathogenesis
The disease is caused by autoantibodies (BP-230 and BP-180)
directed against the hemi-desmosomal BP antigens, BPAg-1
(intracellular) and BPAg-2 (transmembranous type XVII collagen),
respectively. Antibody-antigen binding initiates complement
activation and inflammation, with hemi-desmosomal damage
and subepidermal blistering.
Clinical features
There is often a lengthy prodrome of an itchy, urticated,
erythematous rash prior to the development of tense bullae
(Fig. 29.42A). Milia (definition: small epidermal keratin cysts)
may develop due to basement membrane disruption. Mucosal
involvement is uncommon.
29.27 Age of onset in immunobullous skin disorders
Disease
Age
Pemphigus vulgaris
40-60 years
Pemphigus foliaceus
Any age (endemic form in
parts of Brazil and South
Africa, from teenage years on)
Bullous pemphigoid
Sixties and over
Dermatitis herpetiformis
Young, associated with coeliac
disease
Linear IgA disease
Any age
Pemphigoid gestationis
Pregnant females
Epidermolysis bullosa acquisita
Any age
Bullous lupus erythematosus
Young black females
29.28 Clinical and investigation findings in the immunobullous disorders
Disease
Site of
blisters
Nature of blisters
Mucous
membrane
involvement
Antigen
Circulating antibody
(indirect IF)
Fixed antibody
(direct IF)
Pemphigus
vulgaris
Trunk, head
Flaccid, fragile, many
erosions
100%
Desmoglein-1 and 3
(120 kD)
igG
IgG, C3 intercellular
(epidermal)
Pemphigus
foliaceus
Trunk
Often not present,
multiple erosions,
may mimic dermatitis
No
Desmoglein-1
igG
IgG, C3 intercellular
(epidermal)
Bullous
pemphigoid
Trunk, flexures
and limbs
Tense, milia as
blisters resolve
Occasional
BP-230 and 180
IgG (70%)
IgG, C3 at BMZ
Dermatitis
herpetiformis
Elbows, lower
back, buttocks
Excoriated and often
not present
No
Unknown
Anti-endomysial and
tissue transglutaminase
Granular IgA in
papillary dermis
Linear IgA
disease
Widespread
Tense, often annular
configuration, ‘string
of beads’
Frequent
Unknown
50% have low titres of
circulating antibody
Linear IgA at BMZ
Pemphigoid
gestationis
Periumbilical
and limbs
Tense, milia as
blisters resolve
Rare
Collagen XVII (part of
hemi-desmosome,
BP-180)
Circulating antibodies
to BP-1 80 (type XVII
collagen) (and BP-230)
C3 at BMZ
Epidermolysis
bullosa acquisita
Widespread
Tense, scarring, milia
Common
(50%)
Type VII collagen
IgG (anti-type VII
collagen)
IgG at BMZ
Bullous lupus
erythematosus
Widespread
Tense
Rare
Type VII collagen
Anti-type VII collagen
IgG, IgA, IgM at BMZ
(BMZ = basement membrane zone; IF = immunofluorescence; Ig = immunoglobulin)
29
1256 • DERMATOLOGY
Fig. 29.42 Bullous pemphigoid. [A] Large, tense, unilocular blisters.
[§] Immunofluorescence on salt-split skin, showing a subepidermal blister
and linear IgG and C3 deposition at the basement membrane zone.
Investigations
The diagnosis can be made by skin biopsy, which shows
subepidermal blistering with an eosinophil-rich inflammatory
infiltrate. Direct immunofluorescence demonstrates the
presence of IgG and C3 at the basement membrane (Fig.
29.42B). Indirect immunofluorescence may show positive
titres of circulating anti-epidermal antibodies. Distinction from
epidermolysis bullosa acquisita requires immunofluorescence
studies using the patient’s serum on salt-split skin. In BP, the
immunoreactants localise to the epidermal side (hemi-desmosome)
of split skin, whereas in epidermolysis bullosa acquisita they
localise to the base of the split (type VII collagen/anchoring
fibrils).
Management
Very potent topical glucocorticoids are effective and may be
sufficient in frail elderly patients; they need to be applied to
all sites, however, and not just lesional skin. Tetracyclines,
such as doxycycline, have an important role and may limit the
use of systemic glucocorticoids. However, most patients with
extensive disease require systemic glucocorticoids (0.75 mg/
kg/day or less), often combined with immunosuppressants as
glucocorticoid-sparing agents. In severe refractory disease, other
therapies, such as intravenous immunoglobulin or rituximab, are
sometimes used but are of unproven efficacy. The condition
often burns out over a few years.
Pemphigus
Pemphigus is less common than BP and patients tend to be
younger.
Pathogenesis
The cause is IgGI and lgG4 autoantibodies, directed against
desmogleins-1 and 3, resulting in intra-epidermal blistering. The
syndrome may occur spontaneously or be secondary to drugs
such as penicillamine or captopril and underlying malignancy
(paraneoplastic pemphigus). Pemphigus foliaceus is a very
superficial form, in which antibodies are directed against
desmoglein-1 only and affect just the most superficial epidermis.
Ciinicai features
Skin and mucosae are usually involved, although disease may
be restricted to mucosae only, which may be severely affected.
Due to the higher level of split within the epidermis, the blisters
are flaccid, easily ruptured and often not seen intact. Erosions
are common and the Nikolsky sign is positive. The trunk is
usually affected. The condition is associated with significant
morbidity and mortality.
Investigations
The diagnosis can be made by skin biopsy, which shows
intra-epidermal blistering and acantholysis, with positive direct
immunofluorescence for IgG (usually IgGI or lgG4) and C3 at the
periphery of keratinocytes, giving a ‘chicken wire’ appearance
within the epidermis. The titres of circulating epidermal
autoantibodies can also be used to monitor disease activity.
Investigations should screen for associated autoimmune disease
or malignancy if paraneoplastic pemphigus is suspected.
Management
Pemphigus is more difficult to treat than BP and high-dose
systemic glucocorticoids such as prednisolone (0.5-1 .0 mg/kg/
day) are usually required. Azathioprine and cyclophosphamide
are most often used as glucocorticoid-sparing agents but a
range of other immunosuppressants may be considered for
severe recalcitrant disease, including methotrexate, ciclosporin,
mycophenolate mofetil, intravenous immunoglobulins, plasma
exchange, extracorporeal photopheresis and rituximab. Often,
long-term treatment is required to prevent relapse.
Dermatitis herpetiformis
Dermatitis herpetiformis (DH) is an autoimmune blistering disorder
that is strongly associated with coeliac disease (CD). While fewer
than 10% of individuals with CD develop DH, almost all patients
with DH have evidence of partial villous atrophy on intestinal
biopsy, even if they have no gastrointestinal symptoms (p. 806).
It is unclear why some CD patients develop DH and others do
not. Although DH is a bullous disease, intact vesicles and blisters
are seldom seen, as the condition is so pruritic that excoriations
on extensor surfaces of arms, knees, buttocks, shoulders and
scalp may be the only signs.
The diagnosis can be made by skin biopsy, which shows
subepidermal vesiculation in the dermal papillae and a neutrophil-
and eosinophil-rich infiltrate. Direct immunofluorescence shows
granular IgA in the papillary dermis. Anti-endomysial antibodies
and tissue transglutaminase should be assessed and jejunal
biopsy undertaken if indicated. The condition usually responds
to a gluten-free diet but, if not, dapsone can also be used.
|J.inear IgA disease
This occurs in children (chronic bullous disease of childhood) and
adults, and is usually self-limiting, although it can be active for a few
years. Drugs, notably vancomycin, can be a secondary cause. Blisters
Pigmentation disorders • 1257
can arise on erythematous, urticated or otherwise normal-looking
skin and often form an annular configuration at the edge of the
lesion: ‘clusters of jewels’ (herpetiform) and ‘string of beads’ (annular/
polycyclic). Mucosal involvement is common and ophthalmology input
important, as corneal scarring is a risk with longstanding disease.
Linear IgA is seen at the basement membrane on direct
immunofluorescence and localises to either roof or floor of salt-split
skin. Dapsone, sulfapyridine, prednisolone, colchicine or intravenous
immunoglobulin may be effective.
Epidermolysis bullosa acquisita
This chronic blistering disease affects skin and mucosae, and
scarring, hair loss and nail dystrophy may be problematic. Blisters
often follow trauma and milia develop. It can be very difficult
to distinguish from other immunobullous diseases, such as
bullous pemphigoid. It is caused by an IgG antibody to type VII
collagen, which provokes subepidermal blistering and a mixed
inflammatory infiltrate, although the latter may not be prominent.
Direct immunofluorescence on perilesional skin shows IgG
and C3 at the dermo-epidermal junction and pattern analysis
may be helpful in distinction from bullous pemphigoid. Indirect
immunofluorescence microscopy on salt-split normal human
skin typically shows IgG and IgA in the floor of the artificially
induced blister, whereas in BP antibody localisation would
be to the roof of the blister. Epidermolysis bullosa acquisita
is very difficult to treat, as it often does not respond well to
immunosuppressants. Mainstays of treatment include systemic
glucocorticoids in combination with dapsone or colchicine. Other
immunosuppressive approaches may be required and include
ciclosporin, azathioprine, immunoglobulins, plasmapheresis and
rituximab. The condition may be associated with inflammatory
bowel disease, rheumatoid arthritis, multiple myeloma and
lymphoma, and thus associated comorbidities should be sought.
Porphyria cutanea tarda and pseudoporphyria
These conditions may also cause blistering (see Boxes 29.9
and 29.35, pp. 1221 and 1266). Porphyria is discussed in more
detail on page 378.
Pigmentation disorders
Decreased pigmentation
Disorders causing hypopigmentation and/or depigmentation
include:
• vitiligo
• albinism
• pityriasis alba: depigmented areas on the face, particularly
in children, with or without scale and usually considered to
be eczematous
• pityriasis versicolor (p. 1240): hypopigmentation or, less
commonly, hyperpigmentation can occur
• idiopathic guttate hypomelanosis: multiple small areas of
depigmentation arising in chronically sun-exposed skin
• rarely, phenylketonuria (p. 369) and hypopituitarism.
| Vitiligo
Vitiligo is an acquired condition affecting 1 % of the population
worldwide. Focal loss of melanocytes results in the development
of patches of hypopigmentation. A positive family history of
vitiligo is relatively common in those with extensive disease, and
this type is also associated with other autoimmune diseases.
Trauma and sunburn may (through the Kobner phenomenon)
precipitate the appearance of vitiligo. It is thought to be the result
of cell-mediated autoimmune destruction of melanocytes but
why some areas are targeted and others are spared is unclear.
Clinical features
Generalised vitiligo is often symmetrical and involves hands,
wrists, feet, knees and neck, as well as areas around body orifices
(Fig. 29.43). The hair of the scalp, beard, eyebrows and lashes
may also depigment. Segmental vitiligo is restricted to one part
of the body but not necessarily a dermatome. The patches of
depigmentation are sharply defined, and in Caucasians may be
surrounded by hyperpigmentation. Spotty perifollicular pigment
may be seen within the depigmentation and is often the first sign
of repigmentation. There is no history or evidence of inflammation
within the patches, which may be helpful in distinguishing vitiligo
from post-inflammatory hypopigmentation. Sensation in the
depigmented patches is normal (unlike in tuberculoid leprosy,
p. 267). Wood’s light examination enhances the contrast between
pigmented and non-pigmented skin. The course is unpredictable
but most patches remain static or enlarge; a few repigment
spontaneously.
Management
Protecting the patches from excessive sun exposure with clothing
or sunscreen may be helpful to avoid sunburn. Camouflage
cosmetics may be beneficial, particularly in those with dark skin.
In fair skin, photoprotection and cosmetic cover may be all that is
required. Very potent or potent topical glucocorticoids have limited
efficacy with respect to repigmentation. Topical pimecrolimus
or tacrolimus may also have a role as a glucocorticoid-sparing
agent. Phototherapy with narrowband UVB or PUVA can also
be used. Narrowband UVB is the most effective repigmentary
treatment available for generalised vitiligo, but even very prolonged
courses often do not produce a satisfactory outcome. The
absence of leucotrichia (white hairs in the area of vitiligo) and
the presence of a trichrome pattern (three colours - normal
skin colour, hypopigmentation and depigmentation) are good
prognostic features. Vitiligo on the face, trunk and proximal
limbs is more likely to respond than that on hands and feet.
Fig. 29.43 Vitiligo. Symmetrical localised patches of depigmented skin.
1258 • DERMATOLOGY
Exceptionally, depigmentation of normal non-lesional skin or a
surgical approach with autologous melanocyte transfer, using
a range of techniques including split-skin grafts and blister roof
grafts, is sometimes used on dermabraded recipient skin in
specific severe cases.
The impact of vitiligo differs markedly between populations. In
the Indian subcontinent, the effects are more readily discernible
than in pale-skinned individuals in northern Europe. Depigmentation
is also seen in leprosy, which means that individuals with vitiligo
are often stigmatised. The emotional impact of vitiligo may be
immense; psychological support is essential and is important in
conveying realistic expectations of possible treatment approaches.
Oculocutaneous albinism
Albinism results from a range of genetic abnormalities that lead to
reduced melanin biosynthesis in the skin and eyes; the number of
melanocytes is normal (in contrast to vitiligo). Albinism is usually
inherited as an autosomal recessive trait and there are several
different types and presentations.
Type 1 albinism is due to a defect in the tyrosinase gene, whose
product is rate-limiting in the production of melanin. Affected
individuals have an almost complete absence of pigment in the
skin and hair at birth, with consequent pale skin and white hair,
and failure of melanin production in the iris and retina. Patients
have photophobia, poor vision not correctable with refraction,
rotatory nystagmus, and an alternating strabismus associated with
abnormalities in the decussation of nerve fibres in the optic tract.
A second form of albinism is due to a defect in the P gene,
which encodes an ion channel protein in the melanosome.
Patients may have gross reduction of melanin in the skin and in
the eyes, but may be more mildly affected than type 1 albinos.
Establishing the subtype of albinism requires genetic analysis,
as there is considerable phenotypic heterogeneity.
Oculocutaneous albinos are at grossly increased risk of sunburn
and skin cancer. In equatorial regions, many die from squamous
cell carcinoma or, more rarely, melanoma in early adult life.
Interestingly, they may develop pigmented melanocytic naevi
and freckle in response to sun exposure.
Management
Strict photoprotection (p. 1221), with sun avoidance (including
occupational exposure), clothing, hats and sunscreens, is
important. Early diagnosis and treatment of skin tumours is
essential.
Increased pigmentation
• Diffuse hyperpigmentation: most commonly due to
hypermelanosis but other pigments may be deposited in
the skin, such as orange discoloration with carotenaemia
and bronze with haemochromatosis (p. 895).
• Endocrine pigmentation : may occur in several conditions.
Melasma (chloasma) describes discrete patches of facial
pigmentation that occur in pregnancy and in some women
taking oral contraceptives. The mechanism for this
localised increased hormonal sensitivity is unknown.
Diffuse pigmentation, sometimes worse in the skin creases
and mucosae, may be a feature of Addison’s disease
(p. 671), Cushing’s syndrome (p. 666), Nelson’s syndrome
(p. 669) and chronic renal failure due to increased
levels of pituitary melanotrophic peptides, including
adrenocorticotrophic hormone (ACTH; p. 669).
29.29 Drug-induced pigmentation
Drug
Appearance
Amiodarone
Photo-exposed sites, slate-grey
Arsenic
Diffuse bronze pigmentation
Raindrop depigmentation
Bleomycin
Usually flexural, brown
Busulfan
Diffuse brown
Chloroquine
Photo-exposed sites, blue-grey
Clofazimine
Red
Mepacrine
Yellow
Minocycline
Temples, shins, gingiva, sclera, scar sites,
slate-grey
Phenothiazines
Photo-exposed sites, slate-grey
Psoralens
Photo-exposed sites, brown
• Photo-exposed site hyperpigmentation : occurs in some of
the porphyrias but can also be drug-induced.
• Drug-induced pigmentation (Box 29.29): may be diffuse or
localised. It is not always due to hypermelanosis but
sometimes is caused by deposition of the drug or a
metabolite.
• Focal hypermelanosis: seen in lesions such as freckles
and lentigines, characterised by focal areas of increased
pigmentation.
Establishing the cause is important. Photoprotection may
minimise the risk of increasing pigmentation. Topical hydroquinone
preparations can be used for skin lightening in some types of
hyperpigmentation, although caution is required, particularly in
darker skin types.
Hair disorders
These can be subdivided into disorders that cause loss of hair
(alopecia) or excessive hair growth (hypertrichosis and hirsutism).
Alopecia
Alopecia is characterised by loss of hair. It can be further
subdivided into localised and diffuse, and into scarring and
non-scarring subtypes (Box 29.30).
Pathogenesis
Alopecia can be observed in association with inflammatory
disorders that cause scarring (lichen planus, discoid lupus)
and others that do not cause scarring (tinea capitis, psoriasis,
seborrhoeic eczema). These conditions are discussed elsewhere.
Alopecia areata has an autoimmune basis and there is a strong
genetic component, with a family history in approximately 20% of
cases. In addition to atopy, it is associated with other autoimmune
diseases, particularly thyroid disease, and with Down’s syndrome.
The cause of androgenetic alopecia is unclear but likely to be
multifactorial, with genetic, hormonal and end-organ receptor
sensitivity to the factors implicated.
Clinical features
Alopecia areata
This usually presents with well-defined, localised, non¬
inflammatory, non-scarring patches of alopecia, usually on the
Hair disorders • 1259
i
29.30 Classification and causes of alopecia
Localised
Diffuse
Non-scarring
Tinea capitis
Androgenetic alopecia
Alopecia areata
Telogen effluvium
Androgenetic alopecia
Hypothyroidism
Traumatic (trichotillomania,
Hyperthyroidism
traction, cosmetic)
Hypopituitarism
Syphilis
Diabetes mellitus
HIV disease
Nutritional (especially iron) deficiency
Liver disease
Post-partum
Alopecia areata
Syphilis
Drug-induced: chemotherapy,
retinoids
Scarring
Discoid lupus erythematosus
Discoid lupus erythematosus
Lichen planopilaris
Radiotherapy
Herpes zoster
Folliculitis decalvans
Pseudopelade
Lichen planopilaris
Tinea capitis/kerion
Morphoea (en coup de sabre)
Idiopathic
Developmental defects
Fig. 29.44 Alopecia areata. The relatively extensive involvement and
encroachment on posterior hairline are poor prognostic features.
scalp (Fig. 29.44). Pathognomonic ‘exclamation mark’ hairs are
seen (broken hairs, tapering towards the scalp) during active
hair loss. A diffuse pattern can uncommonly occur on the scalp.
Eyebrows, eyelashes, beard and body hair can be affected.
Alopecia totalis describes complete loss of scalp hair, and
alopecia universalis is complete loss of all hair. Nail pitting may
occur (p. 1261). Spontaneous regrowth is usual for small patches
of alopecia but the prognosis is less good for larger patches, more
extensive involvement, early onset and an association with atopy.
Androgenetic alopecia
Male-pattern baldness is physiological in men over 20 years old,
although it can also occur in teenagers. It is also found in women,
particularly post-menopausal ones. Characteristically, this involves
bitemporal recession initially and subsequent involvement of the
crown (‘male pattern’), although it is often diffuse in women.
Investigations
Important investigations include full blood count, renal and liver
function tests, iron studies, thyroid function, autoantibody screen
and syphilis serology, as several systemic diseases, particularly
iron deficiency and hypothyroidism, can cause diffuse non-scarring
alopecia. Hair pull tests may help to establish the ratio of anagen
to telogen hairs but require expertise for interpretation. Scrapings
and pluckings should be sent for mycology if there is localised
inflammation. Scalp biopsy and direct immunofluorescence of
scarring alopecia may confirm a diagnosis of lichen planus or
discoid lupus erythematosus but expert interpretation is needed.
Management
Any underlying condition, such as iron deficiency, should be
treated and may result in clinical improvement. Alopecia can
have a major impact on quality of life and psychological support
is usually required. It is particularly important to establish realistic
expectations.
Hair may spontaneously regrow in alopecia areata and it
may be appropriate to offer no active intervention as, while
some treatments may induce some hair regrowth, there is no
evidence that any treatment fundamentally alters the course of the
disease. There may be some response to topical or intralesional
glucocorticoids. PUVA or immunotherapy with diphencyprone
may be effective, with evidence of hair regrowth, but there is a
risk of relapse on discontinuation of treatment. Short courses of
systemic glucocorticoids are occasionally used in an attempt to
limit acutely progressive extensive alopecia areata but should not
be used in the long term; the risk of relapse on discontinuation is
high. Ongoing trials of Janus kinase (JAK) inhibitors may provide
future hope for patients with this difficult disease.
Some males with androgenetic alopecia may be helped by
systemic finasteride. Topical minoxidil can be used in males and
females with androgenetic alopecia but, if an effect is obtained,
treatment must be continued and is expensive. In females,
anti-androgen therapy, such as cyproterone acetate, can be
used. Wigs are often appropriate for extensive alopecia. Scalp
surgery and autologous hair transplants are expensive but can
be used for androgenetic alopecia.
Hypertrichosis
Hypertrichosis is a generalised or localised increase in hair and
may be congenital or acquired. It can be primary or secondary:
for example, to drugs such as ciclosporin, minoxidil or diazoxide,
malignancy or eating disorders. Laser therapy or eflornithine,
which inhibits ornithine decarboxylase and arrests hair growth
while it is being used, may be helpful. When the hypertrichosis
follows a male pattern, it is called hirsutism.
Hirsutism
Hirsutism is the growth of terminal hair in a male pattern in a
female (p. 657). The cause of most cases is unknown and, while
it may occur in hyperandrogenism, Cushing’s syndrome and
polycystic ovary syndrome, only a small minority of patients have
1260 • DERMATOLOGY
a demonstrable hormonal abnormality. Psychological distress
is often significant and oral contraceptives containing an anti¬
androgen such as cyproterone acetate, laser therapy or topical
eflornithine may be beneficial.
Nail disorders
The nails can be affected by both local and systemic disease.
The nail apparatus consists of the nail matrix and the nail plate,
which arises from the matrix and lies on the nail bed (Fig. 29.45).
The cells of the matrix and, to a lesser extent the bed, produce
the keratinous plate.
Important information may be obtained from nail-fold
examination, including dilated capillaries and ragged cuticles in
connective tissue disease (Fig. 29.46) and the boggy inflammation
of paronychia. The latter commonly occurs chronically in individuals
undertaking wet work, in those with diabetes or poor peripheral
circulation, and subsequent to increased cosmetic nail procedures
and vigorous manicuring.
Normal variants
Longitudinal ridging and beading of the nail plate occur with age.
White transverse patches (striate leuconychia) are often caused
by airspaces within the plate.
Nail trauma
• Nail biting/picking is a very common habit. Repetitive
proximal nail-fold trauma (often involving the thumb
nail) results in transverse ridging and central furrowing
of the nail.
• Chronic trauma from poorly-fitting shoes and sport can
cause thickening and disordered growth of the nail
(onychogryphosis) and subsequent ingrowing toenails.
• Splinter haemorrhages are fine, linear, dark brown
longitudinal streaks in the plate (see Fig. 16.89, p. 529).
They are usually caused by trauma, especially if distal.
Uncommonly, they can occur in nail psoriasis and are also
a hallmark of infective endocarditis.
• Subungual haematoma is red, purple or grey-brown
discoloration of the nail plate, usually of the big toe (Fig.
29.47). These haematomas are usually due to trauma,
although a history of this may not be clear. The main
Proximal nail fold Nail plate Hyponychium
growth.
differential is subungual melanoma, although rapid onset,
lack of nail-fold involvement and proximal clearing as the
nail grows are clues to the diagnosis of haematoma. If
there is diagnostic doubt, a biopsy may be needed.
|Nail involvement in skin diseases
• Dermatophyte infection/onychomycosis: this is described
on page 1240.
• Psoriasis: nail involvement is common (see Fig. 29.35B,
p. 1249).
Fig. 29.46 Dermatomyositis. [A] Photo-aggravation. [j| Note the
prominent periungual involvement. Erythema, dilated and tortuous
capillaries in the proximal nail fold, and ragged cuticles are features of
connective tissue disease.
Fig. 29.47 Subungual haematoma.
Skin disease in general medicine • 1261
• Eczema : nails may be shiny due to rubbing skin. Fine
pitting can occur. If there is periungual eczema, the nail
may become dystrophic, with thickening and transverse
ridging. Paronychia is common.
• Lichen planus : there may be longitudinal ridging and
thinning of the nail, giving a sandpaper texture
(trachyonychia), erythematous streaks (erythronychia),
subungual hyperkeratosis, pigmentation and, in severe
cases, pterygium (splitting of nail due to central fibrosis
and scarring, giving a winged appearance) and a
destructive nail dystrophy.
• Alopecia areata: nail-plate pitting and trachyonychia can
occur.
Nail involvement in systemic disease
The nails may be affected in many systemic diseases and
important examples are detailed below:
• Beau’s lines: horizontal ridges/indentations in nail plate
occur simultaneously in all nails (Fig. 29.48B). They typically
follow a systemic illness and are thought to be due to
temporary growth arrest of cells in the nail matrix; they
subsequently migrate out as the nail grows. Normal nail
growth is approximately 0.1 mm/day for fingers and
0.05 mm/day for toes, so the timing of the systemic upset
can usually be estimated by the position of the Beau’s lines.
• Koilonychia: this concave or spoon-shaped nail-plate
deformity is caused by iron deficiency (Fig. 29.48C).
• Clubbing: in the early stages, the angle between the
proximal nail and nail fold is lost. In its more established
form, there may be swelling of the distal digits (Figs
29.48D and E) or toes. Causes include bronchogenic
carcinoma, asbestosis (especially with mesothelioma),
suppurative or fibrosing lung disease, cyanotic congenital
heart disease, infective endocarditis, inflammatory bowel
disease, biliary cirrhosis and thyrotoxicosis; rarely, clubbing
can be familial or idiopathic.
• Nail discoloration: whitening may occur in
hypoalbuminaemia. ‘Half-and-half nails (white proximally
and red/brown distally) may be found in renal failure.
Antimalarials and some other drugs occasionally
discolour nails.
Nail involvement in congenital disease
Nails can be affected in congenital diseases, such as pachyonychia
congenita, a rare, usually autosomal dominant, condition caused
by mutations in differentiation-specific keratin genes 6A, 6B, 16
and 17. This results in palmoplantar keratoderma and gross nail
discoloration and thickening, due to subungual hyperkeratosis,
from birth.
Fig. 29.48 The nail in systemic disease. [A] Normal nail. [§] Beau’s
line. [C] Koilonychia. [D] and [E] Digital clubbing.
Skin disease in general medicine
Many skin conditions present to other medical specialties. These
are listed in Box 29.31 and the most common ones that are not
discussed elsewhere are detailed below.
Conditions involving cutaneous vasculature
Vasculitis
Vasculitic involvement of the skin usually presents as palpable
purpura (see Fig. 24.53, p. 1042). The diagnosis is confirmed
by skin biopsy, along with histology and immunofluorescence
examination. Underlying causes and their treatment are discussed
on page 1040.
Pyoderma gangrenosum
The initial lesion of pyoderma gangrenosum (PG) is usually a
painful, tender, inflamed nodule or pustule, which breaks down
centrally and rapidly progresses to an ulcer with an indurated,
undermined purplish or pustular edge (Fig. 29.49). Lesions may
be single or multiple and are classified as ulcerative, pustular,
bullous or vegetative. PG usually occurs in adults and, although
it may occur in isolation, is usually associated with underlying
disease, particularly inflammatory bowel disease, inflammatory
arthritis, blood dyscrasias, immunodeficiencies and HIV infection.
Investigation should be made with these associations in mind. The
diagnosis is largely clinical, as histology is not specific. Analgesia,
treatment of secondary bacterial infection and supportive
29.31 Skin problems in general medicine
Primary skin problems
• Cellulitis • Leg ulcers
• Vasculitis • Pressure sores
Skin involvement in multisystem disease
• Genetic: neurofibromatosis, • Porphyria
tuberous sclerosis • Sarcoidosis
• Xanthomas • Systemic lupus erythematosus
• Amyloidosis • Systemic sclerosis
Non-specific and variable skin reactions to systemic disease
• Urticaria • Pyoderma gangrenosum
• Erythema multiforme • Sweet’s syndrome
• Annular erythemas • Generalised pruritus
• Erythema nodosum
Skin conditions associated with malignancy
• Dermatomyositis • Acanthosis nigricans
• Generalised pruritus • Superficial thrombophlebitis
Skin problems associated with specific medical disorders
• Liver: generalised pruritus, pigmentation, spider naevi, palmar
erythema, nail clubbing
• Kidney: generalised pruritus, uraemic frost, pigmentation
• Diabetes mellitus: necrobiosis lipoidica, diabetic dermopathy
• Cutaneous Crohn’s disease
Skin problems secondary to treatment of systemic disease
• Drug eruptions
Miscellaneous
• Granuloma annulare • Morphoea
1262 • DERMATOLOGY
Fig. 29.49 Pyoderma gangrenosum. This young patient had Crohn’s
disease. Note the cribriform pattern of re-epithelialisation, which is
characteristic of this condition.
dressings are important. Systemic treatment with glucocorticoids,
dapsone, ciclosporin or other immunosuppressants is often
required. Tetracyclines may be added for their anti-inflammatory
effects. Treatment with TNF-a inhibitors and ustekinumab may
be effective in severe recalcitrant PG. Once healing has taken
place, recurrences are typically only intermittent.
Other neutrophilic dermatoses
These include Sweet’s acute febrile neutrophilic dermatosis
and the neutrophilic dermatosis of rheumatoid disease, which
are characterised by intense inflammation, mainly consisting of
neutrophils, around dermal blood vessels. There can be damage
to vessels (‘vasculopathy’) but usually no frank vasculitis.
Pressure sores
Localised, prolonged, pressure-induced ischaemia can lead to the
development of pressure sores, which can occur in up to 30%
of the hospitalised elderly. They are associated with considerable
morbidity, mortality and expense to health services. The main risk
factors are immobility, poor nutrition, local tissue hypoxia - for
example, with anaemia, peripheral vascular disease, diabetes,
sepsis and skin atrophy - or barrier impairment, such as in eczema.
A localised area of erythema develops at sites of bony
prominences (particularly sacrum, greater trochanter, ischial
and calcaneal tuberosities, and lateral malleolus). This progresses
to a blister and then erosion, which will develop into a deep
necrotic ulcer, usually colonised by Pseudomonas aeruginosa
if pressure is not alleviated.
Prevention is key and involves identification of at-risk patients
and regular repositioning and use of pressure-relieving mattresses.
Predisposing factors, such as anaemia and poor nutrition, should
be corrected. Once established, significant infection must be
treated and necrotic tissue debrided. Dressings encourage
granulation, although surgical intervention may sometimes be
needed.
Fig. 29.50 Scarring inflammatory alopecia. This patient had systemic
lupus erythematosus and additional cutaneous features of scarring
inflammatory discoid lupus erythematosus.
Connective tissue disease
| Lupus erythematosus
This autoimmune disorder can be subdivided into systemic
lupus erythematosus (SLE) and cutaneous lupus, which
includes discoid lupus erythematosus (DLE) and subacute
cutaneous lupus erythematosus (SOLE). The features of
SLE are discussed on page 1035. Drug-induced DLE
and SOLE should always be considered (see Box 24.78,
p. 1057, and Boxes 29.34 and 29.35 below). DLE typically
presents as scaly red plaques with follicular plugging, usually on
photo-exposed sites of the face, head and neck, which resolve
with scarring and pigmentary change. If the scalp is involved,
scarring alopecia usually occurs (Fig. 29.50). Most patients with
DLE do not develop SLE. Patients with SCLE may have extensive
cutaneous involvement, usually aggravated by sun exposure, with
an annular, polycyclic or papulosquamous eruption. Systemic
involvement is uncommon and the prognosis usually good. There
is a strong association with antibodies to Ro/SS-A antigen. A
diagnosis of cutaneous lupus is confirmed by histopathology and
direct immunofluorescence. Cutaneous lupus may respond to
topical glucocorticoids, antimalarials or immunosuppressants.
Antimalarials and photoprotection are important mainstays in the
management of cutaneous lupus, and systemic immunosuppression
may be required for resistant disease. Paradoxically, low-dose
UVA1 phototherapy can be effective for lupus.
Systemic sclerosis
This autoimmune multisystem disease presents with severe
Raynaud’s syndrome, digital ulcers and skin fibrosis. Dilated
nail-fold capillaries and ragged cuticles are frequent. The clinical
features and management are described on page 1037.
Morphoea
Morphoea is a localised cutaneous form of scleroderma that
can affect any site at any age. It usually presents as a thickened
Skin disease in general medicine • 1263
violaceous plaque, which may become hyper- or hypopig merited.
Plaques can become generalised. Linear forms exist and, if in the
scalp, are associated with scarring hair loss (en coup de sabre).
There is usually no systemic involvement. Topical glucocorticoids
or immunosuppressants or phototherapy, particularly PUVA or
UVA1 , can be effective, and systemic immunosuppression may
be used for resistant extensive disease.
| Dermatomyositis
Dermatomyositis is a multisystem disease, predominantly
affecting skin, muscles and blood vessels. Typical cutaneous
features include a violaceous ‘heliotrope’ erythema periorbitally
and involving the upper eyelids, but this can sometimes affect
the upper trunk, shoulders (‘shawl sign’) and limbs. Linear
erythematous streaks may also be observed on the back of
hands and fingers, and papules over the knuckles (Gottron’s
papules). Tortuous dilated nail-fold capillaries, often best seen
with a dermatoscope, and ragged cuticles are usually evident.
Photo-aggravation of the cutaneous features is often prominent
(see Fig. 29.46A, p. 1260). The clinical features and management
are described on page 1039.
Granulomatous disease
Granuloma annulare
This is common and may be reactive, although a trigger is
usually not apparent. The hallmark is the presence of dermal
granulomas, which are usually palisading and associated with
alteration of dermal collagen (necrobiosis). The condition is
generally asymptomatic and may present as an isolated dermal
lesion with a raised papular annular edge, or may be more
generalised. An association between generalised disease and
diabetes has been proposed but not confirmed. Lesions often
resolve spontaneously. Intralesional glucocorticoids or cryotherapy
can be used for localised disease, and UVB or UVA1 phototherapy
or PUVA for generalised disease.
Necrobiosis lipoidica
This condition has some histological features in common with
granuloma annulare, although necrobiosis predominates. The
lesion has a characteristic yellow, waxy, atrophic appearance,
often with violaceous edge (Fig. 29.51). Underlying blood vessels
are easily seen because of tissue atrophy. Necrobiosis lipoidica
typically appears on the shins and is prone to ulceration after
trauma. There is a strong association with diabetes: most
patients with necrobiosis lipoidica have or develop diabetes,
although less than 1 % of diabetic patients develop necrobiosis
lipoidica. Treatment is difficult and includes very potent topical
or intralesional glucocorticoids, topical calcineurin inhibitors,
PUVA or UVA1 phototherapy and systemic immunosuppression.
Sarcoidosis
This condition is characterised by the presence of non-caseating
granulomas. The cause is unknown, although infectious and
genetic factors have been proposed. It is usually a multisystem
disease (p. 608), with skin lesions in about one-third of
patients. Cutaneous features can occur in isolation and include
violaceous infiltrated dermal plaques and nodules, which can
affect any site but particularly digits and nose (lupus pernio),
more generalised hyper- or hypopigmented or annular papules
Fig. 29.51 Necrobiosis lipoidica. Atrophic yellow plaques with
violaceous edges, on the shins of a patient with diabetes mellitus.
and plaques, infiltrative changes in scars and erythema
nodosum (see Fig. 17.59, p. 609). It has been reported more
commonly and may be more severe in those of African, African
American or Indian ancestry. Investigation is described on
page 609. Cutaneous disease may respond to topical or
intralesional glucocorticoids, cryotherapy, UVA1 , laser or PDT
(pp. 1226-1228). Clinical features and management of systemic
disease are discussed on pages 608 and 610.
| Cutaneous Crohn’s disease
Cutaneous Crohn’s disease (p. 813) is rare but may present as
perianal and peristomal infiltrative plaques, lymphoedema, sinuses
or fistulae, and oral granulomatous disease. These changes are
termed ‘metastatic’ Crohn’s and histology shows non-caseating
granulomas. Reactive skin changes can also occur in the form
of erythema nodosum and pyoderma gangrenosum (pp. 1 265
and 1261). Treatment is of the underlying disease (p. 820).
Porphyrias
The porphyrias (described on p. 378) are a diverse group of
diseases, caused by reduced or absent activity of specific
enzymes in the porphyrin-haem biosynthetic pathway. Due to
this loss of enzyme activity, porphyrin precursors proximal to
the implicated enzyme step accumulate. If the accumulated
porphyrins absorb visible light, then there will be skin features
and photosensitivity, which explains why some porphyrias
have skin features (porphyria cutanea tarda) and others do not
(acute intermittent porphyria; p. 379). The most common skin
presentations are photo-exposed site blistering, skin fragility and
pain on daylight exposure.
Cutaneous porphyrias: fragility and blisters
Although porphyria cutanea tarda (PCT) may be genetically
inherited, this is uncommon and acquired PCT is the most
common porphyria worldwide. It is caused by an underlying
chronic liver disease, in association with hepatic iron overload. The
liver disease is often only diagnosed through investigation of the
1264 • DERMATOLOGY
Fig. 29.52 Porphyria cutanea tarda. Skin fragility, blistering, scarring,
milia and hypertrichosis on the back of hands and fingers in hepatitis C,
skin presentation and it is thus an important diagnosis not to miss.
Typical features are increased skin fragility, blistering, erosions,
hypertrichosis, scarring and milia occurring on light-exposed areas,
particularly the backs of the hands (Fig. 29.52). Less common
features include facial hypertrichosis, hyperpigmentation and
morphoea-like changes. Variegate porphyria (VP) and hereditary
coproporphyria (HCP) may be indistinguishable on skin features
and it is important to make the correct diagnosis, as acute
neurovisceral attacks, which may be drug-induced (p. 1265), can
occur in VP and HCP but not in PCT. Pseudoporphyria may also
be impossible to distinguish from PCT on clinical grounds but
is most frequently caused by a drug (commonly naproxen; see
Box 29.35) or by sunbed use; on investigation, porphyrins are
normal. A PCT-like presentation may also be seen in uraemia
due to renal failure, but is caused by raised porphyrins due to
impaired elimination rather than an enzyme defect.
Management of PCT requires removal or treatment of any
underlying cause, which may involve venesection, iron chelation,
very low-dose hydroxychloroquine once or twice per week and
photoprotection.
Cutaneous porphyria: pain on sun exposure
Erythropoietic protoporphyria is caused by a genetic defect in the
ferrochelatase gene that leads to ferrochelatase enzyme deficiency.
It is an important diagnosis to consider. The presentation is usually
in early childhood, although the diagnosis is often delayed. In
part this is because, although the baby or child cries due to
immediate pain on sunlight exposure, physical signs are often
absent or minimal and thus a link with sunlight may not always
be considered. The deficient ferrochelatase activity leads to
accumulation of lipid-soluble protoporphyrins in the skin, explaining
the photosensitivity manifest as pain on daylight exposure.
Multiple pigment gallstones, anaemia (usually only problematic
if considered to be due to iron deficiency) and, rarely, severe
liver disease can occur, which may be fatal and requires liver
transplantation. In addition to photoprotection, UVB phototherapy
may be effective for the symptoms of photosensitivity and, more
recently, the use of alpha-melanocyte-stimulating hormone
(a-MSH) analogues has been explored.
Abnormal deposition disorders
Xanthomas
Deposits of fatty material in the skin, subcutaneous fat and tendons
may be the first clue to primary or secondary hyperlipidaemia
(pp. 346 and p. 373).
Amyloidosis
Cutaneous amyloid may present as periocular plaques in primary
systemic amyloidosis (p. 81) and amyloid associated with multiple
myeloma, but is uncommon in systemic amyloidosis secondary
to rheumatoid arthritis or other chronic inflammatory diseases.
Amyloid infiltration of blood vessels may manifest as ‘pinch
purpura’ following skin trauma. Macular amyloid is more common
in darker skin types and appears as pruritic grey/brown macules
or patches, usually on the back. Potent topical glucocorticoids
can be beneficial, although it is often treatment-resistant.
Genetic disorders
|Neurofibromatosis
This is described in detail on page 1131.
Tuberous sclerosis
This is an autosomal dominant condition and two genetic loci
have been identified: TSC-1 (chromosome 9) encoding hamartin,
and TSC-2 (chromosome 16) encoding tuberin. The hallmark
is hamartomas in many systems. The classic triad of clinical
features comprises learning disability, epilepsy and skin lesions
but there is marked heterogeneity in clinical features. Skin changes
include pale oval (ash leaf) macules that occur in early childhood;
yellowish/pink papules in the mid-face (angiofibromas, ‘adenoma
sebaceum’), occurring in adolescence; periungual and subungual
fibromas; and connective tissue naevi (shagreen patches, often
on lower back). Gum hyperplasia, retinal phakomas (fibrous
overgrowths), renal, lung and heart tumours, cerebral gliomas
and calcified basal ganglia may also occur.
Reactive disorders
| Erythema multiforme
Erythema multiforme has characteristic clinical and histological
features and can be triggered by a variety of factors (Box 29.32)
but a cause is not always identified. The disease is likely to have
an immunological basis. Lesions are multiple, erythematous,
annular, targetoid ‘bull’s eyes’ (Fig. 29.53) and may blister.
Stevens-Johnson syndrome (pp. 1224 and 1254) is a severe
form of erythema multiforme with marked blistering, mucosal
involvement (mouth, eyes and genitals) and systemic upset.
Identification and removal/treatment of any trigger are essential.
Analgesia and topical glucocorticoids may provide symptomatic
relief. Supportive care is required in Stevens-Johnson syndrome,
including ophthalmology input.
29.32 Provoking factors in erythema multiforme
Infections
• Viral: herpes simplex, orf, infectious mononucleosis, hepatitis B, HIV
• Mycoplasma and other bacterial infections
Drugs
• Sulphonamides, penicillins, barbiturates and carbamazepine
Systemic disease
• Sarcoidosis, malignancy, systemic lupus erythematosus
Other
• Radiotherapy, pregnancy
Skin disease in general medicine • 1265
Fig. 29.53 Erythema multiforme in a young woman. Herpes simplex
virus infection was the trigger.
29.33 Provoking factors in erythema nodosum
Infections
• Bacteria: streptococci, mycobacteria, Brucella , Mycoplasma ,
Rickettsia, Chlamydia
• Viruses: hepatitis B and infectious mononucleosis
• Fungi
Drugs
• Sulphonamides, sulphonylureas, oral contraceptives
Systemic disease
• Sarcoidosis, inflammatory bowel disease, malignancy
Other
• Pregnancy
Erythema nodosum
This is characterised histologically by a septal panniculitis of
subcutaneous fat (see Fig. 17.59, p. 609). An identified trigger is
often present (Box 29.33). Lesions are typically painful, indurated
violaceous nodules on the shins and lower legs. Systemic upset,
arthralgias and fever are common. Spontaneous resolution occurs
over a month or so, leaving bruise-like marks. Any underlying
cause should be identified and removed or treated. Bed rest, leg
elevation and an oral NSAID frequently offer symptomatic relief.
Systemic glucocorticoids are effective but seldom required, and
must be avoided when there is a possibility of infection. Potassium
iodide, dapsone or hydroxychloroquine may be effective for
resistant disease but these are rarely required.
Acquired reactive perforating dermatosis
The hallmark of this condition is transepidermal elimination
of dermal material, particularly collagen and elastic tissue.
It presents as keratotic papules, particularly in patients with
diabetes and chronic renal disease. Treatment with topical
glucocorticoids, retinoids, PUVA or UVA1 therapy may help. There
are other related perforating dermopathies, with characteristic
histology.
Annular erythemas
This group of chronic, poorly defined, annular, erythematous
and often scaly eruptions can be further subdivided and may be
secondary to an identifiable cause. Erythema chronicum migrans
can be associated with Lyme disease (Borrelia burgdorferi,
p. 255). Erythema marginatum can occur in rheumatic fever
(p. 515) or Still’s disease (p. 1040). Erythema gyratum repens
typically presents as concentric circles of erythema and scale
with an advancing edge and is usually associated with underlying
malignancy. Erythema annulare centrifugum presents with
expanding, scaly, erythematous rings, with central fading. A
trigger may not be apparent but possible associations include
fungal infection, drugs, autoimmune or endocrine diseases,
such as lupus or thyroid disease, and malignancy, particularly
haematological. An underlying trigger must be sought and
removed or treated. Topical glucocorticoids or phototherapy
may be helpful for chronic disease.
Acanthosis nigricans
Hyperkeratosis and pigmentation are typical and affected sites
have a velvety texture. The flexures, especially axillae and, in
dark-skinned people, sides of neck, are involved (pp. 1325,
1326 and 720). There are several types, mainly associated with
insulin resistance. Most often, acanthosis nigricans is found in
conjunction with obesity and regresses with weight loss. It can be
associated with malignancy, usually adenocarcinoma (particularly
gastric), when it is usually more extensive and pruritic, and can
involve mucous membranes.
Drug eruptions
Virtually all drugs may have cutaneous adverse effects (Fig. 29.54)
and this should be considered in the differential diagnosis of most
presentations of skin disease. Drugs can exert their adverse effects
via several mechanisms, which can be broadly subdivided into
non-immunological and immunological (Box 29.34).
29.34 Types of drug eruption
Non-immunological
Predictable
• Striae due to glucocorticoids (see Fig. 29.10, p. 1226)
• Asteatosis with statins
• Candidal infections with antibiotics
• Worsening of psoriasis with lithium, (3-blockers, antimalarials,
NSAIDs
• Urticaria with aspirin due to mast cell degranulation
• Bradykinin-mediated angioedema due to ACE inhibitors
• Doxycycline photosensitivity
• Dapsone haemolysis
Immunological
Unpredictable
• Immediate IgE-mediated hypersensitivity (type I): penicillin-induced
urticaria and anaphylaxis
• Antibody-mediated (type II): penicillin-induced haemolysis
• Immune complex-mediated (type III): drug-induced serum sickness
or vasculitis
• Delayed hypersensitivity (type IV): drug-induced erythema
multiforme, lichenoid or pemphigus-like reaction; drug-induced
lupus
(ACE = angiotensin-converting enzyme; IgE = immunoglobulin E; NSAIDs =
non-steroidal anti-inflammatory drugs)
1266 • DERMATOLOGY
29.35 Clinical patterns of drug eruptions
Reaction pattern
Clinical features
Examples of causative drugs
Exanthematous
Erythema, maculopapular
Antibiotics (especially ampicillin), anticonvulsants, gold,
penicillamine, NSAIDs, carbimazole, anti-TNF drugs and
other biological therapies
Urticaria and
angioedema
Sometimes accompanied by angioedema
Angioedema alone
Salicylates, opiates, NSAIDs, antibiotics, dextran,
ACE inhibitors
Lichenoid
Violaceous, lichen planus-like, dyspigmentation
Gold, penicillamine, antimalarials, thiazides, NSAIDs,
(3-blockers, ACE inhibitors, sulphonamides, lithium,
sulphonylureas, proton pump inhibitors, quinine,
antituberculous, dyes in colour developers
Purpura and vasculitis
Palpable purpura and necrosis
Allopurinol, antibiotics, ACE inhibitors, NSAIDs, aspirin,
anticonvulsants, diuretics, oral contraceptives
Erythema multiforme
Target-like lesions and bullae on extensor aspects of limbs
See Box 29.32, p. 1264
Erythema nodosum
Tender, painful, dusky, erythematous nodules on shins
See Box 29.33, p. 1265
Exfoliative dermatitis
There may be erythroderma
Allopurinol, carbamazepine, barbiturates, penicillins, PAS,
isoniazid, gold, lithium, penicillamine, ACE inhibitors
Toxic epidermal
necrolysis
Rapid evolution, extensive blistering, erythema, necrolysis,
mucosal involvement
Anticonvulsants, antibiotics, especially sulphonamides,
NSAIDs, terbinafine, sulphonylureas, antiretrovirals,
allopurinol
Photosensitivity
(p. 1220)
Photo-exposed site rash, may be sunburn-like, exfoliation,
lichenoid
Thiazides, amiodarone, quinine, NSAIDs, tetracyclines,
fluoroquinolones, phenothiazines, sulphonamides,
retinoids, psoralens
Drug-induced lupus
Photosensitivity, discoid lesions, urticarial or erythema
multiforme-like. May have positive lupus serology and
anti-histone antibodies
Allopurinol, thiazides, ACE inhibitors, PAS, anticonvulsants,
(3-blockers, gold, hydralazine, minocycline, penicillamine,
lithium, proton pump inhibitors
Psoriasiform rash
Rash resembles psoriasis
See Box 29.23 (p. 1248)
DRESS
Facial oedema, fever, extensive rash, lymphadenopathy,
eosinophilia and systemic involvement
Anticonvulsants, trimethoprim, minocycline, allopurinol,
dapsone, terbinafine
AGEP/toxic
pustuloderma
Rapid onset of sterile, non-follicular pustules on
erythematous base
Ampicillin/amoxicillin, erythromycin, quinolones,
sulphonamides, terbinafine, diltiazem, hydroxychloroquine
Acneiform eruptions
Rash resembles acne
Lithium, anticonvulsants, oral contraceptives, androgens,
glucocorticoids, antituberculous drugs, EGFR antagonists
(cetuximab and erlotinib)
Pigmentation
See Box 29.29 (p. 1258)
Bullous eruptions
Often at pressure sites and there may be other features,
such as purpura, milia
Barbiturates, penicillamine, furosemide
Pseudoporphyria
May be indistinguishable from porphyria cutanea tarda
clinically
NSAIDs, tetracyclines, retinoids, furosemide, nalidixic acid
Exacerbation of acute
hepatic porphyrias
See page 1 263
Always check all drugs for safety of use in porphyrias
against standard guidelines
Drug-induced
immunobullous disease
May resemble pemphigoid, pemphigus, dermatomyositis,
scleroderma, epidermolysis bullosa acquisita
Penicillamine, ACE inhibitors, vancomycin
Fixed drug eruptions
Round/oval, erythema, oedema ± bullae
Same site every time drug is given
Pigmentation on resolution
Tetracyclines, sulphonamides, penicillins, quinine, NSAIDs,
barbiturates, anticonvulsants
Hair loss
Diffuse
Cytotoxic agents, oral retinoids, anticoagulants,
anticonvulsants, antithyroid drugs, lithium, oral
contraceptives, infliximab
Hypertrichosis
Excessive hair growth in non-androgenic distribution
Diazoxide, minoxidil, ciclosporin
(ACE = angiotensin-converting enzyme; AGEP = acute generalised exanthematous pustulosis; DRESS = drug rash with eosinophilia and systemic symptoms; EGFR =
epidermal growth factor receptor; NSAIDs = non-steroidal anti-inflammatory drugs; PAS = para-aminosalicylic acid; TNF = tumour necrosis factor)
Further information • 1267
Fig. 29.54 Drug eruption. Possible drug causes of rash should always
be considered. This was doxycycline-induced photosensitivity in a farmer.
Clinical features
Cutaneous drug reactions typically present in specific patterns (Box
29.35). Non-immunologically mediated reactions can theoretically
occur in anyone, given sufficient exposure to the drug, although
idiosyncratic factors, such as genetic predisposition, may render
some more susceptible. There is limited information on genetic
determinants of drug responses and adverse effects, although
advances have been made, e.g. with azathioprine (p. 1227),
and provide exciting opportunities for therapeutic personalised
medicine. Immunologically mediated cutaneous drug eruptions
typically commence within days to weeks of starting the drug.
Detailed history-taking relating to prescribed and non-prescribed
medications is essential and there may be other clues (Box 29.36).
Investigations and management
The suspected drug must be stopped. If drug-induced
photosensitivity is considered, the patient should be phototested
while on the drug to confirm the diagnosis, and again after drug
withdrawal to confirm resolution of photosensitivity (p. 1215). An
eosinophilia and abnormalities in liver function tests may occur
in adverse drug reactions and, for example, specific IgE to
penicillin may be raised in penicillin-induced rash but, otherwise,
specific investigations are not available. Rechallenge with drug
is not usually undertaken unless the reaction is mild, as this
can be risky. Drug withdrawal may not be straightforward and
substitute drugs may be required. Antihistamines and/or topical
or systemic glucocorticoids may provide supportive management,
depending on the type of cutaneous reaction. The management
of anaphylaxis is described on page 76.
29.36 Diagnostic clues to drug eruptions
• Past history of reaction to suspected drug
• Introduction of suspected drug a few days to weeks before onset
of rash
• Recent prescription of a drug commonly associated with rashes
(penicillin, sulphonamide, thiazide, allopurinol)
• Symmetrical eruption that fits with a well-recognised pattern,
caused by a current drug
• Resolution of rash following drug cessation
Further information
Websites
bad.org.uk British Association of Dermatologists: guidelines and
patient information for many skin diseases.
cochrane.org/cochrane-reviews Many relevant skin reviews, including
sun protection (CD011161), psoriasis (CD001976, CD007633,
CD005028, CD001213, CD009481, CD010497, CD010017,
CD009687, CD001433), eczema (CD009864, CD005205,
CD004054, CD005500, CD005203, CD008642, CD008426,
CD003871, CD004416, CD006135, CD007770), skin cancer
(CD005413, CD008955, CD007281, CD003412, CD004415,
CD007041, CD005414, CD007869, CD004835, CD010308,
CD010307, CD011161), leg ulcers (CD010182, CD002303,
CD003557, CD001737, CD008599, CD001733, CD000265,
CD008394, CD001177, CD009432, CD001273, CD011354,
CD001836), acne (CD004425, CD011946, CD002086,
CD000194, CD007917), rosacea (CD003262), urticaria
(CD007770, CD006137, CD008596), alopecia (CD007628,
CD004413), skin infections (CD009992, CD003584,
CD004685, CD004767, CD010095, CD003261), bullous
pemphigoid (CD002292).
nice.org.uk National Institute for Health and Care Excellence: guidance
for skin cancer (NG14, NG34, PH32, CSG8, TA172, TA321, TA268,
TA319, TA384, TA400, TA366, TA357, TA396, TA269, IPG446,
IPG478, DG19), atopic eczema (QS44, CG57, TA81, TA82, TA177),
psoriasis (CG153, TA146, TA372, TA368, TA103, TA134, TA350,
TA180), sun exposure (NG34, PH32), vitamin D (PH56), urticaria
(TA339, ESU0M31), rosacea (ESNM43, ESNM68), scabies
(ESUOM29), photodynamic therapy (IPG 155, MTG6) and Grenz
rays (IPG 236).
sign.ac.uk Scottish Intercollegiate Guidelines Network: no. 120
- Management of chronic venous leg ulcers; 121 - Diagnosis
and management of psoriasis and psoriatic arthritis in
adults; 125 - Management of atopic eczema in primary
care; 140 - Management of primary cutaneous squamous
cell carcinoma.
29
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L Mackillop
FEM Neuberger
Maternal medicine
Clinical examination in pregnancy 1270
Medical disorders in pregnancy 1276
Clinical evaluation in maternal medicine 1271
Hypertension 1 276
Respiratory disease 1 277
Planning pregnancy in patients with medical conditions 1272
Gastrointestinal disease 1 277
Functional anatomy and physiology 1272
Diabetes 1 278
Endocrine disease 1 279
Investigations 1274
Human immunodeficiency virus infection 1 280
Imaging 1274
Inflammatory rheumatic disease 1280
Presenting problems in pregnancy 1274
Breathlessness 1 274
Chest pain 1 275
Circulatory collapse 1275
Headache 1 275
Nausea and vomiting 1275
Oedema 1275
Seizures 1 275
Cardiac disease 1 282
Renal disease 1 282
Liver disease 1 283
Neurological disease 1 284
Psychiatric disorders 1 284
Haematological disease 1 284
1270 • MATERNAL MEDICINE
Clinical examination in pregnancy
6 Breasts
Increase in size and vascularity
7 Respiratory system
Mild breathlessness common
Respiratory rate unchanged
5 Heart
Ejection systolic murmur may be
part of normal pregnancy
Diastolic murmurs are always
pathological
4 Face
Conjunctival pallor (physiological
anaemia of pregnancy)
A Jaundice in acute fatty liver
of pregnancy
A Melasma
3 Blood pressure
Lower in 2nd and 3rd trimesters
2 Pulse
Pulse rate increased by
10-20 bpm
Bounding pulse
1 Hands
A Palmar erythema
A Increased risk of varicella
pneumonia
Observation
Plethoric
Mood/affect
8 Abdomen
Scars
Excoriations
Umbilicus eversion
Obstetric examination
A Linea nigra
A Striae gravidarum
A Striae albicans
9 Legs
Varicose veins
A Peripheral oedema
Mild oedema in normal
pregnancy
Rapid-onset oedema suggests
pre-eclampsia
10 Urine dipstick
Insets: (Palmar erythema) From Fitzpatrick JE, Morel li JG. Dermatology secrets plus, 5th edn. Philadelphia: Elsevier Inc.; 2016; (Melasma) From Lawrence
CM, Cox NH. Color atlas and text of physical signs in dermatology. London: Wolfe; 1993; (Jaundice) From Morse SA, Ballard RC, Holmes KK, et al. Atlas of
sexually transmitted diseases and AIDS, 4th edn. Saunders, Elsevier Inc.; 2010; (Varicella pneumonia) From Voore N, Lai R. Varicella pneumonia in an
immunocompetent adult. Can Med Assoc J 2012; 184(1 7): 1924; (Linea nigra) From Bolognia JL, Schaffer JV, Duncan K0, etal. Dermatology essentials.
Philadelphia: Elsevier Inc.; 2014; Courtesy of Jean L. Bolognia; (Striae gravidarum) From Buchanan K, Fletcher HM, Reid M. Prevention of striae gravidarum
Clinical evaluation in maternal medicine • 1271
Clinical evaluation in maternal medicine
Take a careful history
Ask specifically about:
• Cardiac disease
• Renal disease
• Diabetes
• Rheumatic disease
• Inflammatory bowel
disease
• Epilepsy
Take a careful drug history
Stop fetotoxic drugs
before conception
• Methotrexate
• Leflunomide
• Mycophenolate
• Valproate
Consider cardiovascular adaptations during pregnancy
Perform urinalysis
-40%
-20%
+20% +40% +60%
Blood volume
Cardiac output
Heart rate
Systolic blood pressure
Diastolic blood
pressure
Perform further
investigations if appropriate
Remember changes of pregnancy when interpreting
laboratory results
• Anaemia
• Altered thyroid function
tests
• Low creatinine/urea
• Low C02
• Raised alkaline
phosphatase
• Glycosuria
with cocoa butter cream. IntJ Gynecol Obstet 2009; 1 08(201 0): 65-68; (Striae albicans) From Cantisano-Zilkha M. Aesthetic oculofacial rejuvenation.
Philadelphia: Saunders, Elsevier Inc.; 2010; (Peripheral oedema) From Huang H-W, Wong L-S, Lee C-H. Sarcoidosis with bilateral leg lymphedema as the
initial presentation: a review of the literature. Dermatologica Sinica 34(201 6) : 29-32.
1272 • MATERNAL MEDICINE
Major physiological changes occur during pregnancy, which
impact on several organ systems. These are necessary to support
the growing fetus, to prepare for delivery and to support lactation.
These changes can adversely affect the activity and progression
of many pre-existing medical conditions. Emphasising this fact,
information from the UK Confidential Enquiry into Maternal Deaths
has revealed that over recent years, two-thirds of maternal deaths
occur as the result of pre-existing medical conditions, rather
than from obstetric causes. The most common causes of death
were cardiac conditions (23%), pneumonia and influenza (14%),
and venous thromboembolism (1 1 %). Although some diseases
can undergo remission during pregnancy, others can worsen,
potentially jeopardising the health and well-being of the mother
and fetus. In this chapter, we review the physiological changes
that occur during pregnancy and the impact of pregnancy on
the diagnosis, clinical course and management of common
medical conditions. In addition, we review the pathogenesis
and management of several medical conditions specific to
pregnancy.
Planning pregnancy in patients with
medical conditions
Patients with pre-existing medical conditions require careful
counselling when planning a pregnancy to make them aware of
the risks that pregnancy might pose, as well as the changes in
symptoms that might be expected to occur during pregnancy.
Although each disease is different, as is discussed later in this
chapter, the general principles are to ensure that drugs that may
be fetotoxic are stopped before pregnancy is attempted; that
high-risk patients are kept under close surveillance during their
pregnancy; and that new symptoms that emerge during pregnancy
are treated seriously and fully investigated where appropriate.
Functional anatomy and physiology
The most important changes that occur in the anatomy and
physiology of major organ systems during pregnancy are
discussed below.
Bone metabolism
Major changes in bone metabolism take place to meet the demands
of the growing fetus. Intestinal calcium absorption increases,
due in part to increased production of 1 ,25-dihydroxyvitamin D
(1 ,25(OH)2D). Calcium is also released from the maternal skeleton
due to increased bone resorption, stimulated by production of
parathyroid hormone-related protein (PTHrP) by breast and
placenta. This results in loss of bone from the maternal skeleton
during pregnancy that continues until lactation ceases and then
recovers. Serum concentrations of alkaline phosphatase (ALP)
can increase by up to fourfold but this is due to release of ALP
from the placenta rather than bone.
Cardiovascular system
Heart rate and stroke volume increase during pregnancy; when
combined with peripheral vasodilatation and a reduction in
systemic blood pressure, this causes a hyperdynamic circulatory
state and an increase in cardiac output. Diaphragmatic elevation
may affect the electrocardiogram (ECG), causing left axis
deviation of up to 15°. Other changes include T-wave inversion
in leads III and aVF, ST depression, small Q waves and a sinus
tachycardia. Supraventricular and ventricular beats are common.
Echocardiography shows a modest increase in the dimensions
of the cardiac chambers.
Endocrine system
During early pregnancy there is secretion of human chorionic
gonadotrophin (hCG) by trophoblast cells, which act on the corpus
luteum in the ovary to stimulate oestradiol and progesterone
production (Fig. 30.1). Levels of hCG rise rapidly during early
pregnancy to reach a peak around 8 weeks, and then fall before
stabilising at a lower level from 20 weeks until term. There is a
progressive rise in oestradiol and progesterone levels; initially,
these hormones are produced by the corpus luteum but placental
production takes over after about 1 2 weeks. The high levels of
gonadal hormones suppress pituitary gonadotrophin production
but prolactin levels rise about 1 0-fold and there is an increase in
volume of the anterior pituitary. Serum levels of free T4 increase
during the first trimester but, paradoxically, thyroid-stimulating
hormone (TSH) levels fall by almost 50%. This is because hCG
is homologous to TSH and mimics the effect of TSH on the
thyroid, stimulating both T3 and T4 production. The raised levels
of T3 and T4 feed back to the pituitary and reduce TSH secretion.
Later in pregnancy, there is increased degradation of thyroxine
by the placenta and levels of thyroxine-binding globulin (TBG) rise,
causing the normal range for free T4 and T3 to fall progressively
during the course of pregnancy. Although TSH levels are difficult
to interpret early in pregnancy, they provide the best measure
of thyroid function after about 16 weeks’ gestation.
Gastrointestinal system
The high levels of progesterone during pregnancy lead to
relaxation of smooth muscle in the gastrointestinal tract. This
causes the lower oesophageal sphincter to relax, predisposing
to gastro-oesophageal reflux and reduced gastrointestinal
transit; this in turn leads to delayed gastric emptying and
constipation.
Genitourinary system
Glomerular filtration rate (GFR) increases during pregnancy due
to an increased cardiac output. By the second trimester, renal
perfusion increases by up to 80% and GFR by 50%, leading
to a fall in serum urea and creatinine. Mild glycosuria may be
observed during normal pregnancy due mainly to an increase
in filtered load of glucose. The ureters and renal pelvis are
slightly dilated, most prominently on the left side, leading to the
physiological hydronephrosis of pregnancy.
Glucose metabolism
Maternal glucose metabolism changes during pregnancy to
optimise delivery of glucose and other nutrients to the fetus.
During the second half of pregnancy in particular, there is maternal
insulin resistance due largely to an increase in circulating levels
of human placental lactogen (hPL) (Fig. 30.1). The net effect is to
ensure that glucose is preferentially supplied to the fetus rather
than the mother. Following delivery of the placenta, there is a
rapid decline in hPL and reversal of insulin resistance. During
pregnancy, fasting plasma glucose decreases slightly, while
post-prandial blood glucose may increase. Glycosuria may
occur, even in women who do not have diabetes, due to the
Functional anatomy and physiology • 1273
Early pregnancy
Late pregnancy
Fig. 30.1 Hormonal changes in pregnancy. In early pregnancy, oestradiol and progesterone are mainly derived from the corpus luteum in response
to human chorionic gonadotrophin (hCG), secreted by the trophoblast. The raised levels of hCG also act on the thyroid to stimulate T3 (triiodothyronine) and
T4 (thyroxine) production, which in turn suppresses thyroid-stimulating hormone (TSH) production by the pituitary. Later in pregnancy, oestradiol and
progesterone are derived from the placenta, which also produces human placental lactogen (hPL), impairing glucose tolerance. There is a progressive
reduction of free T3 and T4 during pregnancy as the result of T3 and T4 degradation by the placenta and increased secretion of thyroxine-binding globulin
(TBG) by the liver.
increased GFR. Insulin secretion in the fetus is driven by fetal
glucose levels, which in turn are dependent on maternal glucose
concentrations. Accordingly, in women with diabetes, maternal
hyperglycaemia stimulates fetal insulin secretion, which increases
fetal growth, resulting in increased birth weight or macrosomia.
Haematological system
Haemoglobin normally falls by about 20% during pregnancy
since plasma volume increases more than red cell volume: the
so-called physiological anaemia of pregnancy. The reduction
in haematocrit lowers blood viscosity but this is offset by an
elevation in levels of several clotting factors, resulting in a
hypercoagulable state that increases the risk of venous and arterial
thrombosis.
Respiratory system
Tidal volume (TV) increases during pregnancy due to an increased
vital capacity and reduced residual volume, and by term the
increase in TV is about 200 mL. These changes are required to
meet the 20% increase in oxygen demand that occurs during
pregnancy. The PC02 level decreases but this is offset by an
increase in renal excretion of bicarbonate, such that the blood
pH remains relatively stable. Respiratory rate is unaffected by
pregnancy.
1274 • MATERNAL MEDICINE
Investigations
The profound changes in physiology and anatomy that occur
during pregnancy cause changes in the normal reference
ranges for several hormones, electrolytes and other analytes,
as summarised in Box 30.1. While many investigations can
Common laboratory changes during pregnancy
Laboratory
test
Change
Cause
Haematology
Haematocrit
Decrease
Extracellular volume
expansion
Routine biochemistry
GFR
Increase
Increased renal blood flow
Urea and
Decrease
Increased GFR
creatinine
Alkaline
Increase
Release by placenta
phosphatase
Glucose
Decrease (fasting)
Raised insulin
Increase (post-prandial)
Insulin resistance
Hormones
t4
Increase (first trimester)
Stimulation of thyroid by
hCG
Decrease (later pregnancy)
Placental degradation
TSH
Decrease (first
Increased T4 due to
trimester)
stimulation of thyroid by
hCG
Prolactin
Increase
Increased production by
pituitary
Oestradiol
In ■ ■
Production by corpus
Progesterone
j Progressive increase
luteum then placenta
hCG
Increase then decrease
Production by trophoblast
hPL
Progressive increase
Production by placenta
(GFR = glomerular filtration rate; hCG = human chorionic gonadotrophin; hPL =
human placental lactogen; TSH = thyroid-stimulating hormone)
proceed as normal during pregnancy, invasive procedures should
generally be avoided unless the potential benefit clearly outweighs
the risk. Investigations that can be performed in pregnancy are
shown in Box 30.2.
Imaging
Imaging during pregnancy should be undertaken only when the
clinical benefit outweighs the potential risks to mother and fetus. In
suspected pulmonary embolus, radionuclide ventilation/perfusion
(V/Q) scanning is preferred over computed tomographic pulmonary
angiography (CTPA) in women with a normal chest X-ray since
V/Q scans expose the maternal breast and lungs to less radiation
than CTPA. However, if the chest X-ray is abnormal, CTPA should
be performed, since it is more likely to yield a definitive diagnosis.
The radiation exposure for both investigations is well below the
maximum recommended fetal radiation dose in pregnancy (5 rad).
Chest X-rays may also be performed safely at any gestation during
pregnancy if clinically indicated, since the radiation exposure is
very low for the fetus. Magnetic resonance imaging (MRI) is safe in
the second and third trimesters and is useful in the assessment of
proximal deep vein thrombosis (DVT) and neurological disorders.
However, gadolinium-containing contrast agents should be used
only if absolutely necessary. If gadolinium contrast agents are used
in women who are breastfeeding, the milk should be discarded
for 24 hours. Ultrasound imaging is safe during pregnancy and
useful in the assessment of patients with DVT or intra-abdominal
pathology.
Presenting problems in pregnancy
Breathlessness
The causes of breathlessness during pregnancy are summarised
in Box 30.3. Many women experience mild breathlessness as
part of normal pregnancy, which is known as physiological
30.2 Investigations in pregnancy
Investigation
Use during pregnancy
Comment
Renal biopsy
Can be performed during pregnancy
<22 weeks is safest; 23-28 weeks is period of highest risk
Gastroscopy
Safe during pregnancy
Left lateral position is recommended in
the second half of pregnancy
Fetal monitoring should be offered pre- and post-procedure
Low-dose sedation recommended
Colonoscopy
Safe during pregnancy
Fetal monitoring should be offered pre- and post-procedure
Low-dose sedation recommended
Flexible sigmoidoscopy
Safe during pregnancy
Fetal monitoring should be offered pre- and post-procedure
Low-dose sedation recommended
Magnetic resonance imaging
Not contraindicated at any gestation
Theoretical risks to fetus in first trimester
Computed tomography
Can be performed at any gestation
Radiation exposure to fetus and mother must be considered and
addressed in counselling
X-ray
Safe at any gestation
Ultrasound
Safe at any gestation
Echocardiogram
Safe at any gestation
Ambulatory electrocardiogram
Safe at any gestation
*For any investigation, the potential benefit must outweigh the risk.
Presenting problems in pregnancy • 1275
30.3 Breathlessness during pregnancy
Cause
Management
Physiological
breathlessness of
No treatment required
pregnancy
Asthma
Treatment as in non-pregnant women
Pneumonia
Treatment with antibiotic as in
non-pregnant women
Valvular heart disease
Treatment as in non-pregnant women
Heart failure
Treatment as in non-pregnant women
Peripartum cardiomyopathy
(PPCM)
Treatment as in non-pregnant women
Early delivery if haemodynamic
deterioration
Pulmonary embolus
Treatment as in non-pregnant women
breathlessness of pregnancy. It is thought to be progesterone-
mediated and is classically of gradual onset and present at
rest and on exercise. Physiological breathlessness does not
require investigation but severe or persistent breathlessness
should be investigated, especially if accompanied by chest pain.
The diagnostic approach in pregnant patients with suspected
pulmonary embolism differs from that in non-pregnant women.
Measurement of D-dimer is not helpful since values normally
increase progressively throughout pregnancy. Accordingly, the
first-line investigation in suspected pulmonary embolism is a
V/Q scan in a patient with a normal chest X-ray and CTPA in a
patient with an abnormal chest X-ray.
Chest pain
Chest pain does not occur during normal pregnancy but the
incidences of acute coronary syndrome (ACS) and aortic
dissection are both increased. Accordingly, if a pregnant woman
develops acute severe chest pain suggestive of either of these
conditions, she should be investigated and treated in the same
way as a non-pregnant woman.
Circulatory collapse
The differential diagnosis of circulatory collapse is wide and
causes unrelated to pregnancy are discussed on page 199.
Obstetric causes include pulmonary embolism, haemorrhage and
amniotic fluid embolism (AFE). AFE usually presents with collapse
and profound shock during delivery or immediately afterwards,
often with profound and early coagulopathy. It can be difficult
to differentiate AFE from other causes of maternal collapse, and
the diagnosis is clinical when other causes of collapse have been
excluded. Management is supportive, with oxygenation, careful
fluid balance and, in some cases, correction of coagulopathies,
ventilatory support and vasopressors.
Another important cause of circulatory collapse is obstetric
haemorrhage, which can be divided into ante-partum and
post-partum subtypes. Ante-partum haemorrhage is defined
as bleeding from the vagina after 24 weeks’ gestation. Primary
post-partum haemorrhage is defined as occurring in the first
24 hours after delivery, and secondary post-partum haemorrhage
after 24 hours. Haemorrhage may be concealed, and physiological
changes such as hypotension, tachycardia and tachypnoea may
be late signs. Management is supportive with administration of
blood, intravenous fluids and oxygen. Patients with post-partum
haemorrhage may also benefit from uterotonic agents such as
oxytocin. If the bleeding fails to settle, surgical intervention or
interventional radiology may be required.
Headache
Migraine and tension headache may occur during pregnancy
and should be assessed along the usual lines, as described on
page 1095. Important causes of headache that are specific to
pregnancy are pre-eclampsia, which should be suspected in
patients with hypertension, oedema and proteinuria, and cerebral
venous thrombosis, which should be suspected when there is
a neurological deficit or seizures.
Nausea and vomiting
Nausea and vomiting are common during the first trimester of
pregnancy and do not usually require any specific investigation
or treatment. Other causes of nausea and vomiting are summarised
in Box 30.4. Severe vomiting with significant weight loss and/or
electrolyte disturbance suggests hyperemesis gravidarum, which
is discussed in more detail on page 1277.
^9 30.4 Differential diagnosis of severe nausea and
vomiting in pregnancy
Gastrointestinal
• Peptic ulcer disease
• Appendicitis
• Gastroenteritis
• Pancreatitis
Endocrine and metabolic
• Thyrotoxicosis
• Hyperparathyroidism
• Addison’s disease
• Diabetic ketoacidosis
Neurological
• Space-occupying lesion
• Migraine
Pregnancy-associated conditions
• Molar pregnancy • Hyperemesis gravidarum
• Acute fatty liver of pregnancy
Genitourinary
• Urinary tract infection
Psychological
• Bulimia nervosa
Cardiovascular
• Myocardial infarction
Oedema
A mild degree of ankle oedema can occur in normal pregnancy
but significant oedema raises suspicion of pre-eclampsia. This
should be considered in patients who are also hypertensive
and those with proteinuria. Further details are on page 1276.
Seizures
The causes and management of seizures during pregnancy are
summarised in Box 30.5. An important cause is eclampsia, which
should be borne in mind in patients with no previous history
of seizures and accompanying features such as hypertension,
1276 • MATERNAL MEDICINE
30.5 Causes of seizures during pregnancy
Cause
Management
Epilepsy
Similar to that in non-pregnant
women
Avoid valproate
Eclampsia
Antihypertensives
Magnesium sulphate
Careful fluid balance
Hypoglycaemia
Glucose
Hyponatraemia
Saline infusion
Alcohol withdrawal
Supportive treatment
Drugs
Supportive treatment
Stroke
As in non-pregnant women
Cerebral venous thrombosis
Low-molecular-weight heparin
Thrombotic thrombocytopenic
Plasma exchange
purpura
Immunosuppressives
oedema and proteinuria. Seizures can also occur secondary to
electrolyte disturbances associated with hyperemesis gravidarum
or hypoglycaemia. Other disorders that are more common
during pregnancy and can present with seizures include
cerebral venous thrombosis and thrombotic thrombocytopenic
purpura (TTP).
Medical disorders in pregnancy
Many disorders present specific management problems before
pregnancy, during pregnancy and in the puerperium; the most
important of these are discussed in more detail below.
Hypertension
Hypertension is one of the most common medical problems
during pregnancy, occurring in about 10-15% of women. The
causes and classification are summarised in Box 30.6.
Pre-existing hypertension
If hypertension is discovered during the first half of pregnancy, it
usually indicates that there was pre-existing hypertension. This
is most likely to be due to essential hypertension but secondary
causes also need to be considered. Hypertension during
pregnancy should be managed with vasodilators or methyldopa
(Box 30.7), taking care to avoid hypotension, which can cause
placental hypoperfusion and increase the risk of fetal growth
restriction, stillbirth and miscarriage. Angiotensin-converting
enzyme (ACE) inhibitors should be stopped in hypertensive women
who are planning to become pregnant and should be avoided
during pregnancy since they have fetotoxic effects. Diuretics
should also be avoided unless there is heart failure, as they can
reduce circulating volume and cause placental hypoperfusion.
Gestational hypertension
Gestational hypertension usually presents in the second half of
pregnancy and most often resolves by 3 months post-partum.
It should be managed actively with one of the drugs listed in
Box 30.7, to reduce the risk of progression to pre-eclampsia.
30.6 Classification of hypertension during pregnancy
Hypertension
Definition
Hypertension
in pregnancy
Blood pressure >140/90 mmHg on two separate
occasions, at least 4 hrs apart
Pre-existing
hypertension
Hypertension prior to pregnancy or occurring before
20 weeks’ gestation
Gestational
hypertension
Hypertension occurring after 20 weeks’ gestation
without proteinuria or any other features of
pre-eclampsia
Pre-eclampsia
Hypertension occurring after 20 weeks’ gestation
with proteinuria, maternal organ dysfunction or
uteroplacental dysfunction
Eclampsia
Generalised seizures in a pregnant woman
previously diagnosed with pre-eclampsia
White coat
hypertension
Hypertension that only occurs in a clinical
environment
Adapted from Tranquilli AL, Dekker G, Magee L, et al. The classification,
diagnosis and management of the hypertensive disorders of pregnancy: a revised
statement from the ISSHP. Pregnancy Hypertens 2014; 4:97-104.
KM 30.7 Drug treatment of hypertension
during pregnancy
Medication
Mechanism of action
Labetalol
a- and (3-receptor blocker
Nifedipine
Calcium channel blockers
Amlodipine
Methyldopa
Central action
Doxazosin
a- receptor blocker
| Pre-eclampsia and eclampsia
Pre-eclampsia is a disorder of vascular endothelial dysfunction that
affects about 1 0% of all pregnancies worldwide. The risk factors
for pre-eclampsia are shown in Box 30.8 and the clinical features
illustrated in Figure 30.2. Management includes control of blood
pressure, administration of magnesium sulphate as prophylaxis
against seizures, correction of coagulation abnormalities and
monitoring of fluid balance. If pre-eclampsia occurs early in
pregnancy, medical management should be initiated with the
aim of controlling the condition and maintaining the fetus in
utero as long as possible. If these measures are ineffective and
eclampsia supervenes (see below), then urgent delivery should
be considered, provided the fetus is viable, since this results in
an immediate cure.
30.8 Risk factors for pre-eclampsia
• Previous history of
• Pre-existing medical conditions:
pre-eclampsia
Chronic kidney disease
• Multiple pregnancy
Hypertension
• Primiparity
Diabetes mellitus
• Genetic predisposition
Systemic lupus erythematosus
• Obesity
and connective tissue
• Increased maternal age
disease
Adapted from Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal
booking: systematic review of controlled studies. BMJ 2005; 330:565-567.
Medical disorders in pregnancy • 1277
Eclampsia occurs in about 1 % of pregnancies and is associated
with significant mortality. It usually presents with seizures on
a background of pre-eclampsia but rarely can occur before
the onset of hypertension and proteinuria. Treatment is with
intravenous magnesium sulphate and delivery of the fetus as soon
as possible. Women with pre-eclampsia are more likely to develop
hypertension, chronic kidney disease, and cerebrovascular and
ischaemic heart disease in later life.
Respiratory disease
| Asthma
Women with asthma should be managed aggressively during
pregnancy, since poorly controlled asthma is associated with pre¬
eclampsia, fetal growth restriction, low birth weight and pre-term
birth. The management is very similar to that in non-pregnant
individuals. Short-acting and long-acting (3-agonists, inhaled and
oral glucocorticoids and theophylline can be used freely. There
is less experience with leukotriene receptor agonists during
pregnancy but they can be given if necessary. It is advisable to
involve an anaesthetist or intensivist at an early stage in patients
with severe exacerbations of asthma since airway management
is more difficult in late pregnancy.
Respiratory infection
The most common causes of pneumonia during pregnancy
are summarised in Box 30.9. Diagnosis and management are
broadly the same as in non-pregnant patients. Prompt treatment
i
Bacterial
• Streptococcus pneumoniae • Haemophilus influenzae
• Mycoplasma pneumoniae • Staphylococcus aureus
• Legionella
Viral
• Influenza viruses • Varicella zoster
Adapted from Lim I/I/, Macfarlane J, Colthorpe C. Pneumonia in pregnancy.
Thorax 2001; 56:398-405.
of infections is important since mothers with pneumonia are
more likely to deliver early and have low-birth-weight infants
compared with healthy pregnant women.
Bacterial infections
Antibiotics should be given, depending on the causal organism
and sensitivities, along with supplemental oxygen and fluids as
required. Penicillins, cephalosporins and macrolides such as
erythromycin are all safe during pregnancy but tetracyclines
should be avoided because they may be embryotoxic and can
cause staining of the teeth in the fetus (see Box 6.19, p. 120).
Viral infections
Viral pneumonia is more common and often more severe during
pregnancy. Varicella zoster pneumonia in particular is associated
with a high fetal and maternal mortality rate. It presents with
cough, breathlessness and pyrexia, and is usually preceded by
a vesicular rash up to 1 week before. Varicella infection can be
diagnosed clinically, with laboratory confirmation by culture or
polymerase chain reaction (PCR) of fluid from vesicles, or by
serology. Varicella pneumonia causes an interstitial pneumonitis
with a characteristic nodular appearance on chest X-ray
(p. 1270). Women with confirmed varicella zoster pneumonia
should be admitted to hospital for supportive care and treatment
with intravenous aciclovir for 7-1 0 days.
Tuberculosis
Tuberculosis (TB) may occur during pregnancy and in the UK
is more common among African and Asian women. Untreated
TB is associated with premature delivery and low birth weight.
Transmission to the fetus can occur but is unusual. If the
diagnosis of TB is confirmed, then antituberculous chemotherapy
should be given as normal, since the benefit of treating TB in
pregnancy outweighs any potential risks from the medication. A
proportion of pregnant women with TB have coexisting human
immunodeficiency virus (HIV) infection, which confers a poorer
prognosis and also requires treatment with antiretroviral therapy,
as described on page 318.
Gastrointestinal disease
Hyperemesis gravidarum
Hyperemesis gravidarum is a serious condition that affects
about 0.5% of pregnant women. It typically presents during the
first trimester with severe nausea, vomiting and other clinical
features (Box 30.10). It is associated with significant morbidity
and mortality, due to malnutrition and electrolyte imbalance.
Wernicke’s encephalopathy may develop as the result of thiamin
deficiency. Recurrence is common in successive pregnancies.
30.9 Causes of pneumonia during pregnancy
1278 • MATERNAL MEDICINE
30.1 1 Risk factors for gestational diabetes
• Body mass index >30 kg/m2
• Previous macrosomic baby weighing >4.5 kg
• Previous gestational diabetes
• Family history of diabetes (first-degree relative with diabetes)
• Family origin with a high prevalence of diabetes:
South Asian (specifically women whose country of family origin is
India, Pakistan or Bangladesh)
Black Caribbean
Middle Eastern
30.10 Clinical features of hyperemesis gravidarum
• Weight loss of >5%
• Electrolyte imbalance:
• Severe nausea and vomiting
Hyponatraemia
• Dehydration
Hypokalaemia
• Ketosis
Flypomagnesaemia
The cause is unknown and the diagnosis is one of exclusion,
since alternative causes of severe nausea and vomiting need
to be ruled out, particularly if the onset of symptoms occurs
after the first trimester. Management is with lifestyle advice
and support, intravenous fluids, electrolyte replacement and
antiemetics. Thiamin and glucocorticoids may be required in
the most severe cases.
| Inflammatory bowel disease
Women with inflammatory bowel disease (IBD) should be
counselled prior to planning a pregnancy. Medications such
as azathioprine, sulfasalazine, 5-aminosalicylic acid (5-ASA),
glucocorticoids and tumour necrosis factor alpha (TNF-a) inhibitors
can be continued as normal during pregnancy but methotrexate
must be stopped at least 3 months before conception because of
its teratogenic effects. Since poorly controlled IBD is associated
with an increased risk of pre-term birth, low birth weight and
miscarriage, it is important for the disease to be well controlled
before conception. The activity of IBD can increase during
pregnancy and ulcerative colitis is more likely to flare than Crohn’s
disease. Women who experience disease flares should be
managed by both medical and obstetric teams, and monitored
closely. The TNF-a inhibitors infliximab and adalimumab are
actively transported across the placenta in the third trimester
and there is theoretical concern about immunosuppression in the
neonate. Infants of mothers who have been treated with TNF-a
inhibitors during the second and third trimesters should not be
given live vaccines and should be monitored closely for any signs
of infection. Most women with uncomplicated IBD can have a
normal vaginal delivery and do not need a caesarean section,
but the need for this should be assessed on an individual basis
by obstetric and medical teams.
Diabetes
It is important to institute meticulous glucose control in pregnancy,
as maternal diabetes is associated with increased risks of
congenital malformations, stillbirth, pre-eclampsia, pre-term
delivery, operative delivery, neonatal hypoglycaemia and admission
to neonatal intensive care.
Gestational diabetes
Gestational diabetes is defined as diabetes with first onset or
recognition during pregnancy. This definition will include a few
patients who develop type 1 diabetes during pregnancy, where
prompt action and early insulin treatment will be required, and
some patients who develop type 2 diabetes, or had unknown
pre-existing type 2 diabetes, in whom the diabetes does not remit
after pregnancy. Flowever, in most cases, gestational diabetes
develops due to an inability to increase insulin secretion adequately
to compensate for pregnancy-induced insulin resistance, and
most women can expect to return to normal glucose tolerance
immediately after pregnancy. Risk factors for gestational diabetes
are shown in Box 30.1 1 .
The diagnosis of gestational diabetes is based on maternal
blood glucose measurements that are associated with increased
fetal growth. An international consensus recommended that
glucose values diagnostic of gestational diabetes should be
lower than those for non-gestational diabetes (see Box 20.31 ,
p. 753). Controversy remains about who should be screened, and
the screening strategy depends, in part, on the population risk. It
is widely accepted that women at high risk for gestational diabetes
should have an oral glucose tolerance test at 24-28 weeks, and
some guidelines recommend that all high-risk women should be
screened by measuring HbA1c, fasting blood glucose or random
blood glucose at the first booking visit. It should be noted that
measurements of HbA1c cannot reliably be used to diagnose
diabetes in early pregnancy and until 3 months post-partum,
since HbA1c levels fall due to increased red cell turnover.
Management
The aim is to normalise maternal blood glucose concentrations
and reduce the risk of excessive fetal growth. The first element
of management is dietary modification, in particular by reducing
consumption of refined carbohydrate. Women with gestational
diabetes should undertake regular pre- and post-prandial self¬
monitoring of blood glucose, aiming for pre-meal blood glucose
levels of <5.3 mmol/L (96 mg/dL) and a 1-hour post-prandial
level of <7.8 mmol/L (1 42 mg/dL) or a 2-hour post-prandial level
of <6.0 mmol/L (109 mg/dL). If pharmacological treatment is
necessary, metformin, glibenclamide or insulin can all be used.
Glibenclamide should be used rather than other sulphonylureas
because it does not cross the placenta. Other oral therapies
or injectable incretin-based therapies should not be given in
pregnancy.
After delivery, maternal glucose usually returns to pre-pregnancy
levels. In the UK, it is currently recommended that women
with gestational diabetes should have a fasting blood glucose
measured at 6 weeks post-partum and have HbA1c concentrations
measured annually to screen for the development of diabetes.
This is because even those whose glucose tolerance returns to
normal post-partum are at increased risk for developing type 2
diabetes, with a 5-year risk between 15 and 50%, depending on
the population. Therefore, all women who have had gestational
diabetes should be given diet and lifestyle advice to reduce their
risk of developing type 2 diabetes (p. 743).
I Pregnancy in women with
established diabetes
Maternal hyperglycaemia early in pregnancy (during the first
6 weeks post conception) can adversely affect fetal development,
causing cardiac, renal and skeletal malformations, of which the
caudal regression syndrome (abnormal development of the lower
Medical disorders in pregnancy • 1279
part of the spine) is the most characteristic. The risk of fetal
abnormalities is about 2% for non-diabetic women and about
4% for women with well-controlled diabetes (HbA1c <53 mmol/
mol) but more than 20% for those with poor glycaemic control
(HbA1c >97 mmol/mol). Therefore, it is important for women
with diabetes to aim to achieve good glycaemic control before
becoming pregnant. In addition, high-dose folic acid (5 mg
daily, rather than the usual 400 jig) should be initiated before
conception to reduce the risk of neural tube defects.
As for gestational diabetes, mothers should attempt to maintain
near-normal blood glucose levels while avoiding hypoglycaemia
throughout their pregnancy, as this minimises excessive fetal
growth and neonatal hypoglycaemia. This is often difficult to
achieve, however. Pregnancy is also associated with an increased
risk of ketosis, particularly, but not exclusively, in women with
type 1 diabetes. Ketoacidosis during pregnancy is dangerous
for the mother and is associated with a high rate (1 0-35%) of
fetal mortality.
Pregnancy is linked with a worsening of diabetic complications,
most notably retinopathy and nephropathy, so careful monitoring
of eyes and kidneys is required throughout pregnancy. If heavy
proteinuria and/or renal dysfunction exist prior to pregnancy,
there is a marked increase in the risk of pre-eclampsia, and
renal function can deteriorate irreversibly during pregnancy.
These risks need to be carefully discussed before a woman
with diabetes is considering pregnancy. The outlook for
mother and child has been vastly improved over recent years
but pregnancy outcomes are still not equivalent to those of
non-diabetic mothers. Perinatal mortality rates remain 3-4 times
those of the non-diabetic population (at around 30-40 per 1 000
pregnancies) and the rate of congenital malformation is increased
5-6-fold.
Endocrine disease
| Thyroid disease
Iodine deficiency
Iodine deficiency is a major public health issue in many countries,
particularly in South-east Asia, the Western Pacific and Central
Africa. Severe iodine deficiency in pregnancy is associated with
miscarriage, stillbirth and cretinism, with significant cognitive
impairment, gait abnormalities and deafness in the affected
child. More moderate iodine deficiency is associated with
milder forms of cognitive impairment and affects millions of
people. The World Health Organisation recommends a daily
iodine intake of 250 |ig/day for pregnant women. Treatment of
iodine deficiency in the first and second trimesters can prevent
impaired cognitive development but is less effective if started in
the third trimester.
Hypothyroidism
Untreated hypothyroidism is associated with subfertility and so
is uncommon in pregnancy. Subclinical hypothyroidism is more
common, and is often due to poor adherence to levothyroxine
in known primary hypothyroidism. Most pregnant women
with primary hypothyroidism require an increase in the dose
of levothyroxine of approximately 25-50 jig daily to maintain
normal TSH levels because there is an increased requirement for
thyroxine during pregnancy. Furthermore, inadequately treated
maternal hypothyroidism may be associated with impaired brain
development in the fetus. Because of this, hypothyroid women
should be monitored closely if planning a pregnancy; they should
be advised to have their thyroid function checked as soon as
possible after conception and increase their daily levothyroxine
dose if necessary. During pregnancy, serum TSH and free T4
should be measured during each trimester and the dose of
levothyroxine adjusted to maintain a normal TSH level. Rarely,
hypothyroidism may present during pregnancy with weight gain,
constipation and lethargy. The diagnosis is easily missed since
these symptoms are common in normal pregnancy. If suspected,
the diagnosis can be confirmed by checking thyroid function
tests, which show a raised TSH and low free T4.
Hyperthyroidism
The coexistence of pregnancy and thyrotoxicosis is unusual,
since anovulatory cycles are common in thyrotoxic patients and
autoimmune disease tends to remit during pregnancy, due to
suppression of the maternal immune response. Thyroid function
tests must be interpreted in the knowledge that thyroid-binding
globulin, and hence total T4 and T3 levels, are increased in
pregnancy and that the normal range for TSH is lower (see
Box 18.18, p. 651). Despite this, a fully suppressed TSH is
usually indicative of Graves’ disease. When thyroid disease
during pregnancy is being dealt with, both mother and fetus
must be considered, since maternal thyroid hormones, TSH
receptor antibodies (TRAb) and antithyroid drugs can all cross
the placenta to some degree, exposing the fetus to the risks of
thyrotoxicosis, iatrogenic hypothyroidism and goitre. Moreover,
poorly controlled thyrotoxicosis can result in fetal tachycardia,
intrauterine growth retardation, prematurity, stillbirth and possibly
even congenital malformations.
Antithyroid drugs are the treatment of first choice for
thyrotoxicosis in pregnancy. Newly diagnosed hyperthyroidism
during pregnancy can be treated with p-adrenoceptor antagonists
(p-blockers) in the short term, followed by antithyroid drugs.
Propylthiouracil (PTU) is the preferred antithyroid drug because
treatment with carbimazole during the first trimester has been
associated with the occurrence of choanal atresia and aplasia
cutis. Hyperthyroid women who become pregnant while taking
carbimazole or PTU should be advised to continue their current
drug in pregnancy, with close monitoring. Both carbimazole and
PTU cross the placenta and are effective in treating thyrotoxicosis
in the fetus caused by transplacental passage of TRAb. To avoid
fetal hypothyroidism, which can affect brain development and
cause goitre, it is important to use the smallest dose of antithyroid
drug (typically <150 mg PTU or 15 mg carbimazole per day)
that will maintain maternal free T4, T3 and TSH concentrations
within their respective reference ranges. Thyroid surgery is
sometimes necessary because of poor drug adherence, drug
hypersensitivity or failure of medical treatment and is most safely
performed during the second trimester. Radioactive iodine is
absolutely contraindicated throughout pregnancy, as it invariably
induces fetal hypothyroidism. Frequent review of mother and
fetus (monitoring heart rate and growth) is important during
pregnancy and in the puerperium. Serum TRAb levels can be
measured in the third trimester to predict the likelihood of neonatal
thyrotoxicosis. PTU is the drug of choice in the breastfeeding
mother, as it is excreted in the milk to a much lesser extent than
carbimazole. Thyroid function should be monitored periodically in
the breastfed child.
Post-partum thyroiditis
Post-partum thyroiditis typically presents 3-4 months after
delivery. It is discussed in more detail on page 647.
1280 • MATERNAL MEDICINE
Pituitary disease
Prolactinoma
Prolactinomas are the most common pituitary tumours in young
women. Although fertility is reduced in patients with prolactinoma,
pregnancies can occur and if this happens the tumour may
enlarge as part of the physiological pituitary enlargement that
takes place during normal pregnancy. Macroprolactinomas
(> 1 0 mm) are at greater risk of enlarging and may cause optic
chiasm compression. If women known to have a prolactinoma
become pregnant, they should have visual field testing each
trimester, followed by pituitary imaging by MRI if enlargement
is suspected from changes in visual fields or from symptoms.
Measurement of serum prolactin is generally not helpful, since
levels increase anyway as part of normal pregnancy. Dopamine
receptor agonists such as cabergoline and bromocriptine should
normally be stopped during pregnancy, but can be reintroduced
if necessary in patients with an enlarging prolactinoma that is
threatening the visual fields.
Diabetes insipidus
Women with pre-existing diabetes insipidus may find that their
symptoms worsen in pregnancy due to placental production of
vasopressinase, a protease that degrades vasopressin (antidiuretic
hormone, ADH). Because of this, pregnant women with diabetes
insipidus may need higher doses of desmopressin until delivery.
The development of symptoms suggestive of diabetes insipidus,
such as thirst and polyuria, during pregnancy should raise
suspicion of acute fatty liver of pregnancy (AFLP), the syndrome
of haemolysis, elevated liver enzymes and low platelets (HELLP)
or pre-eclampsia, as all of these conditions are also associated
with decreased breakdown of vasopressinase by the liver.
Sheehan’s syndrome
This is a form of post-partum hypopituitarism caused by
infarction of the pituitary, usually associated with hypotension
from major post-partum haemorrhage. It can present with failure
to establish lactation after birth, amenorrhoea or other features
of hypopituitarism. The diagnosis can be confirmed by tests of
pituitary function and treated with hormone replacement, as
described on page 682.
Parathyroid disease
Primary hyperparathyroidism
Primary hyperparathyroidism (PHPT) is uncommon in women of
child-bearing age, but if pregnancy does occur in a patient with
pre-existing PHPT, careful monitoring is required. Women with
mild disease can be managed conservatively but if serum calcium
levels rise above 2.85 mmol/L (1 1 .5 mg/dL), consideration should
be given to parathyroidectomy, as fetal mortality is high (up to
40%) in patients with severe hypercalcaemia. If parathyroidectomy
is required, it should ideally be performed during the second
trimester. Anecdotal evidence suggests that the calcimimetic
drug cinacalcet can be used for medical management of PHPT
during pregnancy.
Familial hypocalciuric hypercalcaemia
Familial hypocalciuric hypercalcaemia (FHH) is a benign disorder
caused by mutations in the calcium-sensing receptor, which
is described on page 664. Although FHH poses no risk for
pregnant women, the hypercalcemia can suppress PTH secretion
in neonates that do not inherit the FHH mutation, resulting in severe
hypocalcaemia. Infants of mothers with FHH should have their
serum calcium levels monitored during the first few days of life; if
hypocalcaemia is detected, intravenous calcium should be given.
Adrenal disease
Women with known adrenal insufficiency can continue their
glucocorticoid and mineralocorticoid replacement during pregnancy
as normal. Rarely, adrenal insufficiency can present for the first
time during pregnancy. If this occurs, the diagnosis is challenging
because total cortisol normally increases during pregnancy, and
short Synacthen tests (p. 672) can be falsely normal. Specialist
assessment is required. In women with Conn’s syndrome
who become pregnant, amiloride should be substituted for
spironolactone to prevent anti-androgenic effects on a male fetus.
Human immunodeficiency virus infection
The course of HIV disease is not altered by pregnancy but
treatment with antiretroviral therapy should be given during
pregnancy to women that are HIV-positive, as outlined on
page 326. In some societies, routine HIV testing is recommended
at an early stage in pregnancy in all women.
Inflammatory rheumatic disease
Most women with inflammatory rheumatic disorders have
successful pregnancies but it is critically important for them to
be given pre-conception counselling and to review medication
use, optimise disease control and make them aware of the risks
that pregnancy might pose to their condition and vice versa.
| Rheumatoid arthritis
Women with rheumatoid arthritis should have a medication
review; methotrexate, leflunomide and mycophenolate should
be stopped and, if necessary, an alternative substituted before
conception (Box 30.12). Rheumatoid arthritis often improves
during pregnancy, particularly in those who are negative for
rheumatoid factor or anti-cyclic citrullinated peptide antibodies.
There is an increased risk of pre-eclampsia, pre-term birth and
small babies for women with active disease, emphasising the
importance of maintaining disease control during pregnancy.
Glucocorticoids, hydrochloroquine, azathioprine and sulfasalazine
can all be continued as normal but non-steroidal anti-inflammatory
drugs (NSAIDs) should be avoided after 20 weeks (Box 30.12).
Inhibitors of TNF-a are safe during pregnancy and can be
continued if necessary to maintain control of the disease. Most
TNF-a inhibitors are actively transported across the placenta
and this can lead to immunosuppression in the neonate if these
drugs are used during the second and third trimesters. An
exception is certolizumab, which is a pegylated antibody, and
this is a good option for women who require TNF-a inhibition
during pregnancy. Experience with other biological therapies
during pregnancy is limited. Disease flares are common in the
post-partum period, regardless of serology, and this can pose a
problem for breastfeeding and care of the infant. Glucocorticoids
are a good short-term option to control such flares, pending
reintroduction of other disease-modifying antirheumatic drugs
(DMARDs) that might have been stopped prior to pregnancy.
Systemic sclerosis
Pregnancy in women with diffuse systemic sclerosis (SSc), those
with pulmonary hypertension or renal involvement and those with
disease of recent onset (<4 years) poses risks to mother and
Medical disorders in pregnancy • 1281
30.12 Safety of antirheumatic drugs during pregnancy and breastfeeding
Drug
Safe during pregnancy
Safe during breastfeeding
Comment
Non-steroidal anti-inflammatory
drugs (NSAIDs)
Yes (<20 weeks)
Yes
Hydroxychloroquine
Yes
Yes
Glucocorticoids
Yes
Yes
A good short-term option for disease flares
Azathioprine
Yes
Yes
Sulfasalazine
Yes
Yes
Co-prescribe with folic acid
Ciclosporin
Yes
Yes
Data on breastfeeding limited
Tacrolimus
Yes
Yes
Mycophenolate
No
No
Stop before planning pregnancy
Methotrexate
No
No
Stop 3 months before planning pregnancy
Leflunomide
No
No
Stop 2 years before planning pregnancy
Cyclophosphamide
No
No
Tumour necrosis factor (TNF)
Yes
Yes
Avoid live vaccines in the neonate for
inhibitors
6 months
Adapted from Ateka-Barrutia 0, Nelson-Piercy C. Connective tissue disease in pregnancy. Clin Med 2013; 131:580-584.
30.13 Systemic sclerosis (SSc) and pregnancy
Subtype
Effect of disease on pregnancy
Localised SSc
Good prognosis
Raynaud’s may improve
Oesophagitis may worsen
CREST syndrome
Good prognosis
Raynaud’s may improve
Oesophagitis may worsen
Diffuse SSc
Increased risk of:
Pre-term delivery
Pre-eclampsia
Fetal growth restriction
Low-birth-weight babies
Maternal and fetal mortality
(CREST = calcinosis, Raynaud’s phenomenon, oesophageal involvement,
sclerodactyly and telangiectasia)
fetus. In milder forms of the disease, however, the prognosis is
better (Box 30.13). Raynaud’s phenomenon often improves during
pregnancy due to vasodilatation but oesophageal symptoms may
worsen. Renal crises are no more frequent during pregnancy, but
if one occurs, ACE inhibitors should be given. Although these
are normally contraindicated in pregnancy, the potential benefit
in this situation outweighs the risk to the fetus. Glucocorticoids,
which can be given to promote fetal lung maturation in premature
babies, should be avoided in women with SSc where possible
because they may provoke renal crisis.
Systemic lupus erythematosus
Pregnancy in women with systemic lupus erythematosus (SLE)
poses several risks to both mother and fetus, especially if there
is renal involvement. There is an increased risk of pre-eclampsia,
thrombosis, fetal growth restriction, pre-term delivery, miscarriage
and fetal death. There is also a higher risk of lupus flare during the
puerperium. Good control of disease is paramount, since women
with SLE who conceive when their disease has been quiescent
for at least 6 months are less likely to have complications than
30.14 Differential diagnosis of lupus flare
during pregnancy
Clinical finding
Lupus flare
Pre-eclampsia
Normal
pregnancy
Hypertension
Yes
Yes
No
Proteinuria
Yes
Yes
No
Red cells/casts
in urine
Yes
No
No
Liver function
tests
Normal
Abnormal
Normal
Anti-double-
stranded DNA
Increase
Unchanged
Unchanged
C3 and C4
Low
Elevated or
unchanged
from baseline
Unchanged
those who conceive when their disease has recently been active.
It can be difficult to assess disease activity during pregnancy
because symptoms such as oedema, hair loss, joint pain and
fatigue, which occur in active SLE, are also common during normal
pregnancies. The features in Box 30.14 can help differentiate
between an SLE flare, normal pregnancy and pre-eclampsia.
All women with SLE should be tested for anti-Ro and anti-La
antibodies, since they can cross the placenta and cause
neonatal complete heart block or cutaneous lupus, respectively.
Medications should be reviewed prior to pregnancy, to ensure
they are safe, and an alternative substituted if necessary (see
Box 30.12). The management of patients with antiphospholipid
antibodies (aPL) is described below.
Anti-phospholipid syndrome
Primary antiphospholipid syndrome (APS) is associated with
an increased risk of adverse pregnancy outcomes, including
thrombosis, miscarriage, fetal death and pre-eclampsia. This
applies to primary APS and that associated with connective
tissue diseases such as SLE. During pregnancy, women with
APS should be managed with low-dose aspirin in combination
with low-molecular-weight heparin (LMWH).
1282 • MATERNAL MEDICINE
Cardiac disease
| Congenital heart disease
Women who have a history of surgically corrected congenital
heart disease generally tolerate pregnancy well, but are more
likely to have babies with congenital heart disease and should
be offered fetal cardiac scans. Acyanotic heart diseases, such
as atrial septal defect, ventricular septal defect and patent
ductus arteriosus, all have a good prognosis in pregnancy.
Unrepaired cyanotic heart disease has a very poor prognosis in
pregnancy, as does pulmonary hypertension, regardless of the
underlying cause. Women with mechanical heart valves require
anticoagulation throughout pregnancy but their anticoagulation
should be planned with consideration of substituting warfarin
with LMWH and aspirin during the first trimester to reduce the
risk of warfarin embryopathy. If necessary, warfarin can be used
during pregnancy, particularly in the second and third trimesters.
Valvular heart disease
The physiological changes of pregnancy may also unmask
previously undiagnosed valvular disease. Women with regurgitant
lesions, such as mitral regurgitation and aortic regurgitation,
tolerate pregnancy better than those with stenotic lesions. Mitral
stenosis causes a reduction in blood flow from the left atrium
to left ventricle in diastole, which worsens during pregnancy
due to the increased heart rate and hypervolaemia. Those with
moderate to severe mitral stenosis (valve area < 1 .5 cm2) are at
particular risk and may develop arrhythmias, tachycardia and
pulmonary oedema. Most patients can be managed medically
with (3-blockers, LMWH and furosemide as necessary. Surgical
intervention is indicated if there is continued haemodynamic
compromise despite optimal medical management.
| Myocardial infarction
Pregnancy increases the risk of myocardial infarction. While
atherosclerosis is the main cause in non-pregnant individuals,
coronary artery dissection and coronary thrombosis secondary
to the hypercoagulable state are more common causes during
pregnancy. Management is similar to that of non-pregnant
women, except that statins and glycoprotein llb/llla inhibitors
such as apixaban should be avoided. Clopidogrel can be given
but should be stopped around the time of delivery to reduce the
risk of uterine bleeding and to allow spinal anaesthesia to be used
if necessary. Stenting can be performed, but bare-metal stents
are preferred because drug-eluting stents require dual antiplatelet
therapy that cannot be continued around the time of delivery.
Aortic dissection
Pregnancy is an independent risk factor for aortic dissection and
this should be considered when a woman presents with acute
severe chest pain during pregnancy. The vast majority of cases
in pregnancy are ‘type A’, involving the ascending aorta (see
Fig. 16.72, p. 506), and require careful control of hypertension,
caesarean section to deliver the fetus, and emergency surgery
to treat the aneurysm.
Peripartum cardiomyopathy
Peripartum cardiomyopathy (PPCM) presents with heart failure
secondary to left ventricular systolic dysfunction towards the
end of pregnancy or in the months following delivery. It is a
diagnosis of exclusion, made when other causes of heart failure
have been ruled out. The cause is unknown but PPCM is more
prevalent in women who are older, multiparous, hypertensive
and Afro-Caribbean. It is treated by conventional medications for
heart failure, including ACE inhibitors if necessary, and delivery of
the baby. Many women recover within 3-6 months of diagnosis
but the prognosis is variable. There is a significant chance of
reduction in cardiac function in subsequent pregnancies.
Dilated cardiomyopathy
Dilated cardiomyopathy carries a poor prognosis if the pre¬
pregnancy ejection fraction is below 30% or if symptoms are
in New York Heart Association grades 3 or 4. Management is
as described for PPCM.
Renal disease
|Renal tract infection
Pregnancy predisposes women to urinary tract infection. If
asymptomatic bacteriuria is discovered during pregnancy, it
should be treated promptly with antibiotics, to prevent ascending
renal tract infection. Pyelonephritis is more common in pregnancy
due to the physiological dilatation of the upper renal tract; if it
does occur, it can trigger premature labour.
Acute kidney injury
Acute kidney injury (AKI) may occur during pregnancy or in the
puerperium due to a variety of causes (Box 30.1 5). Women with
AKI caused by pre-eclampsia are prone to pulmonary oedema,
and need very careful fluid balance to avoid fluid overload. In the
post-partum period, AKI may occur as the result of post-partum
haemorrhage or pre-eclampsia, and sometimes these occur in
combination. Although pre-eclampsia resolves after delivery, AKI
can be at its worst in the first few days post-partum, especially
when exacerbated by obstetric haemorrhage.
Glomerular disease
Proteinuria caused by glomerular disease is usually exacerbated
during pregnancy, and nephrotic syndrome may develop without
any alteration in the underlying disease activity in individuals
who had only slight proteinuria before pregnancy. This further
increases the risk of venous thromboembolism, the leading
cause of maternal deaths in developed countries.
Chronic kidney disease
Women with chronic kidney disease (CKD) are at increased risk
of pre-eclampsia, fetal growth restriction, miscarriage, pre-term
delivery and fetal death (Fig. 30.3). Pregnancy can also cause
acceleration of maternal renal decline. The factors that influence
pregnancy outcome for women with CKD are baseline renal
function, hypertension, degree of proteinuria and the underlying
cause of CKD. Women with CKD should have pre-pregnancy
counselling, be closely monitored by a multidisciplinary team
throughout pregnancy, and be given low-dose aspirin as
prophylaxis against pre-eclampsia.
|Renal replacement therapy
Fertility is reduced among women on renal replacement therapy
and there is increased risk of adverse pregnancy outcomes.
Medical disorders in pregnancy • 1283
30.15 Causes of acute kidney injury in pregnancy
Mechanism
Cause
Features
Pre-renal
Hyperemesis gravidarum
Post-partum haemorrhage
Placental abruption
Septic abortion
Nausea and vomiting
Dehydration
Presentation in first trimester
Vaginal bleeding immediately post-partum
Abdominal pain or vaginal bleeding in second or third trimester
Presentation with hypotension, shock and pyrexia
Renal
Pre-eclampsia
Thrombotic thrombocytopenic purpura
Acute fatty liver of pregnancy
Acute interstitial nephritis
Presentation in second and third trimesters with new-onset hypertension and proteinuria
Possible antenatal or post-partum presentation with headache, irritability and drowsiness
Haematology shows thrombocytopenia and microangiopathic haemolytic anaemia
Presentation with vomiting and abdominal pain in third trimester
Abnormal liver function tests
Liver ultrasound can be normal
Most common cause is use of non-steroidal anti-inflammatory drugs
Post-renal
Acute urinary retention
Usual presentation is in third trimester due to enlarged uterus causing ureteric obstruction;
sometimes presents post-partum
Adapted from Palma-Reis 1, Vais A, Nelson-Piercy C, et al. Renal disease and hypertension in pregnancy. Clin Med 2014; 13:57-62.
Creatinine <125 ii Creatinine >180
1 Creatinine 125-180 ||| Dialysis
100
90
Fetal growth Pre-term Pre- Fetal death
retardation delivery eclampsia
Fig. 30.3 Adverse pregnancy outcomes in chronic kidney disease.
Creatinine is in pmol/L To convert to mg/dL, multiply by 0.011. Data from
Williams D, Davison D. Chronic kidney disease in pregnancy. BMJ 2008;
336:211-115.
Despite this, many women receiving renal replacement
therapy have successful pregnancies. More intensive dialysis is
recommended in pregnancy, and particular attention should be
paid to addressing issues around blood pressure, fluid balance
and anaemia.
Renal transplant recipients
Pregnancy should be delayed for a minimum of 12 months
following renal transplantation, to allow the graft to stabilize,
on minimum immunosuppressive drugs. The outcome is best
for women with a well-functioning graft, with no proteinuria or
hypertension. Women with renal transplants can deliver vaginally
but in practice there is a higher incidence of caesarean section
in this group, due to the higher incidence of pre-term delivery.
Liver disease
Specific causes of liver disease during pregnancy are discussed
below.
30.16 Criteria for diagnosis of acute fatty liver
of pregnancy
• Vomiting
• Abdominal pain
• Polydipsia/polyuria
• Encephalopathy
• Elevated bilirubin (>14 pmol/L (>0.82 mg/dL))
• Low glucose (<4 mmol/L (<72.4 mg/dL))
• Elevated urate (>340 pmol/L (>5.7 mg/dL))
• Leucocytosis (>11x1 09/L)
• Ascites or bright liver on ultrasound
• Elevated transaminases (alanine/aspartate aminotransferase (ALT/
AST) >42 U/L)
• Elevated ammonia (>47 pmol/L (>81.7 mg/dL))
• Renal impairment (creatinine >150 pmol/L (>1.7 mg/dL))
• Coagulopathy (prothrombin time >14 secs or activated partial
thromboplastin time >34 secs)
• Microvascular steatosis on liver biopsy
Acute fatty liver of pregnancy can be diagnosed when
>6 of the above features are present in the absence of
another explanation.
Adapted from Ch’ng CL, Morgan M, Hainsworth I, et al. Prospective study of liver
dysfunction in pregnancy in Southwest Wales. Gut 2002; 51:876-880.
Acute fatty liver of pregnancy
Acute fatty liver of pregnancy (AFLP) is a rare and serious
condition that typically presents in the third trimester with
vomiting, abdominal pain, jaundice and other symptoms (Box
30.16). It is more common in first pregnancies and multiple
pregnancies, and is associated with male fetuses. Rarely, fulminant
liver failure may occur. The diagnosis can usually be made
on the basis of the clinical features, abnormal liver function
tests (LFTs) and the appearances of fatty liver on ultrasound.
A liver biopsy is rarely needed to make the diagnosis but
shows microvascular steatosis. Management is with supportive
care and by delivery of the fetus. The development of AFLP
has been linked in some cases with an inherited deficiency
of the enzyme long-chain acyl-CoA dehydrogenase (LCHAD)
in the baby.
1284 • MATERNAL MEDICINE
HELLP syndrome
The syndrome of haemolysis, elevated liver enzymes and low
platelets (HELLP) is thought to be part of the spectrum of
pre-eclampsia. It usually presents antenatally but can also
appear for the first time in the postnatal period. The presenting
symptoms can be the same as those of pre-eclampsia but can
also include headache, right upper quadrant pain and visual
disturbance. HELLP can be complicated by liver haematoma
and capsular rupture. Management involves supportive care,
control of hypertension, correction of coagulopathy and delivery
of the fetus.
Obstetric cholestasis
Obstetric cholestasis is estimated to affect about 1 % of pregnancies
in Caucasians, although the prevalence is higher in Chinese and
South Asian populations. The cause is incompletely understood
but the condition is thought to be due in part to the cholestatic
effect of high oestrogen levels. The typical presentation is in the
third trimester with pruritus, particularly affecting the soles and
palms. Laboratory testing reveals raised levels of bile acids and
abnormal LFTs. The diagnosis can be made on the basis of these
clinical features when other causes of liver dysfunction and pruritus
have been excluded. Treatment is with ursodeoxycholic acid in
a starting dose of 250 mg twice daily, which usually improves
symptoms and liver function. Aqueous cream with menthol can
also be effective in soothing pruritus. There is an increased risk
of fetal mortality with evidence of a particularly high risk when
bile acid levels are over 40 |imol/L (97.9 jig/mL). Treatment
therefore aims to bring bile acids below 40 |imol/L and some
centres induce labour before 40 weeks in an effort to reduce
the risk. The risk of recurrence in future pregnancies is high.
| Viral hepatitis
The course of hepatitis B is unchanged in pregnancy, but it is
important to identify women who have active infection to reduce
the risk of vertical transmission to the fetus; this risk is up to 90%
in women who are hepatitis B e-antigen positive. Vaccinations
and immunoglobulin should be given to infants of mothers
who test positive for hepatitis B, and antiviral agents should be
given to the mother after delivery. Vertical transmission rates of
hepatitis C are low in the absence of HIV infection and so no
action is required for the infant, unless there is co-infection with
HIV; in this case, antiviral drugs should be considered. Pregnant
women are at greater risk of contracting hepatitis E than the
non-pregnant population. It is transferred via the faeco-oral route,
and is usually a mild self-limiting illness outside of pregnancy.
However, it can cause fulminant hepatic failure in up to 20%
of pregnant women.
Neurological disease
Epilepsy
Women with epilepsy should have pre-pregnancy counselling
and should be advised to take high-dose folic acid from pre¬
conception; their antiepileptic drugs (AEDs) should also be
reviewed. Maternal treatment with sodium valproate is associated
with a higher rate of fetal malformations than other AEDs, and a
reduction in intelligence quotient and an increased risk of autistic
spectrum disorder in the offspring. Where possible, sodium
valproate should be substituted for another AED with a better
safety profile in pregnancy, such as lamotrigine, levetiracetam or
carbamazepine. While pregnancy does not generally affect the
frequency of seizures in women with well-controlled epilepsy,
those who enter pregnancy with poorly controlled epilepsy are
likely to deteriorate. The plasma levels of some AEDs such as
lamotrigine can fall in pregnancy and checking drug levels can
be helpful. Seizures are more common at the time of delivery
and women should be advised to deliver in a unit staffed with
personnel able to manage this.
| Idiopathic intracranial hypertension
Idiopathic intracranial hypertension (IIH) may worsen during
pregnancy due to weight gain. Treatment with acetazolamide
can be continued during pregnancy but should be avoided in the
first trimester due to lack of safety data. The mode of delivery is
not affected by IIH and spinal analgesia can be given as normal.
Migraine
Migraine often improves during pregnancy but if attacks occur
they should be managed with simple analgesia and antiemetics.
If necessary, prophylaxis can be given with aspirin, (3-blockers or
tricyclic antidepressants. Safety data on use of triptans during
pregnancy are limited but reassuring. Triptans can therefore be
used for the treatment of migraine if other therapies are ineffective.
Stroke
Stroke is twice as common in pregnant women as in non¬
pregnant women of the same age. The risk is highest during
the third trimester and puerperium. The management of stroke
during pregnancy is similar to that in non-pregnant patients. The
risk of cerebral venous thrombosis is greatly increased during
pregnancy. The presentation is with headache, seizures and
neurological deficits such as hemiparesis. If the diagnosis is
suspected, neuroimaging should be performed with MRI or CT
venography. Management of acute infarct should be as for the
non-pregnant patient and include consideration of thrombolysis.
Psychiatric disorders
Mood changes are common during pregnancy but more
severe psychiatric disorders, such as depression or psychosis,
typically present within 2-4 weeks of delivery. These disorders
are discussed in more detail on page 1206 and in Box 28.33.
Haematological disease
Anaemia
The causes of anaemia during pregnancy are summarised in
Box 30.17. Iron deficiency anaemia is most commonly due to
a 20% increased demand for iron. In most cases, it responds
well to oral iron supplementation, with a rise in haemoglobin of
approximately 0.8 g/L per week. If the haemoglobin does not
rise following a 4-week trial of iron supplementation, alternative
causes of anaemia should be considered. Non-adherence to
oral iron is common and intravenous iron should be considered
in women with iron deficiency and failure of oral treatment.
It is generally not necessary to investigate iron deficiency
anaemia during pregnancy unless there is clinical evidence
of gastrointestinal blood loss, which should be investigated in
the normal way.
Medical disorders in pregnancy • 1285
30.17 Causes of anaemia in pregnancy
Microcytic
• Iron deficiency
• Thalassaemia
• Haemoglobinopathies
Normocytic
• Anaemia of chronic disease
• Haemolysis
• Haemorrhage
Macrocytic
• Vitamin B12/folate deficiency
• Alcohol excess
• Liver disease
Rhesus disease
Women who are negative for the Rhesus antigen should be
offered treatment with anti-RhD immunoglobulin around the time of
delivery to reduce the risk of haemolytic disease of the newborn.
More details are provided on page 933 and in Box 23.19.
| Thrombocytopenia
The causes of thrombocytopenia during pregnancy are
summarised in Box 30.18. The most common cause is gestational
thrombocytopenia, which typically occurs towards the end of
pregnancy and resolves spontaneously after delivery. It is not
associated with adverse pregnancy outcomes and requires no
specific intervention. Pregnancy may occur in women with pre¬
existing idiopathic thrombocytopenic purpura (ITP, p. 971). This
should be managed with glucocorticoids and/or immunoglobulin,
with the aim of maintaining the platelet count above 80x1 09/L
at the time of delivery, in case spinal anaesthesia or caesarean
section is required. Thrombocytopenia may also occur as a
component of haemolytic uraemic syndrome (HUS, p. 408) and
thrombotic thrombocytopenic purpura (TTP, p. 979). Both are
characterised by microangiopathic haemolytic anaemia, acute
kidney injury and thrombocytopenia, but in TTP neurological
symptoms and fever also occur. These conditions are rare but
important to recognise since up to one-quarter of cases occur
during pregnancy and the post-partum period. TTP is managed
with plasma exchange, fresh frozen plasma and sometimes
glucocorticoids or rituximab. Platelet transfusion should be
avoided.
30.18 Causes of thrombocytopenia during pregnancy
• Gestational thrombocytopenia
• Idiopathic thrombocytopenic purpura
• Systemic lupus erythematosus
• HELLP (haemolysis, elevated liver enzymes and low platelets)
• Haemolytic uraemic syndrome
• Thrombotic thrombocytopenic purpura
|j/enous thromboembolism
The risk of venous thromboembolism (VT E) is 4-5 times higher
in pregnancy than in non-pregnant women. DVT is the most
common presentation and predominantly affects the left leg
in pregnancy, for reasons that are incompletely understood.
Doppler ultrasound scan is the investigation of choice, but MRI
can also be used if proximal clot is suspected. Measurement
of D-dimer is not useful in pregnancy because levels rise as
part of normal pregnancy. Treatment of VTE in pregnancy
is with LMWH at a higher dose than for the non-pregnant
woman, based on the patient’s early pregnancy (booking)
weight. Women with a previous history of VTE who are receiving
warfarin or other oral anticoagulants as prophylaxis should
have these stopped prior to conception and LMWH should
be substituted.
Further information
British Thoracic Society/Scottish Intercollegiate Guidelines Network.
SIGN 141 - British guideline on the management of asthma.
Edinburgh: Health Improvement Scotland; 2014. Useful asthma
guidelines.
Royal College of Obstetricians and Gynaecologists. Thromboembolic
disease in pregnancy and the puerperium: acute management.
Green top guideline. London: RCOG; April 2015. A useful
evidence-based guideline on the investigation of pulmonary
embolism in pregnancy.
Websites
npeu.ox.ac.uk/mbrrace-uk National Perinatal Epidemiology Unit: a very
useful resource with detailed and extensive information on causes of
maternal deaths, stillbirths and infant deaths in the UK.
30
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Adolescent and
transition medicine
Transition from paediatric to adult health services 1288
Functional anatomy and physiology 290
Endocrine changes 1 290
Physical changes 1 290
Cognitive and behavioural changes 1 292
Investigations 1293
Clinical assessment 1293
Presenting problems in transition medicine 1294
Problems with adherence 1 294
High-risk behaviour 1 295
Unplanned pregnancy 1 295
Clinical presentations 1296
Neurological disease 1 296
Respiratory disease 1 297
Cardiovascular disease 1 297
Oncology 1 298
Renal disease 1 298
Organ transplantation 1 299
Diabetes 1 299
Gastrointestinal disease 1 299
Rheumatology and bone disease 1300
Summary 1300
1288 • ADOLESCENT AND TRANSITION MEDICINE
Historically, childhood illnesses were characterised by a series of
acute episodes, often infective, on a background of an otherwise
healthy patient. Adult medicine traditionally comprised patients
with progressive conditions, and increasing pathology with
advancing age. A number of factors have led to the recognition
that boundaries between adult medicine and paediatric care are
not clear-cut, and recent evidence has confirmed that anticipating
and carefully planning the transition of children with long-term
conditions (LTCs) into adult services improve care and outcomes.
About 14% of children in the developed world are diagnosed with
an LTC and in the majority of patients the disorder will persist into
adulthood. Common illnesses include asthma, epilepsy, congenital
heart disease, diabetes and childhood cancer (Box 31 .1). Similar
trends are developing worldwide, with increasing survival rates
of children with complex pathology, and increasing prevalence
of lifestyle- related conditions such as obesity, hypertension and
type 2 diabetes. Specific factors that make transition planning
important in young people with LTCs are outlined in Figure 31 .1 .
Planning the process of transition from paediatric to adult health
services and improving the assessment of young people as they
enter those adult services have been shown to impact positively
on long-term health outcomes. There is a need for physicians
to gain new skills in the care of young people and adults who
have conditions that have arisen in childhood. This includes
developing specific skills in the management of adolescents and
young adults, managing the process of transition and developing
knowledge of relevant medical conditions. The overall approach
to transition medicine, as well as important disease-specific
issues, will be considered in this chapter.
31 .1 Important long-term conditions of childhood
that affect adult health
Neurology
• Epilepsy • Duchenne muscular dystrophy
• Cerebral palsy
Respiratory medicine
• Cystic fibrosis
Endocrinology
• Diabetes mellitus
Cardiology
• Hypertrophic obstructive • Congenital heart disease
cardiomyopathy
Nephrology
• Renal insufficiency • Renal transplant
Gastroenterology
• Inflammatory bowel disease
Rheumatology
• Inflammatory rheumatic
• Osteogenesis imperfecta
disease
• Hypophosphataemic rickets
Oncology
• Survivors of childhood cancer
Infectious disease
• HIV/AIDS
• Malaria
High rates
of loss to
follow-up
New clinical
specialties, e.g.
adult congenital
heart disease
Adolescence
associated with
non-adherence
Survivors
of previously
lethal conditions
Ongoing
medical problems,
or complications
of previous
therapy
Improve outcome
Fig. 31.1 Reasons to consider transition planning.
Transition from paediatric to adult
health services
Effectiveness of transition planning
A review of the effectiveness of transition planning has confirmed
improved health outcomes when specific interventions to
improve coordination between adult and paediatric services are
implemented. Most research in this field has been undertaken
with young people with diabetes, and many of the outcome
measures relate to that condition. The principles of transition
planning and the potential benefits are, however, likely to be
generalisable to other LTCs that present in childhood. Young
people with serious LTCs are among the most complex and
high-risk patients to care for in adulthood, and it is important
to work closely with them as they move to adult services, to try
to improve their long-term outcome.
General principles of transition planning
Paediatric services are organised and delivered in a very different
way to adult medical services. They encompass a period of life
that spans from infancy to independence, and progress from
taking parents’ views as paramount to needing to recognise
Dependent Transition Autonomous
Education
Graduation
Employment
Financially Employment/ Financially
dependent benefits independent
Pre-pubertal
Adult
Puberty relationships,
family planning
Live with Leave home , Independent
family living
Parents
parental . Patient takes
oversee care control responsibility
Fig. 31.2 Lifestyle changes during transition to adulthood.
Transition from paediatric to adult health services • 1289
the wishes of the young person. After transition, young people
move from medical services that have been family-centred and
focused around maximising the child’s development, to a service
that encourages patient autonomy, in which employment and
reproduction are important measures of outcome. At the same
time as undergoing transition within medical services, young
people are making multiple other transitions in their lives as
they move from a dependent to an independent way of living
(Fig. 31 .2). They often move away from the family home, and
parents who formerly held responsibility for patient management,
coordination of care, communication and consent to treatments
will be demoted to an advisory role. Paediatric services are not
well placed to meet this change in focus from the patient as a
child to the patient as an independent adult, and young people
benefit from the move to adult services as long as their specific
needs as a young adult are recognised.
Principles of prescribing during transition
Hepatic drug metabolism increases from neonatal levels during
childhood, eventually decreasing to adult levels after puberty.
Once puberty has been completed, teenagers can be considered,
in pharmacokinetic and pharmacodynamic terms, to behave like
adults. It is important to remember that many young people
have considerably lower body mass and therefore body mass
index (BMI) than adults, and care needs to be taken to avoid
excessive dosage in physically smaller patients. Likewise, obesity
31.2 Core elements in developing a transitional
care programme
Establishing transition policy
• Develop policy, with input from young people
• Train staff in operation of policy
Tracking and monitoring
• Establish process to identify patients
• Develop systems to track individual progress
• Incorporate transition planning into clinical care
Transition readiness
• Identify suitable adult care provider
• Establish process for introduction to adult team
• Provide written information about joint first consultation
Transition planning
• Ensure communication between paediatric and adult teams
• Identify need for handover consultation
• Prepare written medical handover:
Diagnosis
Current treatment
Previous key issues
• Send relevant information in advance
• Provide information and community support
Transfer to adult services
• Arrange first consultation
• Review transfer package with team
• Identify concerns of young person
• Review young person’s health priorities
• Update medical summary and emergency care plans
Integration into adult services
• Communicate with paediatrics and confirm transfer
• Help young adult to access other adult services
• Continue individualised care plan tailored to young person
• Seek feedback from young adult about transition
needs consideration in terms of prescribing and drug doses. The
general advice is that when prescribing a dose per kilogram,
the optimal weight for height rather than actual weight should
be used for obese young people.
A systematic approach to transition planning
Several steps need to be undertaken to develop a successful
programme for transition of care. The key components are
summarised in Box 31 .2. The first step is to establish a policy
in consultation with young people and train staff in the policy.
Subsequently, systems need to be developed to identify patients
in need of transition and track them as they pass through the
programme. Adult health-care providers need to be identified and
processes developed for introducing the young person to the adult
team. This should be followed by written communication between
the paediatric and adult teams, and then a first consultation
with the adult team at which the transfer can be reviewed and
31 .3 Key features in assessing readiness for
transition to adult services
(K) Knowledge
1 . Describes condition, effects and prognosis
2. Understands medication purpose and effects
3. Understands treatment purposes and effects
4. Knows key team members and their roles
(S) Self-advocacy
1 . Can attend part/whole clinic appointment on their own
2. Knows how to make appointments/alter appointments
3. Has understanding of confidentiality
4. Orders repeat prescriptions
5. Takes some/complete responsibility for medication/other treatment
6. Knows where to get help
(H) Health and lifestyle
1 . Understands importance of diet/exercise/dental care
2. Understands impact of smoking/alcohol/substance use
3. Understands sexual health issues/pregnancy/sexually transmitted
infections
(A) Activities of daily living
1 . Self-care/meal preparation
2. Independent travel/mobility
3. Trips/overnight stays away from home
4. Benefits/financial independence
(V) Vocational
1 . Current and future education/impact of condition on career plans
2. School attendance and performance
3. Work experience and access to careers advice
4. Outside activities and interests
5. Disclosure to school/employer
(P) Psychosocial
1 . Self-esteem/self-confidence
2. Body/self-image
3. Peer relationships/bullying
4. Support networks/family/disclosure to friends
5. Coping strategies
(T) Transition
1 . Understands concept of transition
2. Agrees transition plan
3. Attends transition clinic
4. Visits adult unit (if appropriate)
5. Sees primary care team/other clinical staff independently
1290 • ADOLESCENT AND TRANSITION MEDICINE
1 2 years
1 4 years
1 6 years
1 8 years
20 years
22 years
24 years
26 years
Make aware of
transition planning
Initiate planning
Prepare for adult model
Discuss transfer
Transfer to adult service with
transfer package
Integrate into adult care
Fig. 31.3 Timing of transition.
a care plan developed. There should subsequently be written
communication between the adult and paediatric teams to confirm
that handover has occurred, followed eventually by integration
of the young person’s care into the adult service.
A number of organisations have published guidelines to planning
transition services. Two of the best known include the ‘Ready
Steady Go’ programme in the UK and the American Academy
of Paediatrics’ ‘Got Transition’ (see ‘Further information’). Details
of the sorts of competencies that a young person might need
before making a full transition to adult medical services are
outlined in Box 31 .3.
When should transition happen?
The optimum timing for transition is not specifically defined; it
is a process that evolves over a number of years, during which
puberty and then adolescence occur. Transition should generally
be initiated at around 1 2 years of age. Completion time then
varies from person to person, also depending on the model of
adult services available. Most commonly, full transition occurs
between 1 6 and 1 8 years of age (Fig. 31 .3). This coincides with
many other areas where young people are considered to have
made the transition to adulthood, such as the completion of
formal education. Marriage and children often follow.
Functional anatomy and physiology
Puberty and adolescence are developmental stages through
which children progress during the second decade of life. During
this phase, several physical, biochemical and emotional changes
occur. The most important are discussed in more detail below.
Endocrine changes
The hormonal and physical stages of progression through puberty
in males and females are summarised in Figure 31 .4. Puberty is
initiated by pulsatile increases in gonadotrophin-releasing hormone
(GnRH) by the hypothalamus, which in turn stimulates pulsatile
release of luteinising hormone (LH) and follicle-stimulating hormone
(FSH) by the pituitary. In males, the increased production of LH
stimulates Leydig cells in the testes to produce testosterone,
and FSH acts on Sertoli cells to stimulate sperm production, as
described on page 651 and shown in Figure 18.13. The rise in
testosterone increases skeletal growth, promotes development of
the male genital organs and stimulates growth of pubic, facial and
axillary hair. In females, FSH and LH act on the ovary to promote
follicle production, ovulation and menstruation, as described on
page 652 and shown in Figure 18.14. Other hormonal changes
in all adolescents include a rise in adrenal androgens and a
rise in growth hormone, which in turn stimulates production
of insulin-like growth factors 1 and 2 (IGF-1 and IGF-2). Insulin
production also rises by about 30% during puberty. These
hormonal changes contribute to the biological, morphological
and psychological changes seen during the teenage years.
Adolescence (as opposed to puberty) comprises not only the
physical changes of puberty, but also the wider emotional and
psychological changes of progression into early adulthood. The
emotional and psychological changes are associated with physical
maturation but also with sociocultural influences. The normal
feelings and behavioural development of normal adolescence
are complex but tend to follow fairly predictable patterns.
Physical changes
In girls, there is an increased rate of growth, followed soon after
by the development of breasts and pubic hair. Menstruation
typically starts after the rate of growth has peaked. In boys,
puberty begins with testicular enlargement, followed soon after
by a growth spurt and the development of pubic hair. In clinical
practice, Tanner staging is used as a method of documenting
progression of physical changes that occur during puberty (Fig.
31 .5). The average age at onset of puberty in the UK is about
1 1 years in girls and 12 years in boys but normal puberty has a
very wide range of onset. Factors that are important in predicting
age of onset of normal puberty include family history (age of
onset is strongly predicted by the parents’ pattern of onset) and
body mass, with heavier children entering puberty at a younger
age. The current trends towards improved nutritional status and
increased obesity in particular are driving earlier onset of puberty.
Delayed puberty is defined to have occurred when the age at
onset is more than 2.5 standard deviations above the national
average, which in the UK is about 1 3 years in girls and 1 4 years
in boys. If puberty is delayed beyond this point, investigations
may be needed to determine the underlying cause, as detailed
on page 653. Many children who have had long-term health
conditions during childhood experience a delayed onset of puberty
because chronic ill health slows longitudinal growth and causes
functional hypogonadotrophic hypogonadism. Glucocorticoid
therapy also contributes to growth retardation in children with
chronic inflammatory diseases. An X-ray of the left wrist can be
used to assess bone age accurately, and a bone age that is
more than 2 years behind the chronological age should prompt
consideration of further investigations (p. 654).
Functional anatomy and physiology
1291
Higher cerebral
centres ‘trigger’"
puberty
Acne appears
Axillary hair appears
Breasts develop
Uterus enlarges
Menstruation begins
Vaginal epithelium
comities
GnRH/
Pituitary LH and
FSH secretion
increased
Prolactin
ACTH-
LH and FSH-
Adrenal Adrenal
androgens cortices
increased
Reticular zone
enlarges
Oestrogen
produced Ovaries
- z(Z?*
Progesterone
increased
Higher cerebral
centres ‘trigger’
puberty
GnRH
Pituitary LH and
LSH secretion
increased
Prolactin
-ACTH
-LH and FSH
Adrenal Adrenal
cortices androgens
increased
Reticular zone
enlarges
Testes
Testosterone
increased
Acne appears
Facial hair appears
Musculature
develops
Larynx enlarges
(voice deepens)
Axillary hair appears
Some breast
enlargement
may occur
Pubic hair appears
Penis, prostate and
seminal vesicles
enlarge
Epiphyseal union
hastened
Fig. 31.4 Hormonal events of puberty. [A] In the ovary, FSH acts on granulosa cells to stimulate oestrogen production, whereas LH acts on theca
cells to stimulate progesterone production. Androgens are also produced in small amounts by theca cells in response to LH (not shown). [§] In the male,
LH acts on interstitial Leydig cells to stimulate testosterone production. FSH with testosterone acts on Sertoli cells to stimulate spermatogenesis. (ACTH =
adrenocorticotrophic hormone; FSH = follicle-stimulating hormone; GnRH = gonadotrophin-releasing hormone; LH = luteinising hormone) From Smith RP.
Netter’s Obstetrics and gynecology, 2nd edn. Philadelphia: Saunders, Elsevier, Inc.; 2008.
1292 • ADOLESCENT AND TRANSITION MEDICINE
Tanner
stage
IV
V
Female
Breast
Pre-adolescent
Elevation of breast
and papilla as a
small mound
Further enlargement
of breast and areola
with no separation
of contours
Projection of
areola and papilla
to form mound
above breast
Mature stage.
Projection of papilla
with recession of
areola to contour
of breast
Pubic
hair
Male
None
Sparse, long and
straight
Darker, coarse and
curled hair
Darker, coarse and
curled hair but
covering smaller
area than in adult.
No spread to medial
surface of thighs
Dark, coarse and
curled hair
extending to inner
thighs
Genitalia
Pre-adolescent
Pubic
hair
None
Growth of testes
and scrotum. Skin
on scrotum
reddens and
becomes wrinkled
Sparse, long and
straight
Growth of penis and
further growth of
testes and scrotum.
Skin of scrotum
becomes darker and
more wrinkled
Darker, coarse and
curled hair
Further growth in
length and width
of penis, testes
and scrotum
Darker, coarse and
curled hair but
covering smaller
area than in adult
Penis, testes
and scrotum of
adult size
Dark, coarse and
curled hair
extending toward
umbilicus
Fig. 31.5 Tanner staging of puberty.
Cognitive and behavioural changes
As young people move from their early teenage years to later
adolescence there is a move away from the family towards
personal independence. This is often characterised by change from
a self-centred focus, associated with a sense of awkwardness and
worries about being normal, towards increased self-confidence
and an awareness of weaknesses in parents and others in
authority. In late adolescence, young people reach a stage of
self-reliance, increased emotional stability and improved ability to
think ideas through. Finally, young adults begin to develop firm
belief systems, autonomy and independence. With time, there
is reduced conflict with parents and other figures in authority
and full maturity develops.
In terms of cognition, there is a transition from being mostly
interested in the present, in short-term outcomes and instant
gratification, through to increased concern for the future and
a greater focus on one’s longer-term role in life. Sexuality and
relationships clarify during adolescence, and individuals move from
early awkwardness and uncertainty to a firmer sense of their sexual
identity, and then development of more serious and longer-term
relationships. In terms of morals and values, young people move
from a period of risk-taking behaviour and experimentation through
to understanding the potential consequences of such behaviour
for their future health and well-being. Young adults develop a
greater capacity for setting personal goals and an increased focus
on self-esteem. Finally, family, social and cultural traditions regain
some of their previous importance, and by the time young people
emerge from adolescence, they have usually developed insight
and a greater focus on self-esteem and long-term well-being. It is
the development of these more mature personality traits that are
important for the more active role in health care that is needed to
function well within an adult model of medicine. Some teenagers
do vary slightly from these broad patterns but the feelings and
behaviours described are, in general, considered normal for each
stage of adolescence. Understanding these changes in emotional
and psychological behaviour underpins the approaches that are
needed to meet the challenges of managing long-term conditions
in older teenagers and young adults.
Clinical assessment • 1293
31.4 Biochemical changes during transition
Analyte
Comment
Alanine aminotransferase
(ALT)
Increased during adolescence
Activity may continue to rise, at
least in men, until middle age
Alkaline phosphatase (ALP)
Activity higher in infancy, decreases
during childhood, and rises again
with skeletal growth during puberty
Peak in females at median 11
years and in males at 1 3 years
Levels decrease rapidly after
puberty, particularly in girls; adult
levels achieved after epiphyses
fused
Insulin-like growth factor 1
Levels 30% higher during
adolescence
Serum creatinine
Increases steadily from infancy to
puberty parallel to development of
skeletal muscle; until puberty, there
is little difference in concentration
between males and females
Uric acid concentration
Decreases from high levels at birth
until 7-10 years of age, then
increases, especially in boys, until
1 6 years
Investigations
Several changes take place during adolescence in terms of skeletal
growth, organ development and body composition, which can
influence the interpretation of results. Examples include fusion of
the epiphyses as puberty progresses, increases in bone mineral
content and density as the skeleton grows, and changes in
the reference range of certain biochemical tests. Most of these
changes occur gradually during puberty and there are rarely abrupt
alterations in adult biochemical concentrations. It is important
to use age-adjusted biochemical reference ranges until puberty
has been completed. Several biochemical changes take place
in the composition of body fluids between infancy and puberty.
Some of the key changes in biochemical markers are outlined
in Box 31 .4. More detail on reference ranges for specific analytes
is provided in Box 35.9 (p. 1363). The elevation in alkaline
phosphatase (ALP) levels during adolescence relates to the bone
isoenzyme produced by osteoblasts in the growing skeleton
during the growth spurt. Further investigations for raised levels
of ALP are not required in adolescence, as long as other liver
function tests, including y-glutamyl transferase (GGT), are normal.
In general, under normal physiological conditions, the reference
ranges of most biochemical tests remain fairly constant between
puberty and menopause in women and between puberty and
middle age in men.
Clinical assessment
The initial patient consultation at transition is of vital importance
for establishing a potentially life-long professional relationship
with the patient, as well as identifying key features in the history,
examination and assessment of their overall needs. Parents
commonly attend a first adult appointment with their son or
daughter, and it is usually necessary to allow longer for this initial
31.5 Features in transition assessment
Features of history and/or
examination
Reason
History*
Main/presenting condition and
detailed review of clinical
course
Understand detail and severity of
illness; understand which treatments
have been undertaken and which
have been successful
Family history:
Draw family tree of all
first-degree and any
relevant/affected
second-degree family
members
Many long-term conditions arising
during childhood have significant
genetic and familial factors to be
taken into account
Current drug therapy,
significant previous therapies
Many drugs have significant
long-term implications, levels may
need monitoring, may have
teratogenic effects to consider
Any surgical or other relevant
medical history
Understand which treatments have
been undertaken and which have
been successful
Pubertal status/age of
menarche
Helps assess disease severity plus
patterns of growth
Informs about patient’s reproductive
health and family-planning wishes
Social history:
In education or in work?
Receiving appropriate
benefits/support?
Financial or other practical
concerns?
Living with parents/left
home?
Assesses wider effects of patient’s
health on their independent living, as
well as their financial and practical
circumstances
Can be a proxy measure of disease
severity and identifies their support
mechanisms, which also helps in the
assessment of their current needs
Systems enquiry
Any other related/unrelated
symptoms or problems
Physical examination
Height, weight, calculation of
body mass index
Blood pressure
Urinalysis if relevant
Assessment of pubertal status
General physical examination
Although young people are often
accompanied by a parent, examine
them separately and use this
opportunity to consider asking about
private matters, such as partners,
sexual activity, and drug or alcohol
use
Throughout the first consultation, confidence and competence in decision¬
making/capacity to consent should be assessed. If there are concerns about
capacity, clarify key decision-makers.
assessment. Often, the first transition appointment is undertaken
jointly with the paediatrician in a specialist transition clinic and this
will enable a thorough face-to-face handover of all the key facts.
A detailed transition referral letter should clearly describe the
diagnosis, current and previous treatments, and key interventions
that have been undertaken while the patient was under the care
of paediatric services. It is important to check the main details
with the young person and to make sure there are no other
factors that they feel are of relevance. There are a few features
in the history that merit special attention, particularly at the first
consultation, as outlined in Box 31 .5. Many young people with
an LTC attend their first adult outpatient department consultation
with their parents, and it is important either to create a time to
ask personal and lifestyle-related questions separately from the
main history - that is, privately - or to make sure that these can
be confidentially explored in future.
1294 • ADOLESCENT AND TRANSITION MEDICINE
Presenting problems
in transition medicine
Problems with adherence
Adherence is defined as ‘the extent to which a person’s behaviour,
in terms of taking medications, following diets, or executing
lifestyle changes, coincides with medical or health advice’. The
term ‘adherence’ is used in preference to ‘compliance’ because it
focuses on whether a person actively adheres to the regimen rather
than passively follows the doctor’s orders. It also implies partnership
and cooperation between the patient and the care-giver. More
recently, clinicians have moved to seeking patients’ concordance
with management plans. Concordance refers to a consultation
process that has an underlying ethos of shared decision-making. It
has become clear that current levels of adherence do not deliver the
full benefits of medication. Historical paternalistic medical practice
does not maximise the chances of patients adopting the changes
and treatments they need to improve their outcomes. Reaching a
concordant position with patients involves a range of approaches
(such as patient-centred ness or shared decision-making) and a
number of specific actions (such as exploring anxieties about
medication side-effects, individualising regimes to suit the patient’s
lifestyle, offering a range of treatment options) and has not been
evaluated comprehensively.
Adherence to clinic attendance, investigation and treatment
often falls significantly in adolescence and during transition to
adult services. Measurement of adherence is challenging and
reported rates vary according to the method of assessment.
Teenagers may also have varying adherence levels within their
treatment regimen. An important example is in patients who
have undergone organ transplantation, in whom low adherence
to immunosuppressive medication is a significant cause of
graft rejection and may cause death. Adherence merits careful
consideration when caring for adolescents and young adults, and
focusing on strategies to improve adherence at this initial stage
of patient management can deliver life-long improvements in
health outcomes. Young teenagers mainly believe in things that
they have directly experienced and do not fully appreciate the
unseen consequences of not taking their medications. In time,
i
Negative factors
• Older adolescent
• Mental health issues with care-giver
• Family conflicts
• Complex therapy
• Medication with side-effects
• Denial of illness
Positive factors
• Positive family functioning
• Close friends
• Internal locus of control
• Treatment with immediate benefits
• Patient’s belief in seriousness of illness and efficacy of treatment
• Physician empathy
31.6 Factors affecting adherence
31.7 SIMPLE strategies to improve adherence
Simplify regimen
• Use once daily/twice daily regimes if possible
• Match regimen to bedtime and meals
• Use pill box or alarms on phone
• Organise services around patient (combined clinics, flexible timing and
appointments)
Impart knowledge
• Share decision-making
• Provide clear instructions:
Limit to three or four major points
Use simple, everyday language
Use written information or pamphlets and verbal education at all
encounters
• Supply addresses of quality websites
• Provide advice on how to cope with medication costs
Modify patient beliefs
• Empower patients to self-manage their condition:
Ask about their needs
Ask what might help them become and remain adherent
Ensure they understand the risks of not taking their medication
Address fears and concerns about taking the medication
Provide communication
• Improve interviewing skills
• Practise active listening
• Provide emotional support - treat the whole patient and not just the
disease
• Provide clear, direct and thorough information
• Elicit the patient’s input in treatment decisions
• Allow adequate time for patients to ask questions
• Build trust
Leave the bias
• Learn more about low health literacy and how it affects patient
outcomes
• Consider care of ethnically and socially diverse patient populations
• Acknowledge biases in medical decision-making (intentional or
unintentional)
• Address dissonance of patient-provider race/ethnicity and language
• Take extra time to overcome cultural barriers
• Ask specifically about attitudes, beliefs and cultural norms around
medication
• Use culturally and linguistically appropriate targeted patient
interventions
• Increase engagement, activation and empowerment
• Tailor education to the patient’s level of understanding
Evaluate adherence
• Direct:
Number of repeat prescriptions
Biomarkers of response
Measurement of drug levels
• Indirect:
Self-reporting: ‘When did you last forget your medicine?’; ‘How
often have you forgotten your medicines this week?’
Excerpted with permission from the American College of Preventive Medicine. Medication Adherence: Improving Health Outcomes Time Tool: A Resource from the American
College of Preventive Medicine. 2011. Retrieved from https://webmail2.tst.nhs.uk/go/www.acpm.org/7MedAdhereTTProviders.
Presenting problems in transition medicine • 1295
adolescents learn to develop hypothetical thinking and to analyse
more complex information and decision-making. The ability to
engage in formal thinking is inconsistent at first, and at times
of stress (such as during an illness) adolescents may regress
to more simple ways of problem-solving. Despite their maturing
skills, they may remain self-centred and feel invincible. Factors that
positively and negatively affect adherence are outlined in Box 31.6.
Interventions to improve adherence are summarised in Box 31 .7.
Recent literature suggests that two-way communication
between patients and professionals about medicines leads to
improved satisfaction with care, knowledge of the condition and
treatment, adherence, health outcomes and fewer medication-
related problems. Younger adults and those coming to adult
services following transition from paediatric services have very
different expectations in terms of the nature of the patient-doctor
relationship and are more likely to require a more collaborative
approach to development of management plans to maximise
their concordance with treatment in the long term.
High-risk behaviour
The high-risk behaviour that can be undertaken by adolescents
is well documented and is seen across many cultures. It is
important to assess this by history-taking at the time of transition
(Box 31 .8) Adolescents who have had LTCs during childhood
31.8 History-taking in adolescent patients:
risk-taking behaviours (‘HEADS’)
Home life
• Relationships
• Household chores
• Social support
Education
• School
• Career
• Exams
• University
• Work experience
• Financial issues
Activities
• Peers, people that patients
• Exercise and sport
can rely on
Driving
• Aged 16 if disabled
Drugs
• Cigarettes and alcohol: how
• Non-prescription drugs
much, how often
Diet
• Nutritional content (calcium,
• Caffeine (diet drinks)
vitamin D)
• Binges/vomiting
• Weight
Sex
• Concerns
• Contraception (in relation to
• Periods
medication)
Sleep
• Amount
• Frequent waking
• Difficulty getting to sleep
• Early waking?
Suicide
• Depression
• Disabled adolescent men
• Mood
high-risk
From Segal TY. Adolescence: what the cystic fibrosis team needs to know. J R
Soc Med 2008; 101(Suppl 1):15-27.
are at greater risk of undertaking harmful behaviour and there
is evidence that a poor long-term health outlook is associated
with risk-taking behaviour earlier in life.
Globally, the leading causes of death among adolescents are
road injury, human immunodeficiency virus (HI V) infection, suicide,
lower respiratory infections and interpersonal violence; many of
these deaths are linked to risk-taking behaviours such as excess
alcohol and drug intake. Quite apart from mortality, there are
other significant adverse events linked to risk-taking behaviour
in adolescents: excess alcohol ingestion is also associated with
non-fatal road traffic accidents, unwanted and unprotected sexual
activity, and violence as both perpetrator and victim.
There are a number of theories about the neurodevelopmental
changes associated with these behaviour changes. At around
1 1 years of age, the prefrontal cortex (PFC) and parietal lobes
begin a period of pruning of neuronal axons. It is theorised that
these changes represent the start of the process of increasing
frontal lobe control. A separate process that occurs at the same
time predisposes the adolescent to risk-taking behaviour and
impulsivity: frontostriatal reward circuits mature relatively early
and encourage the adolescent towards adult activities such as
alcohol and drug use, and sexual intercourse, which carry potential
health risks. At this stage, the PFC has not yet matured to the
point where the individual can assess risk adequately. The PFC
and its connections are structurally unable to provide sufficient
control. It is thought that this maturational gap in PFC control
of the pleasure-seeking brain systems is responsible for the
risk-taking lifestyle that characterises the period of adolescence.
A number of studies have investigated personality and other
factors that contribute to different risk-taking behaviours during
adolescence: essentially, younger adolescents and females tend
to rate activities as being more risky, and are therefore less likely
to undertake them. Older males and those of lower educational
status are higher risk takers. Specific protective factors include
high self-esteem and a strong orientation to an internal locus
of control; young people who feel they have less control and
influence over themselves and their behaviour are more likely
to undertake high-risk activities. Many teenagers with serious
long-term health conditions are disempowered in a number of
ways and there is evidence that they are predisposed to be
high risk takers during adolescence. Examples of risk-taking
behaviour include not only alcohol and drug intake, but also
non-adherence to medicines and other aspects of health care,
such as diet in diabetes.
It is not easy to affect behaviour during this period of non¬
adherence. Isolated educational intervention is not sufficient to
improve outcome; for example, there is a wealth of evidence
showing that teenagers know about the behaviours needed to
prevent transmission of HIV, but many do not adhere to this
advice. Long-term health-care providers have an invaluable role
in supporting adolescents during this period of their development
as adults, as many important health-related and lifestyle habits
are established during this period: more than 90% of smokers
start smoking in adolescence, and life-long habits around eating
and exercise are laid down during the teenage years. Focusing
on the needs of the emerging adult for autonomy and using
the highest levels of communication and patient engagement
significantly improve outcomes for patients with LTCs.
Unplanned pregnancy
In many parts of the world, females commonly undergo their first
pregnancy during or just after adolescence. The median age for
1296 • ADOLESCENT AND TRANSITION MEDICINE
mm
31.9 Adolescent pregnancy rates
Region
Pregnancy rate (/1 000 women
aged 15-19 years)
Tanzania
124
Kenya
94
Jamaica
71
Mexico
65
South Africa
52
USA
33
Pakistan
28
New Zealand
26
UK
26
Spain
11
France
6
Japan
5.3
Italy
4.5
South Korea
2.2
first pregnancy varies from 1 9 years in India and parts of Asia,
through to 25 years in the USA and around 30 years in Australia
and Western Europe. Teenage pregnancy rates are high across
the world (Box 31 .9). Information from the UK suggests that 1
in 6 pregnancies is unplanned, and 1 .5% of women between
the ages of 18 and 45 face an unplanned pregnancy each
year. It is therefore vital to anticipate and discuss the issues
surrounding reproductive health with all young people before
and during transition, as well as during early adulthood. Young
people with serious LTCs have a number of additional factors
to be taken into consideration when discussing reproduction,
and these discussions need to take place long before a family is
planned. General physicians do not need to be able to undertake
complex genetic counselling and investigation, but should be
able to provide advice about the recurrence risk of common
inherited conditions, as well as that of the more common
multifactorial LTCs, many of which have an inherited or genetic
component.
Clinical presentations
In almost every clinical setting, there is the potential for a young
adult with a serious LTC that has arisen during childhood to
present to adult physicians. Medical services can improve the care
and outcome for this vulnerable group by planning a systematic
approach to transition, as described above, and by focusing the
clinical consultation on issues of relevance and importance to
each particular patient. The key issues to consider for a number
of the most common LTCs of childhood are discussed below.
Neurological disease
Epilepsy
Epilepsy is a chronic disorder, the hallmark of which is recurrent,
unprovoked seizures (p. 1097). Epilepsy that has presented during
childhood, as opposed to adulthood, is less often associated
with underlying central nervous system malignancy and is well
controlled with first-line anticonvulsants in around 80% of cases.
Young people who still have epilepsy or are on anticonvulsant
therapy as they progress into adulthood are more likely to have
underlying structural brain disease, such as cerebral palsy, or
have more complex or syndromic epilepsy. In many of them,
epilepsy may be associated with learning difficulties or other
neurological conditions.
Epilepsy presents several problems during transition. Adherence
to medication can be an issue and patients with low adherence
to epilepsy medicines have higher mortality, higher hospital
admission rates and higher emergency department attendances.
Conversely, high adherence rates at initiation of epilepsy therapy
are associated with improved long-term seizure freedom and
higher seizure freedom at 4 years. Epilepsy can also affect
employment options for young people, as about 30% of patients
still have breakthrough seizures while on treatment. Certain types
of employment, such as working within the emergency services
or armed forces, or becoming a pilot or driver of a heavy goods
vehicle, may therefore not be possible. Driving restrictions may
also limit options for some other occupations (p. 1103). Young
women with epilepsy should be advised that oral contraceptives
are less effective with enzyme-inducing antiepileptic drugs; they
should also be made aware of the risk of teratogenicity with
many antiepileptic drugs, most notably sodium valproate, which
should be avoided in pregnancy if at all possible. Pre-conceptual
counselling is desirable for all young girls with epilepsy and
pre-conceptual folic acid supplementation is advisable to reduce
the risk of neural tube defects.
Alcohol use in moderation does not affect seizure control in
the majority of patients, but withdrawal from alcohol in dependent
patients is epileptogenic and heavy alcohol use should be
discouraged. Information about marijuana and epilepsy risk
is lacking, but regular marijuana use and excess drinking are
associated with poor adherence to medication regimes and
increased seizure risk.
Cerebral palsy
Cerebral palsy comprises a range of non-progressive neurological
impairments, present from the time of birth or arising in early
childhood. Although the neuropathology is non-progressive,
the manifestation of problems can evolve, with progressive
motor dysfunction related to increased spasticity and possibly
progressive seizure activity.
Patients with severe cerebral palsy present specific problems
during transition and early adulthood. They may be paraplegic
or quadriplegic and most non-ambulatory individuals have
significant intellectual disability. This group of patients will be
unable to live independently during adulthood and need ongoing
long-term care. Delivering medical care to these individuals
poses several problems, including practical issues such as
consideration of capacity and consent to treatment. Other
comorbidities include gastro-oesophageal reflux (often related
to abnormal lower oesophageal function), seizures, and feeding
difficulties often requiring gastrostomy. These individuals usually
require a complex care package involving many members of the
multidisciplinary team. There are also risks of abuse and neglect
in the care of adults with severe disability and this needs to be
borne in mind when considering atypical problems or unusual
presentations in this vulnerable patient group. Depending on
the severity of the patient’s condition, end-of-life care may
need to be discussed and planned with the family and other
care-givers.
Clinical presentations • 1297
j Muscular dystrophy
The muscular dystrophies are a group of diseases that cause
progressive weakness and loss of muscle mass. The disorders
differ in terms of which muscle groups are affected, the degree of
weakness, and the rate of disease and symptom progression. All
the inherited muscular dystrophies that present during childhood
need active management during transition (p. 1143). One of the
most important and most severe conditions is Duchenne muscular
dystrophy (DMD), which is associated with a progressive decline in
mobility, coupled with cardiac dysfunction due to cardiomyopathy,
and respiratory failure requiring respiratory support as the disease
progresses. Physicians should ensure that the whole family are
aware of the wider genetic issues. Female carriers of the DMD
gene can suffer muscle fatigue and are at risk of cardiomyopathy,
as well as there being obvious risks for their male offspring. On
average, patients with DMD survive until their late teens to early
twenties, and those with less severe muscular dystrophies, such
as Becker dystrophy, survive until their thirties. Although fertility
is reduced, young men with these conditions may themselves
father children. Male offspring will be unaffected but all female
infants of affected males will be carriers.
As the muscular dystrophies progress, a complex package
of care involving a multidisciplinary team is necessary; it should
include respiratory input to assess the need for ventilatory support,
which is a common endpoint for many patients. At the present
time, there is no definitive treatment. Glucocorticoids (0.75 mg/
kg/day) have been shown to improve muscle strength and are
frequently used, but carry an increased risk of osteoporosis
and vertebral fractures. New therapeutic approaches are being
developed with the aim of ameliorating disease progression in
patients with nonsense mutations (p. 42). One involves the use
of drugs such as ataluren, which promotes binding of transfer
RNA (tRNA) molecules at the site of stop codons with a mismatch
in one base (near-cognate tRNAs). These cause a full-length
protein to be produced with an amino acid substitution rather
than a truncated non-functional protein. Patients with DMD
usually require social and financial support. It is important to
consider end-of-life care plans with patients and family members.
Involvement from palliative care teams, as well as psychological,
spiritual and wider non-medical support, is essential.
Respiratory disease
Cystic fibrosis
Cystic fibrosis (CF) is a single-gene autosomal recessive disorder
that affects about 1 in 2000 to 1 in 3000 individuals of Caucasian
descent (p. 580). Clinical manifestations are caused by defects
in an ion transporter termed the cystic fibrosis transmembrane
conductor regulator (CTFR) protein. With improved supportive
care, the median survival in the UK is now more than 50 years. It
is well recognised that young people with life-limiting conditions
face particular challenges during transition: individuals often
exhibit high-risk behaviour during adolescence, and this was
particularly true in the past when long-term survival rates were
poor. The rates of non-concordance with medication and
with time-consuming physiotherapy and nebuliser regimes are
high and adversely affect outcome and survival. Exercise
tolerance and employment are likely to be restricted as time
progresses, and patients need particular support managing the
slow decline in function and well-being that occurs throughout their
adult lives.
In terms of fertility and child-bearing potential, the picture is
complex and merits detailed discussion with patients. It is not
often discussed openly by the paediatrician or during childhood,
other than with the parents when the patient is young. The
vas deferens is absent in 98% of males with CF and seminal
vesicular dysfunction means that ejaculates are low in volume.
While boys are infertile, newer reproductive therapies, such as
the availability of intracytoplasmic sperm injection, mean that
fatherhood is possible. The opportunity for assisted reproduction
should be discussed early so that people can make informed
choices at an appropriate stage of their lives. Females with CF
who have good nutritional status and reasonable health status
have normal fertility and genetic counselling should be offered
early. Contraception needs to be discussed with women who
are not planning a pregnancy, since pulmonary hypertension is
an absolute contraindication for the oral contraceptive pill (OCP).
Women also need to be advised about the effects of antibiotics on
OCP effectiveness. New orally available small-molecule therapies,
including lumacaftor and ivacaftor, have recently been licensed;
they can partially rectify functional defects in the CTFR and have
improved outcome. These drugs are having a positive effect on
symptom control and are potentially disease-modifying. Other
therapeutic approaches, including gene therapy and mRNA
editing therapies, are also being explored as treatments for CF.
Common issues encountered during transition of CF patients are
summarised in Box 17.34 (p. 581).
Cardiovascular disease
Congenital heart disease
Congenital heart disease (CHD) is the most common congenital
anomaly, affecting about 1 % of live births. Among birth defects,
CHD is the leading cause of mortality. Maternal illnesses such
as rubella and injection of teratogenic agents during pregnancy,
along with paternal age, all play roles in pathogenesis. Although
some chromosomal anomalies, such as trisomy 13, 18 and 21
and monosomy X (Turner’s syndrome), are strongly associated
with CHD, these account for only 5% of cases. Microdeletion
and single-gene mutations can also be important, such as in
DiGeorge syndrome (22q1 1 .2 microdeletion). Overall, the most
common congenital valvular anomalies are aortic and pulmonary
stenosis. The most common structural anomaly is ventricular
septal defect.
There is a wide range of severity of CHD but many patients
with life-limiting conditions (usually complex structural anomalies
such as tetralogy of Fallot or hypoplastic left heart syndrome)
survive to adulthood. Genetic counselling of affected individuals
is important, as there is a 1-2% recurrence risk of any cardiac
anomaly in offspring. Affected patients should be transitioned
to a cardiologist with experience in CHD since this has become
a subspecialty in own right. More details are provided on
page 531 and in Box 16.103 (p. 537).
Hypertrophic obstructive cardiomyopathy
Hypertrophic obstructive cardiomyopathy (HOCM, p. 539) is a
genetic cardiovascular disease characterised by left ventricular
wall hypertrophy, impaired diastolic filling and abnormalities of the
mitral valve. These features can cause dynamic obstruction of
the left ventricular outflow tract, diastolic dysfunction, myocardial
dysfunction and an increased risk of supraventricular and
ventricular tachyarrhythmias. HOCM is caused by mutations
1298 • ADOLESCENT AND TRANSITION MEDICINE
affecting the genes that encode cardiac sarcomere proteins and
is most frequently transmitted as an autosomal dominant trait. It
may present for the first time during adolescence with cardiac
arrest or sudden cardiac death. Predictive genetic testing is
possible but challenging because of the large number of causal
mutations. In clinical practice, careful analysis of the family
history can be useful in identifying those at risk of inheriting the
disease. If no gene anomaly has been identified within a family,
first-degree relatives may need screening by electrocardiography
(ECG) and echocardiography. Identification of a genetic anomaly
is most helpful in allowing identification of family members who
do not need echocardiograms or clinical follow-up. Children of
affected parents should be screened every 3 years until puberty,
and then annually until 20 years of age. If there is no evidence
of HOCM in early adulthood, it is unlikely that the condition will
develop in later life.
Oncology
Around 1 child in 500 will develop cancer by the age of 14
years. Leukaemia is the most common, accounting for about
33% of cases; central nervous system tumours are the next
most common, accounting for around 25% of all childhood
cancers. Fifty years ago, 75% of children diagnosed with cancer
died, but overall survival rates now range from 75% to 80%.
Between 60% and 70% of young adults who have survived
childhood cancer will develop at least one medical disability,
most commonly as a result of their therapy rather than their
primary cancer. There is a 3-6-fold increased risk of a second
cancer, with an absolute risk of about 10% before 50 years of
age. It is therefore important for these individuals to be kept
under surveillance during transition and beyond.
Endocrine and reproductive disturbances are the most
common late effects, affecting 40-60% of survivors. Infertility
can be an issue in both males and females receiving cytotoxic
medications, unless it has been possible to store semen and
ovarian tissue in advance of treatment. Other long-term risks
include hypopituitarism, growth hormone deficiency and pubertal
delay (especially in boys) from brain irradiation. Radiotherapy to
the neck can cause hypothyroidism and increases the risk of
thyroid cancer. Total-body irradiation offered as conditioning for
bone marrow transplantation affects both ovarian and testicular
function, and many of the chemotherapeutic agents used have
adverse effects on fertility. Chemotherapy-induced ovarian failure
is typically associated with high-dose alkylating agents such
as cyclophosphamide, and this is an independent risk factor
for premature ovarian failure. In recent years, patients have
been offered ovarian and testicular tissue retention and fertility
issues are being discussed with families during childhood, but
often the patients themselves have limited levels of knowledge
of the details. Chemotherapy and radiotherapy in childhood
significantly reduce ovarian reserves. When combined with the
progressive ovarian decline that occurs in all women throughout
adulthood there is a significant risk of premature menopause
or ovarian failure, with 8% of survivors affected. Young women
need to be aware of these risks during their early adulthood to
help with family and lifestyle planning; for example, they may
wish to plan to have children earlier in their adult life rather than
risking ovarian decline.
Cardiomyopathy is another complication of anthracyclines such
as doxorubicin and daunorubicin. Serious cardiac complications
include arrhythmias, dilated cardiomyopathy from myocardial
necrosis, and angina or myocardial infarction arising from vaso-
occlusion or vasospasm.
In addition to physical effects, children who have faced life-
threatening illness in childhood may experience psychological
and family difficulties during adulthood. Cognitive impairment is
more common in children who have received chemotherapy or
radiotherapy to the brain, and problems can include lower IQ,
problems with memory and attention, poor hand-eye coordination
and behaviour/personality problems, combined with the well-
recognised and physical complications of cancer treatment in
childhood.
Increasing recognition of these issues has resulted in active
monitoring programmes for survivors of childhood cancer, who
are best seen in specialist ‘late effects’ multidisciplinary clinics,
where teams include oncologists, psychologists and specialists
from other relevant disciplines.
Renal disease
Chronic kidney disease (CKD, p. 415) accounts for some of
the most complex long-term illnesses in childhood. The most
common causes during childhood and adolescence are shown
in Box 31.10. The primary pathology can be varied and many
conditions have no specific treatment, but the overall approach
to management of progressive renal insufficiency is the same.
Internationally agreed definitions of CKD staging in children differ
from those in adults and are summarised in Box 31 .1 1 . In adults
the rate of albumin excretion is included in CKD definitions, as
outcome correlates with the level of albuminuria, but in children
similar data are lacking and so the staging system is based on
glomerular filtration rate alone. The majority of children with
31.10 Causes of renal impairment in childhood
and adolescence
• Obstructive uropathy
• Renal hypoplasia/dysplasia
• Reflux nephropathy
• Focal segmental glomerular sclerosis
• Polycystic kidney disease
1 _ 1
il
31 .1 1 Staging of chronic kidney disease (CKD) in
children over 2 years of age
Stage
Glomerular filtration
rate (GFR)
(mL/min/1 .73 m2)
Description
1
>90
Normal or high
2
60-89
Mildly decreased
3a
45-59
Mildly to moderately decreased
3b
30-44
Moderately to severely decreased
4
15-29
Severely decreased
5
<15
Kidney failure
Kidney Disease: Improving Global Outcomes (KDIG0) 2012 classification. Chronic
kidney disease is defined either as GFR <60 ml_/min/1 .73 m2 for >3 months,
regardless of whether other CKD markers are present, or as GFR <60 ml_/
min/l .73 m2 accompanied by evidence of structural damage or other markers of
kidney abnormalities, including proteinuria, albuminuria, and pathological
abnormalities in histology or imaging. In adults, albumin excretion is also included
in CKD staging as the level of albuminuria correlates to outcome. These data are
lacking in children and so albuminuria is not used to classify paediatric CKD.
Clinical presentations • 1299
CKD stage 3 or higher will ultimately require renal replacement
therapy but the timescale for reaching this stage can vary widely.
The mainstay of support is to delay progression by treatment
of secondary factors that are known to be associated with
progressive decline in renal function: namely, hypertension,
proteinuria and anaemia.
Organ transplantation
Children requiring renal replacement therapy are the most
common recipients of kidney transplants in childhood. Liver
and heart transplantation, followed by lung and small bowel
transplantation, are well-recognised but less commonly undertaken
procedures. Non-adherence to immunosuppressive regimes
during adolescence is a well-known risk factor for graft failure.
The reported incidence of graft failure due to non-adherence
is 10-15% but this is likely to be an under-estimate. Rates of
non-adherence are highest among adolescents and young adults.
As well as non-adherence to immunosuppression, non-adherence
to testing and clinic attendance adversely affects the care and
outcome of around 1 in 8 kidney transplant patients. Poor
adherence is associated with patients with worse psychological
status and family dysfunction; adherence has been shown to
improve with education and increased motivational factors, as
might be expected. This offers the opportunity to improve graft
survival. At present, 50% of cadaveric grafts and around 68%
of live donor grafts are still functioning 10 years post -transplant.
There is no clear difference between children and adults in
survival of transplanted kidneys.
Many medications used in transplant medicine and in renal
disease can have long-term effects on health. Inhibition of linear
growth is seen even with low doses of glucocorticoids, such as
0.125 mg/kg/day on a long-term basis. Alternate-day regimes are
generally considered preferable in childhood. The height reduction
associated with long-term glucocorticoid use in childhood is
dose-dependent, and even for children with asthma treated
with inhaled glucocorticoids, an average height reduction of
1 .2 cm is reported. This is can also be associated with delayed
puberty, as well as an increased risk of osteoporosis in adulthood.
Post-transplant lymphoproliferative disorders (PTLDs) are a
well-recognised and potentially life-threatening complication in
solid organ recipients. PTLD is the most common malignancy
complicating solid organ transplantation, accounting for 20% of all
cancers. They represent a range of lymphoproliferative disorders,
from infectious mononucleosis and lymphoid hyperplasia to
malignant lymphoma. Most cases of PTLD are associated with
Epstein-Barr virus (EBV), leading to uncontrolled B-cell proliferation
and tumour formation. Up to 10% of solid organ transplant
recipients develop PTLD but the risk is almost four times higher
in patients under 20 years of age, as opposed to those aged
20-50. This increased risk relates mainly to the development
of EBV infection after transplantation; most adults are already
EBV-seropositive at the time of transplantation and therefore at
lower risk of this complication. The type of organ transplant that
has been undertaken predicts PTLD risk, with the cumulative
incidence over 5 years ranging from 1-2% in haematopoietic cell
transplant and liver transplants, 1-3% in renal transplants, 2-6%
in heart transplants and 2-9% in lung transplants to as high as
11-33% in intestinal or multi-organ transplants. The different rates
possibly relate to the varying degrees of immunosuppression
required. The incidence of PTLD is highest in the first year after
transplantation, when it is associated with the highest levels of
immunosuppression.
Diabetes
Adherence and concordance with medication are a particular
challenge in adolescents who have developed diabetes during
childhood (p. 753). Studies of adolescents with type 1 diabetes
have revealed that 25% were neglecting insulin injections, 81 %
were not following their diet, and 29% were not measuring their
glucose level and were completing a daily diary with fictitious
results. Research has also shown that the outcome of diabetes is
improved with a formal transition programme (Box 31 .12). Good
control of diabetes is particularly important during this phase since
microvascular disease often emerges around time of transition,
although it can occur sooner in patients with early-onset diabetes.
HI 31 .1 2 Impact of transition planning on outcome
in diabetes
Intervention
Outcome measures
Disease-specific education
Lower HbA1c
Generic education/skills
training
Fewer acute complications:
Hypoglycaemia
Admissions with ketoacidosis
Transition coordinator
Lower rate of loss to follow-up
Joint paediatric/adult clinic
Fewer chronic complications:
Hypertension
Nephropathy
Retinopathy
Separate young adult clinic
Improved self-management
Improved disease-specific knowledge
Out-of-hours phone support
Improved screening for complications
Enhanced follow-up
Better quality-of-life scores
Gastrointestinal disease
| Inflammatory bowel disease
The prevalence of inflammatory bowel disease (IBD, p. 813) in
childhood is increasing, and the incidence of Crohn’s disease (CD)
in particular is rising in both children and adults, probably due to
currently undefined environmental factors. Current treatment aims
are outlined in Box 31 .13. Standard measures include exclusive
enteral nutrition for 6-8 weeks using a whole-protein (polymeric)
formula, which induces initial remission in 80% of children. This is
equivalent to glucocorticoid therapy but offers improved nutritional
status and superior mucosal healing. Glucocorticoids can also
be used to induce remission, as well as to treat exacerbations,
but should be followed up by immunosuppressive therapy with
azathioprine or methotrexate. Adolescents and children are more
likely than adults to require biologies and around 20% need
treatment with tumour necrosis factor alpha (TNF-a) inhibitors
such as infliximab or adalimumab. Around 20% of children with
CD require surgery within 5 years of diagnosis; limited resections
and stricturoplasty are considered best practice to preserve gut
length and prevent short bowel syndrome (p. 707).
Children with ulcerative colitis (UC) are more likely than adults
to present with pancolitis (approximately 80% versus 40-50% in
adults). Mild disease should be treated initially with oral 5-ASA
preparations such as mesalamine or sulfasalazine. If the response
is inadequate, oral glucocorticoids can be used, but caution must
be exercised because of the adverse effects on skeletal growth
and bone mineral density. Thiopurines such as 6-mercaptopurine
or azathioprine are frequently used as steroid-sparing agents,
1300 • ADOLESCENT AND TRANSITION MEDICINE
i
• Induce and maintain clinical remission
• Optimise nutrition
• Optimise bone health
• Optimise growth and pubertal progress
• Minimise adverse drug effects
with progression to anti-TNF-a therapy for those who still do not
respond. There is less evidence for efficacy of TNF-a inhibitors in
adolescents with UC than those with CD; they seem to be effective
at inducing an initial response but less useful for maintaining
long-term remission, since a significant proportion of patients still
require colectomy (20% at 1 year) or long-term glucocorticoids.
Ciclosporin is probably more effective than infliximab in teenagers
with refractory UC. As with other adolescents who have long-term
conditions, adherence to medication is particularly important to
reduce the risk of relapse. In terms of lifestyle advice, smoking
is a particular risk since it increases both the rate and severity
of relapses. Body image can be a particular challenge for young
adults with IBD, and those with colostomies or fistulae, for
example, can find this part of their illness particularly difficult.
Delayed puberty and short stature are important comorbidities,
partly related to medication side effects and also to the nature
of the inflammatory bowel disease itself.
Rheumatology and bone disease
| Juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA) is the term used to describe a
wide variety of inflammatory rheumatic diseases that present
during childhood (p. 1026). Oligoarticular juvenile arthritis has
a good prognosis and often remits during adulthood, and
so transitioning patients to adult rheumatology services may
not always be required. The same does not hold true for
systemic JIA and polyarticular JIA, which often require long-term
immunosuppressive therapy through transition and beyond
into adulthood. Smoking is a risk because it increases the
activity of inflammatory disease and reduces the effectiveness of
biologies. Adherence to and concordance with medication remain
a challenge, as in other chronic diseases. Functional limitation
secondary to joint damage may limit employment opportunities.
Contraceptive advice is important in patients on methotrexate.
Glucocorticoid-induced osteoporosis
Osteoporosis is a complication of long-term glucocorticoid
therapy that may be required in patients with inflammatory
disease, transplantation and DMD.
There is a paucity of evidence about best practice in
glucocorticoid-induced osteoporosis in children and adolescents,
but in general the teenage years are a period of considerable bone
mineral deposition and offer a chance to enhance bone mineral
density significantly. It is important to ensure adequate calcium
and vitamin D intake and to supplement if necessary. Therapy
with bisphosphonates can be considered in symptomatic patients,
although the evidence base for prevention of fractures is poor.
Osteogenesis imperfecta
Osteogenesis imperfecta (p. 1 055) typically presents with multiple
low-trauma fractures during infancy and childhood. Although
fractures become less common during adolescence due to the
increase in bone mass, they still occur frequently during transition
and in young adults. Intravenous bisphosphonates are widely
used in the treatment of children with osteogenesis imperfecta
(those with long-bone deformities, vertebral compression fractures,
and three or more fractures per year, in whom the benefit: risk
ratio is thought to be positive), although the evidence base for
prevention of fractures is poor and based on observational studies.
There is much debate about whether continuing bisphosphonate
therapy into adulthood is beneficial due to concerns about
suppression of bone turnover in the long term. Affected individuals
and their parents can find this change in treatment strategy
confusing and it is important to explain the underlying rationale
in order to manage expectations.
Hypophosphataemic rickets
Hypophosphataemic rickets is described in more detail on
page 1052. Adherence to phosphate supplements and, to a lesser
extent, vitamin D metabolites represents an important issue in
optimising management during childhood and this becomes even
more challenging in transitioning patients. While skeletal deformity
does not progress following closure of the epiphyses, different
problems arise in adolescent patients when there is suboptimal
control of hypophosphataemia, including painful pseudofractures
and arthralgia associated with enthesopathy. The renal phosphate
leak tends to improve to an extent during adolescence and the
requirement for phosphate is reduced, but most patients still
require treatment with active vitamin D metabolites.
Summary
Young people who have suffered long-term conditions during
childhood represent a particularly high-risk group of patients
as they progress through adolescence to become young and,
finally, mature adults. They bring with them specific medical risks
and complications related to their previous medical treatment,
and knowledge of these is important to identify the long-term
complications of the therapies to which they have been exposed.
They are a patient group that can display complex and often
abnormal illness behaviour. Understanding this and implementing
an effective process for transition from paediatric to adult services
can reduce the significant risks that these patients face in early
adulthood. As they mature and develop more adult intellectual
and emotional behaviour patterns, the risks to their health and
well-being reduce. Patients in transition can be a particularly
challenging group to manage, but investment of time and effort at
this stage of their lives can be extremely rewarding and can bring
significant improvements in long-term health-related outcomes.
Further information
Books and journal articles
Atreja A, Bellam N, Levy SR. Strategies to enhance patient adherence:
Making it simple. MedGenMed 2005; 7:4.
Crowley R, Wolfe I, Lock K, McKee M. Improving the transition
between paediatric and adult healthcare: a systematic review.
Arch Dis Child 201 1 ; 96:548-553.
Segal TY. Adolescence: what the cystic fibrosis team needs to know.
J R Soc Med 2008; 101(Suppl 1):15-27.
Websites
acpm.org/? Adherence American College of Preventive Medicine:
detailed review of adherence.
GotTransition.org Sample clinical tools and measurement resources for
quality improvement purposes.
uhs.nhs.uk More clinical tools and measurement resources.
31.13 Treatment strategy in Crohn’s disease
Ageing and disease
Comprehensive Geriatric Assessment 1302
Presenting problems in geriatric medicine 1307
Demography 1 304
Functional anatomy and physiology 1304
Biology of ageing 1 304
Physiological changes of ageing 1 305
Frailty and multimorbidity 1 306
Falls 1308
Dizziness 1 309
Delirium 1309
Urinary incontinence 1309
Prescribing and deprescribing 1 31 0
Other problems in old age 1 31 1
Investigations 1306
Rehabilitation 1311
Comprehensive Geriatric Assessment 1 306
Decisions about investigation and treatment 1 306
1302 • AGEING AND DISEASE
Comprehensive Geriatric Assessment
7 Cognitive function
Mini-mental state examination
(see Ch. 28)
6 Vision
Visual acuity
Glasses worn/present
Cataract
5 Hearing
Wax
Hearing aid used
4 Erect and supine
blood pressure
Postural hypotension
3 Pulse
Atrial fibrillation
2 Hydration
Skin turgor
Oedema
1 Nutrition
Body mass index
(Height calculated from arm
demispan or knee height to
compensate for loss of
vertebral height)
Recent weight loss,
e.g. loose skin folds
Dentition/oral hygiene
A Measurement of knee height
(see Ch. 19)
0
Full systems examination
with particular attention
to the above
12
A Wasting of small muscles of
hands in rheumatoid arthritis
9 Per rectum
Faecal impaction
Prostate size/consistency
in men
Anal tone
10 Skin
Wounds/ulcers
Infection
Swelling
A Senile purpura
A Venous ulceration
11 Joints
Deformity
Pain
Swelling
Range of movement
A Severe kyphosis
12 Gait and balance
Get up and go test
(see opposite)
Walking aid used
Insets (Wasted hand, kyphosis) From Afzal Mir M. Atlas of clinical diagnosis, 2nd edn. Edinburgh: Saunders, Elsevier Inc.; 2003; ( Senile purpura) Forbes
CD, Jackson WF. Clinical medicine, 3rd edn. Edinburgh: Mosby, Elsevier Inc.; 2004; (Venous ulceration) Mosti G. Compression and venous surgery for leg
ulcers. Clin Plast Surg 2012; 39:269-280.
Comprehensive Geriatric Assessment • 1303
History
• Slow down the pace
• Ensure the patient can hear
• Establish the speed of onset of the
illness
• If the presentation is vague, carry out a
systematic enquiry
• Obtain full details of:
All drugs, especially any recent
prescription changes
Past medical history, even from many
years previously
Usual function: Can the patient walk
normally? Has the patient noticed
memory problems? Can the
patient perform all household
tasks?
• Obtain a collateral history: confirm
information with a relative or carer
and the GP, particularly if the patient
is confused or communication is
limited by deafness or speech
disturbance
Examination
• Thorough to identify all comorbidities • Includes functional status: cognitive
• Tailored to the patient’s stamina and function, gait and balance, nutrition, and
ability to cooperate hearing and vision
Domains of Comprehensive Geriatric Assessment.
Social assessment
Home circumstances
• Living alone, with another person or in a
care home
Activities of daily living (ADL)
• Tasks for which help is needed:
Domestic ADL: shopping, cooking,
housework
Personal ADL: bathing, dressing,
walking
• Informal help: relatives, friends,
neighbours
• Formal social services: home help, meals
on wheels
• Carer stress
Multidisciplinary team (MDT) roles
Team member
Activity assessed and promoted
Physiotherapist
Mobility, balance and upper limb function
Occupational
therapist
ADL, such as dressing, cooking
Home environment and care needs
Dietitian
Nutrition
Speech and
language therapist
Communication and swallowing
Social worker
Care needs and discharge planning; organisation of institutional care
Nurse
Motivation and initiation of activities; promotion of self-care
Education
Feeding, continence, skin care
Communication with relatives and other professionals
Assessment of care needs for discharge
Doctor
Diagnosis and management of medical problems
Coordinator of assessment, management and rehabilitation programme
12 Get up and go test
To assess gait and balance, ask the patient to stand up from a sitting position, walk 3 m, turn and go back to the chair. A normal performance takes
less than 12 seconds.
1304 • AGEING AND DISEASE
Sweeping demographic change has meant that older people
now represent the core practice of medicine in many countries.
A good knowledge of the effects of ageing and the clinical
problems associated with old age is therefore essential in most
medical specialties. The older population is extremely diverse;
a substantial proportion of 90-year-olds enjoy an active healthy
life, while some 70-year-olds are severely disabled by chronic
disease. The terms ‘chronological’ and ‘biological’ ageing have
been coined to describe this phenomenon. Biological rather
than chronological age is taken into consideration when making
clinical decisions about, for example, the extent of investigation
and intervention that is appropriate.
Geriatric medicine is concerned particularly with frail older
people, in whom physiological capacity is so reduced that they
are incapacitated even by minor illness. They frequently have
multiple comorbidities, and acute illness may present in non-specific
ways, such as delirium, falls or loss of mobility and day-to-day
functioning. These patients are prone to adverse drug reactions,
partly because of polypharmacy and partly because of age-related
changes in responses to drugs and their elimination (p. 32).
Disability is common, but patients’ function can often be improved
by the interventions of the multidisciplinary team (p. 1303).
Older people have been neglected in research terms and, until
recently, were rarely included in randomised controlled clinical
trials. Accordingly, there is often little high-quality evidence on
which to base practice.
Demography
The demography of all countries has changed rapidly in recent
decades. For example, in the UK, the total population has grown
by 1 1 % over the last 30 years, but the number of people aged
over 65 years has grown by 24%. The steepest rise occurred
in those aged over 85 - from 600 000 in 1981 to 1.5 million
in 201 1 ; this number is projected to increase to 2.4 million by
2026, while the working-age population (20-64 years) is expected
to grow by only 4% between 201 1 and 2026. Similarly, the
proportion of people over 65 in India has increased by 35.5%
from 76 million in 2000 to 103 million in 201 1 , which is almost
twice the rate of growth of the general population over this period.
In both of these countries and many others across the world,
the old-age dependency ratio, which is the ratio of people of
working age for each person over retirement age, has substantially
increased. Since young people support older members of the
population both directly and indirectly through taxation and
pension contributions, the consequences of a reduced ratio are
far-reaching. It is important to emphasise, however, that many
older people support the younger population, through the care
of children and other older people.
Life expectancy in the developed world is now prolonged,
even in old age (Box 32.1); women aged 80 years can expect
32.1 Mean life expectancy in years, UK and India
Males
Females
UK
India
UK
India
At birth
79.1
65.1
83.0
67.2
At 60 years
22.8
16.7
25.5
18.9
At 70 years
15.0
10.9
17.1
12.4
At 80 years
8.7
7.5
9.9
8.0
Year
Fig. 32.1 Number of people aged 65 years and over projected in the
world population.
to live for a further 10 years. However, rates of disability and
chronic illness rise sharply with ageing and have a major impact
on health and social services. In the UK, the reported prevalence
of a chronic illness or disability sufficient to restrict daily activities
is around 25% in those aged 50-64, but 66% in men and 75%
in women aged over 85.
Although the proportion of the population aged over 65 years is
greater in developed countries, two-thirds of the world population
aged over 65 live in developing countries at present, and this is
projected to rise to 75% in 2025. The rate of population ageing
is much faster in developing countries (Fig. 32.1) and so there
will be less time to adjust to its impact.
Functional anatomy and physiology
Biology of ageing
Ageing can be defined as a progressive accumulation through
life of random molecular defects that build up within cells and
tissues. Eventually, and despite multiple repair and maintenance
mechanisms, these result in age-related functional impairment
of tissues and organs. There is evidence that variants in many
genes contribute to ageing. The implicated genes include those
that are involved in regulation of DNA repair, telomere length
(p. 41) and insulin signalling. Genetic factors only account for
around 25% of the variance in human lifespan, however; nutritional
and environmental factors determine the rest. At a cellular level,
production of reactive oxygen species is thought to play a major
role in ageing. These molecules cause oxidative damage at a
number of targets:
• Nuclear chromosomal DNA, causing mutations and
deletions that ultimately lead to aberrant gene function and
potential for malignancy.
• Telomeres, the structures at the ends of chromosomes
that shorten with each cell division because telomerase
(which copies the end of the 3' strand of linear DNA in
germ cells) is absent in somatic cells. When telomeres
are sufficiently eroded, cells stop dividing. It has been
suggested that telomeres represent a ‘biological clock’
that prevents uncontrolled cell division and cancer.
Telomeres are particularly shortened in patients with
Functional anatomy and physiology • 1305
premature ageing due to Werner’s syndrome, in which
DNA is damaged due to lack of a helicase.
• Mitochondrial DNA and lipid peroxidation, resulting in
reduced cellular energy production and ultimately cell
death.
• Proteins, especially those that are modified by glycosylation
due to spontaneous reactions between proteins and
sugars. These damage structure and function of the
affected protein, which becomes resistant to breakdown.
The rate at which damage occurs is variable and this is where
the interplay with environment, and particularly nutrition, takes
place. There is evidence in some organisms that this interplay is
mediated by insulin signalling pathways. Chronic inflammation also
plays an important role, again in part by driving the production
of reactive oxygen species.
Physiological changes of ageing
The physiological features of normal ageing have been identified
by examining disease-free populations of older people to separate
the effects of pathology from those due to age alone. The fraction
of older people who age without disease ultimately declines
to very low levels, however, so that use of the term ‘normal’
becomes debatable. There is a marked increase in inter-individual
variation in function with ageing; many physiological processes
deteriorate substantially when measured across populations but
some individuals show little or no change. This heterogeneity is a
hallmark of ageing, meaning that each person must be assessed
individually and that the same management cannot be applied
unthinkingly to all people of a certain age.
Although some genetic influences contribute to heterogeneity,
environmental factors, such as poverty, nutrition, exercise,
cigarette smoking and alcohol misuse, play a large part, and a
healthy lifestyle should be encouraged even when old age has
been reached.
The effects of ageing are usually not enough to interfere with
organ function under normal conditions but reserve capacity
is significantly reduced. Some changes of ageing, such as
depigmentation of the hair, are of no clinical significance. Figure
32.2 shows the many changes that occur with ageing that are
clinically important.
Changes with ageing
Clinical consequences
CNS and muscle
• Neuronal loss
• Cochlear degeneration
• Increased lens rigidity
• Lens opacification
• Anterior horn cell loss
• Dorsal column loss
• Slowed reaction times
• Loss of type II muscle fibres
• Reduction in muscle satellite cell
numbers
Respiratory system
• Reduced lung elasticity and
alveolar support
• Increased chest wall rigidity
• Increased V/Q mismatch
• Reduced cough and ciliary action
Cardiovascular system
• Reduced maximum heart rate
• Dilatation of aorta
• Reduced elasticity of conduit/
capacitance vessels
• Reduced number of pacing
myocytes in sinoatrial node
Renal system
• Loss of nephrons
• Reduced glomerular filtration rate
• Reduced tubular function
Endocrine system
• Deterioration in pancreatic (3-cell
function
Gastrointestinal system
• Reduced motility
Bones
• Reduced bone mineral density
CNS
• Increased risk of delirium
• Presbyacusis/high-tone hearing loss
• Presbyopia/abnormal near vision
• Cataract
• Muscle weakness and wasting
• Reduced position and vibration
sense
• Increased risk of falls
Respiratory system
• Reduced vital capacity and peak
expiratory flow
• Increased residual volume
• Reduced inspiratory reserve volume
• Reduced arterial oxygen saturation
• Increased risk of infection
Cardiovascular system
• Reduced exercise tolerance
• Widened aortic arch on X-ray
• Widened pulse pressure
• Increased risk of postural
hypotension
• Increased risk of atrial fibrillation
Renal system
• Impaired fluid balance
• Increased risk of
dehydration/overload
• Impaired drug metabolism
and excretion
Endocrine system
• Increased risk of impaired
glucose tolerance
Gastrointestinal system
• Constipation
Bones
• Increased risk of osteoporosis and
fracture
Fig. 32.2 Features and consequences of normal ageing.
1306 • AGEING AND DISEASE
Frailty and multimorbidity
Frailty is defined as the loss of an individual’s ability to withstand
minor stresses because the reserves in function of several organ
systems are so severely reduced that even a trivial illness or
adverse drug reaction may result in organ failure and death.
The same stresses would cause little upset in a fit person of
the same age.
It is important to understand the difference between
‘disability’, ‘multimorbidity’ and ‘frailty’. Disability indicates
established loss of function while frailty indicates increased
vulnerability to loss of function. Disability may arise from a single
pathological event (such as a stroke) in an otherwise healthy
individual. After recovery, function is largely stable and the
patient may otherwise be in good health. When frailty and
disability coexist, function deteriorates markedly even with minor
illness, to the extent that the patient can no longer manage
independently.
Multimorbidity (the number of diagnoses present) is also not
equivalent to frailty; it is quite possible to have several diagnoses
without major impact on homeostatic reserve. Multimorbidity
is, however, an important concept in its own right and is an
almost invariable accompaniment to advanced age. Recent
Scottish population-based data show that 60% of those aged
65 and over have at least two chronic diseases. Multimorbidity
is a driver for future disability, hospitalisation and death, and
often leads to polypharmacy, as multiple medications are used
to treat each chronic disease individually. Current health-care
systems are poorly equipped to manage multimorbidity; each
disease is dealt with by a separate team of specialists, which
at best places a high burden on the patient, and at worst
leads to mutually incompatible approaches to management of
each disease.
Unfortunately, the term ‘frail’ is often used rather vaguely,
sometimes to justify a lack of adequate investigation and
intervention in older people. It can be specifically identified,
however, by assessing function in a number of domains. Two
main approaches to evaluating frailty exist: measurement of
physiological function across a number of domains, an example
being the Fried Frailty score (Box 32.2), or use of a score
based on the number of deficits or problems, such as the
Rockwood score.
Frail older people particularly benefit from a clinical approach
that addresses both the precipitating acute illness and their
underlying loss of reserves. It may be possible to prevent further
loss of function through early intervention; for example, a frail
woman with myocardial infarction will benefit from specific
32.2 How to assess a Fried Frailty score
• Hand grip strength in bottom 20% of healthy elderly distribution*
• Walking speed in bottom 20% of healthy elderly distribution*
• Self-reported exhaustion
• Physical inactivity
• At least 6 kg weight loss within 1 year
Patient is defined as frail if 3 or more factors are present; 1-2 factors
indicate a ‘pre-frail’ state.
*Varies between populations. Grip cut-off is 30 kg for men and 18 kg for women
in US adults; 5 m walk time cut-off is 7 seconds in US adults for both sexes.
cardiac investigation and drug treatment, but may benefit even
further from an exercise programme to improve musculoskeletal
function, balance and aerobic capacity, with nutritional support
to restore lost weight. Establishing a patient’s level of frailty
also helps inform decisions regarding further investigation and
management, and the need for rehabilitation.
Investigations
Comprehensive Geriatric Assessment
One of the most powerful tools in the management of older people
is the Comprehensive Geriatric Assessment, which identifies all
the relevant factors contributing to their presentation (p. 1302).
Comprehensive Geriatric Assessment is in fact a misnomer; it
is not merely an assessment, but a process of identifying and
managing all relevant factors affecting the health and well-being of
older people. It is iterative in nature, management being followed
by reassessment and a new management plan. In frail patients
with multiple pathology, it may be necessary to perform the
assessment in stages to allow for their reduced stamina. The
outcome should be a management plan that not only addresses
the acute presenting problems but also improves the patient’s
overall health and function.
Comprehensive Geriatric Assessment is performed by a
multidisciplinary team (p. 1 303). Such an approach was pioneered
by Dr Marjory Warren at the West Middlesex Hospital in London
in the 1930s; her comprehensive assessment and rehabilitation
of supposedly incurable, long-term bedridden older people
revolutionised the approach of the medical profession to frail
older people and laid the foundations for the modern specialty
of geriatric medicine. There is excellent evidence from systematic
reviews that Comprehensive Geriatric Assessment, when
performed by a specialist team on a specialist geriatric medicine
ward, reduces death or deterioration, increases the chances of
living independently at home, and may also improve cognitive
function in the short to medium term. Current evidence suggests
that the process works when delivered on a specialist inpatient
unit, but the evidence for effectiveness when it is delivered by
a visiting team or in the community is less strong.
Decisions about investigation
and treatment
Accurate diagnosis is important at all ages but frail older people
may not be able to tolerate lengthy or invasive procedures,
and diagnoses may be revealed for which patients could not
withstand intensive or aggressive treatment. On the other hand,
disability should never be dismissed as due to age alone. For
example, it would be a mistake to supply a patient no longer
able to climb stairs with a stair lift when simple tests would
have revealed osteoarthritis of a hip and vitamin D deficiency,
for which appropriate treatment would have restored his
or her strength. So how do doctors decide when and how
far to investigate?
The views of the patient and family
Older people may have strong views about the extent of
investigation and the treatment they wish to receive, and these
should be sought from the outset. A key issue is to establish
what the patient wants from investigation and treatment. Many
Presenting problems in geriatric medicine • 1307
older people do not desire prolongation of life; rather they aspire I
to maintain physical function, gain relief from symptoms, and
preserve the ability to live independently. Such aims differ widely
between patients, however, and a careful exploration of what is
important to the individual is essential. If the patient wishes, the
views of relatives can also be taken into account. If the patient
is not able to express a view or lacks the capacity to make
decisions because of cognitive impairment or communication
difficulties, then relatives’ input becomes particularly helpful. They
may be able to give information on views previously expressed
by the patient or on what the patient would have wanted under
the current circumstances. However, families should never be
made to feel responsible for difficult decisions.
The patient’s general health
Does this patient have the physical and mental capacity to
tolerate the proposed investigation? Do they have the aerobic
capacity to undergo bronchoscopy? Will delirium prevent them
from remaining still in the magnetic resonance imaging (MRI)
scanner? The more comorbidities a patient has, the less likely
he or she will be able to withstand an invasive intervention.
Will the investigation alter management?
Would the patient be fit for, or benefit from, the treatment that
would be indicated if investigation proved positive? The presence
of comorbidity and frailty is more important than age itself in
determining this. When a patient with severe heart failure and a
previous disabling stroke presents with a suspicious mass lesion
on chest X-ray, detailed investigation and staging may not be
appropriate if they are not fit for surgery, radical radiotherapy or
chemotherapy. On the other hand, if the same patient presented
with dysphagia, investigation of the cause would be important,
as they might be able to tolerate endoscopic treatment (for
example, to palliate an obstructing oesophageal carcinoma).
Will management benefit the patient?
It is important to consider whether interventions that might be
considered as standard -of-care for younger people are likely
to be beneficial in frail older people. For example, while oral
anticoagulation might be indicated by guidelines for a patient
with atrial fibrillation, such treatment may not accord with the
wishes of a patient in a care home who finds regular blood
tests distressing, or who is more worried about bleeding than
about avoiding a stroke. Another example would be the use
of anti-osteoporosis medications to reduce the risk of fracture
in very old patents, where the risk of death from other causes
would be greater than the risk of fracture.
Advance directives
Advance directives or ‘living wills’ are statements made by adults
at a time when they have the capacity to decide about the
interventions they would refuse or accept in the future, should
they no longer be able to make decisions or communicate
them. An advance directive cannot authorise a doctor to do
anything that is illegal and doctors are not bound to provide a
specific treatment requested if, in their professional opinion, it
is not clinically appropriate. However, any advance refusal of
treatment, made when the patient was able to make decisions
based on adequate information about their implications, is
legally binding in the UK. It must be respected when it clearly
applies to the patient’s present circumstances and when
there is no reason to believe that the patient has changed
his or her mind.
Presenting problems in
geriatric medicine
I Characteristics of presenting problems
in old age
Problem-based practice is central to geriatric medicine. Most
problems are multifactorial and there is rarely a single unifying
diagnosis. All contributing factors have to be taken into account
and attention to detail is paramount. Two patients who share
the same presenting problem may have completely disparate
diagnoses. A wide knowledge of adult medicine is required, as
disease in any, and often many, of the organ systems has to
be managed at the same time. There are a number of features
that are particular to older patients.
Late presentation
Many people (of all ages) accept ill health as a consequence
of ageing and may tolerate symptoms for lengthy periods
before seeking medical advice. Comorbidities may also
contribute to late presentation; in a patient whose mobility
is limited by stroke, angina may only present when coronary
artery disease is advanced, as the patient has been
unable to exercise sufficiently to cause symptoms at an
earlier stage.
Atypical presentation
Infection may present with delirium and without clinical pointers
to the organ system affected. Stroke may present with falls
rather than symptoms of focal weakness. Myocardial infarction
may present as weakness and fatigue, without chest pain or
dyspnoea. The reasons for these atypical presentations are
not always easy to establish. Perception of pain is altered
in old age, which may explain why myocardial infarction
presents in other ways. The pyretic response is blunted in old
age so that infection may not be obvious at first. Cognitive
impairment may limit the patient’s ability to give a history of
classical symptoms.
Acute illness and changes in function
Atypical presentations in frail elderly patients include ‘failure
to cope’, ‘found on floor’, ‘delirium’ and ‘off feet’, but these
are not diagnoses. The possibility that an acute illness has
been the precipitant must always be considered. To establish
whether the patient’s current status is a change from his or
her usual level of function, it helps to ask a relative or carer (by
phone if necessary). Investigations aimed at uncovering an acute
illness will not be fruitful in a patient whose function has been
deteriorating over several months but are important if function
has suddenly changed.
Multiple pathology
Presentations in older patients have a more diverse differential
diagnosis because multiple pathology is so common. There
are frequently a number of causes for any single problem, and
adverse effects from medication often contribute. A patient may
fall because of osteoarthritis of the knees, postural hypotension
due to diuretic therapy for hypertension, and poor vision due
to cataracts. All these factors have to be addressed to prevent
further falls and this principle holds true for most of the common
presenting problems in old age.
1308 • AGEING AND DISEASE
i
• Full blood count
• Urea and electrolytes, liver function tests, calcium and glucose
• Chest X-ray
• Electrocardiogram
• C-reactive protein: useful marker for occult infection or inflammatory
disease
• Blood cultures if pyrexial
Approach to presenting problems in old age
For the sake of clarity, the common presenting problems are
described individually but, in reality, older patients often present
with several at the same time, particularly delirium, incontinence
and falls. These share some underlying causes and may precipitate
each other.
The approach to most presenting problems in old age can
be summarised as follows:
• Obtain a collateral history. Find out the patient’s usual
status with regard to mobility and cognitive function from a
relative or carer. Call these people by phone if they are not
present.
• Check all medication. Have there been any recent
changes?
• Search for and treat any acute illness (Box 32.3).
• Identify and reverse predisposing risk factors. These
depend on the presenting problem.
Falls
Around 30% of those over 65 years of age fall each year and
this figure rises to more than 40% in those aged over 80.
Although only 10-15% of falls result in serious injury, virtually
all fragility fractures in the elderly are caused by falls. Age-related
osteoporosis contributes to the dramatic rise in hip and other
fragility fractures that occurs with ageing but the most important
contributory factor is an increased risk of falling (Fig. 32.3). Falls
also lead to loss of confidence and fear, and are frequently
the ‘final straw’ that makes an older person decide to move
to institutional care. Management will vary according to the
underlying cause.
Acute illness
Falls are one of the classical atypical presentations of acute
illness in frail people. The reduced reserves in older people’s
neurological function mean that they are less able to maintain
their balance when challenged by an acute illness. Suspicion
should be high when falls have suddenly occurred over a period
of a few days. Common underlying illnesses include infection,
stroke, metabolic disturbance and heart failure. Thorough
examination and investigation are required (Box 32.3). It is also
important to establish whether any drug that precipitates falls,
such as a psychotropic or hypotensive agent, has been started
recently. Once the underlying acute illness has been treated,
falls may stop.
Blackouts
A proportion of older people who ‘fall’ have, in fact, had a syncopal
episode. A collateral history from a witness is of utmost importance
Femoral neck BMD (g/cm2)
Fig. 32.3 Age and bone mineral density (BMD) interact to influence
fracture risk.
32.4 Risk factors for falls
• Muscle weakness
• Impaired activities of daily
• History of falls
living
• Gait or balance abnormality
• Depression
• Use of a walking aid
• Cognitive impairment
• Visual impairment
• Age over 80 years
• Arthritis
• Psychotropic medication
in anyone falling over; people who lose consciousness do not
always remember having done so. If loss of consciousness is
suggested by the patient or witness, it is important to perform
appropriate investigations (pp. 181 and 1080).
Mechanical and recurrent falls
Among patients who have tripped or are uncertain how they
fell, those who have fallen more than once in the past year
and those who are unsteady during a ‘get up and go’ test
(p. 1303) require further assessment. Patients with recurrent
falls are commonly frail, with multiple medical problems and
chronic disabilities. Obviously, such patients may present
with a fall resulting from an acute illness or syncope but they
will remain at risk of further falls even when the acute illness
has resolved. The risk factors for falls (Box 32.4) should be
considered. If problems are identified with muscle strength,
balance, vision or cognitive function, the causes of these must
be identified by specific investigation, and treatment commenced
if appropriate. Careful assessment of the patient’s gait may
provide important clues to an underlying diagnosis (Box 32.5).
Common pathologies identified include cerebrovascular disease
(Ch. 26), Parkinson’s disease (p. 1112) and osteoarthritis of
weight-bearing joints (p. 1007). Calculation of fracture risk
using tools such as FRAX or GFracture should be performed
and dual X-ray absorptiometry (DXA) bone density scanning
considered in patients with a 10-year risk of major fracture of
more than 10%.
Prevention of falls and fractures
Falls can be prevented by multiple risk factor intervention (Box
32.6). The most effective intervention is balance and strength
training by physiotherapists or exercise practitioners; an alternative
with good evidence is tai chi training. An assessment of the
32.3 Screening investigations for acute illness
Presenting problems in geriatric medicine • 1309
32.5 Abnormal gaits and probable causes
Gait abnormality
Probable cause
Antalgic
Arthropathy
Waddling
Proximal myopathy
Stamping
Sensory neuropathy
Foot drop
Peripheral neuropathy or radiculopathy
Ataxic
Sensory neuropathy or cerebellar disease
Shuffling/festination
Parkinson’s disease
Marche a petits pas
Small-vessel cerebrovascular disease
Hemiplegic
Cerebral hemisphere lesion
Apraxic
Bilateral hemisphere lesions
32.6 Interventions to reduce the risk of falls and
fractures
• Exercise (should include components of lower limb strength and
balance training):
Multimodal group exercise and tai chi both effective
• Calcium and vitamin D supplementation:
Evidence of effectiveness only in patients in institutional care
Large doses of vitamin D may increase risk of falls and fractures
• Home environment assessment and modification
• Medication review:
Particularly medications with central actions such as hypnotics
but also those with anticholinergic and hypotensive actions
• Cataract surgery:
Effective if for first cataract
Other vision interventions ineffective and may increase falls risk
• Anti-slip shoes:
Effective only in icy conditions
• Cardiac pacemaker for carotid sinus hypersensitivity
patient’s home environment for hazards should be undertaken
by an occupational therapist, who may also provide personal
alarms so that patients can summon help, should they fall
again. Rationalising psychotropic medication may help to
reduce sedation, although many older patients are reluctant to
stop hypnotics. If postural hypotension is present (defined as
a drop in blood pressure of >20 mmHg systolic or >10 mmHg
diastolic pressure on standing from supine), reducing or stopping
hypotensive drugs may be helpful. Evidence supporting the
efficacy of other interventions for postural hypotension is
lacking but drugs, including fludrocortisone and midodrine, are
sometimes used to try to improve dizziness on standing. Other
interventions, such as cataract extraction and podiatry, can also
have a significant impact on function in those who fall.
If osteoporosis is diagnosed, specific drug therapy should be
considered (p. 1046). In the frailest patients, such as those in
institutional care, calcium and vitamin D3 administration has been
shown to reduce both falls and fracture rates, probably by exerting
positive effects on bone mineral density and on neuromuscular
function. Supplementation does not reduce falls risk beyond this
very frail group, however, and very high doses of vitamin D may
paradoxically increase the risk of falls and fractures.
In the UK, government policy and National Institute for Health
and Clinical Excellence guidelines (www.nice.org.uk) for falls
prevention have led to the development of specific Falls and
Fracture Prevention Services in many parts of the country.
Dizziness
Dizziness is very common, affecting at least 30% of those aged
over 65 years in community surveys. It can be disabling in its
own right and is also a risk factor for falls. Acute dizziness is
relatively straightforward and common causes include:
• hypotension due to arrhythmia, myocardial infarction,
gastrointestinal bleed or pulmonary embolism
• posterior fossa stroke onset
• vestibular neuronitis.
Although older people more commonly present with recurrent
dizzy spells and often find it difficult to describe the sensation
they experience, the most effective way of establishing the
cause(s) of the problem is nevertheless to determine which of
the following is predominant (even if more than one is present):
• lightheadedness, suggestive of reduced cerebral perfusion
• vertigo, suggestive of labyrinthine or brainstem
disease (p. 1086)
• unsteadiness/poor balance, suggestive of joint or
neurological disease.
In lightheaded patients, structural cardiac disease (such as
aortic stenosis) and arrhythmia must be considered, but disorders
of autonomic cardiovascular control, such as vasovagal syndrome
and postural hypotension, are the most common causes in
old age. Antihypertensive medications may exacerbate these
conditions. Further investigation and treatment are described
on page 181 .
Vertigo in older patients is most commonly due to benign
positional vertigo (p. 1086), but if other brainstem symptoms
or signs are present, MRI of the brain is required to exclude a
cerebello-pontine angle lesion.
Delirium
Delirium is a syndrome of transient, reversible cognitive dysfunction
that affects 30% of older hospital inpatients. Differential diagnosis,
assessment and management are discussed on page 183.
Urinary incontinence
Urinary incontinence is defined as the involuntary loss of urine
and comes to medical attention when sufficiently severe to
cause a social or hygiene problem. It occurs in all age groups
but becomes more prevalent in old age, affecting about 15%
of women and 10% of men aged over 65. It may lead to skin
damage if severe and can be socially restricting. While age-
dependent changes in the lower urinary tract predispose older
people to incontinence, it is not an inevitable consequence of
ageing and requires investigation and appropriate treatment.
Urinary incontinence is frequently precipitated by acute illness
in old age and is commonly multifactorial (Fig. 32.4).
The initial assessment should seek to identify and address
contributory factors. If incontinence fails to resolve, further
diagnosis and management should be pursued, as described
on page 437.
• Urge incontinence is usually due to detrusor over-activity
and results in urgency and frequency.
• Stress incontinence is almost exclusive to women and is
due to weakness of the pelvic floor muscles, which allows
leakage of urine when intra-abdominal pressure rises, such
as on coughing. It may be compounded by atrophic
1310 • AGEING AND DISEASE
Urinary incontinence
Fig. 32.4 Assessment and management of urinary incontinence in
old age. See also page 436 and NICE guideline on the Management of
Incontinence in Women: nice.org.uk. (UTI = urinary tract infection)
vaginitis, associated with oestrogen deficiency in old age,
which can be treated with oestrogen pessaries.
• Overflow incontinence is most commonly seen in elderly
men with prostatic enlargement, which obstructs bladder
outflow.
In patients with severe stroke disease or dementia, treatment
may be ineffective, as frontal cortical inhibitory signals to bladder
emptying are lost. A timed/prompted toileting programme may
help. Other than in overflow incontinence, urinary catheterisation
should never be viewed as first-line management, but may be
required as a final resort if the perineal skin is at risk of breakdown
or quality of life is affected.
Prescribing and deprescribing
The large number of comorbidities that accompany ageing
often leads to polypharmacy. This has been defined as the use
of four or more drugs, and is associated with several adverse
outcomes including falls, hospitalisation and increased risk of
death. While some of these outcomes are caused by drug-drug
interactions and adverse effects, others are as much due to the
underlying multimorbidities for which the drugs were prescribed
in the first place
In view of this, it is essential for prescribing for older people
to be appropriate. For many older people, taking multiple drugs
is appropriate, as such therapy is required to treat multiple
32.7 Factors leading to polypharmacy in old age
• Multiple pathology
• Poor patient education (see Box 2.20, p. 31)
• Lack of routine review of all medications
• Patient expectations of prescribing
• Over-use of drug interventions by doctors
• Attendance at multiple specialist clinics
• Poor communication between specialists
32.8 Common adverse drug reactions in old age
Drug class
Adverse reaction
NSAIDs
Gastrointestinal bleeding and peptic ulceration
Renal impairment
Diuretics
Renal impairment, electrolyte disturbance
Gout
Hypotension, postural hypotension
Warfarin
Bleeding
ACE inhibitors
Renal impairment, electrolyte disturbance
Hypotension, postural hypotension
p-blockers
Bradycardia, heart block
Hypotension, postural hypotension
Opiates
Constipation, vomiting
Delirium
Urinary retention
Antidepressants
Delirium
Hyponatraemia (SSRIs)
Hypotension, postural hypotension
Falls
Benzodiazepines
Delirium
Falls
Anticholinergics
Delirium
Urinary retention
Constipation
(ACE = angiotensin-converting enzyme; NSAIDs = non-steroidal anti-inflammatory
drugs; SSRIs = selective serotonin re-uptake inhibitors)
diseases (Box 32.7). However, the more drugs that are taken,
the greater the risk of an adverse drug reaction (ADR). ADRs
and the effects of drug interactions are discussed on page 21 .
They may result in symptoms, abnormal physical signs and
altered laboratory test results (Box 32.8). ADRs are the cause of
around 5% of all hospital admissions but account for up to 20%
of admissions in those aged over 65. The risk of polypharmacy is
compounded by age-related changes in pharmacodynamic and
pharmacokinetic factors (p. 14), and by impaired homeostatic
mechanisms, such as baroreceptor responses, plasma volume
and electrolyte control.
Older people are thus especially sensitive to drugs that can
cause postural hypotension or volume depletion (Box 32.8).
Non-adherence to drug therapy also rises with the number of
drugs prescribed.
The clinical presentations of ADRs are diverse, so for any
presenting problem in old age the possibility that the patient’s
medication is a contributory factor should always be considered.
Failure to recognise this may lead to the use of a further drug
to treat the problem, making matters worse, when the better
Rehabilitation • 1311
course would be to stop or reduce the dose of the offending
drug or to find an alternative.
Appropriate prescribing and deprescribing
The key to appropriate prescribing is first to ensure that medications
are started only for reasons that accord with the patient’s goals
and wishes. Thoughtless adherence to guidelines quickly leads
to polypharmacy that may be inappropriate. Some medications
(such as chronic use of non-steroidal anti-inflammatory
medications) are much less suitable for older people because
of the much higher risk of side-effects. Other medications, such
as statins and bisphosphonates, lack evidence of efficacy in
very old people, who may not live for long enough to derive
benefit.
Deprescribing is as important as prescribing in older people.
Regular review of medications should be undertaken to ensure
that medications are still required, to establish that they are
still working, to check that they are not causing side-effects,
and to ascertain whether the patient is actually taking them. If
any of the above issues is problematic, the medication should
be deprescribed. This may need to be done in a controlled
manner, with dose reduction to ensure that rebound symptoms
or withdrawal effects do not occur. The patient or carer should
therefore be asked to bring all medication for review rather than
the doctor relying on previous records; such reviews should take
place regularly, not just at a point of crisis such as after a fall or
on hospital admission.
Other problems in old age
A vast range of other presenting problems in older people present
to many medical specialties. End-of-life care is an important
facet of clinical practice in old age and is discussed on page
1354. Relevant sections in other chapters are referenced in
Box 32.9.
Within each chapter, ‘In Old Age’ boxes highlight the areas in
which presentation or management differs from that in younger
individuals.
32.9 Other presenting problems in old age
• Hypothermia
p. 166
• Dizziness and blackouts
p. 181
• Delirium
p. 183
• Infection
pp. 218 and 228
• Fluid balance problems
p. 360
• Heart failure
p. 466
• Atrial fibrillation
p. 472
• Hypertension
p. 512
• Under-nutrition
p. 710
• Diabetes mellitus
p. 732
• Peptic ulceration
p. 801
• Anaemia
p. 954
• Painful joints
p. 992
• Bone disease and fracture
pp. 994 and 1049
• Stroke
p. 1147
• Dementia
p. 1191
Rehabilitation
Rehabilitation aims to improve the ability of people of all ages
to perform day-to-day activities and to optimise their physical,
mental and social capabilities. Acute illness in older people is
often associated with loss of their usual ability to walk or care for
themselves, and common disabling conditions such as stroke,
fractured neck of femur, arthritis and cardiorespiratory disease
become increasingly prevalent with advancing age. Doctors tend
to focus on health conditions and impairments but patients are
more concerned with the effect on their activities and ability to
participate in everyday life.
The rehabilitation process
Rehabilitation is a problem-solving process focused on improving
the patient’s physical, psychological and social function. It entails:
• Assessment. The nature and extent of the patient’s
problems can be identified using the International
Classification of Functioning, Disability and Health
framework, which focuses on health conditions (such as
stroke), the associated physical impairments (such as arm
weakness caused by the stroke), the effect on activity
(such as the inability to dress oneself due to arm
weakness) and restriction of participation in activities (such
as inability to go out of the house due to the inability to
dress oneself). Such an approach helps to ensure a
whole-person approach to participation in society, rather
than a focus merely on disease. Specific assessment
scales, such as the Elderly Mobility Scale or Barthel Index
of Activities of Daily Living (Box 32.10), are useful to
quantify components of disability but additional
assessment is needed to determine the underlying causes
or the interventions required in individual patients.
• Goal-setting. Goals should be specific to the patient’s
problems, realistic, and agreed between the patient and
the rehabilitation team.
• Intervention. This includes the active treatments needed to
achieve the established goals and to maintain the patient’s
health and quality of life. Interventions include hands-on
treatment by therapists using a functional, task-orientated
approach to improve day-to-day activities, and also
psychological support and education. The emphasis on
the type of intervention will be individualised, according to
the patient’s disabilities, psychological status and
progress. The patient and carer(s) must be active
participants.
• Re-assessment. There is ongoing re-evaluation of the
patient’s function and progress towards the goals by the
rehabilitation team, the patient and the carer. Interventions
may be modified as a result.
Multidisciplinary team working
The core rehabilitation team includes all members of the
multidisciplinary team (p. 1303). Others may also be involved,
such as audiometrists to correct hearing impairment, podiatrists for
foot problems, and orthoticists where a prosthesis or splinting is
required. Good communication and mutual respect are essential.
Regular team meetings allow sharing of assessments, agreement
on rehabilitation goals and interventions, evaluation of progress
and planning for the patient’s discharge home. Rehabilitation
is not when the doctor orders ‘physiotherapy’ or ‘a home visit’
and takes no further role.
1312 • AGEING AND DISEASE
32.10 How to assess dependency using the Modified
Barthel Index
Mobility
Independent = 3 Needs help = 2 Wheelchair independent = 1
Immobile = 0
Stairs
Independent = 2 Needs help = 1 Unable = 0
Transfers (e.g. from bed to chair)
Independent = 3 Needs minor help = 2 Needs major help = 1
Unable = 0
Bladder
Continent = 2 Occasional incontinence = 1 Incontinent = 0
Bowels
Continent = 2 Occasional incontinence = 1 Incontinent = 0
Grooming
Independent = 1 Needs help = 0
Toilet use
Independent = 2 Needs help = 1 Unable = 0
Feeding
Independent = 2 Needs help = 1 Unable = 0
Dressing
Independent = 2 Needs some help = 1 Completely dependent = 0
Bathing
Independent = 1 Needs help = 0
*The 20-point version is illustrated. The total score reflects the degree
of dependency; scores of 14 and above are usually consistent with
living in the community; scores below 10 suggest the patient is heavily
dependent on carers.
Rehabilitation outcomes
There is evidence that rehabilitation improves functional outcomes
in older people following acute illness, stroke and hip fracture.
It also reduces mortality after stroke and hip fracture. These
benefits accrue from complex multicomponent interventions, but
occupational therapy to improve personal ADLs and individualised
exercise interventions have now been shown to be effective in
improving functional outcome in their own right.
Further information
Websites
americangeriatrics.org American Geriatrics Society: education, careers
vignettes from geriatricians, advocacy and clinical guidelines.
bgs.org.uk British Geriatrics Society: useful publications on
management of common problems in older people and links to
other relevant websites.
cochrane.org Cochrane review CD00621 1 Comprehensive geriatric
assessment for older adults admitted to hospital; CD007146
Interventions for preventing falls in older people living in the community.
eugms.org European Union Geriatric Medicine Society: research,
position papers and educational resources.
iagg.info International Association of Gerontology and Geriatrics:
promoting care of older people and the science of gerontology
globally; research, policy and educational resources.
knowledge.scot.nhs.uk/effectiveolderpeoplecare.aspx Collates and
summarises the Cochrane evidence for best practice in the
healthcare and rehabilitation of frail older people.
profane. co Prevention of Falls Network Earth: focuses on the prevention
of falls and improvement of postural stability in older people.
qfracture.org Fracture risk calculator validated in the UK population.
Includes a wider range of risk factors than FRAX.
shef.ac.uk/FRAX/tool.jsp Fracture risk calculator: can be used to
calculate risk in several populations. Includes option to calculate
with or without measurement of hip bone mineral density.
Oncology
Clinical examination of the cancer patient 1314
Emergency complications of cancer 1326
The 10 hallmarks of cancer 1316
Metastatic disease 3328
1 . Genome instability and mutation 1316
Therapeutics in oncology 1329
2. Resisting cell death 1316
Surgical treatment 1330
3. Sustaining proliferative signalling 1317
Systemic chemotherapy 1330
4. Evading growth suppressors 1318
Radiation therapy 1 331
5. Enabling replicative immortality 1318
Hormone therapy 1 332
6. Inducing angiogenesis 1318
Immunotherapy 1332
7. Activating invasion and metastasis 1319
Biological therapies 1 332
8. Reprogramming energy metabolism 1319
Evaluation of treatment 1 332
9. Tumour-promoting inflammation 1319
Late toxicity of therapy 1 332
10. Evading immune destruction 1320
Specific cancers 1333
Environmental and genetic determinants of cancer 1320
Breast cancer 1 333
Investigations 1321
Ovarian cancer 1 334
Histology 1322
Endometrial cancer 1 334
Imaging 1323
Cervical cancer 1 335
Biochemical markers 1 323
Head and neck tumours 1 335
Presenting problems in oncology 1323
Carcinoma of unknown origin 1 336
Palpable mass 1 323
Multidisciplinary teams 1336
Weight loss and fever 1 323
Thromboembolism 1324
Ectopic hormone production 1 325
Neurological paraneoplastic syndromes 1325
Cutaneous manifestations of cancer 1326
1314 • ONCOLOGY
Clinical examination of the cancer patient
4 Face
Conjunctival pallor
Icterus, jaundice
Horner’s syndrome
Cushingoid features
3 Lymph nodes
Neck
Supraclavicular
Axillary
Antecubital
Inguinal
Para-aortic
2 Breast
A Skin tethering above the
nipple
1 Hands
Clubbing
Signs of smokinq
Pallor
Tylosis of palms
A Finger clubbing in
lung cancer
A Cushing’s syndrome in
a patient with ectopic
adrenocorticotrophic
hormone (ACTH) production
• Ascites
• Cushingoid appearance
• Cachexia
• Dehydration
5 Cardiovascular
Superior vena cava (SVC)
obstruction
Atrial fibrillation
Pericardial effusion
Hypo-/hypertension
A SVC obstruction in a patient
with a mediastinal mass
6 Respiratory
Stridor
Consolidation
Pleural effusion
7 Abdomen
Surgical scars
Umbilical nodule
Mass in epigastrium
Visible peristalsis
Abdominal distension
Ascites
Hepatomegaly
Splenomegaly
Renal mass
Pelvic or adnexal mass
A Ascites (ovarian carcinoma)
8 Neurological
Focal neurological signs
Sensory deficit
Spinal cord compression
Memory deficit
Personality change
9 Skeletal survey
Focal bone tenderness
(pelvis, spine, long bones)
Wrist tenderness
(hypertrophic pulmonary
osteoarthropathy)
10 Periphery
Calf tenderness, venous
thrombosis
Clubbing (if present in hands)
Clinical examination of the cancer patient • 1315
Examination of the skin
7 Abdominal examination
• Are there scars from previous surgery?
Important features of skin lesions that should
• Is the umbilicus everted, suggesting ascites?
alert suspicion include:
• Is there a firm nodule at the umbilicus due to ovarian or gastric cancer metastasis, causing a
• Asymmetry: irregular shape
Sister Mary Joseph nodule (p. 1334)?
• Bleeding
• Is there smooth hepatomegaly - possibly primary liver cancer or heart failure?
• Border: not a smooth edge
• Is the liver firm or knobbly, suggesting metastasis?
• Colour: uneven, variegated or changing
• Is the ascites too tense to demonstrate hepatomegaly?
colour
• Are other masses palpable in the abdomen?
• Diameter: >6 mm in diameter or
• Are there signs of obstruction or paralytic ileus with absence of bowel sounds?
growing
• Palpate for inguinal nodes (occasionally involved in ovarian cancer)
• Itching or pain in a pre-existing
• Percuss for flank dullness and shifting dullness
mole
• Perform vaginal and rectal examinations to detect adnexal or rectal masses
3 Examination of the lymph nodes
5 Superior vena cava
obstruction
• Venous distension of neck
• Elevated but non-pulsatile jugular venous
pulse
• Venous distension of chest wall
• Facial oedema
• Cyanosis
• Plethora of face
• Oedema of arms
5 Pericardial effusion
• Tachycardia
• Falling blood pressure
• Rising jugular venous pressure
• Muffled heart sounds
• Kussmaul’s sign (p. 544)
6 Malignant pleural effusions
Large right pleural effusion
Inspection
Tachypnoea
Palpation
^Expansion on R
Trachea and apex may be
moved to L
Percussion
Stony dull
R mid- and lower zones
Auscultation
Absent breath sounds and
diminished or absent
vocal resonance R base
Crackles above effusion
33
1316 • ONCOLOGY
Cancer represents a significant economic burden for the global
economy and is now the third leading cause of death worldwide.
By 2030, it is projected that there will be 26 million new cancer
cases and 17 million cancer deaths per year. The developing
world is disproportionately affected by cancer and in 2008
developing nations accounted for 56% of new cancer cases
and 75% of cancer deaths. These deaths happen in countries
with limited or no access to treatment and with low per capita
expenditure on health care.
The most common solid organ malignancies arise in the
lung, breast and gastrointestinal tract (Fig. 33.1), but the most
common form worldwide is skin cancer. Cigarette smoking
accounts for more than 20% of all global cancer deaths, 80%
of lung cancer cases in men and 50% of lung cancer cases
in women worldwide, which could be prevented by smoking
cessation. Diet and alcohol contribute to a further 30% of
cancers, including those of the stomach, colon, oesophagus,
breast and liver. Lifestyle modification could reduce these if
steps were taken to avoid animal fat and red meat, reduce
alcohol, increase fibre, fresh fruit and vegetable intake, and avoid
obesity. Infections account for a further 1 5% of cancers, including
those of the cervix, stomach, liver, nasopharynx and bladder,
and some of these could be prevented by infection control
and vaccination.
The 10 hallmarks of cancer
The formation and growth of cancer constitute a multistep
process, during which sequentially occurring gene
mutations result in the formation of a cancerous cell. For
cells to initiate carcinogenesis successfully, they require
key characteristics, collectively referred to as the hallmarks
of cancer.
Fig. 33.1 The most commonly diagnosed cancers in the UK. (NHL =
non-Hodgkin lymphoma) Statistics from Cancer Research UK website
(http://info. cancerresearchuk. org).
1. Genome instability and mutation
Random genetic mutations occur continuously throughout all
cells of the body and very rarely confer a selective advantage on
single cells, allowing overgrowth and dominance in local tissue
environments. Multistep carcinogenesis results from successive
clonal expansions of pre-malignant cells, each expansion being
triggered by acquisition of a random enabling genetic mutation.
Under normal circumstances, cellular DNA repair mechanisms are
so effective that almost all spontaneous mutations are corrected
without producing phenotypic changes, keeping the overall
mutation rates very low. In cancer cells, the accumulation of
mutations can be accelerated by compromising the surveillance
systems that normally monitor genomic integrity and force
genetically damaged cells into either senescence or apoptosis.
They can therefore become more sensitive to mutagenic actions
or develop DNA repair mechanism failure.
2. Resisting cell death
There are three principal mechanisms through which cell death
occurs in healthy tissues: apoptosis, autophagy and necrosis.
Apoptosis
This is programmed cell death. It is frequently found at markedly
reduced rates in cancers, particularly those of high grade or
those resistant to treatment. The cellular apoptotic system has
regulatory elements that sense intrinsic and extrinsic pro-apoptotic
signals and initiate a cascade of proteolysis and cell disassembly
with nuclear fragmentation, chromosomal condensation, and
shrinking of the cell with loss of intercellular contact, followed
by cellular fragmentation and the formation of apoptotic bodies
that are phagocytosed by neighbouring cells. The most important
regulator of apoptosis is the TP53 tumour suppressor gene,
often described as the ‘guardian of the genome’, as it is able
to induce apoptosis in response to sufficient levels of genomic
damage. The largest initiator of apoptosis via TP53 is cellular
injury, particularly that due to DNA damage from chemotherapy,
oxidative damage and ultraviolet (UV) radiation.
Autophagy
This is a catabolic process during which cellular constituents
are degraded by lysosomal machinery within the cell. It is an
important physiological mechanism; it usually occurs at low
levels in cells but can be induced in response to environmental
stresses, particularly radiotherapy and cytotoxic chemotherapy,
which induce elevated levels of autophagy that are cytoprotective
for malignant cells, thus impeding rather than perpetuating the
killing actions of these stress situations. Severely stressed cancer
cells have been shown to shrink via autophagy to a state of
reversible dormancy.
|jlecrosis
This is the premature death of cells and is characterised by the
release of cellular contents into the local tissue microenvironment,
in marked contrast to apoptosis, where cells are disassembled
in a step-by-step fashion and the resulting cellular fragments
are phagocytosed. Necrotic cell death results in the recruitment
of inflammatory immune cells, promotion of angiogenesis, and
release of stimulatory factors that increase cellular proliferation
The 10 hallmarks of cancer • 1317
and tissue invasion, thereby enhancing rather than inhibiting
carcinogenesis.
3. Sustaining proliferative signalling
Cancer cells can sustain proliferation beyond what would be
expected for normal cells; this is typically due to growth factors,
which are able to bind to cell surface-bound receptors that activate
an intracellular tyrosine kinase-mediated signalling cascade,
ultimately leading to changes in gene expression and promoting
cellular proliferation and growth. Sustained proliferative capacity
can result from over-production of growth factor ligands or
receptors and production of structurally altered receptors, which
can signal in the absence of ligand binding and activation of
intracellular signalling pathway components, so that signalling
is no longer ligand-dependent.
| The cell cycle
The cell cycle is composed of four ordered, strictly regulated
phases referred to as G^ (gap 1), S (DNA synthesis), G2 (gap
2) and M (mitosis) (Fig. 33.2). Normal cells grown in culture will
stop proliferating and enter a quiescent state called G0 once
they become confluent or are deprived of serum or growth
factors. The first gap phase (G-,) prior to the initiation of DNA
synthesis represents the period of commitment that separates
M and S phases as cells prepare for DNA duplication. Cells
in G0 and G1 are receptive to growth signals, but once they
have passed a restriction point, they are committed to enter
DNA synthesis (S phase). Cells demonstrate arrest at different
points in G^ in response to different inhibitory growth signals.
Mitogenic signals promote progression through G^ to S phase,
utilising phosphorylation of the retinoblastoma gene product
(pRB, p. 40). Following DNA synthesis, there is a second gap
phase (G2) prior to mitosis (M), allowing cells to repair errors
that have occurred during DNA replication and thus preventing
propagation of these errors to daughter cells. Although the
duration of individual phases may vary, depending on cell and
tissue type, most adult cells are in a G0 state at any one time.
Cell cycle regulation
The cell cycle is orchestrated by a number of molecular
mechanisms: most importantly, by cyclins and cyclin-dependent
kinases (CDKs). Cyclins bind to CDKs and are regulated by
both activating and inactivating phosphorylation, with two main
checkpoints at G/S and G2/M transition. The genes that inhibit
progression play an important part in tumour prevention and are
referred to as tumour suppressor genes (e.g. TP53, TP21 , TP16
genes). The products of these genes deactivate the cyclin-CDK
complexes and are thus able to halt the cell cycle. The complexity
of cell cycle control is susceptible to dysregulation, which may
produce a malignant phenotype.
| Stimulation of the cell cycle
Many cancer cells produce growth factors, which drive their
own proliferation by a positive feedback known as autocrine
stimulation. Examples include transforming growth factor-alpha
(TGF-a) and platelet-derived growth factor (PDGF). Other cancer
cells express growth factor receptors at increased levels due
to gene amplification or express abnormal receptors that are
permanently activated. This results in abnormal cell growth in
response to physiological growth factor stimulation or even in
the absence of growth factor stimulation (ligand-independent
signalling). The epidermal growth factor receptor (EGFR) is often
over-expressed in lung and gastrointestinal tumours and the
human epidermal growth factor receptor 2 (HER2)/neu receptor
is frequently over-expressed in breast cancer. Both receptors
activate the Ras-Raf-mitogen activated protein (MAP) kinase
pathway, causing cell proliferation.
Antibiotics and
alkylating agents
(act on entire cycle)
Restriction point
(regulated by growth
factors)
G-| checkpoint for
Damaged DNA
RB blocks
TP53 -> CDKs blocked
Terminal
differentiation
Apoptosis
^Mitotic spindle poisons^
Mitosis '
Prophase -> telophase
Nuclear and cellular division
Terminal differentiation
Apoptosis q2 checkpoint foT
DNA damage Further growth
DNA replication or DNA rePair
incomplete
Fig. 33.2 The cell cycle and sites of action of chemotherapeutic agents. (CDK = cyclin-dependent kinase; RB= retinoblastoma gene)
Topoisomerase^l
inhibitors J
1318 • ONCOLOGY
4. Evading growth suppressors
In healthy tissues, cell-to-cell contact in dense cell populations acts
as an inhibitory factor on proliferation. This contact inhibition is
typically absent in many cancer cell populations. Growth-inhibitory
factors can modulate the cell cycle regulators and produce
activation of the CDK inhibitors, causing inhibition of the CDKs.
Mutations within inhibitory proteins are common in cancer. Loss
of restriction by disruption of pRB regulation can be found in
human tumours, which produces a loss of restraint on transition
from to S phase of the cell cycle. Disruption of TP53 function
will have downstream effects on p21 that alter the coordination
of DNA repair with cycle arrest, and that result in the affected
cell accumulating genomic defects. Down-regulation of p2 1 and
p27, which can be found in tumours with normal TP53 function,
correlates notably with high tumour grade and poor prognosis.
5. Enabling replicative immortality
For cancer cells to evolve into macroscopic tumours, they need
to acquire the ability for unlimited proliferation. Telomeric DNA
sequences, which protect and stabilise chromosomal ends, play a
central role in conferring this limitless replicative potential. During
replication of normal cells, telomeres shorten progressively as
small fragments of telomeric DNA are lost with successive cycles
of replication. This shortening process is thought to represent a
mitotic clock and eventually prevents the cell from dividing further.
Telomerase, a specialised polymerase enzyme, adds nucleotides
to telomeres, allowing continued cell division and thus preventing
premature arrest of cellular replication. The telomerase enzyme
is almost absent in normal cells but is expressed at significant
levels in many human cancers.
6. Inducing angiogenesis
All cancers require a functional vascular network to ensure
continued growth and will be unable to grow beyond 1 mm3
without stimulating the development of a vascular supply. Tumours
require sustenance in the form of nutrients and oxygen, as well
as an ability to evacuate metabolic waste products and carbon
dioxide. This entails the development of new blood vessels,
which is termed angiogenesis (Figs 33.3 and 33.4).
Angiogenesis is dependent on the production of angiogenic
growth factors, of which vascular endothelial growth factor
(VEGF) and platelet-derived growth factor (PDGF) are the
best characterised. During tumour progression, an angiogenic
switch is activated and remains on, causing normally quiescent
vasculature to sprout new vessels continually that help sustain
expanding tumour growth. Angiogenesis is governed by a balance
of pro-angiogenic stimuli and angiogenesis inhibitors, such
as thrombospondin (TSP)-I, which binds to transmembrane
receptors on endothelial cells and evokes suppressive signals.
A number of cells can contribute to the maintenance of a
functional tumour vasculature and therefore sustain angiogenesis.
These include pericytes and a variety of bone marrow-derived
cells such as macrophages, neutrophils, mast cells and myeloid
progenitors.
First mutation
First mutation
Normal
epithelium
— Basal lamina
— Blood vessel
— Connective
tissue
— Lymphatic
Inherited or acquired
gain of oncogene
Loss of tumour
suppressor gene
Initial proliferation
Further mutation; subset
selected for rapid growth
Further mutation
-> invasion or metastasis
Lymphatic
spread
Blood spread
Breakdown of connective tissue
via tumour production of
e.g. collagenase
tissue metalloproteinases
Loss of cell adhesion molecules
e.g. E-cadherin
Ectopic
growth factor
production and
autostimulation
Carcinoma
Failed apoptosis
(e.g. TP53 mutation)
7 Local invasion
— through basal
lamina
T Angiogenesis
to support
tumour growth
(see Fig. 33.4)
Fig. 33.3 Oncogenesis. The multistep origin of cancer, showing events implicated in cancer initiation, progression, invasion and metastasis.
The 10 hallmarks of cancer • 1319
Viable tumour cell
Apoptoptic
tumour cell
Inhibition
<^2=^
VEGF
receptor
VEGF
avp3 integrin
:/■
Tissue
factor
Coagulation factor
Coagulation
Fibrinogen
i
Fibrin
^E. Cell adhesion
"^Urokinase
O Proteolysis
Plasmin
7. Activating invasion and metastasis
Invasion and metastasis are complex processes involving multiple
discrete steps; they begin with local tissue invasion, followed by
infiltration of nearby blood and lymphatic vessels by cancer cells.
Malignant cells are eventually transported through haematogenous
and lymphatic spread to distant sites within the body, where they
form micrometastases that will eventually grow into macroscopic
metastatic lesions (see Fig. 33.3).
Cadherin-1 (CDH1) is a calcium-dependent cell-cell adhesion
glycoprotein that facilitates assembly of organised cell sheets in
tissues, and increased expression is recognised as an antagonist
of invasion and metastasis. In situ tumours usually retain CDH1
production, whereas loss of CDH1 production due to down-
regulation or occasional mutational inactivation of CDH1 has
been observed in human cancers, supporting the theory that
CDH1 plays a key role in suppression of invasion and metastasis.
Cross-talk between cancer cells and cells of the surrounding
stromal tissue is involved in the acquired capability for invasive
growth and metastasis. Mesenchymal stem cells in tumour
stroma have been found to secrete CCL5, a protein chemokine
that helps recruit leucocytes into inflammatory sites. With the
help of particular T-cell-derived cytokines (interleukin (IL)-2
and interferon-gamma (IFN-y)), CCL5 induces proliferation and
activation of natural killer cells and then acts reciprocally on
cancer cells to stimulate invasive behaviour. Macrophages at
the tumour periphery can foster local invasion by supplying
matrix-degrading enzymes such as metalloproteinases and
cysteine cathepsin proteases.
8. Reprogramming energy metabolism
Under aerobic conditions, oxidative phosphorylation functions as
the main metabolic pathway for energy production; cells process
glucose, first to pyruvate via glycolysis and thereafter to carbon
dioxide in the mitochondria. While under anaerobic conditions,
glycolysis is favoured to produce adenosine triphosphate (ATP).
Cancer cells can reprogram their glucose metabolism to limit
Fig. 33.4 Angiogenesis, invasion and metastasis. A] For
any cancer to grow beyond 1 mm3, it must evoke a blood
supply. 5fj New vessel formation results from the release of
angiogenic factors by the tumour cells and loss of inhibition of
the endothelial cells. [C The loss of cellular adhesion and
disruption of the extracellular matrix allow cells to extravasate
into the blood stream and metastasise to distant sites. (VEGF=
vascular endothelial growth factor)
energy production to glycolysis, even in the presence of oxygen.
This has been termed ‘aerobic glycolysis’. Up-regulation of
glucose transporters, such as GLUT1, is the main mechanism
through which aerobic glycolysis is achieved.
This reprogramming of energy metabolism appears paradoxical,
as overall energy production from glycolysis is significantly lower
(18-fold) than that from oxidative phosphorylation. One explanation
may be that the increased production of glycolytic intermediates
can be fed into various biosynthetic pathways, including those
that generate the nucleosides and amino acids, necessary for
the production of new cells.
9. Tumour-promoting inflammation
Almost all tumours show infiltration with immune cells on
pathological investigation and historically this finding was thought
to represent an attempt of the immune system to eradicate the
cancer. It is now clear that tumour-associated inflammatory
responses promote tumour formation and cancer progression.
Cytokines are able to alter blood vessels to permit migration
of leucocytes (mainly neutrophils), in order to permeate from the
blood vessels into the tissue, a process known as extravasation.
Migration across the endothelium occurs via the process of
diapedesis, where chemokine gradients stimulate adhered
leucocytes to move between endothelial cells and pass through
the basement membrane into the surrounding tissues. Once
within the tissue interstitium, leucocytes bind to extracellular
matrix proteins via integrins and CD44 to prevent their loss
from the site.
As well as cell-derived mediators, several acellular biochemical
cascade systems consisting of pre-formed plasma proteins act in
parallel to initiate and propagate the inflammatory response. These
include the complement system activated by bacteria, and the
coagulation and fibrinolytic systems activated by necrosis, and also
in burns and trauma, as well as cancer. Other bioactive molecules,
such as growth factors and pro-angiogenic factors, may be
released by inflammatory immune cells into the surrounding
tumour microenvironment. In particular, the release of reactive
1320 • ONCOLOGY
oxygen species, which are actively mutagenic, will accelerate
the genetic evolution of surrounding cancer cells, enhancing
growth and contributing to cancer progression.
10. Evading immune destruction
The immune system operates as a significant barrier to tumour
formation and progression, and the ability to escape from immunity
is a hallmark of cancer development. Cancer cells continuously
shed surface antigens into the circulatory system, prompting an
immune response that includes cytotoxic T-cell, natural killer cell
and macrophage production. The immune system is thought
to provide continuous surveillance, with resultant elimination of
cells that undergo malignant transformation.
However, deficiencies in the development or function of CD8+
cytotoxic T lymphocytes, CD4+ Thl helper T cells or natural
killer cells can each lead to a demonstrable increase in cancer
incidence. Also, highly immunogenic cancer cells may evade
immune destruction by disabling components of the immune
system. This is done through recruitment of inflammatory cells,
including regulatory T cells and myeloid-derived suppressor
cells, both actively immunosuppressive against the actions of
cytotoxic lymphocytes (see Fig. 4.12, p. 80).
Cancers develop and progress when there is loss of recognition
by the immune system, lack of susceptibility due to escape from
immune cell action and induction of immune dysfunction, often
via inflammatory mediators.
Environmental and genetic
determinants of cancer
The majority of cancers do not have a single cause but
rather are the result of a complex interaction between genetic
factors and exposure to environmental carcinogens. These
are often tumour type-specific but some general principles do
apply.
Environmental factors
Environmental triggers for cancer have mainly been identified
through epidemiological studies that examine patterns of
distribution of cancers in patients in whom age, sex, presence
of other illnesses, social class, geography and so on differ.
Sometimes, these give strong pointers to the molecular or
cellular causes of the disease, such as the association between
aflatoxin production within contaminated food supplies and
hepatocellular carcinomas. For many solid cancers, such as
breast and colorectal, however, there is evidence of a multifactorial
pathogenesis, even when there is a principal environmental
cause (Box 33.1).
Smoking is now established beyond all doubt as a major cause
of lung cancer, but there are obviously additional predisposing
factors since not all smokers develop cancer. Similarly, most
carcinomas of the cervix are related to infection with human
33.1 Environmental factors that predispose to cancer
Environmental aetiology
Processes
Diseases
Occupational exposure
(see ‘Radiation’ below)
Dye and rubber manufacturing (aromatic amines)
Asbestos mining, construction work, shipbuilding (asbestos)
Vinyl chloride (PVC) manufacturing
Petroleum industry (benzene)
Bladder cancer
Lung cancer and mesothelioma
Liver angiosarcoma
Acute leukaemia
Chemicals
Chemotherapy (e.g. melphalan, cyclophosphamide)
Acute myeloid leukaemia
Cigarette smoking
Exposure to carcinogens from inhaled smoke
Lung and bladder cancer
Viral infection
Epstein— Barr virus
Human papillomavirus
Hepatitis B and C viruses
Burkitt’s lymphoma and nasopharyngeal cancer
Cervical cancer
Hepatocellular carcinoma
Bacterial infection
Helicobacter pylori
Gastric MALT lymphomas, gastric cancer
Parasitic infection
Liver fluke ( Opisthorchis sinensis)
Schistosoma haematobium
Cholangiocarcinoma
Squamous cell bladder cancer
Dietary factors
Low-roughage/high-fat content diet
High nitrosamine intake
Aflatoxin from contamination of Aspergillus flavus
Colonic cancer
Gastric cancer
Hepatocellular cancer
Radiation
UV exposure
Nuclear fallout following explosion (e.g. Hiroshima)
Diagnostic exposure (e.g. CT)
Occupational exposure (e.g. beryllium and strontium mining)
Therapeutic radiotherapy
Basal cell carcinoma
Melanoma
Non-melanocytic skin cancer
Leukaemia
Solid tumours, e.g. thyroid
Cholangiocarcinoma following Thorotrast usage
Lung cancer
Medullary thyroid cancer
Sarcoma
Inflammatory diseases
Ulcerative colitis
Colon cancer
Hormonal
Use of diethylstilbestrol
Oestrogens
Vaginal cancer
Endometrial cancer
Breast cancer
(CT = computed tomography; MALT =
mucosa-associated lymphoid tissue; UV = ultraviolet)
Investigations • 1321
papillomavirus (HPV subtypes 16 and 18). For carcinomas of the
bowel and breast, there is strong evidence of an environmental
component. For example, the risk of breast cancer in women of
Far Eastern origin remains relatively low when they first migrate
to a country with a Western lifestyle, but rises in subsequent
generations to approach that of the resident population of the
host country. The precise environmental factor that causes this
change is unclear but may include diet (higher intake of saturated
fat and/or dairy products), reproductive patterns (later onset of
first pregnancy) and lifestyle (increased use of artificial light and
shift in diurnal rhythm).
Genetic factors
A number of inherited cancer syndromes are recognised that
account for 5-10% of all cancers (Box 33.2). Their molecular
basis is discussed in Chapter 3, but in general they result from
inherited mutations in genes that regulate cell growth, cell death
and apoptosis. Examples include the BRCA1 , BRCA2 and AT
(ataxia telangiectasia) genes that cause breast and some other
cancers, the FAR gene that causes bowel cancer and the RB
gene that causes retinoblastoma. Although carriers of these
gene mutations have a greatly elevated risk of cancer, none has
1 00% penetrance and additional modulating factors, both genetic
and environmental, are likely to be operative. Exploration of a
possible genetic contribution is a key part of cancer management,
especially with regard to ascertaining the risk for an affected
patient’s offspring.
Investigations
When a patient is suspected of having cancer, a full history
should be taken; specific questions should be included as to
potential risk factors such as smoking and occupational exposures
or potential complications of the disease. A thorough clinical
examination is essential to identify sites of metastases, and to
discover any other conditions that may have a bearing on the
management plan (pp. 1 31 4-1 31 5). In order to make a diagnosis
and to plan the most appropriate management, information is
needed on:
• the type of tumour
• the extent of disease, as assessed by staging
investigations
• the patient’s general condition and any comorbidity.
33.2 Inherited cancer predisposition syndromes
Syndrome
Malignancies
Inheritance
Gene
Ataxia telangiectasia
Leukaemia, lymphoma, ovarian, gastric, brain, colon
AR
AT
Bloom’s syndrome
Leukaemia, tongue, oesophageal, colonic, Wilms’ tumour
AR
BLM
Breast/ovarian
Breast, ovarian, colonic, prostatic, pancreatic
AD
BRCA1, BRCA2
Cowden’s syndrome
Breast, thyroid, gastrointestinal tract, pancreatic
AD
PTEN
Familial adenomatous polyposis
Colonic, upper gastrointestinal tract
AD
APC, MUTYH
Familial atypical multiple mole
melanoma (FAMMM)
Melanoma, pancreas
AD
CDKN2A (TP 16)
Fanconi anaemia
Leukaemia, oesophageal, skin, hepatoma
AR
FACA, FACC, FACD
Gorlin’s syndrome
Basal cell skin, brain
AD
PTCH
Hereditary diffuse gastric cancer
Diffuse gastric cancer
AD
E-cadherin
Hereditary non-polyposis colon
cancer (HNPCC)
Colonic, endometrial, ovarian, pancreatic, gastric
AD
MSH2, MLH1, MSH6, PMS1, PMS2
Li-Fraumeni syndrome
Sarcoma, breast, osteosarcoma, leukaemia, glioma,
adrenocortical
AD
TP53
Multiple endocrine neoplasia
(MEN) 1
Pancreatic islet cell, pituitary adenoma, parathyroid
adenoma and hyperplasia
AD
MEN1
MEN 2
Medullary thyroid, phaeochromocytoma, parathyroid
hyperplasia
AD
RET
Neurofibromatosis 1
Neurofibrosarcoma, phaeochromocytoma, optic glioma
AD
NF1
Neurofibromatosis 2
Vestibular schwannoma
AD
NF2
Papillary renal cell cancer
syndrome
Renal cell cancer
AD
MET
Peutz-Jeghers syndrome
Colonic, ileal, breast, ovarian
AD
STK11
Prostate cancer
Prostate
AD
HPC1
Retinoblastoma
Retinoblastoma, osteosarcoma
AD
RBI
von Hippel— Lindau syndrome
Haemangioblastoma of retina and CNS, renal cell,
phaeochromocytoma
AD
VHL
Wilms’ tumour
Nephroblastoma, neuroblastoma, hepatoblastoma,
rhabdomyosarcoma
AD
WT1
Xeroderma pigmentosum
Skin, leukaemia, melanoma
AR
XPA, XPC, XPD (ERCC2), XPF
(AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system)
1322 • ONCOLOGY
i
33.3 Eastern Cooperative Oncology Group (ECOG)
performance status scale
0
Fully active, able to carry on all usual activities without restriction
and without the aid of analgesics
i
Restricted in strenuous activity but ambulatory and able to carry
out light work or pursue a sedentary occupation. This group also
contains patients who are fully active, as in grade 0, but only
with the aid of analgesics
2
Ambulatory and capable of all self-care but unable to work. Up
and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more
than 50% of waking hours
4
Completely disabled, unable to carry out any self-care and
confined totally to bed or chair
i
33.4 TNM classification
Extent of primary tumour*
TX
Not assessed
TO
No tumour
T1 1
T2 1
Increases in primary tumour size or depth
T3 1
of invasion
T4 J
Increased involvement of nodes*
NX
Not assessed
NO
No nodal involvement
N1 1
N2/3 J
| Increases in involvement
Presence of metastases
MX
Not assessed
MO
Not present
Ml
Present
*Exact criteria for size and region of nodal involvement have been defined for
each anatomical site.
The overall fitness of a patient is often assessed by the Eastern
Cooperative Oncology Group (ECOG) performance status scale
(Box 33.3). The outcome for patients with a performance status
of 3 or 4 is worse in almost all malignancies than for those with
a status of 0-2, and this has a strong influence on the approach
to treatment in the individual patient.
The process of staging determines the extent of the tumour; it
entails clinical examination, imaging and, in some cases, surgery,
to establish the extent of disease involvement. The outcome
is recorded using a standard staging classification that allows
comparisons to be made between different groups of patients.
Therapeutic decisions and prognostic predictions can then be
made using the evidence base for the disease. One of the most
commonly used systems is the T (tumour), N (regional lymph
nodes), M (metastatic sites) approach of the International Union
against Cancer (UICC, Box 33.4). For some tumours, such as
colon cancer, the Dukes system (p. 832) is used rather than
the UICC classification.
Histology
Histological analysis of a biopsy or resected specimen is pivotal
in clinching the diagnosis and in deciding on the best form
of management. The results of histological analysis are most
informative when combined with knowledge of the clinical picture;
biopsy results should therefore be reviewed and discussed within
the context of a multidisciplinary team meeting.
|Light microscopy
Examination of tumour samples by light microscopy remains
the core method of cancer diagnosis and, in cases where the
primary site is unclear, may give clues to the origin of the tumour:
• Signet-ring cells favour a gastric primary.
• Presence of melanin favours melanoma.
• Mucin is common in gut/lung/breast/endometrial cancers,
but particularly common in ovarian cancer and rare in renal
cell or thyroid cancers.
• Psammoma bodies are a feature of ovarian cancer (mucin
+) and thyroid cancer (mucin -).
| Immunohistochemistry
Immunohistochemical (IHC) staining for tumour markers can
provide useful diagnostic information and can help with treatment
decisions. Commonly used examples of IHC in clinical practice
include:
• Oestrogen (ER) and progesterone (PR) receptors. Positive
results indicate that the tumour may be sensitive to
hormonal manipulation.
• Alpha-fetoprotein (AFP) and human chorionic
gonadotrophin (hCG) with or without placental alkaline
phosphatase (PLAP). These favour germ-cell tumours.
• Prostate-specific antigen (PSA) and prostatic acid
phosphatase (PAP). These favour prostate cancer.
• Carcinoembryonic antigen (CEA), cytokeratin and epithelial
membrane antigen (EMA). These favour epithelial
carcinomas.
• HER2 receptor. Breast cancers that have high levels of
expression of HER2 indicate that the tumour may respond
to trastuzumab (Herceptin), an antibody directed against
the HER2 receptor.
The pattern of immunoglobulin, T-cell receptor and cluster
designation (CD) antigen expression on the surface is helpful
in the diagnosis and classification of lymphomas. This can be
achieved by IHC staining of biopsy samples or flow cytometry.
| Electron microscopy
Electron microscopy (EM) can sometimes be of diagnostic value.
Examples include the visualisation of melanosomes in amelanotic
melanoma and dense core granules in neuro-endocrine tumours.
EM may help to distinguish adenocarcinoma from mesothelioma,
as the ultrastructural properties of these two diseases are different
(mesothelioma appears to have long, narrow, branching microvilli
while adenocarcinomas appear to have short, stubby microvilli).
EM is also useful for differentiating spindle-cell tumours (sarcomas,
melanomas, squamous cell cancers) from small round-cell
tumours, again due to their ultrastructural differences.
Cytogenetic analysis
Some tumours demonstrate typical chromosomal changes that
help in diagnosis. The utilisation of fluorescent in situ hybridisation
(FISH) techniques can be useful in Ewing’s sarcoma and peripheral
neuro-ectodermal tumours where there is a translocation between
chromosome 11 and 22— 1(1 1 ;22)(q24;q1 2). In some cases,
gene amplification can be detected via FISH (e.g. determining
over-expression of HER2/neu).
Presenting problems in oncology • 1323
Imaging
Imaging plays a critical role in oncology, not only in locating the
primary tumour but also in staging the disease and determining
the response to treatment. The imaging modality employed
depends primarily on the site of the disease and likely patterns
of spread, and may require more than one modality.
Ultrasound
Ultrasound is useful in characterising lesions within the liver,
kidney, pancreas and reproductive organs. It can be used for
guiding biopsies of tumours in breast and liver. Endoscopic
ultrasound is helpful in staging upper gastrointestinal and
pancreatic cancers, involving a special endoscope with an
ultrasound probe attached.
Ijtomputed tomography
Computed tomography (CT) is a key investigation in cancer
patients and is particularly useful in imaging the thorax and
abdomen. With modern scanners it is possible to visualise the
large bowel if it is prepared (CT colonography), allowing accurate
detection of colorectal cancers and adenomas >10 mm.
| Magnetic resonance imaging
Magnetic resonance imaging (MRI) has a high resolution and is
the preferred technique for brain and pelvic imaging. It is widely
employed for the staging of rectal, cervical and prostate cancers.
Positron emission tomography
Positron emission tomography (PET) visualises metabolic activity
of tumour cells and is widely used, often in combination with CT
(PET-CT), to evaluate the extent of the disease, particularly in
the assessment of potential distant metastasis (Fig. 33.5). It can
accurately assess the severity and spread of cancer by detecting
tumour metabolic activity following injection of small amounts of
radioactive tracers such as fluorodeoxyglucose (FDG). In addition
to having a role in diagnosis, PET can be used in some patients
to assess treatment response.
Biochemical markers
Many cancers produce substances called tumour markers, which
can assist in diagnosis and surveillance. Some are useful in
population screening, diagnosis, determining prognosis, response
evaluation, detection of relapse and imaging of metastasis.
Unfortunately, most tumour markers are neither sufficiently
sensitive nor sufficiently specific to be used in isolation for
diagnosis and need to be interpreted in the context of the other
clinical features. Some can be used for antibody-directed therapy
or imaging, however, where they have a greater role in diagnosis.
Tumour markers in routine use are outlined in Box 33.5.
Presenting problems in oncology
In the early stages of cancer development, the number of
malignant cells is small and the patient is usually asymptomatic.
With tumour progression, localised signs or symptoms develop
due to mass effects and/or invasion of local tissues. With further
progression, symptoms may occur at distant sites as a result of
Fig. 33.5 Positron emission tomography-computed tomography
(PET-CT) images. [A] There is a neoplastic lesion (arrow) in the left axilla,
evidenced by the increased uptake of fluorodeoxyglucose (FDG) tracers.
[§] Imaging after chemotherapy, demonstrating that the abnormal uptake
has disappeared and indicating a response to treatment. Courtesy of Dr J.
Wilsdon, Freeman Hospital, Newcastle upon Tyne.
metastatic disease or from non-metastatic manifestations due
to production of biologically active hormones by the tumour
or as the result of an immune response to the tumour. The
possible presentations are summarised in Boxes 33.6 and
33.7, and common presenting features discussed below.
Although the incidence of cancer increases with patient age, the
approach to investigation and management is similar at all ages
(Box 33.8).
Palpable mass
A palpable mass detected by the patient or physician may be
the first sign of cancer. Primary tumours of the thyroid, breast,
testis and skin are often detected in this way, whereas palpable
lymph nodes in the neck, groin or axilla may indicate secondary
spread of tumour. Hepatomegaly may be the first sign of primary
liver cancer or tumour metastasis, whereas skin cancer may
present as an enlarging or changing pigmented lesion.
Weight loss and fever
Unintentional weight loss is a characteristic feature of advanced
cancer, but can have other causes such as thyrotoxicosis, chronic
inflammatory disease and chronic infective disorders. Fever can
occur in any cancer secondary to infection, but may be a primary
feature in Hodgkin and non-Hodgkin lymphoma, leukaemia, renal
cancer and liver cancer. The presence of unexplained weight
loss or fever warrants investigation to exclude the presence of
occult malignancy.
1324 • ONCOLOGY
33.5 Commonly used serum tumour markers
Name
Natural occurrence
Tumours
Alpha-fetoprotein (AFP)
Glycoprotein found in yolk sac and fetal liver tissue.
Transient elevation in liver diseases. Has a role in
screening during pregnancy for the detection of
neural tube defects and Down’s syndrome
Ovarian non-seminomatous germ cell tumours
(80%), testicular teratoma (80%), hepatocellular
cancer (50%)
Beta-2-microglobulin
A human leucocyte antigen (HLA) common fragment
present on surface of lymphocytes, macrophages and
some epithelial cells. Can be elevated in autoimmune
disease and renal glomerular disease
Non-Hodgkin lymphoma, myeloma
Calcitonin
32-amino-acid peptide from C cells of thyroid. Used
to screen for MEN 2
Medullary cell carcinoma of thyroid
Cancer antigen 125 (CA-125)
Differentiation antigen of coelomic epithelium
(Muller’s duct). Raised in any cause of ascites,
pleural effusion or heart failure. Can be raised in
inflammatory conditions
Ovarian epithelial cancer (75%), gastrointestinal
cancer (10%), lung cancer (5%) and breast
cancer (5%)
CA-19.9
A mucin found in epithelium of fetal stomach,
intestine and pancreas. It is eliminated exclusively via
bile and so any degree of cholestasis can cause
levels to rise
Pancreatic cancer (80%), mucinous tumour of
the ovary (65%), gastric cancer (30%), colon
cancer (30%)
Carcinoembryonic antigen (CEA)
Glycoprotein found in intestinal mucosa during
embryonic and fetal life. Elevated in smokers,
cirrhosis, chronic hepatitis, ulcerative colitis,
pneumonia
Colorectal cancer, particularly with liver
metastasis, gastric cancer, breast cancer, lung
cancer, mucinous cancer of the ovary
Human chorionic gonadotrophin (hCG)
Glycoprotein hormone, 14 kD a subunit and 24 kD (3
subunit from placental syncytiotrophoblasts. Used for
disease monitoring in hydatidiform mole and as the
basis of a pregnancy test
Choriocarcinoma (100%), hydatidiform moles
(97%), ovarian non-seminomatous germ cell
tumours (50-80%), seminoma (15%)
Placental alkaline phosphatase (PLAP)
Isoenzyme of alkaline phosphatase
Seminoma (40%), ovarian dysgerminoma (50%)
Prostate-specific antigen (PSA)
Glycoprotein member of human kallikrein gene family.
PSA is a serine protease that liquefies semen in
excretory ducts of prostate. Can be elevated in
benign prostatic hypertrophy and prostatitis
Prostate cancer (95%)
Thyroglobulin
Matrix protein for thyroid hormone synthesis in
normal thyroid follicles
Papillary and follicular thyroid cancer
33.6 Local features of malignant disease
Symptom
Typical site or possible tumour
Haemorrhage
Stomach, colon, bronchus, endometrium, bladder, kidney
Lump
Breast, lymph node (any site), testicle
Bone pain or fracture
Bone (primary sarcoma, secondary metastasis from breast, prostate, bronchus,
thyroid, kidney)
Skin abnormality
Melanoma, basal cell carcinoma (rodent ulcer)
Ulcer
Oesophagus, stomach, anus, skin
Dysphagia
Oesophagus, bronchus, gastric
Increasing constipation, abdominal discomfort or pain
Colon, rectum, ovary
Airway obstruction, stridor, cough, recurrent infection
Bronchus, thyroid
Odynophagia, early satiety, vomiting
Bronchus, stomach, oesophagus, colon, rectum
Abdominal swelling (ascites)
Ovary, stomach, pancreas
Thromboembolism
Thrombosis and disseminated intravascular coagulation (DIC) are
common complications in patients with cancer. The prothrombotic
state is caused by cancer cells activating the coagulation system
via factors such as tissue factor, cancer procoagulant and
inflammatory cytokines. The interaction between tumour cells,
monocytes/macrophages, platelets and endothelial cells can
promote thrombus formation, as part of a host response to the
cancer (i.e. acute phase, inflammation, angiogenesis) or via a
reduction in the levels of inhibitors of coagulation or impairment
Presenting problems in oncology • 1325
33.7 Non-metastatic manifestations of
malignant disease
Common cancer site
Feature associations
of fibrinolysis. Furthermore, the prothrombotic tendency can be
enhanced by therapy such as surgery, chemotherapy, hormone
therapy and radiotherapy, and by in-dwelling access devices (i.e.
central venous catheters). In some patients, the thromboembolism
is the first presenting feature of the underlying cancer.
Ectopic hormone production
In some cases, the first presentation of cancer is with a metabolic
abnormality due to ectopic production of hormones by tumour
cells, including insulin, ACTH, vasopressin (antidiuretic hormone,
ADH), fibroblast growth factor (FGF)-23, erythropoietin and
33.9 Ectopic hormone production by tumours
Hormone
Consequence
Tumours
ACTH
Cushing’s syndrome
SCLC
Erythropoietin
Polycythaemia
Kidney, hepatoma,
cerebellar
haemangioblastoma,
uterine fibroids
FGF-23
Hypophosphataemic
osteomalacia
Mesenchymal tumours
PTHrP
Hypercalcaemia
NSCLC (squamous cell),
breast, kidney
Vasopressin
(ADH)
Hyponatraemia
SCLC
(ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; FGF =
fibroblast growth factor; NSCLC = non-small cell lung cancer; PTHrP =
parathyroid hormone-related protein; SCLC = small cell lung cancer)
parathyroid hormone-related protein (PTHrP). This can result
in a wide variety of presentations, as summarised in Box 33.9.
Further details on the presentation and management of ACTH- and
vasopressin-producing tumours are given on page 670, and those
of FGF23-producing tumours on page 1053. The management of
hypercalcaemia associated with malignancy is discussed below.
Neurological paraneoplastic syndromes
These form a group of conditions associated with cancer that
are thought to be due to an immunological response to the
tumour that results in damage to the nervous system or muscle.
The cancers most commonly implicated are those of the lung
(small cell and non-small cell), pancreas, breast, prostate, ovary
and lymphoma.
• Peripheral neuropathy results from axonal degeneration or
demyelination.
• Encephalomyelitis can present with diverse symptoms,
depending on which region of the brain is involved.
Lumbar puncture shows raised protein in the cerebrospinal
fluid and a pleocytosis, predominantly that of lymphocytes.
In some centres, flow cytometry of the cerebrospinal fluid
can be used to detect carcinomatous cells. MRI shows
meningeal enhancement, particularly at the level of the
brainstem, and anti-Hu antibodies may be detectable
in serum. Encephalomyelitis is due to perivascular
inflammation and selective neuronal degeneration. Most
cases are caused by small cell lung cancer (75%).
• Cerebellar degeneration may be the presenting feature of
an underlying malignancy and presents with rapid onset of
cerebellar ataxia. Diagnosis is by MRI or CT, which may
show cerebellar atrophy. Patients with these neurological
paraneoplastic syndromes may be found to have circulating
anti-Yo, Tr and Hu antibodies, but these are not completely
specific and negative results do not exclude the diagnosis.
• Retinopathy is a rare complication of cancer and presents
with blurred vision, episodic visual loss and impaired colour
vision. If left untreated, it may lead to blindness. The
diagnosis should be suspected if the electroretinogram is
abnormal and anti-retinal antibodies are detected.
• Lambert-Eaton myasthenic syndrome (LEMS) is due to
underlying cancer in about 60% of cases. It presents with
Weight loss and anorexia
Lung, gastrointestinal tract
Fatigue
Any
Hypercalcaemia
Myeloma, breast, kidney
Prothrombotic tendency
Ovary, pancreas,
gastrointestinal tract
SIADH
Ectopic ACTH
Small cell lung cancer
Lambert-Eaton myasthenic syndrome
Small cell lung cancer
Subacute cerebellar degeneration
Small cell lung cancer,
ovarian cancer
Acanthosis nigricans
Stomach, oesophagus
Dermatomyositis/polymyositis
Stomach, lung
(ACTH = adrenocorticotropic hormone; SIADH =
antidiuretic hormone (vasopressin) secretion)
syndrome of inappropriate
(fx
• Incidence: around 50% of cancers occur in the 15% of the
population aged over 65 years.
• Screening: women aged over 65 in the UK are not invited to breast
cancer screening but can request it. Uptake is low despite
increasing incidence with age.
• Presentation: may be later for some cancers. When symptoms are
non-specific, patients (and their doctors) may initially attribute them
to age alone.
• Life expectancy: an 80-year-old woman can expect to live 8 years,
so cancer may still shorten life and an active approach remains
appropriate.
• Prognosis: histology, stage at presentation and observation for a
brief period are better guides to outcome than age.
• Rate of progression: malignancy may have a more indolent
course. This is poorly understood but may be due to reduced
effectiveness of angiogenesis with age, inhibiting the development
of metastases.
• Response to treatment: equivalent to that in younger people
- well documented for a range of cancers and for surgery,
radiotherapy, chemotherapy and hormonal therapy.
• Treatment selection: chronological age is of minor importance
compared to comorbid illness and patient choice. Although older
patients can be treated effectively and safely, aggressive
intervention is not appropriate for all. Symptom control may be all
that is possible or desired by the patient.
33.8 Cancer in old age
1326 • ONCOLOGY
proximal muscle weakness that improves on exercise and
is caused by the development of antibodies to pre-
synaptic calcium channels (p. 1143). The diagnosis is
made by electromyelogram (EMG), which shows a
low-amplitude compound muscle action potential that
enhances to near normal following exercise.
• Dermatomyositis or polymyositis may be the first
presentation of some cancers. Clinical features and
management of these conditions are discussed on
page 1039.
Cutaneous manifestations of cancer
Many cancers can present with skin manifestations that are not
due to metastases:
• Pruritus may be a presenting feature of lymphoma,
leukaemia and central nervous system tumours.
• Acanthosis nigricans may precede cancers by many years
and is particularly associated with gastric cancer.
• Vitiligo may be associated with malignant melanoma and is
possibly due to an immune response to melanocytes.
• Pemphigus may occur in lymphoma, Kaposi’s sarcoma
and thymic tumours.
• Dermatitis herpetiformis associated with coeliac disease
may precede tumour development by many years, and is
associated with gastrointestinal lymphoma.
The clinical features and management of these skin conditions
are discussed in Chapter 29.
Emergency complications of cancer
Spinal cord compression
Spinal cord compression complicates 5% of cancers and is
most common in myeloma, prostate, breast and lung cancers
that involve bone. Cord compression often results from posterior
extension of a vertebral body mass but intrathecal spinal cord
metastases can cause similar signs and symptoms. The thoracic
region is most commonly affected.
Clinical features
The earliest sign is back pain, particularly on coughing and lying
flat. Subsequently, sensory changes develop in dermatomes
below the level of compression and motor weakness distal to
the block occurs. Finally, sphincter disturbance, causing urinary
retention and bowel incontinence, is observed. Involvement of
the lumbar spine may cause conus medullaris or cauda equina
compression (Box 33.10). Physical examination reveals findings
consistent with an upper motor neuron lesion, but lower motor
33.1 1 Management of suspected spinal
cord compression
• Confirm diagnosis with urgent MRI scan
• Administer high-dose glucocorticoids:
Dexamethasone 1 6 mg IV stat
Dexamethasone 8 mg twice daily orally
• Ensure adequate analgesia
• Refer for surgical decompression or urgent radiotherapy
neuron findings may predominate early on or in cases of nerve
root compression.
Management
Spinal cord compression is a medical emergency and should be
treated with analgesia and high-dose glucocorticoid therapy (Box
33.11). Neurosurgical intervention produces superior outcome
and survival compared to radiotherapy alone, and should be
considered first for all patients. Radiotherapy is used for the
remaining patients and selected tumour types when the cancer
is likely to be radiosensitive. The prognosis varies considerably,
depending on tumour type, but the degree of neurological
dysfunction at presentation is the strongest predictor of outcome,
irrespective of the underlying diagnosis. Mobility can be preserved
in more than 80% of patients who are ambulatory at presentation,
but neurological function is seldom regained in patients with
established deficits such as paraplegia.
| Superior vena cava obstruction
Superior vena cava obstruction (SVCO) is a common complication
of cancer that can occur through extrinsic compression or
intravascular blockage. The most common causes of extrinsic
compression are lung cancer, lymphoma and metastatic
tumours. Patients with cancer can also develop SVCO due to
intravascular blockage in association with a central catheter or
thromboembolism secondary to the tumour.
Clinical features
The typical presentation is with oedema of the arms and face,
distended neck and arm veins and dusky skin coloration over
the chest, arms and face. Collateral vessels may develop over a
period of weeks and the flow of blood in the collaterals helps to
confirm the diagnosis. Headache secondary to cerebral oedema
arising from the backflow pressure may also occur and tends to
be aggravated by bending forwards, stooping or lying down. The
severity of symptoms is related to the rate of obstruction and
the development of a venous collateral circulation. Accordingly,
symptoms may develop rapidly or gradually. Clinical features
are summarised in Box 33.12.
33.10 Comparison of features of neurological deficit
Clinical feature
Spinal cord
Conus medullaris
Cauda equina
Weakness
Symmetrical and profound
Symmetrical and variable
Asymmetrical, may be mild
Reflexes
Increased (or absent) knee and ankle
reflexes with extensor plantar reflex
Increased knee reflex, decreased ankle
reflex, extensor plantar reflex
Decreased knee and ankle reflexes with
flexor plantar reflex
Sensory loss
Symmetrical, sensory level
Symmetrical, saddle distribution
Asymmetrical, radicular pattern
Sphincters
Late loss
Early loss
Often spared
Progression
Rapid
Variable
Variable
Emergency complications of cancer • 1327
BS 33.12 Common symptoms and physical findings in
superior vena cava obstruction
Symptoms
• Dyspnoea (63%)
• Arm swelling (18%)
• Facial swelling and head
• Chest pain (15%)
fullness (50%)
• Dysphagia (9%)
• Cough (24%)
Physical findings
• Venous distension of neck
• Facial oedema (46%)
(66%)
• Cyanosis (20%)
• Venous distension of chest
• Plethora of face (1 9%)
wall (54%)
• Oedema of arms (1 4%)
*Percentage of patients affected.
Investigations and management
The investigation of choice is a CT scan of the thorax to confirm
the diagnosis and distinguish between extra- and intravascular
causes. A biopsy should be obtained when the tumour type is
unknown because tumour type has a major influence on treatment.
CT of the head may be indicated if cerebral oedema is suspected.
Tumours that are exquisitely sensitive to chemotherapy, such
as germ cell tumours and lymphoma, can be treated with
chemotherapy alone, but for most other tumours mediastinal
radiotherapy is required. This relieves symptoms within 2 weeks in
50-90% of patients. In many centres, stenting is now increasingly
favoured over radiotherapy, as it produces rapid results and can
be repeated with reasonable effectiveness. This technique is
particularly useful when dealing with tumours that are relatively
chemo- or radio-resistant, such as non-small cell lung cancer or
carcinoma of unknown primary. Where possible, these measures
should be followed by treatment of the primary tumour, as
long-term outcome is strongly dependent on the prognosis of
the underlying cancer.
Hypercalcaemia
Hypercalcaemia is the most common metabolic disorder in
patients with cancer and has a prevalence of up to 20% in
cancer patients. The incidence is highest in myeloma and breast
cancer (approximately 40%), intermediate in non-small cell lung
cancer, and uncommon in colon, prostate and small cell lung
carcinomas. It is most commonly due to over-production of
PTHrP (80%), which binds to the PTH receptor and elevates
serum calcium by stimulating osteoclastic bone resorption and
increasing renal tubular reabsorption of calcium. Direct invasion
of bone by metastases accounts for around 20% of cases while
other mechanisms, such as ectopic PTH secretion, are rare.
Clinical features
The symptoms of hypercalcaemia are often non-specific and
may mimic those of the underlying malignancy. They include
drowsiness, delirium, nausea and vomiting, constipation, polyuria,
polydipsia and dehydration.
Investigations and management
The diagnosis is made by measuring serum total calcium and
adjusting for albumin. It is especially important to correct for
albumin in cancer because hypoalbuminaemia is common and
total calcium values under-estimate the level of ionised calcium.
The principles of management are outlined in Box 33.13.
33.13 Medical management of severe
hypercalcaemia
IV 0.9% saline 2-4 L/day
Zoledronic acid 4 mg IV or pamidronate 60-90 mg IV
For patients with severe, symptomatic hypercalcaemia that is
refractory to zoledronic acid, denosumab (initial dose 60 mg SC,
with repeat dosing based on response) is an alternative option
Patients should initially be treated with intravenous 0.9% saline
to improve renal function and increase urinary calcium excretion.
This alone often results in clinical improvement. Concurrently,
intravenous bisphosphonates should be given to inhibit bone
resorption. Calcitonin acts rapidly to increase calcium excretion
and to reduce bone resorption, and can be combined with
fluid and bisphosphonate therapy for the first 24-48 hours in
patients with life-threatening hypercalcaemia. Bisphosphonates
will usually reduce the serum calcium levels to normal within
5 days, but, if not, treatment can be repeated. The duration of
action is up to 4 weeks and repeated therapy can be given at
3^-weekly intervals in the outpatient department. Hypercalcaemia
is frequently a sign of tumour progression and the patient requires
further investigation to establish disease status and review of
the anti-cancer treatment strategy.
Neutropenic fever
Neutropenia is a common complication of malignancy. It is usually
secondary to chemotherapy but may occur with radiotherapy if
large amounts of bone marrow are irradiated; it may also be a
component of pancytopenia due to malignant infiltration of the
bone marrow. Neutropenic fever is defined as a pyrexia of 38°C
for over 1 hour in a patient with a neutrophil count of <0.5x 1 09/L
or < 1 .Ox 1 09/L if the nadir is anticipated to drop to <0.5x 1 09/L
in the next 24 hours. The risk of sepsis is related to the severity
and duration of neutropenia and the presence of other risk factors,
such as intravenous cannulae or bladder catheters. Neutropenic
fever is an emergency in cancer patients as, if left untreated, it
can result in sepsis with a high mortality rate.
Clinical features
The typical presentation is with high fever, and affected patients
are often non-specifically unwell. Examination is usually unhelpful
in defining a primary source of the infection. Hypotension is
an adverse prognostic feature and may progress to systemic
circulatory shutdown and organ failure.
Investigations and management
An infection screen should be performed to include blood
cultures (both peripheral and from central lines), urine culture,
chest X-ray, and swabs for culture (throat, central line, wound).
High-dose intravenous antibiotics should then be commenced,
pending the results of cultures. The standard approach is to
commence empirical antibiotics according to local hospital
policies agreed with microbiologists and based on the local
antibiotic resistance patterns observed. First-line empirical
therapy is either monotherapy with piperacillin-tazobactam or
meropenem, or with the addition of gentamicin. Metronidazole
may be added if anaerobic infection is suspected, and teicoplanin
where Gram-positive infection is suspected (e.g. in patients
with central lines). Antibiotics should be adjusted according to
culture results, although these are often negative. If there is no
response after 36-48 hours, antibiotics should be reviewed with
microbiological advice, and antifungal cover should be considered
1328 • ONCOLOGY
(liposomal amphotericin B). Granulocyte-colony-stimulating factor
(G-CSF) is not routinely used for all patients with neutropenia
and guidelines for use have been established. Other supportive
therapy, including intravenous fluids, inotrope therapy, ventilation
or haemofiltration, may be required.
| Tumour lysis syndrome
The acute destruction of a large number of cells can be associated
with metabolic sequelae and is called tumour lysis syndrome.
It is usually related to bulky, chemosensitive disease, including
lymphoma, leukaemia and germ cell tumours. More rarely, it
can occur spontaneously.
Clinical features
Cellular destruction results in the release of potassium, phosphate,
nucleic acids and purines that can cause transient hypocalcaemia,
hyperphosphataemia, hyperuricaemia and hyperkalaemia. This can
lead to acute impairment of renal function and the precipitation
of uric acid crystals in the renal tubular system. These can
manifest with symptoms associated with multiple underlying
electrolyte abnormalities, including fatigue, nausea, vomiting,
cardiac arrhythmia, heart failure, syncope, tetany, seizures and
sudden death.
Investigations and management
Serum biochemistry should be monitored regularly for 48-72 hours
after treatment in patients at risk. Elevated serum potassium
may be the earliest biochemical marker but pre-treatment serum
lactate dehydrogenase (LDH) correlates with tumour bulk and may
indicate increased risk. Good hydration and urine output should be
maintained throughout treatment administration. Prophylaxis with
allopurinol should be considered and recombinant urate oxidase
(rasburicase) can be used to reduce uric acid levels when other
treatments fail. Adequate hydration is vital, as it has a dilution
effect on the extracellular fluid, improving electrolyte imbalance,
and increases circulating volume, improving filtration in the kidneys.
In high-risk patients, hydration should be commenced 24 hours
before the start of treatment. If normal treatment methods fail to
correct the problems, haemodialysis should be considered at an
early stage to prevent progression to irreversibility.
Metastatic disease
Metastatic disease is the major cause of death in cancer patients
and the principal cause of morbidity. For the majority, the aim
of treatment is palliative but treatment of a solitary metastasis
can occasionally be curative.
Brain metastases
Brain metastases occur in 10-30% of adults and 6-10% of
children with cancer, and are an increasingly important cause
of morbidity. Tumours that typically metastasise to the brain
are shown in Box 33.14. Most involve the brain parenchyma
but can also affect the cranial nerves, the blood vessels and
other intracranial structures. In cases of solitary metastasis to
the brain, the use of surgery and adjuvant radiotherapy has
been shown to increase survival. Practices vary, however, for
patients with more advanced brain metastases. In these cases,
median survival without treatment is approximately 1 month.
Glucocorticoids can increase survival to 2-3 months and whole-
brain radiotherapy improves survival to 3-6 months, but the true
KM 33.14 Primary tumour sites that metastasise to
the brain
Primary tumour
Patients (%)
Lung
48
Breast
15
Melanoma
9
Colon
5
Other known primary
13
Unknown primary
11
efficacy of these interventions has not been proven adequately
in a randomised trial setting. Patients with brain metastases as
the only manifestation of an undetected primary tumour have
a more favourable prognosis, with an overall median survival of
13.4 months. Tumour type also influences prognosis; breast
cancer patients have a better prognosis than those with other
types of cancer, and those with colorectal cancer tend to have
a poorer prognosis.
Clinical features
Presentation is with headaches (40-50%), focal neurological
dysfunction (20-40%), cognitive dysfunction (35%), seizures
(10-20%) and papilloedema (< 1 0%).
Investigations and management
The diagnosis can be confirmed by CT or contrast-enhanced
MRI. Treatment options include high-dose glucocorticoids
(dexamethasone 4 mg 4 times daily) for tumour-associated
oedema, anticonvulsants for seizures, whole-brain radiotherapy
and chemotherapy. Surgery may be considered for single sites
of disease and can be curative; stereotactic radiotherapy may
also be considered for solitary site involvement where surgery
is not possible.
| Lung metastases
These are common in breast cancer, colon cancer and tumours
of the head and neck. The presentation is usually with a lesion
on chest X-ray or CT. Solitary lesions require investigation, as
single metastases can be difficult to distinguish from a primary
lung tumour. Patients with two or more pulmonary nodules can
be assumed to have metastases. The approach to treatment
depends on the extent of disease in the lung and elsewhere. For
solitary lesions, surgery should be considered, with a generous
wedge resection. Radiotherapy, chemotherapy or endocrine
therapy can be used as systemic treatment and is dependent
on the underlying primary cancer diagnosis.
|j.iver metastases
Metastatic cancer in the liver can represent the sole or life-
limiting component of disease for many with colorectal cancer,
ocular melanoma, neuro-endocrine tumours (NETs) and, less
commonly, other tumour types. The most common clinical
presentations are with right upper quadrant pain due to stretching
of the liver capsule, jaundice, deranged liver function tests or an
abnormality detected on imaging. In selected cases, resection
of the metastasis can be contemplated. In colorectal cancer,
successful resection of metastases improves 5-year survival from
3% to 30-40%. Other techniques, such as chemoembolisation or
radiofrequency ablation, can also be used, provided the number
Therapeutics in oncology • 1329
and size of metastases remain small. If these are not feasible,
symptoms may respond to systemic chemotherapy.
Bone metastases
Bone is the third most common organ involved by metastasis,
after lung and liver. Bone metastases are a major clinical problem
in patients with myeloma and breast or prostate cancers, but
other tumours that commonly metastasise to bone include those
of the kidney and thyroid. Bone metastases are an increasing
management problem in other tumour types that do not classically
target bone, due to the prolonged survival of patients generally.
Accordingly, effective management of bony metastases has
become a focus in the treatment of patients with many incurable
cancers.
Clinical features
The main presentations are with pain, pathological fractures
and spinal cord compression (see above). The pain tends to
be progressive and worst at night, and may be partially relieved
by activity, but subsequently becomes more constant in nature
and is exacerbated by movement. Most pathological fractures
occur in metastatic breast cancer (53%); other tumour types
associated with fracture include the kidney (11%), lung (8%),
thyroid (5%), lymphoma (5%) and prostate (3%).
Investigations and management
The most sensitive way of detecting bone metastases is by isotope
bone scan. This can have false-positive results in healing bone,
particularly as a flare response following treatment and false¬
negative results occur in multiple myeloma due to suppression
of osteoblast activity. Plain X-ray films are therefore preferred for
any sites of bone pain, as lytic lesions may not be detected by a
bone scan. In patients with a single lesion, it is especially important
to perform a biopsy to obtain a tissue diagnosis, since primary
bone tumours may look very similar to metastases on X-ray.
The main goals of management are:
• pain relief
• preservation and restoration of function
• skeletal stabilisation
• local tumour control (e.g. relief of tumour impingement on
normal structure).
Surgical intervention may be warranted where there is evidence
of skeletal instability (e.g. anterior or posterior spinal column
fracture) or an impending fracture (e.g. a large lytic lesion on a
weight-bearing bone with more than 50% cortical involvement).
Intravenous bisphosphonates (pamidronate, zoledronic acid
or denosumab) are widely used for bone metastases and are
effective at improving pain and in reducing further skeletal related
events, such as fractures and hypercalcaemia. In certain types of
cancer, such as breast and prostate, hormonal therapy may be
effective. Radiotherapy, in the form of external beam therapy or
systemic radionuclides (strontium treatment), can also be useful
for these patients. In some settings (e.g. breast carcinoma),
chemotherapy may be used in the management of bony
metastases.
| Malignant pleural effusion
This is a common complication of cancer and 40% of all pleural
effusions are due to malignancy. The most common causes
are lung and breast cancers, and the presence of an effusion
indicates advanced and incurable disease. The presentation may
be with dyspnoea, cough or chest discomfort, which can be dull
33.15 How to aspirate a malignant pleural effusion
• Ask the patient to sit up and lean forwards slightly.
• Identify a suitable site for aspiration. Typically, this should be in the
mid-scapular line, below the top of the fluid level and above the
diaphragm.
• Confirm that the site is below the fluid level by reviewing the chest
X-ray and percussing the chest.
• Infiltrate the skin and the intercostal space immediately above the
rib below with 1% lidocaine.
• As you advance the needle, aspirate at each step prior to injecting
the local anaesthetic.
• On reaching the pleural cavity, you should be able to aspirate
pleural fluid; when you do, note the depth of the needle.
• Insert a thoracentesis needle into the pleural space by advancing it
along the same track as was used for the local anaesthetic and
connect it to a three-way tap and container to collect the fluid.
• Drain the pleural effusion, to a maximum of 1 .5 L. If the effusion is
larger than this, repeat the procedure on further occasions as
necessary.
• Consider using ultrasound-guided placement of a drainage catheter
if the effusion proves difficult to drain.
• Permanent drains can be useful for some patients with recurrent
effusions where pleurodesis is not possible.
or pleuritic in nature. Diagnosis and management of ascites are
discussed on page 863.
Investigations and management
Pleural aspirate is the key investigation and may show the
presence of malignant cells. Malignant effusions are commonly
blood-stained and are exudates with a raised fluid to serum
LDH ratio (>0.6) and a raised fluid to serum protein ratio (>0.5).
Treatment should focus on palliation of symptoms and be tailored
to the patient’s physical condition and prognosis. Aspiration alone
may be an appropriate treatment in frail patients with a limited
life expectancy (Box 33.15). Those who present with malignant
pleural effusion as the initial manifestation of breast cancer, small
cell lung cancer, germ cell tumours or lymphoma should have
the fluid aspirated and should be given systemic chemotherapy
to try to treat disease in the pleural space. Treatment options
for patients with recurrent pleural effusion include pleurodesis,
pleurectomy and pleuroperitoneal shunt. Ideally, pleurodesis
should be attempted once effusions recur after initial drainage.
Therapeutics in oncology
Anti-cancer therapy may be either curative or palliative, and
this distinction influences the approach to management of
individual patients. The goal of treatment should be recorded
in the medical notes.
• Palliative chemotherapy is the most common treatment and
is primarily used to treat patients with metastatic disease.
The goal is an improvement in symptoms with a focus on
improving quality of life, and any survival increments are
secondary. As a result, the treatment should be well
tolerated and should aim to minimise adverse effects.
• Adjuvant chemotherapy is given after an initial intervention
that is designed to cyto-reduce the tumour bulk and
remove all macroscopic disease. Chemotherapy is then
given with the intention of eradicating the micrometastatic
disease that remains. The focus is on achieving an
improvement in disease-free and overall survival.
1330 • ONCOLOGY
• Neoadjuvant chemotherapy or primary medical therapy is
where chemotherapy is administered first before a planned
cyto-reductive procedure. This can result in a reduced
requirement for surgery, increase the likelihood of
successful debulking, reduce the duration of hospitalisation
and improve the fitness of the patient prior to interval
debulking. This approach has the same goals as adjuvant
treatment but creates an opportunity for translational
research to measure responses to treatment and correlate
with subsequent specimens removed at the time of surgery.
• Chemoprevention is the use of pharmacological agents to
prevent cancer developing in patients identified as being at
particular risk. The agents used therefore aim to modify
risk and, as such, should not have significant adverse
effects.
Surgical treatment
Surgery has a pivotal role in the management of cancer. There
are three main situations in which it is necessary.
Biopsy
In the vast majority of cases, a histological or cytological diagnosis
of cancer is necessary, and tissue will also provide important
information such as tumour type and differentiation, to assist
subsequent management. Cytology can be obtained with fine
needle aspiration but a biopsy is usually preferred. This can be
a core biopsy, an image-guided biopsy or an excision biopsy.
Excision
The main curative management of most solid cancers is surgical
excision. In early, localised cases of colorectal, breast and lung
cancer, cure rates are high with surgery. There is increasing
evidence that outcome is related to surgical expertise, and
most multidisciplinary teams include surgeons experienced in
the management of a particular cancer. There are some cancers
for which surgery is one of two or more options for primary
management, and the role of the multidisciplinary team is to
recommend appropriate treatment for a specific patient. Examples
include prostate and transitional cell carcinoma of the bladder,
in which radiotherapy and surgery may be equally effective.
Palliation
Surgical procedures are often the quickest and most effective
way of palliating symptoms. Examples include the treatment
of faecal incontinence with a defunctioning colostomy; fixation
of pathological fractures and decompression of spinal cord
compression; and the treatment of fungating skin lesions by
‘toilet’ surgery. A more specialist role for surgery is in resection
of residual masses after chemotherapy and, in very selected
cases, resection of metastases.
Systemic chemotherapy
Chemotherapeutic drugs are classified by their mode of action.
They have the greatest activity in proliferating cells and this
provides the rationale for their use in the treatment of cancer.
Chemotherapeutic agents are not specific for cancer cells,
however, and the side-effects of treatment are a result of their
antiproliferative actions in normal tissues such as the bone
marrow, skin and gut.
Combination therapy
The dosing schedule and interval are determined by the choice of
drugs and recovery of the cancer and normal tissues. For most
common chemotherapy regimens, the treatment is administered
every 21 or 28 days, which defines one cycle. A course of
treatment often uses up to 6 cycles of treatment. An increase
in effectiveness can be achieved by changing the approach to
treatment. In some cases this will increase toxicity too, but it
can change the nature of the toxicity and such developments
are evaluated in clinical trials.
• Low-dose therapy is the standard approach and most
palliative chemotherapy is given in this manner. The next
cycle is started once bone marrow function has recovered
sufficiently to start the treatment (neutrophils >1 .0x109/L
and platelets >100x109/L).
• High-dose therapy uses a higher individual drug dose to
achieve a higher cell kill but results in more bone marrow
toxicity. This can be minimised by using G-CSF. This
approach allows more drug to be delivered within the
same schedule of administration, but the total received
dose can be less than the intended dose due to limitations
of non-haematological toxicity.
• Dose-dense therapy involves fractionating the intended
dose of drug and administering each fraction on a more
frequent basis (often weekly). Each individual dose
produces less toxicity but the anti-cancer effect is related
to the accumulative dose over time. Such an approach
can overcome drug resistance, produce a greater cell kill
and, in some cases, produce a response with weekly
administration when the 3-weekly schedule demonstrates
a lack of response or even disease progression.
• Alternating therapy involves giving different drugs in an
alternating manner. This is most commonly used with
haematological malignancies and is designed to treat
different subpopulations of cancer cells where individual
clones of cells might be resistant to one or more of the
agents.
Adverse effects
Most cytotoxics have a narrow therapeutic window or index and
can have significant adverse effects, as shown in Figure 33.6.
Considerable supportive therapy is often required to enable
patients to tolerate therapy and achieve benefit. Nausea and
vomiting are common, but with modern antiemetics, regimens
such as the combination of dexamethasone and highly selective
5-hydroxytryptamine (5-HT3, serotonin) receptor antagonists like
ondansetron, most patients now receive chemotherapy without
any significant problems. Myelosuppression is common to almost
all cytotoxics and this not only limits the dose of drug but also
can cause life-threatening complications. The risk of neutropenia
can be reduced with the use of specific growth factors that
accelerate the repopulation of myeloid precursor cells. The
most commonly employed is G-CSF, which is widely used in
conjunction with chemotherapy regimens that induce a high rate
of neutropenia. More recently, it has been used to ‘accelerate’
the administration of chemotherapy, enabling standard doses
to be given at shorter intervals where the rate-limiting factor
has been the time taken for the peripheral neutrophil count to
recover. Accelerated chemotherapy regimens have now been
demonstrated to offer therapeutic advantages in small cell lung
cancer, lymphoma and possibly breast cancer.
Therapeutics in oncology • 1331
Chemotherapy
(often drug-specific)
Alopecia
Mucositis
Mucositis
Fibrosis
Arrhythmias
Heart failure
Nausea and vomiting
Mucositis, diarrhoea
Erythema
Sensory neuropathy
Motor neuropathy
Nerve deafness
Renal impairment
Premature gonadal failure
Amenorrhoea
Neutropenia, anaemia
Thrombocytopenia
Radiotherapy
Alopecia
Mucositis
Xerostomia
Mucositis
Strictures
Cough
Fibrosis
T Risk breast cancer
T Risk ischaemic heart disease
Nausea, diarrhoea
Fibrosis and perforation
Erythema and desquamation
Telangiectasia, thinning of the skin
Premature gonadal failure
Neutropenia
i Haemoglobin, platelet count
Increased risk of malignancy
Reduced growth
Fig. 33.6 Adverse effects of chemotherapy and radiotherapy. Acute effects are shown in pink and late effects in blue.
Radiation therapy
Radiation therapy (radiotherapy) involves treating the cancer with
ionising radiation; for certain localised cancers it may be curative.
Ionising radiation can be delivered by radiation emitted from the
decay of radioactive isotopes or by high-energy radiation beams,
usually X-rays. Three methods are usually employed:
• Teletherapy, application from a distance by a linear
accelerator.
• Brachytherapy : direct application of a radioactive source
on to or into a tumour. This allows the delivery of a very
high, localised dose of radiation and is integral to the
management of localised cancers of the head and neck,
and cancer of the cervix and endometrium.
• Intravenous injection of a radioisotope: such as 131 iodine
for cancer of the thyroid and 89strontium for the treatment
of bone metastases from prostate cancer.
The majority of treatments are delivered by linear accelerators,
which produce electron or X-ray beams of high energy that are
used to target tumour tissue. The biological effect of ionising
radiation is to cause lethal and sublethal damage to DNA.
Since normal tissues are also radiosensitive, treatment has to
be designed to maximise exposure of the tumour and minimise
exposure of normal tissues. This is possible with modern imaging
techniques such as CT and MRI, which allow better visualisation
of normal and tumour tissue. In addition, techniques such as
conformal radiotherapy, in which shaped rather than conventional
square or rectangular beams are used, allow much more precise
targeting of therapy to the tumour, and reduce the volume of
normal tissue irradiated by up to 40% compared to non-conformal
techniques.
Biological differences between normal and tumour tissues
are used to obtain therapeutic gain. Fundamental to this is
fractionation, which entails delivering the radiation as a number of
small doses on a daily basis. This allows normal cells to recover
from radiation damage but recovery occurs to a lesser degree in
malignant cells. Fractionation regimens vary, but radical treatments
given with curative intent are usually delivered in 20-30 fractions
given daily on 5 days a week, over 4-6 weeks. Radiotherapy
can be extremely useful for the alleviation of symptoms, and for
palliative treatments such as this a smaller number of fractions
(1-5) is usually adequate.
Both normal and malignant tissues vary widely in their sensitivity
to radiotherapy. Germ cell tumours and lymphomas are extremely
radiosensitive and relatively low doses are adequate for cure, but
most cancers require doses close to or beyond that which can
be tolerated by adjacent normal structures. Normal tissue also
varies in its radiosensitivity, the central nervous system, small
bowel and lung being among the most sensitive. The side-effects
of radiotherapy (see Fig. 33.6) depend on the normal tissues
treated, their radiosensitivity and the dose delivered.
1332 • ONCOLOGY
Adverse effects
An acute inflammatory reaction commonly occurs towards the end
of most radical treatments and is localised to the area treated.
For example, skin reactions are common with breast or chest
wall radiotherapy, and proctitis and cystitis with treatment to the
bladder or prostate. These acute reactions settle over a period of
a few weeks after treatment, assuming normal tissue tolerance
has not been exceeded. Late effects of radiotherapy develop
6 weeks or more after treatment and occur in 5-1 0% of patients.
Examples include brachial nerve damage and subcutaneous
fibrosis after breast cancer treatment, and shrinkage and fibrosis
of the bladder after treatment for bladder cancer. There is a risk
of inducing cancer after radiotherapy, which varies depending
on the site treated and on whether the patient has had other
treatment such as chemotherapy.
Hormone therapy
Hormone therapy is most commonly used in the treatment of
breast cancer and prostate cancer. Breast tumours that are
positive for expression of the oestrogen receptor (ER) respond
well to anti -oestrogen therapy, and assessment of ER status is
now standard in the diagnosis of breast cancer. Several drugs are
now available that reduce oestrogen levels or block the effects
of oestrogen on the receptor. When targeted appropriately,
adjuvant hormone therapy reduces the risk of relapse and death
at least as much as chemotherapy, and in advanced cases can
induce stable disease and remissions that may last months to
years, with acceptable toxicity. Hormonal manipulation may be
effective in other cancers. In prostate cancer, hormonal therapy
(e.g. luteinising hormone releasing hormone (LHRH) analogues
such as goserelin and/or anti-androgens such as bicalutamide)
aimed at reducing androgen levels can provide good long-term
control of advanced disease, but there is no convincing evidence
that it is an effective therapy following potentially curative surgery.
Progestogens are active in the treatment of endometrial and
breast cancer. In the metastatic setting, progestogen use (e.g.
megestrol acetate) is associated with response rates of 20-40%
in endometrial cancer. In breast cancer, progestogens are used
in patients whose disease has progressed with conventional
anti-oestrogen therapy. Their exact mechanism in this setting
is not fully understood.
Immunotherapy
A profound stimulus to the patient’s immune system can
sometimes alter the natural history of a malignancy, and the
discovery of interferons was the impetus for much research.
Although solid tumours show little benefit, interferons are active
in melanoma and lymphoma, and there is evidence that they
are beneficial as adjuvants (after surgery and chemotherapy,
respectively) to delay recurrence. Whether interferon-induced
stimulation of the immune system is capable of eradicating
microscopic disease remains unproven. More powerful immune
responses can be achieved with potent agents like IL-2 but the
accompanying systemic toxicity is a problem still to be overcome.
The most striking example of successful immunotherapy is that
with rituximab, an antibody against the common B-cell antigen
CD20. It increases complete response rates and improves survival
in diffuse large cell non-Hodgkin lymphoma when combined with
chemotherapy, and is effective in palliating advanced follicular
non-Hodgkin lymphoma (p. 965).
Biological therapies
Advances in knowledge about the molecular basis of cancer have
resulted in the development of a new generation of treatments
to block the signalling pathways responsible for the growth of
specific tumours. This has created the potential to target cancer
cells more selectively, with reduced toxicity to normal tissues.
Some examples are discussed below, but in the years to come
many more such agents will come into clinical use, with the
potential to revolutionise our approach to some cancers.
Gefitinib/erlotinib
These agents inhibit the activity of the EGFR, which is over¬
expressed in many solid tumours. However, the drugs’ activity
does not depend on the amount of receptor over-expression but
rather on factors such as gene copy number and mutation status.
Imatinib
Imatinib was developed to inhibit the BCR-ABL gene product,
tyrosine kinase, that is responsible for chronic myeloid leukaemia
(p. 958), and it does this extremely effectively. It is also active
in malignant gastrointestinal stromal tumour (GIST), a type of
sarcoma that has over-expression of another cell surface tyrosine
kinase, c-kit. This agent has good tolerability and is particularly
useful in GIST, where conventional chemotherapy is less effective.
Bevacizumab
This is a humanised monoclonal antibody that inhibits vascular
endothelial growth factor A (VEGF-A), a key stimulant of
angiogenesis in tumours. Bevacizumab has activity in colorectal,
lung, breast, renal and ovarian cancers, although the licence
was subsequently revoked for breast cancer; while bevacizumab
slows the rate of progression of metastatic breast cancer, it had
little impact on survival or improved quality of life.
Trastuzumab
Trastuzumab (Herceptin) targets the HER2 receptor, an oncogene
that is over-expressed in around one-third of breast cancers and
in a number of other solid tumours (e.g. gastric cancer). It is
effective as a single-agent therapy, but also improves survival in
patients with advanced breast cancer when used in conjunction
with chemotherapy. Unfortunately, trastuzumab can induce
cardiac failure by an unknown biological mechanism, especially
in combination with doxorubicin.
Evaluation of treatment
The evaluation of treatment includes an assessment of overall
survival duration, response to treatment, remission rate, disease-
free survival and response duration, quality of life and treatment
toxicity. Uniform criteria have been established to measure these,
including the response evaluation criteria in solid tumours (RECIST,
Box 33.16) and common toxicity criteria. This allows clinicians
to inform patients accurately about the prognosis, effectiveness
and toxicity of chemotherapy and empowers patients to take
an active role in treatment decisions.
Late toxicity of therapy
The late toxicities of treatment for cancer are particularly important
for patients where the multimodality therapy is given with curative
Specific cancers • 1333
33.16 Response evaluation criteria in solid
tumours (RECIST)
Response
Criteria
Complete response (CR)
Disappearance of all target lesions
Partial response (PR)
At least a 30% decrease in the sum of
the longest diameter (LD) of target
lesions, taking as reference the baseline
sum LD
Progressive disease (PD)
At least a 20% increase in the sum of
the LD of target lesions, taking as
reference the smallest sum LD recorded
since the treatment started and at least
5 mm increase or the appearance of
one or more new lesions
Stable disease (SD)
Neither sufficient shrinkage to qualify
for PR nor sufficient increase to qualify
for PD, taking as reference the smallest
sum LD since the treatment started
intent, the patient is young and more patients are living longer.
This can cause considerable morbidity: for example, radiotherapy
can retard bone and cartilage growth, impair intellect and cognitive
function, and cause dysfunction of the hypothalamus, pituitary and
thyroid glands. Late consequences of chemotherapy include heart
failure due to cardiotoxicity, pulmonary fibrosis, nephrotoxicity
and neurotoxicity.
Premature gonadal failure can result from chemotherapy or
radiotherapy and leave a patient subfertile. Patients should be
made aware of this before treatment is initiated, as it may be
possible to store sperm for male patients before treatment starts;
this should always be offered, if practical. Egg or embryo banking
after in vitro fertilisation may be an option for young women. Sterility
develops at higher radiotherapy doses but erectile dysfunction is
seen in patients receiving high radiotherapy doses to the pelvis,
as in prostate cancer. Additional social or psychological support
may be required. Infertility and pubertal delay are potential late
effects of therapy in children, especially boys.
Second malignancies may be induced by cancer treatment
and occur at greatest frequency following chemoradiation.
Secondary acute leukaemia (mostly AML) can occur 1-2 years
after treatment with topoisomerase II inhibitors, or 2-5 years
after treatment with alkylating agents. The most common second
malignancy within a radiation field is osteosarcoma but others
include soft tissue sarcoma and leukaemia.
Specific cancers
The diagnosis and management of cancers are discussed in more
detail elsewhere in the book (Box 33.17). Here we discuss the
pathogenesis, clinical features, investigation and management
of common tumours that are not covered elsewhere.
Breast cancer
Globally, the incidence of breast cancer is second only to that
of lung cancer, and the disease represents the leading cause of
cancer-related deaths among women. Invasive ductal carcinoma
with or without ductal carcinoma in situ (DCIS) is the most
common histology, accounting for 70%, whilst invasive lobular
carcinoma accounts for most of the remaining cases. DCIS
constitutes 20% of breast cancers detected by mammography
33.17 Specific cancers covered in other chapters
Bladder cancer
p. 435
Colorectal cancer
p. 827
Familial cancer syndromes
p. 56
Gastric cancer
p. 803
Hepatocellular carcinoma
p. 890
Leukaemia
p. 954
Lung cancer
p. 598
Lymphoma
p. 961
Mesothelioma
p. 618
Myeloma
p. 966
Oesophageal cancer
p. 796
Pancreatic cancer
p. 842
Prostate cancer
p. 438
Renal cancer
p. 434
Seminoma
p. 439
Skin cancer
p. 1229
Teratoma
p. 439
Thyroid cancer
p. 649
i
33.18 Five-year survival rates for breast cancer
by stage
Tumour stage
Stage definition
5-year survival (%)
1
Tumour <2 cm, no lymph
nodes
96
II
Tumour 2-5 cm and/or
mobile axillary lymph nodes
81
III
Chest wall or skin fixation
and/or fixed axillary lymph
nodes
52
IV
Metastasis
18
screening. It is multifocal in one-third of women and has a high
risk of becoming invasive (10% at 5 years following excision only).
Pure DCIS does not cause lymph node metastases, although
these are found in 2% of cases where nodes are examined,
owing to undetected invasive cancer. Lobular carcinoma in
situ (LCIS) is a predisposing risk factor for developing cancer
in either breast (7% at 10 years). The survival for breast cancer
by stage is outlined in Box 33.18.
Pathogenesis
Both genetic and hormonal factors play a role; about 5-1 0% of
breast cancers are hereditary and occur in patients with mutations
of BRCA1 , BRCA2, AT or TP53 genes. Prolonged oestrogen
exposure associated with early menarche, late menopause and
use of hormone replacement therapy (HRT) has been associated
with an increased risk. Other risk factors include obesity, alcohol
intake, nulliparity and late first pregnancy. There is no definite
evidence linking use of the contraceptive pill to breast cancer.
Clinical features
Breast cancer usually presents as a result of mammographic
screening or as a palpable mass with nipple discharge in 10%
and pain in 7% of patients. Less common presentations include
inflammatory carcinoma with diffuse induration of the skin of the
1334 • ONCOLOGY
breast, and this confers an adverse prognosis. Around 40% of
patients will have axillary nodal disease, with likelihood correlating
with increasing size of the primary tumour. Distant metastases
are infrequently present at diagnosis and the most common sites
of spread are bone (70%), lung (60%), liver (55%), pleura (40%),
adrenals (35%), skin (30%) and brain (10-20%).
Investigations
Following clinical examination, patients should have imaging with
mammography or ultrasound evaluation, and a biopsy using
fine needle aspiration for cytology or core biopsy for histology.
Histological assessment should be carried out to assess tumour
type and to determine oestrogen and progesterone receptor
(ER/PR) status and HER2 status. If distant spread is suspected,
CT of the thorax and abdomen and an isotope bone scan are
required. Molecular subtyping is being used to classify tumours
into four major subtypes: luminal A, luminal B, HER2 type and
basal-like (often called ‘triple negative’, as these tumours are
ER-, PR- and HER2-negative). This may allow more targeted
selection of therapies in future.
Management
Surgery is the mainstay of treatment for most patients, and
this can range from a lumpectomy, where only the tumour is
removed, to mastectomy, where the whole breast is removed.
Breast-conserving surgery is as effective as mastectomy if
complete excision with negative margins can be achieved. Lymph
node sampling is performed at the time of surgery. Adjuvant
radiotherapy is given to reduce the risk of local recurrence to
4-6%. Adjuvant hormonal therapy improves disease-free and
overall survival in pre- and post-menopausal patients who have
tumours that express ER. Patients at low risk, with tumours that
are small and ER-positive, require only adjuvant hormonal therapy
with tamoxifen. Patients with tumours that are ER-positive and
who are pre-menopausal should receive an LHRH analogue.
Aromatase inhibitors also have benefit in this setting but are
still under investigation.
Adjuvant chemotherapy is considered for patients at higher
risk of recurrence. Factors that increase the risk of recurrence
include a tumour of >1 cm, a tumour that is ER-negative or
the presence of involved axillary lymph nodes. Such patients
should be offered adjuvant chemotherapy, which improves
disease-free and overall survival. The role of adjuvant treatment
has been studied by meta-analyses and data support the use
of adjuvant trastuzumab, a humanised monoclonal antibody to
HER2, in addition to standard chemotherapy for women with
early HER2-positive breast cancer.
Metastatic disease management includes radiotherapy to palliate
painful bone metastases and second-line endocrine therapy with
aromatase inhibitors, which inhibit peripheral oestrogen production
in adrenal and adipose tissues. Advanced ER-negative disease
may be treated with combination chemotherapy.
Ovarian cancer
Ovarian cancer is the most common gynaecological tumour in
Western countries. Most ovarian cancers are epithelial in origin
(90%), and up to 7% of women with ovarian cancer have a positive
family history. Patients often present late in ovarian cancer with
vague abdominal discomfort, low back pain, bloating, altered
bowel habit and weight loss. Occasionally, peritoneal deposits
are palpable as an omental ‘cake’ and nodules in the umbilicus
(Sister Mary Joseph nodules).
Pathogenesis
Genetic and environmental factors play a role. The risk of
ovarian cancer is increased in patients with BRCA1 or BRCA2
mutations, and Lynch type II families (a subtype of hereditary
non-polyposis colon cancer, HNPCC) have ovarian, endometrial,
colorectal and gastric tumours due to mutations of mismatch
repair enzymes. Advanced age, nulliparity, ovarian stimulation
and Caucasian descent all increase the risk of ovarian cancer,
while suppressed ovulation appears to protect, so pregnancy,
prolonged breastfeeding and the contraceptive pill have all been
shown to reduce the risk of ovarian cancer.
Investigations
Initial workup for patients with suspected ovarian cancer includes
imaging in the form of ultrasound and CT. Serum levels of the
tumour marker CA-125 are often measured. Surgery plays
a key role in the diagnosis, staging and treatment of ovarian
cancer, and in early cases, palpation of viscera, peritoneal
washings and biopsies are generally performed to define
disease extent.
Management
In early disease, surgery followed by adjuvant chemotherapy
with carboplatin, or carboplatin plus paclitaxel, is the treatment
of choice. Surgery should include removal of the tumour
along with total abdominal hysterectomy, bilateral salpingo-
oophorectomy, and omentectomy. Even in advanced disease,
surgery is undertaken to debulk the tumour and is followed
by adjuvant chemotherapy, typically using carboplatin and
paclitaxel. Bevacizumab is indicated for patients with high-
grade tumours that are suboptimally debulked or those with
a more aggressive biological pattern. Monitoring for relapse is
achieved through a combination of serum CA-125 and clinical
examination with CT imaging for those with suspected relapse.
Second-line chemotherapy is aimed at improving symptoms and
should not be used for CA-125 elevation only in the absence of
symptoms. Treatments can include further platinum/paclitaxel
in combination, liposomal doxorubicin or topotecan. These
regimens are associated with a response rate of 10-40%. The
best responses are observed in patients with a treatment-free
interval of more than 12 months.
Endometrial cancer
Endometrial cancer accounts for 4% of all female malignancies,
producing a 1 in 73 lifetime risk. The majority of patients are
post-menopausal, with a peak incidence at 50-60 years of
age. Mortality from endometrial cancer is currently falling. The
most common presentation is with post-menopausal bleeding,
which often results in detection of the disease before distant
spread has occurred.
Pathogenesis
Oestrogen plays an important role in the pathogenesis of
endometrial cancer, and factors that increase the duration of
oestrogen exposure, such as nulliparity, early menarche, late
menopause and unopposed HRT, increase the risk. Endometrial
cancer is 1 0 times more common in obese women and this is
thought to be due to elevated levels of oestrogens.
Investigations
The diagnosis is confirmed by endometrial biopsy.
Specific cancers • 1335
Management
Surgery is the treatment of choice and is used for staging.
A hysterectomy and bilateral salpingo-oophorectomy are
performed with peritoneal cytology and, in some cases, lymph
node dissection. Where the tumour extends beyond the inner
50% of the myometrium or involves the cervix and local lymph
nodes, or there is lymphovascular space invasion, adjuvant
pelvic radiotherapy is recommended. Chemotherapy is used as
adjuvant therapy and hormonal therapy and chemotherapy are
used to palliate symptoms in recurrent disease.
Cervical cancer
This is the second most common gynaecological tumour
worldwide and the leading cause of death from gynaecological
cancer. The incidence is decreasing in developed countries
but continues to rise in developing nations. The most common
presentation is with an abnormal smear test, but with locally
advanced disease the presentation is with vaginal bleeding,
discomfort, discharge or symptoms attributable to involvement
of adjacent structures, such as bladder, or rectal or pelvic wall.
Occasionally, patients present with distant metastases to bone
and lung.
Pathogenesis
There is a strong association between cervical cancer and
sexual activity that includes sex at a young age and multiple
sexual partners. Infection with HPV has an important causal
role, and this has underpinned the introduction of programmes
to immunise teenagers against HPV in an effort to prevent the
later development of cervical cancer (p. 342).
Investigations
Diagnosis is made by smear or cone biopsy. Further examination
may require cystoscopy and flexible sigmoidoscopy if there are
symptoms referable to the bladder, colon or rectum. In contrast
to other gynaecological malignancies, cervical cancer is a clinically
staged disease, although MRI is often used to characterise the
primary tumour. A routine chest X-ray should be obtained to help
rule out pulmonary metastasis. CT of the abdomen and pelvis is
performed to look for metastasis in the liver and lymph nodes,
and to exclude hydronephrosis and hydroureter.
Management
This depends on the stage of disease. Pre-malignant disease
can be treated with laser ablation or diathermy, whereas in
microinvasive disease a large loop excision of the transformation
zone (LLETZ) or a simple hysterectomy is employed. Invasive but
localised disease requires radical surgery, while chemotherapy and
radiotherapy, including brachytherapy, may be given as primary
treatment, especially in patients with adverse prognostic features
such as bulky or locally advanced disease, or lymph node or
parametrium invasion. In metastatic disease, cisplatin-based
chemotherapy may be beneficial in improving symptoms but
does not increase survival significantly.
Head and neck tumours
Head and neck cancers are typically squamous tumours that
arise in the nasopharynx, hypopharynx and larynx. They are
most common in elderly males but now occur with increasing
frequency in a younger cohort, as well as in women, especially
33.19 Common presenting features by location in
head and neck cancer
Hypopharynx
• Dysphagia
• Referred otalgia
• Odynophagia
• Enlarged lymph nodes
Mouth
• Non-healing ulcers
• Ipsilateral otalgia
Nasal cavity and sinuses
• Discharge (bloody) or obstruction
Nasopharynx
• Nasal discharge or obstruction
• Diplopia
• Conduction deafness
• Hoarse voice
• Atypical facial pain
• Horner’s syndrome
Oropharynx
• Dysphagia
• Otalgia
• Pain
Salivary gland
• Painless swelling
• Facial nerve palsy
where oropharyngeal cancers are concerned. The rising incidence
of oropharyngeal cancers, especially in the developed world, is
thought to be secondary to HPV infection. Presentation depends
on the location of the primary tumour and the extent of disease.
For example, early laryngeal cancers may present with hoarseness,
while more extensive local disease may present with pain due to
invasion of local structures or with a lump in the neck. Patients
who present late often have pulmonary symptoms, as this is the
most common site of distant metastases (Box 33.19).
Pathogenesis
The tumours are strongly associated with a history of smoking
and excess alcohol intake, but other recognised risk factors
include Epstein-Barr virus for nasopharyngeal cancer and HPV
infection for oropharyngeal tumours.
Investigations
Careful inspection of the primary site is required as part of the
staging process, and most patients will require endoscopic
evaluation and examination under anaesthesia. Tissue
biopsies should be taken from the most accessible site.
CT of the primary site and the thorax is the investigation of
choice for visualising the tumour, while MRI may be useful in
certain cases.
Management
Generally speaking, the majority of patients with early or locally
advanced disease are treated with curative intent. In localised
disease where there is no involvement of the lymph nodes,
long-term remission can be achieved in up to 90% of patients
with surgery or radiotherapy. The choice of surgery versus
radiotherapy often depends on patient preference, as surgical
treatment can be mutilating with an adverse cosmetic outcome.
Patients with lymph node involvement or metastasis are treated
with a combination of surgery and radiotherapy (often with
chemotherapy as a radiosensitising agent - proven agents include
cisplatin or cetuximab), and this produces long-term remission
in approximately 60-70% of patients. Recurrent or metastatic
tumour may be palliated with further surgery or radiotherapy to
aid local control, and systemic chemotherapy has a response
rate of around 20-30%. Second malignancies are common (3%
1336 • ONCOLOGY
per year) following successful treatment for primary disease,
and all patients should be encouraged to give up smoking and
drinking alcohol to lower their risk.
Carcinoma of unknown origin
Some patients are found to have evidence of metastatic disease
at their initial presentation, prior to diagnosis of a primary site.
In many cases, a subsequent biopsy reveals adenocarcinoma
but the primary site is not always clear.
Investigations
In this situation, there is a temptation to investigate the patient
endlessly in order to determine the original primary site. There is
a compromise, however, between exhaustive investigation and
obtaining sufficient information to plan appropriate management.
For all patients, histological examination of an accessible site
of metastasis is required. The architecture of the tissue can
assist the pathologist in determining the likely primary site,
and therefore it is better to perform a biopsy rather than fine
needle aspiration. The greater volume of tissue permits the use
of immunohistochemistry. Extensive imaging to search for the
primary is rarely indicated; a careful history to identify symptoms
and risk factors (including familial) will often permit a judicious
choice of imaging and other diagnostic tests, reserving additional
tests for specific patients (Box 33.20).
Management
Management of the patient will depend on that person’s
circumstances, as well as on the site(s) involved and the likely
primary sites. The overriding principle is to ensure that a curable
diagnosis has been excluded. For example, lung metastases
from a testicular teratoma do not preclude cure; nor do one or
two liver metastases from a colorectal cancer. Early discussion
with an oncologist within a multidisciplinary team is essential and
avoids unnecessary investigation; for example, a single hCG-based
pregnancy test in a young man with lung metastases might
confirm the presence of a teratoma and allow rapid administration
of potentially curative chemotherapy. Treatment should not
necessarily wait for a definitive diagnosis; appropriate analgesia,
33.20 Initial diagnostic tests in patients presenting
with carcinoma of unknown primary
• Detailed history and examination, including breast, nodal areas,
skin, genital, rectal and pelvic regions
• Full blood count, urea and electrolytes, renal function, liver function
tests, calcium, urinalysis, lactate dehydrogenase
• Chest X-ray
• Myeloma screen (if lytic bone lesions)
• CT scan of chest, abdomen and pelvis
• Symptom-directed upper and lower gastrointestinal endoscopy
• Tumour markers: prostate-specific antigen (PSA) in men, cancer
antigen 125 (CA-125) in women with peritoneal malignancy
or ascites, a-fetoprotein (AFP) and human chorionic gonadotrophin
(hCG)
• Testicular ultrasound (if clinical features suggest germ cell tumour)
• Histological examination of biopsy, with immunohistochemistry if
required
*0ffer when clinically appropriate.
radiotherapy and surgical palliation can all be helpful. Some
patients remain free of cancer for some years after resection of
a single metastasis of an adenocarcinoma of unknown primary,
justifying this approach in selected patients.
In those with no obvious primary, systemic chemotherapy
may achieve some reduction in tumour burden and alleviation
of symptoms, but long-term survival is rare.
Multidisciplinary teams
The multidisciplinary team (MDT) is well established in oncology and
meets on a regular basis to discuss patient progress and provide
a forum for patient-centred, interdisciplinary communication to
coordinate care and decision-making. It is a platform on which
individual clinicians can discuss complex cases or situations and
draw on the collective experience of the team membership to
decide on the best approach for an individual patient. This can
be particularly important when discussing patients with a rare
condition or in a rare situation.
Specific roles of the MDT include:
• planning the diagnostic and staging procedures
• deciding on the appropriate primary treatment modality
(most commonly surgery but the use of neoadjuvant
chemotherapy before interval surgery is increasing)
• arranging review by the oncology team to plan
assessment of the patient prior to systemic therapy or
radiotherapy
• discussing additional support requirements for the
individual patient, such as physiotherapy; psychological
support; symptom control; nutritional care or rehabilitation
in the post-operative period
• ensuring access to accurate information on treatment,
prognosis, side-effects and other related matters, such as
stoma care
• planning surveillance strategies
• ensuring the appropriate transition from treatment with
curative intent to that of palliation of symptoms
• promoting recruitment into clinical trials
• agreeing on operational policies to deliver high-quality care
to patients
• planning and reviewing audit data to ensure the delivery of
quality care to patients by the team.
Further information
Books and journal articles
Cassidy J, Bissett D, Spence RAJ, et al. Oxford handbook of
oncology, 4th edn. Oxford: Oxford University Press; 2015.
Dark GG. Oncology at a glance. Chichester: Wiley-Blackwell; 2013.
Hanahan D, Weinberg RA. The hallmarks of cancer: the next
generation. Cell 2011; 144:646-674.
Tobias J, Hochhauser D. Cancer and its management, 7th edn.
Chichester: Wiley-Blackwell; 2014.
Websites
cancer.org American Cancer Society: clinical practice guidelines.
ctep.cancer.gov/reporting/ctc.html Common toxicity criteria.
info.cancerresearchuk.org/cancerstats/ A wide range of cancer
statistics that can be sorted by type or geographical location.
Pain and palliative care
Pain 1338
Functional anatomy and physiology 1 338
Investigations 1 342
Principles of management 1 343
Interventions 1 344
Chronic pain syndromes 1348
Palliative care 1349
Presenting problems in palliative care 1 350
Pain 1 350
Breathlessness 1 353
Cough 1 353
Nausea and vomiting 1 353
Gastrointestinal obstruction 1 354
Weight loss 1 354
Anxiety and depression 1 354
Delirium and agitation 1 354
Dehydration 1 354
Death and dying 1354
1338 • PAIN AND PALLIATIVE CARE
Pain
Pain is defined as ‘an unpleasant sensory and emotional
experience associated with actual or potential tissue damage
or described in terms of such damage’. It is one of the most
common symptoms for which people seek health-care advice.
Our understanding of the mechanisms of pain has evolved
considerably from Hippocrates’ suggestion in 450 BC that pain
arose as a result of an imbalance in vital fluids. We now know
that pain is a complex symptom that is influenced and modified
by many social, cultural and emotional factors, as illustrated in
Figure 34.1 . The sensation of acute pain that occurs in response
to inflammation or tissue damage plays an important role in
protection from further injury. Chronic pain serves no useful
function but results in significant distress and suffering for the
patient affected, as well as having a wider societal impact.
Functional anatomy and physiology
The functional anatomy of the somatosensory system is shown
in Figures 25.3 and 25.6 (pp. 1065 and 1068). Here, discussion
will focus on the mechanisms and mediators that are involved
in pain processing.
Peripheral nerves
Peripheral nerves contain several types of neuron. These can be
classified into two groups, depending on whether or not they
are surrounded by a myelin sheath. Myelinated neurons have
a fast conduction velocity and are responsible for transmission
of various sensory signals, such as proprioception, light touch,
heat and cold, and the detection of localised pains, such as
pin-prick. Unmyelinated fibres have a much slower conduction
Fig. 34.1 The biopsychosocial model of pain. The perception of pain
as a symptom is dependent not only on sensory inputs but also on the
individual’s cognitive reaction to the pain, their emotional state, their
underlying disease and their social and cultural background.
i
34.1 Types of nerve fibre
Fibre
type
Diameter
(p-m)
Conduction
velocity (ms1)
Function
Large myelinated
Aa 12-20
70-120
Proprioception
AP
5-12
30-70
Motor to muscle fibres
Light touch, pressure
A-
3-6
15-30
Motor to muscle spindles
Small myelinated
A 2-5
12-30
Well-localised pain
B
<3
3-15
Thermal sensation
Pre-ganglionic autonomic
Unmyelinated
C 0.4-1 .3
0.5-3
Diffuse pain
Poorly localised thermal
sensation
Post-ganglionic autonomic
velocity and are responsible for transmitting diffuse and poorly
localised pain, as well as other sensations (Box 34.1).
Sensory neurons (also known as primary afferent neurons)
connect the spinal cord to the periphery and supply a defined
territory or a dermatome, which can be used to identify the position
of a nerve lesion (see Fig. 25.10, p. 1071). In healthy individuals
dermatomes have distinct borders, but in pathological pain
syndromes these may become blurred as the result of neuronal
plasticity, which means that pain may be felt in an area adjacent
to that supplied by a specific nerve root. Autonomic neurons also
contain pain fibres and are responsible for transmitting visceral
sensations, such as colic. In general, visceral pain is diffuse and
less well localised than pain transmitted by sensory neurons.
Anatomical features of the afferent pain pathway are illustrated
in Figure 34.2. Pain signals are transmitted from the periphery
to the spinal cord by sensory neurons. These have the following
components:
• A cell body, containing the nucleus, which is situated in
the dorsal root ganglion close to the spinal cord. The cell
body is essential for survival of the neuron, production of
neurotransmitters and neuronal function.
• The nerve fibre (axon) and peripheral nerve endings, which
are located in the periphery and contain a range of
receptors in the neuronal membrane.
• Specialised receptors in the periphery, consisting of bare
nerve endings known as nociceptors or pain receptors,
which are activated by various mediators. They are
situated mainly in the epidermis.
• The central termination, which travels to the dorsal horn of
the spinal cord to form the first central synapse with
neurons that transmit pain sensation to the brain.
When a noxious stimulus is encountered, activation of
nociceptors leads to generation of an action potential, which
travels upwards to the dorsal root ganglion and also stimulates
the release of neurotransmitters that have secondary effects on
surrounding neurons.
Spinal cord
Sensory neurons, through their central termination, synapse
with second-order neurons in the dorsal horn of the spinal
cord. There is considerable modulation of pain messages at
Pain • 1339
Fig. 34.2 Ascending and descending pain pathways. Ascending pathways are shown in blue and descending in red. Pain signals are detected in the
periphery by nociceptors, which are activated by chemicals, changes in pH and cytokines. The signal is transmitted by the primary afferent neuron to the
spinal cord, where there is a synapse with a second-order neuron, which transmits the signal onwards to the thalamus. Thereafter, the pain signal is
transmitted to the cerebral cortex. The intensity of pain signals is subject to extensive modulation at several levels within the nervous system. Cognitive
influences derived from the frontal lobe, coupled with sensory influences from cortex and emotional influences from the amygdyla, affect pain perception in
the mid-brain around the periaqueductal gray matter (PAG) and the rostroventrolateral medulla (RVM) in the medulla. These structures form part of the
descending modulatory systems, which, under normal circumstances, inhibit pain perception. In some chronic pain states, however, dysfunction of the
descending pathways can occur, increasing pain.
this site, both from local neurons within the spinal cord and
from neurons that descend from the brain, as depicted in Figure
25.11 (p. 1072). Several neurotransmitters are involved in pain
processing at this level and these are summarised in Box 34.2.
They include amino acids, such as glycine and y-aminobutyric acid
(GABA), which are inhibitory, and glutamate, which is excitatory;
neuropeptides, such as substance P and calcitonin gene-related
peptide (CGRP); and endorphins. Whether or not they increase
or decrease pain perception depends on the connectivity of the
neurons on which they act.
|Jtentral processing of pain
The signals transmitted by second-order neurons in the spinal cord
are relayed to the sensory cortex by third-order neurons, which
synapse with second-order neurons in the thalamus. At this site,
perception of pain is influenced by interactions between a range
of structures in the brain, where sensory, cognitive and emotional
aspects are integrated. This is termed the pain neuromatrix (Fig.
34.2). Signals within the neuromatrix are multidirectional in nature,
involving modulation of incoming messages by the cerebral
cortex (top-down regulation), as well as a complex network of
connections between other subcortical structures. Under normal
conditions, there is a degree of descending inhibition from the
brainstem that reduces input from peripheral stimuli.
It is thought that chronic widespread pain (CWP) and
opioid-induced hyperalgesia may result, at least in part, from
abnormalities in central processing of pain signals. It has also been
suggested that variations in the levels of descending inhibition
between individuals may make some people more vulnerable than
others to developing chronic pain. Over recent years, there has
been increasing interest in the role that glial cells (see Fig. 25.1 ,
p. 1064) play in pain processing. Both astrocytes and microglial
cells can become activated in chronic pain states and release
34
1340 • PAIN AND PALLIATIVE CARE
34.2 Neurotransmitters and receptors involved in pain processing in the spinal cord
Neurotransmitter
Receptor(s)
Receptor type
Comments
Amino acids
Glutamate
AMPA
Ion channel
Excitatory; permeable to cations: can be Ca2+, Na+ or K+, depending on
subunit structure
NMDA
Ion channel
Excitatory; blocked by Mg2+ in the resting state; block can be altered if
membrane potential changes; permeable to Ca2+, Na+ and K+
Kainate
Ion channel
Post synaptic - excitatory
Gp 1
GPCR
Pre-synaptic - inhibitory through GABA release; permeable to Na+ and K+
Gp II
GPCR
Activates a range of signalling pathways; long-term effects on synaptic
excitability
Gp III
GPCR
Probably inhibitory; can decrease cAMP production; pre-synaptic; decreases
glutamate release
Glycine
GlyR
Ion channel
Mainly inhibitory; permeable to Cl"; blocked by caffeine
GABA
GABAa
Ion channel
Mainly inhibitory in spinal cord; permeable to Cl"; indirectly modulated by
benzodiazepines (increased ion channel opening); not specifically involved in
nociception, generally depressant effect on spinal cord activity
GABAb
GPCR
Predominantly inhibitory; activated by baclofen
Neuropeptides
Substance P
Neurokinin receptors
GPCR
Mainly excitatory; increased in inflammation, decreased in neuropathic pain
Cholecystokinin
CCKRsl-8
GPCR
Excitatory; clinical trials of antagonists in progress
Calcitonin gene-related
peptide
CALCRL
GPCR
Excitatory; slows degradation of substance P; implicated in migraine
Opioids
Dynorphin
0P1 (kappa)
GPCR
Excitatory?; may be pro- nociceptive
p-endorphin
0P3 (mu)
GPCR
Inhibitory
Nociceptin
0RL-1
GPCR
Inhibitory; also expressed by immune cells
*Excitatory = increased pain; inhibitory = reduced pain.
(AMPA = a-amino 3-hydroxy, 5-methyl, 4-isoxazole propionic acid; CALCRL = calcitonin receptor-like receptor; cAMP = cyclic adenosine monophosphate; GABA =
y-aminobutyric acid; Gp =
group; GPCR = G-protein-coupled receptor; NMDA =
/V-methyl-D-aspartate; OP = opioid; ORL = opioid-like receptor)
pro-inflammatory cytokines, as well as altering re-uptake of
excitatory neurotransmitters such as glutamate, which can
influence pain perception considerably. As our understanding
of these processes improves, there is increasing potential to
develop novel therapies targeted at these mediators, with some
early clinical studies in neuropathic pain.
Sensitisation
Sensitisation is one of the key features of pain processing.
It refers to the fact that both peripheral and central nervous
systems adapt rapidly to the presence of pain, especially in
response to tissue damage. This adaptive process is called
neuronal plasticity. In some situations, neuronal plasticity can
lead to prolonged changes in the pathways that are involved in
detecting and processing nociceptive stimuli, resulting in chronic
pain syndromes. The specific changes in key neurotransmitters
and receptors differ between chronic pain states, with implications
for the efficacy of treatments. For example, pi-opioid receptors
are down-regulated in neuropathic pain, potentially leading to
limited opioid responsiveness.
Peripheral sensitisation
Peripheral sensitisation can occur in association with a variety
of clinical conditions, including sepsis, cancer, inflammatory
disease, injury, surgery and obesity. The final common pathway
by which sensitisation takes place in all of these conditions
is inflammation. Inflammation is accompanied by increased
capillary permeability and tissue oedema with the release of a
diverse range of mediators, including bradykinin, hydrogen ions,
prostaglandins and adenosine, which bind to receptors and ion
channels on nociceptors of primary afferent neurons (Fig. 34.3).
The signalling pathways activated by these mediators generate
action potentials, which are transmitted by sensory neurons
to the spinal cord. If these pain-provoking stimuli persist, the
activation threshold of sensory neurons is reduced, resulting in
an increased transmission of pain signals to the spinal cord.
Central sensitisation
Sensitisation may also take place at the level of the spinal cord
in response to a sustained painful stimulus. It can occur acutely
and rapidly, such as immediately after surgery, or may progress
to chronic changes, such as chronic infection, cancer, repeated
surgery or multiple traumatic episodes. Glutamate, acting via the
/V-methyl-D-aspartate (NMDA) receptor complex, plays a key role
in central sensitisation (Fig. 34.4). In response to a sustained
peripheral painful stimulus, increased amounts of glutamate are
released in the spinal cord, overcoming the inhibitory action of
magnesium ions and resulting in activation of the NMDA receptor.
This initiates a cascade of intracellular signalling events that
lead to prolonged modifications of somatosensory processing,
with amplification of pain responses within the spinal cord
and continued neuronal firing, even after the noxious stimulus
has stopped. This phenomenon is termed ‘after-discharge’. In
neuropathic pain, prolonged activation of the NMDA pathway
results in a decrease in the number of inhibitory interneurons,
which further potentiates pain.
Genetic determinants of pain perception
There are marked ethnic and individual variations in how people
respond to painful stimuli and studies in twins have estimated
Pain • 1341
Fig. 34.3 Mechanisms of peripheral sensitisation. [A] Sensory nerve terminating with nociceptor in skin. [§] Peripheral nociceptors express various
receptors and ion channels that act as mediators of pain. They include sodium channels implicated in congenital pain syndromes; the purinergic 2X (P2X)
receptor for adenosine triphosphate (ATP); members of the transient receptor potential (TRP) superfamily of ion channel receptors, which detect changes in
osmolality and temperature; acid-sensing ion channel (ASIC) receptors, which detect hydrogen ions; G-protein-coupled receptors, which detect bradykinin
(BK), prostaglandins and ATP; and the neurotrophic tyrosine kinase 1 (NTRK1) receptor, which detects nerve growth factor (NGF). [C] Activation of these
receptors by ligands, hydrogen ion [H+] and high temperature (>42°C) amplifies action potentials, which increase pain signals and cause peripheral
sensitisation. Adapted from Bennett DL, Woods CG. Painful and painless channelopathies. Reprinted with permission from Elsevier (The Lancet Neurol
2014; 13:587-599).
Fig. 34.4 Mechanisms of central sensitisation. Post-synaptic activation of the /V-methyl-D-aspartate (NMDA) receptor requires the amino acids glycine
and glutamate, which bind to the NR1 and NR2 subunits, respectively; these amplify pain signals at the level of the spinal cord. In contrast, magnesium
ions block receptor activation.
that the heritability of CWP ranges between 30% and 50%. In the
general population, the individual variants in response to pain and
perception of pain are most likely due to a complex interaction
between genetic and environmental influences. Few variants
have been identified with robust evidence of association with
CWP. Several rare syndromes have been described, however,
in which insensitivity to pain or heightened pain responses
occur as the result of a single gene disorder, as summarised
in Box 34.3. Most are due to mutations affecting ion channels
that play a key role in neurotransmission (see Fig. 34.3), but
other causes include mutations in the NTKR1 gene, which
encodes the receptor for nerve growth factor, and mutations
in the PDRM12 transcription factor, which is involved in neuron
development.
34
1342 • PAIN AND PALLIATIVE CARE
Investigations
Pain can be a presenting feature of a wide range of disorders
and the first step in evaluation of a patient with pain should
be to perform whatever investigations are required to define
the underlying cause of the pain, unless this is already
known. However, with most chronic pain syndromes,
such as fibromyalgia, complex regional pain syndrome
and CWP, investigations are negative and the diagnosis
is made on the basis of clinical history and exclusion
of other causes. Specific investigations that are useful in
the assessment of selected patients with chronic pain are
discussed below.
| Magnetic resonance imaging
Magnetic resonance imaging (MRI) can be helpful in the
assessment of an underlying cause in patients with focal pain
that follows a nerve root or peripheral nerve distribution. Imaging
is seldom helpful in individuals with CWP.
Blood tests
Blood tests are not generally helpful in the diagnosis of chronic
pain, except in patients with peripheral neuropathy; in this case,
a number of blood tests may be required to investigate the
underlying causes of the neuropathy. Full details are provided in
Box 25.86 (p. 1 1 39). Genetic testing may be of value in patients
with clinical features that point to an inherited disorder of pain
processing (Box 34.3).
Quantitative sensory testing
Quantitative sensory testing can be helpful in the detailed
assessment of patients with chronic pain. A simple set of tools
can be used in the clinical setting (Fig. 34.5). Lightly touching
the skin with a brush, swab or cotton-wool ball can be used
to test for abnormalities of fine touch (allodynia). Assessing
the patient’s response to a pin-prick can be used to test for
abnormalities in mechanical hyperalgesia. Finally, touching the
patient’s skin with warm and cool thermal rollers can be used to
test for abnormalities of thermal sensation. An unaffected area
of skin should be tested first, to establish normal sensation,
before testing the affected area.
| Nerve conduction studies
Nerve conduction studies can be helpful in demonstrating and
quantifying a definitive nerve lesion, either peripherally or centrally.
They can be used to help differentiate between central and
peripheral neuropathic pain. They do not, however, effectively
examine small nerve fibre function.
Nerve blocks
Performing a nerve block with infiltration of a local anaesthetic
such as 1 % lidocaine can be used diagnostically, in assessing
whether a pain syndrome is due to involvement of a specific
nerve or nerve root. Where inflammation and or swelling may
be contributing to the underlying pain - for example, if there is
compression of a nerve root - then a mixture of local anaesthetic
Cotton wool
Neurology pin
A =>/
Allodynia
Hyperalgesia
Warm and cool thermal rollers
Increased or decreased thermal sensation
Fig. 34.5 Equipment for bedside sensory testing.
34.3 Genetic regulators of pain perception
Gene (protein)
Mutation (inheritance)
Protein function
Phenotypes
SCN9A(N a, 1.7)
LoF (AR)
Ion channel
Absent pain, hypohydrosis, anosmia
SC/V9A(N a, 1.7)
GoF (AD)
Ion channel
Erythromelalgia, paroxysmal pain, burning pain,
autonomic dysfunction
SC/V77A(Na,1.9)
GoF (AD)
Ion channel
Absent pain, hyperhydrosis, muscular weakness,
gut dysmotility
SCN10A{U a, 1.8)
GoF (AD)
Ion channel
Burning pain, autonomic dysfunction
TRPA1 (TRPA1)
GoF (AD)
Ion channel
Absent pain
PDRM12 (PDRM12)
LoF (AR)
Transcription factor; neuron development
Absent pain
NTRK1 (high-affinity
NGF receptor)
LoF (AR)
Tyrosine kinase; promotes neuron
development
Absent pain; anhydrosis, mental retardation,
increased cancer risk
(AD = autosomal dominant; AF
i = autosomal recessive; GoF =
gain of function; LoF = loss of function; NGF = nerve growth factor)
Pain • 1343
and depot glucocorticoid may be helpful in alleviating pain. Nerve
blockade can also be used to determine whether more radical
therapies, such as nerve ablation, might be helpful in controlling
pain, particularly that related to cancer.
Pain scoring systems
Various questionnaires and other instruments have been devised
to localise pain, rate its severity and assess its impact on quality
of life. Some of the most widely used are listed in Box 34.4.
The distribution of pain can be documented on a diagram of the
body, on which the patient can mark the sites that are painful.
Similarly, other methods have been developed with which to
assess the severity of pain using verbal, numerical and behavioural
rating scales. Visual scoring systems employing different facial
expressions may be of value in paediatric patients and those
with cognitive impairment. Documenting changes in pain scores
using questionnaires can be helpful in indicating to what extent
drug treatments have been successful and can reduce the time
taken to achieve pain control.
Principles of management
Effective management of chronic pain depends in part on the
underlying cause but some general principles can be applied.
In general terms, the treatment goals are to:
• educate the patient
• promote self-management
• optimise function
• enhance quality of life
• control pain.
Clinical history
Biopsychosocial assessment
A full biopsychosocial assessment should be performed in all
patients with chronic pain. Although this is time-consuming,
the time invested is likely to pay dividends in improving the
long-term outcome for patients. A biopsychosocial assessment
takes account of the underlying neurobiology of the condition in
the context of wider influences, including cognition and beliefs,
emotions, and social and cultural factors. For example, an
individual with abdominal pain might respond differently if a close
relative had recently died of gastric cancer than if a colleague
had been off work with gastric upset.
An accurate clinical history is important, taking note of the
duration of pain, any precipitating and relieving factors, its location
and, if the pain is located at more than one site, which site
is the one that impacts most on the patient’s quality of life.
The characteristics of the pain should be documented, by
assessing whether it is described as dull, sharp, aching or
burning. Associated features, such as hypersensitivity to fine
touch or temperature, numbness, paraesthesia, tingling and
formication (the feeling of insects crawling over the skin), should
be noted. It is important to determine to what extent the pain
is interfering with normal daily activities, such as work, leisure
pursuits and sleep. The patient’s social circumstances and
cultural background should be documented, including any caring
responsibilities, employment status and social and family support.
The intensity of pain should also be recorded, preferably using a
validated questionnaire (Box 34.4). The patient’s mood should
be assessed and, if evidence of low mood is detected, a suicide
risk assessment should be considered (see Box 28.1 2, p. 1 1 87).
The past medical and medication history should be recorded and
specific enquiry made about substance misuse and any previous
history of physical or mental abuse. It is also useful to enquire
specifically about the patient’s beliefs as to what is causing their
pain, as well as what their expectation of treatment is; unless
these are addressed, management may be less effective. There
are some patient populations in whom particular challenges
arise, often related to differences in communication ability.
Strategies that can be used to overcome these difficulties are
summarised in Box 34.5.
Examination
The patient’s general appearance should be noted, including
ability to walk and use of a walking aid. In those with focal
pain, neurological examination should be performed, focusing
particularly on any areas of abnormal sensation, reflexes and
evidence of muscle wasting. A general examination should be
carried out to determine whether there is any evidence of an
underlying physical disorder that can account for the pain. In
addition to the use of investigations to find the underlying cause
of pain, patients with persistent or chronic pain may benefit
from sensory testing or diagnostic nerve blocks to explore the
underlying mechanisms and direct treatment. For example, a
combined femoral and sciatic nerve block may be used in a
patient with lower limb amputation to assess whether the pain
is predominantly peripherally or centrally generated. If the pain
is not improved by an effective nerve block, then peripherally
directed therapies are unlikely to be effective.
34.4 Instruments used in the assessment of pain
and its impact
Instrument
Comments
Brief Pain Inventory
Developed for use in cancer pain, validated
and widely employed for chronic pain;
based on 0-10 ratings of pain intensity
and the impact of pain on a range of
domains, including sleep, work and
enjoyment of life
Pain Detect,
s-LANSS, DN-4
A number of screening questionnaires to aid
diagnosis of neuropathic pain
Pain Catastrophising
Scale
Developed to assess individual levels of
catastrophising, encompassing three
different domains: helplessness, rumination
and magnification
Tampa Scale of
Kinesiophobia
Measures how much an individual is fearful
of movement
Pain Self-efficacy
Questionnaire
Assesses individual beliefs about
self-efficacy in the context of chronic
pain, and how this impacts on
function
Visual analogue
scale (VAS)
Patient marks pain intensity on a horizontal
line
Localisation of pain
Body chart, allowing the patient to indicate
where pain is situated
Beck Depression
Inventory
Assesses emotional function
SF-36/EQ-5D
Assesses health- related quality of life
(DN-4 = Douleur Neuropathique questionnaire; EQ-5D = EuroQol 5-Domain
questionnaire; SF-36 = Short Form 36; s-LANSS = self-completed Leeds
Assessment of Neuropathic Signs and Symptoms)
34
1344 • PAIN AND PALLIATIVE CARE
34.5 Challenges in pain assessment in particular patient populations
Patient population
Challenges
Solutions
Paediatric
Assessment needs to be appropriate to developmental stage
Consider visual tools to aid pain assessment
Elderly
May have impaired cognitive function
Cultural factors may reduce self-reporting of pain
Risk of adverse effects of medication increased
Consider formal assessment of cognitive function
Consider non-verbal assessment
Consider visual tools to assess pain
Employ a number of tools assessing pain behaviours
Cognitive
impairment
Reporting and expression of pain may change
Increased sensitivity to central nervous system effects of
analgesics
Perform formal assessment of cognitive function
Use non-verbal assessment: facial expressions, vocalisations,
body movements, changes in social interactions
Substance misuse
Response to analgesics altered
Increased tolerance
Increased risk of addiction
Substance misuse may affect reporting of pain
Seek specialist support early
Ensure prescribing is safe
Interventions
Probably the most effective mode of treatment for pain is
to identify the underlying cause. Examples include the use
of immunosuppressive medication in inflammatory disease,
chemotherapy, radiotherapy or hormone therapy in cancer, and
antimicrobial therapy in patients with infection. There are many
circumstances, however, in which the underlying cause of pain
cannot be treated or the treatments available are incompletely
effective. Under these circumstances, several management
options are available. In all cases, a multidisciplinary approach
is necessary that combines pharmacological management with
supported self-management, and other specific interventions
when appropriate.
Supported self-management
Self-management strategies are useful in the treatment of chronic
pain. Self-management works best if the patient has some
understanding of their chronic pain, and acceptance that it
is unlikely to resolve completely. The aim is for patients to
maximise their quality of life and function despite ongoing pain.
Support for self-management can be delivered by health-care
professionals, patients who suffer from the same condition or
lay people, either on an individual basis, in a group setting or,
increasingly, through web-based resources. There is a strong
educational component to supported self-management, which
seeks to generate an interaction between patient and tutor. The
key aspects include:
• increasing activity levels, while understanding and
practising pacing techniques (not overdoing things and
cycling between over- and under-activity)
• using relaxation and mindfulness techniques as part of
daily management
• using medication when appropriate
• having a plan to manage pain flares.
There are a number of useful online self-help resources (see
‘Further reading’).
Physical therapies
There is strong evidence that exercise can help in the management
of chronic pain. Several types of exercise have been successfully
used delivered in various ways, through physiotherapists, exercise
classes or individual tuition. In choosing a form of exercise therapy,
it is important to tailor the approach most likely to be acceptable
34.6 Physical therapies for chronic pain
Land-based
• Walking
• Yoga
• Gym work
• Pilates
• Exercise classes
• Tai-chi
Water- based
• Hydrotherapy
• Swimming
• Exercise classes
to the individual patient. A successful exercise programme can
help overcome ‘fear avoidance’, a well -recognised problem in
chronic pain, where patients associate activity with an increase
in pain and therefore do progressively less activity, with resultant
deconditioning. Because of this it is important to pace physical
activity to ensure that patients do not cycle from over-activity,
with a flare in pain, to fatigue and deconditioning. This can be
done by working with patients to establish their baseline level
of activity and using an individually tailored, graded exercise
programme (Box 34.6). This may include normal household
activities, as well as targeted exercises and stretches. Manual
therapy covers a variety of hands-on treatments, including
manipulation, mobilisation and massage. Manual therapy can
be provided by a range of therapists, including physiotherapists,
osteopaths and chiropractors. There is some evidence of short¬
term benefit for manual therapy but limited evidence of long-term
efficacy.
| Pharmacological therapies
A range of analgesics can be used in the management of
chronic pain but, for most of these, the evidence of long-term
benefit is limited. In general, it is advisable to use a multimodal
approach in the treatment of chronic pain, choosing different
drugs to target pain processing at multiple points (Box 34.7).
By employing different classes of analgesic, it is possible to use
lower doses of each, thereby improving the side-effect profile.
There is considerable inter-individual variability in response to
analgesics, even within the same class. There are many reasons
for this, including genetic variations in the enzymes that metabolise
drugs. For example, the CYP2D6 gene encodes for a liver
enzyme, cytochrome P450 2D6, which metabolises a number
of commonly used analgesics. Genetic variation in CYP2D6 can
influence circulating levels of many drugs, depending on whether
Pain • 1345
34.7 Pharmacological management of chronic pain
Drug or class of drug
Mechanism of action
Paracetamol
Central inhibition of C0X-1 and C0X-2 enzymes
Mechanisms of action incompletely understood
Non-steroidal anti-inflammatory drugs
Inhibition of prostaglandin production
Opioids
Agonists at 0P3 receptors at multiple levels in the central nervous system
Blockade of ascending pain pathways
Ketamine
Antagonist of NMDA receptors
Reduction of central sensitisation
Gabapentin
Pregabalin
Inhibition of glutamate release by primary afferent neurons at first central synapse
Decrease of excitatory neuronal activity
Tricyclic antidepressants
Inhibition of serotonin and noradrenaline (norepinephrine) re-uptake at synapses in the spinal
cord, and also potential effects in the limbic system
Inhibition of Na+ channels in neurons
Serotonin (5-hydroxytryptamine, 5-HT) and
noradrenaline (norepinephrine) re-uptake
inhibitors
Inhibition of serotonin and noradrenaline re-uptake at synapses in the spinal cord, and also
potential effects in the limbic system
Lidocaine patches
Inhibition of Na+ in sensory neurons
Capsaicin patch
Activation of TRPV1 channels on subset of C fibres, causing selective pharmacological
denervation, with a decrease in intra-epidermal nerve fibre density
Nerve blocks with lidocaine and glucocorticoids
Temporary denervation due to blockade of Na+ channels in sensory neurons
Local anti-inflammatory effect
(COX = cyclo-oxygenase; NMDA = /V-methyl-D-aspartate; OP
= opioid; TRPV1 = transient receptor potential vanilloid 1)
someone is a rapid or poor metaboliser. This is particularly
important if metabolites are active, as is the case with codeine
and tramadol, which are metabolised to morphine. Genetic
variations have also been described in the opioid receptors and
downstream pathways that they affect, with good pre-clinical
evidence that variations in mu opioid receptors alter analgesic
response to different opioids. Because of this there is a good
rationale to try different drugs, even ones from the same class,
if there is an inadequate response or there are unacceptable
side-effects with one agent.
Whatever drug or combination of drugs is chosen, the key to
successful pharmacological management is careful assessment
and review, aiming for an acceptable balance between the
benefits of treatment in providing pain relief, maximising function,
and improving quality of life and adverse effects. Specific drug
treatments are described below.
Non-opioid analgesics
Paracetamol
Paracetamol is widely used in the treatment of mild to moderate
pain. Its mechanism of action is incompletely understood but it
is known to be a weak inhibitor of the cyclo-oxygenase type 1
(COX-1) and cyclo-oxygenase type 2 (COX-2) enzymes, providing
weak anti-inflammatory properties. There is also some of evidence
that it activates inhibitory descending spinal pathways, via a
serotonergic mechanism. Other postulated mechanisms include
endocannabinoid re-uptake inhibition, and inhibition of nitric oxide
and tumour necrosis factor alpha. For migraine and tension-type
headache it has moderate efficacy at a dose of 1000 mg. It is
used widely for musculoskeletal disorders and osteoarthritis,
with very little high-quality evidence that it is much better than
placebo, even at doses of up to 4000 mg per day. Acute liver
failure is a well -recognised complication of paracetamol overdose
but this risk may also be increased with long-term use, even
within the recommended dose range. In view of this, it should
be employed with caution in elderly patients and those weighing
less than 50 kg.
Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in
the treatment of inflammatory pain and osteoarthritis. These drugs
can be given systemically or locally and are discussed in more
detail on page 1002. They are also useful in the management
of pain in cancer patients, as discussed later in this chapter
(p. 1350). Although widely prescribed, there is limited high-quality
evidence of long-term efficacy in chronic pain, with a need for
further studies in this area.
Topical analgesics
Topical capsaicin cream (0.025 or 0.075%) has some efficacy
for osteoarthritis and may be used for neuropathic pain, although
evidence of benefit is limited. A single application (done by a
trained health-care professional) of a high-dose 8% capsaicin
patch can give around 1 2 weeks of pain relief for neuropathic
pain and can be repeated thereafter. Capsaicin is an agonist at
the transient receptor potential vanilloid 1 (TRPV1) ion channel,
found on some C fibres. Capsaicin activates the channel, causing
an initial sensation of heat, but an analgesic effect subsequently
results due to desensitisation of the channel.
Lidocaine 5% patches can also be helpful in focal neuropathic
pain and should be applied for 12 hours out of 24 hours, with
up to 4-6 weeks before maximum benefit is seen. The mode
of action is blockade of sodium channels in primary afferent
neurons and nociceptors, which reduces peripheral input to
the spinal cord.
Adjuvant analgesics
Adjuvant analgesics is the term used to cover a range of agents
that are used in the treatment of neuropathic pain, usually in
combination with classical analgesics. Typically, these agents
34
1346 • PAIN AND PALLIATIVE CARE
do not produce an immediate reduction in pain, but rather
exert an analgesic effect over a longer timeframe through their
effects on central processing of pain. They are of particular value
when used in combination in the management of pain with a
neuropathic component but require careful dose titration over a
number of weeks, to reach a dose that balances efficacy with
side-effects. While the response to individual agents is variable,
it is often possible to find an agent or combination of agents
that works for most patients.
Opioid analgesics
Opioids are a class of drugs that target opioid receptors. The
original receptor classification was based on pharmacological
activity (mu, delta, kappa), with the more recent International Union
of Basic and Clinical Pharmacology (IUPHAR) classification being
generally accepted in current use (Box 34.8). Opioid receptors
are G-protein-coupled receptors. Ligand binding activates several
intracellular signalling pathways, increasing cyclic adenosine
monophosphate (cAMP) levels, as well as altering calcium and
potassium permeability of neurons. Opioids are traditionally
divided into subclasses of weak opioids, such as codeine and
dihydrocodeine, and strong opioids, such as morphine and
oxycodone. While tramadol is a weak agonist at the mu opioid
receptor, it is classified as a strong opioid in some countries. The
dosages and characteristics of commonly prescribed opioids are
shown in Box 34.9. There has been a large increase in the use
of strong opioids for chronic pain over the last 1 0-20 years. A
number of factors contribute to this, including a rising incidence
of chronic pain with an ageing population, reluctance to use
NSAIDs because of cardiovascular and gastrointestinal adverse
effects, changes in patient expectation, societal attitudes and
availability of new formulations of opioids. There is evidence of
short- to medium-term benefit for strong opioids in low back
pain and osteoarthritis but there have been very few good -quality
studies of long-term use. Additionally, there is increasing concern
about potential harm from long-term use. This includes addiction,
dependence, opioid-induced hyperalgesia, endocrine dysfunction,
fracture risk (especially in the elderly), overdose and cardiovascular
34.8 Opioids and opioid receptors
Endogenous ligand
Receptor
(IUPHAR)
Alternative
classification
Potential sites
Pharmacological effects
Endomorphin 1 and 2
Met-enkephalin
Dynorphin A
Dynorphin B
MOP
Mu; 0P3
Brain, spinal cord, peripheral nerves,
immune cells
Analgesia, reduced gastrointestinal
motility, respiratory depression, pruritus
Leu-enkephalin
Met-enkephalin
p-endorphin
DOP
Delta; 0P1
Brain, spinal cord, peripheral nerves
Analgesia, cardioprotection,
thermoregulation
Dynorphin A
Dynorphin B
p-endorphin
KOP
Kappa; 0P2
Brain (nucleus accumbens, neocortex,
brainstem, cerebellum)
Analgesia, neuroendocrine (e.g. on
hypothalamic-pituitary axis), diuresis,
dysphoria
Orphanin FQ (nociceptin)
NOP
Orphan; 0RL-1; 0P4
Nucleus raphe magnus, spinal cord,
afferent neurons
Opioid tolerance, anxiety, depression,
increased appetite
(IUPHAR = International Union of Basic and Clinical Pharmacology; OP = opioid; ORL = opioid-like receptor)
34.9 Commonly used opioids
Opioid
Typical starting dose
Route
Oral morphine equivalent
Comments
Morphine
10 mg
Oral
10 mg
Most widely used
Codeine
100 mg
Oral
10 mg
Metabolised to morphine
Dihydrocodeine
100 mg
Oral
10 mg
Semi-synthetic
Tramadol
100 mg
Oral
10 mg
Synthetic
Oxycodone
6.6 mg
Oral
10 mg
More predictable bioavailability than
morphine
Buprenorphine
5 jig/hr
Transdermal
30 mg/day
Patch change usually every 7 days
(frequency of change dependent on
manufacturer and dose); advantages
in impaired renal function
Fentanyl
1 2 (Lig/hr
Transdermal
30 mg/day
Use with care in opioid-naive patients;
patch change usually every 72 hrs
Tapentadol
50 mg
Oral
20 mg
Use with care in opioid-naive patients
Hydromorphone
2 mg
Oral
10 mg
Semi-synthetic; hepatic metabolism
Diamorphine
3 mg
Subcutaneous, intramuscular,
intravenous
10 mg
Mainly used for acute pain or palliative
care
Pain • 1347
34.10 Use of opioids in chronic pain
Step
Factors to take into account
Comment
1. Assess suitability for opioids
Type of pain
Neuropathic pain less likely to respond
Likelihood of dependence
History of substance or alcohol misuse, including stimulant misuse
Co-morbidity
Avoid use in conditions where adverse effects more likely:
Chronic obstructive pulmonary disease
Chronic liver disease
Chronic kidney disease
2. Discuss with patient
Discuss potential benefits
Improvement in pain
Improvement in function
Discuss adverse effects
Nausea
Constipation
Drowsiness
Establish treatment goal
Improvement in function
3. Plan treatment trial
Set timescale
Define duration of treatment
Agree frequency of review
Agree on dose
Aim for lowest effective dose
Set upper dose limit
Agree on stopping rules
Consider stopping if:
Treatment goal is not met
There is no dose response
Tolerance develops rapidly
events, with many of these adverse effects being dose-related. I
There is evidence that doses of more than 1 20 mg morphine
equivalents per day are associated with increased harm, and
regular review to assess ongoing benefit is needed in this patient
group. A suggested strategy for using strong opioids in chronic
pain is shown in Box 34.10.
Psychological therapies
The aims of psychological therapy are to increase coping skills
and improve quality of life when facing the challenges of living with
chronic pain. There are a range of ways in which psychological
therapies can be delivered, including individual one-to-one
sessions, group sessions, multidisciplinary pain management
programmes, or web-based or telephone-based programmes.
There is a good evidence for the use of a cognitive behavioural
therapy (CBT)-based approach for chronic pain, delivered either
individually or in a group. The overall aim is to reduce negative
thoughts and beliefs, and develop positive coping strategies.
The interaction between thoughts, behaviours and emotions is
explored, and a problem-focused approach is used in therapy
delivery.
Relaxation techniques, such as biofeedback and mindfulness
meditation, require a degree of stillness and withdrawal, with
regular practice required for sustained benefit (see ‘Further
information’). Acceptance and commitment therapy (ACT) is based
on CBT principles but also uses components of mindfulness
to improve psychological flexibility in the context of living with
chronic pain.
Stimulation therapies
These range from minimally invasive procedures like acupuncture
and transcutaneous electrical nerve stimulation (TENS) to more
invasive techniques such as spinal cord stimulation.
Acupuncture (Fig. 34.6) has been used successfully in Eastern
medicine for centuries. The mechanisms are incompletely
understood, although endorphin release may explain, in part,
Fig. 34.6 Acupuncture.
the analgesic effect. Acupuncture is particularly effective in pain
related to muscle spasm, with some evidence of short-term benefit
for patients with low back pain. Similar mechanisms probably
apply to TENS, which is worth considering in many types of
chronic pain. Neuromodulation, using implanted electrodes in the
epidural space (or, more recently, adjacent to peripheral nerves),
has been shown to be an effective option for neuropathic pain,
including failed back surgery syndrome and chronic regional
pain syndrome (see below). Specialist assessment and ongoing
support is necessary, as there are many potential complications,
including infection, malfunction and battery failure. The likelihood
of success is increased when this technique is used within the
context of multidisciplinary assessment and management.
34
1348 • PAIN AND PALLIATIVE CARE
Ijtomplementary and alternative therapies
Complementary techniques, such as herbal medicines, vitamins,
homeopathy and reflexology, have been used for the treatment of
chronic pain but with little evidence of efficacy. It should be noted
that herbal medications may interact with conventional drugs,
causing adverse effects as the result of drug-drug interactions.
St John’s wort (Hypericum perforatum) interacts with many
drugs, including many antidepressants used in chronic pain, with
increased serotonergic effects. Grapefruit may also increase the
risk of serotonergic effects with some antidepressants. Ginkgo
biloba may interact with paracetamol to increase bleeding time.
Nerve blocks and nerve ablation
The use of specialist nerve blocks and nerve ablation therapy
can be considered for pain that is unresponsive to less invasive
approaches. If these are being considered, they should form part
of a multidisciplinary management plan, with the aim of restoring
function and reducing pain. Local anaesthetic with or without
depot glucocorticoid (non-particulate for neuraxial administration)
can be effective in some circumstances. Examples include
occipital nerve blocks for migraine or cervicogenic headache
and trigger point injections for myofascial pain. If there is limited
compression of a spinal nerve root, the nerve root injections
into the epidural space may help settle symptoms and avoid
the need for surgical intervention. Neurodestructive procedures
can also be employed for intractable pain but are rarely used
outside the palliative care setting.
34.11 Clinical features of neuropathic pain
Characteristic
Symptom or
clinical feature*
Descriptive term
Spontaneous pain
No stimulus required
to evoke pain
Positive sensory
disturbance
Light touch painful
Pressure painful
Increased pain on
pin-prick
Cool and warm
temperatures painful
Dynamic allodynia
Punctate allodynia
Hyperalgesia
Thermal allodynia
Negative sensory
disturbance
Numbness
Tingling
Loss of temperature
sensitivity
Loss of sensation
Paraesthesia
Other features
Feeling of insects
crawling over skin
Affected area feels
abnormal
Formication
Dysaesthesia
*Symptoms may cluster, with a predominance of either positive or negative
symptoms, or a mixture of both, reflecting differences in underlying mechanisms.
Are there clinical features of
neuropathic pain? (Box 34.1 1)
Chronic pain syndromes
Chronic pain is a feature of several recognised syndromes, which
are discussed in more detail below.
Neuropathic pain
Neuropathic pain is defined as ‘pain associated with a lesion
or disease of the somatosensory nervous system’. Neuropathic
pain may be acute, such as in sciatica, which occurs as the
result of a prolapsed disc, but is most problematic when it
becomes chronic. Neuropathic pain causes major morbidity; in
a recent study, 1 7% of those affected rated their quality of life as
‘worse than death’. The clinical features of neuropathic pain are
summarised in Box 34.11. The diagnosis is easily missed and
so careful assessment is vital, in order to make the diagnosis in
the first place and then to direct management appropriately. An
algorithm for the management of neuropathic pain is provided
in Figure 34.7. It is important to recognise the negative impact
of neuropathic pain on quality of life, which has been shown to
be greater than with other types of chronic pain. As a result,
appropriate support and multidisciplinary management should
always be considered in addition to pharmacological therapies.
Yes
Assess likelihood of
neuropathic pain
f
T
Possible | Probable | Definite
First line
(moderate to high
evidence; strong
recommendation)
T
Tricyclic antidepressant
Gabapentin or pregabalin
SNRI
Response? Yes Continue
Second line
(moderate evidence;
weak recommendation)
Capsaicin patch
Lidocaine patch
Tramadol
Response? Yes Continue
| Complex regional pain syndrome
Complex regional pain syndrome (CRPS) is a type of neuropathic
pain that affects one or more limbs. It was previously termed reflex
sympathetic dystrophy (RSD), reflecting the fact the disease is
thought to be caused in part by an abnormality in the autonomic
nervous system. It is a rare syndrome, occurring in about 20 per
100000 individuals, and is more common in females, typically
presenting between the ages of 35 and 50. It is classified into
type I CRPS, which may be precipitated by a traumatic event
Third line
(moderate evidence;
weak recommendation)
Botulinum toxin
Strong opioids
Fig. 34.7 Algorithm for pharmacological management of neuropathic
pain. (SNRI = serotonin noradrenaline (norepinephrine) re-uptake inhibitor)
Adapted from SIGN 136 and NeuPSIG recommendations (Finnerup NB,
Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in
adults: a systematic review and meta-analysis. Reprinted with permission
from Elsevier (The Lancet Neurol 2015; 14:162-173)).
Palliative care • 1349
BS 34.1 2 Criteria for diagnosis of complex regional pain
syndrome (CRPS) type 1
Category
Symptom or sign
Sensory
Allodynia to:
Temperature
Light touch
Deep somatic pressure
Movement
Hyperalgesia to pin-prick
Vasomotor
Temperature asymmetry
Skin colour change and asymmetry
Skin colour asymmetry
Oedema/sudomotor
Oedema
Sweating change or asymmetry
Motor/trophic
Reduced range of motion
Motor dysfunction:
Weakness
Tremor
Dystonia
Trophic changes:
Hair
Nails
Skin
*The diagnosis of CRPS type 1 can be made if a patient has at least one
symptom in at least three out of the four categories and at least one sign in two
out of the four categories, and no other diagnosis can explain the symptoms.
such as a fracture but is not associated with peripheral nerve
damage, and type II CRPS, which is associated with a peripheral
nerve lesion. The diagnosis is primarily clinical, based on the
features shown in Box 34.12. Imaging with MRI or radionuclide
bone scan may provide support for the diagnosis of type I CRPS
in showing bone marrow oedema or increased tracer uptake
localised to an affected site (p. 1055).
Prompt diagnosis and early treatment with physiotherapy
may prevent progression of symptoms. Management is as
for neuropathic pain, additional approaches including graded
motor imagery. Bisphosphonates have been used empirically
for treatment but the evidence base for efficacy in controlling
pain is weak. If medical management is incompletely effective,
consideration should be given to the appropriateness of a spinal
cord stimulator.
Phantom limb pain
Phantom limb is a common complication of amputation, occurring
in up to 70% of patients. It is a form of neuropathic pain but can
be particularly distressing, as the pain is felt in the area where
the absent limb was previously. Although usually presenting after
limb amputation, reports of phantom pain in other body parts
have been reported, such as phantom breast pain following
mastectomy. It is very often associated with phantom sensations,
which are described as non-painful sensations in the absent
body part and pain in the stump.
Diagnostic nerve blocks may be helpful in directing therapy,
with use of anti-neuropathic medications as outlined in Box 34.7.
If there is a definite neuroma at the stump site that is interfering
with prosthesis use, surgical review may be necessary.
Chronic widespread pain
Chronic widespread pain (CWP) is often associated with
other features, such as fatigue and irritable bowel syndrome.
Fibromyalgia is a subtype of CWP in which there are myofascial
trigger points, and is often associated with sleep disturbance.
Clinical features and management of fibromyalgia are discussed
in more detail on page 1 01 8.
| Joint hypermobility syndrome
Hypermobility can be associated with chronic musculoskeletal
pain that often targets the joints and periarticular tissues. It is
thought to be caused by abnormal stresses being placed on
the joints and surrounding soft tissues due to ligament laxity,
although the mechanisms are poorly understood since many
people with hypermobile joints do not suffer pain. It is described
in more detail on page 1059.
Palliative care
Palliative care is the term used to describe the active total care
of patients with incurable disease. It can be distinguished from
end-of-life care, which refers to the care of patients with far
advanced, rapidly progressive disease that will soon prove fatal.
The focus of palliative care is on symptom control alongside
supportive care. While palliative care can and should be delivered
at any stage of an incurable illness alongside optimal disease
control, the focus of end-of-life care is on quality of life rather
than prolongation of life or cure. Palliative care encompasses a
distinct body of knowledge and skills that all good physicians must
possess to allow them to care effectively for patients. Palliative
care is traditionally seen as a means of managing distress and
symptoms in patients with cancer, when metastatic disease
has been diagnosed and death is seen as inevitable. There is,
however, a growing recognition that the principles of palliative
care and some of the interventions it uses are equally applicable
in other conditions. Palliative may therefore be applied to any
chronic disease state.
For conditions other than cancer, the challenge is recognising
when patients have entered the terminal phase of their illness,
as there are fewer clear markers and the course of the illness is
much more variable. Different chronic disease states progress
at different rates, allowing some general trajectories of illness
or dying to be defined (Fig. 34.8). These trajectories are useful
in decision-making for individual patients and also in planning
services.
- Cancer
- Organ failure
Physical and cognitive frailty
Fig. 34.8 Archetypal trajectories of dying. Reproduced from Murray
SA, Kendall M, Boyd K, et al. Illness trajectories and palliative care. BMJ
2005; 330:7498; reproduced with permission from the BMJ Publishing
Group.
34
1350 • PAIN AND PALLIATIVE CARE
The ‘rapid decline’ trajectory following a gradual decline,
as occurs in cancer, is the best-recognised pattern of the
need for palliative care, although a similar trajectory may be
observed in other conditions, such as motor neuron disease
can. Many traditional hospice services are designed to meet
the needs of people on this trajectory. Over recent years,
improvements in management of malignant disease mean that
some types of cancer may follow an erratic or intermittent decline
trajectory.
Many chronic diseases, such as advanced chronic obstructive
pulmonary disease (COPD) and intractable congestive heart
failure, carry as high a burden of symptoms as cancer, as well
as psychological and family distress. The ‘palliative phase’ of
these illnesses may be more difficult to identify because of periods
of relative stability interspersed with acute episodes of severe
illness. However, it is still possible to recognise those patients
who may benefit from a palliative approach to their care. The
challenge is that symptom management needs to be delivered
at the same time as treatment for acute exacerbations. This
leads to difficult decisions as to the balance between symptom
relief and aggressive management of the underlying disease.
The starting point of need for palliative care in these conditions
is the point at which consideration of comfort and individual
values becomes important in decision-making, often alongside
management of the underlying disease.
The third major trajectory is categorised by years of poor
function and frailty before a relatively short terminal period; it is
exemplified by dementia but is also increasingly true for patients
with many different chronic illnesses. As medical advances extend
survival, this mode of dying is being experienced by increasing
numbers of people. The main challenge lies in providing nursing
care and ensuring that plans are agreed for the time when
medical intervention is no longer beneficial.
In a situation where death is inevitable and foreseeable,
palliative care balances the ‘standard textbook’ approach with
the wishes and values of the patient and a realistic assessment
of the benefits of medical interventions. This often results in a
greater focus on comfort, symptom control and support for
patient and family, and may enable withdrawal of both futile and
burdensome interventions. In cases of prognostic uncertainty,
open, honest and gentle communication with the patient and
family is important. The most common symptoms in palliative
care are discussed in the next section.
Presenting problems in palliative care
Pain
Pain is a common problem in palliative care. It has been estimated
that about two-thirds of patients with cancer experience moderate
or severe pain, and a quarter have three or more different sites
of pain. Many of these are of a mixed aetiology and about half
of patients with cancer-associated pain have a neuropathic
element.
Clinical assessment
Careful evaluation to identify the likely mechanisms of pain
is important so that the most appropriate treatment can be
given. Clinical features and suggested management strategies
for common types of pain in cancer are shown in Box
34.13. The majority of patients with cancer-associated pain
can be effectively managed using a stepwise approach, as
outlined below.
34.13 Common types of pain in cancer
Type of pain
Features
Management
options
Bone pain
Tender area over bone
Possible pain on movement
NSAIDs
Bisphosphonates
Radiotherapy
Increased
intracranial
pressure
Headache, worse in the
morning, associated with
vomiting and occasionally
delirium
Glucocorticoids
Radiotherapy
Codeine
Abdominal
colic
Intermittent, severe,
spasmodic, associated with
nausea or vomiting
Antispasmodics
Hyoscine
butylbromide
Liver capsule
pain
Right upper quadrant
abdominal pain, often
associated with tender
enlarged liver
Responds poorly to opioids
Glucocorticoids
Neuropathic
pain
Spontaneous pain
Light touch, pressure and
temperature changes are
painful; increased pain on
pin-prick
Numbness, tingling or loss
of temperature sensation
Skin feels abnormal
Anticonvulsants:
Gabapentin
Pregabalin
Antidepressants
Amitriptyline
Duloxetine
Ketamine
Ischaemic
pain
Diffuse, severe, aching pain
associated with evidence of
poor perfusion
Responds poorly to opioids
NSAIDs
Ketamine
Incident pain
Episodic pain usually related
to movement or bowel
spasm
Intermittent
short-acting opioids
Nerve block
(NSAIDs = non-steroidal anti-inflammatory drugs)
Management: pharmacological treatments
Pharmacological treatments are the mainstay of management
in cancer-associated pain. A stepwise approach is adopted,
following the principles of the World Health Organisation (WHO)
analgesic ladder (Fig. 34.9), in which analgesia that is appropriate
for the degree of pain is prescribed first. Patients with mild
pain should be started on a non-opioid analgesic drug, such
as paracetamol (1 g 4 times daily) or an NSAID (step 1). If the
patient fails to respond adequately or has moderate pain, a
weak opioid, such as codeine (60 mg 4 times daily), should
be added (step 2). This can be prescribed separately or in the
form of the compound analgesic co-codamol. If pain relief is still
not achieved or if the patient has severe pain, a strong opioid
should be substituted for the weak opioid (step 3). If the pain is
severe at the outset, strong opioids should be prescribed and
increased or titrated according to the patient’s response. It is
important not to move ‘sideways’ (change from one drug to
another of equal potency), which is a common problem during
step 2 of the analgesic ladder.
Opioids
Opioid analgesia plays a key role in patients with moderate
to severe pain. Its successful use depends on appropriate
assessment and a detailed explanation to the patient and carer
about the benefits and potential side-effects of therapy. Morphine
Palliative care • 1351
Fig. 34.9 The WHO analgesic ladder. From WHO. Cancer pain relief,
2nd edn. Geneva: WHO; 1996.
is the most commonly prescribed strong opioid, although there
are several alternatives, as outlined in Box 34.9.
Oral morphine takes about 20 minutes to exert an effect
and usually provides pain relief for 4 hours. Most patients with
continuous pain should be prescribed oral morphine every
4 hours initially, as this will provide continuous pain relief over
the whole 24-hour period. Controlled-release morphine lasts
for 12 or 24 hours, depending on the formulation, and if clinical
circumstances dictate, a controlled-release formulation can
be used to initiate and titrate morphine. The median effective
morphine equivalent dose for cancer pain is about 200 mg per
24 hours.
In addition to the regular dose of morphine, an extra dose
of immediate-release (IR) morphine should be prescribed ‘as
required’ for the treatment of breakthrough pain that has not
been controlled by the regular prescription. As a rule of thumb,
this additional dose should be one-sixth of the total 24-hour
dose of opioid. The frequency of breakthrough doses should
be dictated by their efficacy and any side-effects, rather than
by a fixed time interval. A patient may require breakthrough
analgesia as frequently as hourly if pain is severe, but this should
lead to early review of the regular prescription. The patient or
carer should note the timing of any breakthrough doses and the
reason for them. These should be reviewed daily and the regular
4-hourly dose increased for the next 24 hours on the basis of:
• the frequency of and reasons for breakthrough analgesia
• the degree and acceptability of side-effects.
The regular dose should be increased by adding the total
of the breakthrough doses over the previous 24 hours, unless
there are significant problems with unacceptable side-effects.
When the correct dose has been established, a continuous
release (CR) preparation can be prescribed, usually twice daily.
Breakthrough analgesia used for movement-related pain is
generally not included in background opioid dose titration.
Attempts to control movement-related pain with background
opioid dose will usually lead to over-medication and opioid-related
side-effects. This can be a risk in metastatic bone pain.
Some patients may have concerns about using opioids and
it is vital for these to be explored. Patients should be reassured
34.14 Opioid side-effects
Side-effect
Management
Constipation
Regular laxative
Opioid/naloxone oral combination, in resistant
constipation
Dry mouth
Frequent sips of iced water, soft white paraffin
to lips, chlorhexidine mouthwashes twice daily,
sugar-free gum, water or saliva sprays
Nausea/vomiting
Oral haloperidol 0.5-1 mg at night, oral
metoclopramide 10 mg 3 times daily or oral
domperidone 10 mg 3 times daily
If constant, haloperidol or levomepromazine may
be given parenterally to break the nausea cycle
Sedation
Explanation is very important
Symptoms usually settle in a few days
Avoid other sedating medication where possible
Ensure appropriate use of adjuvant analgesics
that can have an opioid-sparing effect
May require an alternative opioid
that psychological dependence is rare when opioids are used for
cancer pain, unless a pre-existing dependence problem exists.
Pharmacological tolerance is not usually a clinically relevant
problem; however, physical dependence, which is physiological,
as manifest by a physical withdrawal syndrome, can occur if
opioids are suddenly discontinued.
Nearly all types of cancer pain respond to morphine to some
degree but there is a spectrum of response, such that in some
patients the dose of opioid required to control neuropathic
pain and all elements of metastatic bone pain may be high and
associated with unacceptable side-effects. In these situations,
other methods of analgesia, both pharmacological and non-
pharmacological, should be explored and considered at an
early stage.
The most effective and appropriate route of morphine
administration is oral but transdermal preparations of strong
opioids (usually fentanyl) are useful in certain situations, such
as in patients with dysphagia or those who are reluctant to take
tablets on a regular basis. Diamorphine is a highly soluble strong
opioid used for subcutaneous infusions, particularly in the last
few days of life, but is only available in certain countries.
Opioid-related adverse effects
Adverse effects are a common problem with opioids, especially
on initiating treatment and on increasing the dose. The most
common side-effects are nausea, drowsiness, constipation and
dry mouth, as summarised in Box 34.14. Nausea and vomiting
can occur initially but usually settle after a few days. Drowsiness
is usually transient at opioid initiation and dose increase. If it is
persistent, an alternative opioid and/or a non-opioid should be
considered. In acute dosing, respiratory depression can occur
but this is rare in patients on regular opioids or in those starting
on small, regular doses with appropriate titration.
Tolerance usually develops to nausea, vomiting and drowsiness
but not to constipation or dry mouth. All patients should therefore
be prescribed a laxative, unless suffering from diarrhoea, and
have access to an antiemetic and good mouth care, along
with rationalisation of any concomitant medication that might
exacerbate drowsiness. Newer developments include the use
I of preparations in which opioids are combined with opioid
34
1352 • PAIN AND PALLIATIVE CARE
antagonists, such as naloxone. The naloxone is poorly absorbed
and does not antagonise the systemic analgesic effect but rather
acts locally to block opioid receptors in the gut, thereby reducing
opioid-related constipation. Vivid dreams, visual hallucinations
(often consisting of a sense of movement at the periphery of
vision), delirium and myoclonus are typical of opioid-related
toxicity and, if present, require urgent reassessment of the
opioid dose. Biochemistry should also be checked to exclude
renal impairment, dehydration, electrolyte disturbance or
hypercalcaemia.
Since opioid toxicity can occur at any dose, side-effects should
be assessed regularly, but particularly after a dose increase.
Pain should be reassessed to ensure that appropriate adjuvants
are being used. Parenteral rehydration is often helpful to speed
up excretion of active metabolites of morphine. The dose of
opioid may need to be reduced or the opioid changed to a
strong alternative.
Different opioids have different side-effect profiles in
different people. If a patient develops side-effects, switching
to an alternative strong opioid may be helpful. Options include
oxycodone, transdermal fentanyl, alfentanil, hydromorphone
and occasionally methadone, any of which may produce a
better balance of benefit against side-effects. Fentanyl and
alfentanil have no renally excreted active metabolites and may
be particularly useful in patients with renal failure. It is possible to
switch between opioids but great care must be taken when doing
so to make sure the dose is correct and to avoid prescribing
too much or too little opioid.
Adjuvant analgesics
An adjuvant analgesic is a drug that has a primary indication other
than pain but which provides analgesia in some painful conditions
and may enhance the effect of the primary analgesic. Commonly
used adjuvant analgesics in the palliative care setting are shown
in Box 34.15. Some adjuvant analgesics may enhance the
side-effect profile of the primary analgesic, and dose reductions
of opioids may be required when an adjuvant analgesic is
added. At each step of the WHO analgesic ladder, an adjuvant
analgesic should be considered, the choice depending on the
type of pain.
Management: non-pharmacological treatments
Neurodestructive interventions
Neurodestructive techniques have an important role in the
management of cancer pain, where life expectancy is limited.
They should be used as part of an overall management plan
and considered when the response to drug treatment has been
inadequate. Intrathecal analgesia, delivered via either an external
pump or a fully implanted device, is a good option, particularly
where life expectancy is more than 3 months. Coeliac plexus
blocks can be helpful for visceral pain, such as in pancreatic
cancer. Lateral cordotomy to disrupt the spinothalamic tracts
(either open or percutaneous) may be considered for unilateral
chest wall pain, such as may occur in mesothelioma, where life
expectancy is limited.
Radiotherapy
Radiotherapy is the treatment of choice for pain from bone
metastases (see Box 34.13) and can also be considered for
metastatic involvement at other sites. All patients with pain
secondary to bone metastases should be considered for palliative
radiotherapy, which can usually be given in a single dose.
Physiotherapy
Physiotherapy has a key role in the multidisciplinary approach
to a wide spectrum of cancer-related symptoms, including the
prevention and management of pain, muscle spasm, reduced
mobility, muscle wasting and lymphoedema. Rehabilitation in
palliative care has expanded and now includes pre-habilitation,
which involves the use of proactive focused exercise to maintain
muscle mass during cancer chemotherapy and in other chronic
conditions such as COPD.
Psychological techniques
As with chronic pain, there is increasing use of psychological
techniques in cancer pain management, which train the patient
34.15 Adjuvant analgesics in cancer pain
Drug
Example
Indications
Side-effects
NSAIDs
Diclofenac
Bone metastases, soft tissue infiltration,
liver pain, inflammatory pain
Gastric irritation and bleeding, fluid retention,
headache
Caution in renal impairment
Glucocorticoids
Dexamethasone 8-1 6 mg per
day, titrated to lowest dose
that controls pain
Raised intracranial pressure, nerve
compression, soft tissue infiltration,
liver pain
Gastric irritation if used together with NSAID, fluid
retention, proximal muscle myopathy, delirium,
Cushingoid appearance, candidiasis, hyperglycaemia
Anticonvulsants
Evidence strongest for:
Gabapentin
Pregabalin
Duloxetine
Neuropathic pain of any aetiology
Mild sedation, tremor, delirium
Exacerbation of opioid-related side-effects
Tricyclic
antidepressants
Amitriptyline
Neuropathic pain of any aetiology
Sedation, dizziness, delirium, dry mouth,
constipation, urinary retention
Avoid in cardiac disease
Exacerbation of opioid-related side-effects
NMDA receptor
blockers
Ketamine
Severe neuropathic pain (only under
specialist supervision)
Delirium, anxiety, agitation, hypertension
*ln old age, all drugs can cause delirium.
(NMDA = /V-methyl-D-aspartate; NSAIDs = non-steroidal anti-inflammatory drugs)
Palliative care • 1353
to use coping strategies and behavioural techniques. Other
issues related to the specific experience of a cancer diagnosis
and cancer treatment may be complex, and individual therapy
in addition to group-based approaches can be helpful.
Stimulation therapies
Acupuncture and TENS are low-risk stimulation therapies that may
be useful in palliative care for management of pain and nausea.
Complementary and alternative therapies
Palliative care patients often seek symptom relief from both
complementary and alternative therapies. While the evidence
base is poorly developed, individual patients can gain significant
benefits from the complementary therapies outlined on page
1348. It is critically important that patients are encouraged to
discuss any alternative medicines they are considering, given
the potential interactions with other therapies.
Breathlessness
Breathlessness is one of the most common symptoms in palliative
care and is distressing for both patients and carers. Patients with
breathlessness should be fully assessed to determine whether
there is a reversible cause, such as a pleural effusion, heart failure
or bronchospasm; if so, this should be managed in the normal
way. If symptoms persist, additional measures may be necessary.
There are many potential causes of dyspnoea in cancer patients
and in other chronic diseases; apart from direct involvement of
the lungs, muscle loss secondary to cachexia, anxiety and fear
can all contribute. A cycle of panic and breathlessness, often
associated with fear of dying, can be dominant. Exploration of
precipitating factors is important and patient education about
breathlessness and effective breathing has been shown to
be effective. Non-pharmacological approaches that include
using a hand-held fan, pacing, and following a tailored exercise
programme can help. There is no evidence to suggest that oxygen
therapy reduces the sensation of breathlessness in advanced
cancer any better than cool airflow, and oxygen is indicated
only if there is significant hypoxia. Opioids, through both their
central and their peripheral action, can palliate breathlessness.
Both oral and parenteral opioids are effective. A low dose should
be used initially and titrated against symptoms, unless opioids
are already being prescribed for pain, in which case the existing
dose can be increased further. If anxiety is considered to be
playing a significant role, a quick-acting benzodiazepine, such
as lorazepam (used sublingually for rapid absorption), may also
be useful.
Cough
Persistent unproductive cough can be helped by opioids, which
have an antitussive effect. Troublesome respiratory secretions
can be treated with hyoscine hydrobromide (400-600 pig every
4-8 hours), although dry mouth is a common adverse effect.
As an alternative, glycopyrronium can be useful and is given by
subcutaneous infusion (0.6-1 .2 mg in 24 hours).
Nausea and vomiting
The presentation of nausea and vomiting differs depending
on the underlying cause, of which there are many (p. 780).
Large-volume vomiting with little nausea is common in intestinal
obstruction, whereas constant nausea with little or no vomiting
is often due to metabolic abnormalities or adverse effects of
Fig. 34.10 Mechanisms of nausea. (ACh = acetylcholine; D2 =
dopamine; 5-HT = 5-hydroxytryptamine, serotonin; Hi = histamine)
34.16 Receptor site activity of antiemetic drugs
Area
Receptors
Drugs
Chemotactic trigger zone
Dopamine2
5-HT
Haloperidol
Metoclopramide
Vomiting centre
Histamine!
Acetylcholine
Cyclizine
Levomepromazine
Hyoscine
Gut (gastric stasis)
Metoclopramide
Gut distension (vagal
stimulation)
Histamine!
Cyclizine
Gut (chemoreceptors)
5-HT
Levomepromazine
(5-HT = 5-hydroxytryptamine, serotonin)
drugs. Vomiting related to raised intracranial pressure is worse
in the morning. Different receptors are activated, depending on
the cause or causes of the nausea (Fig. 34.10). For example,
dopamine receptors in the chemotactic trigger zone in the fourth
ventricle are stimulated by metabolic and drug causes of nausea,
whereas gastric irritation stimulates histamine receptors in the
vomiting centre via the vagus nerve. Reversible causes, such as
hypercalcaemia and constipation, should be treated appropriately.
Drug-induced causes should be considered and the offending
drugs stopped if possible. As different classes of antiemetic
drug act at different receptors, antiemetic therapy should be
based on a careful assessment of the probable causes and a
rational decision to use a particular class of drug (Box 34.16).
34
1354 • PAIN AND PALLIATIVE CARE
The subcutaneous route is often required initially to overcome
gastric stasis and poor absorption of oral medicines.
Gastrointestinal obstruction
Gastrointestinal obstruction is a frequent complication of
intra-abdominal cancer. Patients may have multiple levels of
obstruction and symptoms may vary greatly in nature and severity.
Surgical mortality is high in patients with advanced disease
and obstruction should normally be managed without surgery.
The key to effective management is to address the presenting
symptoms - colic, abdominal pain, nausea, vomiting, intestinal
secretions - individually or in combination, using parenteral
drugs that do not cause or worsen other symptoms. This can
be problematic when a specific treatment worsens another
symptom. Cyclizine improves nausea and colic responds well
to anticholinergic agents, such as hyoscine butylbromide, but
both slow gut motility. Nausea will improve with metoclopramide,
although this is usually contraindicated in the presence of colic
because of its prokinetic effect. There is some low-level evidence
that glucocorticoids (dexamethasone 8 mg) can shorten the
length of obstructive episodes. Somatostatin analogues, such
as octreotide, will reduce intestinal secretions and therefore
large-volume vomits. Occasionally, a nasogastric tube is required
to reduce gaseous or fluid distension.
Weight loss
Patients with cancer lose weight for a variety of reasons,
including reduced appetite or the effects of drug treatment, or
as a consequence of low mood and anxiety. There is, however,
a particularly challenging syndrome associated with weight
loss, which is known as cancer cachexia. This results from an
alteration of metabolism caused by a complex interaction of
tumour-related factors and the body’s response to these factors,
resulting in muscle loss, along with anorexia. Treatment involves
prescribing exercise to maintain muscle mass and strengthen
muscles, ensuring that there is an adequate calorie intake and
providing nutritional supplements. Anti-inflammatory medication
to attenuate systemic inflammation is the subject of research and
many patients self-medicate with fish oil. Glucocorticoids can
temporarily boost appetite and general well-being but may cause
false weight gain by promoting fluid retention. Their benefits need
to be weighed against the risk of side-effects, and glucocorticoids
should generally be used on a short-term basis only.
| Anxiety and depression
Anxiety and depression are common in palliative care but the
diagnosis may be difficult, since the physical symptoms of
depression are similar to those of advanced cancer. It is therefore
important to realise that these symptoms are not inevitable in
advanced cancer. Patients should still expect to look forward to
things and to enjoy them, within the context of the situation. Simply
asking the question ‘Do you think you are depressed?’ can be
very useful in deciding with the patient whether antidepressants
or psychological interventions may be of benefit (p. 1199). In this
regard, psycho-oncology has been evolving rapidly and there
is now good evidence for the role of ‘talk therapy’ in palliative
care, along with other appropriate management of anxiety and
depression. If antidepressants are required, citalopram and
mirtazapine are good choices since they are generally well
tolerated in patients with advanced disease.
Delirium and agitation
Many patients become confused or agitated in the last days of
life. It is important to identify and treat potentially reversible causes
(p. 183), unless the patient is too close to death for this to be
feasible. Early diagnosis and effective management of delirium
are extremely important. As in other palliative situations, it may
not be possible to identify and treat the underlying cause, and
the focus of management should be to ensure that the patient
is comfortable. It is important to distinguish between behavioural
change due to pain and that due to delirium, as opioids will
improve one and worsen the other. The management of delirium
is detailed on page 209. It is important, even in the care of
the actively dying patient, to treat delirium with antipsychotic
medicines, such as haloperidol, rather than to regard it as
distress or anxiety and use benzodiazepines only.
Dehydration
Deciding whether to give intravenous fluids can be difficult when
a patient is very unwell and the prognosis is uncertain. A patient
with a major stroke, who is unable to swallow but is expected
to survive the event, will develop renal impairment and thirst if
not given fluids and should be hydrated. On the other hand,
when a patient has been deteriorating and is clearly dying,
parenteral hydration needs very careful consideration and it is
very important to manage this on an individual basis. Comfort
and avoidance of distress in the family are the primary aims.
Where a patient and family are happy with meticulous oral hygiene
and care to reduce the sensation of dryness in the mouth, this
is usually more appropriate and effective at the end of life than
parenteral hydration, which by itself will not necessarily improve
the sensation of dryness. In some patients, parenteral hydration
will simply exacerbate pooling of secretions, causing noisy and
distressing breathing. Each decision should be individual and
discussed with the patient’s family.
Death and dying
| Planning for dying
There have been dramatic improvements in the medical treatment
and care of patients with cancer and other illnesses over recent
years but the inescapable fact remains that everyone will die at
some time. Planning for death should be actively considered in
patients with chronic diseases when the death is considered to
be foreseeable or inevitable. Doctors rarely know exactly when
a patient will die but are usually aware that an individual is about
to die and that medical interventions are unlikely to extend life or
improve its quality significantly. Most people wish their doctors
to be honest about this situation to allow them time to think
ahead, make plans and address practical issues. A few do not
wish to discuss future deterioration or death; if this is felt to be
the case, avoidance of discussion should be respected. For
doctors, it is helpful to understand an individual’s wishes and
values about medical interventions at this time, as this can help
guide decisions about interventions. It is important to distinguish
between interventions that will not provide clinical benefit (a
medical decision) and those that do not confer sufficient benefit to
be worthwhile (a decision that can only be reached with a patient’s
involvement and consent). A common example of this would be
decisions about not attempting cardiopulmonary resuscitation.
Death and dying • 1355
In general, people wish for a dignified and peaceful death
and most prefer to die at home. Families also are grateful for
the chance to prepare themselves for the death of a relative,
by timely and gentle discussion with the doctor or other health
professionals. Early discussion and effective planning improve
the chances that an individual’s wishes will be achieved. There
are two important caveats: firstly, wishes can and do change as
the terminal situation evolves, and secondly, planning in general
can only be done over time as patients form a relationship with
professionals and evolve an understanding of the situation in
which they find themselves.
Structures for assessment and planning around end-of-life
care are for guidance only and the focus should evolve with
the individual patient.
|j)iagnosing dying
When patients with cancer or other conditions become bed-
bound, semi-comatose, unable to take tablets and only able to
take sips of water, with no reversible cause, they are likely to
be dying and many will have died within 2 days. Doctors are
sometimes poor at recognising this and should be alert to the
views of other members of the multidisciplinary team. A clear
decision that the patient is dying should be agreed and recorded.
| Management of dying
Once the conclusion has been reached that a patient is going
to die in days to a few weeks, there is a significant shift in
management (Box 34.1 7). Symptom control, relief of distress and
care for the family become the most important elements of care.
Medication and investigation are justifiable only if they contribute
to these ends. When patients can no longer drink because
they are dying, intravenous fluids are usually not necessary
and may cause worsening of bronchial secretions; however,
this is a decision that can be made only on an individual basis.
Management should not be changed without discussion with the
patient and/or family. Medicines should always be prescribed for
the relief of symptoms. For example, morphine or diamorphine
may be used to control pain, levomepromazine to control nausea,
haloperidol to treat delirium, diazepam or midazolam to treat
distress, and hyoscine hydrobromide to reduce respiratory
secretions. Side-effects, such as drowsiness, may be acceptable
if the principal aim of relieving distress is achieved. It is important
to discuss and agree the aims of care with the patient’s family.
Poor communication with families at this time is one of the most
common reasons for family distress afterwards and for formal
complaints.
Ethical considerations
The overwhelming force in caring for any patient must be to
listen to that patient and family and take their wishes on board.
Patients know when health-care professionals are just receiving
the information, as opposed to receiving and understanding the
information in the context of the patient, their illness and needs,
their carers and the socioeconomic context. It is impossible to
provide holistic care for a patient without this comprehension.
Every patient is unique and it is important to avoid slipping into
a tick-box mentality in addressing items that should be covered
in patients with advanced, incurable disease. While the key to
successful palliative care is effective interdisciplinary working,
every patient needs to know who has overall responsibility
34.17 How to manage a patient who is dying
Patient and family awareness
• Assess patient’s and family’s awareness of the situation
• Ensure family understands plan of care
Medical interventions
• Stop non-essential medications that do not contribute to symptom
control
• Stop inappropriate investigations and interventions, including routine
observations
Resuscitation
• Complete Do Not Attempt Cardiopulmonary Resuscitation (DNACPR)
form
• Deactivate implantable defibrillator
Symptom control
• Ensure availability of parenteral medication for symptom relief
Support for family
• Make sure you have contact details for family, that you know when
they want to be contacted and that they are aware of facilities
available to them
Religious and spiritual needs
• Make sure any particular wishes are identified and followed
Ongoing assessment
• Family’s awareness of condition
• Management of symptoms
• Need for parenteral hydration
Care after death
• Make sure family know what they have to do
• Notify other appropriate health professionals
for their care. Trust in the whole team will come through a
solid lead working with a team who are appropriately informed
and in sympathy with the patient’s situation, each having
a clear role.
Families and other carers are often unprepared for the challenge
of caring for a dying person. It can be an exhausting experience,
both emotionally and physically, and without a critical number of
carers battle fatigue can ensue, resulting in urgent admissions.
With much discussion about advance directives, we should not
lose sight of the reality of changing circumstances and wishes.
Good anticipatory care means not just providing for new physical
symptoms, but also planning for any time when care at home
becomes no longer possible.
Capacity and advance directives
The wishes of the patient are paramount in Western societies,
whereas in other cultures the views of the family are equally
important. If a patient is unable to express their view because
of communication or cognitive impairment, that person is said
to lack ‘capacity’. In order to decide what the patient would
have wished, as much information as possible should be
gained about any previously expressed wishes, along with the
views of relatives and other health professionals. An advance
directive is a previously recorded, written document of a patient’s
wishes (p. 1307). It should carry the same weight in decision¬
making as a patient’s expressed wishes at that time, but may
34
1356 • PAIN AND PALLIATIVE CARE
not be sufficiently specific to be used in a particular clinical
situation. The legal framework for decision-making varies in
different countries.
Euthanasia
In the UK and Europe, between 3% and 6% of dying patients
will ask a doctor to end their life. Many of these requests are
transient; some are associated with poor control of physical
symptoms or a depressive illness. All expressions of a wish to
die are an opportunity to help the patient discuss and address
unresolved issues and problems. Reversible causes, such as
pain or depression, should be treated. Sometimes, patients
may choose to discontinue life-prolonging treatments, such
as diuretics or anticoagulation, following discussion and the
provision of adequate alternative symptom control. However,
there remain a small number of patients who have a sustained,
competent wish to end their lives, despite good control of physical
symptoms. Euthanasia is now permitted or legal under certain
circumstances in some countries but remains illegal in many
others; public, ethical and legal debate over this issue is likely to
continue and is often influenced by many complex non-palliative
care issues. The European Association for Palliative Care does
not see euthanasia or physician-assisted suicide as part of the
role of palliative care physicians.
Further information
Websites
breathworks-mindfulness.org.uk An online resource to support learning
the use of mindfulness to deal with pain, illness or stress.
cuh.org.uk/breathlessness Information and resources from Cambridge
University Hospital on managing breathlessness.
hospiceuk.org A resource from UK hospices.
mdanderson.org Brief Pain Inventory (Short Form) questionnaire.
nhmrc.gov.au Australia and New Zealand College of Anaesthetists and
Faculty of Pain Medicine. Acute pain management: scientific
evidence, 3rd edn; 2010.
npcrc.org Short-form McGill Pain questionnaire.
paintoolkit.org Pain toolkit self-help resource for managing pain.
palliativecareguidelines.scot.nhs.uk Regularly reviewed, evidence-based
clinical guidelines.
palliativedrugs.com Practical information about drugs used in palliative
care.
sign.ac.uk SIGN guideline 136 - Management of chronic pain.
Journal articles
Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for
neuropathic pain in adults: a systematic review and meta-analysis.
Lancet Neurol 2015; 14:162-173. A comprehensive, high-quality
review of the current evidence for the pharmacological management
of neuropathic pain.
Laboratory reference ranges
Notes on the international system of units (SI units) 1358
Laboratory reference ranges in adults 1358
Urea and electrolytes in venous blood 1 358
Analytes in arterial blood 1 358
Hormones in venous blood 1 359
Other common analytes in venous blood 1 360
Common analytes in urine 1361
Analytes in cerebrospinal fluid 1 361
Analytes in faeces 1 361
Haematological values 1 362
Laboratory reference ranges in childhood and adolescence 1363
Laboratory reference ranges in pregnancy 1364
1358 • LABORATORY REFERENCE RANGES
Notes on the international system of
units (SI units)
Systeme International (SI) units are a specific subset of the
metre-kilogram-second system of units and were agreed on
as the everyday currency for commercial and scientific work in
1960, following a series of international conferences organised
by the International Bureau of Weights and Measures. SI units
have been adopted widely in clinical laboratories but non-SI
units are still used in many countries. For that reason, values
in both units are given for common measurements throughout
this textbook and commonly used non-SI units are shown in
this chapter. The SI unit system is, however, recommended.
Examples of basic SI units
Length metre (m)
Mass kilogram (kg)
Amount of substance mole (mol)
Energy joule (J)
Pressure pascal (Pa)
Volume The basic SI unit of volume is the
cubic metre (1000 litres). For
convenience, however, the litre (L) is
used as the unit of volume in
laboratory work.
Examples of decimal multiples and submultiples
of SI units
Factor Name Prefix
106 mega- M
103 kilo- k
10_1 deci- d
10-2 centi- c
10-3 milli- m
10“6 micro- ji
1 0-9 nano- n
10-12 pico- p
10“15 femto- f
Exceptions to the use of SI units
By convention, blood pressure is excluded from the SI unit
system and is measured in mmHg (millimetres of mercury)
rather than pascals.
Mass concentrations such as g/L and jig/L are used in
preference to molar concentrations for all protein measurements
and for substances that do not have a sufficiently well-defined
composition.
Some enzymes and hormones are measured by ‘bioassay’,
in which the activity in the sample is compared with the activity
(rather than the mass) of a standard sample that is provided
from a central source. For these assays, results are given in
standardised ‘units’ (U/L), or ‘international units’ (IU/L), which
depend on the activity in the standard sample and may not be
readily converted to mass units.
Laboratory reference ranges in adults
Reference ranges are largely those used in the Departments
of Clinical Biochemistry and Haematology, Lothian Health
University Hospitals Division, Edinburgh, UK. Values are shown
in both SI units and, where appropriate, non-SI units. Many
reference ranges vary between laboratories, depending on
the assay method used and on other factors; this is especially
the case for enzyme assays. The origin of reference ranges
and the interpretation of ‘abnormal’ results are discussed on
page 3. No details are given here of the collection requirements,
which may be critical to obtaining a meaningful result. Unless
otherwise stated, reference ranges shown apply to adults; values
in children may be different.
Many analytes can be measured in either serum (the supernatant
of clotted blood) or plasma (the supernatant of anticoagulated
blood). A specific requirement for one or the other may depend
on a kit manufacturer’s recommendations. In other instances, the
distinction is critical. An example is fibrinogen, where plasma is
required, since fibrinogen is largely absent from serum. In contrast,
serum is required for electrophoresis to detect paraproteins because
fibrinogen migrates as a discrete band in the zone of interest.
Urea and electrolytes in venous blood
Reference range
Analysis
SI units
Non-SI units
Sodium
135-145 mmol/L
135-145 mEq/L
Potassium*
3.6-5. 0 mmol/L
3. 6-5.0 mEq/L
Chloride
95-107 mmol/L
95-107 mEq/L
Urea
2. 5-6. 6 mmol/L
15-40 mg/dL
Creatinine
Male
Female
64-111 pimol/L
50-98 pimol/L
0.72-1.26 mg/dL
0.57-1.11 mg/dL
*Serum values are, on average, 0.3 mmol/L higher than plasma values.
35.2 Analytes in arterial blood
Reference range
Analysis
SI units
Non-SI units
Bicarbonate
21-29 mmol/L
21-29 mEq/L
Hydrogen ion
37-45 nmol/L
pH 7.35-7.43
PaC02
4. 5-6.0 kPa
34-45 mmHg
Pa02
12-1 5 kPa
90-113 mmHg
Oxygen saturation
>97%
Laboratory reference ranges in adults • 1359
35.3 Hormones in venous blood
Reference range
Hormone
SI units
Non-SI units
Adrenocorticotropic hormone
(ACTH) (plasma)
1.5-13.9 pmol/L (0700-1000 hrs)
63 ng/L
Aldosterone
Supine (at least 30 mins)
30-440 pmol/L
1.09-15.9 ng/dL
Erect (at least 1 hr)
110-860 pmol/L
3.97-31.0 ng/dL
Cortisol
Dynamic tests are required - see Box 18.53, p. 680
Follicle-stimulating hormone (FSH)
Male
1.0-10.0 IU/L
Female
3.0-10.0 IU/L (early follicular)
-
>30 IU/L (post-menopausal)
-
Gastrin (plasma, fasting)
<40 pmol/L
<83 pg/mL
Growth hormone (GH)
Dynamic tests are usually required - see Box 18.55, p. 682
<0.5 jig/L excludes acromegaly (if insulin-like growth factor 1
<2 mlU/L
(IGF-1) in reference range)
>6 pig/L excludes GH deficiency
>18 mlU/L
Insulin
Highly variable and interpretable only in relation to plasma glucose and body habitus
Luteinising hormone (LH)
Male
1 .0-9.0 IU/L
Female
2. 0-9.0 IU/L (early follicular)
-
>20 IU/L (post-menopausal)
-
17(3-Oestradiol
Male
<160 pmol/L
<43 pg/mL
Female: early follicular
75-140 pmol/L
20-38 pg/mL
post-menopausal
<150 pmol/L
<41 pg/mL
Parathyroid hormone (PTH)
1 .6-6.9 pmol/L
1 6-69 pg/mL
Progesterone (in luteal phase in
women)
Consistent with ovulation
>30 nmol/L
>9.3 ng/mL
Probable ovulatory cycle
15-30 nmol/L
4. 7-9. 3 ng/mL
Anovulatory cycle
<10 nmol/L
<3 ng/mL
Prolactin (PRL)
60-500 mlU/L
2.8-23.5 ng/mL
Renin concentration
Supine (at least 30 mins)
5-40 mlU/L
Sitting (at least 15 mins)
5-45 mlU/L
-
Erect (at least 1 hr)
16-63 mlU/L
-
Testosterone
Male
1 0-38 nmol/L
290-1090 ng/dL
Female
0.3-1 .9 nmol/L
10-90 ng/dL
Thyroid-stimulating hormone (TSH)
0.2-4. 5 mlU/L
-
Thyroxine (free), (free T4)
9-21 pmol/L
0.7-1.63 ng/dL
Triiodothyronine (free), (free T3)
2. 6-6. 2 pmol/L
0.16-0.4 ng/dL
Notes
1 . A number of hormones are unstable and collection details are critical to obtaining a meaningful result. Refer to local laboratory handbook.
2. Values in the table are only a guideline; hormone levels can often be meaningfully understood only in relation to factors such as gender, age, time
of day, pubertal status, stage of the menstrual cycle, pregnancy and menopausal status.
3. Reference ranges are usually dependent on the method used for analysis and frequently differ between laboratories. Non-SI units also differ; those
shown here are amongst those most widely used. Readers are encouraged to consult their local laboratory for non-SI units for individual analytes
and their respective reference ranges.
35
1360 • LABORATORY REFERENCE RANGES
35.4 Other common analytes in venous blood
Reference range
Analyte
SI units
Non-SI units
(Xi -antitrypsin
1. 1-2.1 g/L
110-210 mg/dL
Alanine
aminotransferase
(ALT)
10-50 U/L
Albumin
35-50 g/L
3. 5-5.0 g/dL
Alkaline
phosphatase (ALP)
40-125 U/L
-
Amylase
<100 U/L
-
Aspartate
aminotransferase
(AST)
10-45 U/L
Bile acids (fasting)
<14 jxmol/L
-
Bilirubin (total)
3-1 6 jimol/L
0.18-0.94 mg/dL
Calcium (total)
2. 1-2. 6 mmol/L
4. 2-5. 2 mEq/L
or 8.5-10.5 mg/dL
Carboxyhaemoglobin
0.1 -3.0%
Levels of up to 8% may
be found in heavy
smokers
Caeruloplasmin
0.16-0.47 g/L
16-47 mg/dL
Cholesterol (total)
Ideal level varies according to cardiovascular risk
(see cardiovascular risk chart, p. 511)
HDL-cholesterol
Ideal level varies according to cardiovascular
risk, so reference ranges can be misleading.
According to the National Cholesterol Education
Programme Adult Treatment Panel III (ATPIII),
a low HDL-cholesterol is <1.0 mmol/L
(<40 mg/dL)
Complement
C3
0.81-1.57 g/L
C4
0.13-1.39 g/L
-
Total haemolytic
complement
0.086-0.410 g/L
—
Copper
10-22 jimol/L
64-140 (Lig/dL
C-reactive protein
<5 mg/L
(CRP)
Highly sensitive CRP assays also exist that
measure lower values and may be useful in
estimating cardiovascular risk
Creatine kinase (CK; total)
Male
55-170 U/L
-
Female
30-135 U/L
-
Creatine kinase MB
isoenzyme
<6% of total CK
-
Ethanol
Not normally detectable
Marked intoxication
65-87 mmol/L
300-400 mg/dL
Stupor
87-109 mmol/L
400-500 mg/dL
Coma
>109 mmol/L
>500 mg/dL
Reference range
Analyte
SI units
Non-SI units
y-glutamyl
Male 10-55 U/L
-
transferase (GGT)
Female 5-35 U/L
Glucose (fasting)
3. 6-5. 8 mmol/L
65-104 mg/dL
See page 722 for definitions of impaired glucose
tolerance and diabetes mellitus, and page 738
for definition of hypoglycaemia
Glycated
4. 0-6.0%
-
haemoglobin
20-42 mmol/mol Fib
(HbA1c)
See page 722 for diagnosis of diabetes mellitus
Immunoglobulins (Ig)
IgA
0.8-4. 5 g/L
igE
0-250 kU/L
-
igG
6.0-15.0 g/L
-
igM
0.35-2.90 g/L
-
Lactate
0.6-2. 4 mmol/L
5.4-21.6 mg/dL
Lactate
dehydrogenase
(LDH; total)
125-220 U/L
Lead
<0.5 |imol/L
< 1 0 jig/dL
Magnesium
0.75-1.0 mmol/L
1 .5-2.0 mEq/L
or 1 .82-2.43 mg/dL
Osmolality
280-296 mOsmol/kg
-
Osmolarity
280-296 mOsmol/L
-
Phosphate (fasting)
0.8-1 .4 mmol/L
2.48-4.34 mg/dL
Protein (total)
60-80 g/L
6-8 g/dL
Triglycerides
(fasting)
0.6-1 .7 mmol/L
53-150 mg/dL
Troponins
Values consistent with myocardial infarction are
crucially dependent on which troponin is
measured (1 or T) and on the method employed.
Interpret in context of clinical presentation. See
page 450
Tryptase
0-135 mg/L
-
Urate
Male
0.12-0.42 mmol/L
2. 0-7.0 mg/dL
Female
0.12-0.36 mmol/L
2. 0-6.0 mg/dL
Vitamin D (25(0H)D)
Normal
>50 nmol/L
>20 ng/mL
Insufficiency
25-50 nmol/L
10-20 ng/ml
Deficiency
<25 nmol/L
<10 ng/mL
Zinc
10-18 jimol/L
65-118 jug/dL
Laboratory reference ranges in adults • 1361
35.5 Common analytes in urine
Reference range
Analyte
SI units
Non-SI units
Albumin
Definitions of microalbuminuria are given on page 394
Proteinuria is defined below
Calcium (normal diet)
Up to 7.5 mmol/24 hrs
Up to 15 mEq/24 hrs
or 300 mg/24 hrs
Copper
<0.6 pimol/24 hrs
<38 pig/24 hrs
Cortisol
20-180 nmol/24 hrs
7.2-65 jng/24 hrs
Creatinine
Male
6.3-23 mmol/24 hrs
712-2600 mg/24 hrs
Female
4.1-15 mmol/24 hrs
463-1695 mg/24 hrs
5-Hydroxyindole-3-acetic acid (5-HIAA)
10-42 pimol/24 hrs
1 .9-8.1 mg/24 hrs
Metadrenalines
Normetadrenaline
0.4-3. 4 pimol/24 hrs
73-620 pig/24 hrs
Metadrenaline
0.3-1 .7 pimol/24 hrs
59-335 pig/24 hrs
Oxalate
0.04-0.49 mmol/24 hrs
3.6-44 mg/24 hrs
Phosphate
1 5-50 mmol/24 hrs
465-1548 mg/24 hrs
Potassium*
25-1 00 mmol/24 hrs
25-100 mEq/24 hrs
Protein
<0.3 g/L
<0.03 g/dL
Sodium*
100-200 mmol/24 hrs
100-200 mEq/24 hrs
Urate
1. 2-3.0 mmol/24 hrs
202-504 mg/24 hrs
Urea
170-600 mmol/24 hrs
10.2-36.0 g/24 hrs
Zinc
3-21 pmol/24 hrs
195-1365 pig/24 hrs
*The urinary output of electrolytes such as sodium and potassium is normally a reflection of dietary intake. This can vary widely. The values quoted are appropriate to a
‘Western’ diet.
35.6 Analytes in cerebrospinal fluid
Reference range
Analysis
SI units
Non-SI units
Cells
<5x1 06 cells/L
(all mononuclear)
<5 cells/mm3
Glucose1
2. 3-4.5 mmol/L
41-81 mg/dL
IgG index
<0.65
-
Total protein
0.14-0.45 g/L
0.014-0.045 g/dL
Interpret in relation to plasma glucose. Values in CSF are typically approximately
two-thirds of plasma levels. 2A crude index of increase in IgG attributable to
intrathecal synthesis.
35.7 Analytes in faeces
Reference range
Analyte
SI units
Non-SI units
Calprotectin
<50 ing/g
-
Elastase
>200 (ig/g
-
35
1362 • LABORATORY REFERENCE RANGES
35.8 Haematological values
Reference range
Analysis
SI units
Non-SI units
Bleeding time (Ivy)
<8 mins
-
Blood volume
Male
65-85 mL/kg
-
Female
60-80 mL/kg
-
Coagulation screen
Prothrombin time (PT)
10.5-13.5 secs
-
Activated partial thromboplastin time (APTT)
26-36 secs
-
D-dimers
Interpret in relation to clinical presentation
<200 ng/mL
-
Erythrocyte sedimentation rate (ESR)
Higher values in older patients are not necessarily abnormal
Adult male
0-10 mm/hr
-
Adult female
3-15 mm/hr
-
Ferritin
Male (and post-menopausal female)
20-300 |ig/L
20-300 ng/mL
Female (pre-menopausal)
15-200 (ig/L
15-200 ng/mL
Fibrinogen
1. 5-4.0 g/L
0.15-0.4 g/dL
Folate
Serum
2.8-20 jug/L
2.8-20 ng/mL
Red cell
120-500 (ig/L
120-500 ng/mL
Haemoglobin
Male
130-180 g/L
13-18 g/dL
Female
115-165 g/L
11.5-16.5 g/dL
Haptoglobin
0.4-2. 4 g/L
0.04-0.24 g/dL
Iron
Male
14-32 jimol/L
78-178 jig/dL
Female
10-28 (imol/L
56-157 jig/dL
Leucocytes (adults)
4.0-1 1.0 x109/L
4.0-1 1.0 x107mm3
Differential white cell count
Neutrophil granulocytes
2.0-7.5x109/L
2.0-7.5x103/mm3
Lymphocytes
1. 5-4.0 x109,L
1.5-4.0x103/mm3
Monocytes
0.2-0.8x107L
0.2-0.8x103/mm3
Eosinophil granulocytes
0.04-0.4x1 07L
0.04-0.4 x103/mm3
Basophil granulocytes
0.01-0.1 x107L
0.01-0.1 x103/mm3
Mean cell haemoglobin (MCH)
27-32 pg
-
Mean cell volume (MCV)
78-98 fl
-
Packed cell volume (PCV) or haematocrit
Male
0.40-0.54
-
Female
0.37-0.47
-
Platelets
1 50-350 x107L
150-350x1 07mm3
Red cell count
Male
4.5-6.5x1012/L
4.5-6.5x107mm3
Female
3.8-5.8x1012/L
3.8-5.8x107mm3
Red cell lifespan
Mean
1 20 days
-
Half-life (51Cr)
25-35 days
-
Reticulocytes (adults)
25-85 x107L
25-85 x103/mm3
Transferrin
2. 0-4.0 g/L
0.2-0. 4 g/dL
Transferrin saturation
Male
25-50%
-
Female
14-50%
-
Vitamin B12
Normal
>210 ng/L
-
Intermediate
180-200 ng/L
-
Low
<180 ng/L
-
Laboratory reference ranges in childhood and adolescence • 1363
Laboratory reference ranges in childhood and adolescence
The levels of many analytes in blood vary due to the physiological
changes that occur during growth and adolescence. Hospital
laboratories may provide reference ranges that are age-
adjusted or based on pubertal stage but this is not always
the case. It is therefore important for the doctor requesting
these tests to understand the impact of age and puberty on
interpretation of the results. For example, a creatinine of 70 jimol/L
(0.79 mg/dL) is perfectly normal for the majority of adults but
may indicate significant renal impairment in a child. Reference
ranges for hormone results are described according to the
Tanner stages of puberty (p. 1290).
35
1364 • LABORATORY REFERENCE RANGES
Laboratory reference ranges in pregnancy
The levels of many analytes in blood vary during pregnancy,
when many hormonal and metabolic changes occur. The
standard adult reference ranges may therefore not be appropriate
and it is important for the clinician reviewing the results to be
aware of this to enable appropriate interpretation and patient
management.
35.10 Analytes that may be significantly affected by pregnancy
Reference range
Analyte
First trimester
Second trimester
Third trimester
Alkaline phosphatase (ALP)
17-88 U/L
25-126 U/L
38-229 U/L
Packed cell volume (PCV) or haematocrit
0.31-0.41
0.30-0.39
0.28-0.40
Haemoglobin
116-139 g/L
97-148 g/L
95-150 g/L
Human chorionic gonadotrophin
4 weeks: 16-156 IU/L
4-9 weeks: 101-233 000 IU/L
9-13 weeks: 20900-291 000 IU/L
4270-103 000 IU/L
2700-78300 IU/L
17(3-Oestradiol
690-9166 pmol/L
(188-2497 pg/mL)
4691-26401 pmol/L
(1278-7192 pg/mL)
12701-22528 pmol/L
(3460-6137 pg/mL)
Progesterone
25-153 nmol/L
(8-48 ng/mL)
Not available
314-1088 nmol/L
(99-342 ng/mL)
Prolactin
765-4532 mlU/L
(36-213 ng/mL)
2340-7021 ml U/L
(110-330 ng/mL)
2914-7914 mlU/L
(137-372 ng/mL)
Thyroid-stimulating hormone (TSH)
0.60-3.40 ml U/L
0.37-3.60 ml U/L
0.38-4.04 ml U/L
Thyroxine (free), (free T4)
10-18 pmol/L
0.77-1.40 ng/dL
9-1 6 pmol/L
0.70-1.24 ng/dL
8-14 pmol/L
0.62-1 .09 ng/dL
*Non-SI equivalents are given in brackets where appropriate.
Further information
Tanner JM, Whitehouse RH. Clinical longitudinal standards for height,
weight, height velocity, weight velocity, and stages of puberty. Arch
Dis Child 1976; 51:170-179.
Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and
laboratory studies: a reference table for clinicians. Obstet Gynecol
2009: 114:1326-1331.
Index
Page numbers followed by ‘/’ indicate figures, and ‘b’ indicate boxes.
AAAs see Abdominal aortic aneurysms
Abacavir, 324b
for HIV/AIDS, 324-325, 324b
hypersensitivity reaction of, 326
pharmacodynamics of, 1 80 b
Abaloparatide, for osteoporosis, 1048b,
1049
Abatacept, for musculoskeletal disease,
1007, 1007b
Abciximab, platelet inhibition, 500,
918
Abdomen
examination of
blood disease, 91 2 /
cancer, 1315b
cardiovascular disease, 442/
gastrointestinal disease, 764/
liver and biliary disease, 846-847
renal and urinary tract disease,
382/-383Z
palpation of, 765 b
percussion of, 765 b
swelling of see Ascites
Abdominal aortic aneurysms (AAAs),
505, 505b
Abdominal compartment syndrome,
diagnosis and management of,
195
Abdominal examination, 765 b
Abdominal pain, 787-789
acute, 787-789, 787b
assessment of, 787, 788 /
chronic or recurrent, 789, 789 b
constant, 789
diabetic ketoacidosis and, 736,
736b
investigations of, 787
irritable bowel syndrome and, 824
large bowel obstruction of, 789
liver abscess and, 880
in lower abdomen, 336
management of, 787-789
in old age, 788 b
pancreatitis
acute, 837-839, 837 b
chronic, 839-841
peptic ulcer, perforated, 789
Abdominal tuberculosis, 812-813
Abducens (6th cranial) nerve, tests of,
1063b
Abetalipoproteinaemia, 810
Abnormal movements, 1084-1086,
1085b
Abnormal perceptions, 1086, 1181
ABO blood groups, 931-932, 933b
ABO-incompatible red cell transfusion,
932-933
ABPA see Allergic bronchopulmonary
aspergillosis
ABPI see Ankle-brachial pressure
index
Abscess
anorectal, 836
cerebral, 1 124, 1 124b, 1 124/
‘collar-stud’, 590
infective endocarditis and, 527
intra-abdominal, 787 b
liver, 879-880, 893
amoebic, 880
in old age, 901b
pyogenic, 879-880, 880b
lung, 219/, 251 /
pancreatic, 219 /
perinephric, 430
pulmonary, 586-587
spinal epidural, 1125
Absence seizures, 1 099
Absidia, 303
Absolute erythrocytosis, 925, 925b
Absorption, 17-18
gastrointestinal tract, 17
interactions, 23
parenteral, 17
topical, 17-18
see also Malabsorption
ABVD regimen, for Hodgkin lymphoma,
963
Acamprosate, 1195
Acanthosis, 1244
Acanthosis nigricans, 1265, 1325b,
1326
Acarbose, 745-746
Accelerated hypertension, 514
Accessory (11th cranial) nerve, tests of,
1063b
Acclimatisation
to heat, 167
to high altitude, 168
Accommodation, 1198
ACCORD (Action to Control
Cardiovascular Risk in Diabetes),
757
ACD see Anaemia(s), of chronic disease
ACE (angiotensin-converting enzyme),
351-352
ACE inhibitors
for acute coronary syndrome
prevention, 498b
adverse reactions of, 22 b, 1310b
angioedema, 1266b
cough, 556
hyperkalemia, 363
for chronic kidney disease, 417
contraindication to, cirrhosis, 894b
effect on renal function, 426, 427b
for heart failure, 466, 466/
dosages, 466b
sites of action, 466/
for hypertension, 513
for mitral regurgitation, 521
for myocardial infarction, 500-501
during pregnancy, 32 b
Acetaldehyde metabolism, 881
Acetazolamide, 354
for altitude illness, 1 68
for epilepsy, 1 1 02 b
for idiopathic intracranial
hypertension, 1133
Acetyl-CoA, 881
Acetylcholine, 767
Acetylcholinesterase (AChE), 1 1 42f
Acetylcysteine, 138
Achalasia of oesophagus, 794-795
AChE see Acetylcholinesterase
Achilles tendinitis, 999
Achlorhydria, 803/, 808 b, 941
Aciclovir
for herpes virus infection, 126, 127b
bone marrow transplant patients,
937 b
chickenpox/shingles, 239b
genital, 342
HIV/AIDS, 315
viral encephalitis, 1122
nephrotoxicity, 427b
in pregnancy, 120b
Acid-base balance
chronic kidney disease and, 418
disorders
mixed, 367
presenting problems of, 364-367
homeostasis, 363-367
principal patterns of disturbances,
365 b
renal control of, 364
Acidosis
lactic, 365
diabetic, 746
poisoning, 149b
metabolic, 364-366
acute kidney injury and, 413
chronic kidney disease, 41 5
critically ill patients and, 180-181
diabetic ketoacidosis, 735
differential diagnosis, 558b
hypothermia and, 166
malaria, 276 b
near-drowning, 170
poisoning and, 135b
renal tubular, 365b
respiratory, 367
Acids, poisoning, 136b
Acinus, 548-549, 549/, 848, 848/
Acitretin
for atopic eczema, 1 246
for psoriasis, 1 227
Acne, 1241-1244, 1242/
in adolescence, 1241b
conglobata, 1242
cystic, 1 242/
excoriee, 1242
fulminans, 1242
secondary, 1242
vulgaris, 1241-1243
Acneiform eruptions, 1 266b
Acoustic neuroma, 1131
Acquired Cl inhibitor deficiency, 88
Acrochordon, 1235
Acrocyanosis, 84b, 950
Acrodermatitis chronica atrophicans,
256
Acrodermatitis enteropathica, 7 1 7
Acromegaly, 630/, 685-687, 686/
musculoskeletal manifestations of,
1057
ACTH see Adrenocorticotrophic
hormone
Actinic dermatitis, chronic, 1221b,
1222/
Actinic keratosis, 1230b, 1231, 1231/
Actinic prurigo, 1221b
Actinomadura spp., 301
Actinomyces israelii, 261-262
Actinomyces spp., 103/
Actinomycete infections, 261-262
Actinomycetes, 100-101
Actinomycetoma, 301
Action potential, 1065
Activated partial thromboplastin time
(APTT), 920-921
reference range of, 1 362b
Active proctitis, 820
Activities of daily living (ADL), 1303b
Barthel Index, 1311, 1312b
Acupuncture, for pain management,
1347, 1347/
Acute abdomen, 787-789, 787 b, 788/
Acute benign asbestos pleurisy, 61 8
Acute cholinergic syndrome, 146, 146b
Acute circulatory failure, 199-200
Acute colonic ischaemia, 827
Acute colonic pseudo-obstruction, 835,
835 b
‘Acute confusional states,’ in older
people, 1080
Acute coronary syndrome, 493-501 ,
493b-494b, 494/-495Z
chest pain and, 455
clinical features of, 494-496, 495b
complications of, 494-495
management of, 498-501 , 498b,
499/
see also Myocardial infarction
Acute disseminated encephalomyelitis,
1110
Acute eosinophilic pneumonia, 61 1
Acute fatty liver of pregnancy, 1 283,
1283b
Acute inflammation, 70-71, 71/
acute phase response in, 70
resolution of, 71
septic shock and, 70-71
Acute inflammatory arthritis, 1 01 7
Acute intermittent porphyria, 379 b
Acute interstitial nephritis (AIN), 402,
402b
Acute interstitial pneumonia (AIP), 606b
1366 • INDEX
Acute kidney injury (AKI), 411-415
causes of, 41 If
clinical features of, 411-413
dialysis for, indications for, 422b
haemodialysis in, 422
interstitial, 402, 402b
investigations of, 412b
malaria, 276 b
management of, 413-414, 413b
non-oliguric, 402
in old age, 414b
pathophysiology of, 411
post- renal, 412b, 413
pre-renal, 411-412, 412b
pregnancy and, 1282, 1283b
recovery from, 414-415, 41 4f
renal, 412-413, 412b
renal replacement therapy, 41 4
Acute leukaemia, 955-958
investigations of, 955-956, 956f
management of, 956-958
haematopoietic stem cell
transplantation, 958
specific therapy, 956-957,
956b-957b
supportive therapy, 957-958
outcome of, 958b
prognosis of, 958
WHO classification of, 955b
Acute limb ischaemia, 503, 503b, 503 f
Acute liver failure, 856-859
adverse prognostic criteria in, 858b
causes of, 856f-857f
classification of, 857 b
clinical assessment of, 857-858
complications of, 858b
hepatic encephalopathy and, 857 b
hepatitis A and, 873
investigations for, 858, 858b
management of, 858-859, 858b
pathophysiology of, 857
Acute lung injury, 170
Acute lymphoblastic leukaemia (ALL),
955, 956 f
Acute medicine, 173-214
ambulatory care, 1 76, 1 76 b
decision to admit to hospital, 176
problems in, 176-187
Acute mountain sickness (AMS), 168
Acute myeloid leukaemia (AML), 955,
956 f, 958 b
‘Acute on chronic’ type II respiratory
failure, 566-567, 566 b
Acute pancreatitis, 837-839, 837b
causes of, 838b
complications of, 838b
management of, 839
pathophysiology of, 837, 838f
Acute pericarditis, 542, 542b, 542f
Acute phase proteins, 72
Acute phase response, 105
ferritin levels in, 941
musculoskeletal disease, 1017-1018
retroperitoneal fibrosis, 434
rheumatic disease, 1 01 2
Acute Physiology Assessment and
Chronic Health Evaluation
(APACHE II), 214, 214b
Acute renal failure see Acute kidney
injury
Acute respiratory distress syndrome
(ARDS), 198
aetiology of, 198, 198b
Berlin definition of, 198b
diagnosis of, 198, 199f
drug-induced, 612b
management of, 1 98
mechanical ventilation in, 198
near-drowning victims and, 170
pathogenesis of, 1 98
severity of, 1 99b
Acute rheumatic fever, 515-517, 51 6f
investigations in, 517b
Jones criteria for, 516b
Acute severe breathlessness, 558
Acute skin failure, 1 224-1 225
Acute small bowel ischaemia, 827
Acute transmural anterior myocardial
infarction, 497f
Acute transmural inferolateral myocardial
infarction, 498f
Acute tubular necrosis (ATN), 402f
drug-induced, 427b
Adalimumab
for inflammatory bowel disease, 820,
821b
for inflammatory rheumatic disease,
1007b
for psoriasis, 1250-1251
Adapalene, 1242-1243
Adaptive immune system, 67-70
ADCC see Antibody-dependent cellular
cytotoxicity
Addenbrooke’s Cognitive Examination-
3rd edition (ACE-Ill), 1181-1183
Addison’s disease, 671b
Adductor tendinitis, 999b
Adenine, 38, 39 f
Adenocarcinoma, 813
ampullary/periampullary, 842-844
of oesophagus, 796f-797f
of pancreas, 842-844
of prostate, 438-439
of small intestine, 813
of unknown primary, 1336
Adenoma
adrenal, 667 b
Conn’s syndrome, 675 f
Cushing’s syndrome, 667 b,
669-670
bronchial gland, 603b
colorectal, 776 b, 827
familial adenomatous polyposis,
828-829, 829f
hepatic, 893
parathyroid, 663
periampullary, 813
sebaceum, 1264
small intestine, 813
toxic, 638 f, 649
Adenomyomatosis, of gallbladder, 909
Adenosine, 480b, 482, 482b
Adenosine diphosphate see ADP
Adenosine triphosphate see ATP
Adenosquamous carcinoma of lung,
603 b
Adenoviruses, diarrhoea, 249
ADH see Antidiuretic hormone
Adherence
factors affecting, 1294b
SIMPLE strategies for, 1294b
Adhesion molecules, 77
ADHR see Autosomal dominant
hypophosphataemic rickets
Adipocytes, 725
Adipokines, 731
Adiponectin, 699
Adjustment disorders, 1187, 1201
prevalence of, 1 1 80 b
ADL see Activities of daily living
Adolescents, 1290
allergy in, 76 b
congenital heart disease in, 537b
cystic fibrosis in, 581b
diabetes mellitus in, 753-754,
753b-754b
epilepsy in, 1103b
haematological malignancy in, 955b
infections in, 234, 235b
inflammatory bowel disease in, 823b
juvenile idiopathic arthritis in, 1027b
laboratory reference range of, 1 363
medical ophthalmology in, 1175b
renal impairment in, 1298b
ADP (adenosine diphosphate), 446f
Adrenal crisis, 673 b
Adrenal disease, 1 280
Adrenal glands, 665-676
disease
classification of, 665b
presenting problems of, 666-674
functional anatomy and physiology of,
665-666, 666f-667f
incidental adrenal mass, 673-674
older people, 673b
Adrenal hyperplasia, congenital, 676
Adrenal insufficiency, 671-673,
671b-673b
Adrenal tumours
Cushing’s syndrome, 669-670
see also Phaeochromocytoma
Adrenalectomy, 675
for Cushing’s disease, 669
Adrenaline
for allergy, 86
anaphylaxis, 75, 76 b
circulatory effects of, 206b
self-injectable, prescription of, 76 b
for urticaria, 1 254
Adrenarche, 666
p- Adrenoceptor antagonist, 1190b
for thyrotoxicosis, in pregnancy,
1279
for variceal bleeding, 869, 871
Adrenocorticotrophic hormone (ACTH)
Cushing’s syndrome and, 667 b
ectopic, 667 b, 1325b
ectopic ACTH syndrome, 670
ectopic hormone production, 1325b
excess, 672b
hypopituitarism, 672 b
reference range of, venous blood,
1359b
stimulation test, 672 b
Adrenoleukodystrophy, 1116b
Adriamycin see Doxorubicin
Adult-onset Still’s disease, 1 040
Adult polycystic kidney disease (PKD),
405-406, 405b
Advance directives, 1307
Advanced life support (ALS), 457
Adverse drug reactions (ADRs),
21-23
classification of, 22-23, 22 b
interactions, 23-24
in older people, 1310, 1310b
pharmacovigilance, 23
prevalence of, 21-22, 21b-22b
risk factors for, 21b
TREND analysis of, 23 b
see also individual drugs
Aedes aegypti
Chikungunya virus, 250
dengue, 243
yellow fever, 244
AEDs (antiepilepsy drugs) see
Anticonvulsants
AF see Atrial fibrillation
Affective mood disorders
bipolar, 1198
organic, 1185b
Affinity, 14
Affluence, health consequences of, 94
AFP (alpha-fetoprotein)
hepatocellular carcinoma and,
890-891
as tumour markers, 1322, 1324b
African tick bite fever, 270, 271b
African trypanosomiasis (sleeping
sickness), 278-279, 278 f
Afterload
heart failure, 461
reduction, 465
Age/ageing, 1301-1312
biological, 1304
biology of, 1304-1305
chronological, 1304
physiological changes of, 1305,
1305f
syndrome of premature ageing see
Werner’s syndrome
type 2 diabetes and, 732, 732 b
see also Older people
Age-related macular degeneration,
1178
Agglutination, cold, 950
Agglutination test, 108
for leishmaniasis, 283
for leptospirosis, 258
microscopic, 258
for sporotrichosis, 301
trypanosomiasis, 279
for tularaemia, 261
Agg recan, 987
Aggregatibacter aphrophilus-
Aggregatibacter
actinomycetemcomitans, 528
Aggressive behaviour, 1 1 88-1 1 89,
1 1897
Agitation, in palliative care, 1354
Agnosia, 1086
Agonists, 14
Agoraphobia, 1200
Agranulocytosis, 644
AHR see Airway hyper-reactivity
AIDS see HIV infection/AIDS
Aids and appliances, for
musculoskeletal disease, 1001
AIN see Acute interstitial nephritis
AIP see Acute interstitial pneumonia
Air embolism, during dialysis, 424b
Air travel, 169
Airflow obstruction, 554f
assessment in COPD, 575
Airway hyper- reactivity (AHR), 568,
568 f
Airway pressure release ventilation
(APR V), 204
Airways, 548, 548f
assessment of, in deteriorating
patient, 188
in asthma, 568f
defences, 550, 550 f
of envenomed patient, 1 527
obstruction of, 555, 1324b
reactive dysfunction syndrome, 61 4
in sleep apnoea, 622
of stroke patients, 1 1 59 b
upper airway diseases, 622-625
Akathisia, 1105-1106, 1197
AKI see Acute kidney injury
Akinesia, 1113b
AUK dehydratase deficiency, 379 b
Alanine aminotransferase (ALT), 852,
1360b
Albendazole
for cysticercosis, 298
for helminthic infections, 1 29
filariasis, 291
for hydatid cysts, 299
Albers-Schonberg disease, 1 056
Albinism
inheritance, 1258
oculocutaneous, 1258
Albright’s hereditary osteodystrophy,
51b, 664, 1017b
Albumin
in AKI, 416b
liver blood biochemistry, 852
plasma, liver function test, 858
reference range of
urine, 1361b
venous blood, 1360b
urinary, 1361b
see also Hypoalbuminaemia
Albumin solutions, for ascites, 864
Albuminuria, moderately elevated, 394
Alcohol, 94
abstinence from, 1 1 94b
amount in average drink, 880b
coronary artery disease and, 486
dependence, 1194-1195, 1194b
diabetes and, 744-745
drug interactions, 24b
energy provided by, 694
liver disease and, 880-882
pharmacokinetics, 20 b
poisoning, 134b
thiamin deficiency and, 714
see also Ethanol
Alcohol misuse, 1184, 1194-1195
chronic, presentation and
consequences of, 1 1 94b
clinical assessment of, 1 1 84
clinical features of, 1 1 94-1 1 95
diagnosis of, 1 1 95
effects of, 1194b, 1195
investigations of, 1 1 84
liver disease see Alcoholic liver
disease
management of, 1 1 95
maternal, 1194b
in pancreatitis, 841
pathogenesis of, 1 1 94
prevalence of, 1 1 80 b
prognosis of, 1 1 95
INDEX • 1367
Alcohol withdrawal syndrome, 1194,
1194b
management of, 1 1 95
Alcoholic fatty liver disease (AFLD),
881
Alcoholic liver disease, 880-882
clinical features of, 881-882, 8815
liver function test (LFT) abnormality in,
8545
in old age, 9015
pathophysiology of, 881, 8815
risk factors for, 880
Aldosterone, 666
deficiency, 363
plasma potassium and, 360
reference range of, 1 3595
resistance, 363
see also Hyperaldosteronism
Alendronate
for osteoporosis, 1 0485
timing of, 315
Alfacalcidol (1 ,25-
dihydroxycholecalciferol), 665
Alfentanil, 2095
Alginates, 793
sodium content of, 8645
Alkaline phosphatase (ALP)
liver function tests and, 852
placental, 1322, 13245
reference values of, venous blood,
13605
sclerosing cholangitis, 889
serum
Paget’s disease, 1 054
rickets/osteomalacia, 1 052
in skeletal disease, 9905
Alkalinisation, urinary, 136
Alkalis, poisoning, 1365
Alkalosis
hypokalaemic, Cushing’s syndrome,
667
metabolic, 366-367, 367 f
respiratory, 367
Alkylating agents, 9365
Allele, 47
Allergen, 84
asthma, 568 f
avoidance of, 86
contact eczema, 1 247
supervised exposure to, 86
Allergic alveolitis, extrinsic see
Hypersensitivity pneumonitis
Allergic bronchopulmonary aspergillosis
(ABPA), 596, 5965, 596 f
Allergic contact eczema, 1247, 12475,
1 247f
Allergic rhinitis, 622
Allergy, 84-86
in adolescence, 765
clinical features of, 85
clinical manifestations of, 855
diagnosis of, 85
food, 812
hygiene hypothesis, 84-85
to insect venom, 85
investigations of, 86
challenge tests, 86
eosinophilia, 86
mast cell tryptase, 86
patch tests, 1215, 1244
serum total IgE, 86
skin-prick tests, 86
specific IgE tests, 86
management of, 86
pathophysiology of, 84-85, 85 f
to peanut, 85
in pregnancy, 885
Allodynia, 1084
Allogeneic haematopoietic stem cell
transplantation, 937
complications of, 937, 9375
indications for, 9365
Alloimmune haemolytic anaemia, 950
Allopurinol
for acute leukaemia patients, 9565,
957-958
drug interactions of, 245
for gout, 1015-1016
hepatotoxicity, 325, 894
pharmacodynamics, 205
renal stone prevention, 432-433,
4335
for toxic epidermal necrolysis,
1254-1255
Alopecia, 1258-1259, 12595
androgenetic, 1259
scarring inflammatory, 1262f
Alopecia areata
hair in, 1258-1259, 1259f
nails in, 1261
Alpha-fetoprotein (AFP)
hepatocellular carcinoma and,
890-891
as tumour markers, 1322, 13245
Alpha-glucosidase inhibitors, for
hyperglycaemia, 747
Alpha heavy chain disease, 813
Alpha particles, 1 64, 1 64f
Alpha-thalassaemia, 954
Alpha! -antitrypsin deficiency, 485, 897,
89 If
inheritance, 475
Alport’s syndrome, 403-404, 404f
ALS see Advanced life support
ALT see Alanine aminotransferase
Alternaria, 572
Alternative therapies
for cancer pain, 1353
for pain, 1348
Altitude, illnesses, 168-169
Aluminium
osteomalacia and, 1 053
poisoning from, 148
Aluminium hydroxide
for diarrhoea, 809
phosphorus deficiency and, 716
for renal bone disease, 419
Alveolar macrophages, 303, 615
Alveolar microlithiasis, 6135
Alveolar proteinosis, 6135
Alveolitis
extrinsic see Hypersensitivity
pneumonitis
fibrosing, 5585, 10245
non-eosinophilic, drug-induced,
6125
Alzheimer’s disease, 11915,
1192-1193, 1 193f
familial, 1192
see also Dementia
Amanita phalloides poisoning, 1505
Amantadine, 127, 1275
for multiple sclerosis, 11105
for Parkinson’s disease, 1114
Amastigotes, leishmaniasis, 282 f
Amaurosis fugax, 1 1 52
AmBisome, 283
Amelanotic melanoma, 1 322
Amenorrhoea, 654-655, 6545
American trypanosomiasis (Chagas’
disease), 279-280
Amikacin
for actinomycetoma, 301
for nocardiosis, 261
Amiloride, 360, 864
for diabetes insipidus, 688
mineralocorticoid excess, 675
Amino acids, 697, 6975
essential, 6975
metabolism, 850
disorders of, 369-370
Aminoglycosides, 1165, 122
adverse effects of, 1 22
for brucellosis, 254
dosing of, 1 22 f
mechanism of action, 1165
nephrotoxicity, 325
pharmacokinetics of, 122
in pregnancy, 1205
Aminopenicillins, 120, 1205
Aminophylline
for asthma, 573, 573 f
for COPD, 578
Aminosalicylates, for inflammatory bowel
disease, 8215
Aminotransferases
acute liver failure and, 858
elevated, common causes of, 8595
hypothermia, 166
liver function tests, 852
non-alcoholic fatty liver disease and,
884
reference range of, 1 3605
viral hepatitis, 874f
Amiodarone
adverse reactions
pigmentation, 12585
pulmonary fibrosis, 612
for arrhythmias, 4795-4805, 481
atrial fibrillation, 471-472
atrial flutter, 470
tachycardia, 475
causing thyroid dysfunction, 6365,
638f, 647-648, 647f
for heart failure, 467
hepatotoxicity of, 8945
structure of, 647 f
thyrotoxicosis, 639, 647-648
Amitriptyline, 11995
for fibromyalgia, 1 01 8-1 01 9
for functional dyspepsia, 802-803
for headache, 1 095
for herpes zoster, 240
for irritable bowel syndrome, 825
for migraine prevention, 1096
multiple sclerosis, 11105
for musculoskeletal pain, 995
for neuropathic pain, 13505, 13525
for pain management, 13505
for post-herpetic neuralgia, 240
for psychiatric disorder, 1 1 995
Amlodipine
for angina, 4915
unstable, 500
for hypertension, 513
Ammonia, 384
hepatic encephalopathy and, 865
Ammonium chloride, 366
Amnesia, 1080-1081
persistent, 1081
post-ictal, 1081
transient global, 1081
Amniocentesis, 56
Amniotic fluid embolism (AFE),
pregnancy and, 1275
Amodiaquine, for malaria, 277
Amoebiasis, 286-287, 286 f
incubation period of, 1115
Amoebic dysentery, 287
Amoebic liver abscess, 287, 880
Amoeboma, 286-287, 286f
Amoxicillin, 1175
for diphtheria, 266
for Helicobacter pylori eradication,
800
for listeriosis, 260
for Lyme disease, 256
for pneumonia, 5855
for skin reactions, infectious
mononucleosis, 242
for urinary tract infection, 428
Amphetamines, misuse of, 1 43
Amphotericin/amphotericin B, 1255,
126
for aspergillosis, 598
for blastomycosis, 304
for candidiasis, 302
for coccidioidomycosis, 304
for cryptococcal meningitis,
HIV-related, 321
for fusariosis, 302-303
for histoplasmosis, 304
for leishmaniasis, 283
lipid formulations of, 126
for mucormycosis, 303
for mycetoma, 301
nephrotoxicity, 3655, 4275
for neutropenic fever, 1327-1328
for Penicillium (Talaromyces) marneffei
infection, 303
for sporotrichosis, 301
Ampicillin, 1175, 1205
for cerebral abscess, 1 1 245
drug interactions of, 121
for listeriosis, 260
for liver abscess, 880
for meningitis, 1 1 205
for paratyphoid fever, 260-261
skin reactions, 12665
infectious mononucleosis, 242,
242f
Ampulla of Vater, carcinoma of,
907-908
AMS see Acute mountain sickness
Amsacrine, for acute leukemia, 9575
Amsler chart, 1168, 11 68 f
Amygdala, 1066
Amylase, 768, 7705
pancreatic, 695-697
reference range of, venous blood,
13605
salivary, 62-63
serum
hypothermia, 166
pancreatitis, 5635, 839
Amyloid A, serum, 70
Amyloid angiopathy, 11555, 11915
Amyloid deposition, type 2 diabetes,
731
Amyloid in plaques, in Alzheimer’s
disease, 1192, 1 1 93f
Amyloidosis, 81, 1264
causes of, 825
heart disease, 541
multiple myeloma, 41 05
rheumatoid arthritis, 1024-1025
Amy lose, 695-697
ANA see Antinuclear antibody
Anaemia(s), 717, 913, 9135, 923-925,
940-951, 941 f
after peptic ulcer surgery, 801
aplastic, 968-969
autoimmune haemolytic, 949-950
causes of, 9235
of chronic disease (ACD), 9425, 942f,
943
chronic kidney disease and, 419,
4195
clinical assessment of, 923
haemolytic, 923, 945-951
alloimmune, 950
autoimmune, 949-950
causes of, 946f, 947
microangiopathic, 950
non-immune, 950
HIV-related, 322
investigations of, 923-925, 924f
iron deficiency, 940-943
alimentary tract disorders, 793
blood loss in, 940-941
confirmation of, 941-942, 9425
investigations in, 941-942
malabsorption in, 941 , 942f
management of, 943
physiological demands in, 941 ,
9415
pregnancy and, 1284
megaloblastic, 940, 943-945
clinical features of, 9435
investigations in, 9445
management of, 945
microangiopathic haemolytic, 408,
950
microcytic, 925
in rheumatoid arthritis,
1024-1025
normochromic normocytic, 853
in old age, 9545
pernicious, 944
pregnancy and, 1284, 12855
primary idiopathic acquired aplastic,
968-969, 9685
secondary aplastic, 969, 9695
sickle-cell, 923, 951-953
clinical features of, 952-953, 952f
epidemiology of, 951 , 951 f
investigations of, 953
management of, 953
pathogenesis of, 951-952
in pregnancy, 9535
prognosis of, 953
Anagrelide, 970
Anakinra, for musculoskeletal disease,
1007
Anal canal, 77 If
Anal fissure, 836
1368 • INDEX
Analgesia
for acute coronary syndrome, 498
for back pain, 997
cholecystitis, 905
in intensive care, 209, 209b
for low back pain, 997
for musculoskeletal disease, 1 002
myocardial infarction, 498
for osteoarthritis, 1 01 2
for palliative care, 1350
for pancreatic cancer, 842-844
for pancreatitis, 839
for pleural pain, 584
for post-herpetic neuralgia, 240
for psoriatic arthritis, 1033-1034
for reactive arthritis, 1032
for renal colic, 432
Analgesic ladder (WHO), 1351f
Analgesics
adjuvant
for cancer pain, 1352, 1352b
for pain, 1345-1346
poisoning from, 137-138
see also specific drugs
Anaphase, 40
Anaphylactic shock, 204, 206b
Anaphylactoid reactions, 75, 75 b
Anaphylaxis, 75-76, 339
causes of, 75 b
clinical assessment of, 75-76
clinical manifestations of, 75 f
differential diagnosis of, 76 b
gastrointestinal, 812
management of, 76, 76 b
Anaplastic carcinoma, 650
ANCAs (antineutrophil cytoplasmic
antibodies), 992
Ancyiostoma caninum, 294
Ancylostoma duodenaie , 288, 288 f
Ancylostomiasis (hookworm), 288-289,
288f
Andersen disease, 370 b
Andersen-Tawil syndrome, 1145b
Androgen receptor antagonism, 659b
Androgen replacement therapy
for adrenal insufficiency, 673
options for, 656b
Androgens
adrenal, 666
in older women, 660b
Anergy, 82
Aneuploidy, 51
Aneurysm
aortic, 505-506
abdominal, 505 b
saccular, 508
ventricular, 496
see also Microaneurysms
Angelman’s syndrome, 44b, 51b
Angina, 487-493, 487b-488b
clinical features of, 488, 488b
investigations for, 488, 489/-490f
management of, 488-489
drug therapy, 489-491 , 490b
non-pharmacological treatments,
491-493, 491f-492f, 493b
in old age, 493b
prognosis of, 493
recurrent, in acute coronary
syndrome, 495
stable
advice to patients with, 489b
risk stratification in, 488b
Angina equivalent, 1 80
Angiodysplasia, 782-783
Angioedema, 87-88, 87 f
drug-induced, 1266b
hereditary, 88
types of, 87b
Angiogenesis, 1318, 1 31 9f
Angiography
coronary, 143
CT, 452, 452f
hepatic, 854
magnetic resonance, 869
mesenteric, 783, 813
of nervous system, 1072
visceral, 782-783
Angiomatosis, bacillary, 272
Angioplasty
for renal artery stenosis, 407-408
for stoke, 1 1 60
Angiosarcoma, 1320b
Angiostrongyius cantonensis, 294
Angiotensin-converting enzyme see
ACE
Angiotensin-converting enzyme
inhibitors see ACE inhibitors
Angiotensin II, 666
Angiotensin II receptor blockers
effect on renal function, 407b
microalbuminuria in diabetes, 758
renal failure, 417
Angiotensin receptor blockers
for heart failure, 466, 466b
for hypertension, 513
Angular cheilitis, HIV/AIDS, 316
Angular stomatitis, 714, 764f, 817
Anhedonia, 1181
Anion gap
acidosis, 365
poisoning, 135b
Anisakiasis, 294
Anismus, 834
Ankle-brachial pressure index (ABPI),
1224
Ankle pain, 999
Ankylosing spondylitis (AS), 1028b,
1030-1031
clinical features of, 1030, 1030b
investigations of, 1 030-1 031 ,
1030f-1031f
management of, 1031
Annular erythemas, 1 265
Annulus fibrosus, 444
Anogenital warts, 342-343
Anorectal abscesses, 836
Anorectal disorders, 835-836
Anorectal motility test, 778
Anorexia
in cancer patients, 1 325b
in rheumatoid arthritis, 1 023
Anorexia nervosa, 1203-1204, 1204b
features of, 785
in osteoporosis, 1 047-1 048
Anosmia, 653
Anosognosia, 1192-1193
ANP see Atrial natriuretic peptide
Anserine bursitis, 999b
Antacids
for bile reflux, 801
drug interactions of, 23
sodium content of, 864b
Antagonists, 14
Antalgic gait, 1086, 1309b
Anterior pituitary hormone deficiency,
681b
Anterior tibial compartment syndrome,
1058
Anthracyclines, 936b
Anthrax, 266-267
bioterrorism, 1 1 1
clinical features of, 267
cutaneous, 267
gastrointestinal, 267
immunisation for, 1 1 5b
incubation period of, 111b
inhalational, 267
management of, 267
skin, 1238
Anthropometry, 693b
Anti-a4[57 integrin, for inflammatory
bowel disease, 821b
Anti-androgen therapy, for polycystic
ovarian syndrome, 659b
Anti-anginal therapy, for acute coronary
syndrome, 500
Anti-anxiety drugs, 1 1 90 b
Anti-arrhythmic drugs, 479-482
adverse reactions of, 926b
classification of, 479b
by site of action, 479f
dosages of, 480b
principal uses of, 480b-481b
side-effects of, 480b
see also individual drugs
Anti-cancer therapy see Chemotherapy
Anti-CCP antibodies, 563b, 607
Anti-CD20 monoclonal antibody
rituximab, for chronic lymphocytic
leukaemia, 960
Anti-centromere antibody, 992b
Anti-citrullinated peptide antibodies
(ACPAs), 991
Anti-D, 933
Anti-DNA antibodies, 991
Anti-glomerular basement membrane
disease, 398b-399b, 401
Anti-herpesvirus agents, 126-127, 127b
Anti-histone antibody, 992b
Anti-infective agents, 1 226
Anti-inflammatory cascade, 1 96
Anti-inflammatory therapy
for asthma, 571
for osteoarthritis, 101 1b
see also individual drugs
Anti-influenza agents, 1 27
Anti-Jo-1 (anti-histidyl-tRNA synthase),
992 b
Anti-La antibody (anti-SS-B), 992b
Anti-liver-kidney microsomal (LKM)
antibodies, 886
Anti-oestrogen, 1332
Anti-phospholipid syndrome, 1281
Anti-ribonucleoprotein antibody
(anti-RNP), 992 b
Anti-RNA polymerase, 992b
Anti-RO antibody (anti-SS-A), 992b
Anti-Scl-70 (anti-topoisomerase I
antibody), 992b
Anti-Smith antibody, 992b
Anti-smooth muscle antibodies, 886,
886 b
Anti-thymocyte globulin (ATG), 89b
Anti-TNF therapy
for ankylosing spondylitis, 1031
for inflammatory bowel disease,
821b-822b, 822
for rheumatoid arthritis, 1006
Anti-topoisomerase I antibody, 992b
Antibacterial agents, 1 20-1 24
aminoglycosides, 116b
beta-lactam, 116b, 120-121
folate antagonists, 1 23
glycopeptides, 123
lincosamides, 122
macrolide, 116b, 121-122
nitroimidazoles, 124
quinolones, 122-123, 123b
target and mechanism of action of,
116b
therapeutic drug monitoring, 119
Antibiotic therapy
for acne, 1 242-1 243
for acute leukaemia, 957
adverse reactions of, 22 b, 926b
for bronchiectasis, 579
for cerebral abscess, 1124
for cholecystitis, 905
for choledocholithiasis, 906
for community-acquired pneumonia,
584, 585 b
for cystic fibrosis, 580
for diabetic foot ulcers, 761-762
diarrhoea associated with, 104b
for gastroenteritis/acute diarrhoea,
230
for Helicobacter pylori eradication,
800
hepatotoxicity and, 864b
for infective endocarditis, 529b, 530
for inflammatory bowel disease,
821b
for meningitis, 1118
for osteomyelitis, 1021
for pneumonia
community-acquired, 583
hospital-acquired, 586
suppurative/aspirational, 587
prophylactic
for pancreatitis, 839
for spontaneous bacterial
peritonitis, 864
for variceal bleeding, 869
for respiratory tract infections
bronchiectasis, 790
COPD, 578
cystic fibrosis, 580
pneumonia see Pneumonia, above
for rheumatic fever, 51 7
for sepsis, 197, 197b
for septic arthritis, 1020, 1020b
for skin disease, 1 227
sodium content of, 864b
for staphylococcal infections see
individual infections
for urinary tract infection, 428
Antibody/antibodies
classes and properties of, 68b
in coeliac disease, 806-807
deficiency in, 73 b
primary, 78-79, 78 f, 79 b
detection of, 106-108, 1 097
see also Autoantibodies
Antibody-dependent cellular cytotoxicity
(ADCC), 67-69
Anticardiolipin antibodies, 1157b
Anticholinergics
adverse reactions of, 1310b
for bladder dysfunction, 1094b
for COPD, 577
for Parkinson’s disease, 1114
poisoning, 150b
Anticholinesterases
for Alzheimer’s disease, 1193
for myasthenia gravis, 1142
non-antivenom, 159
ai-Antichymotrypsin, 70
Anticoagulants/anticoagulation,
938-940
adverse reactions of, 22 b
for atrial fibrillation, stroke prevention,
472b
coagulation screening, 1362b
direct oral, 940
drug interactions, 940
indications for, 938b
modes of action of, 938b
monitoring, 922
for obliterative cardiomyopathy, 541
in old age, 1 1 60b
poisoning, 148b
in pregnancy, 941b
prosthetic heart valves and, 527 b
for pulmonary embolism, 621
risk assessment of, 940b
rodenticides, 148b
for stroke patients, 1 1 57 b
for venous thromboembolism,
975-976
see also specific anticoagulants
Anticodon, 40
Anticonvulsants
for epilepsy, 1101-1102, 1102b
choice of drug, 1102b
withdrawing, 1102-1103
for pain management, 1352b
poisoning, 141b
skin reactions, 1266b
use in pregnancy, 1 284
Antidepressants, 1190b, 1199b, 1200
adverse reactions of, 926b, 1310b
for alcohol withdrawal, 1195
for anxiety disorders, 1 201
in older people, 1310b
poisoning from, 138-139
tricyclic, 1199, 11 99b
poisoning from, 138-139, 139b,
139f
Antidiabetic agents, poisoning from, 141
Antidiarrhoeal agents, 230
for inflammatory bowel disease, 821b
for irritable bowel syndrome, 826f
Antidiuretic hormone (ADH), 350-351
ectopic hormone production, 1325b
inappropriate secretion, 357b
cancer patients, 1325b
Antiemetic drugs, receptor site activity
of, 1353b
Antiepilepsy drugs (AEDs) see
Anticonvulsants
Antifreeze poisoning, 147
Antifungal agents, 125-126, 125b
Antigen processing and presentation,
70
Antiglobulin (Coombs) test, 948f
INDEX • 1369
Antihistamines
for allergy, 86
for eczema, 1 244
for food allergy, 812
for pruritus, 1 220
for skin disease, 1 227
for urticaria, 1 254
Antihypertensive drugs, 513, 5145, 51 5f
adverse reactions of, 9265
for chronic kidney disease, 416-417
for gout, 1016
Antimalarials, 128, 1252
adverse reactions of, 9265
poisoning, 1415
prophylactic, 1195
see also individual drugs
Antimetabolites, 9365, 1 31 7f
Antimicrobial agents
combination therapy, 1 1 6
for infective gastroenteritis, 230
pharmacokinetics and
pharmacodynamics of, 1 1 8-1 1 9,
1 1 9f
in pregnancy, 1205
resistance to, 116-118, 118 7
selection, 1175
susceptibility testing, 109, 109 7
target and mechanism of action of,
1165
therapeutic drug monitoring, 119
see also Antibiotic therapy
Antimicrobial stewardship, 115, 115 7
Antimicrobial therapy, 1 1 75
action and spectrum, 116, 1175
duration of, 118, 1195
empiric versus targeted therapy, 116,
117 7
in old age, 1 205
principles of, 116-120
prophylactic, 119-120, 1195
see also Antibiotic therapy
Antimitochondrial antibodies, 8865,
887
Antimonials, for leishmaniasis, 128, 283
Antimotility agents, 230
Antimycobacterial agents, 1 25
Antineutrophil cytoplasmic antibodies
(ANCAs), 389
Antineutrophil cytoplasmic antibody-
associated vasculitis (AAV), 1041,
1 041 f
Antinuclear antibody (ANA)
in autoimmune hepatitis, 8865
in musculoskeletal disease, 991 ,
9915
Antioxidants, 550
Antiparasitic agents, 1 28-1 29
Antiphospholipid antibodies, 991-992
Antiphospholipid syndrome (APS),
977-978, 9785
Antiplatelet drugs, 9385
for angina, 489
for myocardial infarction, 4985
for obliterative cardiomyopathy, 541
for stroke prevention, 11617
Antiproteinases, 550
Antipsychotic drugs, 1 1 905
adverse reactions of, 225, 11985
for agitation, 1354
poisoning from, 141
for schizophrenia, 1 1 985
Antiretroviral therapy, 1275, 324-327,
3245
complications of, 325-326
criteria for, 325
monitoring efficacy of, 325
in pregnancy, 326-327
resistance to, 325
selection of, 324-325
see also individual drugs
Antirheumatic drugs
during pregnancy and breastfeeding,
12815
slow-acting (DMARDs) see
Disease- modifying antirheumatic
drugs
Antisecretory agents, 230
Antiseptics, 586, 1226
Antithrombin deficiency, 977
Antithrombotic therapy, 938-940, 9385
for acute coronary syndrome, 500
prophylaxis, for venous
thromboembolism, 976-977,
9775
Antithyroid drugs
adverse reactions of, 9265
for Graves’ thyrotoxicosis, 644, 6445
in pregnancy, 1279
cci -Antitrypsin
faecal clearance of, 81 1
liver disease, 8545
liver histology in, 897 7
reference range of, venous blood,
13605
Antivenom, 159, 1595, 1 607
Antiviral agents, 126-128, 1275
see also Antiretroviral therapy
Anuria, 391 , 3915
Anxiety/anxiety disorders, 1186,
1 200-1 201
alcohol and, 1194
classification of, 1 2005
clinical features of, 1 200
diagnosis of, 1 200
differential diagnosis of, 1 1 865
generalised, 1200
investigations of, 1 1 86
management of, 1186, 1200-1201
in palliative care, 1354
panic disorder, 1200
phobic, 1200
prevalence of, 1 1 805
in stroke patients, 1 1 59 7
symptoms of, 1 1 865
Aorta
ascending
dilatation of, 451 7
syphilis and, 338
coarctation of, 508, 534, 534f
diseases of, 505-514
Aortic aneurysm, 505-506
abdominal, 5055
Aortic dissection, 506-508, 5067-5087,
5075
pregnancy and, 1282
Aortic regurgitation, 4435, 524-525,
5245
clinical features of, 524-525, 5245,
525 7
investigations of, 525, 5255
chest X-ray for, 451 7
Aortic stenosis, 4435, 521-524, 5225,
522 7
causes of, 5215
Doppler echocardiography for, 451 7
investigations of, 522-524, 5235,
523 7
in old age, 5245
Aortic valve, disease, 521-525
Aortitis, 508
APACHE II, 214
APD see Automated peritoneal dialysis
Aphonia, psychogenic, 624
Aphthous ulceration, 790, 7905
Apixaban, 9385
Aplastic anaemias, 968-969
Aplastic crisis, 947, 952-953
Apo A1 deficiency, 375, 3755
Apo A1 Milano, 375, 3755
Apocrine sweat glands, 1213-1214
Apolipoproteins, 371
Apoptosis, 41, 1316
Apoptotic bodies, 41
Appearance, in psychiatric interview,
1181
Appendicitis, acute, 788
Apraxia, 1086
gait, 1087, 13095
Apremilast, for musculoskeletal disease,
10045, 1005
Apronectomy, 704
APTT see Activated partial
thromboplastin time
Arachnoiditis, 996-997
Arboviruses, 1121-1122
ARDS see Acute respiratory distress
syndrome
Arginine, 6975
Arms, assessment of, 9837
Aromatase inhibitors
for cancer treatment, 1 334
osteoporosis and, 10465
Arrhythmias, 468-479, 4687
in acute coronary syndrome, 495,
4955
during dialysis, 4245
electrophysiology of, 454
hypothermia and, 1 667
management of, 479-484
drugs, 479-482, 4795-4825, 4797
non-pharmacological treatments,
482-484
see also specific arrhythmias
Arrhythmogenic ventricular
cardiomyopathy, 540
Arsenic, poisoning, 149, 1495
Arsen ism, 149, 1495
Artemisinin (qinghaosu) derivatives,
128
Arterial blood
analysis of, 1 3585
critically ill patients, 179
respiratoryfailure, 1995
Arterial disease
hepatic, 898
leg ulcers due to, 1 223-1 224
Arterial gas embolism (AGE), 170
Arterial pressure waveform, 206
Arterial pulse, examination of, 4435
Arterialisation, 422-423
Arteriography, renal, 389
Artesunate, for malaria, 277
Arthritis
acute inflammatory, 1 01 7
crystal-induced, 1012-1018
HIV-related, 321
juvenile idiopathic, 1 026-1 027
in adolescence, 10275
clinical features of, 1 0275
oligoarticular, 1300
transition medicine and, 1300
monoarthritis
acute, 992-993, 9935
chronic inflammatory, 992
mutilans, 1033
osteoarthritis, 1 007-1 01 2
polyarthritis see Polyarthritis
psoriatic, 1032-1034
CASPAR criteria for, 1 0325
clinical features of, 1032-1033,
10337
investigations for, 1033
management for, 1 033-1 034
pathophysiology of, 1 032
reactive, 1031-1032
rheumatoid, 1021-1026
algorithm for, 1 0267
biologic therapy for, 1026
cardiac involvement in, 1024
clinical features of, 1023-1025,
10237
criteria for diagnosis of, 1 0235
DMARD therapy for, 1025-1026
extra-articular, 10245
investigations in, 1025, 10255,
10267
management of, 1 025-1 026
nodules in, 1023-1024, 10247
non-pharmacological therapy for,
1026
ocular involvement in, 1024
pathophysiology of, 1022-1023,
10227
peripheral neuropathy in, 1024
in pregnancy, 10265, 1280
pregnancy and, 1280
pulmonary involvement in, 1024
serositis in, 1024
spinal cord compression in, 1024,
10257
surgery for, 1 026
systemic, 1023
vasculitis in, 1024
septic, 1019-1020
systemic lupus erythematosus and,
1035
viral, 1020-1021
Arthrodesis, 10025
Arthropathy
in parvovirus B19 infection, 2375
psoriasis and, 1249
reactive, sexually acquired, 340
rheumatological manifestations of,
1057
Arthroplasty, 10025
Asacol, for inflammatory bowel disease,
8215
Asbestos-related lung and pleural
diseases, 617-618
Asbestosis, 618
Ascariasis, 2335
Ascaris lumbricoides (roundworm),
289-290, 906
Ascending and descending pain
pathways, 13397
Ascites, 8475, 862-864, 13245
appearance and analysis of, 8635
Budd-Chiari syndrome and, 899
causes of, 8625
cirrhosis and, 867
hepatorenal syndrome and, 864
management of, 863-864
oedema, 395-396
pancreatic, 839
pathogenesis of, 8637
pathology of, 862-863
portal hypertension and, 869
prognosis of, 864
renal failure and, 864
serum- ascites albumin gradient
(SAAG) and, 863
spontaneous bacterial peritonitis and,
864
Ascorbic acid see Vitamin C
Aspartate, 6975
Aspartate aminotransferase (AST),
852
Aspergillosis, 301
bronchopulmonary classification of,
5965
Aspergillus clavatus, 6165
Aspergillus flavus, 13205
Aspergillus nodule, 597
Aspergillus spp., in
immunocompromised patients,
224
Asphyxia/asphyxiation
laryngeal obstruction, 624-625
self-harm, 1187
Aspiration, pleural, 563-564
Aspiration pneumonia, 586-587
Aspirin
for acute coronary syndrome
prevention, 4985
adverse reactions of, 225
for angina, 489
asthma association, 568
atrial fibrillation, stroke prevention,
473
coronary artery bypass grafting,
491-492
drug interactions, 245
for hypertension, 513
for myocardial infarction, 500
poisoning, 138
for rheumatic fever, 51 7
for stroke patients, 1 1 60
timing of, 315
AST see Aspartate aminotransferase
Asteatotic eczema, 1 247
Asterixis, 864-865
Asthma, 567-573, 5677
clinical features of, 568-569
control, levels of, 5705
diagnosis of, 569, 5695 , 5697-5707
exacerbations of, 572-573,
5725-5735, 5737
and gastro-oesophageal reflux
disease, 791-792
management of, 569-570, 5717
occupational, 613-614, 6145, 6147
pathophysiology of, 568, 5687
in pregnancy, 5705, 1277
prognosis of, 573
Astrocytes, 1064-1065
Astrocytoma, 10757
1370 • INDEX
Astrovirus, 249
Asymmetrical inflammatory mono-/
oligoarthritis, 1032
Asymptomatic bacteriuria, 429
Ataxia(s), 1115
acquired, 1115b
cerebellar, 1325
inherited, 1116b
stroke and, 1153
Ataxia telangiectasia, 1321b
genes, 1321
Ataxic gait, 1087, 1309b
Atazanavir, 324b
Atenolol
for angina, 500
drug interactions of, 24b
for hypertension, 513
Atheroembolism, 390b, 503-504,
504b
Atherosclerosis
in old age, 505b
renal artery stenosis and, 406
six stages of, 485f
Athetosis, 1086
Athlete’s foot, 1 240
Atmospheric pollution, 94
ATN see Acute tubular necrosis
Atomic absorption (AA), 348b
Atonic seizures, 1 1 00
Atopic eczema, 1 245-1 246
clinical features of, 1245, 1246 f
complications of, 1 246b
investigations of, 1245, 1246b
management of, 1 246
pathogenesis of, 1 245
rash in, 1217b, 1246b
Atopy, 84, 86
see also Allergy
Atorvastatin, 501
Atovaquone, for malaria, 1 28
ATP (adenosine triphosphate),
myocardial contraction and,
446
ATP synthase, 49b
Atria, 444, 444 f
Atrial ectopic beats, 469-470, 470 f
Atrial fibrillation (AF), 470-473, 471 f
causes of, 471b
management of, 471-473
mechanisms of, 471 f
in old age, 472b
paroxysmal, 471-472
persistent, 472-473
stroke risk in, 473b
Atrial flutter, 470, 470f
Atrial myxoma, 541-542
Atrial natriuretic peptide (ANP), 351
Atrial septal defect, 534-535, 535 f
Atrial tachycardia, 470
Atrioventricular (AV) block, 477-478,
477f-478f, 478b
Atrioventricular (AV) node, 445, 445f
re-entrant tachycardia, 473, 474f
Atrophy, definition of, 1226, 1226/
Atropine
for acute cholinergic syndrome, 146
for AV block, 478
for carbamate poisoning, 147
cardiotoxic drug poisoning, 140
for organophosphorus poisoning,
146
for sinus bradycardia, 469
Auerbach’s plexus, 771-772
Auscultation
examination of, respiratory system,
546/
of heart, 443b
malignant pleural effusions, 1315b
Austin Flint murmur, 524
Australian tick typhus, 271b
Autoantibodies
autoimmune disease and, 83, 83 f
autoimmune hepatitis and, 886b
and musculoskeletal disease, 991
primary biliary cholangitis and,
887-888
thyroid, 637 b
Autofluorescence, of visual disorders,
1169
Autoimmune connective tissue disease,
1018, 1034-1040
Autoimmune disease, 81-84
clinical features of, 83
gene polymorphisms associated with,
82 b
investigations of, 83-84
autoantibodies in, 83, 83 f
complement in, 84
cryoglobulins in, 84, 84b
of liver, 885-890
management of, 84
pathophysiology of, 82-83
Autoimmune haemolytic anaemia,
949-950
Autoimmune hepatitis, 886-887
conditions associated with, 886b
liver function test (LFT) abnormality in,
854b
primary biliary cholangitis and, 888
Autoimmune lymphoproliferative
syndrome, 80
Autoimmune pancreatitis, 841
Autoimmune polyendocrine syndromes,
689, 689b
Autoimmune thyroid disease, 639b,
643-646
Autologous haematopoietic stem cell
transplantation, 936-938
Automated peritoneal dialysis (APD),
424
Automated threshold perimetry, 1 1 68
Autonomic dysfunction, somatoform,
1202
Autonomic nervous system, 1068
Autonomic neuropathy, diabetic, 760,
760 b
‘Autonomic storm’, 155
Autonomy, patients, 1288-1289
Autophagy, 1316
Autopsy, 213
Autosomal dominant
hypophosphataemic rickets
(ADHR), 1050b
Autosomal dominant inheritance, 46-47,
47b
Autosomal recessive inheritance, 47b,
48
Autosomes, 38
AV see Atrioventricular
Avascular cornea, 1 1 66
Avid sodium retention, nephrotic
syndrome and, 395b
Axial spondyloarthritis, 1028b,
1029-1030, 1029f
Axial spondyloarthropathy, 1 028-1 031 ,
1Q29f
Axons, peripheral nerve, 1 064-1 065
Azathioprine
adverse reactions of, 22
for autoimmune haemolysis, 950
for autoimmune hepatitis, 886-887
drug interactions of, 24b
for eczema, 1 246
hepatotoxicity, 894b
for inflammatory bowel disease, 821b,
822
liver transplantation and, 901
for musculoskeletal disease, 1004b,
1005
systemic lupus erythematosus,
1036
for myasthenia gravis, 1142b
for primary biliary cholangitis, 888
for rheumatoid arthritis, 1 026b
transplant patients, 89b, 425-426
Azelaic acid, 1242-1244
Azithromycin, 117b
for bacillary angiomatosis, HIV/AIDS
patients, 315-316
for cystic fibrosis, 581b
for Mycobacterium avium complex,
315b
for STIs
chlamydial infection, 341b
syphilis, 339
for trachoma, 273
Azole antifungals, 1 26
Aztreonam, 117b, 120b, 121
B
B-cell receptor, 68, 68 f
B lymphocytes (B cells), 68, 68 f, 917
Babesia microti, 226 b
Babesiosis, 278
Bacillary angiomatosis, 272
HIV-related, 315-316
Bacillary dysentery, 265
Bacille Calmette-Guerin see BCG
Bacillus anthracis, 266
Bacillus cereus, food poisoning, 262,
262 f
Bacillus spp., 102f
Back, examination of, cardiology, 442f
Back pain, 995-997
red flags for, 996b
triage assessment of, 996f
see also Low back pain
Background radiation, 164
Baclofen, for multiple sclerosis, 1110b
Bacteraemia, 106
Staphylococcus aureus, 225
Bacteraemic leptospirosis, 257
Bacteria, 100-101, 101b, 1027
endogenous commensal, 63
exotoxin, disease caused by, 104b
identification of, 1 02 f
Bacterial cultures, for gastrointestinal
infection, 111
Bacterial infections, 250-273
after HSCT, 937b
and cancer, 1320b
chlamydial, 272-273, 272b
gastrointestinal, 262-265
with neurological involvement, 267
respiratory, 265-267
rickettsial, 270-272, 271b
of skin, 1235-1238
soft tissues and bones, 250-254
systemic, 254-262
see also specific infections
Bacterial keratitis, 1 1 73
Bacterial meningitis, 1118-1120
causes of, 111 9b
cerebrospinal fluid in, 1119
clinical features of, 1119, 1119b
headache and, 185, 185b
investigations of, 111 9-1 120, 111 9f,
1120b
management of, 1120, 1120b
pathophysiology of, 1119
Bacterial swab, for leg ulcers, 1224
Bacteriology, skin, 1215
Bacteriophage, 100
Bacteriuria
asymptomatic, 429
catheter-related, 429-430
Bacteroides fragilis, 586
Bacteroides spp., 1 03 f, 117 b
Bad news, 1185
Baker’s (popliteal) cyst, 999b, 1023
rupture, 1023
Balance
altered, 1086
see also Dizziness; Vertigo
Balanitis, 333
anaerobic, 334b
circinate, 334b
plasma cell (of Zoon), 334b
Balanoposthitis, 333
Balkan nephropathy, 403
Ballism, 1086
Balloon dilatation, 434
Balloon tamponade, for variceal
bleeding, 870-871 , 870f
Balloon valvuloplasty
for aortic valve, 524
for mitral valve, 519, 519b, 519 f
Balsalazide, 821b
Balsam of Peru, 1247b
‘Bamboo’ spine, 1030-1031, 1 031 f
Band ligation, 870
Bandages, for leg ulcers, 1223
Banding, for variceal bleeding, 869
Barbiturates, 142b
misuse of, 1 1 95
skin reactions of, 1 266b
withdrawal effects of, 1 6b
Bardet-Biedl syndrome, 404b
Bare lymphocyte syndromes, 79
Bariatric surgery, for obesity, 102f-103f,
703-704, 703b
Baricitinib, for musculoskeletal disease,
1004b
Baritosis, 614-615
Barium enema
for constipation, 787
for diverticulosis, 833
for gastrointestinal tuberculosis, 590
for inflammatory bowel disease,
819-820
for oesophageal diseases, 778
for pharyngeal pouch, 794
Barotrauma, 171
Barrett’s (columnar lined) oesophagus,
792-793, 193f
carcinoma and, 796
Barthel Index of Activities of Daily Living,
1311, 1312b
Bartonella henselae, 272, 315-316
Bartonella quintana, 272, 315-316
Bartonellosis, 272, 272b
Bartter’s syndrome, 361
Basal cell carcinoma, 1229-1230,
1 229f, 1230b
Basal cell papilloma, 1234, 1234/
Basal ganglia, 1 066-1 067
Basal metabolic rate (BMR), 694, 695f
in over-nutrition, 694
Basement membrane, 1212, 1 21 3f
Basic calcium phosphate (BCP)
deposition disease, 1017-1018,
1017b
Basic life support (BLS), 456-457
Basophil granulocytes, 1362b
Basophilia, 926b
Basophilic stippling, 921 f
Basophils, 66-67, 917, 926 b, 926 f
count, 1362b
Bath Ankylosing Spondylitis Disease
Activity Index (BASDAI), 1029
Bath Ankylosing Spondylitis Functional
Index (BASFI), 1029
Battery acid poisoning, 794
Bayes’ theorem, 5
BCG (bacille Calmette-Guerin)
for leprosy, 270
for tuberculosis, 594
BCP see Basic calcium phosphate
BCR see Breakpoint cluster region
Beau’s lines, 1261 , 1 261 f
Becker muscular dystrophy, 48b
Becker’s disease, 1145b
Beckwith-Wiedemann syndrome, 51b
Beclometasone, 17-18
Bedside procedures, for safe
transfusion, 934, 934f-935f
Behaviour
assessment of, in psychiatric
interview, 1 1 81
disturbed and aggressive,
1188-1189, 1189 f
in old age, 1 1 89b
high-risk, transition medicine and,
1295
history-taking in, 1295b
personality and, 1295
protective factors in, 1295
theories in, 1295
psychiatric disorders and, 1183
Behaviour therapy, 1 1 90
Behavioural rating scales, for pain,
1343
Behget’s disease, 1043-1044, 1043 f,
1044b
Beighton score, modified, 1059
Bejel, 254, 254b
Beliefs, abnormal, 1181
Belimumab, for musculoskeletal
disease, 1006-1007, 1007b
Bell’s palsy, 1082-1083
Bence Jones protein, 394-395
Bence Jones proteinuria, 966-967
Bendroflumethiazide, 22 b
Benign oesophageal stricture, 793,
795-796, 796b
Benign paroxysmal positional vertigo,
1 1 04, 1 1 04 f
INDEX • 1371
Benign prostatic enlargement (BPE),
437-438
treatment for, 438b
Benign prostatic hyperplasia (BPH), 437
Benserazide, 1113
Benzamides, substituted, 1198b
Benzathine benzylpenicillin, for syphilis,
339
Benzbromarone, 1016
Benzene, 1320b
Benzimidazoles, for helminthic
infections, 129
Benzisoxazole, 1 1 98b
Benznidazole, for trypanosomiasis, 1 28
Benzocaine, allergy, 1247b
Benzodiazepines, 1 1 90b
adverse reactions of, 22 b, 1310b
alcohol withdrawal, 1195
for anxiety disorders, 1190b, 1201
delirium, 1310b
misuse of, 1 42
overdose, 142
respiratory depression and,
1 1 88-1 1 89
stress reactions, 1201
withdrawal, 1186b
Benzoyl peroxide, 1 242-1 243
Benzylpenicillin, 120b
for cerebral abscess, 1 1 24b
for meningitis, 1 1 20 b
for neurosyphilis, 1125
procaine see Procaine penicillin
Bereavement, 1 1 84
Beri-beri, 714
Bernoulli equation, modified, 451-452
Berylliosis, 616
Beta-adrenoceptor blockers, for heart
failure, 467
Beta-blockers
adverse reactions of, 22 b, 1310b
for anxiety disorder, 1201
for essential tremor, 1115
for hypertension, 513
poisoning from, 140
for thyrotoxicosis, 637-638
Beta-chain haemoglobinopathy, 953
Beta-lactam antibiotics, 116b, 120-121
adverse reactions of, 120-121
drug interactions of, 121
mechanism of action, 116b
pharmacokinetics of, 1 20
Beta particles, 1 64, 1 64 f
Beta-thalassaemia, 953-954
diagnostic features of, 954b
management and prevention of,
953-954, 954b
Beta-2-microglobulin, as tumour
markers, 1324b
Bevacizumab, 1332
Bi-level ventilation, 202
Bicarbonate, 349b
arterial blood of, 1 358b
in diabetic ketoacidosis, 738
see also Sodium bicarbonate
Bicarbonate system, 364, 364f
Biguanides, for hyperglycaemia, 746
Bilateral diaphragmatic weakness, 627
Bile, 850-851
reflux, 801
Bile acid diarrhoea, 809
Bile acid-sequestering resins, 376-377
Bile duct, tumours of, 907-908
Bile salts, 768 f
Bilharziasis see Schistosomiasis
Biliary colic, 904
Biliary disease, 902-909
autoimmune, 885-890
clinical examination of, 846f
extrahepatic, 902-903
intrahepatic, 902
inflammatory and immune disease
and, 902
investigation of, 852-855, 852b
see also Liver disease
Biliary obstruction, pregnancy and, 900
Biliary sludge, 904
Biliary sphincterotomy, 906
Biliary system, functional anatomy of,
849-850
Bilirubin
alcoholic hepatitis and, 882
excretion of, 851 f
Gilbert’s syndrome and, 897
liver blood biochemistry and, 852
metabolism of, 850-851
plasma
acute liver failure and, 858
jaundice and, 860
viral hepatitis, 872
reference range of, venous blood,
1360b
see also Hyperbilirubinaemia
Bioavailability, 17
Biochemical disorders, clinical
examination of, 346-348, 346f
Biochemical investigations, 348-349,
348b
Biochemical markers, cancer, 1323,
1324b
Biochemical tests, for liver disease,
852-853
Biochemistry, 388-389
of bone disease, 990-991
of coeliac disease, 807
Biological therapies
for cancer, 1 332
for musculoskeletal disease,
1006-1007, 1006f
for psychiatric disorders, 1 1 90
for skin disease, 1 228
Biopsy, 776
bone, 992
brain, 1078
cancer diagnosis, 1330
liver, 855, 855 b, 884
for hepatocellular carcinoma, 891
for lung cancer, 601
muscle, 992, 1078
for neurological disease, 1078
pleural, 563-564
renal, 391, 391b
skin, 1214-1215
synovial, 992
temporal artery, 992
tissue, in musculoskeletal disease,
992
Bioterrorism, 1 1 1
Biotin, 715
deficiency, 715
dietary sources of, 711b
reference nutrient intake of, 711b
2,3-Biphosphoglycerate (2,3-BPG),
915-916
Bipolar disorder, 1 1 99-1 200
prevalence of, 1 1 80 b
Birch oral allergy syndrome, 85
Bird fancier’s lung, 616b
Bisacodyl, 834b
Bismuth, 230, 800
Bisoprolol, 466b
for angina, 490
for arrhythmias, 481
for hypertension, 513
Bisphosphonates
adverse effects of, 1 048b
for bone metastases, 1 329
for giant cell arteritis, 1 043b
for multiple myeloma, 968
osteomalacia and, 1053
for osteoporosis, 1047-1048, 1047f,
1048b
for Paget’s disease, 1054
Bites
snake, 158b
spider, 161
Bithionol, 129
Bitot’s spots, 713
Blackheads see Comedone
Blackouts, 1080
alcoholic, 1195
in older people, 1 308
Bladder, 386
disturbance, 1093-1094
dysfunction, 1093-1094, 1094b
flaccid, 1093
multiple sclerosis and, 1 1 09-1 1 1 0
ultrasound of, 389
Bladder neck, obstruction, 437
Blastomyces dermatitidis, 304
Blastomycosis, 304
Blatchford score, 780
Bleeding, 913-914, 913b, 927-929
clinical assessment of, 928-929
gastrointestinal, 780-783
in haemophilia A, 972
investigation of, 929
supportive therapy for, 957
variceal see Variceal bleeding
see also Haemorrhage
Bleeding disorders, 920-922, 970-975
acquired, 974-975
rare inherited, 974
Bleeding time, 921, 1362b
Bleomycin
Hodgkin lymphoma, 963
pigmentation from, 1258b
for viral warts, 1 239
‘Blind loop syndrome’, 808-809
Blindness, night, 713
Blisters, 121 If, 1218-1219
acquired, 1218b
clinical assessment of, 1218f, 1219
definition of, 1218
investigations and management of,
1219
a- Blockers
for benign prostatic enlargement, 438
for hypertension, 513, 514b
for phaeochromocytoma, 675-676
Blood
arterial, analytes in, 1358b
components of, 931b
culture, 106, 107f-108f, 225-226,
225 b
functional anatomy and physiology of,
914-919
oxygenation in, 190
Blood-brain barrier, 1064-1065
Blood cells, 915-917
see also Platelets; Red cells
Blood count
for acute kidney injury, 416b
for gastrointestinal bleeding, 777-778
for hepatobiliary disease, 853
for musculoskeletal disease, 990
see also Platelets; Red cells
Blood diseases
clinical examination of, 912-914, 91 2f
investigation of, 919-923
ophthalmic features of, 1 1 64b
pregnancy and, 1284-1285
anaemia as, 1 284, 1 285b
Rhesus disease as, 1 285
thrombocytopenia as, 1285, 1285b
venous thromboembolism as, 1 285
presenting problems in, 923-930
principles of management of,
930-940
pruritus and, 1219b
rheumatological manifestations of,
1058
in systemic lupus erythematosus,
1035-1036
see also individual disorders
Blood donation, 930-931, 932 f
Blood film examination, 920, 921b,
921 f
Blood flow
Doppler echocardiography for,
451-452, 451 f
respiration and, 447-448
through heart, 444f
resistance to, 447
Blood glucose, of stroke patients,
1159b
Blood loss, 940-941
Blood pool imaging, for cardiovascular
system, 454
Blood pressure
effects of respiration on, 447b
in endocrine disease, 630f
examination of, respiratory system,
546f
optimal target, 513b
of stroke patients, 1 1 59 b
see also Hypertension
Blood products, 930-931, 931b
Blood-stream infection, 225, 225 b
see also Bacteraemia
Blood supply, to liver, 848-849, 848f
Blood tests
for abdominal pain, 787
for cerebrovascular disease,
1151-1152
for diabetes mellitus, 726
for gastrointestinal bleeding, 777
for hepatobiliary disease, 853
for inflammatory bowel disease, 818
for malabsorption, 785 f
for musculoskeletal disease, 990-992
for neurological disease, 1 077
older people, 923b
for pain, 1342, 1342b
for pneumonia, 584b
for renal disease, 388-389
for skin disease, 1215-1216
for stroke, 1151-1152
see also Haematological values
Blood transfusion, 930-936
adverse effects of, 931-933
exchange
for malaria, 277
for megaloblastic anaemia, 945
for sickle-cell disease, 953
in intensive care, 21 1
in major haemorrhage, 934-936
other immunological complications of,
933
safe transfusion procedures in, 934
for sickle-cell anaemia, 953
Blood vessels
imaging of, 1074
see also Vascular
Blood volume, reference range of, 1 362b
Bloom’s syndrome, 1321b
BLS see Basic life support
Blue naevi, 1235
Blurred vision, of ophthalmic disease,
1170
BMD see Bone mineral density
BMI see Body mass index
BMR see Basal metabolic rate
BNP see Brain natriuretic peptide
Body composition, measures of, 693b
Body dysmorphic disorder, 1 202
Body fat, in endocrine disease, 630f
Body lice, 1 241
Body mass index (BMI)
cardiovascular disease risk and, 699f
clinical assessment of, 693b
diabetes risk and, 699f
obesity and, 700, 700b
of older people, 1 302 f
pancreatitis and, 837 b
Body packers/stuffers, 144, 144f
‘Boerhaave’s syndrome’, 797
Bohr effect, 1 90
Bone
anatomy of, 984-985
biopsy, 992
cortical, 984f
in endocrine disease, 630f
fractures see Fractures
infection, 1019-1021
in old age, 1 020b
matrix, 985
metabolism, pregnancy and, 1272
mineral, 985
mineralisation, 985
pain, 1324b
remodelling, 985, 985f-986f, 986b
resorption, 985, 985f
trabecular, 984f
tumours, 1056-1057
metastatic, 1329
woven, 985
Bone disease, 1044-1056
biochemical abnormalities in, 990b
metabolic
after gastric resection, 801
chronic kidney disease and,
418-419
metastatic, 1057
in bone scintigraphy, 988-989
in tuberculosis, 591
see also individual disorders
1372 • INDEX
Bone lining cells, 985
Bone marrow, 914, 914 f
examination of, 920, 922 f
Bone marrow stromal cells, 985
Bone marrow transplantation (BMT), for
severe combined immune
deficiency, 80
Bone mineral density (BMD), 989-990
Borrelia burgdorferi, 255
Borrelia infections, 255-257, 256b
Botfly, 235 f
Botulinum toxin, 104b, 1126, 1126b
for achalasia, 795
for dystonia, 1116
for hemifacial spasm, 1116
Bouchard nodes, 982 f, 1 009
Bouginage, 775 f, 793
Boutonneuse fever, 271 b
Bovine serum albumin (BSA), 729
Bovine spongiform encephalopathy
(BSE), 1127
Bowel
disturbance, 1093-1094
whole bowel irrigation, 136
see also Colon; Small intestine
Bowen’s disease, 1230b, 1232, 1232f
BPH see Benign prostatic hyperplasia
Brachial plexopathy, 1141
Brachial plexus lesions, 1141b
Brachytherapy, 1331
Bradykinesia, 1069
Brain
alcohol-related damage, 1 1 95
arterial circulation of, 1 1 50 f
biopsy, 1078
cerebral hemispheres, 1066-1067,
1066b, 1067f
damage due to alcohol, 1195
lesions, 1071-1072, 1072b
schizophrenia, 1 1 96
structure and function of, psychiatric
disorders and, 1183
tumours, 1129-1132, 1129b, 1 1297
clinical features of, 1129
investigations of, 1130, 1 1 30f
management of, 1130-1131
metastatic, 1328, 1328b
prognosis of, 1131
venous circulation of, 1 1 51 f
see also specific regions, and entries
under cerebral
Brain death
classification of, 212b
organ donation after, 213
UK criteria for diagnosis of, 211b
Brain injury, from critical illness, 21 1 ,
21 lb-21 2b
Brain natriuretic peptide (BNP), 351 ,
450
Brainstem, 1067, 1067f
death, 21 1
encephalitis, 1 1 22
lesions, 1083-1084
Breakpoint cluster region (BCR)
abl oncogene, 958
Philadelphia chromosome, 958
Breast cancer, 1333-1334
clinical features of, 1333-1334
investigations of, 1 334
management of, 1 334
in older people, 1325b
pathogenesis of, 1 333
screening, 1325b
staging, 1333b
survival rates for, 1333, 1333b
Breastfeeding
HIV infection/AIDS and, 326-327
safety of antirheumatic drugs during,
1281b
Breasts, in endocrine disease, 630f
Breath tests, gastroenterology, 777
Breathing
assessment of, in deteriorating
patient, 188
control of, 549
in divers, 170
Kussmaul, 415
of stroke patients, 1 1 59 b
see also Respiration
Breathlessness, 557-558
acute, 179-181, 558 b
clinical assessment of, 179-180
clinical features in, 180b
investigations of, 180-181
presentation of, 179, 179f
severe, 558
chronic exertional, 557-558, 558 b
in COPD, 575
differential diagnosis of, 557, 558b
in lung cancer, 600
in palliative care, 1353
pathophysiology of, 557, 557 f
in pregnancy, 1274-1275, 1275b
psychogenic, 558b
Briquet’s syndrome, 1202
Bristol stool chart, 229, 229 f
British National Formulary, 28
Broca’s area, 1 070
Bromocriptine
for brain tumours, 1 1 30
for neuroleptic malignant syndrome,
1197-1198
for Parkinson’s disease, 1114b
for prolactinoma, 685, 685b
Bronchial artery, 549f
angiography, 560f
embolisation, 597
Bronchial gland adenoma, 603b
Bronchial gland carcinoma, 603b
Bronchial obstruction
in lung cancer, 600, 600b, 600f
radiological features of, 551 , 552 f
Bronchiectasis, 578-579, 578b-579b,
579 f
Bronchoalveolar carcinoma, 603b
Bronchodilators
for acute exacerbations of COPD,
577
for chronic obstructive pulmonary
disease (COPD), 576
Bronchopulmonary aspergillosis,
classification of, 596b
Bronchopulmonary segments, 548f
Bronchoscopy, 553
in haemoptysis, 560
in lung cancer, 601 , 601 f
in mediastinal tumours, 604
Bronchus, tumours of, 598-605
Brown-Sequard syndrome, 1 083, 1 1 36
Bruce Protocol, for exercise ECG,
449-450
Brucella abortus, 254
Brucella canis, 254
Brucella melitensis, 254
Brucella suis, 254
Brucellosis, 254
clinical features of, 254, 255f
diagnosis of, 254
incubation period of, 111b
management of, 254, 255b
in pregnancy, 235b
Brudzinski’s sign, 1118
Brugada syndrome, 477
Brugia malayi infection, 233b, 291 ,
291 f
BSA see Bovine serum albumin
BSE see Bovine spongiform
encephalopathy
BTK gene, X-linked
agammaglobulinaemia and, 78
Bubonic plague, 259
Buccal administration, 17
Budd-Chiari syndrome, 898-899
acute liver failure and, 857-858
Budesonide (BUD), 821b
Buerger’s disease, 504
Bulbar palsy, 1 093, 1 093b
Bulimia nervosa, 1204, 1204b
Bullae, in lungs, 552 b, 575
Bullous disease, 1254-1257
Bullous eruptions, drug-induced, 1266b
Bullous impetigo, 1218b
Bullous lupus erythematosus, 1 255 b
Bullous pemphigoid, 1255-1256,
1255b, 1256f
Bumetanide
for hypertension, 513
for oedema, 396
Bundle branch block, 478-479, 478b,
478f
Bundle of His, 445
Bupropion, 139b
Burch-Wartofsky scoring system, for
thyrotoxic crisis, 639b
Burkholderia pseudomallei, 261
Burkitt’s lymphoma, 1320b
Burns
haemolysis and, 950
sunburn, 1 221 f
Burrow, definition of, 1241
Bursae, 987
Bursitis
anserine, 998b
deep infrapatellar, 998b
ischiogluteal, 999b
olecranon, 998b
pre-patellar, 998b
superficial, 998b
trochanteric, 998, 999b, 999f
Buruli ulcer, 254
Buschke-Lowenstein tumour, 343
Buspirone, 139b
Busulfan
drug-induced pigmentation,
1258b
hepatotoxicity of, 894b
Butterfly rash, 982f
Button hole deformity of fingers,
1023
Butyrophenones, 1 1 90b
for schizophrenia, 1 1 98b
Byssinosis, 614, 616b
C
C-peptide, 724, 724 f, 727
C-reactive protein (CRP), 63
abnormal, conditions associated with,
72 b
in acute phase response, 70
inflammation and, 71-72
reference range of, venous blood,
1360b
Cl inhibitor deficiency (hereditary
angioedema), 87
acquired, 88
C4d staining, 89
CA-19.9, as tumour markers, 1324b
Cabergoline
for brain tumours, 1 1 30
nephrotoxicity, 427b
for Parkinson’s disease, 1114b
for prolactinoma, 685b
CABG see Coronary artery bypass
grafting
Cabozantinib, for medullary carcinoma,
650
Cachexia, cancer, 693f
CADASIL, 1095
Cadherin-1 (CDH1), 1319
Cadmium, lung cancer, 618
Caecum, cancer, 831
Caeruloplasmin, 1360b
Wilson’s disease, 896
Cafe au lait spot, 1 1 31 f
Caffeine, 716
cagA see Cytotoxin-associated gene
Calabar swelling, 292
Calcific periarthritis, 1017, 1 01 7f
Calcification
artery, 452
metastatic, 369
in musculoskeletal disease, 988
Calcimimetic agents, 419
Calcineurin inhibitors, 1226
Calcinosis
crystal -associated arthritis and
deposition in connective tissue,
1013b
nephrocalcinosis, 427b, 431
Calcipotriol, 1250
Calcitonin
for Paget’s disease, 1054b
as tumor markers, 1324b
Calcitonin gene-related peptide (CGRP),
771-772
Calcitriol (1 ,25-dihydroxycholecalciferol),
for hypoparathyroidism, 665
Calcium, 716
absorption, 716
acute kidney injury and, 416b
deficiency, 716
dietary sources of, 717b
excess, 716
homeostasis, 367
in myocardial contraction, 446
for osteoporosis, 1048, 1048b
pregnancy and, 1272
reference nutrient intake of, 717b
reference range of
urine, 1361b
venous blood, 1360b
in skeletal disease, 990b
stone, prevention of, 433b
see also Hypercalcaemia;
Hypocalcaemia
Calcium and vitamin D supplements,
1048
Calcium antagonists (channel blockers)
adverse reactions of, 22 b
for angina, 491b
for arrhythmias, 472
for hypertension, 513
for hypertrophic cardiomyopathy, 540
for mitral stenosis, 519
poisoning from, 140
for pulmonary hypertension, 622
for Raynaud’s phenomenon, 1038
Calcium carbonate, 41 9
Calcium gluconate, 368
cardiotoxic drug poisoning, 140
drug interactions, 24b
for hypermagnesaemia, 368
Calcium oxalate
crystal, 147
stones, 431b
Calcium phosphate, stones, 431b
Calcium pyrophosphate crystals, 663
Calcium pyrophosphate dihydrate
(CPPD) crystal deposition
disease, 1016-1017
Calcium therapy
for hypoparathyroidism, 665
for osteoporosis, 1 047
for rickets/osteomalacia, 1 052
tetany, 663
Calculi (stones)
gallbladder see Gallstones
renal, 431, 431b
staghorn, 431 , 432f
urinary, 431
see also Gallstones
Calicivirus, 872 b
Calprotectin, faecal, 777b, 1361b
‘Cameron lesions’, 793
Campbell de Morgan spots, 1234,
1 234f
Campylobacter jejuni
Guillain-Barre syndrome, 1140
infection, 262
Camurati-Engelmann disease, 1 056
Canakinumab
for gout, 1015
for musculoskeletal disease, 1007,
1007b
Canalicular system, 918
Cancer, 1316, 13167, 1333b
aetiology, environmental, 1320b
biochemical markers, 1323
breast, 1333-1334
clinical features of, 1333-1334
investigations of, 1 334
management of, 1 334
pathogenesis of, 1 333
staging, 1333b
survival rates for, 1333, 1333b
cervical, 1335
investigations in, 1335
management of, 1 335
pathogenesis of, 1 335
childhood, 1298
clinical examination of, 1314, 13147
colorectal, 830-833
clinical features of, 831
dietary risk factors for, 830b
familial adenomatous polyposis,
828-829, 829b, 829f
INDEX • 1373
investigations of, 832, 833 f
management of, 832
modified Dukes classification and
survival of, 832 f
non-dietary risk factors for, 830b
pathogenesis of, 830f
pathophysiology of, 830-831 , 831 f
prevention and screening of,
832-833
determinants of, 1320-1321
environmental, 1320-1321, 1320b
genetic, 1321, 1321b
ectopic hormone production, 1325,
1325b
emergency complications of,
1326-1328
endometrial, 1334-1335
investigations of, 1 334
management of, 1 335
pathogenesis of, 1 334
of gallbladder, 904
hallmarks of, 1316-1320
activating invasion and metastasis,
1319
angiogenesis, 1318, 1 31 9f
enabling replicative immortality,
1318
evading growth suppressors, 1318
evading immune destruction, 1320
genome instability/mutation, 1316
reprogramming energy metabolism,
1319
resisting cell death, 1316-1317
sustaining proliferative signalling,
1317
tumour-promoting inflammation,
1319-1320
histology of, 1322
cytogenetic analysis, 1 322
electron microscopy, 1322
immunohistochemistry, 1322
light microscopy, 1322
HIV-related, 322, 323 b
imaging for, 1323
inheritance, 1321b
investigations of, 1321-1323,
1322b
local features of, 1324b
lung, 599-603, 599f
burden of, 598b
cell types in, 599b
clinical features of, 599-601
investigations of, 601 -602
management of, 602-603
non-metastatic extrapulmonary
manifestations of, 601b
occupational, 618
pathology of, 599, 599 f
prognosis for, 603, 603b
metastatic disease, 1328-1329
neurological paraneoplastic
syndromes, 1325-1326
obesity and, 698f
in older people, 1 325b
oral, 790, 790 b
ovarian, 1334
investigations of, 1 334
management of, 1 334
pathogenesis of, 1 334
predisposition syndromes, 1321b
presenting problems of, 1323-1326,
1 324b-1 325b
renal cell, 434-435, 435f
screening, breast cancer, 1325b
staging, TNM classification, 1322b
therapeutics for, 1329-1333
adjuvant, 1329
biological, 1332
chemoprevention, 1330
chemotherapy, 1330
hormonal, 1332
immunotherapy, 1332
neoadjuvant, 1330
palliative, 1329
radiation therapy, 1331-1332
surgical, 1330
of unknown origin, 1336, 1336b
see also Chemotherapy; specific
cancers
Cancer antigen 19.9 (CA-19.9), 1324b
Cancer antigen 125 (CA-125), 1324b
Cancer cachexia, 693 f
Candesartan
for heart failure, 466b
for myocardial infarction, 500-501
Candida albicans, 300
Candida dubliniensis, 302
Candida glabrata, 302
Candida krusei, 302
Candida parapsilosis, 302
Candida spp., 100, 103 f
endocarditis, 528
Candida tropicalis, 302
Candidiasis, 334b, 336b
acute disseminated, 302
chronic disseminated, 302
genital, 735 b
oesophageal, 794
oral, 790
skin, 1240
superficial, 300
systemic, 302
Cannabis, 143
CAPD see Continuous ambulatory
peritoneal dialysis
Capecitabine, 832
Caplan’s syndrome, 610-611
Capnocytophaga canimorsus, 226b
Capnography, 175 f
Capsaicin
for herpes zoster, 240
for osteoarthritis, 1003-1004
topical, 315
Capsule endoscopy, 774-776, 775 f
wireless, 775 f, 776 b
Capsulitis (frozen shoulder), 997-998
Caput medusae, 868
Carbamate insecticides, 1 46-1 47
Carbamazepine
for epilepsy, 1 1 02 b
hyponatraemia, 1 1 03b
multiple sclerosis, 1110b
pharmacodynamics, 20 b
poisoning, 141b
for status epilepticus, 1081b
for trigeminal neuralgia, 1 097
Carbapenems, 120b, 121
Carbaryl, 1241
Carbenoxolone, 361
sodium content of, 864b
Carbidopa, 1113
Carbimazole
for Graves’ thyrotoxicosis, 644
for thyrotoxicosis, in pregnancy,
1279
Carbohydrates, 695-697
in diabetic diet, 743-744
dietary, 696b
energy provided by, 694
recommended intake, 698b
digestion of, 768
metabolism, 850
disorders of, 370
see also Diabetes mellitus
effects of insulin in, 723 b
Carbon dioxide
arterial blood (PaC02), 204, 1358b
removal of, extracorporeal, 204
Carbon monoxide poisoning, 134b,
144-145
Carbonic acid/bicarbonate buffer
system, 363-364
Carbonic anhydrase, 717
Carbonic anhydrase inhibitors, for
hypervolaemia, 354
Carboplatin, 1334
Carboxyhaemoglobin, reference range
of, 1360b
Carboxypenicillins, 121
Carbuncles, 1237, 1237f
Carcinoembryonic antigen (CEA), 1322,
1324b
Carcinoid syndrome
pellagra, 714
valvular heart disease, 526
Carcinoid tumours
gastric, 805
lung, 603b
Carcinoma
at ampulla of Vater, 907-908
anaplastic, 650
basal cell, 1229-1230, 1 2297, 1230b,
1324b
bronchial gland, 603b
bronchoalveolar, 603b
fibrolamellar hepatocellular, 892
follicular, 649
of gallbladder, 907
gastric, 803-804, 804f
hepatocellular, 890-892, 891 f
chemotherapy for, 892
cirrhosis and, 890
fibrolamellar, 892
hepatic resection for, 891
hepatitis B and, 873
liver biopsy for, 891
liver transplantation for, 891
management of, 892f
in old age, 901b
percutaneous therapy for, 891
screening for, 890-891
trans-arterial chemo-embolisation
for, 892
medullary, 650
of oesophagus, 796-797
of pancreas, 843 f
papillary, 649
squamous, 796b
skin, 1230-1231, 1231f
of unknown origin, 1336, 1336b
see also sites of carcinoma
Carcinoma in situ, 1230b
Card agglutination trypanosomiasis test
(CATT), 279
Cardiac arrest, 456-457, 456b, 456f
chain of survival in, 457, 458f
clinical assessment and management
of, 456-457, 457f-458f
post, 200-201
acute management of, 201, 201b
prognosis of, 201, 201b
Cardiac arrhythmias, 1 1 98
Cardiac biomarkers, 450
for acute coronary syndrome, 497,
498f
Cardiac catheterisation, 453-454, 453f
aortic regurgitation, 525 b
aortic stenosis, 523b
mitral valve disease, 519, 521b
Cardiac death, organ donation after,
213
Cardiac disease, 899
HIV-related, 322
in pregnancy, 1 282
aortic dissection, 1282
congenital, 1282
dilated cardiomyopathy, 1 282
myocardial infarction, 1282
peripartum cardiomyopathy, 1 282
valvular, 1282
Cardiac glycosides see Digoxin
Cardiac output, 447-448
heart failure, 461
Cardiac pacemakers
code, 483b
permanent, 469, 483, 483b
rate-responsive, 483
temporary, 482-483, 483f
Cardiac peptides, 446-447
Cardiac resynchronisation therapy, for
arrhythmias, 484
Cardiac tamponade, 447-448, 544,
544b
see also Heart
Cardiac transplantation, 467-468
Cardiac tumours, 541-542
Cardiobacterium hominis, 528
Cardiogenic shock, 199-200, 206 b
causes of, 200f
downward spiral of, 1 99, 200f
Cardiology, 441-544
Cardiomegaly, 450
Cardiomyopathy, 538-541, 539f, 541b
arrhythmogenic ventricular, 540
dilated, 1282
HIV-associated, 322
hypertrophic obstructive, 1297-1298
obliterative, 541
peripartum, pregnancy and, 1282
restrictive, 540
septic, 198
types of, 539f
Cardiopulmonary resuscitation (CPR),
213b
see also Basic life support
Cardiothoracic ratio, 450
Cardiotoxicity, venom and, 155
Cardiovascular disease
chronic kidney disease and, 420
congenital, 531-538
hypertension see Hypertension
investigation of, 448-454
New Heart Association (NYHA)
functional classification of, 454,
454b
ophthalmic features of, 1165b
presenting problems in, 454-468
in rheumatoid arthritis, 1 024
risk of, obesity, 699f
syphilis, 338
in systemic lupus erythematosus,
1035
transition medicine and, 1297-1298
congenital heart disease, 1 297
hypertrophic obstructive
cardiomyopathy, 1 297-1 298
Cardiovascular medications, poisoning
from, 140
Cardiovascular risk prediction chart,
51 If
Cardiovascular support, in intensive
care, 204-208
advanced haemodynamic monitoring,
206, 207 b, 207 f
fluid and vasopressor use, 206, 206b
initial resuscitation, 204-206, 206b
mechanical, 206-208
Cardiovascular system
clinical examination of, 442-444,
442f
pregnancy and, 1272
Cardioversion, 482
atrial fibrillation, 470-471
direct current (DC), 470
ventricular tachycardia, 475
Carditis, 515-516
Care see Health care
Carey Coombs murmur, 515-516
Carnitine-palmitoyl transferase (CPT)
deficiency, 1 1 44b
Caroli’s disease, 902
Carotenes, 712-713
Carotid endarterectomy, 1 1 60
Carotid pulse, 166, 189
Carpal tunnel syndrome, 1058
diabetes, 760
rheumatoid arthritis, 1024
Carrion’s disease, 272
Cartilage
articular, 987, 98 7f
calcification of, 988
osteoarthritis in, 1010
Carvedilol, 869
for arrhythmias, 481
for hypertension, 513
Casal’s necklace, 714, 71 5f
Caspases, 41
Caspofungin, 125b, 126
for acute leukaemia patients, 957
for aspergillosis, 598
Cassava, 839-840
Castleman’s disease, 220b, 248
Cat scratch disease, 272
Cataplexy, 1105
Cataract
diabetics, 756 b
in ophthalmological conditions, 1174
‘snowflake’, 1177
Catatonia, 1196-1197
Catechol-O-methyl-transferase (COMT)
inhibitors, for Parkinson’s
disease, 1114
Catecholamines, 666
drug interactions, 24b
Catephen, for anogenital warts, 343
Cathepsin K, 985
1374 • INDEX
Catheter ablation therapy, 484, 484f
for arrhythmias, 470
Catheters/catheterisation
bacteriuria, 429-430
bladder dysfunction, 1094b
cardiac, 453-454, 4537
aortic regurgitation, 525 b
aortic stenosis, 523b
mitral valve disease, 519, 521b
pulmonary artery, critically ill patients,
206, 207 7
Cathinones, 143
CATT see Card agglutination
trypanosomiasis test
Cauda equina syndrome, 997 b
Caudal regression syndrome,
1 278-1 279
Caval filters, for pulmonary embolism,
621
Cawthorne-Cooksey exercises, 1104
CBT see Cognitive behaviour therapy
CCK see Cholecystokinin
CD4 cells, in HIV infection/AIDS,
309-310
CD4+ T lymphocytes, 70
CD8+ T lymphocytes, 70
CDKs see Cyclin-dependent kinases
CEA see Carcinoembryonic antigen
Cefaclor, 121b
Cefalexin, 121b
for urinary tract infection, 428
Cefazolin, 121b
Cefepime, 117b, 121b
Cefixime, 121b
for gonorrhoea, 340b
Cefotaxime, 117b, 121b
for cerebral abscess, 1 1 24b
for meningitis, 1 1 20 b
for spontaneous bacterial peritonitis,
864
Cefoxitin, 121b
Cefradine, 121b
Ceftaroline, 121b
Ceftazidime, 117b, 121b
for bronchiectasis, 579
for melioidosis, 261
Ceftobiprole, 121b
Ceftriaxone, 117b, 121b
for leptospirosis, 258-259
for meningitis, 1 1 20 b
for nocardiosis, 261
for pneumonia, 319
for pyogenic meningitis, 1 1 20 b
for STIs
congenital syphilis, 339
gonorrhoea, 340b
for Whipple’s disease, 809
Cefuroxime, 117b, 121b
for cerebral abscess, 1 1 24b
for cholecystitis, 905
for empyema, 565
for meningitis, 1 1 20 b
for pneumonia, 585 b, 586
prophylactic, 119b
Cefuroxime axetil, 256
Celecoxib, 1003b
Cell adhesion molecules, 1 31 87
Cell body, 1338
Cell cycle, 1317, 13177
regulation, 1317
stimulation, 1317
Cell differentiation, 40-41
Cell migration, 40-41
Cell surface antigens, 91 7
Cells
cerebrospinal fluid analysis of, 1077,
1078b, 1361b
death of, 41, 1316-1317
programmed (apoptosis), 1316
division of, 40-41
of nervous system, 1064-1065,
10647
senescence of, 41
Cellular immunity, 69-70, 69 7
Cellulitis, 1237, 12377
anaerobic, 227
clinical assessment of, 187
investigation of, 1 87
Central core disease, 1145b
Central nervous system (CNS)
HIV infection/AIDS, 309-310
tuberculosis, 591
Central sensitisation, 1340, 1 341 7
Central termination, 1338
Central venous catheter infections,
225-226
Central venous pressure, monitoring of,
1757 190b
Cephalosporin, 117b, 121, 121b
for cholecystitis, 905
for pneumonia, 586
in pregnancy, 120b
renal or hepatic disease, 32 b
for septic arthritis, 1 020
for variceal bleeding, 869, 869b
Cephamycins, 121
Cerebellar ataxia, 1 325
Cerebellar degeneration, cancer-related,
1325, 1325b
Cerebellar dysfunction, 1134
Cerebellum, 1069
Cerebral abscess, 1124, 11 24b, 1 1 24 7
Cerebral cortex
anatomy of, 1 067/
lobar functions of, 1 066b
effects of damage, 1 066b
Cerebral hemispheres, 1066-1067,
1066b, 1067 7
lesions, 1084
Cerebral infarction, 1 1 53-1 1 54,
11537-11547
Cerebral ischaemia, 9677
Cerebral oedema
acute liver failure and, 857
high-altitude, 168
hypoglycaemia, 740
stroke patients, 1 1 54-1 1 55
Cerebral palsy, transition medicine and,
1296
Cerebral perfusion pressure (CPP), 208
Cerebral toxoplasmosis, HIV-related,
315b, 320, 3207
Cerebral tumours see Brain, tumours
Cerebral venous disease, 1162
causes of, 1 1 62 b
clinical features of, 1162, 11 62b
investigations and management of,
1162
Cerebrospinal fluid (CSF), 1067
analysis, 1077, 1078b, 1361b
circulation, 1128b
encephalomyelitis, 1110
Guillain-Barre syndrome, 1140
meningitis, 1118, 1121
multiple sclerosis, 1108
result of, interpretation of, 1077,
1078b
in subacute sclerosing
panencephalitis, 1 1 23
syphilis and, 339
in viral encephalitis, 1122
see also Lumbar puncture
Cerebrotendinous xanthomatosis, 375 b
Cerebrovascular disease see specific
conditions
Certolizumab, for musculoskeletal
disease, 1007b
Cervical cancer, 1 335
HIV-related, 322
investigations of, 1335
management of, 1 335
pathogenesis of, 1 335
Cervical cord compression, 1 1347
in cervical spondylosis, 11347
in rheumatoid arthritis, 1 024b
Cervical spine
myelopathy, 1134-1135
radiculopathy, 1134, 11347
spondylosis, 1134-1135, 11347
subluxation of, 1024, 10257
Cervicitis, gonococcal, 335
Cestode infections, 233b, 297-299
Cetirizine, 1227
Cetuximab, 832, 1335-1336
CF see Cystic fibrosis
CFTR see Cystic fibrosis
transmembrane conductor
regulator (CFTR) protein
CFU-E (colony-forming unit erythroid),
914-915
CFU-GM (colony-forming unit-
granulocyte, monocyte), 914
CFU-Meg (colony-forming unit-
megakaryocyte), 914, 918
CGRP (calcitonin gene-related peptide),
771-772
Chagas’ disease, 279-280
transfusion-transmitted, 930-931
Chain of infection, 1007
Chain of survival, in cardiac arrest, 457,
4587
Chancre, 333-334
trypanosomal, 278
Chancroid, 341b
Channelopathies, 1144, 1145b
Charcoal, activated, 136, 136b
antidiabetic overdose, 141
digoxin/oleander poisoning, 140
NSAID overdose, 138
salicylate poisoning, 138
tricyclic antidepressant poisoning,
139
Charcot joints, 1 057, 1 0587
Charcot-Marie-Tooth disease (CMT),
1140
Charcot neuroarthropathy, 762
Charcot’s triad, 861-862
acute cholangitis and, 905
Charles Bonnet’s syndrome, 1 088
Cheese worker’s lung, 616b
Cheiroarthropathy, 1057
Chelating agents, 1 65
Chemical cholestasis, 902
Chemical poisoning, 144-149
Chemical warfare agents, poisoning
from, 149, 149b
Chemicals, in haemolysis, 950
Chemo-embolisation, hepatocellular
carcinoma, 892
Chemokine receptor inhibitor, 324b
Chemoprevention, 1330
Chemoprophylaxis, 1 1 2b
for malaria, 277, 278 b
Chemotherapy, 936, 936b, 1330
adjuvant, 1329
breast cancer, 1334
adverse effects, 1330, 13317
for brain tumours, 1130-1131
combination therapy, 1 330
for hepatocellular carcinoma, 892
for high-grade NHL, 966
for Hodgkin lymphoma, 963
leukaemia
acute, 956b
chronic lymphocytic, 960
chronic myeloid, 959
for low-grade NHL, 965
for lung cancer, 602-603
for multiple myeloma, 968
neoadjuvant, 1330
palliative, 1329
platinum-based, 602-603
for prostate cancer, 439
for tuberculosis, 592-594
Chernobyl, 164
Chest infection, in stroke patients,
11597
Chest pain, 176-179, 454-455
associated features of, 177-178, 1787
cardiac disease, aortic dissection,
507
characteristics of, 1 77
clinical assessment of, 178
differential diagnosis of, 1 77b
investigations of, 178-179, 179b
ischaemic, 4547
onset of, 1 77
pregnancy and, 1275
in respiratory disease, 558
site and radiation of, 1 77
Chest radiography/X-ray, 450
for bronchiectasis, 579
cardiovascular disorders
for aortic regurgitation, 4517
for chronic constrictive pericarditis,
5447
for heart failure, 464, 4647
for mitral valve, 4517
for myocardial infarction, 497-498
of cardiovascular system, 450
for COPD, 575
for empyema, 5647
of pacemaker/defibrillator, 4677
for pleural effusion, 563
pregnancy and, 1274
for respiratory disease
abnormalities, 552 b
ARDS, 1997
aspergillosis, 5977
asthma, 569
bronchial obstruction/lung collapse,
6007
bronchiectasis, 579
COPD, 575
empyema, 5647
haemoptysis, 560
HIV-related pulmonary disease,
318b, 3187-3197
interpretation, 551b
interstitial, 6057
lobar collapse, 5527
mediastinal tumours, 6047
pleural effusion, 563
pleural plaques, 6177
Pneumocystis jirovecii pneumonia,
3187
pneumonia, 585
pneumothorax, 626
pulmonary embolism, 619b, 6197
pulmonary hypertension, 6227
sarcoidosis, 609b
silicosis, 6157
tuberculosis, 5907, 5927
Chest wall deformities, 628
Chickenpox, 238-239
clinical features of, 238-239, 2387
diagnosis of, 239
incubation period of, 111b
management and prevention of, 239,
239 b
periods of infectivity, 111b
rash, 238
varicella zoster immunoglobulin, 240b
Chiclero ulcers, 285
Chief cells, 661
Chikungunya virus, 250
Chilblains, 167
Child-bearing potential, cystic fibrosis
and, 1297
Child-Pugh classification, cirrhosis
prognosis and, 867b
Childbirth, associated psychiatric
disorders, 1206
Childhood absence epilepsy, 1 1 00 b
Childhood cancer therapy, late effects
of, 689
Children
diabetes mellitus in, 753-754, 754b
important long-term conditions of,
adult health affected by, 1 288b
inflammatory bowel disease and, 823,
1299
laboratory reference range of, 1 363
osteomyelitis in, 1021
renal impairment in, causes of, 1 298b
STI in, 332-333
Chiropractic, 826b
Chlamydia pneumoniae, 272 b
Chlamydia psittaci, 272 b
Chlamydia spp., 272
Chlamydia trachomatis, 1 00-1 01 , 1 1 7b,
273
in pregnancy, 235 b, 332b
Chlamydial infection, 340-341
in men, 340
in reactive arthritis, 1031
treatment of, 341b
urethritis, 333
in women, 340-341
Chloasma, 1258
Chlorambucil
for chronic lymphocytic leukaemia,
960
for non-Hodgkin’s lymphoma, 965
for Waldenstrom macroglobulinaemia,
966
INDEX • 1375
Chloramphenicol, 1176, 124
contraindication to, in pregnancy,
1206
mechanism of action, 1166
for meningitis, 1 1 206
for plague, 259
in pregnancy, 1206
for pyogenic meningitis, 1 1 206
in renal/hepatic disease, 326
for rickettsial fevers, 271-272
Chloride, 3496, 718
channelopathies, 11456
reference range of, venous blood,
13586
Chloroquine
adverse reactions of, 22
pigmentation, 12586
leprosy reactions, 270
for malaria, 128, 2786
myopathy, 10576
poisoning, 1416
resistance to, 273, 277
Chlorphenamine, 336
anaphylaxis, 766
diphtheria, 625
pruritus, 935 f
Chlorpromazine
for acute diarrhoea, 230
for alcohol withdrawal, 1195
for cholestatic hepatitis, 894
hepatotoxicity, 8946
long QT syndrome, 4766
poisoning, 141
for rabies, 1 1 22
for schizophrenia, 1 1 97
Chlorpropamide, neutropenia, 9266
Cholangiocarcinoma, 892, 907, 907 f
primary sclerosing cholangitis and,
888
Cholangiography, 906
for hepatobiliary disease, 854-855
percutaneous transhepatic (PTC),
854-855
for sclerosing cholangitis, 888
Cholangiopancreatography
endoscopic retrograde see ERCP
magnetic resonance see MRCP
Cholangiopathy, HIV-related, 318
Cholangitis
acute, 905
liver flukes, 297, 2976
primary
biliary, 887-888
lgG4-associated, 890, 909
primary sclerosing, 888-890
recurrent pyogenic, 906-907
Cholecalciferol see Vitamin D
Cholecystectomy
in old age, 9096
for pancreatitis, 839
post-cholecystectomy syndrome,
9086
Cholecystitis, 905
acalculous, 905
acute, 788, 905
in old age, 9096
chronic, 905
gallstones and, 904
pregnancy and, 900
Cholecystography, oral, 909
Cholecystokinin (CCK), 768, 768 f,
7726
Cholecystolithiasis, 904
Choledochal cysts, 903, 903 f
Choledochojejunostomy, 842-844
Choledocholithiasis, 904, 906-907
endoscopic retrograde
cholangiopancreatography for,
906 f
endoscopic ultrasound for, 906f
Choledochoscopy, 906
Cholera, 1046, 264-265
clinical features of, 265
diagnosis and management of,
265
fluid loss, 265
incubation period of, 1116
prevention of, 265
‘Cholera sicca’, 265
Cholestasis, 894
benign recurrent intrahepatic, 902
biliary cirrhosis, 903
chemical, 902
obstetric (of pregnancy), 12206, 1284
pruritus, 12206
pure, 894
sclerosing cholangitis, 889
Cholestatic jaundice, 8606-8626,
861-862
Cholesterol, 370
absorption of, 697
atheroembolism, 3906
dietary, 6986
gallstones, 903, 9036
low-density lipoproteins, 371-372
metabolism of, 81
reference range of, venous blood,
13606
transport of, 372-373
see also Hypercholesterolaemia
Cholesterol absorption inhibitors, 371
Cholesterol emboli, 409, 409f
Cholesterol ester transfer protein
(CETP), 373
Cholesterol gallstones, 903, 9036
Cholesterolosis of gallbladder, 909
Choline salicylate, 790
Cholinergic syndrome, organophosphate
poisoning, 146, 1466
Chondrocalcinosis, 1016, 10166, 1 01 6f
Chondrocytes
in osteoarthritis, 1 008
tumours, 10566
Chondroitin sulphate, 987
for osteoarthritis, 1012
Chondroma, 10566
Chondrosarcoma, 10566, 1057
CHOP regimen, for non-Hodgkin
lymphoma, 966
Chorea, 1085
causes of, 1 0856
in Huntington’s disease, 1085
Chorionic villus sampling, 56
Choroid, of eye, 1167
Choroid plexus, 1 1 32f
Christmas disease, 973-974
Chromatin, 38, 38f
Chromatography, 3486
Chromium, 718
deficiency, 718
Chromoblastomycosis, 300-301
Chromosomal disorders, 446, 45f
see also specific conditions
Chromosomes, 38, 38f, 51-52, 52 f
abnormalities see Mutation(s)
analysis of, 45 f
leukaemia, 955-956
myelodysplastic syndromes,
960-961
deletions, 52
duplication, 44, 45f
sex, 38
see also X chromosome; Y
chromosome
translocations of, 805
Chronic allograft failure, 89
Chronic bronchitis, 5556, 573-574
Chronic cavitary pulmonary aspergillosis,
597, 597 f
Chronic cold agglutinin disease, 950
Chronic constrictive pericarditis,
543-544, 5436, 544f
Chronic demyelinating polyneuropathy,
11396, 1141
Chronic eosinophilic pneumonia,
611-612
Chronic exertional breathlessness,
557-558, 5586
Chronic fatigue syndrome, 1 202
Chronic fibrosing pulmonary
aspergillosis, 597
Chronic graft-versus-host disease, 937
Chronic granulomatous disease, 77
Chronic inflammation, 71
Chronic interstitial nephritis, 402-403,
4036
Chronic intestinal pseudo-obstruction,
810-811, 8116
Chronic kidney disease, 415-420, 4176
causes of, 4156
haemodialysis in, 422-423
indications for dialysis for, 4226
osteodystrophy and, 419 f
physical signs of, 41 6f
pregnancy and, 1282, 1283f
staging of, in children over 2 years of
age, 12986
transition medicine and, 1298-1299
Chronic laryngitis, 624, 6246
Chronic liver failure
causes of, 856f, 8676
cirrhosis and, 867
Chronic lymphocytic leukaemia (CLL),
959-960
clinical features of, 959
investigations of, 959-960
management of, 960
prognosis of, 960
staging of, 9606
Chronic meningococcaemia, 1119
Chronic mesenteric ischaemia, 827
Chronic myeloid leukaemia (CML),
958-959
characteristics of, 958
clinical features of, 958
investigations of, 959
management of, 959
accelerated phase, 959
blast crisis, 959
chronic phase, 959, 9596
natural history of, 958
Chronic obstructive pulmonary disease
see COPD
Chronic pain syndrome, 1348-1349
Chronic pancreatitis, 839-841, 8406
complications of, 8406
investigations of, 840, 8416, 841 f
management of complications of, 841
pathophysiology of, 840f
Chronic pulmonary aspergillosis (CPA),
596-597
Chronic pulmonary tuberculosis,
complications of, 5906
Chronic renal failure see Renal failure,
chronic
Chronic respiratory failure, 566-567
management of, 566-567, 5666
Chronic rheumatic heart disease, 517
Chronic venous insufficiency, 1 87
Chronic widespread pain, 1349
CHRPE see Congenital hypertrophy of
the retinal pigment epithelium
Chrysops, loiasis, 292
Churg-Strauss syndrome, 1043
Chvostek’s sign, 367
Chylomicrons, 697
Chylothorax, 562-563
Chyluria, lymphatic filariasis, 291
Chymotrypsinogen, 7706
Ciclesonide, 571
Ciclosporin
adverse reactions of
chronic interstitial nephritis, 4276
musculoskeletal, 10576
proximal myopathy, 1 1 45f
for aplastic anaemias, 969
asthma, 572
drug interactions, 246
eczema, 1246
heart transplant patients, 467
HSCT, 937
immunosuppression, 896
for inflammatory bowel disease, 8216
for lichen planus, 1 252
liver transplant patients, 901
lung transplant patients, 567
for primary biliary cholangitis, 888
for psoriasis, 1 250
for pyoderma gangrenosum,
1261-1262
for skin disease, 1 227-1 228
Ciclosporin A, for musculoskeletal
disease, 10046, 1005
Cidofovir
as antiviral agents, 1 276
CMV, 243
for herpesvirus infection, 1 26, 1 276
Cigarette smoke, in lower airway
defences, 550
Ciguatera poisoning, 149-150
Cilia, 62-63
Ciliary body, of eye, 1 1 67
Ciliary dysfunction syndromes, 5786,
579
Ciliary dysmotility syndrome, 550
Cilostazol, 504
Cimetidine
drug interactions of, 24
neutropenia, 9266
for urticaria, 1254
Cinacalcet, for primary
hyperparathyroidism, 664
Ciprofloxacin, 1176, 1236
for anthrax, 267
for bacillary dysentery, 265
for bronchiectasis, 579
for brucellosis, 2556
for cholera, 265
drug interactions of, 23
for inflammatory bowel disease, 823
for intestinal bacterial overgrowth,
808-809
for meningococcal infection, 1120
for plague, 259
for primary sclerosing cholangitis, 890
prophylactic, 1196
for Q fever, 272
for spontaneous bacterial peritonitis,
864
for STIs
chancroid, 3416
gonorrhoea, 3406
for urinary tract infection, 4296
for variceal bleeding, 869
Circinate balanitis, 3346, 1031
Circulation
assessment of, in deteriorating
patient, 189
coronary, 444-445
enterohepatic, 19
portal, 384, 385f
of stroke patients, 11596
Circulatory collapse, pregnancy and,
1275
Circulatory failure (shock), 193
acute, 199-200
Circumduction, 1086
Circumflex artery (CX)
in coronary circulation, 444-445, 445f
with stenosis, 453f
Cirrhosis, 866-867
alcoholic, 881-882, 8816
ascites and, 867
biliary, secondary, 903
causes of, 8666-8676
Child-Pugh classification of, 8676
cryptogenic, 884
drugs to be avoided in, 8946
haemochromatosis, 866-867
hepatic encephalopathy and, 865
hepatic fibrosis and, 866, 866f
hepatitis B and, 873, 876
hepatitis C and, 877
hepatocellular carcinoma and, 890
macronodular, 866
management of, 867
micronodular, 866
non-alcoholic fatty liver disease and,
882-883, 883f
portal hypertension and, 869
survival in, 8686, 868f
Cisplatin
for head and neck tumours,
1335-1336
hypomagnesaemia and, 3686
nephrotoxicity, 4276
polyneuropathy, 1 1 396
Citalopram, 11996
Citric acid (Krebs) cycle, 49, 714
Citrobacter freundii, 225
Citrobacter spp. ,1176
CJD see Creutzfeldt-Jakob disease
CK see Creatine kinase
Clarithromycin
drug interactions, 246
H. pylori eradication, 800
1376 • INDEX
Clarithromycin (Continued)
for leprosy, 269
for Mycobacterium avium complex,
315 b
for pneumonia, 5855
in pregnancy, 1205
Clasp-knife phenomenon, 1068-1069
Classical syndromes, 633
Claude syndrome, 10725
Clearance, 19
CLI (critical limb ischaemia), 502-503
Climate change, 94
Clindamycin, 1175
for acne vulgaris, 1242-1243
for babesiosis, 278
for gas gangrene, 227
for malaria, 2775
for MRSA, 252
for necrotising fasciitis, 227
in pregnancy, 1205
for septic arthritis, 1 0205
Clinical biochemistry, 345-380
Clinical decision-making, 10-12
in cognitive biases, 1 1
dealing with uncertainty during, 5-6
in deciding pre-test probability, 1 1
in evidence-based history and
examination, 1 1
heuristic, 75
in human factors, 1 1
in interpreting results, 1 1
in person-centred EBM and patient
information, 12
in post-test probability, 1 1
in reducing cognitive error, 1 1
reducing errors in, 9-10
cognitive debiasing strategies, 8 f,
9-10
effective team communication, 10,
105
using clinical prediction rules and
other decision aids, 1 0
in treatment threshold, 1 1
Clinical endpoints, 35-36
Clinical genetics, 37-59
Clinical immunology, 61-90
functional anatomy and physiology in,
62-70, 62f
Clinical pharmacology, 14-19
Clinical reasoning, 2, 2 f
Clinical skills, 3, 3 f
Clinical therapeutics, 1 3-36
Clinical trials, 27-28, 28 f
Clobazam, 11025
Clobetasol, 3345, 3365, 12265
Clobetasone butyrate, 1 2265
for eczema, 1 244
Clock drawing test, 1 1 49f
Clofazimine
for leprosy, 269
pigmentation from, 12585
for tuberculosis, 125
Clomethiazole, effect of old age, 325
Clomifene, for infertility, 656-657
Clomipramine, 11995
for narcolepsy, 1 1 05
Clonal expansion, 68, 68 f
Clonazepam
for epilepsy, 11025
for periodic limb movement
syndrome, 1106
for sleep disorders, 1 1 05
Clonic seizures, 1 1 00
Clonidine
diarrhoea, 7615
opiate withdrawal, 1 1 96
Clonorchiasis, 2975
Clonorchis sinensis, choledocholithiasis
and, 906
Clonorchis spp., 129
Clopidogrel
for angina, 489
for myocardial infarction, 4985,
1282
for peripheral arterial disease, 5045
pharmacokinetics, 205
platelet inhibition, 918
for stroke prevention, 1161 f
Clostridium botulinum, 1045, 1126
Clostridium difficile, 103 f, 1045, 1175,
264, 264f
Clostridium novyi, in injecting drug-user,
222-223
Clostridium perfringens
anaerobic cellulitis from, 227
food poisoning, 262
Clostridium perfringens sepsis, 950
Clostridium spp., 1 02/— 1 03f
Clostridium tetani, 1 045
Clotrimazole, 1255
for erythrasma, 1 238
Clotting see Coagulation
Clotting factors, 850, 918-919
Clozapine
drug interactions, 245
schizophrenia, 11985
Clubbing, 1261, 1 2617
finger, 546f, 559, 5595, 559 f
asbestosis, 618
in lung cancer, 600
Cluster headache, 1 096
CMV (cytomegalovirus) see
Cytomegalovirus (CMV) infection
CNS see Central nervous system
Co-amoxiclav, 1 1 75
cholestatic hepatitis and, 894
for empyema, 565
hepatotoxicity of, 8945
prophylactic, 1195
for respiratory tract infection,
pneumonia, 5855, 586
for urinary tract infection, 428
Co-artemether, 277
Co-phenoxylate, for inflammatory bowel
disease, 8215
Co-trimoxazole, 1175, 123
for brucellosis, 2555
for cyclosporiasis, 287-288
for HIV infection/AIDS, 323-324,
3235
for melioidosis, 261
for meningitis, 1 1 205
for mycetoma, 301
for nocardiosis, 261
for Pneumocystis jirovecii pneumonia,
318
haematopoietic stem cell
transplantation, 9375
leukaemia patients, 957
prophylactic, 1195
toxoplasmosis, HIV/AIDS patients,
320
for Whipple’s disease, 809
Coagulation, disseminated intravascular,
196
Coagulation disorders, 971-975
Coagulation factors, 850, 930
complications of therapy, in
haemophilia A, 973
Coagulation screen, 9225, 13625
in disseminated intravascular
coagulation, 921-922
Coagulation system, 918-919
activation of, 1 96
investigation of, 920-923
Coagulation tests, for hepatobiliary
disease, 853
Coagulopathy, causes of, 9725
Coal tar, 1 250
Coal worker’s pneumoconiosis (CWP),
615
Cobalt, 718
Cocaine, misuse of, 143
Coccidioidomycosis, 304
Codeine
cirrhosis and, 8945
diarrhoea, 801
irritable bowel syndrome, 826f
headache, 1096
pharmacokinetics, 205
Codons, 40
Coeliac disease, 805-807
clinical features of, 806
disease associations of, 8065
investigations of, 806-807
liver function test (LFT) abnormality in,
8545
pathophysiology of, 805, 806f
Coeliac plexus neurolysis, 842-844
Coexisting disease, in choosing drugs,
29
Coffee, 716
type 1 diabetes and, 729
Cognitive behaviour therapy (CBT),
1190
for eating disorders, 1 204
for obsessive-compulsive disorder,
1201
for schizophrenia, 1 1 98
for somatoform disorder, 1 203
Cognitive biases, 6-9, 1 1
in human factors, 9, 9 f, 1 1
in medicine, 7-9, 8 f
in type 1 and type 2 thinking, 7, 75,
7 f
Cognitive debiasing strategies, 8 f, 9-10
history and physical examination in, 9
mnemonics and checklists in, 9
problem lists and differential diagnosis
in, 9
red flags and ROWS (‘rule out worst
case scenario’) in, 9-10
Cognitive function, assessment of,
1181-1183, 1 1827
Cognitive impairment, 1181
chemotherapy and, 1298
HIV-associated, 319-320
Cognitive therapy, 1190
Colchicine
for Behget’s disease, 1044
for CPPD crystal deposition disease,
1017
for familial Mediterranean fever, 81
for gout, 1015
Cold agglutinin disease, 950
Cold antibodies, 949
Cold injury, 166-167
Colesevelam, 376-377
Colestipol, 376-377
Colestyramine, 376-377
for irritable bowel syndrome, 826 f
for post-cholecystectomy syndrome,
908
pruritus, 888, 12205
for radiation enteritis, 810
Colic
biliary, 904
renal, 396
Colipase, 7705
Colistin, 1175
Colitis
collagenous, 824
microscopic, 824
pseudomembranous, 1045
ulcerative see Ulcerative colitis
Collagen, 1 21 3f
in osteoarthritis, 1 008
Collagenase, 64, 71
Colon, 770, 771 f
acute colonic pseudo-obstruction,
835
disorders of, 827-836
tumours of, 827-833
Colon cancer, hereditary non-polyposis,
8315
Colonoscopy, 776, 7765
for abdominal pain, 789
for colorectal cancer, 832
for gastrointestinal haemorrhage,
782-783
Colony-forming unit-granulocyte,
monocyte (CFU-GM), 914
Colorectal cancer, 830-833
clinical features of, 831
dietary risk factors for, 8305
familial adenomatous polyposis,
828-829, 8295, 829f, 13215
investigations of, 832, 833f
management of, 832
modified Dukes classification and
survival of, 832f
non-dietary risk factors for, 8305
pathogenesis of, 830f
pathophysiology of, 830-831, 831 f
prevention and screening of,
832-833
Colorimetric chemical reaction, 3485
Columnar lined (Barrett’s) oesophagus
(CLO), 792
Coma, 1080
causes of, 1 945
definition of, 1 94
poisoning, 1375
stroke patients in, 1153
Combination therapy, for hypertension,
513
Combined inhaled glucocorticoids and
bronchodilators, for chronic
obstructive pulmonary disease
(COPD), 576
Comedone, definition of, 1 242
Common variable immune deficiency,
79
Community-acquired pneumonia,
582-585, 582 f
clinical features of, 582-583
discharge and follow-up of, 585
investigations of, 583, 5845
management of, 583-584
organisms causing, 5825
prognosis for, 585
Comorbidities, in older people, 1307
Compartment syndrome
abdominal, 195
identification of, 1 875
in injecting drug-user, 222-223
Competitive antagonist, 1 4
Complement, 66, 66 f
alternate pathway for, 66
autoimmune disease and, 84
classical pathway for, 66
deficiency in, 735
lectin pathway for, 66
pathway deficiencies in, 78
total haemolytic, 13605
Complement fixation test (CFT),
107-108
Complementary therapies
for cancer pain, 1353
for pain, 1348
Complex regional pain syndrome
(CRPS), 1348-1349, 13495
type 1, 1055, 1055f
Compressed air, physics of breathing,
1705
Concentration, 1181
Concordance, 1294
Condyloma, 343
Condylomata lata, 337
Confrontation, for visual fields, 6315
Confusion/confusional states, 1 1 96
cerebral oedema, 1 68
Congenital abnormalities, in pancreas,
842-844
Congenital adrenal hyperplasia, 676
hirsutism and, 6585
Congenital heart disease, 531-538,
5315, 532 f
in adolescent, 5375
adult, 537-538
cyanotic, 5375
pregnancy and, 1282
transition medicine and, 1297
Congenital hypertrophy of the retinal
pigment epithelium (CHRPE),
829
Congenital thyroid disease, 650-651
Congestive ‘portal hypertensive’
gastropathy, 871
Coning, 1077
Conjunctiva, 1164
Conjunctivitis, 1173
gonococcal, 339
Connective tissue disease, 1 262-1 263
respiratory involvement in, 610-611,
6105
Conn’s syndrome, 361
Consanguinity, 48
Conscious level, decreased, 194-195
assessment of, 1 86 f, 1 94-1 95,
1945
management of, 1 95
Consent, artificial nutritional support,
7105
Conservative treatment, for chronic
kidney disease, 421
INDEX • 1377
Constipation, 786-787
causes of, 786b
clinical assessment of, 786-787
disorders of, 834-835
diverticulosis and, 833
in old age, 834b
simple, 834
in stroke patients, 1 1 59 b
Constitutional delay, of puberty, 653
Contact inhibition, 1318
Continence, faecal, 770
Continuous ambulatory peritoneal
dialysis (CAPD), 424, 425b
Continuous murmurs, 461
Continuous positive airway pressure
(CPAP), 199b, 202
for drowning victims, 170
Continuous positive pressure ventilation,
202
Continuous venovenous haemofiltration
(CWH), 423
Contraception
cystic fibrosis and, 1297
in epilepsy, 1 1 03
Contrast media, nephrotoxicity and,
390 b
Contrast radiology, 773 f
Conversion (dissociative) disorder, 1202,
1202b
COPD, 547 f, 573-578
BODE index in, 577 b
classification of, 576 b
clinical features of, 575, 575 b
chronic exertional breathlessness,
575, 575 b
exacerbations of, 572-573
acute, 577-578
investigations of, 575-576
management of, 576-577, 576 f,
577 b
occupational, 614
in old age, 578 b
pathophysiology of, 574-575, 574 f
prognosis of, 577
risk factors for, 574b
Copper, 718
deficiency, 703 b
dietary sources of, 717b
excessive, Wilson’s disease, 896
refeeding diet, 705 b
reference nutrient intake of, 717b
reference range of
urine, 1361b
venous blood, 1360b
Copper sulphate, poisoning from, 148
Copy number variations (CNV), 44, 44b,
45f
Cor pulmonale, 550
Cornea, of eye, 1 1 66-1 1 67
Coronary angiography, for acute
coronary syndrome, 498
Coronary artery, 444-445, 445f
angiography of, 452f
calcification, 452
with stenosis, 453f
Coronary artery bypass grafting
(CABG)
for angina, 488, 491-493, 492f
vs. PCI, 493b
Coronary artery disease, 484-502,
487b
clinical manifestations of, 485b
Coronary artery dissection, pregnancy
and, 1282
Coronary circulation, 444-445, 445f
Coronary heart disease, obesity and,
698-699, 699 f
Coronary revascularisation, 467
Coronavirus, 111b
Corrosives
oesophagitis, 794
poisoning from, 147-148
Cortical (volitional) influences, in control
of breathing, 549
Corticobasal degeneration, 1115
Corticosteroids
biosynthetic enzyme defects, 671b
for congenital adrenal hyperplasia,
676
see also Cortisol; Glucocorticoids;
Hydrocortisone;
Mineralocorticoids; Prednisolone
Corticotrophin-releasing hormone
(CRH), 633 f
Cortisol, 665
deficiency, hypopituitarism, 682
reference range of
urine, 1361b
venous blood, 1359b
see also Hydrocortisone
Corynebacterium diphtheriae, 104 b
Corynebacterium minutissimum, 1238
Corynebacterium spp., 103f
Cough, 556, 556b
aetiology of, 556
in asthma, 568
bovine, 600, 624
in COPD, 575
headache and, 1097b
at high altitude, 1 68-1 69
in laryngeal nerve, paralysing, 553
in lung cancer, 599
in palliative care, 1353
in pneumonia, 582-583
refractory, 169
and upper airway defences, 550
in upper respiratory tract infection,
581-582
Cough reflex, 556
Coumarins, 938b, 939-940
Counselling, dietary
for coeliac disease, 807
for hyperlipidaemia, 375-376
Coupled enzymatic reaction, 348b
Courvoisier’s Law, 861-862
Cowden’s syndrome, 1321b
Cowpox, 249
Coxiella burnetii, 100-101 , 272
Coxsackie virus infections, 240
‘Crack’ cocaine, 143
Cramps, heat, 167
Cranial nerves
damage to, 1089b
of envenomed patient, 1 527
examination of, 1063b
nuclei, 1067
see also specific nerves by name
Craniopharyngioma, 687, 687 f
Creams, 1225b
Creatine kinase (CK)
in hypothermia, 166
in muscular dystrophies, 1143-1144
reference range of, venous blood,
1360b
Creatinine, 349b
in acute kidney injury, 41 6b
in hepatorenal syndrome, 864
reference range of
urine, 1361b
venous blood and, 1358b
Creatinine phosphokinase (CPK)
elevated serum, causes of, 991b
in myopathy, 990-991
in myositis, 990-991
Cretinism, 717
Creutzfeldt-Jakob disease (CJD), 1127,
1127b
variant, 933
Crigler-Najjar syndrome, 860b
Critical care/critical illness, 173-214
admission requirement, 176
clinical examination in, 174, 174f
in context of congenital conditions,
201 , 202 b
disorders causing, 196-201
acute circulatory failure as,
1 99-200
acute respiratory distress syndrome
as, 198
post cardiac arrest as, 200-201
sepsis and systemic inflammatory
response as, 1 96-1 98
monitoring in, 175-176, 175b, 175f
nutrition, 210
outcomes of, 211-214
adverse neurological, 211-212
discharge from intensive care as,
213
in older patient, 212
withdrawal of active treatment and
death in intensive care as, 213
oxygen therapy in, 191, 191b
referral, 212
renal support, 208
respiratory support, 202-204
scoring systems in, 213-214, 214b
withdrawal of care, 213
Critical care medicine, decisions around
intensive care admission in, 201 ,
202 b
Critical illness polyneuropathy, 21 1
Critical limb ischaemia, 502-503
Crohn’s colitis, primary sclerosing
cholangitis and, 888
Crohn’s disease
clinical features of, 816-817
cutaneous, 1263
ileal, 8167-81 77
management of, 820-823
pathophysiology of, 81 6, 81 6 f
refractory, 824
small bowel, differential diagnosis of,
817b
treatment strategy for, 1 300b
Cross-infection, 103
see also Health care-associated
infection
Crust, skin, definition of, 1216
Cruveilhier-Baumgarten syndrome,
868
Cryoglobulinaemic vasculitis, 1 043
Cryoglobulins, 1043
autoimmune disease and, 84
classification of, 84b
Cryoprecipitate, 931b
Cryotherapy
for anogenital warts, 343
for basal cell papilloma, 1 234
for granuloma annulare, 1 263
for molluscum contagiosum, 343
for sarcoidosis, 1 263
for skin disease, 1 228
for warts, 343
Cryptic tuberculosis, 589b
Cryptococcal meningitis, HIV-related,
321
Cryptococcosis, 302, 302f
HIV-related, 315b
prevention of, 324
Cryptogenic cirrhosis, 884
Cryptorchidism, in hypogonadism, 653
Cryptosporidia/cryptosporidiosis, 287,
813
HIV-related, 317b, 3177
Crystal formation, 387, 427b, 1012,
10137
drug-induced, 427b
Crystal-induced arthritis, 1012-1018,
1013b, 10137
Crystalloids, 782
CT (computed tomography)
for acute respiratory distress
syndrome, 198, 1 997
of aldosterone-producing adenoma,
674, 675 f
for cancer, 1323, 1323f
of cardiovascular system, 452
coronary angiography, 452, 452f
for decreased conscious level, 195,
1957
of gastrointestinal tract, 773-774
for headache, 1 85-1 86
for hepatobiliary disease, 854
for cirrhosis, 854f
multidetector, for hepatocellular
carcinoma, 891
for musculoskeletal disease, 989
for neurological disease, 1 073 b
cerebral abscess, 1 1 24
epilepsy, 1101b
stroke, 1151, 1157-1158, 1158b
of phaeochromocytoma, 675, 676 f
for polycystic disease, 893 f
for renal disease, 389
for respiratory disease, 552, 553 f
aspergilloma, 597 f
bronchiectasis, 579 f
hypersensitivity pneumonitis, 61 7 f
interstitial lung disease, 605 f
pleural thickening, 61 87
pulmonary fibrosis, 607 f
for splenomegaly, 927
CTLA4, 70
Cullen’s sign, 837-838
Culture, blood, 106, 107f-108f
Cupulolithiasis, 1104
CURB-65, 583 f
Curettage, for skin disease, 1 228
Cushing’s disease, management of, 669
Cushing’s syndrome, 666-670
aetiology of, 667
classification of, 667 b
clinical assessment of, 667, 668f
hirsutism and, 658b
investigations of, 667-669,
669f-670f
management of, 669-670
Cutaneous leishmaniasis, 284-285,
285 b, 285 f
Cyanide poisoning, 135b
Cyclical hormone replacement therapy,
for amenorrhoea, 655
Cyclical vomiting syndrome, 803
Cyclicity of cortisol secretion, in
Cushing’s syndrome, 668
Cyclin-dependent kinases (CDKs),
1317
Cyclo-oxygenase, 1002-1003, 1003f
Cyclophosphamide, 1320b
for Churg-Strauss syndrome, 1043
glomerulonephritis, 400
for juvenile dermatomyositis, 1040
for leukaemias, 960, 963
for musculoskeletal disease, 1004b,
1005
for neuromyelitis optica, 1110
for non-Hodgkin lymphoma, 965
for pemphigus, 1256
for rheumatic disease, 1 004b
for SLE, 1 036
for vasculitis, 1041
for warm autoimmune haemolysis,
950
Cyclospora cayetanensis, 287-288
Cyclosporiasis, 287-288
Cypermethrin, 148b
Cyproterone acetate, 659b
for acne, 1 243
for alopecia, 1 259
for prostate cancer, 439
Cystathionine (3-synthase deficiency,
369
Cysteine, 697b
Cystic fibrosis (CF), 580-581 , 580 f,
581 b, 842, 902
contraception and, 1297
fertility and child-bearing potential in,
1297
transition medicine and, 1297
Cystic fibrosis transmembrane
conductor regulator (CFTR)
protein, 1297
Cysticercosis, 297f-298f, 298
Cystinuria, 405
Cystoisospora belli diarrhoea,
HIV-related, 315b
Cystoisosporiasis, HIV-related, 317b
Cysts
Baker’s (popliteal), 999b, 1 023
rupture, 1023
choledochal, 903, 903f
hydatid, liver and, 880
Cytarabine
for acute leukaemia, 957 b
for chronic myeloid leukaemia, 959
Cytochrome P450, 18
Cytogenetic analysis, 1322
Cytokeratin, as tumour markers, 1322,
1324b
Cytokines, 64-66, 65b, 65 f
asthma, 568
cancer, 1319
defects in, 78
immune response regulation, 65 b
pro-inflammatory, 70, 1005
Cytology, in respiratory disease, 554
1378 • INDEX
Cytomegalovirus (CMV) infection, 238 b,
242-243
after HSCT, 937 b
clinical features of, 242-243
encephalitis, 320
investigations of, 243
liver transplantation and, 901
management of, 243
polyradiculitis, 321
in pregnancy, 235 b
viral hepatitis and, 878
Cytopathic hypoxia, 1 97 f
Cytosine, 38
Cytotoxic oedema, 1 1 53-1 1 54
Cytotoxic therapy, for myelofibrosis, 969
Cytotoxin-associated gene (cagA), 798 f
D
D-dimers
pulmonary embolism, 620
reference range of, 1 362b
venous thromboembolism, 976
Dabigatran etexilate, indications for,
938 b
Dacarbazine, for Hodgkin lymphoma,
963
Dactylitis, 1032, 1034/
Danaparoid, for heparin-induced
thrombocytopenia, 939
Dandruff, 1246
Dane particle, 873
Dantrolene, 1 1 97-1 1 98
Dantron, 834b
Dapsone, 123, 1227-1228
adverse effects of, 1 23
for dermatitis herpetiformis, 807
for erythema nodosum, 1265
haemolysis from, 950
for leprosy, 269
for linear IgA disease, 1 256-1 257
neutropenia and, 926b
for Pneumocystis jirovecii pneumonia,
323-324
poisoning, 136b
prophylactic, 119b
for pyoderma gangrenosum,
1261-1262
‘Dapsone syndrome’, 123
Daptomycin, 117b, 123
mechanism of action, 1 1 6b
Darunavir, 324b
Daunorubicin, for acute leukaemia,
957 b
DCCT (Diabetes Control and
Complications Trial), 756-757
DDAVP see Desmopressin
DDT, 148b
de Musset’s sign, 524b
De novo mutation, 47
De Quervain’s tenosynovitis, 998
de Quervain’s thyroiditis, 646-647
‘Dead-in-bed syndrome’, 739-740
Deafness
Alport’s syndrome, 403
Lassa fever, 245b
Paget’s disease, 1054
Pendred’s syndrome, 640f
quinine toxicity, 141b
rubella, 237 b
salicylate overdose, 1 38
Death and dying, 1354-1356, 1355b
advance directives, 1307
brainstem, 211
diagnosis of, 1355
ethical considerations in, 1355
intensive care and, 213
management of, 1 355
see also Brain death; Palliative care;
Sudden death
Death certificate, completed, 98 f
Debrisoquine, 58
DEC see Diethylcarbamazine
Decision-making see Clinical
decision-making
Decompression, for musculoskeletal
disease, 999
Decompression illness
in aviators, 1 68
in divers, 170-171, 170b-171b
Decontamination, 133 f
Deep infrapatellar bursitis, 999b
Deep vein thrombosis (DVT)
air travel and, 169
investigation of, 187, 187f
pre-test probability of, 1 87b
pregnancy and, 1285
magnetic resonance imaging for,
1274
presentation of, 1 86
in stroke patients, 1 1 59 f
warfarin for, 939
see also Venous thromboembolism/
thrombosis
DEET (diethyltoluamide), malaria
prevention, 277
Defecation
disorders of see Constipation
obstructed, 778
Defensins, 62-63, 769
Defibrillation, 457
for arrhythmias, 482
implantable cardiac defibrillators, 467,
483-484, 483b
heart failure, 467, 467f
public access, 457
Dehydration
cerebral, hypernatraemia and,
359-360
cholera, 265
diabetics, 729-730
gastric outlet obstruction, 801-802
heat exhaustion and, 167
in palliative care, 1354
in type 1 diabetes, 729-730
see also Water, depletion
Dehydroepiandrosterone sulfate
(DHEAS), 672
Dejerine-Klumpke paralysis, 1141b
Delayed oesophageal clearance, 791
Delayed puberty, 653-654, 653b, 1290
Deletions, 42, 45 f
Delirium, 183-184, 1080, 1184
clinical assessment of, 184
diagnosis of, 183b
hepatic encephalopathy and, 864-865
in intensive care, 209
investigations of, 184, 184 f
in older people, 1309, 1310b
in palliative care, 1354
presentation of, 1 83-1 84
prevalence of, 1 1 80b
risk factors for, 1 83b
Delirium tremens, 1194
Delta antigen, 877
Delta virus see Hepatitis D virus
Delusional disorders, 1197, 1197b
Delusional parasitosis, 1202
Delusional perception, 1 1 96-1 1 97
Delusions, 1181, 1184
differential diagnosis, 1 1 97 b
schizophrenia, 1197b
Demeclocycline, 687 b
Dementia, 1191-1194
alcoholic, 1195
fronto-temporal, 1193-1194, 1193/
HIV-associated, 319
investigations of, 1192, 11 92b
Lewy body, 1 1 94
management of, 1 1 92
nutrition and, 711, 711 f
pathogenesis of, 1 1 92
pellagra and, 714
subtypes and causes of, 1191b
vascular, 1191b
see also Alzheimer’s disease
Demography, in older people, 1 304,
1304/
Demyelination
acute disseminated encephalomyelitis
and, 1110
multiple sclerosis and, 1 1 06-1 1 1 0
transverse myelitis and, 1110
from vitamin B12 deficiency, 715
Dendritic cells, 64
Dengue, 243-244
clinical features of, 243-244,
243b-244b
diagnosis of, 244
endemic zones of, 243 f
management and prevention of, 244
in pregnancy, 235 b
Dengue haemorrhagic fever, incubation
period of, 111b
Denosumab
for bone metastases, 1 329
for osteoporosis, 1 048, 1 048b
Dental caries, fluoride and, 718
1 1 -Deoxycorticosterone-secreting
adrenal tumour, 674b
Depolarisation, cardiac conduction
system, 445 f
Deposition disorders, 1 264
Depressants, misuse of, 141-143
Depression, 1 1 98-1 1 99
alcohol and, 1195
diagnosis of, 1 1 99
investigations of, 1 1 99
low mood due to, 1 1 85
management of, 1 1 99
manic, 1200
and medical illness, 1199b
negative cognitive triad associated
with, 1190b
in old age, 1 1 89b
in palliative care, 1354
pathogenesis of, 1 1 98-1 1 99
post-partum, 1206
prevalence of, 1 1 80 b
prognosis of, 1 1 99
in stroke patients, 1 1 59 f
symptoms of, 1 1 85b
unipolar, 1198
Dermatitis
chronic actinic, 1221b
exfoliative, 1266b
herpetiformis, 807, 1255b, 1256,
1326
pellagra and, 714, 71 5f
seborrhoeic, HIV-related, 314
see also Eczema
Dermatobia hominis, 300
Dermatofibroma, 1235
Dermatology, 1209-1267
Dermatomyositis/polymyositis,
1039-1040, 1 0397, 1260 f,
1263
in cancer patients, 1325b, 1326
Dermatophyte infections, 1 239,
1240/
Dermatoscopy, 1214, 1 21 7f
Dermatoses, 334b, 336b
Dermis, 1212
Dermoscopy, 1214
Des-amino-des-aspartate-arginine
vasopressin, for diabetes
insipidus, 688
Desensitisation, 16
Desmopressin (DDAVP), in haemophilia
A, 973
Desmosomes, 1212
Deterioration
early warning scores for, 1 88,
188f-189f
immediate assessment of, 1 88-1 89
management for, location for,
189-190, 190b
medical emergency team and, 188,
189b
presentations of, 1 90-1 95
decreased conscious level as,
194-195
decreased urine output/
deteriorating renal function as,
195
hypertension as, 1 93-1 94
hypotension as, 1 93
hypoxaemia as, 190-191
tachycardia as, 191-193
tachypnoea as, 1 90
Detrusor muscle, 386
failure of, 437
over-activity, 436b
Detrusor-sphincter dyssynergia, 1 093
Developing countries
epilepsy in, 1097
tetanus in, 1125-1126
Devic’s disease, 1110
Dexamethasone
adjunctive, for bacterial meningitis,
1120b
for altitude illness, 168
for brain tumours, 1130
for Cushing’s syndrome, 668
for gastrointestinal obstruction, 1354
for high-altitude cerebral oedema, 1 68
for meningitis, 1 1 20 b
for pain management, 1 352b
for spinal cord compression, 1326b
for thyrotoxicosis, 639
Dexamethasone suppression test (DST),
for Cushing’s syndrome, 700
Dexamfetamine, 1 1 05
Dextran, 1266b
Dextropropoxyphene, 1 42b
poisoning, 142b
Dextrose, 353b
hypoglycaemia, 141
DFMO see Eflornithine
DHA see Docosahexaenoic acid
Di George syndrome, genetics, 44b
Diabetes Control and Complications
Trial (DCCT), 756-757
Diabetes insipidus, 687-688, 687b
pregnancy and, 1280
Diabetes mellitus, 409, 719-762
adherence and concordance in, 1299
in adolescents, 753-754, 753b-754b
aetiology and pathogenesis of,
728- 734
air travel and, 169
bronzed, 895
causes of visual loss in people with,
1177
in children, 753-754, 754 b
classification of, 733 b
clinical examination of patient with,
720-721, 720 f, 721 b
complications of, 755-762, 756 b
pathophysiology of, 756
prevention of, 756-757
diagnosis of, 726b, 727-728
functional anatomy and physiology
and, 723-725
gestational, 1278, 1278b
diagnosis of, 1278
management of, 1278
screening for, 1278
glomerular filtration rate and, 417 f
impact of transition planning on,
1299b
investigations of, 725-728
management of, 741-755, 755 f
alcohol in, 744-745
dietary, 743-744, 744b
driving and, 745, 745b
drugs to reduce hyperglycaemia in,
745-748
exercise in, 744
insulin therapy in, 748-751
Ramadan and, 745, 745b
review in, 743b
therapeutic goals in, 742-743, 743 f
transplantation in, 752, 753 f
weight management in, 744
monogenic, 733-734, 733 b
mortality in, 755, 756 b
in old age, 757 b
ophthalmic features of, 1165b
pre-operative assessment of, 754b
pregnancy and, 752-753, 1278-1279
presenting problems of, 734-741
prevalence of, 722, 722 f
rheumatological manifestations of,
1057
risk of, 698-699, 699 f, 700b
transition medicine and, 1299
type 1 , 728-730
in adults, 730
classical features of, 735 b
environmental predisposition in,
729
genetic predisposition of, 728-729
metabolic disturbances in,
729- 730, 730 f
pathology of, 728, 729 f
risk of, 729 b
INDEX • 1379
type 2, 730-732
classical features of, 735 b
drugs in treatment of, 7460
environmental factors of, 732
genetic predisposition of,
731-732
hereditary haemochromatosis and,
895
insulin resistance in, 730-731
management of, 742f
metabolic disturbances in, 732
pancreatic (3-cell failure in, 731
pathology of, 730-731, 731 7
risk of, 7310
sibling risk of, 7310
in young adults, 753-754
Diabetic amyotrophy, 759
Diabetic eye disease, in
ophthalmological conditions,
1 1 74-1 1 77
Diabetic foot, 759 7, 761-762
aetiology of, 761
clinical features of, 7610
management of, 761-762, 7620,
7627
Diabetic glomerulosclerosis, nodular,
757, 758 7
Diabetic ketoacidosis, 729-730,
735-738
in adolescence, 7530
clinical features of, 736, 7360
investigations of, 736
management of, 736-738, 7370
bicarbonate in, 738
fluid replacement in, 737
insulin in, 737
ongoing, 738
phosphate in, 738
potassium in, 738
pathogenesis of, 735-736, 7360
severe, indications of, 7360
Diabetic macular oedema, management
of, 1176-1177
Diabetic microangiopathy, 756
Diabetic nephropathy, 757-758
diagnosis and screening for, 757
management of, 757-758
natural history of, 757, 758 7
Diabetic neuropathy, 758-761
classification of, 7590
clinical features of, 758-761
management of, 761 , 7610
risk factors for, 7570
Diabetic osteopathy, rheumatological
manifestations of, 1 057
Diabetic retinopathy, 757, 1174-1177,
1176 7
clinical features of, 1 1 75-1 1 76
management of proliferative, 1176
pathogenesis of, 1 1 75
prevention of, 1 1 77
screening of, 1 1 77
Diagnosis, 29
Diagnostic error, problem of, 2, 20
Diagnostic tests, use and interpretation
of, 3-5
factors other than disease, 4, 40
normal values, 3, 4 7
operating characteristics, 4
prevalence of disease, 5, 6 7
sensitivity and specificity, 4-5, 50, 5 7
Dialyser hypersensitivity, 4240
Dialysis
amyloidosis associated with, 820
gastrointestinal, 136
hyperkalaemia, 363
peritoneal, 424
poisoning, 136
renal
AKI, 413-414, 4220
CKD, 419
in old age, 4220
SLE, 410-411
see also Haemodialysis
3,4-Diaminopyridine, for Lambert-Eaton
myasthenic syndrome, 1 1 43
Diamorphine
for myocardial infarction, 498
for palliative care, 1351, 1355
Diaphragm
disorders of, 627
eventration of, 627
Diaphragmatic hernias, 627
Diarrhoea, 783
acute, 227-230, 2280, 783
clinical assessment of, 228-229
differential diagnosis of, 2280
investigations of, 229
management of, 229-230
after peptic ulcer surgery, 801
amoebic dysentery, 287
antibiotic-associated, 1040
antimicrobial-associated, 230
bloody, 816
cholera, 264-265
chronic or relapsing, 233, 2330, 783,
7840
diabetic, 7610
enteral feeding and, 7070
faecal incontinence, 835, 8350,
1094
HIV-related, 316-317
inflammatory bowel disease,
816-817
irritable bowel syndrome, 824
malabsorption, 783-784
pellagra and, 714
traveller’s, 2320
tropical, 232-233
Zollinger-Ellison syndrome, 802
Diascopy, 1214
Diastolic murmurs, 460
Diathermy, gastrointestinal bleeding,
775 7
Diazepam
acute poisoning, 145, 147
adverse reactions of, 220
alcohol withdrawal, 1195
convulsions, 145
for disturbed behaviour, 1 1 88-1 1 89
drug interactions of, 23
in renal/hepatic disease, 320
for status epilepticus, 10810
Diazoxide
for hypertrichosis, 1 259, 1 2660
for neuro-endocrine tumours (NETs),
679
Dibenzodiazepines, 1 1 980
Dibenzothiazepines, 1 1 980
DIC see Disseminated intravascular
coagulation
Diclofenac, 10030
for actinic keratosis, 1 231
for hepatocyte necrosis, 894
for renal colic, 432
Didanosine, 321
Dieldrin, 1480
Diet(s)
acute coronary syndrome and, 501
cancer and, 13200
gallstones and, 903
in gastro-oesophageal reflux disease,
791
gluten-free, 807
high protein, obesity, 7010
low carbohydrate, 7010
low fat, 7010
modification of, for gestational
diabetes, 1278
refeeding, 7050
for renal failure, acute kidney injury,
414
starvation, 702
type 2 diabetes and, 732
vegan, 697
very-low-calorie, 702
weight loss, 701-702, 7010
Diet history
elements of, 6930
obesity and, 700
Dietary deficiency, 944
Dietary supplements, 712
Diethylcarbamazine (DEC), 129
Dietl’s crisis, 396
Differentiated carcinoma, in thyroid
disease, 649-650
Diffuse idiopathic skeletal hyperostosis
(DISH), 1058-1059, 10587
Diffuse infiltrative lymphocytosis
syndrome, HIV-related, 321-322,
322 7
Diffuse parenchymal lung disease
(DPLD), 605-610, 6050, 6067,
6070
Diffuse pleural thickening (DPT), 618,
6187
DiGeorge syndrome, 79
Digestion, 767
Digital photography, 1 1 68
Digoxin
adverse reactions of, 220
for arrhythmias, 4690
atrial fibrillation, 471-472
atrial flutter, 470
drug interactions of, 240
effect of old age, 320
for heart failure, 467
for mitral valve disease, 519, 5210
plasma concentration, 360
for pulmonary hypertension,
621-622
toxicity/poisoning, 1370, 140
Digoxin-specific antibody fragments,
140
Dihydrocodeine
for musculoskeletal disease, 1 002
poisoning, 1420
Dihydropyridines
for angina, 490-491
for hypertension, 513, 5140
overdose, 140
see also individual drugs
1 .25- Dihydroxycholecalciferol (calcitriol)
for hypoparathyroidism, 665
for osteoporosis, 1049
pseudohypoparathyroidism, 665
1.25- Dihydroxyvitamin D, 384-386
Diiodotyrosine (DIT), 635 7
Dilated cardiomyopathy, 539
pregnancy and, 1282
Diloxanide furoate, 1 29
Diltiazem
for angina, 490-491
for aortic dissection, 508
for arrhythmias, 472, 479 7
for atrial fibrillation, 472
drug eruptions, 1 266b
for hypertension, 513
Diltiazem cream, for anal fissure, 836
Dilute Russell viper venom time
(DRWT), 978
Diphencyprone, 1239
Diphenoxylate, 230, 808-809
Diphenylbutylpiperidines, 1198b
Diphtheria, 104b, 265-266, 266 b
clinical features of, 266
incubation period of, 111b
management of, 266
prevention of, 266
prophylaxis for, 1 1 9b
Diplopia, 1088-1089
in Graves’ disease, 631b, 6457
intracranial hypertension and, 1133
Dipyridamole, platelet inhibition, 918
Direct-acting nucleoside/nucleotide
antiviral agents
for hepatitis B, 876
for hepatitis C, 878, 878 b, 879 7
Direct antiglobulin tests, 948 7
Direct Coombs test, in warm
autoimmune haemolysis, 949
Direct oral anticoagulants (DOACs),
940
Directly observed therapy, for
tuberculosis, 594-595
Dirofilaria immitis, 293
Disability
in deteriorating patient, 189
International Classification of
Functioning, Disability and
Health, 1311
in older people, 1306
Discharge, from intensive care, 213,
214b
Discitis, 1021
Discoid eczema, 1246
Discriminant function (DF), 882
Disease, choosing drugs for
features of, 29
severity of, 29
Disease Activity Score 28 (DAS28), in
rheumatoid arthritis, 1025, 1026f
Disease-modifying antirheumatic drugs
(DMARDs), for musculoskeletal
disease, 1004-1005, 1004b
psoriatic arthritis, 1033-1034
reactive arthritis, 1032
rheumatoid arthritis, 1025-1026
Disopyramide
for arrhythmias, 476b, 479-480, 479b
for cardiomyopathy, 540
Disseminated intravascular coagulation
(DIC), 196, 978-979, 978 b
Dissociative conversion disorders, 1202,
1202b
Dissociative drugs, poisoning from, 144
Distal interphalangeal joint arthritis,
1032, 10347
Distribution
drug, 18, 29
volume of, 18, 187
interactions, 23
Disturbed behaviour, 1 1 88-1 189, 11 897
Disulfiram, 1195
DIT see Diiodotyrosine
Dithranol, 1250
Diuretics
adverse reactions of, 22 b, 355,
1310b
for ascites, 864
clinical use of, 355
drug eruptions, 1266b
drug interactions of, 24b
for heart failure, 465, 4657
for hypertension, 513, 514b
for hypervolaemia, 354-355
loop-acting, 355 b
for mitral regurgitation, 521b
for obliterative cardiomyopathy, 541
for oedema, 396
osmotic, 355
potassium-sparing, 355
in pregnancy, 1276
resistance to, 355
timing of, 31b
see also Thiazides
Diverticulitis, acute, 788
Diverticulosis, 833-834
human colon in, 8337
jejunal, 7737
Diving-related illness, 170-171
Dizziness, 1080
in older people, 181b, 1309
DMARDs see Disease- modifying
antirheumatic drugs
DNA, 38, 387
analysis, for neurological disease,
1077
mitochondrial, 49, 1305
nuclear chromosomal, 1304
proviral, 309-310
repair of, 41
transcription, 38-40
Dobutamine, 206 b
Docosahexaenoic acid (DHA), 377
Dominant negative mutations, 45
Domperidone, 1096
Donath-Landsteiner antibody, 950
Donepezil, 1193
Donor lymphocyte infusion (DLI), 937
Donor-recipient cross-matching, 89
Donovanosis, 341b
Dopamine, low-dose, AKI, 413
Dopamine agonists
for acromegaly, 686-687
for Parkinson’s disease, 1114, 1114b
pregnancy, 685
for prolactinoma, 685, 685b
and renal dysfunction, 427b
for restless legs syndrome,
1 1 05-1 1 06
Dopamine antagonists
for gastroparesis, 761b
and prolactin concentrations, 684
Dopamine dysregulation syndrome,
1113
1380 • INDEX
Doppler echocardiography, 451-452,
451 f
for aortic dissection, 507-508, 508 f
for atrial septal defect, 535 f
colour-flow Doppler, 452f
three-dimensional, 452
for valvular regurgitation, 451-452
Doppler ultrasound
for haemorrhoids, 835-836
for hepatobiliary disease, 853-854
for leg ulcers, 1 224
for venous thromboembolism, 187
Doripenem, 120b
Dose-response curves, 14-16, 15 f
Dosulepin, 1199b
Down’s syndrome (trisomy 21), 44b
acute hepatitis B and, 875
Doxapram, 567
Doxazosin, 513, 675-676
Doxorubicin
cardiotoxicity, 541b
hepatocellular cancers, 892
liposomal, for ovarian cancer, 1334
myocarditis and, 538
for non-Hodgkin’s lymphoma, 965
Doxycycline, 117b
for anthrax, 267
for bacillary angiomatosis, HIV/AIDS
patients, 315-316
for brucellosis, 255 b
for cholera, 265
drug eruption, 1267f
for filariasis, 291
for leptospirosis, 258-259
for louse-borne relapsing fever, 257
for Lyme disease, 256
for malaria, 278 b
for melioidosis, 261
for onchocerciasis, 293
for plague, 259
for Q fever, 272
for reactive arthritis, 1032
for relapsing fever, 257
for rickettsial fevers, 271-272
skin infections, 1238
for STIs
chlamydial infection, 341b
granuloma inguinale, 341b
lymphogranuloma venereum, 341b
syphilis, 339
for Whipple’s disease, 809
DPLD see Diffuse parenchymal lung
disease
DPP-4 inhibitors, for hyperglycaemia,
747-748
Dracunculiasis, 293
Dracunculus medinensis, 293
DRESS, 1266b
Dressings, 1226-1227, 1227b
Dressler’s syndrome, in acute coronary
syndrome, 496
Dribble, post-micturition, 437
Drinking, 1184, 1194
Driving
diabetes mellitus and, 745, 745 b
restrictions in, epilepsy and, 1296
Dronedarone, 471-472, 479b-480b,
481
Drowning/near-drowning, 169-170,
169b
Drug eruptions, 1251, 1 265-1 267
clinical features of, 1266b, 1267
exanthematous, 1266b
fixed, 1266b
investigations and management of,
1267, 1267b
phototoxicity, 1221b
rash in, 1217b
types of, 1265b, 1267f
Drug history, 21b
Drug misuse, 93, 1184, 1184b
causing stroke, 1 1 57 b
polydrug misuse, 1 1 96
psychosis, 1195-1196
tetanus and, 1125
Drug rashes, HIV-related, 316
Drug-related disorders
eosinophilia, 123
neutropenia, 926b
obesity and, 700 b
phototoxicity, 1221b
psychosis, 1 1 97 b
renal, 426, 427b
Drug resistance, 16
Drug-resistant TB, 595, 595 b
Drug sensitivity testing, for tuberculosis,
592
Drug therapy
adverse outcomes of, 21-26
duration of, 30
monitoring of, 34-36
patient adherence to, 29
stopping, 31
Drugs
absorption, 17-18, 17f, 29
abuse, 21
adverse reactions of, 21-23, 22 b
classification of, 22-23, 22 b
dose-related, 16
inter-individual variation in, 19, 20 b
in older people, 1310, 1310b
pharmacovigilance, 23
prevalence of, 21-22, 21b-22b
risk factors for, 21b
TREND analysis of, 23 b
clinical and surrogate endpoints in,
35-36
controlled, 26, 33-34
cost of, 29
development, 26-27, 26b-27b
distribution, 18, 29
dosage regimens of, 29-30
frequency of, 30
repeated, 19
timing of, 30, 31b
dose-response curves of, 14-16, 15 f
dose titration of, 30
efficacy, 16, 29
elimination, 18-19
excretion, Mf, 18-19, 29
formulation of, 30
hospital discharge, 33
interactions, 23-24
avoiding, 24, 29
mechanisms of, 23-24
pharmaceutical, 24b
pharmacodynamic, 24b
pharmacokinetic, 24b
licensing, 26-27
lung disease due to, 612-613, 612b
management, 26-28
cost-effectiveness evaluation, 28,
28 b
evidence evaluation, 27-28
implementing recommendations,
28
use of, 27-28
marketing, 26-27
metabolism, 18, 29
interactions, 24
of misuse, 141-144
for oesophagitis, 794
plasma concentrations of, 36, 36b
potency of, 1 6
regulation of, 26-28
route of administration of, 17f, 30,
30 b
topical administration of, 1 7-1 8
toxicity, 21
DRWT see Dilute Russell viper venom
time
Dry drowning, 169
Dubin-Johnson syndrome, 860b
Duchenne muscular dystrophy (DMD),
48b
transition medicine and, 1297
Ductopenia, 894
Duloxetine, for pain management,
1350b
Duodenal biopsy, 806
Duodenal switch, 703 b
Duodenal ulcers, 782, 799 f
Duodenogastro-oesophageal reflux,
792
Duodenum, functional anatomy of,
766-767, 766 f
Duplex kidneys, 434
Duplication, 44, 45f
Dupuytren’s contracture, 1059
cirrhosis and, 867
Dusts, lung disease and, 616-617,
616b
Dwarfism, zinc deficiency, 717
DXA (dual x-ray absorptiometry)
in bone mineral density, 989-990
for fractures, 1 308
indications for, 1 046b
for musculoskeletal disease, 990f
Dysarthria, 1087-1088, 1093
causes of, 1 087 b
Dysbetalipoproteinaemia, 375
Dysdiadochokinesis, 1069
Dysentery, bacillary, 111b
Dysexecutive syndrome, 1 094
Dysgraphia, 1086
Dyshormonogenesis, 650
Dyslexia, 1086
Dyslipidaemia, in pregnancy, 377 b
Dysmetria, 1069
Dyspepsia, 779
alarm features in, 779 b
causes of, 779 b
functional, 802-803
gallstone, 904
investigations of, 780 f, 802
Dysphagia, 778, 1093
investigations of, 778, 779 f
oesophagus, 1324b
in stroke patients, 1 1 58
Dysphasia, 1088
Dysphonia, 1087
Dysthymia, 1198
Dystonia, 1086, 1116
poisoning, 137b
Dystrophia myotonica, 1191b
Dysuria, 396
E
E-cadherin (CDH1) gene, 803
E-selectin, 447
Early-onset osteoarthritis, 1011, 1011b
Ears
freezing injuries and, 166
squamous cell carcinoma, 1 231
Eastern Cooperative Oncology Group
(ECOG) performance scale,
1322, 1322b
Eating disorders, 1203-1204, 1204b
Ebola virus disease, 246-247
Eccrine sweat glands, 1213-1214
ECF see Extracellular fluid
ECF (epirubicin, cisplatin and
5-fluorouracil), 804
ECG (electrocardiogram), 448-450,
448f
12-lead, 448-449, 448b, 449f
for acute coronary syndrome,
496-497, 497f
AKI, 422b
ambulatory, 450
angina, 487
for aortic dissection, 507-508
for aortic regurgitation, 525 b
for aortic stenosis, 523f
for atrial ectopic beats, 470f
for atrial fibrillation, 471 f
for atrial flutter, 470f
for AV block, 477f-478f
for AV nodal re-entrant tachycardia,
473f
cardiac cycle, 460f
for cardiac tamponade, 544
for chest pain, 178-179
for critically ill patients, 178
for endocarditis, 530
exercise, 449-450, 450b
for hyperkalemia, 363
for hypokalaemia, 361
for left ventricular hypertrophy, 523 f
for mitral stenosis, 51 9
for myocardial infarction, 448
for myocardial ischaemia, 448
for pericarditis, 542, 542f
for pulmonary embolism, 619b, 620
reading, 448b
for sinoatrial disease, 469f
for supraventricular tachycardia, 473f
for syncope/presyncope, 1 83
for torsades de pointes, 47 6 f
in tricyclic antidepressant poisoning,
139f
for ventricular ectopic beats, 475f
for ventricular fibrillation, 475
for ventricular tachycardia, 475f
for Wolff-Parkinson-White syndrome,
474f
Echinocandins, 125b, 126
Echinococcus granulosus, 298-299,
299 f
Echocardiography, 451-452
for acute coronary syndrome, 498
for angina, 488
for aortic dissection, 508 f
for aortic stenosis, 523 f
for atrial septal defect, 535 f
for cardiac tamponade, 544
for critically ill patients, 206
Doppler, 451-452, 451f-452f
ventricular septal defect, 536
for endocarditis, 530
for ‘four-chamber’ view, 452f
for heart failure, 464
for hypertrophic cardiomyopathy, 540
indications for, 451b
for left ventricular hypertrophy, 540
for mitral regurgitation, 520 f
for myocarditis, 538
for papillary muscle rupture, 496
for pericardial effusion, 543f
for pulmonary embolism, 620
stress, 452
for tetralogy of Fallot, 537
three-dimensional, 452
transoesophageal, 1 79, 452
transthoracic, 451
two-dimensional, 452
valvular disease
aortic, 522-524
mitral, 519
tricuspid, 526
for ventricular aneurysm, 496
Echovirus infections, 240
Eclampsia, hypertension and,
1276-1277
ECOG (Eastern Cooperative Oncology
Group) performance scale, 1322,
1322b
Econazole, 125b, 335b
Ecstasy (drug), 143
Ecthyma, 1236
Ectoparasites, 299-300
Ectopia lentis, 370
Ectopic ACTH syndrome, management
of, 670
Ectopic pregnancy, 336
Ectopic ureters, 434
Eculizumab, 66
Eczema, 1244-1247
allergic contact, 1247, 1247b, 1247f
asteatotic, 1247
atopic, 1245-1246
rash in, 1217b
classification of, 1 244b
clinical features of, 1 244
clinical morphology of, 1 244b
discoid, 1246
gravitational, 1247
investigations of, 1 244
irritant, 1247
management of, 1244-1245, 1245f
in nails, 1261
pruritus, 1219b
seborrhoeic, 1246
Edoxaban, 938b
Edrophonium bromide, for myasthenia
gravis diagnosis, 1 1 42
EDTA (ethylenediamine-tetra-acetic
acid), 386b
Education
food allergy and, 812
infection control, 112b
in musculoskeletal disease,
1000-1001
fibromyalgia, 1018
mechanical back pain, 997
osteoarthritis, 1011-1012
INDEX • 1381
Edwards’ syndrome (trisomy 18), 44 5
EEG (electroencephalography),
1 074-1 076
for dementia, 1 1 92
for epilepsy, 1 0757, 1076
for hepatic encephalopathy, 865
for sleep disorders, 1071
for viral encephalitis, 1 1 22
Efavirenz, 324 5, 325
Efficacy, 16, 29
Eflornithine (DFMO), for trypanosomiasis,
128
Eflornithine cream, 659
Ehlers-Danlos disease, 970
Eicosapentaenoic acid (EPA), 377
Eisenmenger’s syndrome, congenital
heart disease and, 533
Ejaculatory failure, 1 094
Elastase, 71
faecal, 13615
Elbow pain, 998, 9985
Elderly Mobility Scale, 1311
Electrical cardioversion, for arrhythmias,
482
Electroclinical epilepsy syndromes,
11005
Electroconvulsive therapy, 1 1 90
Electroencephalography see EEG
Electrofulgu ration, 343
Electrolyte balance, 3535
assessment, in hospitalised patients,
3535
in renal failure, chronic, 418
Electrolyte disturbances, acute kidney
injury and, 414
Electrolytes
absorption and secretion of, 769,
769 f
acute kidney injury and, 4165
basic daily requirements, 3535
distribution of, 349, 3497
homeostasis, 349
interpretation of, 3495
loss of, in diabetic ketoacidosis, 7365
reference range of, venous blood,
13585
Electromagnetic spectrum, 1222f
Electromyography see EMG
Electron microscopy (EM), 105, 1322
for sexually transmitted infections,
342
Electrophoresis, 3485
Electrophysiology, 454
Elevated mood, 1186
Elimination
of drugs, 18-19
kinetics, 18f, 19
ELISA, 106-107, 1 097
for Clostridium difficile, 264
for dengue, 244
for hydatid cyst, 299
for leishmaniasis, 283
for leptospirosis, 258
for Lyme disease, 256
for lymphatic filariasis, 291
for schistosomiasis, 296
for strongyloidiasis, 289
Elliptocyte, 915
Elliptocytosis, hereditary, 947-948
Embolism
in acute coronary syndrome, 496
in acute limb ischaemia, 503, 5045
arterial gas, 170
pulmonary, 619-621
acute massive, 200
clinical features of, 619, 6195
investigations of, 619-620,
61 97-6207
management of, 620-621
in pregnancy, 6205
prognosis for, 621
in stroke patients, 1 1 59 f
EMG (electromyography), 1076
for motor neuron disease, 1117
in musculoskeletal disease, 992
Emollients, 1225
for eczema, 1 247
for pruritus, 1 220
in pregnancy, 12205
for psoriasis, 1 250
for skin disease, 1 226
Emphysema, 549
computed tomography of, 552, 576 f
lung transplantation for, 567, 5675
pathology of, 575 f
in respiratory function abnormalities,
5555
Employment, 1198
epilepsy and, 1296
Empyema, 564-565, 5645, 5647-5657
subdural, 1125
Emtricitabine, 1195, 3245
Enalapril
for heart failure, 4665
for hypertension, 513
for myocardial infarction, 500-501
Encapsulated bacteria infection, after
HSCT, 9375
Encephalitis
brainstem, 1122
viral, 1121-1123
West Nile, 1121-1122
Encephalomyelitis
acute disseminated, 1110
cancer- related, 1325
Encephalopathy
hepatic, 8475, 864-865
acute liver failure and, 856-857
clinical grade of, assessment for,
8575
differential diagnosis of, 8655
factors precipitating, 8655
Wernicke’s, 714
Endemic typhus, 271 , 2715
Endobronchial ultrasound (EBUS),
553
Endocarditis, 1035
gonococcal, 340
infective, 527-531, 5285, 5315
acute, 529
antimicrobial treatment of, 5305
in old age, 5275
post-operative, 529
prevention of, 531
subacute, 528-529, 5295, 5297
Endocrine axes, 6337
Endocrine disease
classification of, 6325
clinical examination in, 630-632,
6307, 6315
investigation of, 633, 6335
ophthalmic features of, 11655
pathology of, 632-633
pregnancy and, 1279-1280
presenting problems of, 633, 6345
pruritus and, 12195
rheumatological manifestations of,
1057
Endocrine glands, functional anatomy
and physiology of, 632,
6327-6337
Endocrine pancreas disease
classification of, 6775
presenting problems in, 676-678
Endocrine system, pregnancy and,
1272
Endocrine treatment, for prostate
cancer, 439
Endocrinology, 629-689
of adrenal glands, 665-676
endocrine glands, disorders affecting,
688-689
of endocrine pancreas and
gastrointestinal tract, 676-679
of hypothalamus and pituitary gland,
679-688
reproductive system, 651-661
of thyroid gland, 634-651
Endometrial cancer, 1334-1335
investigations of, 1 334
management of, 1 335
pathogenesis of, 1 334
Endometriosis, 837
Endomitotic reduplication, 918
Endophthalmitis, 1173-1174, 1 1 74f
Endoplasmic reticulum (ER), 40
Endoscopic examination, of respiratory
system, 553
Endoscopic retrograde
cholangiopancreatography see
ERCP
Endoscopic ultrasound, 774
for choledocholithiasis, 9067
for hepatobiliary disease, 855
Endoscopy, 774-776, 775 f
for abdominal pain, 789
for achalasia, 795
capsule, 774-776, 775 f
wireless, 775 f, 776b
for corrosive oesophagitis, 794
double balloon, 776, 7765
for dysphagia, 778, 779 f
for gastric outlet obstruction,
801-802
gastrointestinal haemorrhage, 782,
782 f
for gastrointestinal haemorrhage, 782,
782 f
for inflammatory bowel disease,
818-819
for obscure bleeding, 783 f
for oesophageal cancer, 796-797,
796 f
for oesophageal candidiasis, 317 f
for oesophageal varices, 865 f
in old age, 7765
for peptic ulcer, 799
for pharyngeal pouch, 794
for portal hypertension, 869
of respiratory system, 553
upper gastrointestinal, 774, 7755
wireless capsule, 775 f, 7765
Endosulfan, 1485
Endothelial cells, of liver, 848
Endothelial damage, 950
Endothelin 1 (ET1), 447, 8497
Endothelium, 447
Endotoxin, 104
Endotracheal intubation, critically ill
patients, 1905, 208
Energy
expenditure, 694, 695 f
increased, 7045
intake, 6957, 701
decreased, 7045
requirements, 6985
Energy balance, 694-695, 6957
altered, disorders of, 698-711
determinants of, 694, 695 f
in old age, 7105
regulation of, 694-695, 6967
and reproduction, 6967
Energy-yielding nutrients, 695-697
WHO recommendations, 6985
Engerix, for hepatitis B, 876
Enhanced Liver Fibrosis (ELF)
serological assay, 855
Entacapone, for Parkinson’s disease,
1114
Entactogens, 143
Entamoeba histolytica, 286
life cycle of, 2867
liver abscess from, 286
see also Amoebiasis
Entecavir, 876
Enteral administration, 17
Enteral feeding, 707, 7075
Enteric nervous system, 771-772
Enteritis, radiation, 809-810, 8105
Enterobacter spp., 1 03 f, 1 1 75
Enterobacteriaceae, 1037
Enterobius vermicularis (threadworm),
290, 290 f
Enterococcus faecalis, 103 f, 1175
Enterococcus faecium, 103 f, 1175
Enterocytes, 371
Enterohaemorrhagic Escherichia coli
(EH EC), 227-228
Enterohepatic circulation, 19
Enterokinase, 768
Enteropathic (spondylo)arthritis, 1 034
Enteropathy, protein-losing, 811, 8115
Enteroscopy, double balloon, 776, 7765
Enterovirus 71 , 250
Enthesis, 987-988
Enthesitis, 1033
Enthesitis- related arthritis (ERA), 1027
Enthesopathy, patella ligament, 9995
Entrapment neuropathy, 1139-1140,
11395
Envenomation, 151-162
diagnosis of, 1 59
envenomed patient
bedside test in, 153, 153f
evaluation of, 152, 1527
general approach to, 1 56-1 60
treatment, 159-160
follow-up, 160
hospital assessment and
management for, 1 58-1 59
evidence of, 1 58-1 59
laboratory investigations, 1 59
life-threatening problems, 158
local effects, 1 55, 1 555
overview of, 1 54
by specific animals, 160-162
systemic effects, 1 55, 1 555
venom, 154
venomous animals, 154-155, 1545,
1565-1585
Environment, early, psychiatric disorders
and, 1183
Environmental factors
in disease, cancer, 1320-1321,
13205
of gastro-oesophageal reflux disease,
791
of inflammatory bowel disease, 830
Environmental medicine, 163-172
extremes of temperature and,
1 65-1 68
high altitude and, 168-169
humanitarian crisis and, 171-172
radiation exposure and, 164-165
under water and, 1 69-171
Environmental poisoning, 149, 1495
Enzymes
drugs acting on, 155
pancreatic, chronic pancreatitis,
842
Eosinophil granulocytes, 13625
Eosinophilia, 233-234, 2335-2345,
9265, 927
allergy and, 86
tropical, 233-234, 2335-2345
Eosinophilic gastroenteritis, 811-812
Eosinophilic granulomatosis with
polyangiitis, 1043
Eosinophilic oesophagitis, 794
Eosinophils, 917, 9265, 9267
count, 13625
EPA see Eicosapentaenoic acid
Ependymal cells, 1 064-1 065
Epidemic typhus, 271, 2715
Epidemiology, 95-97, 955
understanding causes and effect,
95-97, 955, 975, 97 f
Epidermal growth factor receptor,
1317
Epidermal necrolysis, toxic, 1254-1255,
12545, 1 2547, 12665
Epidermis, 1212, 12137
Epidermolysis bullosa
acquisita, 12555, 1257
classification of, 1 2545
dystrophic, 1229, 12545
Epididymo-orchitis, 240
Epilepsy, 1097-1104
in adolescence, 1 1 035
classification of, 1 0985
clinical features of, 1098-1100
contraception in, 1103
focal, 1098, 10987
generalised, 1098, 10987
investigations of, 1 1 00-1 101, 11015
brain imaging, 11015
EEG, 1075f, 1076
single seizure, 1 1 00
management of, 1101-1103
antiepileptic drugs for, 1101-1102,
11025
immediate care, 1101, 11015
lifestyle advice, 1101, 11 025
monitoring, 1102
surgery, 1102
in old age, 11035
1382 • INDEX
Epilepsy (Continued)
outcome after 20 years, 1 1 01 jb
pathophysiology of, 1 097-1 098
pregnancy and, 1284
in pregnancy and reproduction, 1103,
1103d
prognosis of, 1103
seizure types, 1 098-1 1 00, 1 098b
absence, 1099
atonic, 1100
clonic, 1100
focal, 1099, 1099b
generalised, 1099-1100
myoclonic, 1099-1100
tonic, 1100
tonic-clonic, 1099, 1099b
temporal lobe, 1185, 1197, 1197b
transition medicine and, 1296
Epilepsy syndromes, 1100, 11 00 b
Epileptic spasms, 1 1 00
Epimysium, 987-988
Epinephrine
for allergy, 86
self-injectable, prescription of, 76 b
Epiphysis, 984
femoral, 1007-1008
Epirubicin, 804
Episcleritis, 1172
Epistaxis
cirrhosis, 867b
dengue, 244
granulomatosis with polyangiitis,
1041
leptospirosis, 258
systemic vasculitis, 1041b
Epithelial membrane antigen (EMA), as
tumour markers, 1322, 1324b
Eplerenone
for heart failure, 465
for mineralocorticoid excess, 675
for myocardial infarction, 501
Epley manoeuvre, 1104
Epo see Erythropoietin
Epoprostenol see Prostacyclin
EPs see Evoked potentials
Epstein -Barr virus (EBV)
cancer and, 1320b
hepatitis and, 871-872
post-transplant lymphoproliferative
disorders and, 1299
viral hepatitis and, 878
Epstein-Barr virus infection, 238b,
241-242
clinical features of, 241-242
complications of, 241-242, 242b
investigations of, 242
management of, 242
Eptifibatide, platelet inhibition, 918
Eradication, for gastrointestinal
haemorrhage, 782
ERCP (endoscopic retrograde
cholangiopancreatography), 776,
777 b, 854-855
for cholangiocarcinoma, 907 f
for cholangitis, 905
for choledocholithiasis, 906f
for pancreatic cancer, 842
for pancreatitis, acute, 839
Erectile dysfunction, 440, 440b
in diabetes mellitus, 760-761
Erectile failure, 1094
Ergocalciferol, 713
Ergotamine, 1096
Erlotinib, 1332
Erosions
in rheumatoid arthritis, 988
skin, definition of, 1218
Erosive osteoarthritis, 1 01 1
Ertapenem, 117b, 120b
Erysipelas, 1237, 1237f
Erythema, palmar, 635-636, 866-867,
1194b
Erythema ab igne, 840
Erythema infectiosum, 237 b
Erythema multiforme, 1221b, 1264,
1264b, 1 2657, 1266b
Erythema nodosum, 1265,
1 265b-1 266b
Erythrasma, 1238
Erythrocyte sedimentation rate (ESR)
abnormal, conditions associated with,
72 b
inflammation and, 72
reference range of, 1 362b
Erythrocytosis, 925
classification and causes of, 925 b
Erythroderma, 1224
Erythromycin, 119b
for acne, 1 242-1 243
for diphtheria, 266
for erythrasma, 1 238
for Lyme disease, 256
for pneumonia, 585b
in pregnancy, 120b
prophylactic, 119b
for relapsing fever, 257
for rheumatic fever, 51 7
for rosacea, 1 244
for STIs
chancroid, 341b
chlamydial infection, 341b
granuloma inguinale, 341b
lymphogranuloma venereum, 341b
syphilis, 339
for tetanus, 1 1 26
Erythropoiesis, impaired, 237 b
Erythropoietic porphyria, congenital,
379 b
Erythropoietic protoporphyria (EPP),
379 b, 1264
Erythropoietin (Epo), 915
chronic renal failure and, 419
ectopic hormone production, 1325b
Escherichia coli, 100, 1 037, 104b,
263-264
entero-aggregative, 263-264
entero-invasive, 263
enterohaemorrhagic, 263-264
enteropathogenic, 263
spontaneous bacterial peritonitis and,
864
verocytotoxigenic, 2Q3f
Escitalopram, 1199b
ESR see Erythrocyte sedimentation rate
Essential fatty acids, 697, 697 f
Essential thrombocythaemia, 969-970
Essential tremor, 1115
Etanercept, for musculoskeletal disease,
1007b
Ethambutol, 125
Mycobacterium avium complex, 315b
polyneuropathy, 1139b
for tuberculosis, 593, 593b
Ethanol
pharmacokinetics of, 20 b
poisoning, 135b
reference range of, 1 360b
see also Alcohol
Ethics
in artificial nutritional support, 710b
in genomic age, 59
Ethnicity, type 2 diabetes and, 732
Ethosuximide, 1 1 00 b
Ethylene glycol poisoning, 135b, 147,
147f
Ethylenediamine-tetra-acetic acid
(EDTA), 386 b
Etidronate, for Paget’s disease, 1 054b
Etoposide
for acute leukaemia, 957 b
for testicular tumours, 440
Etoricoxib, 1003b
Euchromatin, 38-39
Eukaryotes, 101-102
Eumycetoma, 301
Euphoria, 1196
Euthanasia, 1356
Euvolaemia
with hypernatraemia, 359b
with hyponatraemia, 357
Evidence- based medicine, 10
Evoked potentials (EPs), 1076-1077,
1 077f
Evolutionary selection, 45-46
Ewing’s sarcoma, 1 057
Exanthem, enteroviral, 240
Exanthem subitum, 238
Excessive daytime sleepiness, 1105
Exchange transfusion
for malaria, 277
for megaloblastic anaemia, 945
for sickle-cell disease, 953
Excision, for cancer, 1330
Excision arthroplasty, 1 002b
Excision biopsy, for skin disease, 1 228
Excitatory neurotoxins, 155
Excoriation, definition of, 1241
Excretion
of drugs, 17 f, 18-19, 29
interactions, 24
Exemplar medicine sick-day card, 418b
Exenatide, 747
Exercise(s)
acute coronary syndrome and, 501
arrhythmias and, 450b
asthma, 568, 570 f
chest pain and, 455
COPD, 574
diabetes and, 744
heart disease and, 537 b
hypoglycaemia and, 740
insulin levels and, 740
for musculoskeletal disease, 1 001
ankylosing spondylitis, 1 031
fibromyalgia, 1018-1019
osteoarthritis, 1012
Exercise ECG, 449-450, 450b
Exercise testing
for angina, 488
for COPD, 575
for myocardial infarction, 450b
for respiratory function testing, 556
Exertion headache, 1 097
Exfoliative dermatitis, drug-induced,
1266b
Exogenous androgen administration,
hirsutism and, 658 b
Exons, 39 f
Exophthalmos, in Graves’ disease, 631b
Expiration, of lungs, 548
Explanation, for somatoform disorders,
1203
Extracellular fluid (ECF), 349
Extracorporeal membrane oxygenation
(EC MO)
principles of, 205 f
venous-arterial, 207-208
venous-venous, 204
Extracorporeal shock wave lithotripsy
(ESWL), 906
Extractable nuclear antigens (ENAs),
antibodies to, 991
Extrahepatic portal vein obstruction,
portal hypertension and, 868
Extraocular muscles, 1 1 64
of right eye, 1 1 65 f
Extrapyramidal gait, 1087
Extrapyramidal system, 1069
Extravascular haemolysis, 946-947
Extubation, in intensive care, 210
Eye disease, HIV-related, 319-321, 31 9f
Eye movement desensitisation and
reprocessing (EMDR),
1201-1202
Eyelid, 1164
retraction, of ophthalmic disease,
1171
Eyes, 1164-1168
blood supply of, 1 1 68
of envenomed patient, 1 527
examination of
diabetes mellitus, 721b
respiratory system, 546f
inflammatory arthritis in, 994b
main structure of, 1167 f
rheumatoid arthritis in, 1024
Ezetimibe, 376
F
F-fluorodeoxyglucose (FDG), 553
Fabry’s disease, 371b
Face
angioedema, 87 f
examination of
musculoskeletal system, 982f
respiratory system, 546f
frostbite, 166
hemifacial spasm in, 1116
numbness of, 1 080
skin disease see individual conditions
superior vena cava obstruction, 1326
Facial (7th cranial) nerve
palsy, 1082-1083
tests of, 1 063b
Facial pain, 1080
Facial warts, 1 238
Facial weakness, 1082-1083
Facioscapulohumeral dystrophy, 1 1 43b
Factitious disorder, 1 205-1 206
Factitious fever, 220 b
Factor II, 972b
Factor V, 91 9
Leiden, 923 b, 972 b, 977
stroke, 1157b
Factor VII, 919
deficiency, 928, 974
Factor VIII
concentrate, 972-973
haemophilia A, 971
inhibitor bypass activity (FEIBA), 973
Factor IX, 972
concentrate, 973-974
deficiency, 973-974
haemophilia B, 973-974
Factor XI deficiency, 974
Faecal antigen test, for Helicobacter
pylori infection, 782
Faecal continence, 770
Faecal impaction, 834
Faecal incontinence, 835, 835b, 1094
Faeces analytes, 1361b
Faints see Syncope
Falciparum malaria, 231
Falls
older people, 1308-1309,
1308b-1309b, 1308 f
prevention, 1308-1309
Famciclovir, for herpes virus infection,
126, 127b
genital, 342
Familial adenomatous polyposis,
828-829, 829f, 1321b
Familial hypercholesterolaemia, 374,
374b
Familial hypocalciuric hypercalcaemia,
664
pregnancy and, 1280
Familial Mediterranean fever (FMF), 81
Family behaviour therapy (FBT), for
eating disorders, 1 203-1 204
Family history, 56
of allergic disease, 85
genetic disease, 46
of melanoma, 1232
ovarian cancer and, 1334
of psoriasis, 1 247-1 248
psychiatric disorders and, 1181b
of vitiligo, 1 257
Family tree see Pedigree
Famine, 704-705
Fanconi anaemia, 1321b
Fanconi’s syndrome, 366, 405
multiple myeloma and, 410b
Farmer’s lung, 616b
Fasciculations, 146b, 148b, 158b,
1063b
Fasciculi, 987-988
Fasciola hepatica, choledocholithiasis
and, 906
Fascioliasis, 297 b
Fat-pad syndrome, 999b
Fatal familial insomnia, 1 1 27 b
Fatigue
in cancer patients, 1325b
chronic fatigue syndrome, 1 202
fibromyalgia, 1018
multiple sclerosis, 1110b
primary biliary cholangitis and, 888
rheumatoid arthritis, 1023
Fats, 697, 697 f
body, distribution of, 699
see also Obesity
in diabetic diet, 744
digestion and absorption of, 768
distribution of, clinical assessment for,
693 b
INDEX • 1383
energy provided by, 694
malabsorption, small bowel disease
and, 809
normal metabolism of, 725
recommended intake, 698b
Fatty acids
essential, 697, 697 f
free, 697
n-3, 376
polyunsaturated, 697 f
trans , 697
Fatty liver
alcoholic, 881, 881b
non-alcoholic, 882-885, 883f
Febrile response, 1 04
Febuxostat, for gout, 1016
Feeding
enteral (tube), 707, 707 b, 839
for famine management, 705
gastrostomy, 707, 707b, 708 f
parenteral, 707-708
post-pyloric, 707
Felty’s syndrome, 1024-1025, 1025b
Female, reproductive system of, 652,
652 f
Femoral neck fractures, 994
Femoral stretch test, 996-997
Ferritin
in acute phase response, 70
adult-onset Still’s disease, 1 040
anaemia of chronic disease, 943
haemochromatosis and, 895
iron deficiency anaemia, 941 , 942b
megaloblastic anaemia, 944b
in old age, 954b
reference range of, 1 362b
Ferrous gluconate, 943
Ferrous sulphate, 943
Fertility
cystic fibrosis and, 1297
renal replacement therapy and,
1282-1283
Festination, 1087, 1309b
Fetor hepaticus, 857-858
portal hypertension and, 868
Fever(s), 217b, 218-225
accompanying features of, 217b
acute rheumatic, 515-517, 51 6f
investigations in, 51 7b
Jones criteria for, 51 6b
African tick bite, 270, 271b
boutonneuse, 271b
in cancer patients, 1 323
clinical assessment of, 21 8, 21 8b
factitious, 220 b
febrile response, 104
HIV-related, 313-314, 313f-314f
in immunocompromised host,
223-224
inhalation (‘humidifier’), 617
in injection drug-user, 222-223,
222f-223f
intermittent, 74
investigations of, 218
with localising symptoms or signs,
218, 219 f
louse-borne relapsing, 256 b, 257,
257 f
management of, 218
neutropenic, 224
in cancer patients, 1327-1328
post-transplantation, 224-225, 224b
recurrent, 217b
rickettsial, 270-272
Rocky mountain spotted, 270, 271b
scrub typhus, 270-271, 271 b
streptococcal scarlet, 252, 253 f
tick-borne relapsing, 256b, 257
trench, 272
tropical, 230-232
causes of, 231b
clinical assessment of, 230-232,
232 b
history taking in, 231b
investigations of, 232, 232 b
management of, 231 f, 232
typhoid, 260, 260 b
of unknown origin see Pyrexia of
unknown origin
viral haemorrhagic, 245-247, 245b
yellow, 243f, 244-245
incubation period of, 245b
Fexofenadine, 1227
FGF see Fibroblast growth factor
Fibrates, 377
hyperlipidaemia management,
377-378
muscle pain, 1000b
Fibre, dietary, 697
Fibrin, 13197
Fibrinogen
in acute phase response, 70
concentration of, 922 b
reference range of, 1 362b
Fibroblast growth factor (FGF), 1325b
Fibroblast growth factor 23 (FGF23), in
skeletal disease, 990b
Fibrolamellar hepatocellular carcinoma,
892
Fibromuscular dysplasia, renal artery
stenosis and, 406
Fibromyalgia (FM), 1018-1019,
1 01 87—1 01 97
investigations of, 1019b
spectrum of symptoms in, 1018b
Fibrosis
cystic, 580-581, 580 f, 581b, 842,
902
contraception and, 1297
fertility and child-bearing potential
in, 1297
transition medicine and, 1297
hepatic, 894
cirrhosis and, 866, 866f
congenital, 8687, 902
non-invasive markers of, 855
pathogenic mechanisms in, 849f
idiopathic pulmonary, 605-608, 607 f
of liver, 894
cirrhosis and, 866, 866 f
congenital, 868f, 902
non-invasive markers of, 855
pathogenic mechanisms in, 849f
nephrogenic sclerosing, 390b
pulmonary, 547f
in dermatomyositis, 610b
idiopathic, 605-608, 607 f
in respiratory function
abnormalities, 555 b
in rheumatoid arthritis, 610b, 1024
in sarcoidosis, 609b
in sclerosis, 610b
in systemic lupus erythematosus,
610b
retroperitoneal, 434
drug-induced, 427b
Fibrous and fibrocartilaginous joints, 986
Fidaxomicin, 124
Fifth disease, 237 b
‘Fight or flight’ response, 1213-1214
Filaggrin, 1212
Filariases, 233b
Finasteride, 659b
for alopecia, 1 259
Fine needle aspiration cytology, 643
Fingers
clubbing, 546 f, 559, 559 b, 559 f
asbestosis, 618
in lung cancer, 600
trigger, 1060
Finkelstein’s sign, 998
First aid, for envenomed patient,
156-157
First-pass metabolism, 17
Fish
minerals in, 717b
venom, 154b
vitamins in, 711b
Fish eye disease, 375, 375 b
Fish oils, 697, 711b
Fissure
anal, 836
skin, definition of, 1244b
Fistulae, 836
inflammatory bowel disease and, 823
tracheo-oesophageal, 625
see also different types
Fitz-Hugh-Curtis syndrome, 836
Flapping tremor, hepatic
encephalopathy and, 864-865
Flares, of gout, 1015
Flavonoids, 716
Fleas, 231b
bartonellosis, 272 b
plague, 259
typhus, 271, 271b
Flecainide, 470-473, 476b
Flora, normal microbial, 102-103, 1 037
Flow cytometry, 1 05
Flucloxacillin, 117b, 120b
cerebral abscess, 1 1 24b
hepatotoxicity, 894
for impetigo, 1236
for infective endocarditis, 223
for pneumonia, 585b
for septic arthritis, 1020, 1020b
for staphylococcal infections, 251
for staphylococcal scalded skin
syndrome, 1236
Fluconazole, 125b, 126
acute leukaemia patients, 957
candidiasis, 336
HIV/AIDS patients, 316
cryptococcal meningitis, HIV-related,
315b, 321
for cutaneous leishmaniasis, 286
for paracoccidioidomycosis, 304
in pregnancy, 120b
prophylaxis, 315b
for skin disease, 1 239-1 240
Flucytosine, as antifungal agents, 1 26
Fludarabine
for chronic lymphocytic leukaemia,
960
for Waldenstrom macroglobulinaemia,
966
Fludrocortisone
for adrenal insufficiency, 673, 673 b
postural hypotension, 1308-1309
Fluid, loss of, in diabetic ketoacidosis,
736, 736 b
Fluid balance
for community-acquired pneumonia,
583
for heat exhaustion, 167
for renal failure, chronic kidney
disease, 418
Fluid overload, in hypertension, 193
Fluid replacement
for acute diarrhoea, 229-230, 229 b
for cholera, 265
for decompression illness, 171
for diabetic ketoacidosis, 737
for diving-related illness, 171
for food poisoning, 150
for heat exhaustion, 167
intensive care unit, 208
intravenous, for decompression
illness, 171
Fluid therapy
assessment, in hospitalised patients,
353 b
intravenous, for hypovolaemia, 353
for shocked patients, 206
Fluke, liver, 1320b
Flumazenil, 142
Fluocinolone acetonide, 1 226 b
Fluorescent in situ hybridisation (FISH)
techniques, 1322
Fluoride, 718
dietary sources of, 717b
and osteomalacia, 1 053
poisoning, 718
reference nutrient intake of, 717b
Fluorimetry, 348b
5-Fluorocytosine, 125b, 126
Fluoroquinolones, 122-123, 123b
for leprosy, 269
for plague, 259
skin reactions, 1 1 73 b
tuberculosis, 593
Fluorosis, 149
5-Fluorouracil (5-FU), 804
for basal cell carcinoma, 1 230,
1230b
for colorectal cancer, 832
for gastric cancer, 804
Fluoxetine, 1199b
for bulimia nervosa, 1204
for fibromyalgia, 1 01 8-1 01 9
Flupentixol, 1198b
Flutamide, 659b
Fluvoxamine, 139
FMF see Familial Mediterranean fever
Foamy macrophages, 430, 809
Focal hypermelanosis, 1258
Focal nodular hyperplasia, 893
Focal segmental glomerulosclerosis
(FSGS), 400
Focal seizures, 1099, 1099b
Folate (folic acid), 715, 945
absorption, 945
biochemical assessment of status,
712b
deficiency, 715, 945
causes of, 945b
investigation of, 945b
management of, 945
dietary sources of, 711b
for neural tube defects, 712b, 715
reference nutrient intake of, 711b
reference range of, 1 362b
supplements, 715
Folate antagonists, 1 23
Folate synthesis inhibitors, 1 28
Folinic acid
for colorectal cancer, 832
for toxoplasmosis, 281
Follicle-stimulating hormone (FSH)
puberty and, 1290
reference range of, 1 359b
Follicular carcinoma, 636b, 649
Folliculitis, 1236-1237
deep, 1237f
pruritic, 1220b
superficial, 1236-1237
Fomepizole, 147
Fondaparinux, 938-939, 938b
Fonsecaea com pacta, 300-301
Fonsecaea pedrosoi, 300-301
Food allergy, 812
Food hygiene, 323
Food intolerance, 812
irritable bowel syndrome of, 825
Food poisoning
Bacillus cereus, 262, 262 f
Clostridium perfringens, 262
non-infectious causes of, 230
staphylococcal, 262
Food-related poisoning, 149-150
Foot drop, 1087, 1309b
Foot/feet
diabetic, 759 f, 761-762
aetiology of, 761
clinical features of, 761b
management of, 761-762, 762b,
762f
examination of
diabetes mellitus, 721b
musculoskeletal system, 982f
non-freezing cold injury (trench or
immersion foot), 1 67
Foot pain, 999
Foot ulcer, 761-762
Forced expiratory volume (FEV-,),
554f
in COPD, 574b
in old age, 550 b
Forced vital capacity (FVC), 550b
Foreign body, inhaled, 179, 179 f
Fortification spectra, 1 088
Foscarnet
for CMV infection, 243
for herpesvirus infection, 127, 127b
Fosfomycin, 124
Fournier’s gangrene, 227
Fractures, 994-995
associated with osteoporosis, 1044,
1045f
bone mineral density and, 1046f
fragility, 995b
high-energy, 995b
hip, 1308, 1308f
investigation of, 994-995, 995b
osteoporotic, 1308
pathological, 995b
1384 • INDEX
Fractures (Continued)
prevention of, 1308-1309, 1309b
repair, 1002b
stress, 995b
vertebral, 995b
Fragile site mental retardation 2
(FRAXE), 43b
Fragility fracture, 995b
Frailty, 1306, 1306b
Frameshift mutation, 42
Francisella tularensis, 261
FRAXE see Fragile site mental
retardation 2
FRC see Functional residual capacity
Freckle, 1234
Free fatty acids, 697
Free intravascular haemoglobin, 917
Free radicals, 713, 881
Freezing cold injury, 1 66-1 67
Frequency of micturition, 396
Fresh frozen plasma, 931b
Fried Frailty score, 1 306b
Froin’s syndrome, 1136-1137
Frontal lobes, 1066
functions of, 1 066b
effects of damage, 1 066b
Fronto-temporal dementia, 1193-1194,
1 193f
Frontostriatal reward circuits, high-risk
behaviour and, 1295
Frostbite, 166-167, 167f
Frozen shoulder, 997-998
Fructose, 695-697, 696b
FSFI see Follicle-stimulating hormone
5-FU see 5-Fluorouracil
Full blood count (FBC), 919-920
see also Blood count
Fulminant liver failure, hepatitis B and,
875
Functional disorders, 802-803,
1094-1095, 1095b
‘Functional’ gonadotrophin deficiency,
653
Functional IgG antibody deficiency, 79
Functional residual capacity (FRC),
549
Functional somatic syndromes, 1187,
1187b
Fundus angiography, of visual disorders,
1169
Fungal infections, 300-304, 300f
after HSCT, 937 b
antifungal agents, 125-126, 125b,
1239-1240
skin, 1239-1240, 1240f
subcutaneous, 300-301
superficial, 300
systemic, 301-304
Fungal keratitis, 1 1 73
Fungal meningitis, 1121
Fungi, 101-102
respiratory diseases caused by,
596-598, 596 b
‘Funny turns’, 1080
Furosemide
adverse reactions of, 22 b
ascites and, 864
for heart failure, 465
for hyperkalaemia, 363b
for hypertension, 513
for oedema, 396
route of administration, 30b
for skin disease, 1221b
Furuncles, 1237
Fusariosis, 302-303, 303 f
Fusidic acid, 124
for impetigo, 1 236
Fusobacterium necrophorum, 586
Fusobacterium spp., 103f, 117b
Fusobacterium ulcerans, 234 b
Futility, 213
FVC see Forced vital capacity
G
G-CSF see Granulocyte-colony-
stimulating factor
G6PD see Glucose-6-phosphate
dehydrogenase (G6PD)
deficiency
GABA
hepatic encephalopathy and, 865
role in epilepsy, 1097-1098
Gabapentin
for abdominal pain, 789
adjuvant analgesics, 1352b
for chronic pain, 1345b
for epilepsy, 1 1 02 b
for fibromyalgia, 1 01 8-1 01 9
multiple sclerosis, 1110b
for neuropathic pain, 1084, 1350b
for post-herpetic neuralgia, 240
for somatoform pain disorder, 1 202
GAD see Glutamic acid decarboxylase
Gain-of-function mutations, 45
Gait
abnormal, 1086-1087
assessment of, 983 f
examination of, 1063b
in older people, 1 309b
stamping, 1087
waddling, 1063b
Galactorrhoea, 684
Galactosaemia, 370
Galactose, 370, 768
Galactose-1 -phosphate uridyl
transferase gene (GALT), 370
Gallbladder, 849-850
adenomyomatosis of, 909
cancer of, 904
in old age, 909b
carcinoma of, 907
cholesterolosis of, 909
disease of, in old age, 909b
strawberry, 909
tumours of, 907-908
benign, 908
Gallstone dyspepsia, 904
Gallstones, 903-905, 904f
biliary sludge and, 904
cholesterol, 903, 903b
clinical features of, 904, 904b
in old age, 909b
pigment stones and, 903-904, 903b
pregnancy and, 900
treatment of, 905b
ultrasound for, 853-854, 854f
GALT, 370
Gambiense infections, 279
Gametogenesis, 41 f
Gamma-glutamyl transferase (GGT), liver
blood biochemistry test and,
852, 853b
Gamma hydroxybutyrate, misuse of,
143
Gamma ray-emitting
radiopharmaceuticals, 390
Gamma rays, 164, 164f
Gammopathy, 966
Ganciclovir
for CMV infection, 224
HIV-related, 322
transplant patients, 89, 937 b
for herpesvirus infection, 126, 127b
‘Gas-bloat syndrome’, 794
Gas exchange, in lungs, 549-550, 549f
Gas gangrene, 227
prophylaxis for, 1 1 9b
Gastrectomy
sleeve, 703 b
under-nutrition and, 706
Gastric acid, 791
Gastric aspiration, 136
Gastric banding, 703 b
Gastric bypass, 703 b
Gastric carcinogenesis, 803 f
risk factors for, 804b
Gastric emptying, defective, 791
Gastric emptying study, 778 b
Gastric inhibitory polypeptide (GIP),
723-724, 772 b
Gastric lavage, 1 36, 1 36b
Gastric outlet obstruction, 801-802,
801b
Gastric secretion, 767, 767 f
Gastric varices, 865-866, 865 f
Gastric volvulus, 793
Gastrin, 767, 772 b
reference range of, 1 359b
Gastritis, 797-798
acute, 797
causes of, 798 b
chronic
autoimmune, 797
due to Helicobacter pylori infection,
797, 798 f
Gastro-oesophageal reflux disease,
791-794, 791 f, 794 f
asthma and, 791-792
in old age, 794b
Gastroenteritis
eosinophilic, 811-812
infective
causes of, 228 b
foods associated with, 228b
in old age, 228 b
Gastroenterology, 763-844
functional anatomy of, 766-772
histology of, 776, 777 b
Gastroenteropancreatic neuro-endocrine
tumours, 678-679, 678 b, 679 f
Gastroenteropathy, allergic, 812
Gastroenterostomy, 801-802
Gastrointestinal bleeding, 780-783
acute upper gastrointestinal
haemorrhage in, 780-782
management of, 781-782
endoscopic therapy, 780
lower gastrointestinal tract, 782-783,
782 b
severe, 782-783
subacute or chronic, 783
occult, 783
of unknown cause, 783, 783 f
upper, risk stratification in, 781b
Gastrointestinal decontamination, in
poisoning, 135-136, 136b
Gastrointestinal disease, 785
contrast radiology in, 773 b
HIV-related, 316-317
ophthalmic features of, 1 1 66b
during pregnancy, 1277-1278
transition medicine and, 1299-1300
inflammatory bowel disease in,
1299-1300
Gastrointestinal haemorrhage, upper,
causes of, 781 f
Gastrointestinal obstruction, in palliative
care, 1354
Gastrointestinal polyposis syndromes,
828 b
Gastrointestinal stromal cell tumours
(GISTs), 805
Gastrointestinal system, pregnancy and,
1272
Gastrointestinal tract
absorption from, 17
clinical examination of, 764-766,
764f, 765 b
diseases/disorders
classification of, 677 b
functional, 802-803
gut hormones, 772
investigation of, 772-778
presenting problems in, 778-789
function, control of, 771-772
HIV/AIDS and, 826
obstruction, 788
Gastrointestinal tuberculosis, 590, 591 f
Gastroparesis, 760, 803
Gastropathy, congestive, ‘portal
hypertensive’, 871
Gastrostomy feeding, 707, 707 b, 708 f
Gaucher’s disease, 371b
GCA see Giant cell arteritis
GCS see Glasgow Coma Scale
Gefitinib, 1332
Gegenhalten, 1094
Gels, 1225b
Gemcitabine, for pancreatic cancer,
842-844
Gender, alcoholic liver disease and, 880
Gene panels, 54b
Gene promoter, 39, 39f
Gene sequencing, 52-56, 54f-55f
challenges of NGS technologies in,
53-54
methods for, 55 b
NGS capture in, 53
third-generation, 56
uses of, 54-56
Gene therapy, for genetic disease, 58
General anaesthetics, 14
General assessment of locomotor
system (GALS), 983, 983 f
General sales list (GSL), 27
Generalised anxiety disorder, 1 200
Generalised lymphadenopathy, 927
Generalised pain, causes of, 995b
Generalised seizures, 1 099-1 1 00
Generic virus life cycle, 1 01 f
Genes
amplification of, 52, 53 f
packaging of, 38, 38 f
Genetic disease(s)
constitutional, 46-50
inheritance patterns of, 46-50
renal, 403-406
skin, 1264
somatic, 50-51
treatment of, 58
Genetic factors
adverse drug reactions and, 29
of ageing, 1304-1305
alcoholic liver disease and, 880,
881 f
of cancer, 1 31 6
of inflammatory bowel disease,
830
of osteoarthritis, 1 007-1 008
of osteoporosis, 1 044
of Parkinson’s disease, 1112
psychiatric disorders and, 1183
Genetic testing, 1077
for Peutz-Jeghers syndrome, 829
Genetic variant
classes of, 42-44, 42b
consequences of, 44-45
in evolutionary selection, 45-46
normal, 45-46
Genital herpes, 334b, 336b
Genital itch/rash, 333, 334b
Genital lumps
in men, 334
in women, 336
Genital ulcers
in Behget’s disease, 1 043-1 044
in men, 333-334, 334f
in women, 336
Genital warts, 1 238
Genitalia, in endocrine disease, 630f
Genitourinary disease, in tuberculosis,
591
Genitourinary system, pregnancy and,
1272
Genome editing, for genetic disease,
58
Genome-wide association studies
(GWAS), 45
Genomics
clinical practice and, 56-59
common disease and, 56
ethics and, 59
fundamental principles of, 38-41
health and disease, 42-51
health care and, 56-58
in infectious disease, 58
obstetrics and, 56
oncology and, 56-58
in rare neurodevelopmental disorders,
56
technologies for, 51-56
Gentamicin, 429
for brucellosis, 255 b
for cerebral abscess, 1124b
dosing of, 122, 122f
drug concentration, 36b
for infective endocarditis, 223
for liver abscess, 880
for meningitis, 1 1 20 b
for neutropenic sepsis, 957
for plague, 259
prophylactic, 119b
renal or hepatic disease, 32b
for septic arthritis, 1 020
for tularemia, 261
for urinary tract infection, 429b
INDEX • 1385
Geriatric medicine
assessment, 1306
presenting problems in, 1307-1311
see also Age/ageing; Older people
Gerstmann-Straussler-Scheinker
syndrome, 1127b
Gestational diabetes, 1278, 1278b
diagnosis of, 1278
management of, 1278
screening for, 1 278
Get up and go test, 1303b
GFR see Glomerular filtration rate
GGT see y-Glutamyl transferase
GH see Growth hormone
Ghrelin, 767, 772 b
Giant cell arteritis (GCA), 1042-1043,
1170
emergency management of, 1 043b
Giardia lamblia , 287
Giardiasis, 287
clinical features and investigations of,
287
management of, 287
Gilbert’s syndrome, 860, 860b, 897
Gingivitis, 316
GIP see Gastric inhibitory polypeptide
GISTs see Gastrointestinal stromal cell
tumours
Gitelman’s syndrome, 361
Glanzmann’s thrombasthenia, 971
Glasgow Coma Scale (GCS), 134, 185,
1 867, 194, 194b
Glasgow criteria, for prognosis in acute
pancreatitis, 837 b
Glasgow score, for alcoholic liver
disease, 882, 882b
Glatiramer acetate, 1109, 1109b
Glioblastoma multiforme, 1 1 29
Gliomas, 1130-1131
Glitazones, for non-alcoholic fatty liver,
885
Global burden of disease (GBD)
causes of death and disability, 92-93,
92 b
underlying risk factors of, 93b
Global warming, 94
Glomerular diseases, 397-401 , 397b
histopathology of, 3997
inherited, 403-404
pregnancy and, 1282
Glomerular filtration rate (GFR),
386-387, 387 7
diabetes mellitus and, 417 7
estimation of, 386b
limitations of, 387 b
pregnancy and, 1272
renal failure, chronic, 415
renal haemodynamics and, 4137
Glomerulonephritis, 397-401
antibody production, associated with,
397 7
categorised, 398b-399b
causes of, 401b
drug-induced, 427b
infection-related, 398b-399b, 401
mesangiocapillary, 398b-399b, 401
nephrotic syndrome, 392b, 395,
395 b
rapidly progressive, 397
in systemic lupus erythematosus,
1035
terminology used in, 400b
Glomerulosclerosis, nodular, diabetic,
757, 758 7
Glomerulus, 384
Glossitis, atrophic, 764f
Glossopharyngeal (9th cranial), tests of,
1063b
Gloves and socks syndrome, 237 b
Glucagon
famine, 704-705
secretion, regulation, 724
Glucagon-like peptide-1 (GLP-1),
723-724, 772 b
Glucagon-like peptide-1 (GLP-1)
receptor agonists, for
hyperglycaemia, 747-748
Glucocorticoid-induced osteoporosis,
1045
Glucocorticoids, 665
for acute exacerbations of COPD,
578
for adrenal insufficiency, 672-673
adverse effects of, 670-671
advice to patients on, 671b
for alcoholic hepatitis, 882
for allergy, 86
anabolic, cholestatic hepatitis and,
894
for ankylosing spondylitis, 1031
for antineutrophil cytoplasmic
antibody-associated vasculitis,
1041
for autoimmune hepatitis, 886-887
in bone remodelling, 986b
for Duchenne muscular dystrophy,
1297
for Graves’ ophthalmopathy, 646
growth retardation and, 1290, 1299
for inflammatory bowel disease, 821b,
1299
for musculoskeletal disease,
1005-1006
in old age, 673 b
osteoporosis induced by, transition
medicine, 1300
for polymyositis and dermatomyositis,
1040
for primary biliary cholangitis, 888
pruritus, 1220b
for psoriatic arthritis, 1033-1034
for reactive arthritis, 1 032
for rheumatic fever, 517
sodium content of, 864b
therapeutic use of, 670-671 , 670 b
topical, 1226, 1226b, 12267
for tuberculosis, 593
for ulcerative colitis, 1299-1300
for warm autoimmune haemolysis,
950
weight gain, 700 b
withdrawal of, management of, 671 ,
671b
see also Corticosteroids; Cortisol;
Hydrocortisone;
Mineralocorticoids; Prednisolone
Gluconeogenesis, 850
Glucosamine sulphate, for osteoarthritis,
1012
Glucose
acute kidney injury and, 416b
blood
diabetes and, 724-726
impaired fasting glucose, 726 b,
728
normal metabolism of, 724, 725 7
cerebrospinal fluid, 1361b
control of, in intensive care, 210-211
filtration and reabsorption by nephron,
748f
impaired tolerance, 374, 1 360b
interstitial, diabetes and, 726
intravenous, porphyria, 379
metabolism of, pregnancy and,
1272-1273
reference range of, venous blood,
1360b
urine, diabetes and, 725
values of, in gestational diabetes,
1278
Glucose-6-phosphate dehydrogenase
(G6PD) deficiency, 948-949,
949b
Glucose tolerance, impaired, 726 b,
728
Glucose tolerance test, oral, 726 b
Glue sniffing, 1196
Glutamate, 698b
Glutamic acid decarboxylase (GAD),
1111b
Glutaminase, 364
y-Glutamyl transferase (GGT)
in alcohol misuse, 1184
reference range of, venous blood,
1360b
Glutathione, 712b
Gluten-free diet, 807
Gluteus medius enthesitis, 999b
Glycaemic control, in diabetes,
756-757, 756 7
in adolescence, 753 b
in old age, 757 b
self-assessment of, 742
‘Glycaemic index,’ of foods, 695-697
Glycated haemoglobin (HbA1c),
726-727, 727 b, 1360b
Glycation, 726-727
Glyceryl trinitrate (GTN)
for anal fissure, 836
angina, 489, 490b
duration of action, 490b
intravenous, accelerated
hypertension, 514
for pulmonary oedema, 465b
route of administration, 30b
sublingual, 489, 500
Glycine, 698b
Glycogen, 694
Glycogen storage diseases (GSDs),
370, 370 b
Glycopeptide-resistant enterococci
(GRE), 117b
Glycopeptides, 123
mechanism of action, 1 1 6b
in pregnancy, 1 20 b
Glycoprotein intrinsic factor, 767
Glycosidases, 987
Glycosuria, 725, 729-730
diabetes mellitus, 409, 729-730
Fanconi’s syndrome, 410b
hypernatraemia and, 359b
‘lag storage’, 638b
leg ulcers and, 1224
in old people, 732 b
pregnancy and, 1272
renal, 405, 725
Glycosylphosphatidylinositol (GPI),
950-951
Glycylcyclines, 120b, 124
GM2-gangliosidosis, 371b
Gnathostomiasis, 294
Goitre
endemic, 717
multinodular, 648-649, 648f
simple diffuse, 648, 6487
thyrotoxicosis, 635-636, 636b
Gold (myocrisin)
adverse effects on kidney, 427b
adverse reactions of, 926b
for musculoskeletal disease, 1004b,
1005
Golfer’s elbow, 998
Golgi apparatus, 40
Golimumab, for musculoskeletal
disease, 1007b
Gonadotrophin-releasing hormone
(GnRH), 633 7
for infertility, 656-657
puberty and, 1290
Gonadotrophin-releasing hormone
analogues, 379
Gonococcal infection, disseminated
(DGI), 340
Gonococcal ophthalmia neonatorum,
3407
Gonococcal urethritis, 333, 3337
Gonorrhoea, 339-340
arthritis, 340
complications of delayed therapy in,
340b
incubation period, 111b, 339
pharyngeal, 340
treatment of uncomplicated, 340b
urethritis, 333
Goodpasture’s disease, 612
Gorlin’s syndrome, 57 b
Goserelin, 1332
Got transition, 1290
Gottron’s papules, 1 039
Gout, 1012-1016
causes of, 1013b
clinical features of, 1014,
101 4f-101 if
epidemiology of, 1 01 2-1 01 3
investigations for, 1014-1015
management of, 1015-1016
in old age, 1014b
pathophysiology of, 1013-1014,
10137
tophaceous, 1014-1015, 10157
Graft-versus-host disease (GVHD), 937,
1252
Graham Steell murmur, 526
Granulocyte-colony-stimulating factor
(G-CSF), 1327-1328
Granulocytes, 917
count, 1362b
Granuloma annulare, 1 263
Granuloma inguinale, 341b
Granulomas, 71
Granulomatosis with polyangiitis, 612,
1041
Granulomatous disease, 1 263
Granzymes, 67
Graves’ disease, 643-646
ophthalmopathy, 631b, 645-646,
6457
thyrotoxicosis and, 635-636, 636b,
643-646, 6437
management of, 644-645, 644b
Graves’ thyrotoxicosis, 643-645, 6437
Gravitational eczema, 1 247
Grays (Gy), 164
Grenz (Bucky) ray therapy, for skin
disease, 1228-1229
‘Grey baby’ syndrome, 1 20 b
Grey Turner’s sign, 837-838
Grief reactions, 1 201
Griseofulvin, as antifungal agents, 126
Group A streptococci (GAS), 252
Group B streptococcal infection, in
pregnancy, 235 b
Growth, analytes affected by, 1363b
Growth factors, 914, 9157
asthma, 568
cancer, 1317, 13177
haematopoiesis, 914
Growth failure, 823
Growth hormone (GH), 632, 6337
reference range of, 1 359b
Growth hormone-releasing hormone
(GHRH), 6337
Growth hormone replacement, for
Hypopituitarism, 682
Growth hormone secretion, tests of,
682 b
Growth retardation
congenital heart disease and, 533
eating disorders, 1 204b
GSDs see Glycogen storage diseases
GTN see Glyceryl trinitrate
Guanine, 38
Guillain-Barre syndrome, 1140
Guinea worm (dracunculiasis), 293
Gumma, 338
Gums, 696b
Kaposi’s sarcoma, 3167
scurvy, 716b
Gut hormones, 772, 772 b
testing, 778
GVHD see Graft-versus-host disease
Gynaecomastia, 657, 657 b, 867
in hypogonadism, 653
H
HACE see High-altitude cerebral
oedema
HACEK group bacteria, endocarditis,
528, 528 b
HAE see Hereditary angioedema
Haem, biosynthetic pathway, 3787
Haemagglutination testing, 261
Haemagogus spp., yellow fever and,
244
Haemangioblastomas, 1 1 32
Haemangiomas, 1234
liver, 893, 8937
Haemarthrosis, 992-993
Haematemesis, 780
Haematocrit (Hct), 919-920, 1362b
Haematological abnormalities,
HIV-related, 322
Haematological disorders see Blood
diseases
Haematological investigations, in older
people, 923b
1386 • INDEX
Haematological malignancies, 954-968,
955 b
chemotherapy in, 936
in old age, 968b
Haematological practice, treatments for
emergencies in, 939b
Haematological system, pregnancy and,
1273
Haematological tests, for hepatobiliary
disease, 853
Haematological values, 1362b
Haematology, 388
in coeliac disease, 807
in musculoskeletal disease, 990
transfusion medicine and, 911-979
Haematoma
extradural, 1133
intracerebral, 1133
muscle, haemophilia, 973 f
in stroke patients, 1157-1158, 1158b
subdural, 1133
subungual, 1260, 1260f
Haematopoiesis, 914-915, 91 4f
Haematopoietic stem cell
transplantation (HSCT), 936-938
for acute leukaemia, 958
allogeneic, 936-937, 936b-937b
for aplastic anaemia, 969
autologous, 936-938
for beta-thalassaemia, 954b
for chronic myeloid leukaemia, 959
fever after, 224-225
for high-grade NHL, 966
infections during recovery from, 937 b
for myelofibrosis, 969
for myeloma, 968
Haematuria, 391-392, 392f
investigation of, 393f
loin pain, 396
non-visible, 392b
Haemochromatosis, 717, 895-896,
896 f
causes of, 895b
hereditary, 895-896
liver function test (LFT) abnormality in,
854b
rheumatological manifestations of,
1058
secondary, 896
Haemoconcentration, hypothermia and,
166
Haemodiafiltration, 423
Haemodialysis, 136, 421-423
access, 423f
in acute kidney injury, 422
in CKD, 422-423
peritoneal dialysis vs., 420 b
problems with, 424b
Haemofiltration, 423
continuous venovenous, 423
Haemoglobin, 915-916, 917 f
abnormal, 951
glycated, 726-727, 727 b, 1360b
mean cell (MCH), 1362b
pregnancy and, 1273
reference range of, 1 362b
Haemoglobin A, 915-916
Haemoglobin C, 951-952
Haemoglobin C (HbC) disease, 953
Haemoglobin F, 915-916
Haemoglobin H, 954
Haemoglobin-oxygen dissociation curve,
190, 1917
Haemoglobin S, 951-952
Haemoglobin SC disease, 953
Haemoglobinopathies, 951-954, 951 f
Haemoglobinuria, 338, 392b
march, 950
paroxysmal cold, 950
paroxysmal nocturnal, 950-951
Haemolysis, 945
active, investigation results indicating,
946b
causes and classification of, 946f
extravascular, 946-947
intravascular, 946b, 947
Haemolytic anaemias, 923, 945-951
alloimmune, 950
autoimmune, 949-950
causes of, 946f, 947
microangiopathic, 950
non-immune, 950
Haemolytic crisis, 947
Haemolytic disease of newborn (HDN),
933, 933b
Haemolytic uraemic syndrome (HUS),
104b, 388, 408-409
pregnancy and, 1285
Haemophilia, rheumatological
manifestations of, 1 058
Haemophilia A, 971-973
clinical features of, 972, 972 b, 973 f
coagulation factor therapy for,
complications of, 973
genetics in, 971-972
management of, 972-973
Haemophilia B, 973-974
Haemophilus ducreyi, 341 b
Haemophilus influenzae, 117 b
bacterial meningitis, 1 1 1 9b-1 1 20 b
immunisation for, 1 1 5b
pneumonia, 319, 583
Haemophilus spp., 103 f
Haemoptysis
in lung cancer, 599-600
in respiratory disease, 559-560,
559 b, 560 f
Haemorrhage
during dialysis, 424b
intracerebral, 1 1 54-1 155, 1 1 557
causes of, 1 1 55 b
major, transfusion in, 931b, 934-936,
936 b
obstetric, circulatory collapse and,
1275
retinal, 169
splinter, 994b, 1260
subarachnoid, 1 1 60-1 1 62
clinical features of, 1161, 11 62 f
investigations of, 1161
management of, 1 1 62
see also stroke
Haemorrhagic fevers, viral, 245-247,
245 b
Haemorrhagic toxins, 1 55-1 56
Haemorrhoids, 835-836
Haemosiderin, 851
Haemosiderosis, 716
idiopathic pulmonary, 613b
Haemostasis, 917-919, 9187-9197
in old age, 978b
Haemostasis system toxins, 1 55, 1 56 f
Hair
abnormalities, 1224
disorders, 1258-1260
follicles, 1212-1213
loss, 1266b
Hairy cell leukaemia, 960
Hairy leucoplakia, 316
Hallpike manoeuvre, 1104, 11 04f
Hallucinations, 1181, 1184
in alcohol misuse, 1 1 94
hypnagogic, 1184
hypnopompic, 1184
in schizophrenia, 1 1 96-1 1 97
Hallucinogens, misuse of, 143-144,
1196
Hallucinosis, alcoholic, 1194
Hallux valgus, 999
Haloperidol
adverse reactions of, 22 b
agitation, 1354
for delirium, 209
for disturbed behaviour,
1188-1189
poisoning, 141
schizophrenia, 1 1 98b
Halothane, 82-83, 85 7f
Hamartoma, 603b
small intestine and, 813
Hands
in endocrine disease, 630f
examination of
blood disease, 91 2 f
cancer, 1 31 47
cardiology, 442f
diabetes mellitus, 721 b
endocrine disease, 630f
gastrointestinal disease, 764f
liver and biliary disease, 846f
musculoskeletal system, 982f
renal/urinary tract disease, 382f
respiratory system, 546f
skin disease, 121 Of
foot and mouth disease, 248
gastrointestinal disease, 764f
hygiene, infection control, 112-113,
1137
liver and biliary disease and, 846f
osteoarthritis, 1009f
pain, 998
rheumatoid arthritis in, 1023f
washing, 1 1 37
Hantavirus infection, 258
Haploinsufficiency, 659
Haptoglobin, 947, 1362b
in acute phase response, 70
Hard metal disease, 616
Hartmann’s procedure, 788
Hartmann’s solution, 353b
Hartnup’s disease, 714
Hasenclever index, in Hodgkin
lymphoma, 964, 964b
Hashimoto’s thyroiditis, 646
Haversian system, 984f
Hay fever, 85, 622
Hayflick limit, 41
Head and neck
examination of
diabetes mellitus, 720 f
endocrine disease, 630f
gastrointestinal disease, 764f
imaging of, 1073-1074, 1074f
injury, 1133
tumours in, 1335-1336, 1335b
investigations of, 1 335
management of, 1 335-1 336
pathogenesis of, 1 335
Head lice, 1241
Head-up tilt-table testing, 183
Headache, 185-186, 1080,
1095-1097
analgesic for, 1 096
associated with specific activities,
1097
benign paroxysmal, 1097, 1097b
brain tumours causing, 1129
clinical assessment of, 185, 1 867
cluster, 1096
exertion, 1097
fever and, 217b
heat stroke and, 167
investigations of, 1 85-1 86
medication overuse, 1096
migraine and, 1095-1096
morning, 558
pregnancy and, 1275
presentation of, 1 85, 1 85b
raised ICP, 1128b
‘red flag’ symptoms in, 185b
sexual activity and, 1097
stroke and, 1153
subarachnoid haemorrhage and,
1161
tension-type, 1095
Health, social determinants of, 93-94
Health care, genomics and, 56-58
Health care-associated infection,
111-113, 1 1 27—1 1 37
MRSA, 100
predisposing factors, 1 1 2 f
Health data/informatics, 97-98
Hearing disturbance, 1 093
Heart
anatomy of, 444-446, 444f-445f
auscultation of, 443b
blood flow through, 444f
catheterisation, 453-454, 453f
chamber, 445f
dilation of, 450
conduction system, 445, 445f
coronary circulation in, 444-445
endothelium and, 447
inflammatory arthritis in, 994b
nerve supply of, 445-446
physiology of, 446-448
Starling’s law, 461, 461 f
Heart beats
ectopic
atrial, 469-470, 470f
ventricular, 474-475, 475f
see also Palpitation
Heart block
atrioventricular, 477-478, 477f-478f,
478b
bifascicular, 478-479
bundle branch, 478-479, 478b, 478f
hemiblock, 478-479
Heart disease
congenital, 531-538, 531b, 532 f
HIV-related, 322
pregnancy, 1282
rheumatic, 515-517
rheumatoid arthritis and, 1024
Heart failure, 461-468
in acute coronary syndrome, 496
acute left, 463
biventricular, 461
chronic, 463-464, 463b, 463f
clinical assessment for, 463-464,
463b
complications of, 464
congestive, in old age, 466b
high-output, 463
investigations for, 464, 464f
left, 461
management of, 464-468, 465b
drug treatment for, 465-467, 466f
mechanisms of, 462b, 462f
right, 461
Heart murmur, 459b
Heart rate
effects of respiration on, 447b
pregnancy and, 1272
Heart sounds, 460f
abnormal, 457-461 , 459b
normal, 459b
Heart valves, diseases of, 514-531 ,
515b
Heartburn, 779
Heat cramps, 1 67
Heat exhaustion, 167
Heat-related illness, 167-168
Heat stroke, 1 67-1 68
Heat syncope, 1 67
Heberden’s nodes, 1 009f
Height, in endocrine disease, 630f
Heinz bodies, 950
Helicobacter pylori
eradication therapy, 800, 800b
gastric lymphoma, 805
peptic ulcer and, 798-799, 799 f,
800 b
Helium dilution technique, 575
Heller’s operation, 795
HELLP syndrome, pregnancy and,
1284
Helminthiases, soil-transmitted, 233b
Helminths, 101-102
drugs used against, 129
Hemicellulose, 696b
Hemicrania, chronic paroxysmal, 1 097 b
Hemidiaphragm, elevation of, 627,
627 b
Hemifacial spasm, 1116
Hemiparesis, 1083, 1123
Hemiplegic gait, 1309b
Henderson-Hasselbalch equation, 364
Henoch-Schonlein purpura, 398b-399b,
401, 1043
Heparin, 938-939
for acute limb ischaemia, 503
for angina, 491
indications for, 938b
low-molecular-weight, in thrombosis,
210
monitoring, 922
for stroke, 1 1 60
Heparin-induced thrombocytopenia
(HIT), 939
Hepatic acinus, 848, 848f
Hepatic adenomas, 893
Hepatic artery aneurysms, 898
Hepatic decompensation, 867
Hepatic disease, prescribing for patients
with, 32, 32 b
INDEX • 1387
Hepatic encephalopathy, 847b,
864-865
acute liver failure and, 856-857
clinical grade of, assessment for,
857 b
differential diagnosis of, 865b
factors precipitating, 865b
Hepatic fibrosis, 894
cirrhosis and, 866, 866 f
congenital, 868f, 902
non-invasive markers of, 855
pathogenic mechanisms in, 849f
Hepatic hydrothorax, 863
Hepatic Iron Index (Hll), 895
Hepatic-renal disease, 409-410
Hepatic venous disease, 898
Hepatic venous pressure, 868
Hepatitis
acute kidney injury and, 416b
alcoholic, 881
autoimmune, 886-887
conditions associated with, 886b
liver function test (LFT) abnormality
in, 854b
interface, 886
viral, 343-344, 871-878
causes of, 871b
chronic, HIV-related, 317-318
features of, 872b
investigations for, 872
management of, 872
non-A, non-B, non-C (NANBNC),
878
pregnancy and, 1284
sexual, 343-344
Wilson’s disease and, 896
Hepatitis A virus (HAV), 872-873, 872 b
acute liver failure and, 873
antigen for, 872
immunisation, 115b
incubation period of, 111b
in old age, 901b
pregnancy and, 900
transmission, sexual, 343
Hepatitis B core antigen (HBcAg),
873- 874
Hepatitis B core IgM antibody,
screening for, in acute liver
failure, 858
Hepatitis B e antigen (HBeAg),
874- 875
Hepatitis B surface antigen (HBsAg),
873
recombinant hepatitis B vaccine with,
876
Hepatitis B virus (HBV), 872 b, 873-877
acute, management of, 875
chronic
HBeAg-negative, 875
liver function test (LFT) abnormality
in, 854b
management of, 875-876
natural history of, 874f
phases of, 874b
risk of, 873 b
source of, 873 b
cirrhosis and, 876
co-infection with HIV, 876-877
HIV-related, 317-318
incubation period of, 111b
investigations of, 873-875
in pregnancy, 235b, 900
prevention of, 876, 876 b
schematic diagram of, 873 f
serology for, 873-875, 875 b, 875 f
transmission, sexual, 343
vertical transmission of, 873
viral load and, 875, 875 f
Hepatitis C virus (HCV), 872 b, 877-878
antigens for, 877
chronic, risk factors for, 877 b
cirrhosis and, 877
HIV-related, 318
liver function test for, 877
abnormality in, 854b
liver histology for, 878
molecular analysis for, 877
pregnancy and, 900
transmission, sexual, 343
Hepatitis D virus, 872 b, 877
Delta antigen for, 877
vertical transmission of, 877
Hepatitis E, 872 b, 878
in pregnancy, 235b
pregnancy and, 900
Hepatitis viruses, 249
Hepatobiliary disease, HIV-related,
317-318
Hepatocellular carcinoma, 890-892,
891 f
chemotherapy for, 892
cirrhosis and, 890
fibrolamellar, 892
hepatic resection for, 891
hepatitis B and, 873
liver biopsy for, 891
liver transplantation for, 891
management of, 892f
in old age, 901b
percutaneous therapy for, 891
screening for, 890-891
trans-arterial chemo-embolisation for,
892
Hepatocellular jaundice, 860-861
Hepatocytes, 848, 849f
necrosis of, 894
Hepatology, 845-909
Hepatomegaly, 862
acute liver failure and, 857-858
Budd-Chiari syndrome and, 899
cirrhosis and, 866-867
Hepatopulmonary syndrome, 898
Hepatorenal syndrome
ascites and, 864
type 1 , 864
type 2, 864
Hepatosplenic candidiasis, 302
Hepcidin, 716-717, 943
HER2 receptor, as tumour markers,
1322, 1324b
Herbal medicines, for pain, 1348
Herd immunity, 115
Hereditary angioedema (HAE), 88
Hereditary coproporphyria (HCP),
379 b
Hereditary elliptocytosis, 947-948
Hereditary haemorrhagic telangiectasia
(HHT), 970
Hereditary hypophosphataemic rickets,
405, 1052-1053
Hereditary nephrotic syndrome, 404
Hereditary neuropathy, 1 1 40
Hereditary spherocytosis, 947
investigations of, 947, 948/
management of, 947, 948b
Hernia
diaphragmatic, 627
hiatus, 791, 791b, 792 f
lumbar disc, 1135, 1 1 35f
Heroin, misuse, 142
Herpangina, 248
Herpes simplex keratitis, 1 1 73
Herpes simplex virus (HSV), 238b
after HSCT, 937 b
genital, 341-342
HIV-related, 31 4f, 315, 315b
HSV-1 , 247-248, 247f
HSV-2, 247-248, 247f
in pregnancy, 235 b, 332 b
viral hepatitis and, 878
Herpes zoster, 239-240, 1 1 23
clinical features of, 239
facial pain from, 1080
HIV-related, 315
management of, 240
Herpesvirus infections, skin, 1238
Herring worm, 294
Heterochromatin, 38-39
Hiatus hernia, 627, 791, 791b, 792 f
‘Hibernating’ myocardium, 452
Hibernian fever, 81
Hierarchy of systems, 93, 93b, 93 f
High altitude, 1 68-1 69
illnesses at, 1 68-1 69
cerebral oedema (HACE), 168
pulmonary oedema (HAPE),
168-169
physiological effects of, 1 68, 1 68 f
High-altitude cerebral oedema (HACE),
168
High-density lipoproteins (HDL), 1360b
High-energy fracture, 995b
High-flow nasal cannulae (HFNCs), 202
High-grade tumours, 961
High haemoglobin, 925, 925 b
High-risk behaviour, transition medicine
and, 1295
history-taking in, 1295b
personality and, 1295
protective factors in, 1295
theories in, 1295
Highly polyunsaturated long-chain n-3
fatty acids, 377
Hip
osteoarthritis, 1010, 101 Of
pain, 998, 999b, 999f
Hippocampus, 1066
Hirschsprung’s disease, 834-835
Hirsutism, 657-658, 658 b, 1259-1260
His bundle, 445
Histamine, 767
Histidine, 698b
Histones, 38
Histopathology, in respiratory disease,
554
Histoplasma capsulatum, 303
Histoplasmosis, 303-304
in HIV infection/AIDS, 31 4f
HIV infection/AIDS, 312
antiretroviral therapy for, 324-327,
324b
asymptomatic, 312, 31 2f
CD4 counts in, 31 1
chemoprophylaxis for, 323-324
clinical examination of, 306f
clinical manifestations of, 311-312
counselling for, 31 1b
diagnosis of, 310-31 1 , 310b
epidemiology of, 308
global and regional epidemics of,
308, 308b
hepatitis B and
acute, 875
co-infection with, 876-877
immunisation for, 324
immunology of, 309-310
investigations of, 310-31 1 , 311b
life cycle of, 309f
liver and, 879
liver blood tests in, abnormal, 879 b
modes of transmission of, 308,
308b-309b
musculoskeletal manifestations of,
1021b
in old age, 326b
pregnancy and, 1280
presenting problems of, 312-322,
313b
cancers, 322, 323b
cardiac disease, 322
fever, 313-314, 313f-314f
gastrointestinal disease, 316-317
haematological abnormalities, 322
hepatobiliary disease, 317-318
lymphadenopathy, 313
mucocutaneous disease, 314-316,
314b
nervous system and eye disease,
319-321, 31 9f
renal diseases, 322
respiratory disease, 318-319, 318b
rheumatological diseases, 321-322
weight loss, 313, 313 f
prevention of, 323-324, 327 b
primary, 311-312, 312b
prophylaxis for, 1 1 9b
pruritus and, 1219b
staging classifications of, 307 b
testing of, 330
tuberculosis and, 595
viral load in, 311
virology of, 309-310
HIV serology, acute kidney injury and,
416b
Hives, 1252
HLV\ antigen, transplant rejection, 88-89
HNFI-beta mutations, 406
Hoarseness, psychogenic, 624
Hodgkin lymphoma (HL), 961-964, 962 f
classification of, 962b
clinical features of, 962
epidemiology of, 961 , 962b
investigations of, 962, 963 f
management of, 962-964
prognosis of, 964, 964b
stages of, 962b
Holmes-Adie syndrome, 1 092b
Home ventilation, for chronic respiratory
failure, 567
Homocystinuria, 369-370
Honeycomb lung, 608/
Hookworm
ancylostomiasis, 288-289, 288 f
dog, 294
Hookworm infestation, 233b
Hoover’s sign, 1081-1082
Hormone replacement therapy
amenorrhoea, 655
cancer, 1332
for osteoporosis, 1048b, 1049
Hormones
gastrointestinal tract, 772
production, ectopic, 1325b
in venous blood, 1359b
Horner’s syndrome, 1091b-1092b,
1 091 f
Hospital, under-nutrition in, 693 f,
705-708, 706 b
Host-pathogen interactions, 1 04
House dust mite, 570
Howell-Jolly bodies, 921 f
Human albumin, 930
Human albumin solution (HAS), ascites
and, 864
Human chorionic gonadotrophin (hCG)
secretion of, pregnancy and, 1272
as tumour markers, 1322, 1324b
Human herpesvirus 6 (HHV-6), 238,
238 b
Human herpesvirus 7 (HHV-7), 238,
238 b
Human herpesvirus 8 (HHV-8), 238b,
248
Human leucocyte antigen (HLA)
molecules, 67
antigen processing and presentation
and, 70
Human papillomavirus (HPV), 342-343
in pregnancy, 332b
vaccines, 1 1 5
Human parvovirus arthropathy,
1020-1021
Human T-cell lymphotrophic virus type
1, 250
Humanitarian crisis, 171-172, 172b
Humidifier fever, 616b, 617
Humoral immunity, 68
Hunter’s syndrome, 371b
Huntington’s disease, 1115
genetic testing of, 1 077
Hurler’s syndrome, 371b
Hutchinson’s sign, 1233
Hyaluronic acid, intra-articular injections
of, 1012
Hydatid cyst, liver and, 880
Hydatid disease, 298-299, 299f
Hydralazine, 467
lupus syndrome, 1057b
malignant hypertension, 514
pharmacokinetic, 20 b
skin reactions, 1266b
Hydration
for stroke patients, 1 1 59 b
see also Fluid replacement
Hydroa vacciniforme, 1221b
Hydrocephalus, 1132-1133, 1132/
causes of, 1132b, 1 1 33f
dementia and, 1191b
management of, 1 1 33
normal pressure, 1 1 32-1 1 33
obstructive, 1092b, 1121
Hydrocortisone
ACTH deficiency, 682
adrenal insufficiency, 673
anaphylaxis, 76 b
asthma, 573
1388 • INDEX
Hydrocortisone (Continued)
eczema, 1244
equivalent dose, 670 b
for inflammatory bowel disease, 820,
821b
laryngeal obstruction, 625
potency and strength, 1226b
topical, 1226b
see also Cortisol
Hydrocortisone sodium succinate, 625
Hydrogen ions
acid-base balance, 364
in arterial blood, 565b, 1358b
Hydromorphone, 1352
Hydronephrosis, 413
Hydrophobia, 1122
Hydrops fetalis, 237 b
Hydrotherapy, for musculoskeletal
disease, 1001
Hydrothorax, hepatic, 863
Hydroxyapatite crystals, 985
Hyd roxycarbam ide
essential thrombocythaemia, 970
leukaemia, 959
for myelofibrosis, 969
sickle-cell disease, 953
for skin disease, 1227-1228
Hydroxychloroquine (HCQ)
for musculoskeletal disease, 1004b,
1005
for rheumatoid arthritis, 1 026b
for Sjogren’s syndrome, 1039
skin reactions, 1266b
for systemic lupus erythematosus,
1036
for Whipple’s disease, 809
I a-Hydroxycholecalciferol (alfacalcidol),
for hypoparathyroidism, 665
Hydroxycobalamin see Vitamin B12
5-Hydroxyindole-3-acetic acid (5-HIAA),
1361b
I I -Hydroxylase deficiency, 509b
17a- Hydroxylase deficiency, 509b
21 -Hydroxylase deficiency, 676
1 1 p-Hydroxysteroid dehydrogenase,
665, 665 b
deficiency, 509b
25-Hydroxyvitamin D (25(OH)D), for
skeletal disease, 990b
Hyfrecation, 343
Hygiene, hand-washing, 113 f
Hygiene hypothesis, 84-85
Hyoscine butylbromide, 1350b, 1354
Hyper IgD syndrome (HIDS), 81
Hyperacusis, 1083
Hyperacute rejection, 89
Hyperaesthesia
dengue fever, 243b
diabetic neuropathy, 758-759
herpes simplex, 247
Hyperaldosteronism
glucocorticoid suppressible, 509b,
674
primary, 674-675, 674b
secondary, 674b
in type 1 diabetes, 729-730
Hyperalgesia, fibromyalgia, 1018
Hyperalphalipoproteinaemia, 374
Hyperbilirubinaemia
non-haemolytic, 860, 860b
see also Jaundice
Hypercalcaemia, 661-662
cancer and, 1327, 1327b
causes of, 662, 662b
clinical assessment of, 662
familial hypocalciuric, 662, 664
hypoparathyroidism, 664-665
investigations of, 662
malignant, 662
management of, 662
multiple myeloma and, 410b, 967 f
sarcoidosis, 609-610
Hypercapnia, ventilator-induced lung
injury and, 204
Hypercarotenosis, 713
Hypercholesterolaemia, 373-374,
376-377
atherosclerosis risk, 486
familial, 374, 374b
management of, 376-377
nephrotic syndrome and, 395b
polygenic, 373-374
primary biliary cholangitis and,
887-888
secondary, 373 b
Hypercoagulability, nephrotic syndrome
and, 395b
Hypercortisolism, 667 b
Hyperemesis gravidarum, pregnancy
and, 1277-1278, 1278b
Hyperglycaemia
in acute medical illness, 754
in diabetes, 734-735, 734f
clinical assessment of, 734-735
drugs to reduce, 745-748
symptoms of, 735, 735 b
type 1 , 729-730
type 2, 732
diabetic ketoacidosis, 735
maternal, diabetes and, 1278-1279
pancreatitis, 838b
stress, 728
Hyperglycaemic hyperosmolar state
(HHS), 738, 739 b
Hypergonadotrophic hypogonadism,
653 b, 654
Hyperinsulinaemia, 740
Hyperkalaemia, 362-363, 464
acute kidney injury and, 413
causes of, 362b
chronic kidney disease, 417
heart failure, 464
periodic paralysis, 1 1 45b
treatment of, 363b
Hyperkeratosis, subungual, 1031
Hyperketonaemia, 725
Hyperlactataemia, 196, 197f
Hyperlipidaemia
check for signs of, 347f
classification of, 374b
drug treatment of, 376 f
familial combined, 374, 374b
mixed, 375, 377-378
in old age, 377 b
rare forms of, 375 b
remnant, 375
secondary, 373 b
treatment of, 376 f
Hypermagnesaemia, 368
Hypermelanosis, focal, 1258
Hypermobile Ehlers-Danlos syndrome
(hEDS), 1059
Hypermobility syndromes, 1059
Hypernatraemia, 358-360
causes of, 359b
in old age, 360b
Hyperostosis, diffuse idiopathic skeletal,
1058-1059, 1058f
Hyperparasitaemia, malaria, 276 b
Hyperparathyroidism
chronic kidney disease and,
418-419
in old age, 665b
pain, 663
primary, pregnancy and, 1280
Hyperphosphataemia, chronic kidney
disease and, 419
Hyperpigmentation, photo-exposed site,
1258
Hyperprolactinaemia, 684, 684b
disconnection, 667
Hyperpyrexia, 276 b
Hypersensitive carotid sinus syndrome,
183
Hypersensitivity, 71
allergic rhinitis, 622
drug response, 20 b
Gell and Coombs classification of, 83,
83 b
patch tests, 1215
prick tests, 1215
type I, 83-84, 85 f
type II, 83
type III, 83
type IV, 83
Hypersensitivity pneumonitis, 616-617,
617b, 617 f
Hypersensitivity rashes, 326
Hypersensitivity reaction, definition of,
21
Hypersomnolence, 1105, 1105b
Hypersplenism
leucopenia and, 853
portal hypertension, 868b
and thrombocytopenia, 869
Hypertension, 193-194, 396, 508-514,
509b-511b, 509 f, 511f-512f
accelerated, 514
assessment and management of,
193-194
cocaine, 143
definition, 509b
essential, 509
gestational, 1276, 1276b
history, 510
idiopathic intracranial, 1133
investigations, 510
management
anti hypertensive drugs, 513
British Hypertension Society
guidelines, 512 f
intervention thresholds, 511-512
non-drug therapy, 513
treatment targets, 512-513, 513b
in old age, 512b
pathogenesis, 509
pathophysiology of, 1 93
portal, 868-871, 898
ascites and, 869
cirrhosis and, 868
classification of, 868f
clinical features of, 868-869
complications of, 868b
extrahepatic portal vein obstruction,
868
investigations for, 869
management of, 869-871
pathophysiology of, 869
portopulmonary, 898
pre-eclampsia, 1276-1277
during pregnancy, 1 276-1 277
classification of, 1 276 b
pre-eclampsia and eclampsia in,
1276-1277, 1276b, 1277f
pre-existing, 1276
pulmonary, 550, 621-622, 621b,
622 f
congenital heart disease and, 533
systemic sclerosis and, 1038
renal artery stenosis and, 406
renal disease, 396
AKI, 411-412
chronic, 415
polycystic, 405
reflux nephropathy, 430
secondary, 509b
in systemic sclerosis, 1 038
target organ damage, 510
venous, 1223
white coat, 510, 1276b
Hypertensive renal crisis, systemic
sclerosis and, 1038
Hyperthermia, malignant, 1 1 45b
Hyperthyroidism, pregnancy and, 1279
Hypertrichosis, 1259
drug-induced, 1266b
Hypertriglyceridaemia, 374
familial, 374, 374b
management of, 377-378
secondary, 373 b
Hypertrophic cardiomyopathy, 539-540,
540b
Hypertrophic obstructive
cardiomyopathy, transition
medicine and, 1297-1298
Hypertrophic pulmonary
osteoarthropathy (HPOA), in lung
cancer, 600-601
Hyperuricaemia, 1012-1013
causes of, 1013b
chronic, 1014
gout, 1013b
Hyperventilation
in panic disorder, 1 200
psychogenic, 1202
and respiratory alkalosis, 367
Hyperviscosity syndrome, 966
Hypervolaemia, 353-355
clinical features of, 352b
hypernatraemia with, 359b
hyponatraemia with, 357
Hypnic jerks, 1086
Hypnotics
dosage regimens of, 31b
in old age, 32 b
Hypoad renal ism, tuberculosis, 595
Hypoalbuminaemia, nephrotic syndrome
and, 395b
Hypobetalipoproteinaemia, 375
Hypocalcaemia, 662-663
aetiology of, 662-663
clinical assessment of, 663
differential diagnosis of, 662b
ethylene glycol poisoning, 147
hypomagnesaemia and, 368
kidney failure and
acute, 414
chronic, 418-419
kidney injury
acute, 414
chronic, 418-419
management of, 663, 663b
pancreatitis, 838b
Hypochlorhydria, 798-799, 944
Hypochlorous acid, 64
Hypochondriacal disorder, 1 202
Hypofibrinogenaemia, 922 b, 972 b
Hypogammaglobulinaemia, in vitamin
B12 deficiency, 944
Hypoglossal (1 2th cranial) nerve, tests
of, 1063b
Hypoglycaemia, 738-741
acute treatment of, 740
awareness of, 740
causes of, 740b
diabetes, 738-741
drug-induced, 747
emergency treatment of, 741b
exercise-induced, 740
malaria, 276 b
nocturnal, 740
prevention of, 740-741, 741b
risk factors for, 740b
spontaneous, 676-678, 67 7f, 738
in old age, 678 b
symptoms of, 739, 739b
Hypogonadism
hypergonadotrophic, 653b, 654
hypogonadotrophic, 653, 653b
male, 655, 656b, 660b
Hypogonadotrophic hypogonadism,
653, 653 b
Hypokalaemia, 361-362, 464
causes of, 361b
chloroquine poisoning, 141b
heart failure, 464
hyperaldosteronism, 674
mineralocorticoid excess, 675
periodic paralysis, 1145b
Hypomagnesaemia, 368
causes of, 368b
management, 368
Hypomania, 1199-1200
Hypomimia, 1113b
Hyponatraemia, 357-358, 464,
852-853
adrenal insufficiency, 671-672
algorithm for diagnosis of, 359f
brain and, 358f
causes of, 357 b
depletional, 672 b
dilutional, 414
ecstasy/amphetamine misuse, 143
with euvolaemia, 357
heart failure, 464
with hypervolaemia, 357
hypopituitarism, 681-682
with hypovolaemia, 357
in old age, 360b
symptoms and severity of, 358b
Hypoparathyroidism, 664-665
Hypophosphataemia, 368-369, 369b
Hypophosphataemic rickets
biochemical abnormalities in, 990b
transition medicine and, 1300
Hypophosphatasia, 1053
INDEX • 1389
Hypopigmentation, 1257-1258
Hypopituitarism, 681-682, 6816-6826,
681 f
clinical assessment, 681-682, 681 f
investigations, 682, 6826
management, 682
Hyposmia, 1088
Hypotension, 193
assessment and management of,
193, 1936
during dialysis, 4246
pathophysiology of, 193, 1936
poisoning, 1376
postural, 181, 1308-1309
glucocorticoid insufficiency, 6726
in old age, 326
renal disease, 411-412
shock, 1966
treatment of, 1 308-1 309
Hypothalamus, 679-688, 1066-1067
disease
classification of, 6806
presenting problems in, 681-684
functional anatomy, physiology and
investigations of, 679 f
in old age, 6886
therapeutic modalities, 6836
thermoregulation and, 165
tumours, 1066-1067
Hypothermia, 165-166, 165f-166f
cold water immersion, 166
in old age, 1 666
Hypothyroidism, 639-642
autoimmune, 6376, 6396
causes, 6396
clinical assessment of, 639-640, 640f
clinical features of, 6376
congenital, 6396, 650
iatrogenic, 6396
investigations of, 640
laboratory abnormalities, 6386
management of, 640-641, 6416
with normal thyroid function tests,
641-642
obesity, 654-655
in old age, 6506
in pregnancy, 641, 6516, 1279
radiotherapy and, 1298
rheumatological manifestations of,
1057
secondary, 6396
spontaneous atrophic, 6396
subclinical, 642
transient, 640
transient thyroiditis, 6396
Hypoventilation, alveolar, 567, 6216
Hypovolaemia, 352-353
causes of, 3526
clinical features of, 3526
hypernatraemia with, 3596
hyponatraemia with, 357
Hypovolaemic shock, description of,
2066
Hypoxaemia, 168f
acute mountain sickness and, 168
assessment and management of,
191, 1916
causes of, 1 926
cirrhosis, 866-867
high-altitude pulmonary oedema,
1 68- 1 69
mechanisms of, 1 92 f
near drowning accidents and,
169- 170
pathophysiology of, 1 90-1 91 , 1917
pulmonary hypertension, 6216
Hypoxia
altitude illness and, 168
cytopathic, 1 977, 198
pancreatitis, 8386
respiratory failure, 5656
Hypromellose, 1039
Hysterectomy, cancer treatment, 1335
Hysteria, 1126
I
Ibandronate, for osteoporosis, 10486
Ibuprofen, 10036
adverse reactions of, 226
Ice cream headache, 1 0976
Ice pick headache, 1 0976
Ichthyosis, 1212
Idarucizumab, 940
Idiopathic interstitial pneumonias,
605-608, 6066
Idiopathic intracranial hypertension,
pregnancy and, 1284
Idiopathic osteoporosis, 1044
Idiopathic Parkinson’s disease,
1112-1114
causes of, 111 26
clinical features of, 111 2-1 1 1 3,
11136
non-motor symptoms of,
1112-1113
investigations of, 1113, 111 37
management of, 1113-1114
drug therapy, 1113-1114
surgery, 1114
pathophysiology of, 1112, 11127
Idiopathic pulmonary fibrosis, 605-608,
607 f
Idiopathic pulmonary haemosiderosis,
6136
Idiopathic thrombocytopenic purpura
(ITP), 971
pregnancy and, 1285
lf channel antagonists, angina, 491
Ifosfamide, 3656
Ileal resection, 810 f
under-nutrition and, 706
Ileus
meconium, 842
paralytic, 837-838
Illusions, 1181
lloprost, 622
Imaging
for epilepsy, 11016
in gastroenterology, 7746, 774f
of gastrointestinal tract, 772-776
for hepatobiliary disease, 853-855
for lung cancer, 601 , 601 f
for musculoskeletal disease,
988-990
neuroimaging, 1151, 11517,
1157-1158
of renal tract, 389-390
of respiratory system, 551-553
vascular, 1151, 1 1 527
Imatinib, 1332
acute leukaemia, 9576
chronic myeloid leukaemia, 958
for GIST, 805
Imidazoles, 1256, 126
Imipenem, 1206
nocardiosis, 261
Imipramine, 61 16
irritable bowel syndrome, 825
neurogenic bladder, 1 0946
Imiprothrin, 1486
Imiquimod
for lentigo maligna, 1233
for molluscum contagiosum,
1239
for skin cancer, 1230, 12306
for viral warts, 1 239
Imiquimod cream, for anogenital warts,
343
Immersion foot, 1 67
Immotile cilia syndrome, 5786
Immune deficiency, 77-81
autoimmune lymphoproliferative
syndrome and, 80
common variable, 79
complement pathway deficiencies in,
78
consequences of, 77
investigations of
initial, 746
specialist, 746
primary, warning signs of, 736
primary antibody deficiencies in,
78-79, 787, 796
primary phagocyte deficiencies in,
77-78, 77 f
primary T-lymphocyte deficiencies
and, 79-80, 80 f
secondary, 80-81 , 806
Immune disorders
anaphylaxis and, 75-76
common causes of, 756
intermittent fever and, 74
presenting problems of, 73-76
recurrent infections and, 73
Immune reconstitution inflammatory
syndrome (IRIS), 104, 325-326
Immune response modifiers, 1 226
Immune responses, in lower airway
defences, 550
Immune senescence, 80-81 , 816
Immune serum globulin, for hepatitis A,
872-873
Immune system
adaptive, 67-70
cellular immunity and, 69-70, 69f
immunoglobulins and, 68-69, 686,
68 f
lymphoid organs and, 67
innate, 62-67
complement and, 66
cytokines and, 64-66, 656, 65 f
dendritic cells in, 64
integrins and, 66
mast cells and basophils, 66-67
natural killer cells and, 67
phagocytes in, 63-64, 63 f
physical barriers in, 62-67
regulation of, 851
Immunisation, 114-115, 1156
for chickenpox, 239
for cholera, 265
for diphtheria, 266
Haemophilus influenzae , 1 1 56
for hepatitis A, 872-873
for hepatitis B, 876, 8766
for HIV infection/AIDS, 324
for human papillomavirus, 343
for influenza, 241
for meningococcal infection, 1120
for mumps, 240
for plague, 259
for pneumococcal infection, 266
for poliomyelitis, 1 1 23
primary antibody deficiencies and,
79
for rabies, 1 1 22
for rubella, 266
for tetanus, 1 1 26
for tuberculosis, 595
for typhoid fever, 261
for whooping cough, 582
whooping cough (pertussis), 1156
for yellow fever, 245
see also Vaccines/vaccination
Immunity
adaptive
humoral immunity and, 67-68
cellular, 67, 69-70, 69 f
humoral, 67-68
Immunoblot (Western blot), 107
innate, 769
Immunoblot (Western blot), 107
Immunobullous disease, drug-induced,
12666
Immunochromatographic rapid
diagnostic tests (RDTs), 276
Immunochromatographic tests, 108
Immunocompromised host, fever in,
223-224
Immunocompromised patient,
pneumonia in, 587
Immunodiffusion, 108
Immunofluorescence assays, 107
anti-endomysial antibodies of, 807
Immunoglobulin(s), 68-69, 686, 68f,
930
for idiopathic thrombocytopenic
purpura, 971
intravenous
Guillain-Barre syndrome, 1140
myasthenia gravis, 1 1 426
myositis, 1040
thrombocytopenia, 971
toxic shock syndrome, 252
prophylactic, 1 1 56
reference range of, venous blood,
13606
Immunoglobulin A (IgA), 686
deficiency, selective, 78-79
linear IgA disease, 12556, 1256-1257
nephropathy, 3986-3996, 400
reference range of, venous blood,
13606
Immunoglobulin D (IgD), 686
hyper-lgD syndrome, 81
Immunoglobulin E (IgE), 686, 1215
reference range of, venous blood,
13606
serum total, for allergy, 86
specific tests, for allergy, 86
Immunoglobulin G (IgG), 686
anti-HBc, 8756
antibody, functional deficiency in, 79
cerebrospinal fluid, 13616
reference range of, 1 3606
rubella-specific, 236
Immunoglobulin M (IgM), 686
anti-HBc, 8756
cold agglutinin disease, 950
reference range of, venous blood,
13606
Immunoglobulin replacement therapy,
for primary antibody deficiencies,
79
Immunohistochemistry, tumour
identification, 1322
Immunological memory, 69
Immunological tests, 1077
antibody-independent specific, 1 09
for hepatobiliary disease, 853
for respiratory disease, 554
Immunoproliferative small intestinal
disease (IPSID), 813
I m m u nosu ppressants
for skin disease, 1 227-1 228
for systemic lupus erythematosus,
1036
Immunosuppression
liver transplantation and, 901
myasthenia gravis, 1 1 426
in transplant
complications of, 89-90
drugs used in, 896
Immunosuppressive agent, for
autoimmune hepatitis, 886
Immunotherapy
antigen-specific, for allergy, 86
cancer, 1332
myasthenia gravis, 11426
Impaired glucose tolerance, 374, 13606
Impetigo, 1235-1236
non-bullous, 1235f
Implantable cardiac defibrillators, 467,
483-484, 4836
for acute coronary syndrome, 501
Impotence see Erectile dysfunction
Imprinting, 49-50, 516
Incidence of disease, microbiological
sampling, 1056
Incident pain, 13506
Incidental adrenal mass, 673-674
Incidental pancreatic mass, 844
‘Incidentalomas’, 6336
Inclusion body myositis, 1 059
Incontinence
continual, 437
faecal, 1094
overflow, 437, 1093
stress, 436
of stroke patients, 11596
urge, 436-437, 1093
urinary, 397, 436-437
older people, 4366, 1309-1310,
131 Of
Increased intra-abdominal pressure, 791
Incremental cost-effectiveness ratio
(ICER), 28
‘Incretin’ effect, 723-724, 724 f
Indirect antiglobulin tests, 948f
Indocyanine angiography, of visual
disorders, 1169
Indometacin, 10036
for paroxysmal headache prevention,
1097
for pericarditis, 542
for persistent ductus arteriosus, 534
1390 • INDEX
Inductively coupled plasma/mass
spectroscopy, 3485
Infections), 215-304, 930
in adolescence, 234, 235 5
agents of, 100-102, 1005
bacterial, 250-273
after HSCT, 937 5
chlamydial, 272-273, 272 5
gastrointestinal, 262-265
with neurological involvement, 267
respiratory, 265-267
rickettsial, 270-272, 271 5
of skin, 1235-1238
soft tissues and bones, 250-254
systemic, 254-262
caused by helminths, 288-299,
288 5
central venous catheter, 225-226
chain of, 1 00f
chlamydial, 340-341
in men, 340
in reactive arthritis, 1031
treatment of, 3415
urethritis, 333
in women, 340-341
clinical examination of, 216-218,
216 f, 2175
common infecting organisms, 1175
constitutive barriers to, 63
control, 111-115, 1125
cytomegalovirus, 2385, 242-243
after HSCT, 9375
clinical features of, 242-243
encephalitis, 320
investigations of, 243
liver transplantation and, 901
management of, 243
polyradiculitis, 321
in pregnancy, 2355
viral hepatitis and, 878
definition of, 1 00
deliberate release, 1 1 1
emerging and re-emerging disease,
1 1 0, 1 1 0f
endemic disease, 1 1 0
epidemiology of, 1 1 0-1 1 1
Epstein-Barr virus, 2385, 241-242
clinical features of, 241-242
complications of, 241-242, 2425
investigations of, 242
management of, 242
Escherichia coli, 263-264
entero-aggregative, 263-264
entero-invasive, 263
enterohaemorrhagic, 263-264
enteropathogenic, 263
verocytotoxigenic, 263f
fungal, 300-304, 300 f
after HSCT, 9375
skin, 1239-1240, 1240f
subcutaneous, 300-301
superficial, 300
systemic, 301-304
gastrointestinal tract
function of, 777-778, 7775
oral cancer, 790
test of, 777
geographical and temporal patterns
of, 110
history-taking in, 2175
HIV/AIDS, 305-327
antiretroviral therapy for, 324-327,
3245
asymptomatic, 312, 31 2f
CD4 counts in, 311
chemoprophylaxis for, 323-324
clinical examination of, 306f
clinical manifestations of, 311-312
counselling for, 31 15
diagnosis of, 310-31 1 , 3105
epidemiology of, 308
global and regional epidemics of,
308, 3085
immunisation for, 324
immunology of, 309-310
investigations of, 310-31 1 , 3115
life cycle of, 309 f
liver and, 879
liver blood tests in, abnormal, 8795
modes of transmission of, 308,
3085-3095
musculoskeletal manifestations of,
10215
in old age, 3265
pregnancy and, 1280
presenting problems of, 312-322,
3135
prevention of, 323-324, 3275
primary, 311-312, 3125
pruritus and, 12195
staging classifications of, 3075
testing of, 330
tuberculosis and, 595
viral load in, 311
virology of, 309-310
host-pathogen interaction of, 1 04
incubation periods of, 1115
investigation of, 1 05-1 09, 1 055
culture, 106
direct detection of pathogens,
105-106
joints, 1019-1021
in old age, 1 0205
of liver, 871-880
liver transplantation and, 901
microbiological sampling, 1055
mycobacterial, 267-270
nematode, 2335
intestinal, 288-290
tissue-dwelling, 290-293, 2905
zoonotic, 293-294
in non-immune haemolytic anaemia,
950
normal microbial flora, 102-103,
103f
of oesophagitis, 794
outbreaks of, 114
reporting, 1145
terminology, 1 1 45
parvovirus B19, 237
clinical features of, 237, 2375,
237 f
diagnosis of, 237
management of, 237
in pregnancy, 2355
periods of infectivity, 1115
in pregnancy, 234, 2355
presenting problems in, 218-234
prevention, 111-115, 1125
protozoal, 273-288
gastrointestinal, 286-288
leishmaniasis, 281-286
systemic, 273-281
recurrent, 73
reservoirs of, 110
animal, 110
environmental, 110
human, 110
respiratory, 581-598
in old age, 5865
pneumonia, 582-587
pregnancy and, 1277
tuberculosis (TB), 588-595
upper respiratory tract infection,
581-587
rubella
clinical features of, 236
congenital malformation and, 2375
diagnosis of, 236
in pregnancy, 2355
prevention of, 236-237
sexually transmitted, 329-344
approach to patients, 332-333,
3325
in children, 332-333
contact tracing for, 333
HIV testing for, 330
management goals of, 3315
in men, 330, 3305, 330f
men who have sex with men,
3305, 334-335
during pregnancy, 332
presenting problems of, men,
333-336, 333f-334f
prevention of, 336-337
those at particular risk, 3315
viral, 341-344
in women, 331, 3315, 331 f
skin, 1235-1241
bacterial, 1235-1238
fungal, 1239-1240, 1240f
mycobacterial, 1237-1238
tropical, 234, 2345, 235 f
viral, 1238-1239
of small intestine, 812-813
soft tissue, 226-227
necrotising, 2275
staphylococcal, 250-252, 251 f
cannula-related, 251-252, 2515
meth ici 1 1 i n -resistant Staphylococcus
aureus, 252
skin, 251
staphylococcal toxic shock
syndrome, 252, 252 f
wound, 251 , 251 f
starvation-associated, 7055
supportive therapy for, 957
transmission of, 1 00 f, 1 1 1
tropical, 230-234, 2305
urinary tract, 426-431
antibiotic regimens for, 4295
investigation of, 4285
in old age, 4285
persistent or recurrent, 429, 4295
risk factors for, 4285
in stroke patients, 1 1 59 f
viral, 236-250
gastrointestinal, 249
with neurological involvement,
249-250
respiratory, 249
with rheumatological involvement,
250
sexually transmitted, 341-344
of skin, 247-249, 1238-1239
Infection-related glomerulonephritis,
3985-3995, 401
Infectious conditions, in
ophthalmological conditions,
1173-1174
Infectious disease
genomics in, 58
pathogenesis of, 104, 108f
periods of infectivity in, 1115
principles of, 99-1 29
treatment of, 116-129, 1195
Infectious keratitis/corneal ulceration,
1173, 1174f
common causes of, 1 1 735
Infectious mononucleosis, 241-242
causes of, 2415
clinical features of, 241-242, 242f
investigations of, 242
management of, 242
Infective endocarditis, 527-531 , 5285,
5315
acute, 529
antimicrobial treatment of, 5305
in old age, 5275
post-operative, 529
prevention of, 531
subacute, 528-529, 5295, 529 f
Inferior petrosal sinus sampling, bilateral,
670 f
Inferior vena cava, 384, 444f
Infertility, 656-657, 6565
cytotoxic medications and, 1298
in polycystic ovarian syndrome, 659
Infestations, skin, 1241
Inflammation
acute, 70-71, 71 f
cancer, 1319-1320
chronic, 71
laboratory features of, 71-72
resolution, 71
systemic, 196-198
Inflammatory bowel disease (IBD),
813-824
childhood, 823
clinical features of, 816-817
complications of, 818, 818 f
differential diagnosis of, 817, 8175
disease distribution in, 81 5f
investigations of, 818-820, 81 9f
management of, 820-823
metabolic bone disease and, 824
microscopic colitis and, 824
monitoring of, 8225
pathogenesis of, 81 5f
pathophysiology of, 814-816, 8145
in pregnancy, 823-824, 8245, 1278
systemic complications of, 819 f
transition medicine and, 1299-1300
treatment of, 8215
Inflammatory molecules, 64
Inflammatory myopathy, 10425
Inflammatory response, 70-72
acute inflammation and, 70-71, 71 f
acute phase response in, 70
resolution of, 71
septic shock and, 70-71
chronic inflammation and, 71
laboratory features of, 71-72
C-reactive protein as, 72
erythrocyte sedimentation rate and,
72
plasma viscosity as, 72
Inflammatory rheumatic diseases
biologies for, 1006, 1006f, 10075
in pregnancy, 1 280-1 281
anti-phospholipid syndrome as,
1281
rheumatoid arthritis as, 1 280
systemic lupus erythematosus as,
1281, 12815
systemic sclerosis as, 1280-1281 ,
12815
Infliximab
for inflammatory bowel disease, 8215,
823
for musculoskeletal disease, 1 0075
in pregnancy, 1278
Influenza, 240-241
avian, 241
clinical features of, 241
diagnosis of, 241
epidemic, 104
immunisation for, 1155
incubation period of, 1115
management and prevention of, 241
prophylaxis for, 1 1 95
swine, 241
Infraorbital artery, 1168
Infrapatellar bursitis, 9995
Inhalation (‘humidifier’) fever, 6165,
617
Inhalational administration, 17-18
Inheritance
autosomal dominant, 46-47
autosomal recessive, 48
mitochondrial, 49
pedigrees, 46f
X-linked, 48-49
Inherited cancer predisposition
syndromes, 56-57, 575
Inherited metabolic myopathies, 1144,
11445
Inherited thrombophilia, 977-979
Inherited tubulo-interstitial diseases,
404, 4045
Inhibin, 633 f
Inhibitor of kappa B kinase (IKK),
64-66
Innate immune system, 62-67
complement and, 66
cytokines and, 64-66, 655, 65 f
dendritic cells in, 64
integrins and, 66
mast cells and basophils, 66-67
natural killer cells and, 67
phagocytes in, 63-64, 63 f
physical barriers in, 62-67
Inorganic micronutrients, 716-718
Insect bites, 230
Insect stings, allergic reactions, 755
Insect venom allergy, 85
Insecticides
carbamate, 146-147
organophosphorus, 145-146, 1455,
145f
pyrethroid, 1485
Insertions, 42
Insight, lack of, 1183
Insomnia
fatal familial, 11275
sporadic fatal, 11275
INDEX • 1391
Inspiration, of lungs, 548
Insulin
adverse reactions of, 22 b
amino acid structure of, 748-749,
749f
manufacture and formulation of,
748-749
metabolic actions of, 723 b
puberty and, 1290
reference range of, 1 359b
resistance to, pregnancy and,
1 272-1 273
secretion of, 724f
regulation of, 723-724
synthesis of, 724, 724f
Insulin-like growth factor (IGF), 633f,
849f
Insulin-like growth factor binding protein
(IGF-BP3), 633 f
Insulin pump, 751 , 751 f
Insulin resistance
polycystic ovarian syndrome, 658b
in type 2 diabetes, 730-731
Insulin therapy
closed loop, 751 , 752 f
for diabetes mellitus, 748-751
dosing regimens in, 750, 750 f,
751b
subcutaneous, 749-750, 749b
for diabetic ketoacidosis, 737
injection sites of, 721b
preparations for, duration of action of,
748-749, 749b
side-effects of, 750 b
Insulin tolerance test, for
Hypopituitarism, 682b
Insulitis, 728, 729 f
Integrade inhibitors, 324b
Integrase, 309-310
Integrins, 66
Intensive care
clinical management in, 208-21 1
blood transfusion in, 211
clinical review in, 208-209
delirium in, 209
extubation in, 210
glucose control in, 210-21 1
nutrition in, 210
peptic ulcer prophylaxis in, 211
sedation and analgesia in, 209,
209 b
thromboprophylaxis in, 210
tracheostomy in, 210, 210b
weaning from respiratory support
in, 209-210
discharge from, 213, 214b
withdrawal of active treatment and
death in, 213
Intention tremor, 1069
Intercellular adhesion molecule type
1(ICAM-1), 447
Intercostal tube drainage, 626-627,
627f
Interferon
pegylated, 877
warts, 1239
Interferon-a, 65 b
Interferon-alfa
for hepatitis B, 876
pegylated, for hepatitis C, 878
polycythaemia rubra vera, 970
Interferon-gamma (IFN-7), 65 b
in coeliac disease, 806f
Interferon-gamma release assays
(IGRAs), 594, 594f
Interleukin, immune response, 65 b
Intermediate-density lipoproteins,
371-372
Intermediate syndrome, from OP
poisoning, 146
Intermittent claudication, 502
Intermittent positive pressure ventilation,
203-204
International Autoimmune Hepatitis
Group (IAIHG) criteria, 886
International normalised ratio (INR), 850,
922
International Prostate Symptom Score
(IPSS), 438b
International staging system (ISS), for
multiple myeloma, 968
International system of units (SI units),
1358
Interpersonal psychotherapy, 1191
Interphalangeal joints, osteoarthritis in,
1 009f
Interstitial and infiltrative pulmonary
diseases, 605-613
diffuse parenchymal lung disease
(DPLD), 605-610, 605 b, 606f,
607b
due to irradiation and drugs, 612-613
due to systemic inflammatory
disease, 610-61 1
in old age, 613b
pulmonary eosinophilia and
vasculitides, 611-612, 611b
rare interstitial lung diseases, 613b
Interstitial cells of Cajal, 772
Interstitial lung disease, systemic
sclerosis and, 1038
Interstitial nephritis
acute, 402, 402b, 402f
chronic, 402-403, 403b
drug-induced, 427b
Interstitial pneumonia
acute, 606b
desquamative, 606b
lymphocytic, 606b
usual, 608f
Interstitial pneumonitis
lymphoid, 319
usual, 608 f
Intertrigo, 300, 1240
Intervertebral disc, 986
prolapse of, 996-997
Intervertebral discs
intra-articular, 987
Intestinal defence mechanisms, 770f
Intestinal failure (IF), 708-710
causes of, 708-709
classification of, 708-709
management of, 709-710, 709 b
in jejunostomy patients, 709
in jejunum-colon patients, 709
in small bowel and multivisceral
transplantation, 710, 710b
Intestinal microbiota, 771
Intestinal tapeworm, 298
Intra-aortic balloon pump, 207
Intra-articular discs, 987
Intra-articular glucocorticoids, for
musculoskeletal disease,
1005-1006
Intra-articular injections, for
osteoarthritis, 1012
Intracellular fluid (ICF), 349
Intracerebral haemorrhage, 1 1 54-1 1 55,
1 1557
causes of, 1 1 55b
Intracranial hypertension, idiopathic,
1133
Intracranial mass lesions, 1 1 27-1 1 33
Intracranial pressure (I CP)
measurement of, 208
raised, 1127-1129, 1128b, 1 1 287
Intramuscular administration, 17
Intramuscular androgen replacement
therapy, 656b
Intramuscular glucocorticoids, for
musculoskeletal disease,
1005-1006
Intranasal administration, 17
Intraretinal microvascular abnormalities
(IRMAs), 1175
Intravascular haemolysis, 946b, 947
Intravenous administration, 1 7
Intravenous fluid therapy, 353
Intravenous urography (IVU), 389
for retroperitoneal fibrosis, 434
Intrinsic factor, glycoprotein, 767
Introns, 39 f
Intubation, 203-204
endotracheal, critically ill patients,
190b, 208
nasogastric, 805b
safety during, 203b
ventilator modes in, 203, 203 f
Invasive pulmonary aspergillosis (IPA),
597-598, 598 b
Involuntary movements, 1069
Iodide, 634
Iodine, 647, 717
deficiency, 639b, 647, 717
pregnancy and, 651b, 1279
dietary sources of, 717b
radioactive
for fetal hypothyroidism, 1279
for Graves’ thyrotoxicosis, 644b,
645
reference nutrient intake of, 717b
for thyroid neoplasia, 649
Iodine-associated thyroid disease,
647-648
Iodine-induced thyroid dysfunction, 647
Iodine therapy, for differentiated
carcinoma, 649-650
lodoquinol, 129
Ion channels, drugs acting on, 15b
Ion-selective electrodes, 348b
Ionising radiation, 164, 164f
Ipratropium bromide, asthma, 572
Irbesartan, 513
Irinotecan, 832, 842-844
Iris, of eye, 1 1 67
Iron, 716-717
absorption/uptake, 716-717
deficiency, 717
dietary sources of, 7 1 7b
overload, 717
haemochromatosis, 717
poisoning from, 140
reference nutrient intake of, 717b
reference range of, 1 362b
supplements
congestive gastropathy, 87 1
constipation and, 786 b
in pregnancy, 941b
Iron deficiency anaemia, 923, 940-943
alimentary tract disorders, 793
blood loss in, 940-941
confirmation of, 941-942, 942b
investigations in, 941-942
of cause, 942
malabsorption in, 941 , 942f
management of, 943
physiological demands in, 941, 941b
pregnancy and, 1284
Iron oxide, 615b
Irritable bowel syndrome (IBS), 824-826
clinical features of, 825, 825b
complementary and alternative
therapies for, 826b
investigations of, 825, 825 b
management of, 825-826, 826f
dietary, 825 b
pathophysiology of, 824-825
behavioural and psychosocial
factors, 824
luminal factors, 825
physiological factors, 824
Irritant eczema, 1247
Ischaemia
cerebral, 967f
critical limb, 502-503
liver, 898
lower limb, 504b
Ischaemic gut injury, 827
Ischaemic heart disease
hierarchy of systems applied to, 93b
levothyroxine replacement in, 641
Ischaemic nephropathy, 406-407
Ischaemic pain, 1350b
Ischaemic penumbra, 1154
Ischiogluteal bursitis, 999b
Islet autoantibodies, 727
Islet cell
antibodies, in type 1 diabetes, 728
transplantation of, 752, 753 f
Isocyanates, 614b
Isolated gonadotrophin deficiency, 653
Isolation precaution, types of, 113b
Isoleucine, 698b
Isoniazid
as antimycobacterial agents, 1 25
hepatotoxicity, 120b, 894b
poisoning, 141b
polyneuropathy and, 1139b
prophylactic, 1 1 9b
and pyridoxine deficiency, 715
resistance, 1 1 8
skin reactions, 1266b
tuberculosis
HIV/AIDS patients, 324, 324b
treatment, 592-593, 593b
Isoprenaline, 476-477
AV block, 478
Isosorbide dinitrate, 490b
Isosorbide mononitrate, 490b
Isotretinoin, 1227
Ispaghula husk, 834
Itch, 1219-1220
ITGB2 gene, loss-of-f unction mutations
in, leucocyte adhesion
deficiencies and, 77
Itraconazole, 125b, 126
acute leukaemia patients, 957
allergic bronchopulmonary
aspergillosis, 596
chromoblastomycosis, 301
cutaneous leishmaniasis, 286
fungal skin infections, 1 239-1 240
histoplasmosis, 304
mycetoma, 301
P. marneffei infection, 303
prophylactic, 119b
sporotrichosis, 301
ITU, referral to, in community-acquired
pneumonia, 584b
Ivabradine
angina, 491
for heart failure, 467
Ivermectin
for helminthic infections, 1 29
filariasis, 291
for scabies, 1 241
for strongyloidiasis, 289
J
Jaccoud’s arthropathy, 1 035
JAK proteins, 64-66
Janus-activated kinase (JAK) inhibitors,
for musculoskeletal disease,
1005
Japanese B encephalitis, 249-250
Jarisch-Herxheimer reaction, 339
Jaundice, 860-862, 860b
acute liver failure and, 857-858
alcoholic hepatitis and, 881, 881b
cholecystitis and, 905
cholestatic, 860b-862b, 861-862
cirrhosis and, 866-867
hepatocellular, 860-861
investigation of, 861 f
obstructive, 861-862
pre-hepatic, 860
primary biliary cholangitis and, 887
JC virus, 319-320
Jejunal mucosa, 807 f
Jejunostomy patients, intestinal failure
and, 709
Jejunum
coeliac disease see Coeliac disease
hormones, 772 b
short bowel syndrome, 709 b
Jejunum-colon patients, intestinal failure
and, 709
Jellyfish, 154b
Jiggers, 299-300
Jod-Basedow effect, 647
Joint capsule, 987
Joint disease
crystal-associated, 1012-1018,
1013b, 10137
in tuberculosis, 591
Joint hypermobility syndrome, 1349
Joints, 986-987
aspiration, 988, 9887, 1015, 1017,
1020
fibrous and fibrocartilaginous, 986
haemophilia, 1058
hypermobility, 1059b
infection, 1019-1021
neuropathic (Charcot), 1057, 1058f
in old age, 1 020b
protection, 1001
1392 • INDEX
Joints (Continued)
replacement
arthroplasty, 1002b
for osteoarthritis, 1 01 2
synovial, 987, 987 f
tumours, 1056-1057
types of, 986b
Jugular venous pressure, effects of
respiration on, 447b
Jugular venous pulse
examination of, 443b
respiratory system, 546f
tricuspid regurgitation, 526
Junin and Machupo viruses, 245b
Juvenile absence epilepsy, 1 1 00 b
Juvenile dermatomyositis (JDM), 1040
Juvenile idiopathic arthritis (JIA),
1026-1027
in adolescence, 1 027b
clinical features of, 1027b
oligoarticular, 1300
transition medicine and, 1300
Juvenile myoclonic epilepsy, 1 1 00 b
Juvenile polyposis, 829
K
Kala-azar (visceral leishmaniasis),
282-284, 282 f
clinical features of, 282
differential diagnosis of, 283
HIV co-infection, 283-284
investigations of, 282-283, 282 f
management of, 283
post- kala-azar, dermal leishmaniasis,
284, 284f
Kallmann’s syndrome, 653
Kaposi’s sarcoma, HIV- related, 315,
31 67
Kartagener’s syndrome, 550
Karyotype, 38f
Kashin-Beck disease, 1 01 1
Katayama syndrome, 295
Kawasaki disease, 1 041 -1 042
Kayser-Fleischer rings, 896-897
in Wilson’s disease, 1 1 74f
Kco (transfer coefficient for carbon
monoxide), 555 b
Kearns-Sayre syndrome, 1 1 44b
Keloid scar, definition of, 1 226
Kennedy’s disease, 1 093b
Keratan sulphate, 987
Keratin, 1212
Keratinocytes, 1212
Keratoacanthoma, 1234, 1234f
Keratoconjunctivitis sicca
rheumatoid arthritis, 1 024
Sjogren’s syndrome and, 1038
Keratoderma blennorrhagica, 1031
Keratolysis, pitted, 1238
Keratomalacia, 713
Keratosis, actinic, 1230b
Kerion, 1240
Kernig’s sign, 1118
Kerosene, poisoning, 148b
Keshan’s disease, 718
Ketamine, 1345b
Ketoacidosis, diabetic, 729-730,
735-738
in adolescence, 753 b
clinical features of, 736, 736 b
investigations of, 736
management of, 736-738, 737 b
bicarbonate in, 738
fluid replacement in, 737
insulin in, 737
ongoing, 738
phosphate in, 738
potassium in, 738
pathogenesis of, 735-736, 736 b
severe, indications of, 736 b
Ketoconazole, 125b, 126
Cushing’s syndrome, 669
cutaneous leishmaniasis, 286
fungal skin infections, 1239-1240
mycetoma, 301
paracoccidioidomycosis, 304
shampoos, 1240
Ketogenesis, 725f
Ketone bodies, 725, 725 f
Ketones
blood, 726, 726 b
urine, 726
Ketonuria, 726
Ketoprofen, 1003b
Kidney
acid-base balance control, 364
clinical examination of, 382-384,
382f-383f
cystic diseases of, 405-406
drugs and, 426
duplex, 434
functional anatomy and physiology of,
384-386, 385f
imaging of, 389-390, 389f
MRI images of, 406f
single, 433
sodium handling, 349
stones, 431b
systemic lupus erythematosus in,
1035
transplantation, 424
tumours of, 434-436
Kidney disease
in adolescence, 426b
chronic, 415-420, 417b
causes of, 41 5b
haemodialysis in, 422-423
indications for dialysis for, 422b
osteodystrophy and, 41 9f
physical signs of, 41 6f
pregnancy and, 1282, 1283f
pruritus, 415
stages of, 388b
staging of, in children over 2 years
of age, 1298b
transition medicine and,
1298-1299
medullary sponge, 433
Kidney injury, acute, 411-415
causes of, 41 1 f
clinical features of, 411-413
dialysis for, indications for, 422b
haemodialysis in, 422
investigations of, 41 2b
management of, 413-414, 413b
in old age, 414b
pathophysiology of, 411
post- renal, 412b, 413
pre-renal, 411-412, 412b
pregnancy and, 1282, 1283b
recovery from, 414-415, 414 f
renal, 412-413, 412b
renal replacement therapy, 414
Kimmelstiel-Wilson nodule, 758 f
Kinase inhibitors, for low-grade NHL,
965
Kinases, cyclin-dependent, 1317
Klebsiella granulomatis, 341 b
Klebsiella oxytoca, 230
Klebsiella pneumoniae, 1 1 6
Klebsiella spp., 103 f
Klinefelter’s syndrome, 44b, 660-661
Knee
osteoarthritis, 1009-1010, 101 Of
pain, 998-999, 999b
rheumatoid arthritis, 1023
Knee height, measurement of, 693b
Knudson hypothesis, 56-57
Kobner phenomenon, 1252
Koch’s postulates, 100b
Koilonychia, 1261, 1 261 7
Koplik’s spots, 236, 236f
Korsakoff’s psychosis, 714
Korsakoff’s syndrome, 1081
Krebs (citric acid) cycle, 49, 714
Krukenberg tumour, 804
Kupffer cells, 64, 848, 850 f
Kuru, 1127b
Kussmaul breathing, 415
Kussmaul’s sign, 544b
Kwashiorkor, 704
Kyasanur fever, 245b
Kyphoplasty, 1002b
for osteoporosis, 1 049
Kyphoscoliosis, 546f
thoracic, 628
Kyphosis, 591 f, 1302f
ankylosing spondylitis, 1 030
L
L-dopa see Levodopa
Labetalol
aortic dissection, 508
hypertension, 513
accelerated, 514
Laboratory investigations, biochemical,
348-349, 348b
Laboratory reference ranges,
1357-1364
of adolescence, 1 363
of adults, 1358
of childhood, 1363
in pregnancy, 1364
Labyrinthitis, 1104
Lacrimal gland/lacrimal drainage, 1 1 64
Lactase deficiency, 81 2
Lactate
reference range of, venous blood,
1360b
sepsis and, 196, 197f
Lactate dehydrogenase (LDH)
acute kidney injury, 412b
empyema, 564
megaloblastic anaemia, 943, 944b
pancreatitis and, 837b
pleural effusion, 610
reference range of, venous blood,
1360b
Lactation, nutrition in, 712b
Lactic acidosis, 365
Lactitol, 834b
Lactobacillus spp., 103f
Lactoferrin, 62-63, 992
in acute phase response, 70
Lactose, refeeding diet, 705 b
Lactose hydrogen breath test, 81 2
Lactose intolerance, 81 2
Lactulose
for hepatic encephalopathy, 865
for variceal bleeding, 869b
Lacunar infarctions, 1 1 53
Lacunar syndrome (LV\CS), 1 156f
Lambert-Eaton myasthenic syndrome
(LEMS), 1 1 427, 1143,
1325-1326
Lamina densa, 1212
Lamina lucida, 1212
Laminin, 1212
Lamivudine, 324b
for hepatitis B, 876
co-infection with HIV, 877
resistance, 325
Lamotrigine, 1 1 02b-1 1 03b
Langerhans cell histiocytosis
(histiocytosis X), 613b
Langerhans’ cells, 1212
Language
disorders, 1089b
spoken, 1070f
Lanreotide, 686-687
Laparoscopy
for ascites, 863
for infertility, 656
for lower abdominal pain, 336
for pyrexia of unknown origin,
219-222
Large-bowel diarrhoea, HIV-related, 317
Large rectal adenomatous polyp, 828 f
Laron dwarfism, 680b
Larva currens, 289
Larva migrans
cutaneous, 294, 294f
visceral, 233-234
Laryngeal disorders, 624-625
Laryngeal obstruction, 624-625, 624b
Laryngeal paralysis, 624
Laryngoscopy, 553
Lasegue’s sign, 1135
Laser therapy
for bleeding control, 775 f
for colorectal cancer, 832
for hereditary haemorrhagic
telangiectasia, 970
for hypertrichosis, 1 259
for lung cancer, 603
for oesophageal carcinoma, 797
for proliferative diabetic retinopathy,
1176
for rosacea, 1 244
for skin disease, 1 228
Lassa fever, 245b
incubation period of, 111b
Latent autoimmune diabetes of
adulthood (LADA), 730
Latent tuberculosis, 1172
detection of, 594, 594f
Lateral film, of chest X-ray, 551
Lateral humeral epicondylitis, 998b
Latex agglutination test, 301
Lavage
bronchoalveolar, 609-610
gastric, 136, 136b
Law, psychiatry and, 1207
Lawrence-Moon-Biedl syndromes, 700
Laxative misuse syndromes, 834
Laxatives, 834b
Lead
poisoning, 148b
reference range of, venous blood,
1360b
Lead pipe rigidity, 1069
Leao, spreading depression of, 1 095
Learning difficulties, congenital heart
disease and, 533
Leber’s hereditary optic neuropathy,
1089b
Lecithin cholesterol acyl transferase
(LCAT), 375
deficiency, 375, 375 b
Lectin
mannose-binding
deficiency, 78
Lectin pathway, for complement, 66
Leflunomide, for musculoskeletal
disease, 1004b, 1005
Left anterior descending artery (LAD)
and coronary arteries with a stenosis,
453f
in coronary circulation, 444-445, 445f
Left atrial dilatation, 450
Left bundle branch block, 478-479,
479f
Left main coronary artery, 444-445,
445f
occlusion, 445
Left ventricular dilatation, 450
Left ventricular hypertrophy, 523 f
Legal considerations, in artificial
nutritional support, 710b
Legionella pneumophila infection, 106,
117b
Legionella spp., 114b, 119b
Legs
examination of, 982f-983f
cardiology, 442f
diabetes mellitus, 720 f
endocrine disease, 630f
febrile injecting drug user, 222 f
HIV/AIDS, 306f
liver and biliary disease, 846f
liver and biliary disease and, 846f
oedema and, 395-396
examination of, respiratory system,
546f
ulcers, 1223-1224
causes of, 1223b, 1223f
clinical assessment of, 1 223-1 224
due to arterial disease, 1 223-1 224
due to neuropathy, 1 224
due to vasculitis, 1 224
due to venous disease, 1223,
1223f
investigations in, 1224
management of, 1 224
Leigh’s syndrome, 49
Leishman-Donovan body (amastigotes),
282 f
Leishmania, 281
life cycle of, 281-282, 282 f
Viannia subgenus, 285
Leishmania aethiopica, 284
Leishmania amazonensis, 285
Leishmania brasiliensis, 285
Leishmania chagasi, 282, 282 f
Leishmania donovani, 282, 282 f
Leishmania guyanensis, 285
Leishmania infantum, 282, 282 f
INDEX • 1393
Leishmania major, 284
Leishmania mexicana, 285
Leishmania tropica, 284
Leishmaniasis, 281-286, 1238
cutaneous, 284-285, 285 b, 285 f
incubation period of, 111b
dermal, post-kala-azar, 284, 284f
epidemiology and transmission of,
281-282, 281f-282f
mucosal, 285
prevention and control of, 284
visceral, 282-284, 282 f
clinical features of, 282
differential diagnosis of, 283
HIV co-infection, 283-284
incubation period of, 111b
investigations of, 282-283, 282 f
management of, 283
Lemierre’s syndrome, 586-587
Lenalidomide, for multiple myeloma,
968
Lens, of eye, 1 1 68
Lentigo, 1234
Leprosy, 267-270, 267f
borderline cases of, 269
clinical features of, 268-269, 268b,
269 f
epidemiology and transmission of,
267
granulomas in, 71
incubation period of, 111b
investigations of, 269
management of, 269-270,
269b-270b
pathogenesis of, 267-268
patient education of, 270
prevention and control of, 270
prognosis of, 270
reactions, 268-269, 268b
tuberculoid, 267-268
Leptin, 694
Leptosphaera senegalensis, 301
Leptospira interrogans, 257
Leptospirosis, 257-259, 880
aseptic meningitis, 257
bacteraemic, 257
clinical features of, 257-258, 258 f
diagnosis of, 258
icteric, 258
management and prevention of,
258-259
microbiology and epidemiology of,
257
Lesch-Nyhan syndrome, 1014
Leucine, 698b
Leucocyte adhesion deficiencies, 77
Leucocytes, 917
Leucocytosis, 926-927
cholecystitis and, 905
choledocholithiasis and, 906
hepatobiliary disease and, 853
in inflammation, 71-72
pyogenic liver abscess and, 880
Leucoencephalopathy, progressive
multifocal, 1123
HIV-associated, 319-320, 320 f
Leucoerythroblastic anaemia, 969
Leuconychia, striate, 1260
Leucopenia, 925-926
hepatobiliary disease and, 853
Leukaemias, 954-961
acute, 955-958
haematopoietic stem cell
transplantation for, 958
investigations of, 955-956, 956 f
management of, 956-958
outcome of, 958b
prognosis of, 958
specific therapy for, 956-957,
956b-957b
supportive therapy for, 957-958
WHO classification of, 955b
in children, 1298
chronic lymphocytic, 959-960
clinical features of, 959
investigations of, 959-960
management of, 960
prognosis of, 960
staging of, 960b
chronic myeloid, 958-959
accelerated phase, management
of, 959
blast crisis, management of, 959
characteristics of, 958
chronic phase, management of,
959, 959 b
clinical features of, 958
investigations of, 959
management of, 959
natural history of, 958
epidemiology and aetiology of,
954-955
hairy cell, 960
prolymphocytic, 960
risk factors for, 955 b
terminology and classification of, 955,
955 b
Leukoplakia, hairy, 316
Leukotriene receptor antagonists,
asthma, 571 f, 572
Leukotrienes, 66-67
Levator palpebrae superioris, 1164
Levetiracetam, 1100b
in pregnancy, 1103b
Levodopa
adverse reactions, chorea, 1 085
for Parkinson’s disease, 1113-1114
Levofloxacin, 117b, 123b
plague, 259
Levothyroxine
hypothyroidism management,
640-641, 641b
in ischaemic heart disease, 641
Lewy body dementia, 1 1 94
Leydig cell tumours, 439
LH see Luteinising hormone
Li-Fraumeni syndrome, 1321b
Libman-Sacks endocarditis, 1 035
Lice
body, 1241
head, 1241
pubic (crab), 1241
relapsing fever, 256b, 257, 257 f
Lichen planus, 1 252
clinical features of, 1252, 1 2527
investigations of, 1252
management of, 1 252
in nails, 1261
pathogenesis of, 1 252
rash, 334b
rash in, 1217b
vulval pain/itch, 336b
Lichen sclerosus, 334b, 336b
Lichen simplex, 1247
Lichenoid eruptions, drug-induced,
1252, 1266b
Liddle’s syndrome, 361
Lidocaine
arrhythmias, 480, 480b
effect in old age, 32 b
in renal/hepatic disease, 32 b
Life course, 93
Life expectancy, 92, 1304, 1304b
Life support
advanced, 457, 458f
basic, 456-457, 457f
Lifestyle advice, for obesity, 701
Lifestyle changes
for chronic kidney disease, 420
for dyslipidaemia, 375
Lifestyle factors
ageing, 1305
cancer, 1316
diabetes mellitus, 743-745
weight management, 744
Lifestyle interventions, for
musculoskeletal disease,
1 000-1 001
in gout, 1016
in osteoarthritis, 1012
Ligaments, 987
Ligand assay, 348b
Likelihood ratios (LR), 3, 3 f
Limb girdle dystrophy, 1143b
Limbic encephalitis, 1111b
Limbic (emotional) influences, in control
of breathing, 549
Limbic system, 1066
Limbs
lower see Legs
upper see Arms
Linagliptin, 747
Lincomycin, 29
Lincosamides, 122
antibiotics, 121-122
mechanism of action, 1 1 6b
Lindane, 148b
Linear accelerators, 1331
Linear IgA disease, 1255b, 1256-1257
Linezolid, 117b, 124
in pneumonia, 587
in pregnancy, 120b
Linitis plastica, 804
Linoleic acid, 697
Linolenic acid, 697
Lipase, 770b
Lipid emulsion therapy, 136-137
Lipid-lowering therapy
for acute coronary syndrome, 501
chronic kidney disease, 420
for dyslipidaemia, 375
Lipid peroxidation, 1305
Lipids, 370-378
acute kidney injury and, 416b
cardiovascular disease and, 373
dietary, 371
endogenous, 372 f
measurement, 373
metabolism, 370-378, 850
disorders of, 370
effects of insulin in, 723 b
presenting problems in, 373-375
transport, 372 f
see also Fats
Lipodermatosclerosis, 1 223
Lipodystrophy, 326, 326f
Lipohypertrophy, 721b
Lipolysis, 694
Lipomas
skin, 1235
small intestine and, 813
Lipopeptides, 123
Lipoprotein lipase, 371-372
deficiency, 374b
Lipoproteins
high-density (HDL), 1360b
intermediate-density, 371-372
low-density, 371-372
metabolism, 370-378
structure of, 371 f
very low-density, 371-372
Liquorice, excessive intake of, 361
Liraglutide, for obesity, 702-703, 702 f
Lisch nodule, 1132b
Lisinopril
heart failure, 466b
hypertension, 513
Listeria monocytogenes
bacterial meningitis from, 1119
listeriosis from, 259
Listeriosis, 259-260
in pregnancy, 235 b
Lisuride, for Parkinson’s disease, 1114b
Lithium
for cluster headache, 1 096
drug interactions of, 24, 24b
hypothyroidism and, 639b
nephrotoxicity, 427b
plasma interactions of, 36b
poisoning from, 139
prescribing, 32b
skin reactions, 1266b
teratogenesis, 1200
Lithium carbonate, for bipolar disorder,
1200
Livedo reticularis, 1035, 1036 f
Liver
abscess, 879-880, 893
amoebic, 880
in old age, 901b
pyogenic, 879-880, 880b
biopsy of, 855, 855b
for hepatocellular carcinoma, 891
for non-alcoholic fatty liver, 884
blood supply to, 848-849, 848f
cells see Hepatocytes
drugs and, 893-895
fatty
alcoholic, 881, 881b
non-alcoholic, 882-885, 8837, 885f
fibrosis of, 894
cirrhosis and, 866, 866f
congenital, 8687, 902
non-invasive markers of, 855
pathogenic mechanisms in, 849f
function of, 850-851, 850f
functional anatomy and physiology of,
848-851
HIV infection and, 879
infections of, 871-880
injury to
drug-induced, 894-895, 894b
types of, 894-895
ischaemia, 898
nodular regenerative hyperplasia of,
899
size of
assessment for, 847b
change in, causes of, 862b
structure of, 848-849, 848f
transplantation of, 900-901
for acute liver failure, 858-859
for alcoholic liver disease, 882
for Budd-Chiari syndrome, 899
for cirrhosis, 867
complications of, 901
for hepatic encephalopathy, 865
for hepatitis B, 876
for hepatitis C, 878
for hepatocellular carcinoma, 891
indications and contraindications
for, 900-901, 900b, 901 f
living donor, 901
orthotopic, 890
for primary biliary cholangitis, 888
for primary sclerosing cholangitis,
890
prognosis for, 901
split liver, 901
for Wilson’s disease, 897
tumours, metastatic, 1328-1329
Liver capsule pain, 1350b
Liver disease
abdominal signs in, history and
significance of, 847
alcoholic, 880-882
fatty, 881
liver function test (LFT) abnormality
in, 854b
in old age, 901b
risk factors for, 880
autoimmune, 885-890
bleeding, 975
chronic, 853b
hepatitis B and, 873
cirrhosis see Cirrhosis
clinical examination for, 846f
clinical features of, 847 b
cystic, 893, 893f
decompensated, 867
drug-induced, liver function test (LFT)
abnormality in, 854b
HIV-related, 317-318
hydatid cyst and, 880
inherited, 895-897
haemochromatosis as, 895-896
investigation of, 852-855, 852b
in old age, 901b
pregnancy and, 899-900,
1283-1284
acute fatty liver as, 1 283, 1 283b
obstetric cholestasis as, 1 284
viral hepatitis as, 1 284
prescribing in, 32, 32 b
presentation of, 856b
presenting problems of, 855-866,
856 f
pruritus and, 1219b
silent presentation of, 847 b
tumours as, 890-893
benign, 893
primary malignant, 890-892
secondary malignant, 892-893,
893 f
vascular, 898-899
Wilson’s disease and, 896
1394 • INDEX
Liver failure
acute, 856-859
adverse prognostic criteria in, 858b
causes of, 856f-857f
classification of, 857 b
clinical assessment of, 857-858
complications of, 858b
hepatic encephalopathy and, 857 b
hepatitis A and, 873
investigations for, 858, 858b
management of, 858-859, 858b
pathophysiology of, 857
chronic
causes of, 856f, 867 b
cirrhosis and, 867
fulminant, hepatitis B and, 875
hepatic encephalopathy, 856-857
Liver flukes, 233 b, 297, 297 b
Liver function tests, 852
abnormal, 859-860, 859b
asymptomatic, 859f
HIV infection and, 879 b
identifying the cause of, 854b
in pregnancy, 900b
cholestatic/obstructive, 853b
for gastrointestinal bleeding, 781
hepatitic, 853b
for hepatitis C, 877
Loa loa, 233 b, 290 b, 292
Loading dose, 19
Local glucocorticoid injections, for
ankylosing spondylitis, 1031
Localised lymphadenopathy, 927
‘Locked-in’ syndrome, 211
Lockjaw, 1126
Lofexidine, 1196
Lofgren’s syndrome, 608-609
Loiasis, 233b, 292
Loin pain, 396
Long QT syndrome, 476
Long-term domiciliary oxygen therapy
(LTOT), for chronic obstructive
pulmonary disease (COPD), 577
Loop diuretics, for hypervolaemia,
354-355
Loop of Henle, 350, 384-386
Looser’ s zones, 1 052
Loperamide
for faecal incontinence, 835
for inflammatory bowel disease,
821b
intussusception and, 230
for irritable bowel syndrome, 826f
for radiation enteritis, 810
for short bowel syndrome, 808-809
for small bowel bacterial overgrowth,
808-809
Lopinavir, 324b
Loratadine, 622, 1254
Lorazepam
disturbed behaviour, 1 1 89f
palliative care, 1353
status epilepticus, 1081b
Loricrin, 1212
Losartan, 58
Loss-of-function mutations, 44
Loss of vision, of ophthalmic disease,
1170-1171, 1170b
Lotions, 1225b
Louse-borne relapsing fever, 256b, 257,
257 f
Low back pain
assessment of, 988-989
causes of, 996b
mechanical, features of, 996b
radicular, 997 b
Low birth weight, and disease
susceptibility, 93
Low-density lipoproteins, 371-372
Low-dose dexamethasone suppression
test (LDDST), in Cushing’s
syndrome, 668
Low-grade tumours, 961
Low-molecular-weight heparins
(LMWHs), 922, 938-939, 938b
for venous thromboembolism, 975
Low mood, 1185-1186
alcohol misuse and, 1194
Lower airway defences, 550
Lower limbs
examination, diabetes mellitus, 721b
ischaemia, 504b
see also Foot/feet; Legs
Lower oesophageal sphincter,
abnormalities of, 791
Lubiprostone, 825
Lumbar canal stenosis, 1 1 35-1 1 36
Lumbar disc herniation, 1135, 1 1 35f
Lumbar nerve root compression, 1 1 35f
Lumbar puncture, 1077-1078
for meningitis, 1118
for stroke, 1 1 52
for viral encephalitis, 1118
Lumbar spondylosis, 1 1 35-1 1 36
Lumbosacral plexopathy, 1 1 41
Lumefantrine, for malaria, 128
Lumps, skin, 1216
Lung(s)
abscess, 170 f, 21 9f, 251 f
biopsy
in interstitial pneumonias, 607
pleural effusion, 563-564
cavitation of, 551b
collapse
by bronchial obstruction, 552 f
upper lobe, 547f
consolidation of, 551b
defences, 550, 550f
fibrosis see Pulmonary fibrosis
functional anatomy and physiology of,
548-550, 548f-549f
gas exchange in, 549-550, 549f
inflammatory arthritis in, 994b
innate response of, 550
irradiation and, 612-613
mechanics, 549
near drowning accidents and, 169
near-drowning victims, 1 69
shrinking, 610b, 61 1
systemic lupus erythematosus in,
1035
transplantation, 567, 567 b
tumours of, 598-605
metastatic, 1328
primary, 599-603
secondary, 603
volumes, 555
Lung cancer, 599-603, 599f
burden of, 598b
cell types in, 599b
clinical features of, 599-601
investigations of, 601-602
management of, 602-603
non-metastatic extrapulmonary
manifestations of, 601b
occupational, 618
pathology of, 599, 599f
prognosis for, 603, 603b
Lung disease
alveolar
microlithiasis, 613b
proteinosis, 613b
diffuse parenchymal, 605-610
drug-induced, 612-613, 612b
due to organic dusts, 616-617,
616b
due to systemic inflammatory
disease, 610-611
dust exposure and, 614-615, 615b
HIV-related, 318-319, 318b
infection, 581-598
interstitial, 605-613
investigation of, 550-556
obstructive, 573-578
in old age, 578 b
occupational, 613-619
presenting problems of, 556-567
radiotherapy-induced, 612
rheumatoid arthritis, 1024
tumours, 598-605
secondary, 603
vascular, 619-622
Lung flukes, 233b
Lung injury, ventilator-induced, 204
Lupus anticoagulant, 920-921
Lupus erythematosus, 1221b, 1262
bullous, 1255b
drug-induced, 1266b
systemic, 41 0-41 1 , 1 034-1 037
classification of, criteria for, 1 036b
clinical features of, 1035-1036
investigations of, 1 036
management of, 1 036-1 037
pathophysiology of, 1 034
pregnancy and, 1281, 1281b
respiratory involvement in, 61 1
Lupus nephritis, 392b
Lupus pernio, 609f, 610
Luteinising hormone (LH)
deficiency, 680b
puberty and, 1290
reference range of, 1 359b
Lyme disease, 255-256, 256 b, 256 f,
1125
myopericarditis, 538
Lymecycline, 1243
Lymph node biopsy, in Hodgkin
lymphoma, 962, 963f
Lymph nodes, 67
diphtheria, 266
of envenomed patient, 152f
examination of, cancer, 1314, 1315b
normal architecture of, 961, 961 f
trypanosomiasis, 279
tuberculosis and, 590
Lymphadenitis, 590
Lymphadenopathy, 913b, 927, 927 b
HIV-related, 313
persistent generalised, 313
rheumatoid arthritis, 1 024-1 025
Lymphangiectasia, intestinal, 811
Lymphangioleiomyomatosis, 613b
Lymphangitic carcinomatosis, 603
Lymphatic filariasis, 290-292
Lymphatics, 67
Lymphocytes, 917, 926b, 926f
count, 1362b
older people, 923b
see also B lymphocytes; T
lymphocytes
Lymphocytic interstitial pneumonia,
606 b
Lymphocytosis, 926b, 927
infectious mononucleosis, 241
Lymphogranuloma venereum (LGV),
341b
Lymphoid interstitial pneumonitis, 319
Lymphoid organs, 67
Lymphoid tissue
gastroi ntesti nal m ucosa-associated ,
769-770
mucosa-associated, 67
Lymphomas, 650, 961-966, 961 f
B-cell, 805
cutaneous, 1232
gastric, 805
gastrointestinal tract and, 813
Hodgkin, 961-964, 962 f
classification of, 962b
clinical features of, 962
epidemiology of, 961 , 962b
investigations of, 962, 963f
management of, 962-964
prognosis of, 964, 964b
stages of, 962b
MALT, 769-770
non-Hodgkin, 964-966, 965 f
clinical features of, 964, 965f
epidemiology of, 964, 964b
high-grade management of, 966
investigations of, 964-965
low-grade management of, 965
management of, 965-966
prognosis of, 966
primary CNS, 320, 320 f
T-cell
cutaneous, 1224
enteropathy-associated, 813
thyroid, 646
Lymphopenia, 925-926, 926b
HIV infection, 311-312
sarcoidosis and, 609-610
Lymphoproliferative syndrome,
autoimmune, 80
Lynch’s syndrome, 46
d-Lysergic acid diethylamide, 144, 144f
Lysine, 698b
Lysolecithin, 905
Lysosomal storage diseases, 370, 371b
Lysosomes, 370
Lysozyme, 62-63
M
Machado-Joseph disease, genetics,
43b
Machupo virus, 245b
Macrocytic anaemia, 925
Macrocytosis, 853, 921 f, 941 f
Macroglobulinaemia, Waldenstrom, 966
Macrolides, 117b, 121-122
mechanism of action, 116b
Macronutrients (energy-yielding
nutrients), 695-697
dietary recommendations for, 697,
698 b
Macrophage colony stimulating factor
(M-CSF), 1022-1023, 1022f
Macrophages, 64, 550
alveolar, 303, 615
foamy, 430, 809
functions of, 64b
in gastrointestinal tract, 769-770
Macroprolactin, 684
Macroprolactinaemia, 684, 684b
Macroprolactinomas, pregnancy and,
1280
Macules
cafe au lait, 1 1 31 f
definition of, 121 If
Maculopathy, diabetic, 721
Maddrey score, 882
Madopar, 1113
Madura foot, 301
Madurella grisea, 301
Madurella mycetomatis, 301
Magic (hallucinogenic) mushrooms, 143,
1196
Magnesium, 718
dietary sources of, 717b
homeostasis, 367-368
intravenous
acute severe asthma, 573
arrhythmias, 140
tetany, 663b
torsades de pointes, 476-477
metabolism, disorders of, 367-368
refeeding diet, 705 b
reference nutrient intake of, 717b
reference range of, venous blood,
1360b
Magnesium ammonium phosphate
stones, 431b
Magnesium chloride, 368
Magnesium salts, 368
Magnesium sulphate
asthma, 573 f
hypomagnesaemia, 368
pre-eclampsia, 1276
ventricular tachycardia, 137b
Magnetic resonance angiography (MRA)
in nervous system, 1072
renal artery stenosis, 407, 407f
stroke, 1157b
urinary tract disease, 389
Magnetic stimulation, 1077
Magnifying glass, 1214
Main d’accoucheur, 663
Main en lorgnette, 1 033
Major haemorrhage, transfusion in,
931b
Major histocompatibility complex (MHC),
851, 1028-1029, 1248
Malabsorption, 783-785, 784f, 785 b,
942f
after gastric resection, 783-785
after ileal resection, 706
biliary cirrhosis, 888
of chronic pancreatitis, 841
cystic fibrosis, 581
disorders causing, 805-810
investigations of, 785, 785 b, 785 f
iron deficiency anaemia, 941 , 942f
in old age, 808b
pathophysiology of, 784-785
primary biliary cholangitis and, 888
Maladie de Roger, 535-536
INDEX • 1395
Malar flush, 442 f
Malar rash, of systemic lupus
erythematosus, 1035f
Malaria, 273-277
algid, 276 b
cerebral, 276 b
chemoprophylaxis of, 277, 278 b
clinical features of, 274 b, 275-276,
27 5f
complicated, 277
control in endemic areas, 277
distribution of, 273 f
exchange transfusion, 277
haemolysis, 274-275
incubation period, 111b, 274 b
investigations of, 276
management of, 277, 277 b
mild, 277
non-falciparum, 277
pathogenesis of, 273-275
pathology of, 274-275
in pregnancy, 235 b
prevention of, 277
sickle-cell anaemia, 951
treatment of, 1 28
vector control, 323
Malarial parasite, life cycle of, 273-274,
274f
Malarone, 278 b
Malassezia, 103 f, 1240
Malassezia furfur, 1 240
Malathion
louse infestation, 1241
scabies, 1241
Male
hypogonadism in, 655, 656b, 660b
reproductive system of, 651 , 651 f
Malignancy, pruritus and, 1219b
Malignant disease, rheumatological
manifestations of, 1057,
1057b
Malignant hyperpyrexia, 1 95
Malignant plasma cells, 967
Malingering, 1206
Mallory-Denk bodies, 884
Mallory-Weiss syndrome, 1 77 b
Mallory-Weiss tears, 781 f
Mallory’s hyaline, 884
Malnutrition
in dementia, 711, 71 If
risk of, screening for, 693f
see also Under-nutrition
MALT (mucosa-associated lymphoid
tissue), 769-770
MALT lymphomas, 964
Malt worker’s lung, 616b
Mammary artery grafts, 491-492
Mammography, 1333
Manganese, 718
Mania, 1186
Mannitol, 355
Mannose-binding lectin deficiency, 78
Mansonella perstans infection, 233b,
293
Mansonella streptocerca, 290 b
Mantle cell lymphoma, 964
MAOI-B inhibitors, for Parkinson’s
disease, 1114
Maple bark stripper’s lung, 616b
Marasmus, 704
Maraviroc, 324b
Marburg fever, 230, 245b
March haemoglobinuria, 950
Marche a petits pas, 1 087
Marcus Gunn pupil, 1092b
Marfan’s syndrome, 508
cardiovascular system
aortic aneurysm, 505, 506 f
aortic dissection, 506, 507 b
mitral valve prolapse, 520
congenital defects, 531-532
mutation, 508
Marine poisonous animals,
envenomation of, 1 62
Marine venomous animals,
envenomation of, 1 62
Marjolin’s ulcer, 1021, 1223
Mass spectroscopy (MS), 348b
inductively coupled, 348b
Massive small bowel resection,
under-nutrition and, 706
Mast cell tryptase, 86
Mast cells, 66-67
degranulation of, clinical features of,
75 b
Mastectomy, 1334
Maternal medicine, 1269-1285
adrenal disease in, 1280
cardiac disease in, 1282
clinical evaluation in, 1271, 1 271 f
clinical examination in, 1270,
1270f-1271f
diabetes in, 1278-1279
gestational, 1278, 1278b
endocrine disease in, 1279-1280
functional anatomy and physiology in,
1272-1273
bone metabolism and, 1272
cardiovascular system and, 1272
endocrine system and, 1272
gastrointestinal system and, 1272
genitourinary system and, 1272
glucose metabolism in, 1272-1273
haematological system and, 1273
respiratory system and, 1273
gastrointestinal disease in,
1277-1278
haematological disease in,
1284-1285
human immunodeficiency virus
infection in, 1280
hypertension in, 1276-1277
imaging and, 1274
inflammatory rheumatic disease in,
1 280-1 281
investigations in, 1274, 1274b
liver disease and, 1283-1284
medical disorders in pregnancy and,
1276-1285
neurological disease in, 1284
parathyroid disease in, 1280
pituitary disease in, 1280
planning pregnancy in, for patients
with medical conditions, 1272
presenting problems in pregnancy
and, 1274-1276
breathlessness as, 1274-1275
chest pain as, 1 275
circulatory collapse as, 1 275
headache as, 1275
nausea and vomiting as, 1275,
1275b
oedema as, 1 275
seizures as, 1275-1276, 1276b
psychiatric disorders in, 1284
renal disease in, 1282-1283
respiratory disease in, 1277
thyroid disease in, 1279
Matrix metalloproteinases, 485-486
Mayaro viruses, 250, 1020-1021
McArdle’s disease, 1144b
McCune-Albright syndrome, 50-51 ,
1055, 1056f
Meal bolus calculation, 751b
Mean arterial pressure (MAP),
calculation of, 1 93b
Mean cell haemoglobin (MCH),
919-920, 1362b
Mean cell volume (MCV), 853, 919-920
in alcohol misuse, 1184
in anaemias, 940
reference range of, 1 362b
Measles, 236
clinical features of, 236, 236 f
management of, 236
in pregnancy, 235b
prevention of, 236
rash, 236f
subacute sclerosing panencephalitis,
236
Mebendazole, for helminthic infections,
129
Mechanical heart valves, 950
pregnancy and, 1282
Meckel’s diverticulum, 778, 812
bleeding from, 782 b
Meckel’s scan, 778 b
Meconium ileus, 842
Medial collateral ligament lesions,
998b-999b
Medial fibroplasia, 407
Medial humeral epicondylitis, 998b
Medial longitudinal fasciculus (MLF),
1069-1070
Median nerve
entrapment, 1139b
palsy, 760
Mediastinal spread, in lung cancer, 600
Mediastinoscopy, 604
Mediastinum
divisions of, 604f
tumours of, 603-605, 603b-604b,
604f
Medical emergency team, deterioration
and, 188, 189b
Medical interview, 231b
Medical ophthalmology, 1163-1178
functional anatomy and physiology of,
1164-1168
ophthalmic disease, presenting
problems in, 1169-1171
specialist ophthalmological conditions
in, 1171-1178
visual disorders, investigation of,
1168-1169
Medical psychiatry, 1 1 79-1 207
Medically unexplained somatic
symptoms, 1187, 1187b, 1205f
general management principles for,
1202, 1203b
in old age, 1 1 89b
Medication, of stroke patients, 1159b
Medication errors, 24-26
causes of, 25, 25 b, 25 f
response to, 26
types of, 25 b
Medication overuse
headache, 1096
migraine and, 1095
Medicines management, 26
Medroxyprogesterone, 655
Medullary carcinoma, 650
Medullary cystic kidney disease, 404
Medullary sponge kidney disease, 433
Medulloblastoma, 1129
Mefenamic acid, overdose, 138
Mefloquine, for malaria, 278 b
Megacolon
acquired, 835
toxic, 818
Megakaryoblasts, 91 5f, 918
Megakaryocytes, 918
Megaloblastic anaemia, 940, 943-945
clinical features of, 943b
investigations in, 944b
management of, 945
Megaloblastic crisis, 947
Megaureter, 434
Megestrol, 1332
Meglitinides, 746b, 747
Meglumine antimoniate, 128
Meiosis, 40-41 , 41 f
Meissner’s plexus, 771-772
Melaena, 780
Melanocortin-4 receptor (MC4R)
mutations, 700
Melanocytes, 1212
Melanocytic naevi, 1216, 1234-1235,
1235f
Melanoma, 1232-1234
ABODE rule of, 1216, 1216b
acral lentiginous, 1233
amelanotic, 1322
clinical features of, 1 232-1 233
cutaneous, 1232b
diagnosis and management of, 1 233
lentigo maligna, 1233
malignant, 1216
nodular, 1233, 1233f
pathophysiology of, 1 232
prognosis of, 1 233-1 234
subungual, 1233
superficial spreading, 1232-1233,
1233f
Melanoptysis, 615
Melanosis coli, 834
Melarsoprol, for trypanosomiasis, 1 28
MEL4S, 1116b, 1144b
Melasma, 1258
MELD score, for liver transplantation,
900-901
Meleney’s gangrene, 227 b
Melioidosis, 261
Melphalan, 968, 1320b
Memantine, 1193
Membrane attack complex (MAC), 66
Membranoproliferative
glomerulonephritis, 401
Membranous nephropathy, 398b-399b,
401 , 427b
Memory, 1066
Alzheimer’s disease, 1 1 92-1 1 93
disorders of, 1 066b
long-term, 1065, 1192-1193
loss, 1081
short-term, 1081, 1192-1193
Memory cells, 68
Menetrier’s disease, 797-798
Meniere’s disease, 1104-1 1 05
MENIN, 688
Meningioma, 1130-1131
Meningism, 1118
Meningitis, 1118-1121
aseptic, 257
bacterial, 1118-1120
cerebrospinal fluid in, 1119
headache and, 185, 185b
management of, 1120, 11 20 b
causes of, 111 8b
Coccidioides, 304
cryptococcal, HIV-related, 321
fungal, 1121
HIV-related, 321
malignant, 1121
in mumps, 240
protozoa, 1121
recurrent aseptic, 1121
tuberculous, 1120-1121, 1121b
viral, 1118
cerebrospinal fluid in, 1118
Meningococcaemia, chronic, 1119
Meningococcal infection
chemoprophylaxis following, 1121b
meningitis, 1118-1119, 1119b
prevention of, 1 1 20
rash, 1120
Meningococcal sepsis, 1119b
Meningoencephalitis, 279
Menopause, 652
male, 660b
premature, 654
Menorrhagia, 923
Menstrual cycle, normal, 652f
Menstrual irregularity, in polycystic
ovarian syndrome, 659
Menstruation, 1290, 1 291 f
Mental state examination, 1181-1183
Mental test, older people, 1 84
Menthol, topical, 1220
Mepacrine, hyperpigmentation from,
1258b
Meptazinol, 1002
Meralgia paraesthetica, 1 1 39b
Mercaptopurine
for acute leukaemia, 957 b
for inflammatory bowel disease,
821b
Mercury poisoning, 365b
Merkel cells, 1212
Meropenem, 117b, 120b
melioidosis, 261
neutropenic fever, 1 327-1 328
nocardiosis, 261
pneumonia, 586
in pregnancy, 120b
MERRF (myoclonic epilepsy with ragged
red fibres), 1116b, 1144b
Mesalazine, for inflammatory bowel
disease, 818, 820, 821b
Mesangiocapillary glomerulonephritis
(MCGN), 398b-399b, 401
Mesenteric ischaemia, chronic, 827
Mesna, 1036
Mesothelioma, 618
Meta-iodobenzyl guanidine (MIBG)
scintigraphy, 675
1396 • INDEX
Metabolic acidosis, 364-366
acute mountain sickness, 168
causes of, 365b
diabetic ketoacidosis, 735
hypothermia and, 166
kidney failure/renal failure
acute, 413
chronic, 415
malaria, 276 b
near-drowning, 170
poisoning, 139b, 141b
starvation, 704-705
Metabolic alkalosis, 366-367, 367 f
Metabolic disorders, 785
clinical examination of, 346-348,
346f
supportive therapy for, 957-958
Metabolic medicine, 345-380
Metabolic myopathies, 1144
Metabolic syndrome, 730-731
liver transplantation and, 901
Metabolism
first-pass, 17
interactions, 24
phase I, 18
phase II, 18
Metadrenalines, 1361b
Metalloproteinases, 485-486
Metamyelocytes, 917
Metaphase, 40
Metapneumovirus, 249
Metastatic bone disease, 1 057
Metastatic spread, in lung cancer, 600
Metatarsophalangeal joints, polyarthritis
in, 994f
Metavir system, for hepatitis C, 878
Metered-dose inhaler, for asthma, 571 f
Metformin, 746, 746b
acidosis, 135b, 141
for hyperglycaemia, 746
mechanism of action, 746
overdose, 135b, 141
polycystic ovarian syndrome, 659
in pregnancy, 1278
renal/hepatic disease, 32 b
Methadone
misuse, 142, 142b
withdrawal, 16b
Methaemoglobin, 277, 947
Methaemoglobinaemia, 120b, 1 357,
1227-1228
Methanol, poisoning from, 147, 147f
Methicillin-resistant Staphylococcus
aureus (MRSA), 252
Methimazole, 644
Methionine, 138
Methotrexate (MIX)
acute leukaemia, 957, 957 b
drug interaction, 24b
eczema, 1227-1228
hepatic fibrosis and, 895-897
hepatotoxicity of, 894b
for inflammatory bowel disease, 821b,
822, 1299
for musculoskeletal disease, 1004,
1004b
antineutrophil cytoplasmic
antibody-associated vasculitis,
1041
juvenile dermatomyositis, 1 040
juvenile idiopathic arthritis, 1 027
polymyositis and dermatomyositis,
1040
psoriatic arthritis, 1 033-1 034
systemic lupus erythematosus,
1036
pregnancy and, 1226b, 1278
psoriasis, 1227-1228, 1250
renal disease, 32 b
and respiratory disease, 612b
sarcoidosis, 610
Methyl-phenyl-tetrahydropyridine
(MPTP), 1112b
Methylbenzethonium chloride, 286
Methylcellulose, 646, 834b
Methyldopa, for pre-existing
hypertension, pregnancy and,
1276
M ethyl phenidate, 1 1 05
Methylprednisolone
for acute disseminated
encephalomyelitis, 1110
antineutrophil cytoplasmic
antibody-associated vasculitis
(AAV), 1041
Grave’s ophthalmopathy, 646
histoplasmosis, 304
for inflammatory bowel disease, 820
for juvenile dermatomyositis, 1 040
liver transplant patients, 901
for polymyositis and dermatomyositis,
1040
rheumatic disease, 1 005-1 006
for systemic lupus erythematosus,
1036
for transverse myelitis, 1110
Methysergide, and respiratory disease,
612b
Meticillin, 120b
Metoclopramide
chronic intestinal pseudo-obstruction,
811
and hyperprolactinaemia, 684b
nausea and vomiting, 803, 1351b
poisoning, 137b
sodium content of, 864b
Metoprolol, 466b, 480b
angina, 500
arrhythmias, 481
hypertension, 513
Metronidazole, 1 1 7b
for amoebiasis, 287
for balanitis, 334b
for cerebral abscess, 1 1 24b
for cholecystitis, 905
for choledocholithiasis, 906
for Clostridium difficile infection, 264
for gas gangrene, 227
for giardiasis, 287
for Helicobacter pylori eradication,
800
for inflammatory bowel disease, 823
for liver abscess, 880
for neutropenic fever, 1327-1328
for PID, 336
for pneumonia, 587
polyneuropathy and, 1139b
in pregnancy, 120b
prophylactic, 119b
for rosacea, 1 244
for small bowel bacterial overgrowth,
808-809
for tetanus, 1126b
for tropical ulcer, 254
Metyrapone, 669, 671b
Mevalonate kinase deficiency, 81
Mexiletine, 480, 480b
Mezavant, for inflammatory bowel
disease, 821b
Micafungin, 125b
Micelles, mixed, 768
Miconazole, 125b, 1239-1240
erythrasma, 1238
Microalbuminuria, 394
in diabetic nephropathy, 757, 758 b
in diabetic neuropathy, 727
Microaneurysms, 509-510
Microangiopathic haemolytic anaemia
(MAHA), 408, 950
Microangiopathy, diabetic, 756
Microarrays, 51
Microbial flora, normal, 102-103, 103 f
Microbiological investigations, for
respiratory disease, 554
Microbiome, 63, 103
Microcytic anaemia, 925
in rheumatoid arthritis, 1 024-1 025
Microcytosis, 921 f, 941 f
Microdeletion syndromes, 44
Microglia, 1106
Microlithiasis, alveolar, 613b
Micronutrients, 711-718
Microorganisms
culture, 106
detection of components, 1 06
detection of whole organisms, 1 05
host response, 1 05-1 09
MicroRNA (miRNA), 40
Microsatellite repeats, 43
Microscopy
bright field, 105
dark field, 105
electron, 105
epiluminescence, 1214
Microsomal ethanol-oxidising system
(MEOS) pathway, 881
Microsporidiosis, HIV-related, 317b
Microsporum audouinii, 1 240
Microsporum canis, 1240, 1240f
Micturating cystourethrography, reflux
nephropathy, 431 f
Micturition
cycle, 386
disorders of, benign prostatic
hyperplasia, 437
frequency of, 396
Mid-axillary line, 626-627
Midazolam, 1189f
Middle East respiratory syndrome
coronavirus (MERS-CoV), 249
Midges, filariases, 293
Miglitol, 747
Migraine, 1095-1096
pregnancy and, 1284
stroke risk in, 1095
in visual disturbance, 1 088
Migrainous neuralgia, 1096
Migrating motor complexes (MMC), 772
Miliary tuberculosis (TB), 588-589
Milk, cow’s, type 1 diabetes and, 729
Milk alkali syndrome, 716
Milk intolerance, 812
Millard-Gubler syndrome, 1072b
Miller Fisher syndrome, 1140
Miltefosine, 283
Milwaukee shoulder syndrome,
1017-1018
Mineralocorticoid receptor, 355
Mineralocorticoid receptor antagonists
for acute coronary syndrome, 501
for primary hyperaldosteronism, 675
Mineralocorticoid replacement, for
adrenal insufficiency, 673
Mineralocorticoids, 666, 666f
in adrenal insufficiency, 672
excess in, causes of, 674b
Minerals, storage of, liver and, 851
Mini-Mental State Examination (MMSE),
1181-1183
Minimal change nephropathy, 398-400,
398b-399b
Minimally conscious state, 21 1 , 212b
Minimum bactericidal concentration
(MBC), 109
Minimum inhibitory concentration (MIC),
109
Minocycline
for acne, 1 243
hyperpigmentation from, 1243, 1258b
for leprosy, 269
skin reactions, 1 266b
Minoxidil
alopecia, 1259
hypertension, 513
skin reactions, 1 266b
Mirizzi’s syndrome, 904-905
Misoprostol, 1003
Missense mutation, 42, 42f
Mites
house dust, 568, 570, 1215, 1245
typhus, 270
Mitochondria, 49, 50 f
Mitochondrial disorders, 49, 1144
Mitochondrial DNA, 1305
Mitochondrial inheritance, 49, 49b
Mitochondrial syndromes, 1144b
Mitomycin C, 436, 612b
Mitosis, phases of, 40
Mitotane, 669-670
Mitotic spindle poisons, 1 31 7f
Mitoxantrone, 936b
acute leukaemia, 957 b
Mitral regurgitation, 519-521, 519b,
520 f
clinical features of, 521b, 52 If
investigation of, 521b
management of, 521
Mitral stenosis, 517-519, 518b, 51 8f
investigations in, 51 87, 519b
chest X-ray for, 451 f
pregnancy and, 1282
Mitral valve
balloon valvuloplasty, 519, 519b, 51 9f
disease of, 517-521
endocarditis, 200f
prolapse, 520
pain, 177
repair, 521
replacement, 526-527
Mixed connective tissue disease
(MCTD), 1038
Mixed venous oxygen saturation, 198b
Mobilisation, of stroke patients, 1159b
Mobitz type I second-degree AV block,
477, 477 f
Mobitz type II second-degree AV block,
477, 477 f
Moclobemide, 1199b
Modafinil, 1105, 1110b
Modified Beighton score, for joint
hypermobility, 1059, 1059b
Modified Dukes classification, survival in
colorectal cancer and, 832 f
Mohs’ micrographic surgery, 1228
Molecular adsorbent recirculating
system (MARS), for pruritus,
primary biliary cholangitis and,
888
Molecular diagnostics, 348b
Molecular mimicry, 82
Moles, 1234-1235, 1235f
Mollaret’s syndrome, 1121
Molluscum contagiosum, 248 f, 343,
343 f, 1239, 1 239f
HIV disease and, 306f, 314b
Mometasone, 1226b
Monday fever, 614
Monge’s disease, 1 69
Monitoring
in critical care/critical illness, 175-176,
175b, 175 f
Monitoring drug therapy, 34-36
Monkeypox, 248-249
Monoamine oxidase inhibitors, 1199,
1199b
drug interactions, 24b
Monoarthritis
acute, 992-993, 993b
chronic inflammatory, 992
Monobactams, 120b, 121
Monoclonal antibody therapy
for allergy, 86
for asthma, 572
for haemolytic uraemic syndrome,
409
for high-grade NHL, 966
for low-grade NHL, 965
for osteoporosis, 1 048
Monoclonal gammopathy of uncertain
significance (MGUS), 966
Monoclonal immunoglobulin deposition
disease, multiple myeloma and,
410b
Monocytes, 64, 917, 926b, 926 f
count, 1362b
Monocytosis, 926b
Monofilament testing, 721b
Monoiodotyrosine (MIT), 635 f
Mononeuritis multiplex, 1140
Mononeuropathy
diabetic, 760
multifocal, 1140b
Monosodium urate monohydrate
crystals, 988 f, 1015
Monospot test, 242
Montelukast, asthma, 572
Montreal Cognitive Assessment (MoCA),
1181-1183, 1 1827
Mood, 1071
assessment of, in psychiatric
interview, 1181
Mood disorders, 1 1 98-1 200
bipolar, 1199-1200
organic, 1 1 85 b
Mood-stabilising drugs, 1190b
Moraxella catarrhalis, 103 f
INDEX • 1397
Morphine
adverse reactions of, 22 5
COPD, 577
intensive care, 2095
misuse, 1425
palliative care, 1351
pharmacogenetics, 205
renal colic, 432
renal or hepatic disease, 325
rout of administration, 305
Morphoea, 1262-1263
Morquio’s syndrome, 3715
Mortality ratios, standardised (SMRs),
214
Morton’s neuroma, 999
Mosaic warts, 1 238
Mosquitoes, 2315
filariasis, 290
malaria, 273-274
virus transmission of, 111
Motilin, 7725
Motility disorders, in vitamin B12
deficiency, 944
Motor cortex, 1 063f
Motor neuron disease, 11115,
1116-1117, 11175, 11177
Motor neurons
lower, 1068
upper, 1068-1069
Motor neuropathy, 5035
Motor system, 1068-1069, 10687
Mountain sickness
acute, 168
chronic, 169
Mouth
disease of, 790
of envenomed patient, 1527
examination of
cardiology, 4427
respiratory system, 5467
oral allergy syndrome, 812
ulcers
in Behget’s disease, 1043-1044,
10437
Mouth ulcers, for systemic lupus
erythematosus, 1036
Movement disorders, 1112-1115
involuntary movements, 1 069
see also names of specific disorders
Moxifloxacin, 1235
meningitis, 11205
MRCP (magnetic resonance
cholangiopancreatography), 776,
854-855
for cholangiocarcinoma, 8557
for choledocholithiasis, 906
for gallstones, 904-905, 9047
MRI (magnetic resonance imaging)
of aldosterone-producing adenoma,
674
for cancer, 1 323
for cardiovascular system, 452-453,
4537
of gastrointestinal tract, 774
for haemangiomas, 8937
for hepatobiliary disease, 854
for hepatocellular carcinoma, 891
for musculoskeletal disease, 989,
9895, 9897
for neurological disease, 1072, 10735
epilepsy, 11015
stroke, 1151, 1157-1158, 11585
viral encephalitis, 1 1 22
of osteonecrosis, 1055
for pain, 1342
pregnancy and, 1274
for renal disease, 389
for respiratory disease, 553
for sacroiliitis, 1029-1030, 10297
MRSA (meticillin-resistant
Staphylococcus aureus), 1 1 75
Mucociliary escalator, 5507
Mucocutaneous disease, HIV-related,
314-316, 3145
Mucopolysaccharidosis, 3715
Mucor spp., 303
Mucormycosis, 303, 598
Mucosa-associated lymphoid tissue
(MALT), 67
Mucosal leishmaniasis, 285
Mucous membranes
inflammatory arthritis in, 9945
as physical barrier, 62-63
Mucous patches, syphilis, 337
Multi-organ failure, causes of, 201
Multidisciplinary team, 13035, 1311,
1336
Multifocal encephalomyelitis, 11115
Multifocal neuropathy, 1140, 11405
Multimorbidity, 1306
Multinodular goitre, 648-649, 6487
Multiple endocrine neoplasia (MEN),
688-689, 6895
Multiple myeloma, 409, 4105, 966-968
classification of, 9675
clinical features and investigations of,
967, 9677
management of, 967-968
bisphosphonates for, 968
chemotherapy for, 968
immediate support for, 967-968
radiotherapy for, 968
prognosis of, 968
Multiple organ failure, 41 1
Multiple sclerosis, 1106-1 110
cerebrospinal fluid in, 1108
clinical features of, 1 1 06-1 1 08,
11085
investigation of, 1108, 11 087-1 1 097
Macdonald criteria for, 1 1 075
management of, 1 1 09-1 1 1 0
acute episode, 1109
disease-modifying treatments,
1109, 11095
symptoms, complications and
disability, 1109-1110, 11105
pathophysiology of, 1106,
11077-11087
in pregnancy, 11105
Multiple systems atrophy (MSA), 1114
Multivisceral transplantation, 710
complications of, 7105
Mumps, 240
clinical features of, 240, 2407
diagnosis of, 240
incubation period, 1115, 2325, 240
management and prevention of, 240
periods of infectivity, 1115
testicular swelling, 2167
Munchausen’s syndrome, 1206
Murmur
aortic regurgitation, 524, 5245,
5257
aortic stenosis, 522, 5225, 5227
atrial septal defect, 535, 5357
ausculatory evaluation, 4435
Austin Flint, 524
benign, 459, 4595-4605
cardiac, 4595, 4607
carditis, 515-516
Carey Coombs, 51 5-51 6
coarctation of aorta, 534
continuous, 461
diastolic, 460
Graham Steell, 526
mitral regurgitation, 520 , 5207, 5215
mitral stenosis, 518-519, 5187
persistent ductus arteriosus, 533
pulmonary regurgitation, 526
pulmonary stenosis, 526
systolic, 459-460, 4605
tetralogy of Fallot, 537
timing and pattern, 4607
tricuspid stenosis, 526
ventricular septal defect, 4605,
535-536
Murphy’s sign, cholecystitis and, 905
Muscle
biopsy, 992
in polymyositis and
dermatomyositis, 1039, 10407
contraction, 1068
of envenomed patient, 1527
pain, 1000, 10005
skeletal, 987-988
Muscle disease, 1143-1144
acquired, 1144, 1 1457
Muscle fibre, 4467
Muscle haematomas, in haemophilia A,
972
Muscle spindles, in control of breathing,
549
Muscle weakness/wasting, 1000, 10005
diabetes, 759
osteoarthritis, 1010
systemic sclerosis and, 1037
Muscular atrophy, spinal, 1117
Muscular dystrophies, 1143-1144,
11435
inheritance, 1143
transition medicine and, 1297
Musculoskeletal disease
anatomy and physiology of, 984-988,
9847
investigation of, 988-992
management of, 1000-1007, 10015
X-rays for, 988, 9885
bony metastases, 662
Charcot’s joint, 10587
chondrocalcinosis, 10167
CPPD crystal deposition disease,
1017
fracture, 994-995
osteoarthritis, 1 0097-1 01 1 7
osteomalacia, 1052, 10527
osteonecrosis, 1055
osteosarcoma, 1 056-1 057
reactive arthritis, 1 032
rheumatoid arthritis, 1 025
supraspinatus tendon calcification,
10177
Musculoskeletal system
anatomy and physiology of, 984-988,
9847
clinical examination of, 982-983, 9827
drug-induced effects on, 10575
presenting problems in, 992-1000
primary tumours of, 1 0565
Mushrooms
magic (hallucinogenic), 143, 1196
poisoning, 857
Mutation(s)
de novo, 47
domain negative, 45
frameshift, 42
gain-of-function, 45
loss-of-function, 44
missense, 42
nonsense, 42, 427
point, 42
simple tandem repeat, 43, 435
splice site, 437
tandem repeat, 43, 435
Myalgia
drug-induced, 10575
fever and, 2175
infections, 223
Myasthenia gravis, 11115, 1141-1143,
11425, 11427
diplopia, 1141
drug-induced, 10575
weakness, 1093
Myasthenic crisis, 1142-1143
Mycetoma, 301
intracavitary, 559
Mycobacteria, 100-101
opportunistic infection, 595, 5955
Mycobacterial infections, skin,
1237-1238
Mycobacterium abscessus, 580-581
Mycobacterium avium complex,
HIV-related
disseminated, 3155
prophylaxis for, 324
Mycobacterium chelonei, 5955
Mycobacterium fortuitum, 5955
Mycobacterium genavense, 5955
Mycobacterium haemophilum, 5955
Mycobacterium kansaii, 595, 5955
Mycobacterium leprae, 100, 106, 5955
Mycobacterium malmoense, 595, 5955
Mycobacterium marinum, 5955
Mycobacterium tuberculosis (MTB),
106, 588
Mycobacterium ulcerans, 254, 5955
Mycobacterium xenopi, 595, 5955
Mycology, 1215
Mycophenolate mofetil (MMF)
for autoimmune hepatitis, 886-887
liver transplantation and, 901
for musculoskeletal disease, 10045,
1005
for polymyositis and dermatomyositis,
1040
for systemic lupus erythematosus,
1036
Mycoplasma pneumoniae, 583
cold agglutination, 950
Mycoplasma spp., 121
Mycoses, superficial, 300
Mycosis fungoides (cutaneous T-cell
lymphoma), 1232
Myelin sheaths, 358, 1106
Myelinolysis, 358
Myelitis, transverse, 1110
Myeloablative conditioning, 937
Myelocytes, 917
Myelodysplasia, 124
Myelodysplastic syndromes (MDSs),
960-961, 9615
Myelofibrosis, 969
Myelography, spine, 996-997
Myeloma
AKI, 4125
multiple, 409, 4105, 966-968
Myelopathy, 11115
cervical, 1134-1135
HIV-related, 321
vacuolar, 321
Myeloperoxidase, 64
Myeloproliferative neoplasms, 969-970
Myelosuppression, drug-induced, 1330
Myiasis, 300
Myocardial contraction, 446, 4467
Myocardial infarction, 199-200, 1995
acute, 4935
diagnosis of, 493
electrocardiogram (ECG) for, 448
investigation of, 496
ECG, 496-497
management of
late, 498, 4985
in old age, 5005
pregnancy and, 1282
rehabilitation, 501
time course, 4957
Myocardial ischaemia
electrocardiogram (ECG) for, 448
myocardial infarction, 498
Myocardial stunning, 199-200
Myocarditis, 538, 5385
acute, 538
chronic, 538
fulminant, 538
Myocardium
disease of, 538-542
hibernating, 452
Myoclonic seizures, 1 099-1 1 00
Myoclonus, 1086
Myocytes, 446, 4467
Myofibrils, 987
Myoglobinuria, 3925
Myonecrosis, clostridial, 227
Myopathic gait, 1 087
Myopathy, critical illness, 212
Myophosphorylase deficiency
(McArdle’s disease), 11445
Myosin, 446, 987
Myositis
drug-induced, 10575
inclusion body, 1059
systemic sclerosis, 1 037
Myotonia, potassium-aggravated,
11455
Myotonia congenita, 1 1 455
Myotonic dystrophy, 1 1 435
genetics/inheritance, 435
Myotoxicity, 155
Myxoedema, Graves’ disease, 643
Myxoedema coma, 641
Myxoma, atrial, 541-542
N
N- Acetylcysteine therapy, for acute liver
failure, 858-859
NADH dehydrogenase, 495
1398 • INDEX
Nadolol
arrhythmias, 481
thyrotoxicosis, 637-638
variceal bleeding, 869
Naevi
blue, 1235
melanocytic, 1216, 1234-1235, 1235f
spider, 846f
autoimmune hepatitis and, 886
Nafcillin, 120b
Nails, 1214
abnormalities, 1224
in congenital disease, 1 261
disorders, 1260-1261
HIV-related, 316
inflammatory arthritis in, 994b
involvement in skin diseases,
1260-1261
normal variants of, 1 260
plate and bed, 1260f
in systemic disease, 1261, 1 261 f
trauma, 1260
Na,K-activated adenosine
triphosphatase (ATPase), 349
Nalidixic acid, 123b
skin reactions, 1266b
Naloxone
adverse reactions of, 23
drug interactions of, 24b
Naltrexone, for pruritus, primary biliary
cholangitis and, 888
Naproxen, 1003b
Narcolepsy, 1105, 1105b
Narcotics, cirrhosis and, 894b
Nasal cannulae, high-flow, 202
Nasogastric tube, 805b
Nasogastric tube feeding, 707, 707 b
Nasopharynx, disease of, 622
Natalizumab, 66, 1109b
Nateglinide, 747
National Institute for Health and Clinical
Excellence (NICE), 1 1
Natural killer cells, 67
Nausea and vomiting
palliative care and, 1353-1354,
1353f
pregnancy and, 1275, 1275b
Near-drowning, 169-170, 170f
Necator americanus, 288
Neck
Casal’s necklace, 714, 715 f
examination of
endocrine disease, 630f
neurological disease, 1062f
stiffness, 321
Neck pain, 997, 997 b
Necrobiosis lipoidica, 1 263, 1 263 f
Necrosis, 41, 1316-1317
Necrotising enteritis, 262
Necrotising fasciitis, 226-227, 227 f
Necrotising pancreatitis, 839
Necrotising scleritis, 1172
Necrotising soft tissue infections, 227 b
skin, 1238
Nefopam, 1002
Negative visual phenomena, 1171
Neisseria gonorrhoeae, 117b, 339
in pregnancy, 235 b, 332b
Neisseria spp., 103 f
Nelson’s syndrome, 669
Nematode infections, 233b
intestinal, 288-290
tissue-dwelling, 290-293, 290b
zoonotic, 293-294
Neoadjuvant chemotherapy, 1 330
Neomycin
allergy, 1247b
for vitamin B12 deficiency, 715
Neostigmine, 835
Nephelometry, 348b
Nephrectomy, 431 , 435
Nephritic syndrome, 392, 392b, 393f
Nephritis
crescentic, 398b-399b, 410
drug-induced, 427b
interstitial
acute, 402, 402b
chronic, 402-403, 403b
drug-induced, 427b
lupus, 392b
post-streptococcal, 401
Nephrocalcinosis, drug-induced, 427b,
431
Nephrogenic sclerosing fibrosis, 390b
Nephrology, 381-440
Nephron, 349-350, 350f, 384
segments of, 351 f
Nephronophthis, 404
Nephropathy
analgesic, 426
Balkan, 403
diabetic, 757-758
diagnosis and screening for, 757
management of, 757-758
natural history of, 757, 758 f
HIV-associated, 322
IgA, 398b-399b, 400
ischaemic, 406-407
membranous, 398b-399b, 401
minimal change, 398-400,
398b-399b
multiple myeloma and, 410b
pregnancy and, 1279
reflux, 430-431
salt-losing, 403
sickle-cell, 41 1
Nephrotic syndrome, 392b, 395, 395b
diseases typically presenting with,
398-400
Neprilysin inhibitors, for heart failure,
466-467
Nerve, disorder of, 1 089b
Nerve agents, organophosphorus
insecticides and, 145-146
Nerve biopsy, 1078
Nerve blocks
and nerve ablation, for pain, 1348
for pain, 1342-1343
Nerve conduction studies, 1076,
1076 f
for pain, 1342
Nerve entrapment, in lung cancer, 600
Nerve fibre, 1338
types of, 1338b
Nerve root decompression, 1002b
Nerve root lesions, 1 083
Nerve root pain, 997 b
Nervous impulse, 1065, 1065f
Nervous system
anatomy and physiology of,
1064-1072
functional, 1065-1071, 1065 f
cells of, 1064-1065, 1064f
clinical examination of, 1062-1064,
1062f
in old age, 1 079b
in gastrointestinal function, 771-772
Nervous system disease
cerebrovascular disease see specific
conditions
clinical examination of, 1062-1064,
1 062f
cranial nerves, 1063b
emergencies, 1064b
HIV-related, 319-321, 31 97
infections, 1 1 17-1 127, 1 1 18b
intracranial mass lesions/raised
intracranial pressure, 1127-1133,
1128b
investigation of, 1072-1078
lesion localisation in, 1071-1072
neuromuscular junction, 1141-1143
paraneoplastic, 1110-1111, 1111b,
1132
paraneoplastic syndromes,
1325-1326
peripheral nerves, 1 1 38-1 1 41 ,
1139b
presenting problems in, 1078-1094,
1 079b-1 080b
spine/spinal cord, 1134-1137
Neural tube defects, prevention with
folic acid, 712b, 945
Neuralgia
migrainous, 1096
post-herpetic, 239, 1080
trigeminal, 1080, 1096-1097
Neuralgic amyotrophy, 1141
Neuro-endocrine tumours (NETs), 603b,
678-679, 678 b, 679 f, 813
Neuro-inflammatory diseases,
1106-1110
Neuroacanthocytosis, 1 085b
Neurocognitive disorders, HIV-
associated, 319
Neurodegenerative diseases,
1111-1117
Neurodestructive interventions, for
cancer pain, 1352
Neurodevelopmental disorders, rare,
genomics in, 56
Neurofibroma, 1129b, 1 1 377
Neurofibromatosis, 613b, 1131-1132,
1131 f, 1132b, 1264
and cancer predisposition, 1321b
inheritance, 1131-1132
Neurogenic shock, description of, 206b
Neuroglycopenia, 739
Neuroimaging, 1072-1074, 1073b,
1151, 1151 f, 1157-1158
Neuroleptic malignant syndrome,
1197-1198
Neurological disease
in pregnancy, 1284
epilepsy as, 1284
idiopathic intracranial hypertension
as, 1284
migraine as, 1 284
stroke as, 1 284
rheumatological manifestations of,
1058, 1058 f
in systemic lupus erythematosus,
1035
transition medicine and, 1296-1297
cerebral palsy in, 1296
epilepsy in, 1296
muscular dystrophy in, 1297
Neurological support, in intensive care,
208
Neurology, 1061-1146
Neuroma
acoustic, 1131
Morton’s, 999
Neuromuscular junction, diseases of,
1141-1143
Neuromyelitis optica, 1110
Neuromyotonia, 1111b
Neuronectomy, multiple sclerosis,
1110b
Neuropathic pain, 1084, 1348, 1348b,
1348f
Neuropathy
ataxia and retinitis pigmentosa
(NARP), 1144b
autonomic, 760, 760 b
critical illness, 21 1
diabetic, 758-761
classification of, 759 b
clinical features of, 758-761
management of, 761, 761b
risk factors for, 757b
entrapment, 1139-1140, 1139b
hereditary, 1 1 40
leg ulcers due to, 1224
motor, 503 b, 1111b
multifocal, 1140, 1140b
peripheral, 1325
cancer-related, 1325
diabetic, 755, 756 b
drug-induced, 321
HIV-related, 321
leprosy, 268
in rheumatoid arthritis, 1 024
sensorimotor, 321
peripheral, cancer-related, 1325
sensory, 503b, 1111b
Neuropeptides, 1338-1339, 1340b
Neurosensory retina, 1 1 67
Neurosyphilis, 338, 1 1 25, 1 1 25 b
Neurotoxic flaccid paralysis, 155
Neurotoxins, hepatic encephalopathy
and, 865
Neurotransmission/neurotransmitters,
1065f
in pain processing, 1340b
Neutral variants, 44
Neutrons, 164, 164f
Neutropenia, 925
drug-induced, 926b
fever in, 224, 1327-1328
HIV-related, 322
Neutropenic fever, cancer and,
1327-1328
Neutrophil chemotactic factor, 75 b
Neutrophil extracellular trap (NET)
formation, 64
Neutrophil granulocytes, 1 362b
Neutrophilia, 926, 926b
asthma, 568-569
Neutrophilic dermatoses, 1 262
Neutrophils, 64, 917, 926 b, 926 f
asthma, 568-569
count, 1362b
toxic granulation, 64
Nevirapine, in pregnancy, 326-327
Newborn, haemolytic disease of, 933,
933 b
Next-generation sequencing (NGS),
52-53
capture, 53
challenges of, 53-54
methods of, 55b
uses of, 54-56
Niacin (vitamin B3), 714-715
biochemical assessment of, 712b
deficiency, 714, 715 f
dietary sources of, 711b
reference nutrient intake of, 711b
toxicity, 715
Nicardipine, angina, 491b
Nickel hypersensitivity, 83b, 1247b
Niclosamide, 129
Nicorandil, 790 b
Nicotinamide, for pellagra, 714
Nicotinamide adenine dinucleotide
(NAD), 881
Nicotinamide adenine dinucleotide
phosphate (NADPH)-oxidase
enzyme complex, 64
Nicotine replacement therapy, 4
Nicotinic acid, 377
Niemann -Pick disease, 371b
Nifedipine
altitude illness, 1 69
angina, 490-491, 491b
unstable, 500
for high-altitude pulmonary oedema,
169
hypertension, 513
and neutropenia, 926b
for oesophageal disorders, 795
older people, 32 b
Raynaud’s syndrome, 504-505
sphincter of Oddi dysfunction, 909
Nifurtimox, for trypanosomiasis, 128
Night blindness, 713
Night sweats, 217b
Night terrors, 1094
Nightmares, 1094
Nikolsky sign, 1254-1255
Nimodipine, for subarachnoid
haemorrhage, 1 1 62
Nipah virus encephalitis, 250
Nitazoxanide, 129
Nitrates
angina, 489-490
duration of action, 490b
heart failure, 467
for oesophageal disorders, 795
Nitric oxide (NO), 386, 447
anal fissure, 836
hepatopulmonary syndrome and, 898
Nitrites, 428
Nitrofurantoin, 124
and pulmonary eosinophilia,
61 lb-61 2b
urinary tract infection, 428, 429b
Nitrogen narcosis, 170
Nitroimidazoles, 124
mechanism of action, 116b
Nitroprusside reaction, 726
Nitrosamines, type 1 diabetes and, 729
‘Nits’, 1241
Nocardia, 587
pneumonia, 319
Nocardiosis, 261
INDEX • 1399
Nociceptive pain, 1084
Nocturia, 397
Nodal osteoarthritis, generalised, 1009,
1009b, 1 009f
Nodular lymphocyte-predominant HL,
961-962
Nodular regenerative hyperplasia, of the
liver, 899
Nodules
definition of, 121 If
pulmonary, 560-562, 5605-561 5,
560f-562f
cryptococcosis, 302
lung metastases, 1328
rheumatoid, 1023-1024, 1024f
skin, definition, 121 If
thyroid, 630f, 635
Non-alcoholic fatty liver disease
(NAFLD), 850, 882-885, 883f,
885f
biochemical tests for, 884, 8845
clinical features of, 884
imaging for, 884
investigations for, 884
liver biopsy for, 884
liver function test (LFT) abnormality in,
8545
management of, 884-885
pathophysiology of, 883
Non-alcoholic steatohepatitis (NASH),
882-883, 883f
Non-antivenom treatments, 1 59-1 60
Non-cardiac surgery, with heart disease,
501-502, 5015
Non-compliance, 30-31
Non-disjunction, 44
Non-epileptic attack disorder
(‘dissociative attacks’),
1103-1104
Non-freezing cold injury, 167
Non-Hodgkin lymphoma, 964-966,
965 f
clinical features of, 964, 965f
epidemiology of, 964, 9645
investigations of, 964-965
management of, 965-966
high-grade, 966
low-grade, 965
prognosis of, 966
Non-immune haemolytic anaemia, 950
Non-invasive prenatal diagnosis (NIPD),
56
Non-invasive prenatal testing (NIPT), 56
Non-invasive ventilation, for acute
exacerbations of COPD, 578
Non-metastatic extrapulmonary effects,
of lung cancer, 601
Non-necrotising scleritis, 1172
Non-nucleoside reverse transcriptase
inhibitors (NNRTIs), 3245
Non-opioid analgesics, for pain,
1345-1346
Non-specific interstitial pneumonia, 608
Non-specific urethritis (NSU), 333
Non-starch polysaccharides (NSPs;
dietary fibre), 697
Non-steroidal anti-inflammatory drugs
see NSAIDs
Non-thrombocytopenic purpura, 9285
Non-thyroidal illness, 642
Nonsense mutation, 42, 42 f
Noradrenaline (norepinephrine), for
refractory hypotension, 198,
1985
Noradrenaline (norepinephrine)
re-uptake inhibitors, 1 1 99,
11995
poisoning from, 139
Norfloxacin
for spontaneous bacterial peritonitis,
864
urinary tract infection, 428
Normal distribution/range, 3, 4 f
Normetadrenaline, 13615
Normoblasts, 915, 91 Qf
Normocytic anaemia, 925
Norovirus, 249
Nortriptyline, pharmacokinetics, 205
Norwalk agent, 249
Nosocomial (health care-acquired)
infections
Clostridium difficile, 21 1
MRSA, 111-112
pneumonia, 585
Notification
food poisoning, 262
partner, STIs, 333, 339
Novel therapies, for cystic fibrosis, 581
NSAIDs
adverse reactions of, 225
associated with small intestinal
toxicity, 81 1
for back pain, 997
in blood loss, 940-941
for cholecystitis, 905
cirrhosis and, 8945
for CPPD crystal deposition disease,
1017
for gout, 1015
hepatotoxicity of, 8945
for intermittent fever, 74
mechanism of action of, 1 003f
for musculoskeletal disease,
1002-1003
in old age, 1 0045
for osteoarthritis, 1012
for pain, 1345
for pancreatitis, 841
for peptic ulcer, 799
poisoning from, 138
for psoriatic arthritis, 1033-1034
for reactive arthritis, 1 032
recommendations for the use, 1 0035
renal disease and, 426
risk of, in gastrointestinal bleeding
and perforation, 10035
for systemic lupus erythematosus,
1036
topical, 1003-1004
ulcers induced by, risk factors for,
10035
Nuclear antigens, extractable,
antibodies to, 389
Nuclear factor kappa B (NFkB)
pathway, 64-66
Nucleic acid amplification test (NAAT),
1 06, 333
Nucleoside reverse transcriptase
inhibitors (NRTIs), 3245
Nucleosome, 38
Nucleotide substitutions, 42, 42 f
Numbness, 1083-1084
‘Nutcracker’ oesophagus, 795
Nutraceuticals, for osteoarthritis, 1012
Nutrients, energy-yielding
(macronutrients), 694-697
Nutrition, 694, 694f
for alcoholic liver disease, 882
alcoholic liver disease and, 880-881
artificial, 710-711
dementia and, 711, 71 If
in hospital patients, 706
in intensive care, 210
in lactation, 7125
parenteral, 707-708, 7085
physiology of, 694-697
in pregnancy, 7125
of stroke patients, 1 1 595
under-nutrition and, 704-711
Nutritional disorders, clinical examination
in, 692, 692 f
Nutritional factors, in disease, 691-718
Nutritional status, clinical assessment
and investigation of, 6935, 693f
Nutritional supplements, oral, 706
Nutritional support, artificial, ethical and
legal considerations in
management of, 710-71 1 , 7105
Nystagmus, 1069, 1090
balance disorders and, 1104f
gaze-evoked, 1090
Nystatin, 1255
candidiasis, 126, 790
O
Obesity, 94, 698-704
aetiology of, 699-700, 6995
body fat distribution in, 699
clinical assessment for, 6935
clinical features of, 700, 7005
complications of, 698-699, 698f
investigations of, 700
management of, 700-704, 701 f
drugs in, 702-703, 702f
lifestyle advice in, 701
surgery in, 702f-703f, 703-704,
7035
weight loss diets in, 701-702, 7015
in musculoskeletal disease,
1001-1002
non-alcoholic fatty liver disease and,
882-883
reversible causes of, 700
susceptibility to, 699-700
type 2 diabetes and, 732
Obesogenic environment, 6995
Obeticholic acid (OCA), for primary
biliary cholangitis, 888
Obidoxime, 146
Obinutuzumab, for chronic lymphocytic
leukaemia, 960
Obliterative cardiomyopathy, 541
Obsessive-compulsive disorder (OCD),
1201
Obstetric cholestasis, pregnancy and,
1284
Obstetric haemorrhage, circulatory
collapse and, 1275
Obstetrics, genomics and, 56
Obstructive pulmonary diseases,
567-581
asthma, 567-573
bronchiectasis, 578-579
chronic, 573-578
cystic fibrosis, 580-581
Obstructive shock, description of, 2065
Occipital lobes, 1066
disorders of, 1 0895
functions of, 1 0665
effects of damage, 1 0665
Occupational airway disease, 613-614
Occupational and environmental lung
d isease , 6 1 3—6 1 9
asbestos-related, 617-618
due to organic dusts, 616-617, 6165
occupational airway disease,
613-614
pneumoconiosis, 614-616, 6155
Occupational asthma, 613-614, 6145,
614 f
Occupational lung cancer, 61 8
Occupational pneumonia, 618-619
Occupational therapist, 13035
Occupational therapy
for musculoskeletal disease, 1001
rheumatoid arthritis, 1 026
for Parkinson’s disease, 1114
Ochrobactrum spp., 617
Octopus, blue-ringed, 1545
Octreotide
acromegaly, 686-687
gastrointestinal obstruction, 1354
scintigraphy, 679 f
short bowel syndrome, 7095
for Zollinger-Ellison syndrome, 802
Ocular abnormalities, 1 088-1 093
Ocular dysmetria, 1 090
Ocular imaging, 1 1 697
Ocular inflammation, 1171-1173
Ocular pain, 1080
Ocular ultrasound, for visual disorders,
1169
Oculomotor (3rd cranial) nerve
palsies, 11215, 11445
tests of, 1 0635
Oculopharyngeal dystrophy, 11435
Odds ratio, drug therapy, 28 f
Odynophagia, 316, 13245
Oedema, 395-396
ascites, 395-396
causes of, 3965
cerebral see Cerebral oedema
famine, 704
generalised, 282
legs, 395—396
mechanisms of, 1 865
nephrotic syndrome, 395-396, 3955
peripheral
differential diagnosis, 4635
heart failure, 4635
hypervolaemia, 354
pitting, 395
pregnancy and, 1275
pulmonary see Pulmonary oedema
Oesophageal candidiasis, in HIV/AIDS
patients, 316, 317 f
Oesophageal diseases, HIV-related,
3155, 316, 31 If
Oesophageal dysmotility, secondary
causes of, 795
Oesophageal motility, 778
Oesophageal transection, for variceal
bleeding, 871
Oesophageal variceal bleeding, 869
management of, 870 f
Oesophageal varices, 865-866, 865f
management of, 870 f
Oesophagitis, 792
eosinophilic, 794
herpes simplex, in HIV infection/AIDS,
316
reflux, 792, 792f
systemic sclerosis, 1037-1038
Oesophagus
Barrett’s, 792-793, 793 f
carcinoma and, 796
carcinoma of, 796-797
diseases of, 791-797
achalasia of, 794-795, 795 f
motility disorders, 794-796
reflux, 791-794
functional anatomy of, 766-767, 766 f
lower, adenocarcinoma of, 796 f
‘nutcracker’, 795
perforation of, 797
tumours of, 796-797
benign, 796
17(J-Oestradiol, 13595
Oestradiol, pregnancy and, 1272
Oestrogen
in bone remodelling, 9865
for delayed puberty, 654
hepatotoxicity, 8945
Oestrogen deficiency, 6545
Oestrogen receptors, as tumour
markers, 1322, 13245
Oestrogen replacement therapy
delayed puberty, 655
Turner’s syndrome, 660
Ofloxacin
leprosy, 2705
for PID, 336
for STIs, chlamydial infection, 3415
Ogilvie’s syndrome, 835
Ointments, 12255
Older people
acute illness, 1308, 13085
acute kidney injury in, 4145
adrenal glands, 6735
antimicrobial therapy in, 1205
blackouts, 1308
cancer in, 13255
comorbidities in, 1307
critical illness in, 212, 2135
delirium, 1309
demography of, 1304, 1304f
deprescribing in, 1310-1311
diabetes mellitus in, 7325
management of, 7575
dizziness, 1309
endoscopy in, 7765
energy balance in, 7105
epilepsy in, 11035
examination, 13035
falls, 1308-1309, 13085, 1308f
frailty, 1306, 13065
gait and balance, 1 3035
gastrointestinal disorders, acute
abdominal pain in, 7885
geriatric assessment, 1302, 1302f
gout in, 10145
haematological investigations in,
9235
history, 13035
hypernatraemia in, 3605
hyponatraemia in, 3605
1400 • INDEX
Older people (Continued)
incontinence, 436 b, 1309-1310,
1 31 Of
investigation , 1 306-1 307
Comprehensive Geriatric
Assessment, 1306
decisions on, 1306-1307
medical psychiatry in, 11896
neurological examination in, 10796
NSAIDs in, 10046
ophthalmological findings of, 11756
oral health in, 7916
osteoarthritis in, 10116
osteoporosis in, 10496
polypharmacy in, 13106
prescribing in, 1310-1311
presenting problems in, 1307-1311,
13116
rehabilitation, 1311-1312
renal replacement therapy in, 4226
respiratory disease in
infection, 5866
interstitial lung disease, 61 36
obstructive pulmonary disease,
5786
pleural disease, 6266
respiratory function in, 5506
urinary tract infection in, 4286
vitamin deficiency in, 7126
Oleander, poisoning from, 140
Olecranon bursitis, 9986, 1024f
Olfactory loss, 1 088
Olfactory (1st cranial) nerve, tests of,
10636
Oligoarthritis, 1027
asymmetrical inflammatory, 1032
Oligoclonal bands, 1077
Oligodendrocytes, 1 064-1 065
Oligodendroglioma, 11296
Oligopeptides, 768
Oliguria, 391
critically ill patients, 195
Olsalazine, for inflammatory bowel
disease, 8216
Omalizumab, for allergy, 86
Omeprazole
drug interactions of, 246
for H. pylori eradication, 800
Onchocerca volvulus, 292, 292 f
Onchocerciasis, 2336, 292-293
Oncogenes, 51
Oncogenesis, 1318 f
Oncology, 1313-1336
genomics and, 56-58
transition medicine and, 1298
Onychogryphosis, 1260
Onychomycosis, 1240
Oophoritis, mumps, 240
Open reading frame (ORF), 40
Ophthalmia neonatorum, 341
Ophthalmic disease, presenting
problems of, 1169-1171
Ophthalmology, 1164
medical, 1163-1178
Ophthalmopathy, Graves’, 645-646,
645f
examination of, 6316
Opiates/opioids
adverse reactions of, 226
for cholecystitis, 905
misuse of, 142, 1426, 1195
for osteoarthritis, 1 01 2
for pain, 1346-1347,
13466-13476
adverse effects of, 1351-1352,
13516
Opisthorchiasis, 2976
Opisthotonus, 1126
Opportunistic mycobacterial infection,
595, 5956
Opsoclonus-myoclonus, 11116
Opsonins, 63
complement fragments as, 66
Opsonisation, 63, 63 f
Optic atrophy, 1091-1093, 1092f
Optic chiasm, disorder of, 1 0896
Optic disc disorders, 1 0896
Optic disc swelling, of ophthalmic
disease, 1171
Optic (2nd cranial) nerve, tests of,
10636
Optic neuritis, 10896, 11116
multiple sclerosis, 11086
onchocerciasis, 293
swelling, 10926
and transverse myelitis (neuromyelitis
optica), 1110
Optic neuropathy, Leber hereditary,
1144
Optic tract, disorders of, 1 0896
Optical coherence tomography, 1 1 69
OptiMAL®, 276
Oral administration, 17
Oral allergy syndrome, 812
Oral androgen replacement therapy,
6566
Oral cancer, 790, 7906
Oral cavity, organisms in, 103f
Oral contraception/contraceptives
acne treatment, 1243
migraine and, 1095
skin reactions, 12666
venous thtombosis and, 9756,
11626
Oral contraceptive pill (OOP)
cystic fibrosis and, 1297
epilepsy and, 1296
porphyria and, 379
Oral diseases, HIV-related, 316
Oral glucocorticoids, for chronic
obstructive pulmonary disease
(COPD), 576-577
Oral glucose tolerance test (OGTT),
7266
Oral hairy leukoplakia, 316
Oral health, in old age, 7916
Oral rehydration solution (ORS), 2296
Oral ulcers, in Behget’s disease,
1043-1044, 1043f
Orbit, 1164
blood supply of, 1 1 68
imaging of, 1073-1074, 1074f
Orbital septum, 1164
Orchitis, mumps, 240
Orf, 1239
Organ donation, 90
after brain death, 213
after cardiac death, 213
altruistic living, 90
cadaveric, 90
Organelles, intracellular, 1 1 54f
Organic solvents, misuse of, 1 1 96
Organisms
detection of components of, 1 06
whole, detection of, 1 05
Organophosphate-induced delayed
polyneuropathy, 146
Organophosphorus compound,
145-146, 1456, 145 f
Oriental spotted fever, 2716
Orientation, assessment, 1181
Orlistat, for obesity, 702, 702 f
Ornidazole, 287
Oropharynx, examination
HIV disease, 306f
infectious disease, 216 f
Oroya fever, 272
Orphenadrine, for Parkinson’s disease,
1114
Orthopnoea, 557, 61 1
Orthoses, for musculoskeletal disease,
1001
Oscillopsia, 1090
Oseltamivir, 1196, 127
Osgood-Schlatter disease, 9996
Osmolality, 13606
presenting problems of, 356-360
Osmolarity, 13606
Osmotic agents, 14
Osmotic diuretics, for hypervolaemia,
355
Osteitis fibrosa cystica, 418-419
Osteoarthritis (OA), 1007-1012
clinical features of, 1 008-1 01 1 ,
10096
early-onset, 1011, 10116
epidemiology of, 1 007
erosive, 1011
generalised nodal, 1009, 10096,
1009f
hip, 1010, 101 Of
investigations for, 101 1
knee, 1009-1010, 101 Of
management of, 1011-1012
in older people, 10116
pathophysiology of, 1007-1008,
1008f
risk factors for, 1 0086
spine, 1011, 101 If
Osteoarthropathy, hypertrophic
pulmonary, 600-601
Osteoblasts, 984
in bone remodelling, 985f
Osteochondritis
dissecans, 998-999
of patella ligament, 9986
Osteoclasts, 984
in bone remodelling, 985f
Osteocytes, 985
Osteogenesis imperfecta (Ol),
1055-1056
transition medicine and, 1300
Osteoid, 985f
Osteoid osteoma, 1 0566
Osteomalacia, 1051-1 052
causes of, 1 0506
chronic kidney disease and,
418-419
clinical features of, 1 052
investigations in, 1052, 1052f
management of, 1 052
pathogenesis of, 1051-1052
tumour-induced, 1053
vitamin D-deficient, biochemical
abnormalities in, 9906
Osteomyelitis, 1021
Osteonecrosis, 1055
drug-induced, 10576
pain, 1055
Osteopenia
biliary cirrhosis, 888
fracture and, 994
hyperparathyroidism, 663
radiographic, 989-990
Osteopetrosis, 1056
Osteophytes, 988, 1134
Osteoporosis, 1 044-1 049
biochemical abnormalities in, 9906
clinical features of, 1 045
coeliac disease and, 807
fractures associated with, 1044,
1 045f
bone mineral density and, 1046f
glucocorticoid-induced, 1045
transition medicine and, 1300
idiopathic, 1044
investigations of, 1046, 10476, 1047f
management of, 1 046-1 049
non-pharmacological interventions for,
1047
in old age, 1 0496
pathophysiology of, 1044-1045,
1045f
pharmacological interventions for,
1047-1049, 10486
pregnancy-associated, 1045
risk factors for, 1 0466
secondary, 1044-1045
surgery for, 1 049
treatment of, 1 309
Osteoprotegerin, in bone remodelling,
9866
Osteosarcoma, 1 056-1 057
Osteosclerosis
osteoarthritis and, 1007, 101 If
Paget’s disease and, 1054
Osteotomy, 10026, 1012
Ostium primum defects, 534
Otitis media, 236, 2536, 266, 1119
Ovarian cancer, 1 334
investigations of, 1 334
management of, 1 334
pathogenesis of, 1334
Ovarian failure, chemotherapy-induced,
1298
Ovaries, polycystic, 658-659, 659f
Over-nutrition, responses to, 694-695
Overflow incontinence, 437, 1 093
in older people, 1310
Overnight dexamethasone suppression
test (ONDST), in Cushing’s
syndrome, 668
Ovulation, 656-657
Oxacillin, 1206
Oxalate, 13616
Oxazolidinones, 124
Oxcarbazepine, 11026
Oxidative killing, 64
Oxidative stress, 881 f, 883
Oximes, 146
Oximetry, 555-556
asthma, 573
Oxygen
arterial blood (Pa02), 13586
content and delivery of, in shock,
193, 1936
for gastrointestinal haemorrhage, 782
Oxygen dissociation curve, in
haemoglobin, 915-916, 91 7f
Oxygen saturation, 13586
Oxygen therapy
for acute exacerbations of COPD,
577
for air passengers, 1 69
for chronic obstructive pulmonary
disease (COPD), 577, 5776
for community-acquired pneumonia,
583
for critical illness, 191, 1916
for diving-related illness, 171
for high-altitude pulmonary oedema,
169
Oxyhaemoglobin dissociation curve,
190, 1 91 f
Oxytetracycline, acne, 1243
P
P gene, 1 258
Pabrinex, 1 1 95
Pachyonychia congenita, 1 261
Pacing
AV block, 482, 483f
dual-chamber, 714
tachyarrhythmias, 469
transcutaneous, 482-483
Packed cell volume (PCV), 13626
Paclitaxel, 1334
Paediatric disease, in systemic lupus
erythematosus, 1036
Paediatric health services, transition to
adult health services from,
1288-1290
Paget’s disease
biochemical abnormalities in, 9906
of bone, 1053-1054
clinical features of, 1054
investigations in, 1054, 1054f
management of, 1054, 10546
pathophysiology of, 1053-1054
Pain, 1070, 1338-1349
abdominal, 787-789
acute, 787-789, 7876
acute pancreatitis, 837-839, 8376
assessment of, 787, 788 f
chronic or recurrent, 789, 7896
chronic pancreatitis, 839-841
constant, 789
diabetic ketoacidosis and, 736,
7366
investigations of, 787
irritable bowel syndrome and, 824
large bowel obstruction of, 789
liver abscess and, 880
in lower abdomen, 336
management of, 787-789
in old age, 7886
peptic ulcer, perforated, 789
ankle, 999
back, 995-997
red flags for, 9966
triage assessment of, 996f
biliary, gallstones and, 904
biopsychosocial model of, 1 338f
in cancer, 1 350, 1 3506
central processing of, 1339-1340
challenges in, 13446
INDEX • 1401
chest, 176-179, 454-455
associated features of, 1 77-1 78,
1787
characteristics of, 1 77
clinical assessment of, 178
differential diagnosis of, 1 77 b
investigations of, 178-179, 179b
ischaemic, 4547
onset of, 1 77
pregnancy and, 1275
in respiratory disease, 558
site and radiation of, 1 77
elbow, 998, 998b
facial, 1080
foot, 999
functional anatomy and physiology of,
1338-1341
hand, 998
in headache, 1080
hip, 998, 999 b, 999 7
osteoarthritis and, 1010
instruments for assessment of,
1343b
interventions for, 1344-1348
complementary and alternative
therapies for, 1 348
nerve blocks and nerve ablation in,
1348
pharmacological therapies in,
1344-1347, 1 345b-1 347b
physical therapies in, 1344, 1344b
psychological therapies in, 1347
stimulation therapies in, 1347,
13477
supported self-management in,
1344
investigations of, 1 342-1 343
knee, 998-999, 999b
loin, 396
low back
assessment of, 988-989
causes of, 996b
mechanical, features of, 996b
radicular, 997 b
muscle, 1000, 1000b
musculoskeletal, regional, 997-999
neck, 997, 997 b
neuropathic, 1084, 1348, 1348b,
13487
ocular, 1080
of ophthalmic disease, 1 1 70
osteoarthritis and, 1007-1008
hip, 1010
knee, 1009-1010
palliative care for, 1349-1354, 13497
perception of, 1 3387
principles of management of, 1 343
radicular, 997b
shoulder, 997-998, 998b, 9987
somatoform disorder, 1 202
wrist, 998
Pain relief, for pancreatitis, 841
Pain scoring system, 1343
Painful vaso-occlusive crisis, 952
Palliation, for cancer, 1330
Palliative care, 1349-1354, 13497
for chronic obstructive pulmonary
disease (COPD), 577
presenting problems of, 1350-1354
anxiety and depression in, 1354
cough in, 1353
dehydration in, 1354
delirium and agitation in, 1354
gastrointestinal obstruction in,
1354
nausea and vomiting in,
1353-1354, 13537
weight loss in, 1354
Palliative chemotherapy, 1329
Palmar erythema, 6307, 635-636, 8467,
866-867
Palmoplantar pustulosis, 1 249
Palpable mass, cancer and, 1323
Palpable purpura, 1042, 10427
Palpation
of abdomen, 765 b
of precordium, 443b
in respiratory system, examination of,
5467
Palpitation, 455-456, 455b, 4567
Pamidronate
bone metastases, 1 329
hypercalcaemia, 1329
for Paget’s disease, 1054, 1054b
Pancoast’s syndrome, 600
Pancolitis, 815-816
Pancreas, 770, 7707
annular, 842
artificial, 751, 7517
carcinoma of, 8437
congenital abnormalities affecting,
842
diseases of, 837-844
divisum, 842
endocrine, 676-679
pre-diabetic, 728
structure and endocrine function of,
7237
tumours of, 842-844
Pancreatic cancer, 8437
Pancreatic p-cell failure, in type 2
diabetes, 731
Pancreatic disease, 733
Pancreatic enzymes, 770 b
Pancreatic necrosis, 8397
Pancreatic pseudocyst, 8387
‘Pancreatic rests’, 805
Pancreatitis
acute, 837-839, 837 b
causes of, 838b
complications of, 838b
management of, 839
pathophysiology of, 837, 8387
autoimmune, 841
chronic, 839-841 , 840b
complications of, 840b
investigations of, 840, 841b, 8417
management of complications of,
841
pathophysiology of, 8407
hereditary, 840b, 842
necrotising, 839
Pancreolauryl test, 777 b
Pancytopenia, 930, 930b
Panic disorder, 1 200
Pannus, 1022-1023
Panton-Valentine leukocidin, 586, 1237
Papilla of Vater, 861
Papillary carcinoma, 649
Papillary muscle rupture, in acute
coronary syndrome, 496
Papillary necrosis, 403
Papillary renal cell cancer syndrome,
1321b
Papilloedema, 1090-1091, 1092b,
10927
haemorrhagic, 10627
Papilloma, basal cell, 1234, 12347
Papillomaviruses, 1238-1239
Papular pruritic eruption, HIV-related,
316
Papule, definition of, 12117
Papulosquamous eruptions, 1 251
Para-aminosalicylic acid (PAS), skin
reactions, 1266b
Parabens, 1247b
Paracentesis, for ascites, 863-864
Paracetamol
adverse reactions, 22 b
for chronic pain, 1345b
for fever, 218
for headache, 1 096
hepatoxicity of, 857, 8577
for musculoskeletal disease, 1 002
osteoarthritis, 1012
for pain, 1345
poisoning, 134b
poisoning from, 137-138, 1387
acute liver disease and, 857-858,
858 b
Paracoccidioides brasiliensis, 304
Paracoccidioidomycosis, 304
Paraesthesia, 1 083-1 084
Paraganglioma, 675-676
Paragonimiasis, 233-234
Paragonimus spp., 129
Paragonimus westermani, 233 b
Parainfluenza viruses, 249
Paraldehyde
disturbed behaviour, 11897
poisoning, 135b
Paralysis, ventilator-induced lung injury
and, 204
Paralysis ticks, envenomation of, 1 61
Paralytic ileus, 837-838
Paralytic shellfish poisoning, 149
Paramyotonia congenita, 1145b
Paraneoplastic disease, neurological,
1110-1111, 1111b
Paraneoplastic syndromes, neurological,
1325-1326
Paraparesis, 1086-1087
Paraphasia, 1088
Paraphenylenediamine, 1 247b
Paraplegia, hereditary spastic, 1138b
Parapneumonic effusion, 564
Paraproteinaemias, 966-968
Paraproteins, 965-966
Paraquat, poisoning from, 147
Parasitic infections
and cancer, 1320b
eosinophilia, 233b
Parasitosis, delusional, 1202
Parasomnias, 1105-1106
non-REM, 1105
Parathyroid disease, pregnancy in,
1280
familial hypocalciuric hypercalcaemia
as, 1280
primary hyperparathyroidism as, 1 280
Parathyroid glands, 661-665
disease of
classification of, 661b
presenting problems in, 661-663
familial hypocalciuric hypercalcaemia
and, 664
functional anatomy, physiology and
investigations of, 661
hypoparathyroidism and, 664-665
in old age, 665b
primary hyperparathyroidism and,
663-664, 663b, 6647
Parathyroid hormone (PTH), 661
acute kidney injury and, 416b
in bone remodelling, 986b
osteomalacia and rickets, 1051-1052
osteoporosis, 1047b
reference range of, 1 359b
in skeletal disease, 990b
Parathyroid hormone-related protein
(PTHrP), ectopic production,
1325b
Parathyroidectomy, 419
Paratyphoid fever, 260
Parenchymal bacterial infections,
1124-1125
Parenchymal viral infections, 1121-1123
Parenteral administration, 17
Parenteral nutrition, 707-708, 708 b
Parietal lobes, 1 066
disorders of, 1 089b
functions of, 1 066b
effects of damage, 1 066b
Parinaud syndrome, 1072b
Parkinsonian syndromes, 1114-1115
Parkinsonism, 1084-1085, 1085b, 1112
drug-induced, 1112b
Parkinson’s disease, idiopathic,
1112-1114
causes of, 111 2b
clinical features of, 111 2-1 1 1 3,
1113b
non-motor symptoms of,
1112-1113
investigations of, 1113, 1 1 1 37
management of, 1113-1114
drug therapy, 1113-1114
surgery, 1114
pathophysiology of, 1112, 1 1 1 27
Paromomycin, 129
for leishmaniasis, 283
Parotitis, 790, 790 b
Paroxysmal atrial fibrillation, 471-472
Paroxysmal cold haemoglobinuria, 950
Paroxysmal nocturnal haemoglobinuria
(PNH), 950-951
Partial agonists, 14
Partial anterior circulation syndrome
(PACS), 11567
Partial thromboplastin time with kaolin
(PTTK), 920-921
Parvovirus B19 infection, 237
clinical features of, 237, 237 b, 2377
diagnosis of, 237
management of, 237
in pregnancy, 235b
Past-pointing, 1069
Pastes, 1225b
Pastia’s sign, 252, 2537
Patau’s syndrome (trisomy 13), 44b
Patch testing, for skin disease, 1215
Patella ligament enthesopathy, 999b
Paterson-Kelly syndrome, 795-796
Pathergy test, 1 044
Pathogen -associated molecular patterns
(PAMPs), 63
‘Pathogenicity,’ in host-pathogen
interactions, 104
Pathogens
direct detection of, 1 05-1 06
host-pathogen interactions, 104
indirect detection of, 106-109
successful, 104
Pathological fracture, 995b
Pathway medicine, for genetic disease,
58
Patient-centred evidence- based
medicine, 10, 117, 12
Patient factors, of gastro-oesophageal
reflux disease, 791
Patients, autonomy, 1288-1289
Pattern recognition receptors (PRRs),
63
Paul-Bunnell test, 242
PCSK9 inhibitors, 377
Peak expiratory flow (PEF)
asthma, 5697, 5737
home monitoring, 555
morning dipping, 5697
Peak flow meters, 555, 569
Peanut allergy, 85
PECAM-1 , 447
Pectins, 696b
Pectus carinatum, 628
Pectus excavatum, 628
Pediculus humanus, 257
Pediculus humanus capitis, 1241
Pedigree, construction of, 46, 467
Pegloticase, for gout, 1016
Pegvisomant, 686-687
Pellagra, 714, 7157, 1221b
Pelvi- ureteric junction obstruction
(PUJO), 434
Pelvic floor exercises, faecal
incontinence, 835
Pelvic inflammatory disease (PID), 336
Pemphigoid, bullous, 1255-1256,
1255b, 12567
Pemphigoid gestationis, 1 220 b,
1255b
Pemphigus, 1256, 1326
Pemphigus foliaceus, 1255b
Pemphigus vulgaris, 1255b
Penciclovir, as anti-herpesvirus agent,
126, 127b
Pendred’s syndrome, 6357, 650
Pendrin, 6357
Penetrance, genetic, 47
Penicillamine
for musculoskeletal disease, 1004b,
1005
nephrotoxicity, 427b
for oral ulceration, 790 b
for primary biliary cholangitis, 888
for pyridoxine deficiency, 715
for Wilson’s disease, 897
Penicillin(s), 117b, 121
adverse reactions, 21, 22 b
allergy, 75 b
anthrax, 267
diphtheria, 266
endocarditis, 528
leptospirosis, 258-259
listeriosis, 260
meningitis, 1120
nephrotoxicity, 427 b
1402 • INDEX
Penicillin(s) (Continued)
for neurosyphilis, 1 1 25
penicillinase-resistant, 121
in pregnancy, 1206
prophylactic, 78, 1196
resistance, 116
rheumatic fever, 517
syphilis, 337
for syphilis, 339
tetanus, 11266
tropical ulcer, 254
urinary tract infection, 428
Penicillium marneffei infection, 303
Penile erection, 440
Penis, 386
Pentamidine, prophylactic, 1 1 96
Pentamidine isethionate
for leishmaniasis, 283
for Pneumocystis jirovecii pneumonia,
128
Pentasa, for inflammatory bowel
disease, 8216
Pentavalent antimonials, 128, 283
Pentoxifylline
for alcoholic hepatitis, 882
for frostbite, 1 66-1 67
Pepsinogen, 767
Peptic ulcer
complications of, 801-802
indications for, 8006
in old age, 8016
perforation, 789, 801
prophylaxis for, in intensive care,
211
Zollinger-Ellison syndrome, 802
Peptic ulcer disease, 798-802
Peptide YY, 7726
Peptides, antimicrobial, 62-63
Peptostreptococcus spp., 2536
Perceptions
abnormal, 1086, 1181
delusional, 1196-1197
Percussion
abdomen, 7656
in respiratory system, examination of,
546f
Percutaneous coronary intervention
(PCI)
angina, 491-493, 491f-492f
myocardial infarction, 4936
vs. CABG, 4936
Percutaneous endoscopic gastrostomy
(PEG), 707, 708 f
Percutaneous therapy, for hepatocellular
carcinoma, 891
Percutaneous transhepatic
cholangiography (PTC),
854-855
Perforating dermatosis, acquired
reactive, 1265
Perforin, 67
Perfusion, in respiratory system,
549-550
Perianal disease, inflammatory bowel
disease and, 823
Pericardial disease, in tuberculosis (TB),
590
Pericardial effusion, 5426, 543, 543f,
13156
Pericarditis
acute, 542, 5426, 542 f
in acute coronary syndrome, 496
chronic constrictive, 543-544, 5436,
544f
tuberculous, 543
Pericardium, diseases of, 542-544
Perimetry, 1168
Perimysium, 987-988
Periodic fever syndromes, 81 , 1059
Periodic limb movements, and sleep,
1106
Periodic paralysis
hyperkalaemic, 1 1 456
hypokalaemic, 1 1 456
Periostitis, 337, 600-601
Peripartum cardiomyopathy, pregnancy
and, 1282
Peripheral arterial disease, 502-505,
5026
Peripheral nerves, 1338
disease of, 1138-1141, 11396
HIV-related, 321
endings, 1338
lesions, 1083
Peripheral nervous system
motor, 1068
sensory, 1068
Peripheral neuropathy, 1325
cancer-related, 1325
diabetic, 755, 7566
drug-induced, 321
HIV-related, 321
leprosy, 268
in rheumatoid arthritis, 1 024
sensorimotor, 321
Peripheral sensitisation, 1340, 1 341 f
Peripheral ulcerative keratitis,
1171-1172
Peripheral vascular disease, in diabetes,
5036
Perisinusoidal fibrosis, 884
Peristalsis, 772
Peritoneal cavity, disease of,
836-837
Peritoneal dialysis, 424
automated, 424
continuous ambulatory, 424
haemodialysis vs., 4206
problems with, 4256
Peritonitis, 836
spontaneous bacterial, 864
Permanent pacemakers, for
arrhythmias, 483, 4836
Pernicious anaemia, 944
Persistent atrial fibrillation, 472-473
Persistent ductus arteriosus, 532/-533f,
533-534
Personality, 1071
change, 1094
high-risk behaviour and, 1295
psychiatric disorders and, 1183
Personality disorders, 1 204-1 205
prevalence of, 1 1 806
Pes cavus, 1 1 40
Pesticides, 144-149
Petechiae, definition of, 121 If
Petechial purpura, 928-929, 928 f
Petit mal, 1097
Pets
allergic rhinitis and, 622
asthma and, 568
HIV infection/AIDS and, 323
Peutz-Jeghers syndrome, 829, 829f
Peyer’s patches, 67, 769-770
Phaeochromocytoma, 675-676, 6756,
676 f
Phaeohyphomycoses, 301
Phagocytes, 63-64, 63 f
deficiency in, 736
primary, 77-78, 77 f
Phagocytosis, 63, 63f
Phagolysosome, 64
Phantom limb pain, 1349
Pharmacist, 216
Pharmacodynamics, 14-16, 14f
dose-response relationship in, 14-16,
15 f
drug targets in, 14, 156
mechanisms of action of, 1 4
Pharmacogenomics, for genetic
disease, 58
Pharmacokinetics, 17-19, 17f
absorption in, 17-18
distribution in, 18
elimination in, 18-19
patient-specific factors in, 206
repeated dose regimens in, 19
Pharmacological therapies, for pain,
1344-1347, 13456
Pharmacovigilance, 23, 236
Pharmacy, 27
Pharyngeal pouch, 794
Phenelzine, 11996
Phenobarbital
epilepsy, 11026
in old age, 326
poisoning, 1366
status epilepticus, 10816
Phenothiazines, for schizophrenia,
11986
Phenoxymethylpenicillin, 1206
prophylactic, 1 1 96
Phentermine, for obesity, 702-703
Phenylketonuria, 369
Phenytoin
ataxia, 11156
drug interactions, 246
epilepsy, 11026
multiple sclerosis, 11106
pharmacokinetics of, 19
plasma concentration, 366
poisoning, 1416
renal or hepatic disease, 326
sodium content of, 8646
status epilepticus, 10816
Phobia, 1200
Phobic anxiety disorder, 1 200
Phosphate
acute kidney injury and, 4166
in diabetic ketoacidosis, 738
enema, 8696
homeostasis, 368-369
reference range of
urine, 13616
venous blood, 13606
in skeletal disease, 9906
Phosphenes, 1088
Phosphodiesterase type 5 inhibitors,
erectile dysfunction, 440
Phospholipids, 126, 370
Phosphorus, 716
deficiency, 716
dietary sources of, 7176
excess, 716
reference nutrient intake of, 7176
Photo-exposed site hyperpigmentation,
1258
Photoallergy, 12216
Photochemotherapy, 1 227
Photodynamic therapy (PDT)
for oral cancer, 790
for skin disease, 1 228
Photophobia/glare, of ophthalmic
disease, 1170
Photopsia, of ophthalmic disease, 1170
Photosensitivity, 1220-1223, 12216
clinical assessment of, 1221
drug-induced, 12666
investigations and management of,
1221-1223
Phototesting, for skin disease, 1215
Phototherapy, 1227
Phototoxicity, 12216
Physical activity, energy expenditure
and, 694, 695f
Physical therapies
for musculoskeletal disease, 1001
rheumatoid arthritis, 1 026
for pain, 1344, 13446
Physiological anaemia of pregnancy,
1273
Physiological breathlessness, of
pregnancy, 1274-1275
Physiotherapy
for bronchiectasis, 579
for cancer pain, 1352
for cervical spondylosis, 1 1 34
for community-acquired pneumonia,
584
for fracture, 995
for Parkinson’s disease, 1114
for stroke, 1159f
Phytoestrogens, 716
Pick’s disease, 1 1 93-1 1 94
Pigment stones, 903-904, 9036
Pigmentation
drug-induced, 1258, 12586, 12666
endocrine, 1258
Pigmented villonodular synovitis, 1 059
Pinta, 254, 2546
Piperacillin, 1206
for spontaneous bacterial peritonitis,
864
for variceal bleeding, 869
Piperacillin-tazobactam, 1176
for necrotising fasciitis, 227
for neutropenic fever, 224
Piperazine, 129
Piroxicam, 10036
Pitted keratolysis, 1 238
Pituitary disease
investigation of patients with, 680,
6806
pregnancy and, 1280
diabetes insipidus as, 1280
prolactinoma as, 1 280
Sheehan’s syndrome as, 1280
Pituitary hormones, 632
Pituitary tumours, 683-684, 1129
Pityriasis lichenoides chronica, 1251
Pityriasis rosea, 12176, 1251
Pityriasis versicolor, 1 240
rash in, 12176
Placental alkaline phosphatase (PU\P),
as tumour markers, 1322, 13246
Plague, 259, 259 f
Plain chest X-ray
for gastrointestinal disease, 772, 773 f
contrast studies of, 773
normal, 551 f
for respiratory disease, 551 , 5516,
551 f
abnormalities, 5526
aspergillosis, 597 f
asthma, 569
bronchiectasis, 579
COPD, 575
empyema, 564f
haemoptysis, 560
interstitial, 605, 605f
lobar collapse, 552 f
lung cancer, 599, 599f
mediastinal tumours, 604, 604f
pleural effusion, 563
pleural plaques, 61 77
pneumonia, 585
pneumothorax, 626
pulmonary embolism, 619-620,
6196, 619 f
pulmonary hypertension, 622f
sarcoidosis, 6096
silicosis, 61 5f
tuberculosis, 590f
Plane warts, 1 238
Plant poisoning, 150, 1506
Plantar warts, 1 238
Plaques
amyloid in, 1192
definition of, 121 If
Plasma derivatives, 930
Plasma exchange (PE)
for Guillain-Barre syndrome, 1140
pre-renal transplant, 424
Plasma iron, 942
Plasma viscosity, inflammation and, 72
Plasmapheresis, for pruritus, primary
biliary cholangitis and, 888
Plasmodium falciparum infection, 274f,
275, 2766
Plasmodium falciparum malaria, 950
Plasmodium knowlesi infection, 276
Plasmodium malariae infection, 276
Plasmodium ovale infection, 275
Plasmodium vivax infection, 275
Platelet-derived growth factor (PDGF),
1317
Platelet-endothelial cell adhesion
molecule type 1 (PECAM-1), 447
Platelet function disorders, 970-971
Platelets, 91 8, 920 f
concentrate, 9316
count
in coagulation screening tests,
9226
high, 929-930
low, 929
function, assessing, 921
reference range of, 1 3626
Plethysmography (Sp02), 1756
Pleural disease, 625-627
Pleural effusion, 562-565, 1329, 13296
cardiac failure in, 5636
causes of, 5636
clinical assessment of, 563
investigations of, 563-564
large right, 547 f
INDEX • 1403
malignant, 563fc)
management of, 564
obstruction of thoracic duct in, 563b
oedema, 395-396
pancreatitis in, 563b
pulmonary infarction in, 563b
rheumatoid disease in, 563b,
610-611
in systemic lupus erythematosus,
1035
systemic lupus erythematosus in,
563 b
tuberculosis in, 563b, 589f-590f
Pleural pain
in community-acquired pneumonia,
treatment of, 584
in lung cancer, 600
Pleural plaques, 617-618, 617 f
Pleural rub, 457-459
Plexopathy, 1 1 38
brachial, 1141
lumbosacral, 1141
Plumboporphyria, 379 b
Plummer-Vinson syndrome, 795-796
Pluripotent stem cells, induced, for
genetic disease, 58
Pneumatosis cystoides intestinalis, 837
Pneumococcal infection, 266
Pneumoconiosis, 614-616, 615b
Pneumocystis jirovecii infection, after
HSCT, 937b
Pneumocystis jirovecii pneumonia,
HIV-related, 315b, 318, 318b,
31 87
Pneumocytes, 548-549
Pneumonia, 582-587
bacterial, HIV-related, 319 f
community-acquired, 582-585, 582 f
clinical features of, 582-583
discharge and follow-up of, 585
investigations of, 583, 584b
management of, 583-584
organisms causing, 582 b
prognosis for, 585
complications of, 585b
differential diagnosis of, 583b
factors predispose to, 582b
hospital-acquired, 585-586, 585b
in immunocompromised patient, 587
necrotising, 104b
occupational, 618-619
pregnancy and, 1277
causes of, 1 277 b
viral, 1277
right middle lobe, 547f, 584/
suppurative pneumonia, aspiration
pneumonia and pulmonary
abscess, 586-587
Pneumonic plague, 259
Pneumothorax, 547f, 625-627, 625 f
age distribution of, 625 f
air travel after, 1 69
classification of, 625 b
clinical features of, 626
investigations of, 626
management of, 626-627, 627 f
spontaneous
recurrent, 627
types of, 626f
tension, 566
Podocytes, 384
Podophyllotoxin, 343
Point mutations, 42
Point-of-care testing (POCT), 348
Poiseuille’s Law, 447
Poisoning, 131-150
acute, 134
assessment and investigation for,
134-135, 135b
from chemicals and pesticides,
144-149
chemicals less commonly taken in,
148, 148b
clinical signs of, 133f
decontamination and enhanced
elimination for, 1 337
drugs of misuse and, 141-144
environmental, 149
evaluation for, 132-134, 132b, 132f
food-related, 149-150
management of, 1 35-1 37
antidotes for, 137, 137b
gastrointestinal decontamination
for, 135-136, 136b
haemodialysis and haemoperfusion
for, 136, 136b
lipid emulsion therapy for, 1 36-1 37
supportive care for, 137, 137b
urinary alkali nisation for, 136
in old age, 1 34b
by pharmaceutical agents, 137-141
less commonly taken in, 141 ,
141b
plant, 150, 150b
poisoned patient, general approach
to, 134-137
psychiatric assessment for, 1 35
substances involved in, 134b
substances of very low toxicity and,
134b
triage and resuscitation, 134
Poliomyelitis, 1 1 23, 1 1 23 f
immunisation for, 1 1 23
incubation period of, 1 1 23
Pollution, atmospheric, 94
PolyA tail, 39 f, 40
Polyadenylation signal, 38
Polyarteritis nodosa, 1 042
Polyarthritis, 993-994, 993b,
1020-1021
inflammatory arthritis and,
extra-articular features of, 994b
joint involvement in, 994f
symmetrical, 1032
Polycystic ovarian syndrome, 658-659,
659 f
features of, 658b
hirsutism and, 658 b, 659
Polycythaemia, 384-386, 925
Polycythaemia rubra vera (PRV), 925,
970
Polydipsia, 357, 634b
Polyenes, 126
Polyethylene glycol, 842
Polymerase chain reaction (PCR), 106
for genetic diseases, 52, 53 f
for hepatitis B, 873
for herpes simplex virus, 333, 1077
for Whipple’s disease, 809
Polymorphic eruption of pregnancy,
1220b
Polymorphic light eruption, 1221b
Polymorphisms, 45
single nucleotide, 45
Polymorphonuclear cells, 1 1 22
Polymorphonuclear leucocytes, 64
Polymyalgia rheumatica (PMR),
1042-1043
mimic, 1042b
Polymyositis (PM) see Dermatomyositis/
polymyositis
Polymyxins, 123
Polyneuropathy, 1139b
chronic, 1140-1141
critical illness, 211-212
Polyostotic fibrous dysplasia, 1 055
Polypeptides, 768
Polyposis syndromes, 827-829, 827 b
juvenile, 829
Polyps, 827-829, 827 b
Polyuria, 396-397, 396 b, 634b
Pompe’s disease, 1 1 44b
Pompholyx, 1247
Popliteal cyst, 998b-999b
Population health, 91-98
Porphyria cutanea tarda (PCT), 379b,
1257, 1263-1264, 1264f
Porphyrias, 378-380, 1221b,
1263-1264
acute intermittent, 379 b
congenital erythropoietic, 379 b
cutaneous, 1263-1264
erythropoietic protoporphyria, 379 b
hepatic, exacerbation of, 1 266b
hereditary coproporphyria, 379b
plumboporphyria, 379 b
variegate, 379 b
‘Portal’ circulation, 384, 385f
Portal hypertension, 868-871, 898
ascites and, 869
cirrhosis and, 868
classification of, 868f
clinical features of, 868-869
complications of, 868b
extrahepatic portal vein obstruction,
868
investigations for, 869
management of, 869-871
pathophysiology of, 869
Portal vein thrombosis, 898
Portal venous disease, 898
Portal venous pressure,
pharmacological reduction of,
870
Portopulmonary hypertension, 898
Portosystemic shunt
fetor hepaticus from, 868
portal hypertension and, 869
for variceal bleeding, 871
Posaconazole, 126
Positron emission tomography (PET)
for cancer, 1323, 1323f
of gastrointestinal tract, 778 b
for Hodgkin lymphoma, 962, 963f
of nervous system, 1072
for oesophageal carcinoma, 796 f
for respiratory disease, 553, 553f
Post-cholecystectomy syndrome, 908,
908 b
Post-exposure prophylaxis, for HIV
infection/AIDS, 327
Post-micturition dribble, 437
Post-partum blues, 1206
Post-partum haemorrhage
primary, 1275
secondary, 1275
Post-partum thyroiditis, 647, 651b
in pregnancy, 651b, 1279
Post-pyloric feeding, 707
Post-transplant lymphoproliferative
disorders (PTLDs), 1299
Post-traumatic stress disorder,
1201-1202
Posterior circulation stroke (POCS),
1 1567
Posterior descending artery, 444
Posterior scleritis, 1170
Posterior uveitis, 1172
Posteroanterior (PA) film, of chest X-ray,
551
Postmortem examination, 213
Postural hypotension, renal dysfunction,
395-396
Posture, examination of, 1063b
Potassium, 349b, 718
and diabetic ketoacidosis, 738
dietary sources of, 7 1 7b
foods high in, 418b
homeostasis, 360-363
presenting problems in, 361-363
intake, chronic renal failure, 418
plasma concentration control and,
360 f
reference nutrient intake of, 717b
reference range of
urine, 1361b
venous blood, 1358b
renal handling, 360, 360/
ROMK channel, 360
supplements, 367
Potassium chloride, hypokalaemia, 362
Potassium phosphate, 369
Potassium-sparing diuretics, for
hypervolaemia, 355
Potency, 16
Poverty, health consequences of, 94
Poxviruses, 248-249
Practolol, nephrotoxicity, 427b
Praziquantel, 129
Pre-eclampsia, hypertension and,
1276-1277, 1276b, 1277 f
Pre-exposure prophylaxis, for HIV
infection/AIDS, 327
Pre-implantation genetic diagnosis
(PGD), 56
Pre-patellar bursitis, 999b
Pre-symptomatic/predictive testing, 59
Pre-test probability, in clinical
decision-making, 11
Pre-transfusion testing, 934
Precocious puberty (PP), 654
Prednisolone
for alcoholic hepatitis, 882
for autoimmune hepatitis, 886-887
for eosinophilic gastroenteritis,
811-812
for gout, 1015
for inflammatory bowel disease, 821b
liver transplantation and, 901
for respiratory disease
aspergillosis, 596
asthma, 572
chronic eosinophilic pneumonia,
611-612
COPD, 578
hypersensitivity pneumonitis, 61 7
rheumatoid disease, 610
sarcoidosis, 610
for syphilis, 339
for systemic lupus erythematosus,
1036
for type II thyrotoxicosis, 648
for warm autoimmune haemolysis,
950
Prefrontal cortex (PFC), high-risk
behaviour and, 1295
Pregabalin, 1102b
Pregnancy
abnormal liver function tests in, 900b
adolescent, rates of, 1 296b
adrenal disease in, 1280
air travel and, 169
analytes affected by, 1 364b
antimicrobial agents in, 120b
biliary obstruction and, 900
cardiac disease in, 1282
cholecystitis and, 900
congenital heart disease in, 533,
533 b
diabetes in, 1278-1279
diabetes mellitus in, 752-753
dyslipidaemia in, 377 b
ectopic, 336
endocrine disease in, 1279-1280
functional anatomy and physiology in,
1272-1273
bone metabolism and, 1272
cardiovascular system and, 1272
endocrine system and, 1272
gastrointestinal system and, 1272
genitourinary system and, 1272
glucose metabolism in, 1272-1273
haematological system and, 1273
respiratory system and, 1273
gallstones and, 900
gastrointestinal disease in,
1277-1278
haematological disease in,
1284-1285
anaemia as, 1284, 1285b
Rhesus disease as, 1 285
thrombocytopenia as, 1285,
1285b
venous thromboembolism as,
1285
haematological physiology in, 941b
hepatitis A and, 900
hepatitis B and, 900
hepatitis C and, 900
hepatitis E and, 900
hormonal changes in, 1273f
human immunodeficiency virus
infection in, 1280
hypertension in, 1276-1277
hypothyroidism in, 641, 651b
immunological diseases during, 88b
inflammatory bowel disease in,
823-824, 824b
inflammatory rheumatic disease in,
1280-1281
iodine deficiency in, 651b
ketoacidosis and, 1279
laboratory reference range in, 1364
liver disease and, 899-900,
1283-1284
medical disorders in, 1276-1285
1404 • INDEX
Pregnancy (Continued)
neurological disease during
epilepsy, 1103, 1103d
multiple sclerosis, 1110 b
neurological disease in, 1284
neutrophilia during, 926
nutrition in, 71 2d
osteoporosis in, 1045
parathyroid disease in, 1280
physiological anaemia of, 1 273
pituitary disease in, 1280
diabetes insipidus as, 1 280
prolactinoma as, 1 280
Sheehan’s syndrome as, 1280
planning of, in patients with medical
conditions, 1272
post-partum thyroiditis in, 651d
prescribing in, 32-33, 32d
presenting problems of, 1274-1276
breathlessness as, 1274-1275
chest pain as, 1275
circulatory collapse as, 1275
headache as, 1275
nausea and vomiting as, 1275,
1275b
oedema as, 1275
seizures as, 1275-1276, 1276b
prolactinoma in, 685
psychiatric disorders during,
1206-1207, 1206b, 1284
renal disease in, 426, 426b,
1282-1283
respiratory disease in, 1277
Rhesus D blood groups in, 933b
rheumatoid arthritis in, 1026b
safety of antirheumatic drugs during,
1281b
sickle-cell disease in, 953, 953b
STI during, 332, 332 b
swollen legs in, 187, 188b
syphilis in, 339
thyroid disease in, 651b, 1279
thyrotoxicosis in, 645, 651b
unplanned, transition medicine and,
1295-1296
visual disorders and, 1175b
Prenatal genetic testing, 56, 59
Prescribing, 13-36, 14b
choice of drug, 29
decision-making in, 28-31
for elderly patients, 32, 32 b
high-risk moments, 33b
in hospitals, 33
monitoring treatment effects, 31
patient involvement, 30-31, 31b
for patients with hepatic disease, 32,
32 b
for patients with renal disease, 31-32
in practice, 28-36
for pregnancy and breastfeeding,
32-33, 32 b
in primary care, 33-34
principles of, during transition, 1289,
1289b
repeat, 34
in special circumstances, 31-33
steps in, 14b
writing, 31 , 33-34, 34f-35f
Prescription-only medicine (PoM), 27
Pressure areas, of stroke patients,
1159b
Pressure sores, 1 262
in stroke patients, 1 1 59 f
Presyncope, 181-183, 455
clinical assessment of, 182-183
congenital heart disease and, 533
differential diagnosis of, 1 82 f
features of, 181b
gastrointestinal haemorrhage, 780
heat, 167
investigations of, 1 83
in older people, 1 308
presentation of, 1 81 -1 82
seizures versus, 182 b
Pretibial myxoedema, 646
Prevalence, of disease, 95
Preventive medicine, 93-94
alcohol, 94
atmospheric pollution, 94
obesity, 94
poverty and affluence, 94
smoking, 94
Prevotella spp., 1 037
Prick tests, 1215
Primary afferent neurons, 1338
Primary biliary cholangitis, 887-888
AMA-negative, 888
associated diseases with, 887
autoimmune hepatitis and, 888
bone disease and, 888
clinical features of, 887
diagnosis and investigations for,
887-888
epidemiology of, 887
fatigue and, 888
liver function test (LFT) abnormality in,
854b
management of, 888
natural history of, 887 f
in old age, 901b
overlap syndromes, 888
pathophysiology of, 887
primary sclerosing cholangitis and,
902 b
pruritus and, 888
Primary CNS lymphoma, 320, 320 f
Primary disease, in endocrinology,
632-633
Primary eosinophilias, 927
Primary granules, 64
Primary haemostasis, disorders of,
970-971
Primary headache syndromes, 1 85b
Primary hyperaldosteronism, 674-675,
674b, 675 f
Primary hyperparathyroidism, 663-664,
663b, 664f
biochemical abnormalities in, 990b
pregnancy and, 1280
Primary idiopathic acquired aplastic
anaemia, 968-969, 968b
Primary immune deficiency, warning
signs of, 73 b
Primary sclerosing cholangitis, 888-890,
889 f
diagnostic criteria for, 888
diseases associated with, 889b
liver function test (LFT) abnormality in,
854b
magnetic resonance
cholangiopancreatogram of, 889,
889 f
primary biliary cholangitis and, 902b
Primary Sjogren’s syndrome (PSS),
1 038-1 039
Primidone, 1102b
Prion diseases, 250, 1126-1127,
1127b, 1191b
Prions, 102
Pro-carboxypeptidases, 770b
Pro-elastase, 770 b
Probenecid, for neurosyphilis, 1 1 25
Problem-solving therapy, 1191, 1191b
Procaine penicillin
for neurosyphilis, 1 1 25
for syphilis, 339
Procaine reaction, 339
Procarboxypeptidases, 768
Prochlorperazine, 803, 1104
Proctocolitis, radiation, 809-810, 810b
Proctoscopy, 339
Procyclidine, 1 1 88-1 1 89
Progeric syndromes, 41
Progesterone
pregnancy and, 1272
reference range of, 1 359b
Progesterone receptors, as tumour
markers, 1322, 1324b
Progestogens, in cancer treatment,
1332
Progressive multifocal
leucoencephalopathy, 1 1 23
Progressive pulmonary hypertension, in
systemic sclerosis, 1038
Progressive supranuclear palsy,
1114-1115
Proguanil, 128
for malaria, 278 b
Prokaryotes, 100-101
Prolactin (PRL), reference range of,
1359b
Prolactinoma, 684-685, 685b, 685 f
pregnancy and, 1280
Prolymphocytic leukaemia (PLL), 960
Prone positioning, as advanced
respiratory support, 204
Propantheline, 1 1 42-1 1 43
Prophase, 40
Prophylactic gonadectomy, for Turner’s
syndrome, 660
Propionibacterium spp., 103f
Propranolol
for anxiety disorder, 1 201
for congestive ‘portal hypertensive’
gastropathy, 871
for variceal bleeding, 869
Proptosis, of ophthalmic disease, 1171
Propylthiouracil (PTU)
for Graves’ thyrotoxicosis, 644
for thyrotoxicosis, in pregnancy, 1 279
Prosody, 1070
Prostacyclin, 447
for acute kidney injury, 422
Prostaglandin El, erectile dysfunction,
440
Prostaglandin E2, febrile response, 104
Prostate
benign hyperplasia, 437
cancer, 438-439
Prostate gland, 386
Prostate-specific antigen (PSA), 439b
as tumour markers, 1322, 1324b
Prostatic acid phosphatase (PAP), as
tumour markers, 1322, 1324b
Prostatitis, 437
Prosthetic valve dysfunction, 527
Prosthetic valves, 526-527
Protease inhibitors (Pis), 324b
Proteases, 768
Protein C deficiency, 977
Protein-losing enteropathy, 811b
Protein S deficiency, 977
Proteins, 697, 697 b, 1305
Bence Jones, 394-395
biliary transport, 851 f
cerebrospinal fluid, 1361b
cholesterol ester, 373
digestion of, 768, 769 f
IGF-BP3, 633f
metabolism of, effects of insulin in,
723 b
plasma, 850
production of, 39 f, 40
reference range of
urine, 1361b
venous blood, 1360b
restriction in, for hepatic
encephalopathy, 865
Tamm-Horsfall, 392
urine, 727
Proteinuria, 392-395, 394b
in diabetic neuropathy, 727
investigation of, 394f
orthostatic, 394
overt (dipstick-positive, 394-395
pregnancy and, 1282
reduction of, 41 7
tubular, 394
Proteoglycans, 987
Proteosome inhibitor, for multiple
myeloma, 968
Proteus spp., 1 037
Prothrombin G20210A, 977
Prothrombin time (PT), 920-921
in coagulation screening tests,
922 b
for gastrointestinal bleeding, 781
for liver disease, 850, 853
acute liver failure and, 858
alcoholic hepatitis and, 882
reference range of, 1 362b
Prothrombotic states, 977-979
Proto-oncogenes, 56-57
‘Proton pump’, 767
Proton pump inhibitor, for variceal
bleeding, 869b
Protozoa, 101-102
Protozoal infections, 273-288
gastrointestinal, 286-288
leishmaniasis, 281-286
systemic, 273-281
Prozone phenomenon, 338-339
Prurigo gestationis, 1 220 b
Pruritic folliculitis, 1220b
Pruritus, 1219-1220, 1326
clinical assessment of, 1219-1220
investigations and management of,
1220, 1 220f
of ophthalmic disease, 1 1 70
in pregnancy, 1220b
primary biliary cholangitis and, 887
treatment for, 888
primary causes of, 1219b
secondary causes of, 1219b
Pruritus ani, 836, 836b
Pseudo-hallucinations, 1 1 84
Pseudo precocious puberty, 654
Pseudocyst, pancreatic, 838f
Pseudohypoparathyroidism, 664-665
Pseudomonas aeruginosa, 1 1 7b
Pseudomonas fluorescens, 225
Pseudoporphyria, 1221b, 1257, 1266b
Psoralens, for skin disease, 1227
Psoriasiform, drug-induced, 1266b
Psoriasis, 1247-1251
arthropathy and, 1249
clinical features of, 1 249, 1 249f
erythrodermic, 1249
guttate, 1249
investigations of, 1 250
management of, 1 250-1 251 ,
1 2507—1 251 f
pathogenesis of, 1248, 1248b,
1 248f
plaque, 1249
pustular, 1249
rash in, 1217b
Psoriatic arthritis (PsA), 1032-1034
CASPAR criteria for, 1 032b
clinical features of, 1 032-1 033,
1033f
investigations for, 1033
management for, 1 033-1 034
pathophysiology of, 1 032
Psoriatic spondylitis, 1 032
Psychiatric assessment, poisoning and,
135
Psychiatric disorders, 1094, 1191-1207
classification of risk factors for, 1183,
1183b
clinical examination of, 1 1 80-1 1 83
mental state examination,
1181-1183
psychiatric interview, 1181, 11 81b
emergencies for, 1 1 89b
functional anatomy and physiology in,
1 1 83-1 1 84
biological factors, 1 1 83
psychological and behavioural
factors, 1183
social and environmental factors,
1184
HIV-related, 321
law and, 1207
management of, 1189-1 1 91
electroconvulsive therapy, 1 1 90
pharmacological treatment, 1 1 90
psychological therapies,
1190-1191
social interventions, 1191
surgery, 1190
in old age, 1 1 89b
organic, 1 1 89b
in pregnancy, 1284
presenting problems of, 1 1 84-1 1 89
prevalence of, 1 1 80 b
psychological factors affecting
medical conditions, 1186-1187,
1186b
puerperal, 1206-1207
WHO classification of, 1180, 1180b
Psychodynamic psychotherapy, 1191
Psychogenic attacks, 1 099
Psychogenic pruritus, 1219b
Psychological elements, in back pain,
995-996
INDEX • 1405
Psychological factors
affecting medical conditions,
1186-1187, 1186b
of migraine, 1095
Psychological therapies/psychotherapy,
1190-1191
for alcohol misuse, 1 1 95
general, 1190
interpersonal, 1191
for pain, 1347
psychodynamic, 1191
Psychosis
affective, 1200
organic, 1197
puerperal, 1206
toxic, 1 1 95-1 1 96
Psychotropic drugs, 1190b
Pthirus pubis, 334 b
Ptosis
causes of, 1091b
unilateral, 1 091 f
Puberty
analytes affected by, 1 363b
delayed, 653-654, 653 b, 1290
hormonal events of, 1 291 f
initiation of, 1 290
onset of, 1 290
Pubic (crab) lice, 1 241
Pubic symphysitis, 999b
Puerperal psychiatric disorders,
1 206-1 207
Pulmonary abscess, 586-587
Pulmonary artery catheter, 206, 207 f
Pulmonary artery wedge pressure,
portopulmonary hypertension
and, 898
Pulmonary circulation, 549-550
Pulmonary embolism, 619-621
acute massive, 200
clinical features of, 619, 619b
investigations of, 619-620, 619/-620f
management of, 620-621
in pregnancy, 620b
prognosis for, 621
in stroke patients, 1 1 59 f
Pulmonary eosinophilia and vasculitides,
611-612, 611b
Pulmonary fibrosis, 547f
in dermatomyositis, 610b
idiopathic, 605-608, 607 f
in respiratory function abnormalities,
555 b
in rheumatoid arthritis, 610b, 1024
in sarcoidosis, 609b
in sclerosis, 610b
in systemic lupus erythematosus,
610b
Pulmonary hypertension, 550, 621-622,
621b, 622 f
congenital heart disease and, 533
systemic sclerosis and, 1038
Pulmonary nodules
cryptococcosis, 302
lung metastases, 1328
in respiratory disease, 560-562,
560b-561b, 560f-562f
Pulmonary oedema, 413-414, 413 f
high-altitude, 168-169
renal artery stenosis, 407
sputum in, 546f
Pulmonary regurgitation, 526, 527 b
Pulmonary rehabilitation, for chronic
obstructive pulmonary disease
(COPD), 577
Pulmonary stenosis, 526
Pulmonary syndrome, 258
Pulmonary tuberculosis
clinical presentations of, 590b
HIV-related, 318-319, 31 97
major manifestations and differential
diagnosis of, 590f
post-primary, 589
primary, 588, 589b, 589f
Pulmonary tuberous sclerosis, 613b
Pulmonary valve disease, 526
Pulmonary vascular disease, 619-622
pulmonary embolism, 619-621
pulmonary hypertension, 621-622,
621b, 622 f
Pulse, in endocrine disease, 630 f
Pulsus paradoxus, 447-448
Pupillary abnormalities, 1090, 1 091 f,
1092b
Purkinje fibres, 445
Purpura
definition of, 1226
drug-induced, 1266b
Henoch-Schonlein, 398b-399b, 401 ,
1043
idiopathic thrombocytopenic, 971
non-thrombocytopenic, 928b
petechial, 928-929, 928f
pinch, 1264
senile, 978 b
thrombotic thrombocytopenic, 388,
409, 979
Pustule, definition of, 121 If
Pustuloderma, drug-induced, 1266b
Pustulosis
acute generalised exanthematous,
1266b
palmoplantar, 1249
PUVA, 1215, 1227
atopic eczema, 1 246
granuloma annulare, 1263
lichen planus, 1252
necrobiosis lipoidica, 1 263
psoriasis, 1250
vitiligo, 1257-1258
Pyelography, 390
retrograde, 390f
Pyelonephritis
acute, 402 f, 430
chronic, 430
emphysematous, 430
pregnancy and, 1282
Pyeloplasty, 434
Pyloroplasty, 782
Pyoderma gangrenosum, 1261-1262,
1 262f
Pyonephrosis, 432
Pyopneumothorax, 564
Pyramidal gait, 1 086-1 087
Pyrantel pamoate, 1 29
Pyrazinamide
as antimycobacterial agents, 1 25
for tuberculous meningitis, 1121
Pyrexia of unknown origin, 218-222
aetiology of, 220 b
clinical assessment of, 218-219
investigations of, 219-222, 221b
prognosis of, 222
Pyridostigmine, 1142-1143
Pyridoxal, 715
Pyridoxamine, 715
Pyridoxine (vitamin B6), 715
biochemical assessment of, 712b
deficiency, 715
dietary sources of, 711b
reference nutrient intake of, 711b
supplements, 715
Pyrimethamine
malaria, 273
toxoplasmosis, 281
HIV-related, 320
Pyrimidine 5’ nucleotidase deficiency,
949
Pyrin, 81
Pyrophosphate arthritis, 993b
Pyruvate kinase deficiency, 949
Pyuria, sterile, 430
Q
Q fever, 231b, 272
endocarditis, 272, 528
Qualitative abnormalities, 951
Quality-adjusted life years (QALYs), 28,
28 b
Quality of life, 202 b
Quantitative abnormalities, 951
Quantitative sensory testing, for pain,
1342, 1342f
Questions, medical interview, 231b
Quetiapine
bipolar disorder, 1200
delirium, 209
Quinagolide, prolactinoma, 685
Quincke’s sign, 524b
Quinidine
arrhythmias, 480
malaria, 277 b
and neutropenia, 926b
poisoning, 137b
Quinine
babesiosis, 278
lichenoid eruptions, 1252
for malaria, 1 28
poisoning, 141b
Quinolones, 122-123, 123b
adverse effects of, 1 23
drug eruptions, 1 266b
mechanism of action, 1 1 6b
in old age, 1 20 b
pharmacokinetics of, 1 22
in pregnancy, 120b
prophylactic, spontaneous bacterial
peritonitis, 864
for spontaneous bacterial peritonitis,
864
see also Fluoroquinolones
R
R protein, 944
RA see Rheumatoid arthritis
Rabies, 1 1 22-1 1 23
incubation period, 111b, 232 b
prophylaxis for
post-exposure, 1 1 22-1 1 23
pre-exposure, 1 1 22
vaccination, 115b, 1122-1123
Radial nerve, entrapment, 1139b
Radial pulse, 534
examination of, in respiratory system,
546f
Radiation(s), 164-165
dosage and exposure of, 1 64
effects of exposure to, 164-165
enteritis and proctocolitis, 809-810,
810b
infrared, 1222f
ionising, 164, 164f
management of exposure to, 1 65
mutagenic effects, 1 320b
natural background, 164
non-ionising, 164
pneumonitis, 612
proctocolitis, 809-810, 810b
ultraviolet see Ultraviolet radiation
Radicular pain, 997b, 998f
Radiculography, 1073b
Radiculopathy, 256, 1138, 1141
cervical, 1134, 1 1347
HIV-related, 321
Radio-femoral delay, 442f
Radio-iodine therapy, for thyrotoxicosis,
637-638, 645b
Radioactive iodine, for Graves’
thyrotoxicosis, 644b, 645
Radioallergosorbent test (RAST), 86
Radiofrequency ablation
arrhythmias, 481b, 484f
cardiovascular disease, 484
GORD, 792-793
for hepatocellular carcinoma, 891
liver metastases, 1328-1329
renal cell cancer, 435
Radiography see X-rays
Radioiodine
multinodular goitre, 649
thyrotoxicosis, 637, 644b
Radioisotope imaging see Radionuclide
(radioisotope) imaging
Radioisotope tests, gastroenterology,
778
Radioisotopes
cancer treatment, 1331
exposure to, 165
intravenous injection of, 1331
Radiology see CT; MRI; X-rays
Radionuclide (radioisotope) imaging
of bone, 988-989
of cardiovascular system, 454
of nervous system, 1073b
Paget’s disease, 1 054f
renal disease, 390, 390f
Radionuclide studies, renal disease,
390, 390f
Radionuclide ventilation/perfusion (V/Q)
scanning, pregnancy and, 1274
Radiotherapy, 1331-1332
for acromegaly, 686
adverse effects, 1331 f, 1332
blood disorders
chronic lymphocytic leukaemia, 960
Hodgkin lymphoma, 962
multiple myeloma, 968
non-Hodgkin lymphoma, 965
for brain tumours, 1130-1131
breast cancer, 1 334
for cancer pain, 1352
colorectal cancer, 832
conformal, 1331
fractionation, 1331
for high-grade NHL, 966
hypothyroidism and, 1298
late effects, 689, 955 b
for low-grade NHL, 965
lung cancer, 602
for lung cancer, 602
lung damage, 612
lung disease due to, 612
mesothelioma, 618
for multiple myeloma, 968
oesophageal cancer, 797
for oral cancer, 790
pain management, 1344
palliative, 1352
pituitary tumours, 683-684
for prolactinoma, 685
prostate cancer, 439
for skin disease, 1 228-1 229
Radon, lung cancer and, 561b
Raloxifene, for osteoporosis, 1048b,
1049
Raltegravir, 119b
Ramadan, diabetes during, 745, 745b
Ramipril
heart failure, 466b
hypertension, 513
myocardial infarction, 500-501
Ramsay Hunt syndrome, 239
Randomised controlled clinical trials,
27-28, 28 f
Ranitidine
and neutropenia, 926b
urticaria, 1254
RANK (receptor activator of nuclear k:B),
985
RANKL (Receptor activator of nuclear
factor kappa B ligand), in bone
remodelling, 986b
Rapid diagnostic tests (RDTs),
immunochromatographic, 276
Rapid immunochromatographic tests,
258
Rapid plasma reagin (RPR), 338-339
Rapidly progressive glomerulonephritis,
397
diseases typically presenting with,
401
Rare inherited bleeding disorders, 974
Rare interstitial lung diseases, 613b
Rasagiline, for Parkinson’s disease,
1114
Rashes, 1216-1218, 1217b
atopic eczema, 1217b, 1246b
butterfly (malar), 982 f
in chickenpox, 238
clinical features, 1217b
dengue, 243-244
dermatitis herpetiformis, 807
dermatomyositis, 1039
distribution, 1217b
drug eruption, 316, 1217b, 1267f
erythema migrans, 256f
erythematous, 1255
in fever, 218
genital, 333, 334b
haemorrhagic, 271b
hand, foot and mouth disease, 248
herpes simplex, 247f
HIV-related, 316
infectious mononucleosis, 242f
lichen planus, 334b, 1217b
Lyme borreliosis (disease), 256 f
macular/maculopapular, 271b
1406 • INDEX
Rashes (Continued)
morbiliform, 271b
parvovirus B19, 237 f
petechiae, 928-929, 928f
photosensitivity, 1 221 f
pityriasis rosea, 1217b
pityriasis versicolor, 1217b
post-kala-azar dermal leishmaniasis,
284f
psoriasiform, 1266b
psoriasis, 1217b
purpura see Purpura
rheumatic fever, 51 5
in rubella infection, 234b
scaly, 1217b
scarlet fever, 253 f
shingles, 238 f
syphillis, 1217b
of systemic lupus erythematosus,
1035f
tinea corporis, 1217b
toxic shock syndrome, 1 236
tropical diseases, 234b
typhoid, 260
typhus, 271
urticarial, 1253/
vesicular, 315
RAST (radioallergosorbent test), 86
Rat bite fever, 235f
Raynaud’s phenomenon
in systemic lupus erythematosus,
1035, 1035f
in systemic sclerosis, 1037-1038
Raynaud’s syndrome, 504-505
RB-ILD see Respiratory bronchiolitis-
interstitial lung disease
RBBB see Right bundle branch block
RCA see Right coronary artery
Re-entry, 468
Reactive airways dysfunction syndrome,
614
Reactive arthritis, 1031-1032
Reactive disorders, 1264-1265
‘Ready Steady Go’ programme,
1290
Reassurance, somatoform disorders
and, 1203
Receiver operating characteristic (ROC)
curve, 5 f
Receptor activator of nuclear factor
kappa B ligand (RANKL), in bone
remodelling, 986b
Receptor activator of nuclear factor kB
ligand see RANKL
Receptor activator of nuclear kB see
RANK
Receptors
B-cell, 68, 68f
drugs acting on, 15b
in pain processing, 1340b
Recombinant human DNAase
(rhDNAase), cystic fibrosis,
581b
Recombinant human erythropoietin,
chronic renal failure, 419
Recombinant tissue plasminogen
activator (rt-PA), stroke, 1 1 58 f,
1159-1160
Recombination, 41
Recompression, for diving-related
illness, 171
Rectal administration, 17
Rectal examination, 765 b
gastrointestinal disease, 787
prostate, 427, 437-438
Rectal varices, portal hypertension and,
868
Rectum, 771 f
disorders of, 827-836
dysfunction of, 1 094
tumours of, 827-833
see also Colorectal cancer
Recurrent occult upper gastrointestinal
bleeding, systemic sclerosis and,
1037-1038
Red cell enzymopathies, 948-949
Red cell membrane
defect, 947-948
structure, 915, 91 6f
Red cells, 915-917, 91 6f
agglutination, cold, 950
anaemia, 94 If
aplasia, 947
appearance of, 921b, 92 If
blood film examination, 921 f
concentrate, 931b
count, 1362b
destruction of, 91 7
effects of malaria, 273-274
enzymopathies, 948-949
formation, 915, 91 6f
fragments, 92 If
haemoglobin and, 915-916, 91 7f
haemolytic anaemia, 945, 946b, 946f
incompatibility, in blood transfusion,
931-933
lifespan, 1362b
membrane defects, 947-948
nucleated, 92 If
sickled see Sickle-cell anaemia/
disease
structure and functions, 915-917,
91 6f
transfusion, (in)compatibility, 932-933
Red eye, 1170
Red hepatisation, 583
‘Red man’ reaction, 123
Reduced-intensity conditioning, 937
5a-Reductase inhibitors, 438
Reduviid bugs, 280
Reed -Stern berg cells, 961
Refeeding diets, WHO recommended,
705, 705 b
Refeeding syndrome, 706
Reference nutrient intake (RNI),
711-712
of minerals, 717b
of vitamins, 711b
Reference range, 3, 4f
Reflex(es)
cough, 556
diabetes, 759
stretch, 1068
tendon, root values of, 1063b
Reflex sympathetic dystrophy (RSD),
1348-1349
Reflux
bile, 801
duodenogastro-oesophageal, 792
gastro-oesophageal, 791-794, 791 f
Reflux nephropathy, 430-431
Refractory cough, 169
Refractory hypertension, 514
Regenerative medicine, for genetic
disease, 58
Regurgitation, 779
aortic, 443b, 524-525, 524b, 525 f
causes, 524b
chest X-ray for, 451 f
clinical features, 524-525, 524b
clinical features of, 524-525, 524b,
525 f
investigations, 525, 525 b
investigations of, 525, 525 b
mitral, 519-521, 519b, 520 f
clinical features of, 521b, 521 f
investigation of, 521b
management of, 521
pulmonary, 526, 527 b
tricuspid, 526, 526 b
Rehabilitation
for acute coronary syndrome, 501
myocardial infarction, 501
in older people, 1311-1312
schizophrenia, 1198
for somatoform disorders, 1203
stroke, 1158
Rehydration see Fluid replacement
Reiter’s disease/syndrome see Reactive
arthritis
Relapsing fevers
louse-borne, 256 b, 257, 257 f
tick-borne, 256b, 257
Relapsing polychondritis, 1044
Relative erythrocytosis, 925, 925b
REM sleep behaviour disorder, 1 1 05
Remission consolidation, in acute
leukaemia, 956
Remission induction, in acute
leukaemia, 956
Remission maintenance, in acute
leukaemia, 956
Renal see Kidney
Renal allograft dysfunction, common
causes of, 425b
Renal arteriography/venography, 389
Renal artery stenosis, 406-408, 407b,
407f
Renal biopsy, 391, 391b
Renal cell cancer, 434-435, 435 f
Renal colic, 396
Renal dialysis see Dialysis, renal
Renal disease
in adolescence, 426, 426b
atheroembolic, 390b, 410
chronic, 415-420
pruritus, 415
stages, 388b
in connective tissue disease
Henoch-Schonlein purpura, 1043
SLE, 1036
systemic sclerosis, 1 038
cystic, 405-406
adult polycystic kidney, 405-406
medullary, 404
diabetics see Diabetic nephropathy
drug-induced, 426, 427b
genetic, 403-406
glomerular, 397-401
HIV-related, 322
infections, 426-431
investigation of, 386-391
in pregnancy, 426, 426b,
1282-1283
acute kidney injury as, 1282,
1283b
chronic kidney disease as, 1282,
1283 f
glomerular disease and, 1282
renal replacement therapy for,
1282-1283
renal tract infection as, 1 282
for prescribing patients with, 31-32,
426
presenting problems in, 391-397
signs, 416 f
transition medicine and, 1298-1299
tuberculosis, 591
tubulo-interstitial, 401-403
tumours/cancer, 1 31 6f
vascular, 406-409
see also Nephropathy
Renal failure
acute see Acute kidney injury
ascites, 864
bleeding, 975
chronic, 415-420, 417b
causes of, 415b
haemodialysis in, 422-423
indications for dialysis for, 422b
osteodystrophy and, 41 9f
physical signs of, 41 Qf
pregnancy and, 1282, 1283f
staging of, in children over 2 years
of age, 1 298b
transition medicine and,
1298-1299
cystic disease see Renal disease,
cystic
diabetics, 757
end -stage, 415b
heart failure, 464
heart failure causing, 464
pruritus and, 1219b
pyelonephritis see Pyelonephritis
Renal function tests, 962
Renal impairment, causes of, in
childhood and adolescence,
1298b
Renal infarction, acute, 408
Renal lesion, systemic lupus
erythematosus and, 1035
Renal osteodystrophy, biochemical
abnormalities in, 990b
Renal pelvis, 386
obstruction, 389 f
pyelonephritis, 430
stone in, 431
tumours, 435
Renal replacement therapy (RRT), 208,
420-426, 421 f
for acute kidney injury, 414
for chronic kidney disease, 414
continuous, 424b
in old age, 422b
percentage survival in, 422 f
pregnancy and, 1282-1283
preparing for, 420
Renal stones, 431
composition of, 431b
investigations for, 432b
Renal support, in intensive care, 208
Renal tract infection, pregnancy and,
1282
Renal tract obstruction, acute kidney
injury and, 414
Renal transplantation
in diabetic nephropathy, 758
recipients of, pregnancy and, 1283
Renal tubular acidosis, 365, 365b, 405
Renal tubules, 384-386
collecting ducts, 350-351 , 384-386
distal, 350
loop of Henle, 350, 384-386
proximal, 350
Renal ultrasound, acute kidney injury
and, 416b
Renin, 351-352
Renin activity, 666
Renin-angiotensin-aldosterone system,
362
hypertension, 509
hypokalaemia, 362
Renin-angiotensin blockade, for acute
coronary syndrome, 500-501
Renin concentration, reference range of,
1359b
Repaglinide, 747
Repeat prescriptions, 34
Repeated dose regimens, 1 9
Reperfusion therapy, for acute coronary
syndrome, 499-500
Replacement therapy, for amenorrhoea,
655
Replicative immortality, 1318
Reproductive disease
classification of, 652b
presenting problems in, 653-658
Reproductive system, 651-661
classification of diseases of, 652b
female, 652, 652 f
functional anatomy, physiology and
investigations of, 651-652,
651 f-652f
Klinefelter’s syndrome in, 660-661
male, 651, 651 f
polycystic ovarian syndrome in,
658-659, 659f
Turner’s syndrome in, 659-660, 660 f
Resection
hepatic, for hepatocellular carcinoma,
891
ileal, under-nutrition and, 706
massive small bowel, under-nutrition
and, 706
pancreatic, under-nutrition and, 706
Residual volume (RV), 555b
Resin
bile acid-sequestering, 376-377
ion-exchange, 363, 363b
Resistin, 699
Respiration
haemodynamic effects of, 447-448,
447b
Kussmaul, 415
see also Breathing
Respiratory acidosis, 367
Respiratory alkalosis, 367
Respiratory bronchiolitis-interstitial lung
disease (RB-ILD), 606b
Respiratory burst, 64
Respiratory chain complexes, 49b
Respiratory disease, 556-567
air travel and, 169
breathlessness in, 557-558, 557 f,
558 b
INDEX • 1407
caused by fungi, 596-598, 596b
chest pain in, 558
cough in, 556, 556 b
drug-induced, 612-613, 612b
finger clubbing in, 559, 559b, 559f
haemoptysis in, 559-560, 559 b, 560 f
HIV-related, 318-319, 318b
investigation of, 550-556
ophthalmic features of, 1 1 65 b
pleural effusion in, 562-565,
563b-564b
pregnancy and, 1277
pulmonary nodule in, 560-562,
560b-561b, 560f-562f
respiratory failure in, 565-567, 565b
transition medicine and, 1297
cystic fibrosis in, 1297
tumours, 598-605
Respiratory distress syndrome, acute
see Acute respiratory distress
syndrome
Respiratory failure, 565-567
acute, management of, 565-566
chronic and ‘acute on chronic’ type II,
566-567
management of, 566-567, 566b
pathophysiology of, 565, 565 b
Respiratory function
in old age, 550b
testing, 554-556, 554f
airway obstruction, measurement
of, 555
arterial blood gases and oximetry,
555-556, 555 f
in asthma, 555 b
in chronic bronchitis, 555b
in emphysema, 555b
exercise tests, 556
lung volumes, 555
in pulmonary fibrosis, 555b
transfer factor, 555
Respiratory infections, 581-598
cystic fibrosis, 580-581
fungal, 596-598
in old age, 586b
pneumonia, 582-587
pregnancy and, 1277
bacterial, 1277
viral, 1277
tuberculosis (TB), 588-595
upper respiratory tract infection,
581-587
Respiratory medicine, 545-628
Respiratory support, in intensive care,
202-204
advanced, 204
extracorporeal, 204
intubation and intermittent positive
pressure ventilation, 203-204
non-invasive, 202
weaning from, 209-210
Respiratory syncytial virus (RSV), 249
Respiratory system
clinical examination of, 546-548,
546f-547f
functional anatomy and physiology of,
548-550, 548f-549f
infections see Respiratory infections
in old age, 550b
pregnancy and, 1273
tumours, 598-605
Response evaluation criteria in solid
tumours (RECIST), 1333b
Restless legs syndrome, 1 1 05-1 1 06,
1106b
Restraint, for aggressive behaviour,
1188-1189
Restrictive cardiomyopathy, 540
Resuscitation
drowning and, 170
for gastrointestinal haemorrhage, 782
hypothermia and, 166
initial, 204-206, 206 b
for poisoning, 134
in sepsis, 196-197, 197b
Resynchronisation devices, 467, 467f
Resynchronisation therapy, cardiac,
467f, 484
Reteplase, 500
Reticular formation, brainstem, 1067f
Reticulocytes, 915
reference range of, 1 362b
Retina
detachment, 1088
of eye, 1167
visual field loss in, 1089b
Retinal artery occlusion, in
ophthalmological conditions,
1178, 1178f
Retinal haemorrhage
high-altitude, 169
see also Diabetic retinopathy
Retinal pigment epithelium, congenital
hypertrophy, 829
Retinal vascular occlusion, in
ophthalmological conditions,
1177-1178
Retinal vein occlusion (thrombosis),
1177-1178, 1177f
Retinitis
cytomegalovirus, 21 67
HIV-related, 321
Retinitis pigmentosa, 810
Retinoblastoma, 1321b
Retinochoroiditis, due to toxoplasmosis,
280, 281 f
Retinoic acid, 713
all-trans- Retinoic acid, 958
Retinoids, 713
hyperlipidaemia, 373 b
hypertriglyceridaemia, 374
phototherapy and
photochemotherapy, 1227
for skin disease, 1 227
squamous cell carcinoma, 1 231
warts, 1239
Retinol (vitamin A), 712-713
deficiency, 713, 7137
dietary sources of, 711b
reference nutrient intake of, 711b
Retinopathy, 1325
HIV-related, 321
hypertensive, 509-510, 510b
pregnancy and, 1279
Retroperitoneal fibrosis, 434
drug-induced, 427b
Retroviruses, 100
Return of spontaneous circulation
(ROSC), in post cardiac arrest,
200-201, 201b
Reverse transcriptase, 309-310
Reverse transcriptase inhibitors
non-nucleoside, 316, 324b
nucleoside, 324b
Reversibility test, 569f
Revised International Prognostic Scoring
System (IPSS-R), in
myelodysplasia, 961, 961b
Reye’s syndrome, acute liver failure
and, 857-858
Rhabdomyolysis, 363
diagnosis and management of, 1 95
Rhesus D blood group, 933, 933b
Rhesus disease, pregnancy and, 1285
Rheumatic fever, 515-517, 51 67
investigations in, 517b
Jones criteria for, 51 6b
prophylactic, 119b
Rheumatic heart disease, 515-517
chronic, 517
Rheumatoid arthritis (RA), 1021-1026
clinical features of, 1023-1025, 1023f
cardiac involvement in, 1024
extra-articular, 1024b
nodules in, 1023-1024, 1024f
ocular involvement in, 1024
peripheral neuropathy in, 1024
pulmonary involvement in, 1024
serositis in, 1024
spinal cord compression in, 1024,
1025f
systemic, 1023
vasculitis in, 1024
criteria for diagnosis of, 1023b
investigations in, 1025, 1025b, 1026f
management of, 1 025-1 026
algorithm for, 1026f
biologic therapy for, 1 026
DMARD therapy for, 1025-1026
non-pharmacological therapy for,
1026
surgery for, 1 026
pathophysiology of, 1022-1023,
1022f
in pregnancy, 1026b, 1280
Rheumatoid disease
pleural effusion, 563b, 610-611
respiratory involvement in, 610-611,
6117
Rheumatoid factor (RF), in
musculoskeletal disease, 991 ,
991b
Rheumatoid nodules, 1023-1024, 1024f
Rheumatological/musculoskeletal
disease
HIV-related, 321-322
ophthalmic features of, 1 1 66 b
Rheumatology, 981-1060
see also Musculoskeletal disease
Rheumatology and bone disease,
transition medicine and, 1300
glucocorticoid-induced osteoporosis
in, 1300
hypophosphataemic rickets in, 1300
juvenile idiopathic arthritis in, 1300
osteogenesis imperfecta in, 1300
Rhinitis, allergic, 622
Rhinocladiella mackenziei, 301
Rhinosinusitis, 582
Rhinoviruses, 249
Rhizomucor spp., 303
Rhizopus spp., 303
Rhodesiense infections, 278
Rhodesiense trypanosomiasis, 278-279
Rhodococcus equi, 31 9
Rib fracture, 626b
Ribavirin, 128
for hepatitis C, 878
viral haemorrhagic fevers, 246
Riboflavin (vitamin B2), 714
biochemical assessment of, 712b
deficiency, 714
dietary sources of, 711b
reference nutrient intake of, 711b
Ribonucleic acid (RNA)
degradation of, 40
editing of, 40
messenger ribonucleic acid (mRNA),
38
microRNA (miRNA), 40
non-coding, 40
ribosomal RNA (rRNA), 40
splicing of, 40
synthesis of, 39 f
transfer RNA (tRNA), 40
Ribosomes, 39 f
Ribozymes, 40
Richmond Agitation Sedation Scale
(RASS), 209, 209 b
Richter’s transformation, 960
Rickets, 1051-1052
causes of, 1 050b
hypophosphataemic, 990b
hereditary, 1052-1053
hypophosphataemic, transition
medicine and, 1300
vitamin D-resistant, 1 052
Rickettsial fevers, 270-272, 271b
Rickety rosary, 1 052
Riedel’s thyroiditis, 650
Rifampicin, 117b
as antimycobacterial agents, 1 25
drug interactions of, 24
hepatotoxicity of, 894b
infective endocarditis, 530b
for leprosy, 269
meningitis, 1120b
pneumonia, 585 b
prophylactic, 119b
for pruritus, primary biliary cholangitis
and, 888
Q fever, 272
for tuberculosis, 593
Rifamycin, mechanism of action, 116b
Rifaximin, for hepatic encephalopathy,
865
RIFLE criteria, 41 1
Rift Valley fever, 245b
Right atrial pressure, in critically ill
patients, 207f
Right bundle branch block (RBBB), 478f
Right coronary artery (RCA), 444, 445f
Right ventricle, 444f
Right ventricular cardiomyopathy,
arrhythmogenic, 453, 539f
Right ventricular dilatation, 450
Rigidity
cogwheel, 1069
lead pipe, 1069
Parkinson’s disease, 1084-1085,
1113b
tetanus, 1126
tetanus and, 1126
Rigors, 217b
Riluzole, amyotrophic lateral sclerosis,
1117
Rimantadine, 127
Rimonabant, 702
Ringer-lactate, 265
Ringworm, 1239
Risedronate
for osteoporosis, 1 048b
for Paget’s disease, 1 054, 1 054b
Risk
attributable, 95b
global burden of disease and
underlying factors, 92-93
relative, 95 b
Risperidone
bipolar disorder, 1 200
schizophrenia, 1 1 98b
Risus sardonicus, 1 1 26
Rituximab, for musculoskeletal disease,
1006, 1007b
polymyositis and dermatomyositis,
1040
systemic lupus erythematosus, 1 037
Rivaroxaban, for venous
thromboembolism, 975
Rivastigmine, for Parkinson’s disease,
1113
River blindness, 292-293
RNA
degradation of, 40
editing of, 40
messenger (mRNA), 38
messenger ribonucleic acid (mRNA),
38
microRNA (miRNA), 40
non-coding, 40
ribosomal RNA (rRNA), 40
splicing, editing and degradation, 40
splicing of, 40
synthesis, 39 f
synthesis of, 39 f
transfer, 40
transfer RNA (tRNA), 40
RNA polymerase, 38
RNI see Reference nutrient intake
Robertsonian translocation, 45f
Rocky Mountain spotted fever, 270,
271b
Rodent ulcer, 1229
Rodenticide poisoning, 148
Rokitansky-Aschoff sinuses, 909
Romana’s sign, 279
Romberg’s test, 1062f
Romosozumab, for osteoporosis, 1 049
Ropinirole, Parkinson’s disease, 1114b
Rosacea, 1221b, 1243-1244, 1243f
Roseola infantum, 238
Rosiglitazone, 747
Ross River virus, 250, 1020-1021
Rotator cuff lesions, 997-998, 998b
Rotavirus, 249
Rotigotine, Parkinson’s disease, 1114b
Rotor’s syndrome, 860b
Roundworm (Ascaris lumbricoides) ,
289-290, 906
Roux-en-Y gastric bypass, 703 b
RPGN see Rapidly progressive
glomerulonephritis
RSV see Respiratory syncytial virus
RT see Reverse transcriptase
rt-PA see Recombinant tissue
plasminogen activator
1408 • INDEX
RTA see Renal tubular acidosis
Rubber allergy, 1 247b
Rubella infection
clinical features of, 236
congenital malformation and, 237 b
diagnosis of, 236
in pregnancy, 235 b
prevention of, 236-237
Russell’s sign, 1204
Ruxolitinib, for myelofibrosis, 969
RV see Residual volume
Ryanodine receptor channelopathies,
1145b
S
SA node see Sinoatrial (SA) node
Sabin-Feldman dye test, 281
Saccades, 1090
Sacroiliitis, 1029f
and ankylosing spondylitis, 1 030
and axial spondyloarthropathies,
1028, 1028b
and brucellosis, 255 /
and inflammatory bowel disease,
819/
polyarthritis and, 994/
and Whipple’s disease, 809b
Salbutamol
asthma, 572
drug interactions, 24b
scombrotoxic fish poisoning, 150
Salicylates (aspirin)
overdose, 138
poisoning from, 136, 138
Salicylic acid
actinic keratosis, 1 230b
molluscum contagiosum, 1239
warts, 1239
Saline, 353b
abdominal compartment syndrome,
195
genital itch/rash, 333
heat cramps, 1 67
hyperkalaemia, 363
hyponatraemia, 358
hypophosphataemia, 369
hypovolaemia, 353
metabolic alkalosis, 367
Salivary glands
disease of, 790
enlargement, 1039b
Salmonella
food poisoning/gastroenteritis, 263
HIV/AIDS patients, 323
Salmonella enteritidis, 262-263
Salmonella paratyphi, 227-228
Salmonella spp. infection, 262-263
Salmonella typhi, 1 1 7b
Salmonella typhimurium, 262-263
Salmonellosis, 231b
Salofalk, for inflammatory bowel
disease, 821b
Salt
in diabetic diet, 744
see also Sodium
Salt-losing nephropathy, 403
Salt-wasting disease, 418
Sand flea, 299-300
Sandflies, 282
bartonellosis, 272
leishmaniasis, 282
Sandhoff’s disease, 371b
Sanfilippo’s syndrome, 371b
Sanger, Fred, 52-53
Sanger sequencing, 52-53, 54/
Saphenous vein grafts, 492/
SARA see Sexually acquired reactive
arthritis
Sarcoidosis, 410, 608-610, 608/,
1263
clinical features of, 608-609, 609b,
609/
investigations of, 609-610, 609b
management of, 610
Sarcoma
Ewing’s, 1057
osteogenic, 1056-1057
see also Kaposi’s sarcoma
Sarcomere, cardiac, 446
Sarcoptes scabiei, 1241
SARS see Severe acute respiratory
syndrome
Sausage digit, 1 032
Saxagliptin, 747
Saxophone player’s lung, 616b
SBAR system, of communication, 10,
10b
SBP see Spontaneous bacterial
peritonitis
Scabies, 1241, 1241/
ecthyma, 1236
HIV/AIDS, 330/-331 /
Norwegian, 1241
pruritus, 1219b
Scaling, 1216
Scalp
fungal infections, 300-304
head lice, 1 241
psoriasis, 1247-1251
tinea capitis, 1240, 1240/
Scapula, winging, 1062/
Scarlet fever
incubation period, 111b
period of infectivity, 111b
streptococcal, 252, 253/
Scars, definition, 1226
Scedosporium apiospermum, 301
SCF see Stem cell factor
‘Schatzki ring’, 795-796
Scheuermann’s osteochondritis, 1055
Schilling test, 944
Schirmer tear test, 1038-1039
Schistosoma, life cycle of, 294, 295/
Schistosoma haematobium, 295-296,
296/
Schistosoma intercalatum, 296
Schistosoma japonicum, 296
Schistosoma mansoni, 296, 296/
Schistosoma mekongi, 296
Schistosomiasis, 233b, 294-297
clinical features of, 295-296, 295 b
investigations of, 296
management of, 296
pathology of, 294
prevention of, 296-297
Schizoaffective disorder, 1 200
Schizophrenia, 1 1 96-1 1 98
acute, 1196-1197
clinical features of, 1 1 96-1 1 97
diagnosis of, 1 1 97
differential diagnosis of, 1197b
investigations of, 1 1 97
management of, 1 1 97-1 1 98
pathogenesis of, 1 1 96
prevalence of, 1 1 80b
prognosis of, 1 1 98
symptoms of, 1 1 97 b
auditory hallucinations as, 1 1 85
thought disorder as, 1 1 81
Schmidt’s syndrome, 689
Schober’s test, 983, 983/
Schumm’s test, 947
Schwann cells, 1064-1065
Sciatica, 1135
Scintigraphy
bone, in musculoskeletal disease,
988-989, 989b
meta-iodobenzyl guanidine, 675
octreotide, 679/
of thyroid gland, 638/, 642
see also Radionuclide (radioisotope)
imaging
SCLE see Subacute cutaneous lupus
erythematosus
Sclera, of eye, 1 1 66-1 1 67
Scleritis, 1172
posterior, 1170
Sclerodactyly, 1037
Scleroderma see Systemic sclerosis
Scleromalacia, rheumatoid arthritis,
1172
Sclerosing bone dysplasias, 1 056
Sclerosing cholangitis
primary, 888-890, 889/
diagnostic criteria for, 888
diseases associated with, 889b
liver function test (LFT) abnormality
in, 854b
magnetic resonance
cholangiopancreatogram of, 889,
889/
primary biliary cholangitis and,
902 b
secondary, 888, 889b
Sclerosis, systemic see Systemic
sclerosis
Sclerostin, in bone remodelling, 986b
Sclerotherapy, for variceal bleeding, 870
Sclerotic bodies, 301
Scoliosis, 1059
Scombrotoxic fish poisoning, 150
Scorpions, envenomation of, 1 61
Scotoma, 1095-1096
Screening
aortic aneurysm, 505
breast cancer, 1325b
for chronic liver disease, 853b
ciliary dysfunction syndromes, 579
coagulation, 922 b
colorectal cancer, 832-833
cystic fibrosis, 580
diabetes mellitus, 1278
diabetic nephropathy, 757
genetic, 58
gestational diabetes, 1278
hepatitis B core IgM antibody, 858
hepatocellular carcinoma, 890-891
for hepatocellular carcinoma,
890-891
malnutrition, 693/
microalbuminuria, 394
principles of, 94-95
Scrub typhus fever, 270-271 , 271b
Scurvy, 715-716, 716b, 716/, 970
Sebaceous glands, 1213
Sebocytes, 1213
Seborrhoeic dermatitis, FllV-related,
314
Seborrhoeic eczema, 1 246
Seborrhoeic warts, 1 234
Sebum, 1213
acne vulgaris, 1242
Secondary aplastic anaemia, 969,
969 b
Secondary disease, in endocrinology,
632-633
Secondary granules, 64
Secondary headache syndromes, 1 85 b
Secondary osteoporosis, 1044-1045
Secretin, 772 b
Secukinumab, for musculoskeletal
disease, 1007, 1007b
Sedation
for aggressive behaviour,
1188-1189
in intensive care, 209, 209b
Sedatives, misuse of, 1 1 95
75SeHCAT test, 777b
75SeHCAT test, 777 b
Seizures
brain tumour and, 1129
pregnancy and, 1275-1276, 1276b
in stroke patients, 1153, 1159/
syncope versus, 182 b
types of, 1098-1100, 1098b
absence, 1099
atonic, 1100
clonic, 1100
focal, 1099, 1099b
generalised, 1099-1100
myoclonic, 1099-1100
tonic, 1100
tonic-clonic, 1099, 1099b
Selective noradrenaline reuptake
inhibitors (SNRIs), poisoning, 139
Selective serotonin re-uptake inhibitors
(SSRIs), 1199, 1199b
poisoning from, 139
Selectivity, 14
Selegiline, for Parkinson’s disease, 1114
Selenium, 634, 718
deficiency, 718
dietary sources of, 717b
excess, 718
for Graves’ ophthalmopathy, 646
reference nutrient intake of, 717b
Selenium sulphide shampoo, 314
Selenosis, 716
Self-harm
in old age, 1 1 89b
patient assessment of, 1187b,
1188/
Self-help and coping strategies, for
musculoskeletal disease, 1001,
1001b
Seminoma, 439
Senescence
immune, 80-81 , 81b
see also Age/ageing; Older people
Sengstaken-Blakemore tube, for
variceal bleeding, 870, 870/
Senna, 761b, 834b
Sensitisation, 1340
Sensorimotor polyneuropathy, 1111b
Sensory ataxia, 1 1 25 b
Sensory cortex, 1 063/
Sensory disturbances, 1083-1084
diabetes see Diabetic neuropathy
Sensory loss, pattern of, 1 084/
Sensory neurons, 1 338
Sensory neuropathy, 1111b
Sensory system examination, 1062/
Sentinel lymph node biopsy, 1 233
Sentinel pile, 836
Sepsis, 196-198, 226-227, 226 b
acute kidney injury and, 41 1-412
cardiomyopathy and, 198
coagulation system and, activation of,
196
definition of, 1 96b
during dialysis, 424b
lactate and, 196
meningococcal, 1119b
mimics of, 1 98b
organ damage from, 196, 197/
resuscitation in, 196-197, 197b
skin and soft tissue infections
causing, 226-227
Sepsis syndrome, 550
Septic arthritis, 1019-1020
emergency management of, 1 020b
synovial fluid in, 1020
Septic shock, 70-71 , 196b, 206b
Septicaemic plague, 259
Sequestration crisis, 952
‘Seroconversion’, 106
Serological tests, for respiratory disease,
554
Serology
for gastrointestinal infection, 777
for Helicobacter pylori infection, 111
for hepatitis B, 873-875, 875b
for hepatitis C, 877
Seronegative spondyloarthropathies,
1166b
Serositis, in rheumatoid arthritis, 1024
Serotonin (5-hydroxytryptamine, 5-FIT),
1345b, 1353/
excess in irritable bowel syndrome,
824
Serotonin agonists, irritable bowel
syndrome, 824
Serotonin-noradrenaline reuptake
inhibitors (SNRIs), 139
Serotonin selective (specific) re-uptake
inhibitors (SSRIs), 1199, 1199b
Serotonin syndrome, 1199
Serratia spp., 102/
Sertraline, 1199b
Serum- ascites albumin gradient
(SAAG), 863
Serum ferritin, 941
Serum sickness
antivenom, 159
diphtheria antitoxin, 266
schistosomiasis, 295 b
Severe acute respiratory syndrome
(SARS), 249
Severe combined immune deficiency,
79-80
X-linked, 79-80
Severe idiopathic constipation, 834
Sex, HIV infection/AIDS and, 323
Sex chromosomes, 38
see also X chromosome; Y
chromosome
INDEX • 1409
Sex hormone replacement therapy
for hypopituitarism, 682
see also Hormone replacement
therapy
Sex hormones see individual hormones
Sexual activity, headache and, 1097
Sexual disturbance, 1 093-1 094
Sexual dysfunction, 1 1 09-1 1 1 0
see also Erectile dysfunction
Sexually acquired reactive arthritis
(SARA), 1031
Sexually acquired reactive arthropathy,
340
Sexually transmitted infections (STIs),
329-344
approach to patients, 332-333,
332 b
in children, 332-333
clinical examination of
in men, 330, 330f
in women, 331 , 331 f
contact tracing for, 333
HIV testing for, 330
investigations of
in men, 330b
in women, 331b
management goals of, 331b
men who have sex with men, 330b,
334-335
during pregnancy, 332
presenting problems of, men,
333-336, 333f-334f
prevention of, 336-337
those at particular risk, 331b
viral, 341-344
Sezary’s syndrome, 1 224, 1 232
SGLT2 inhibitors, for hyperglycaemia,
748, 748f
SH (self-harm) see Self-harm
Shagreen patches, 1 264
Shampoo
ketoconazole, 1240, 1246
selenium sulphide, 314
Shared decision-making, 10, Ilf, 12
Shave excision, for skin disease,
1228
Sheehan’s syndrome, pregnancy and,
1280
Shellfish poisoning, paralytic, 149
Sheltered employment, 1 1 98
Shiga-like toxin, 408-409
Shigella
diarrhoea, 227-228, 232
dysentery/shigellosis, 265
reactive arthritis, 1031
Shigellosis, 265
Shingles see Herpes zoster
Shivering, 165b, 165f
Shock
anaphylactic, 204, 206b
cardiogenic, 199-200, 206b
causes of, 200f
downward spiral of, 199, 200f
clinical features of, 1 80 b
hypotension and, 193, 193b
hypovolaemic, 206b
neurogenic, 206b
obstructive, 206b
septic, 70-71, 196b, 206 b
Short bowel syndrome, 708-710
Short stature
in Turner’s syndrome, 659
see also Dwarfism; Growth
retardation
Shoulder
frozen, 997-998
pain, 997-998, 998b, 998f
painful, in stroke patients, 1159f
Shrinking lungs, 610b, 611
Shuffling gait, 1087b
Shunts
Blalock-Taussig, 537
intracardiac, 454, 459
left-to-right, 450
persistent ductus arteriosus, 533
portosystemic
fetor hepaticus from, 868
portal hypertension and, 869
forvariceal bleeding, 871
TIPSS
for ascites, 864
forvariceal bleeding, 871, 871 f
transjugular intrahepatic
portosystemic stent
for ascites, 864
forvariceal bleeding, 871, 871 f
SI units, 1358
SIADH see Syndrome of inappropriate
secretion of ADH
Siberian tick typhus, 271b
Sibutramine, 702
Sick euthyroidism, 642
Sick sinus syndrome, 469, 469b, 469f
Sickle-cell anaemia/disease, 923,
951-953
clinical features of, 952-953, 952 f
epidemiology of, 951, 951 f
investigations of, 953
management of, 953
pathogenesis of, 951-952
in pregnancy, 953b
prognosis of, 953
rheumatological manifestations of,
1058
Sickle-cell nephropathy, 41 1
Sickle-cell trait, 951
Sickle chest syndrome, 952
Side-effect, definition of, 21
Siderosis, 614-616, 615b
Sieverts (Sv), 164
Sigmoidoscopy, 776
amoebiasis, 287
Clostridium difficile infection, 264
constipation, 787
familial adenomatous polyposis, 829
inflammatory bowel disease, 824b
for inflammatory bowel disease,
817b
radiation enteritis and proctocolitis,
810
schistosomiasis, 296
ulcerative colitis, 817b
Sildenafil, 440
Silicosis, 615-616, 615 f
Silicotuberculosis, 615-616
Simple aspergilloma, 596-597, 597 f
Simple diffuse goitre, 648, 648f
Simple tandem repeat mutations, 43,
43b
Simulium spp., onchocerciasis, 292
Simvastatin
for stroke prevention, 11617
timing, 31b
Sinemet, 1113
Single-layered retinal pigment
epithelium, 1167
Single nucleotide polymorphisms (SNPs;
snips), 42
Single photon emission tomography
(SPECT), 1072
Sinoatrial disease, 469b, 469f, 471b
Sinoatrial (SA) node, 445, 445f
Sinus arrhythmia, 469
Sinus bradycardia, 469
Sinus tachycardia, 469, 469b
Sinusitis see Rhinosinusitis
Sinusoidal obstruction syndrome, 899
Sipple’s syndrome, 689b
SIRS (systemic inflammatory response
syndrome), pancreatitis, 838b
Sister Joseph’s nodule, 804
Sitagliptin, 747
Sitosterolaemia, 375, 375 b
Sixth disease, 238
Sjogren’s syndrome, 1038-1039,
1039b, 1171
Skeletal muscle, 987-988
Skin
blood vessels and nerves in, 1214
changes in old age, 1215b
of envenomed patient, 1 527
epidermal appendages of,
1212-1214
examination of
cancer, 1315b
endocrine disease, 630f
gastrointestinal disease, 764f
function of, 1214, 1214b
functional anatomy and physiology of,
1212-1214
imaging, 1216
immunobullous disease of,
1255-1257, 1255b
infestations, 1235-1241
inflammatory arthritis in, 994b
lichenoid eruptions in, 1252
microbiology of, 1215
as physical barrier, 62-63
systemic lupus erythematosus in,
1035f
systemic sclerosis in, 1037, 1037f
Skin cancer, 1 229
non-melanoma, 1228, 1230b
pathogenesis, 1229
see also names of specific tumours
Skin disease
abnormal pigmentations in, 1224
acute skin failure in, 1224-1225
clinical examination in, 1210, 121 Of
in general medicine, 1261-1267,
1261b
investigation of, 1214-1216
management of, 1 225-1 229
nail involvement in, 1260-1261
ophthalmic features of, 1 1 66b
phototherapy and
photochemotherapy for, 1 227
pigmentation disorders as,
1257-1258
presenting problems in, 1216-1225
terminology in, 121 If
treatment of
non-surgical, 1228-1229
surgery for, 1 228
systemic, 1227-1228
topical, 1225-1227, 1225b
Skin grafts, vitiligo, 1257-1258
Skin infections, 1235-1241
bacterial, 1235-1238
fungal, 1239-1240, 1240f
mycobacterial, 1237-1238
tropical, 234, 234b, 235 f
viral, 1238-1239
Skin lesions, benign, 1234-1235
Skin-prick tests, for allergy, 86
Skin snips, 234b
Skin tags See Acrochordon
Skin test
asthma, 613-614
patch tests, 1215
prick tests, 86, 1215
tuberculin, 594, 594f
Skin tumours, 1 229-1 235
malignant, 1229-1234
pathogenesis of, 1 229
Skinfold thickness, 693f
Slapped cheek syndrome, 237, 237 f
SLE see Systemic lupus erythematosus
Sleep, 1071
Sleep apnoea/hypopnoea syndrome,
622-624
aetiology of, 623
clinical features of, 623
investigations of, 623, 623b-624b,
623 f
management of, 623-624
Sleep-disordered breathing, 622-624
Sleep disorders, 1 1 05-1 1 06
Sleep disturbance, 1094
Sleep paralysis, 1 094
Sleepiness
Epworth scale, 623b, 1105
persistent, differential diagnosis,
624b
see also Hypersomnolence
Sleeping sickness, 278-279, 278 f
Sleeve gastrectomy, 703 b
Small bowel bacterial overgrowth,
causes of, 808b
Small-bowel diarrhoea, HIV-related,
317, 317b, 31 7f
Small bowel surgery, proximal,
under-nutrition and, 706
Small bowel transplantation, 710
complications of, 710b
indications for, 710b
Small interfering RNA (siRNA), 27 b
Small intestine
bacterial overgrowth, 808-809
diseases/disorders of, 805-813
functional anatomy of, 767-770, 767f
infections of, 812-813
miscellaneous disorders of, 811-812
motility disorders, 810-81 1
protective function of, 769-770
tumours of, 813
ulceration of, 811, 811b
Small-vessel vasculitis, 409
Smallpox (variola), 248
Smell, disturbance of, 1088
Smith-Magenis syndrome, genetics, 44b
Smoking
and autoimmune disease, 82-83
cannabis, 143
and cardiovascular risk, 420
cocaine, 143
effects on health, 94
familial hypercholesterolaemia, 374b
freezing cold injury, 1 66
heart failure and, 465b
lung cancer and, 1320-1321
in older people, 1305
peptic ulcer and, 799
urinary incontinence, 436
Smoking cessation
acute coronary syndrome and, 501
in Graves’ ophthalmopathy, 646
Smooth muscle atrophy, systemic
sclerosis and, 1037-1038
Snail track ulcers, 337
Snake bites, 134
Snakes, geographical distribution of,
153
Snakeskin gastropathy, 871
Snoring, 623
SNPs see Single nucleotide
polymorphisms
Social isolation, psychiatric disorders
and, 1184
Social worker, 1303b
Sodium, 349b, 718
depletion, 349
dietary sources of, 717b
excess, 354b, 354f
homeostasis, 349-355
intake, chronic renal failure, 418
presenting problems of, 352-355
in primary hyperaldosteronism, 674
reabsorption, 384
reference nutrient intake of, 717b
reference range of
urine, 1361b
venous blood, 1358b
restriction of, for ascites, 863
retention of, 395, 864b
transport, 351-352, 352 f
see also Hypernatraemia;
Hyponatraemia
Sodium aurothiomalate (gold), 1005
Sodium bicarbonate
chronic kidney disease, 418
drug interactions, 24b
salicylate poisoning, 138
in urinary alkalinisation, 136
Sodium calcium edetate, 137b
Sodium chloride
dietary, 718
see also Saline
Sodium cromoglicate
for allergy, 86
for food allergy, 812
Sodium-dependent glucose transporter
inhibitors, for hypervolaemia, 354
Sodium ipodate, 639
Sodium nitroprusside
aortic dissection, 508
hypertension, 514
phaeochromocytoma, 676
Sodium phosphate, 368
Sodium-potassium pump, 349
Sodium stibogluconate, 128
Sodium valproate
bipolar disorder, 1 200
cluster headache, 1096
epilepsy, 1102b, 1284
pregnancy, 1103, 1103b
1410 • INDEX
Sodium valproate (Continued)
for epilepsy, 1 1 00b
neutropenia, 926 b
poisoning, 1416
sodium retention and, 8646
status epilepticus, 10816
steatosis, 894
SOFA score, 2146
Soft tissue infections, 226-227
necrotising, 2276
Soft tissue release, 1 0026
Solar urticaria, 12216
Solitary rectal ulcer syndrome, 836
Solvent inhalation, 1196
Somatic hypermutation, 68, 68 f
Somatic mutations, 50-51
Somatic symptoms, medically
unexplained, 1187, 11876,
11896, 12036, 1 205f
Somatic syndromes, functional, 11876
Somatisation disorder, 1 202
Somatoform autonomic dysfunction,
1202
Somatoform disorders, 1 202-1 203
advice for, 1 203
prevalence of, 1 1 806
Somatoform pain disorder, 1 202
Somatosensory system, 1070-1071,
1071f-1072f
Somatostatin, 767, 7726
Somatostatin analogues, for
neuro-endocrine tumours (NETs),
679
Somatostatin receptor scintigraphy
(SRS), 7786
Somatostatinoma, 6786
Somnolence
daytime, 1105-1106
idiopathic hypersomnolence, 623
Sorafenib, for hepatocellular carcinoma,
892
Sorbitol, 812
Sotalol, 140
South American botfly, 300
Space-occupying lesions, HIV-related,
320-321
Space of Disse, 849
cirrhosis and, 866
Sparganosis, 299
Spastic catch, 1068-1069
Spastic paraplegia, hereditary, 1 1 386
Spasticity, 1068-1069
Specialised receptors, 1338
Specialist nurse, 1 1 09-1 1 1 0
Spectinomycin, 1176, 122
Spectrophotometry, 3486
Spectroscopy (ICP-MS), 3486
Speech disturbance, stroke and,
1152
Speech/speech disorders, 1070, 1070f,
1087-1088, 1088f
assessment of, in psychiatric
interview, 1181
Speech therapy, for Parkinson’s
disease, 1114
Spermatogenesis, 651 f
Spherocytes, 915, 9216, 921 f
Spherocytosis, hereditary, 947
investigations of, 947, 948f
management of, 947, 9486
Sphincter
anal, 437
bladder, 386
control, 1070-1071
urethral, 103, 436
Sphincter of Oddi, 849-850
dysfunction of, 908-909
classification of, 9086
pancreatic, criteria for, 9086
Sphincterotomy
biliary, 906
endoscopic, in old age, 9096
Sphygmomanometry, 510
Spider bites, 1 61
Spider naevi, 846f
autoimmune hepatitis and, 886
Spider telangiectasia, 866-867
Spiders, envenomation of, 161
Spina bifida, 715, 11386
Spinal cord, 1067, 1338-1339
compression, 1136-1137, 11366,
1 137f
cancer and, 1326, 13266
in rheumatoid arthritis, 1024, 1025f
disorders of, 1 134-1137
intrinsic diseases of, 1137, 1 1 377,
11386
lesions, sensory loss, 1 083
Spinal cord syndrome, 11366
Spinal epidural abscess, 1 1 25
Spinal muscular atrophy, 1117
Spinal root lesions, 1141
Spinal stenosis, 1135-1136
Spine
assessment of, 983f
bamboo, 1030-1031, 1 0317
cervical
imaging of, 1074, 1075f
myelopathy, 1134-1135
radiculopathy, 1134, 1134f
spondylosis, 1 1 34-1 1 35, 1 1 34f
subluxation of, 1024, 1025f
disorders of, 1134-1137
lumbar, imaging of, 1074, 1075f
osteoarthritis, 1011, 101 If
thoracic, imaging of, 1074, 1075f
Spinobulbar muscular atrophy, 436
Spinocerebellar ataxia, 436, 11166
Spiramycin, 281
Spirillum minus, 2346
Spirometry
asthma, 569
COPD, 575
Spironolactone
ascites, 864
ascites and, 864
gynaecomastia, 6576
heart failure, 465
Splanchnic vasodilatation, for ascites,
862-863
Spleen, 67
enlarged see Splenomegaly
examination of, 9136
Splenectomy
for chronic lymphocytic leukaemia,
960
for idiopathic thrombocytopenic
purpura, 971
for myelofibrosis, 969
Splenomegaly, 927, 9286
cirrhosis and, 867
portal hypertension and, 868
Splice site mutations, 43f
Splicing, 40
Splinter haemorrhages, 9946, 1260
Splints, for musculoskeletal disease,
1001
Spondylitis, psoriatic, 1032
Spondyloarthritis, axial, 10286,
1029-1030, 1029f
Spondyloarthropathies (SPAs),
1027-1034, 10286
seronegative, 11666
Spondylolisthesis, 996-997, 1059-1060
Spondylolysis, 1 059-1 060
Spondylosis
cervical, 1134-1135, 1134f
lumbar, 1135-1136
Spondylotic myelopathy, cervical, 10826
Spongiosis, 1244
Spontaneous bacterial peritonitis, 864
Spontaneous breathing trials, respiratory
support and, 210
Spontaneous hypoglycaemia, 676-678
cause of, 677-678
clinical assessment of, 677
differential diagnosis of, 677 f
investigations of, 677-678
management of, 678
in old age, 6786
Sporadic fatal insomnia, 1 1 276
Sporothrix schenckii, 301
Sporotrichosis, 301
Sporozoites, malaria, 273-274
Spreading depression of Leao, 1095
Sprue, tropical, 233
Spurious full blood count results, from
autoanalysers, 919-920, 9206
Sputum, 546f
cough, 556
cytology, 554
haemoptysis, 559
investigations, 554
Pneumocystis jirovecii pneumonia,
318
in pulmonary oedema, 546f
pulmonary tuberculosis, 31 8
Squamous carcinoma, 7966
Squamous cell carcinoma, skin,
1230-1231, 12306, 1231f
SRS see Somatostatin receptor
scintigraphy
SSPE see Subacute sclerosing
panencephalitis
SSSS see Staphylococcal scalded skin
syndrome
St John’s wort, drug interactions, 246
St Vitus dance, 516
Stable angina
advice to patients with, 4896
risk stratification in, 4886
Staging, in lung cancer, 602, 602f
Stamping gait, 1087
Stannosis, 614-615
Staphylococcal food poisoning, 262
Staphylococcal infections, 250-252,
251 f
cannula-related, 251-252, 2516
meth ici 1 1 i n -resistant Staphylococcus
aureus, 252
skin, 251
staphylococcal toxic shock syndrome,
252, 252 f
wound, 251 , 251 f
Staphylococcal scalded skin syndrome,
1236, 1 236f
Staphylococcal toxic shock syndrome,
252, 252 f
Staphylococcus aureus, 1046, 1176,
251
acute leukaemia, 957
atopic eczema, 1 2466
bacteraemia, 225
blood-stream infection, 2256
bronchiectasis, 579
cerebral venous sinus thrombosis,
1162
chronic granulomatous disease, 77
fever, 223, 223 f
folliculitis from, 1236-1237
impetigo from, 1235-1236
infections caused by, 251 f
infectious keratitis, 1 1 736
infective endocarditis, 527
meningitis, 11196
pneumonia
bacterial, 319
community-acquired, 5826, 5846
in septic arthritis, 1 020
skin infections, 251 f
vancomycin-resistant, 252
Staphylococcus epidermis, 251
Staphylococcus intermedius, 251
Staphylococcus saprophyticus, 251
Starches
dietary, 695-697
hydrolysis, 768
polysaccharides, 6966
resistant, 265
Starling’s law, 461 , 461 f
Starvation, 704-705
infections associated with, 7056
STAT proteins, 64-66
Statins, 376
for acute coronary syndrome
prevention, 4986
hepatotoxicity of, 8946
for hypertension, 513
for non-alcoholic fatty liver disease,
885
for stroke prevention, 1161 f
Statistics, 10
Status epilepticus, 1080, 10816,
1103
Steady state, 1 9
Steatohepatitis, non-alcoholic, 882-883,
883 f
Steatorrhoea
bile acid diarrhoea, 809
cystic fibrosis, 842
malabsorption, 783-784, 7846
small bowel disorders, 808
Steatorrhoea, pancreatitis, 840
Steatosis, 882-883, 894
Stellate cells, 772
Stem cell factor, 91 4
Stem-cell plasticity, 914-915
Stem cells, 914-915, 915 f
plasticity, 914-915
pluripotent, 954
Stenosis
aortic, 4436, 521-524, 5226, 522 f
causes of, 5216
Doppler echocardiography for, 451 f
investigations of, 522-524, 5236,
523 f
in old age, 5246
lumbar canal, 1135-1136
mitral, 517-519, 5186, 51 8f
chest X-ray for, 451 f
investigations in, 51 8f, 5196
pregnancy and, 1282
pulmonary, 526
renal artery, 406-408, 4076, 407f
spinal, 1135-1136
tricuspid, 525-526
Stents/stenting
aortic dissection, 508
carotid, 1160
cholecystitis, 905
colonic, 833f
coronary, 491 , 491 f
graft, 507 f
liver arterial disease, 898
for lung cancer, 603
myocardial infarction, 1282
pregnancy and, 1282
renal artery, 389
superior vena cava obstruction, 1327
thrombosis, 4936
ureteric, 414
Stercobilin, 851
Stercobilinogen, 851
Sterile pyuria, 430
Steroid hormones, pathways of
synthesis of, 667 f
Steroids
anabolic, 88
synthesis, 667 f
see also Corticosteroids
Stevens-Johnson syndrome, 316, 1224,
1254-1255
Stiff person syndrome, 11116
Still’s disease
adult, 895, 1040
see also Juvenile idiopathic arthritis
Stimulant, misuse of, 1195-1196
Stimulation therapies
for cancer pain, 1353
for pain, 1347, 1347f
Stings
insect, 756
scorpion, 159
see also Envenomation
Stockings, compression, 396
‘Stokes-Adams’ attacks, 477-478
Stomach
emptying, 778
erosions, 781 f
functional anatomy of, 766-767, 766 f
outlet obstruction, 801-802, 8016
tumours of, 803-805
ulcer, 798-802
Stomatitis
angular, 764f, 817
herpetic, 247f
Stones see Calculi (stones)
Stool cultures, 111
Stop codons, 40
Storage disorders, 9296
Stratum corneum, 1212
Strawberry gallbladder, 909
Strawberry tongue, 252, 253 f
Streptococcal infections, 252-253, 2536
acute rheumatic fever, 515, 5176
bone and joint, 1020
INDEX • 1411
in pregnancy, 235 b
tics, 1086
Streptococcal toxic shock syndrome,
21 7f, 253
Streptococci, 102f
alpha-haemolytic, 1 02f
beta-haemolytic, 1 02f
group A, 252
group B, 252
Streptococcus anginosus, 103 f
Streptococcus constellatus, 103 f
Streptococcus intermedius, 103 f
Streptococcus mitis, 528
Streptococcus pneumoniae, 67, 73 b,
117 b, 266, 1277b
in community-acquired pneumonia,
582, 582 f
meningitis, 1 1 1 9b-1 1 20 b
peritonitis, 836
sepsis, 226 b
Streptococcus pyogenes, 103 f, 117 b
Streptococcus suis, 1119
bacterial meningitis, 1 1 20 b
Streptococcus viridans endocarditis,
401
Streptokinase, Budd-Chiari syndrome
and, 899
Streptomyces, 1238
Streptomycin
adverse reactions, 593b
as antimycobacterial agents, 1 25
mycetoma, 301
plague, 259
tuberculosis, 97 f
for tuberculosis, 593
Stress
acute reaction, 1201
oxidative, 881 f, 883
post-traumatic stress disorder,
1201-1202
Stress echocardiography, 452
Stress electrocardiography, 449-450
Stress fracture, 995b
Stress incontinence, 436
in older people, 1309-1310
Stress-related disorders, 1201-1202
Stressors, psychiatric disorders and,
1184
Stretch reflex, 1068
Striae, definition of, 1226f
Strictures, endoscopic techniques for
management see Endoscopy
Stridor
aortic aneurysm, 505
bronchial obstruction, 600
connective tissue disorders, 610b
hypocalcaemia, 663
inspiratory, 566
laryngeal disorders, 624
tracheal disorders, 625
String test, 287
Stroke, 952, 1153-1160
anatomy and physiology of,
1150-1151, 1150 f
classification of, 1 1 50 f
clinical examination of, 1148, 11 48 f
clinical features of, 1 1 50 f, 1 1 55-1 1 57,
1155b, 1156 f
completed, 1157
complications of, 1 1 59 f
differential diagnosis of, 1 1 55 b
general examination of, 1149b
heat, 167-168
HIV-related, 321
investigations of, 1151-1152,
1157-1158, 1157b
blood tests, 1151-1152
cardiac, 1 1 58
cardiovascular, 1152
lumbar puncture, 1 1 52
neuroimaging, 1151, 1 1 51 A
1 1 57-1 1 58
vascular imaging, 1151, 11 52 f,
1158
management of, 1 1 58-1 160, 11 58 f
aspirin, 1160
carotid endarterectomy and
angioplasty, 1160
coagulation abnormalities, 1 1 60
heparin, 1160
reperfusion (thrombolysis and
thrombectomy), 1 1 59-1 1 60
supportive care, 1 1 58-1 1 59,
1159b
unusual causes, 1 1 60
medicine for, 1 1 47-1 1 62
migraine and, 1095
pathophysiology of, 1 1 53-1 1 55
cerebral infarction, 1 1 53-1 1 54,
1 1 537-1 1 547
intracerebral haemorrhage,
1154-1155, 1155b, 11557
pregnancy and, 1284
presenting problems of, 1 1 52-1 1 53
ataxia, 1 1 53
coma, 1153
headache, 1153
seizure, 1 1 53
speech disturbance, 1 1 52
visual deficit, 1 1 52
visuo-spatial dysfunction, 1152
progressive (in evolution), 1157
rapid assessment of, 1 1 49b
risk factors for, 1 1 53 b
analysis, 1157, 1157b
management, 1160
secondary prevention of, 11617
Stroke mimics, 1 1 55 b
Stroke units, 1 1 58
Stroke volume, 446
pregnancy and, 1272
Strongyloides hyperinfection syndrome,
226 b, 289
Strongyloides stercoralis, 231 b, 233b,
289, 612
Strongyloidiasis, 233b, 289, 289b
Subacute cutaneous lupus
erythematosus (SCLE), 1262
Subacute invasive aspergillosis (SIA),
597
Subacute sclerosing panencephalitis
(SSPE), 236, 1123
Subacute (de Quervain’s) thyroiditis,
646-647
Subarachnoid haemorrhage,
1160-1162
clinical features of, 1161, 11 62 f
investigations of, 1161
management of, 1 1 62
see also stroke
Subclavian steal, 504
Subclinical hypothyroidism, 642
Subclinical thyrotoxicosis, 636b, 638,
642
Subclinical urethritis, 334b
Subcutaneous administration, 17
Subcutaneous androgen replacement
therapy, 656b
Subdural empyema, 1 1 25
Subdural haematoma, 864-865
Sublingual administration, 17
Substance misuse, 1184, 11 84b
prevalence of, 1 1 80 b
Substance misuse disorder, 1195-1196
Substance P, 1 003-1 004
Subtotal thyroidectomy, for Graves’
thyrotoxicosis, 644b, 645
Subtotal villous atrophy, important
causes of, 806b
Subungual haematoma, in nails, 1260f
Succinate dehydrogenase, 49b
Sucralfate, 801
Sudden death
due to heart failure, 464
in raised ICP, 1128
Sugars
dietary, 696b
recommended intake, 698b
Suicide
anorexia nervosa, 1 204
attempted, 1187
bipolar disorder, 1200
depression, 1198
low mood, 1185
old age, 1 1 89b
risk factors for, 1 1 87 b
schizophrenia, 1198
see also Self-harm
Sulfadiazine
prophylactic, 119b
rheumatic fever, 51 7
toxoplasmosis, 281 , 320
Sulfadoxine, and neutropenia, 926b
Sulfamethoxazole, melioidosis, 261
Sulfasalazine (SSZ)
in haemolysis, 950
for inflammatory bowel disease, 821b
for musculoskeletal disease,
1004-1005, 1004b
prophylactic, 1 1 9b
Sulfinpyrazone, gout, 1016
Sulindac, 829
Sulphonamides
mechanism of action, 1 1 6b
in pregnancy, 120b
Sulphonylureas
effect of hepatic impairment, 32 b
effect of renal insufficiency, 32 b
for hyperglycaemia, 746-747
weight gain and, 700 b
Sulphur, 718
Sulpiride, 1115
Sumatriptan, for migraine, 1096
Sunbed exposure, cancer and, 1229
Sunburn, 1 2217
SUNCT, 1097, 1097b
Sunflower cataract, in Wilson’s disease,
11747
Sunitinib, 435
Sunlight
melanoma and, 1232
sensitivity to, 1 036b
Sunscreens, 1222-1223
albinism and, 1258
melanoma and, 1233
photosensitivity, 1221b
protection levels, 1222-1223
vitiligo and, 1257-1258
Superficial bursitis, 999b
Superior vena cava, 4447
Superior vena cava obstruction (SVCO),
1314f, 1315b
cancer and, 1326-1327, 1327b
Superior vena cava syndrome, 505
Superoxide dismutase, 1116
Supported self-management, for pain,
1344
Suppurative pneumonia, 586-587, 587 b
Supranuclear palsy, progressive,
1114-1115
Supraventricular tachycardia, 473, 473 f
Suramin, for trypanosomiasis, 128
Surfactant, 548-549
Surgery
for acromegaly, 686
bariatric, 7027-7037, 703-704, 703 b
for brain tumours, 1 1 30
for cholecystitis, 905
for chronic obstructive pulmonary
disease (COPD), 577
for epilepsy, 1102
gastrointestinal
achalasia, 795
haemorrhage, 782
prophylactic, 1 1 9b
for lung cancer, 602
for musculoskeletal disease, 1002,
1002b
osteoarthritis, 1012
osteoporosis, 1049
rheumatoid arthritis, 1026
for obesity, 7027-7037 703-704,
703 b
for Parkinson’s disease, 1114
for primary hyperparathyroidism, 664
for prolactinoma, 685
for psychiatric disorders, 1 1 90
Surrogate endpoints, 35-36
Sustained virological response (SVR),
878
Suxamethonium
allergy, 75 b
pharmacokinetics, 20 b
Swallowing, difficulty in see Dysphagia
Swan-Ganz catheter, 206, 2077
Swan neck deformity of fingers, 1023,
10237
Sweat glands, 1213-1214
Sweating, excessive, 217b
Sydenham’s chorea, 516
Symmetrical polyarthritis, 1032
Symmetrical sensory polyneuropathy,
diabetic, 758-759
Sympathetic nervous system, sodium
transport regulation in, 352
Synaptic transmission, 1 065
Syncope, 181-183, 455
clinical assessment of, 1 82-1 83
congenital heart disease and, 533
differential diagnosis of, 1 827
features of, 181b
gastrointestinal haemorrhage, 780
heat, 167
investigations of, 1 83
in older people, 1308
presentation of, 181-182
seizures versus, 182 b
Syndesmophytes, 988
Syndrome of inappropriate secretion of
ADH (SIADH), 357 b
Synergistic gangrene, 227, 227b
Synovectomy, 1002b
for rheumatoid arthritis, 1026
Synovial biopsy, 992
Synovial fluid, 987, 9887
in septic arthritis, 1020
Synovial joints, 987
structure of, 9877
Synovial membrane, 987
Synoviocytes, 987
Synovitis, pigmented villonodular, 1 059
Synovitis-acne-pustulosis-hyperostosis-
osteitis (SAPHO) syndrome,
1060
Synovium, 987
loose bodies within, 988
needle trauma to, 988
in osteoarthritis, 1 008
Synthetic cannabinoid receptor agonist,
misuse of, 1 43
Syphilis, 253, 337-339
acquired, 337-338
benign tertiary, 338
cardiovascular, 338
classification of, 337 b
congenital, 338-339, 338b
dementia and, 339
early, 337-338
investigations of, 338-339
late, 338
latent, 337-338
management of, 339
neurosyphilis, 338, 1125, 1125b
in pregnancy, 235b, 339
primary, 337, 3377
secondary, 337
rash in, 1217b
serological tests for, 339b
treatment reactions of, 339
Syringomyelia, 1083
Systemic disease, 785
Systemic glucocorticoids, for
musculoskeletal disease, 1 005
Systemic inflammatory response,
196-198
initiation of, 1 96
propagation of, 1 96
see also Sepsis
Systemic juvenile idiopathic arthritis,
1027
Systemic lupus erythematosus (SLE),
410-411, 1034-1037
classification of, criteria for, 1 036b
clinical features of, 1035-1036
investigations of, 1 036
management of, 1 036-1 037
pathophysiology of, 1 034
pregnancy and, 1281, 1281b
respiratory involvement in, 611
Systemic sclerosis (SSci), 410,
1037-1038, 10377, 1262
pregnancy and, 1280-1281, 1281b
respiratory involvement in, 611
Systemic vasculitis, 410
Systolic dysfunction, 450
Systolic murmurs, 459-460, 460b
1412 • INDEX
T
T-helper lymphocytes, HIV infection/
AIDS and, 310
T lymphocytes (T cells), 69-70, 69 f, 917
CD4+, 70
CD8+, 70
deficiency in, 73 b
primary, 79-80, 80 f
liver and, 849 f
lymphoma
cutaneous, 1224
enteropathy-associated, 813
multiple sclerosis, 1106
skin, 1212
psoriasis, 1248/
T-regulatory cells (T regs), 70
Tabes dorsalis, 1125b
Tachycardia, 191-193
assessment and management of,
192-193
pathophysiology of, 1 91 -1 92
sinus, 469, 469b
supraventricular, 473, 473/
ventricular, 475-476, 475b,
475f-476f
poisoning, 137b
pulseless, 457
Tachyphylaxis, 16
Tachypnoea, 190, 1917
assessment and management of,
190, 1917
pathophysiology of, 1 90
Tacrolimus, 1281b
liver transplantation and, 901
nephrotoxicity, 427b
thrombocytopenia, 971
vitiligo, 1257-1258
Tactoids, 951-952
Taenia asiatica, 298
Taenia echinococcus, 298-299
Taenia saginata, 298
Taenia solium, 297 f, 298
Takayasu arteritis, 1041
Takotsubo cardiomyopathy, 541, 541 7
Tamm-Horsfall protein, 392
Tamoxifen
breast cancer, 1 334
desmoid tumours, 829
gynaecomastia, 657
Tamponade
balloon, for variceal bleeding,
870-871 , 870/
cardiac, 447-448
Tamsulosin, 438
Tandem repeat mutations, 43, 43b
Tangent/Goldmann kinetic perimetry,
1168
Tangier disease, 375, 375 b
Tanner staging, 1290, 1292f
Tapeworms, 297-299
Tarsal tunnel syndrome, 1024
Tarui disease, 370 b
Tay-Sachs disease, 371b
Tazobactam
for spontaneous bacterial peritonitis,
864
for variceal bleeding, 869
TB see Tuberculosis
TBG see Thyroxine-binding globulin
TBW see Total body water
99mTc-sestarnibi scintigraphy, for primary
hyperparathyroidism, 663-664,
664 f
TCAs see Tricyclic antidepressants
Team communication, effective, for
clinical decision-making, 10, 10b
Teardrop poikilocytes, 969
Teduglutide, for intestinal failure, 710
Teenagers, adherence in, 1294-1295
Teichopsia, 1088
Teicoplanin, 117b, 123
adverse effects of, 1 23
Telangiectasia
definition of, 1 226
hereditary haemorrhagic, 970
spider, liver disease and, 866-867
Telaprevir, 878 b
Teletherapy, 1331
Telomerase, 1318
Telomeres, 1304-1305
Telophase, 40
Temperature, 94
abnormal, 1 657
body, 165
cold injury and, 166-167
elevated body, 1 67 b
extremes of, 1 65-1 68
heat-related illness and, 167-168
hypothermia and, 165-166,
1 657—1 667
of stroke patients, 1 1 59 b
thermoregulation and, 165, 165b
Temporal artery biopsy, 992
Temporal coning, 1128, 1 1 287
Temporal lobes, 1066
disorders of, 1 089b
functions of, 1 066b
effects of damage, 1 066b
Temporary pacemakers, for arrhythmias,
482-483, 483f
Tendinitis
adductor, 999b
bicipital, 998b, 998 f
Tendon, xanthomas, 375
Tendon reflexes, root values of, 1063b
Tendon repairs and transfers, 1002b
Tenecteplase (TNK), 500
Tennis elbow, 998b
Tenofovir, 119b, 324b
for hepatitis B, 876
Tenosynovectomy, 1002
Tenosynovitis, 998
Tension-type headache, 1095
Teratogen, 22-23
Terbinafine, 125b, 126
chromoblastomycosis, 301
fungal infections, 1239-1240
sporotrichosis, 301
Terbutaline, asthma, 571
Teriparatide, for osteoporosis,
1048-1049, 1048b
Terlipressin, 864
for variceal bleeding, 869b, 870
Terminal illness see Palliative care
Terrorism see Bioterrorism
Testicular tumours, 439-440
Testis
epididymo-orchitis, 240
undescended, 653
Testosterone
for delayed puberty, 654
puberty and, 1290
reference range of, 1 359b
Tetanus, 104b, 1125-1126
prevention of, 1 1 26
treatment of, 1 1 26 b
Tetany, 663
Tetrabenazine, 1115
Tetracycline(s), 117b, 124
acne, 1243
adverse effects of, 1 24
bartonellosis, 272
brucellosis, 254
bullous pemphigoid, 1256
cholera, 265
drug interactions, 24b
mechanism of action, 116b
pharmacokinetics of, 1 24
plague, 259
in pregnancy, 120b
pyoderma gangrenosum, 1261-1262
relapsing fever, 257
rickettsial fevers, 271-272
rosacea, 1244
steatosis, 894
timing, 31b
trachoma, 273
tropical sprue, 808
Tetralogy of Fallot, 536-537, 536 f
Thl (T helper) cells, 70
Th2 cells, 70
Thl 7 cells, 70
Thalamus, 1066-1067
Thalassaemias, 951 , 953-954
alpha, 954
beta, 953-954
rheumatological manifestations of,
1058
Thalidomide
for Behget’s disease, 1 044
for multiple myeloma, 968
sarcoidosis, 610
Theophylline
asthma, 1277
plasma concentration, 36b
poisoning, 137b, 141b
tremor, 1116b
Therapeutic approach, 29, 29 b
Therapeutic drug monitoring, 119
Therapeutic efficacy, 1 6
Therapeutic goal, 29
Therapeutic index, 1 57, 16
Thermal injury, 950
Thermodilution, for measurement, of
cardiac output, 454
Thermogenesis, diet-induced, 694, 695f
Thermoregulation, 165, 165b
in old age, 1 66b
Thiabendazole, 129
Thiamin (vitamin B-,), 714
biochemical assessment of, 712b
deficiency, 714
dietary sources of, 711b
reference nutrient intake of, 711b
Thiamin pyrophosphate (TPP), 714
Thiazides
adverse effects, 355b
for hypertension, 513
for hypervolaemia, 355, 355 b
and hyponatraemia, 357 b
Thiazolidinediones, for hyperglycaemia,
747
Thienobenzodiazepines, 1198b
Thin glomerular basement membrane
disease, 404
Thiopurines, for inflammatory bowel
disease, 821b
Thioxanthenes, 1 1 98 b
Thirst
diabetes insipidus, 687
water homeostasis, 356
Thomsen’s disease, 1145b
Thoracic kyphoscoliosis, 628
Thoracic outlet syndrome, 1141b
Thoracoscopy, 553
Thorax, examination of, in respiratory
system, 546f
Thought
assessment of, 1181
passivity of, 1 1 96-1 1 97
Thought, passivity of, 1 1 96-1 1 97
Threadworm (Enterobius vermicularis) ,
129
Threonine, 697b
Thrombasthenia, Glanzmann’s, 970-971
Thrombin, 91 87—91 97
Thromboangiitis obliterans, 504
Thrombocythaemia, essential, 969-970
Thrombocytopenia, 929, 929b, 971
hepatobiliary disease and, 853
HIV-related, 322
pregnancy and, 1285, 1285b
Thrombocytopenic purpura (TTP),
pregnancy and, 1285
Thrombocytosis, 929-930, 929b
Thromboembolism
in cancer patients, 1324-1325
Heart failure causing, 464
venous, 975-977
causes and consequences of, 975,
976 f
factors predisposing to, 975b
management of, 975-976
pregnancy and, 1285
prophylaxis of, 976-977, 977 b
Thrombolytic therapy
for acute coronary syndrome, 500,
500b
for pulmonary embolism, 621
Thrombophilia, 977-979
acquired, 977-979
investigation of, 922-923, 923b
testing in, indications for, 922-923,
923 b
Thrombopoietin receptor agonists
(TPO-RA), for idiopathic
thrombocytopenic purpura, 971
Thromboprophylaxis, 472-473, 473b
in intensive care, 210
Thrombosed prolapsed haemorrhoids,
836 f
Thrombosis
deep vein
air travel and, 169
investigation of, 187, 1 87f
pre-test probability of, 1 87 b
pregnancy and, 1285
presentation of, 1 86
in stroke patients, 1 1 59f
warfarin for, 939
hepatic artery, 898
in old age, 978 b
Thrombospondin (TSP)-I, 1318
Thrombotic disorders, 922-923, 923b,
975-979
Thrombotic microangiopathies,
408-409, 408b
Thrombotic thrombocytopenic purpura
(TTP), 388, 409, 979
Thrush, 300
oral, 790
Thumb, Z deformity, 1 023
Thymectomy, myasthenia gravis, 1 1 42b
Thymine, 38
Thymus, 67
Thyroglobulin (Tg), 634, 635f
as tumour markers, 1324b
Thyroid autoantibodies, 637 b
Thyroid disease
autoimmune, 639b, 643-646
classification of, 634b
clinical features of, 637 b
congenital, 650-651
investigations of, 634-635
iodine-associated, 647-648
during pregnancy, 651b, 1279
hyperthyroidism as, 1 279
hypothyroidism as, 1 279
iodine deficiency as, 1279
post-partum thyroiditis as, 1279
presenting problems of, 635-643
Thyroid function tests
asymptomatic abnormal, 642
hypothyroidism, 636b
interpretation of, 636b
for obesity, 700
thyrotoxicosis, 636b
Thyroid gland, 634-651
enlargement of, 642-643, 642b
examination of, 631b
functional anatomy, physiology and
investigations of, 634-635, 635 f,
636 b
in old age, 650b
scintigraphy, 6387, 642
ultrasound, 643
Thyroid hormone, 634, 635f
in bone remodelling, 986b
replacement, for hypopituitarism, 682
resistance, 651
Thyroid lump or swelling, 642-643,
642b
Thyroid neoplasia, 649-650, 649b
Thyroid nodule, solitary, 642
Thyroid peroxidase antibodies, 640
Thyroid-stimulating hormone (TSH;
thyrotrophin), 632, 634
and free T4, relationship of, 634, 635 f
receptor antibodies (TRAb), 643
reference range of, 1 359b
Thyroid-stimulating immunoglobulins,
643
Thyroid storm, 639
Thyroiditis
Hashimoto’s, 646
post-partum, pregnancy and, 1279
Riedel’s, 650
subacute (de Quervain’s), 646-647
transient, 646-647, 646/
Thyrotoxic crisis, 639
Thyrotoxicosis, 635-639
in adolescence, 645, 645b
amiodarone and, 636b, 638 f,
647-648
atrial fibrillation in, 638
causes of, 636b
INDEX • 1413
clinical assessment of, 635-636, 637 5
differential diagnosis of, 638f
factitious, 637
goitre and, 635-636, 6365
Graves’ disease and, 635-636, 6365,
643-646, 643f
management of, 644-645, 6445
investigations of, 636-637,
6375-6385
iodide-induced, 6365
laboratory abnormalities, 6385
low-uptake, 637
management of, 637-639
in pregnancy, 645, 6515
subclinical, 6365, 638, 642
T4:T3 ratio in, 637
toxic adenoma in, 638f, 649
type I, 647-648
type II, 648
Thyrotrophin-releasing hormone (TRH),
633 f, 634
Thyroxine (T4), 633f, 634, 635 f
reference range of, 1 3595
thyroid-stimulating hormone (TSH)
and, relationship of, 634, 635 f
Thyroxine-binding globulin (TBG), 634
Tiagabine, 11025
Tibial compartment syndrome, anterior,
1058
Tibolone, for osteoporosis, 10485, 1049
Tic douloureux, 1 096-1 097
Ticarcillin, 1205
Tick-borne diseases, 2565
babesiosis, 278
Lyme disease, 255
rickettsial fevers, 270
tularaemia, 261
viral haemorrhagic fevers, 246
Tick-borne relapsing fever, 2565, 257
Tics, 1086
Tidal volume (TV), pregnancy and, 1273
Tietze’s syndrome, 1 775
Tigecycline, 1175, 124
Tiludronate, for Paget’s disease, 1 0545
Tin oxide, 6155
Tinea capitis, 1240, 1240f
Tinea corporis, 1 240
rash in, 12175
Tinea cruris, 1240, 1240f
Tinea incognito, 1240
Tinea pedis, 1240
Tinidazole, 287, 808-809
Tirofiban, 500, 918
Tissue biopsy, in musculoskeletal
disease, 992
Tissue factor pathway, assessing,
920-921
Tissue plasminogen activator, 447
Tizanidine, 11105
TNF inhibitors, pregnancy and, 1278,
1280
TNF receptor-associated periodic
syndrome, 81
TNF receptor-associated proteins
(TRAPS), 64-66
TNFRSF1A gene, TNF receptor-
associated periodic syndrome
and, 81
TNM classification, 13225
Tobramycin
cystic fibrosis, 5815
dosing interval, 122f
Tocilizumab, 1027
for musculoskeletal disease, 1007,
10075
a-Tocopherol see Vitamin E
Toe
cock-up deformities, 1023
ingrowing toenails, 1260
Tofacitinib, for musculoskeletal disease,
10045
Tolcapone, for Parkinson’s disease,
1114
Tolerance, 16
Toll-like receptors, 63
Tolterodine, 10945, 131 Of
Tongue
biting, 11025
strawberry, 252, 253f
Tonic-clonic seizures, 1099, 10995
Tonic seizures, 1100
Tonsillar coning, 1128, 1129f
Tonsillitis, 242-243
membranous, 2665
streptococcal, 252, 2535
Tonsils, 67, 91 2f
Tophi, 1014, 101 5f
Topical administration, 17-18
Topical agents, for musculoskeletal
disease, 1003-1004
Topical analgesics, for pain, 1345
Topiramate, for obesity, 702-703
Topoisomerase II inhibitors, 9365
Topotecan, ovarian cancer, 1334
Torsades de pointes, 476-477, 4765,
476f
Torticollis, 9975, 1116
Total anterior circulation syndrome
(TACS), 1 156f
Total body water (TBW), 349
Total iron binding capacity (TIBC), 942
Total lung capacity, 5555
Total parenteral nutrition
candidiasis, 302
gastroparesis, 803
Total thyroidectomy, for medullary
carcinoma, 650
Tourette’s syndrome, 1086
Toxic adenoma, 638f, 649
Toxic epidermal necrolysis, 1254-1255,
12545, 1 2547, 12665
Toxic megacolon, 818
Toxic pustuloderma, drug-induced,
12665
Toxic shock syndrome (TSS), 1236
staphylococcal, 252, 252 f
streptococcal, 21 7f, 253
Toxins
bacterial, 1125-1126
food-related poisoning, 149-150
ciguatera poisoning, 149-150
paralytic shellfish poisoning, 149
scombrotoxic fish poisoning, 150
gastrointestinal decontamination for,
135-136
plant, 150, 1505
venom, 154, 1545
Toxocara canis, 2335
Toxocariasis, 2335
Toxoplasma gondii, 280
life cycle of, 280 f
Toxoplasmosis, 280-281
clinical features of, 280, 281 f
congenital, 280
investigations of, 281
management of, 281
in pregnancy, 2355
Trace elements, absorption, 769
Tracheal disorders, 625
Tracheal obstruction, 625
Tracheo-oesophageal fistula, 625
Tracheostomy, in intensive care, 210,
2105
Trachoma, 273, 273 f
Trachyonychia, 1261
Tramadol, 1002
Tranexamic acid, 560, 597
Tranquillisers, effect of old age, 325
Trans-arterial chemo-embolisation, for
hepatocellular carcinoma, 892
Transcatheter aortic valve implantation,
527, 527 f
Transcobalamin II, 943-944
Transcription, of DNA, 38-40
Transcription factors, 39
Transcutaneous electrical nerve
stimulation (TENS), 1012
for osteoarthritis, 1012
Transdermal administration, 17
Transdermal androgen replacement
therapy, 6565
Transference, 1191
Transferrin, 13625
saturation of, 1 3625
Transforming growth factor beta
(TGF-pl), 849f
T ransfusion-associated graft-versus-
host disease (TA GVHD), 933
Transfusion medicine
haematology and, 911-979
key points in, 9365
Transfusion-transmitted infection, 933
Transient ischaemic attack (TIA),
1156-1157
causing sensory loss, 1083
causing visual loss, 1088
Transient ocular ischaemia, 1171
Transient thyroiditis, 646-647, 646f
Transition medicine, adolescent and,
1287-1300
clinical assessment in, 1293
features of, 1 2935
clinical presentations in, 1296-1300
diabetes and, 1299
functional anatomy and physiology in,
1290-1292
cognitive and behavioural changes
in, 1292
endocrine changes in, 1290, 1 291 f
physical changes in, 1290
gastrointestinal disease and,
1299-1300
inflammatory bowel disease and,
1299-1300
investigations in, 1293, 12935
neurological disease and, 1296-1297
cerebral palsy in, 1296
epilepsy in, 1296
muscular dystrophy in, 1297
oncology and, 1298
organ transplantation and, 1299
presenting problems in, 1294-1296
adherence as, 1294-1295
high-risk behaviour as, 1 295
unplanned pregnancy as,
1295-1296
renal disease and, 1298-1299
respiratory disease and, 1297
cystic fibrosis in, 1297
rheumatology and bone disease and,
1300
glucocorticoid-induced
osteoporosis in, 1300
hypophosphataemic rickets in,
1300
juvenile idiopathic arthritis in, 1300
osteogenesis imperfecta in, 1300
transition from paediatric to adult
health services in, 1288-1290
principles of prescribing during,
1289, 12895
readiness for, key features in,
12895
timing of, 1290, 1290f
transition planning in
effectiveness of, 1 288
general principles of, 1288-1289,
1288f
reasons to consider, 1 288 f
systematic approach to,
1289-1290
transition referral letter in, 1293
Transition planning
effectiveness of, 1 288
general principles of, 1288-1289,
1288f
impact of, on outcome in diabetes,
12995
reasons to consider, 1 288f
systematic approach to, 1289-1290
Transjugular intrahepatic portosystemic
stent shunt (TIPSS)
for ascites, 864
for variceal bleeding, 871, 871 f
Translation, 397, 40
T ransoesophageal echocardiography
(TOE), 452
Transplantation
cardiac, 467-468
in diabetes mellitus, 752
graft rejection and, 88-90
investigations in, 89
haematopoietic stem cell, 936-938
for acute leukaemia, 958
allogeneic, 936-937, 9365-9375
autologous, 936-938
fever after, 224-225
for high-grade NHL, 966
infections during recovery from,
9375
immunosuppression in
complications of, 89-90
drugs used in, 895
of islet cell, 752, 753 f
of kidney, 424
of liver, 900-901
for acute liver failure, 858-859
for alcoholic liver disease, 882
complications of, 901
for hepatic encephalopathy, 865
for hepatitis B, 876
for hepatitis C, 878
for hepatocellular carcinoma, 891
indications and contraindications
for, 900-901, 9005, 901 f
living donor, 901
for primary biliary cholangitis, 888
prognosis for, 901
split liver, 901
for Wilson’s disease, 897
for low-grade NHL, 965
lungs, 567, 5675
multivisceral, 710
complications of, 7105
organ donation and, 90
pre-implantation testing in, 89
renal, 424-426
in diabetic nephropathy, 758
recipients of, pregnancy and, 1283
small bowel, 710
complications of, 7105
indications for, 7105
transition medicine and, 1299
transplant rejection and, 88-89
classification of, 885
Transportation, for envenomed patient,
157
Transposition of great arteries, 5315
Transrectal ultrasound scan (TRUS) of
prostate, 437-438
Transverse myelitis, 1110
Tranylcypromine, 11995
TRAPS see TNF receptor-associated
periodic syndrome
Trastuzumab, 1332
Trauma
head, 1133
nails, 1260
Travellers
eosinophilia, 233
fever in, 2315, 231 f
health needs, 2305
incubation times and illnesses, 2325
rash, 2345
Traveller’s diarrhoea, 2325
Treadmill, for exercise
electrocardiography, 449-450
Trefoil factor family (TFF) peptides, 767
Trematodes, 294-297
Tremor, 1085, 1115
causes and characteristics of, 1 0855
drug-induced, 11165
dystonic, 10855
essential, 10855, 1115
flapping, hepatic encephalopathy and,
864-865
functional, 10855
intention, 1069
Parkinson’s disease causing, 10855
resting, 1081
Trench fever, 272
Trench foot, 167
Trephine biopsy, 920, 922 f
Treponema pallidum, 1175, 333, 336
in pregnancy, 3325
Treponema pertenue, 253
Treponema vincentii, 254
Treponemal (specific) antibody tests,
339
Treponematoses, 253-254
endemic, 253-254
see also Syphilis
Triamcinolone, 790
Triamterene, 355
Triazoles, 1255, 126
Tricarboxylic acid (Krebs) cycle, 714
1414 • INDEX
Triceps skinfold thickness, 693d
Trichiasis, 273
Trichinella spiralis, 293
Trichinellosis, 293-294
Trichinosis, 293-294
Trichloroacetic acid, 1239
Trichomonas vaginalis, 333
Trichomoniasis, genital, 335
Trichophyton rubrum, 1240
Trichophyton verrucosum, 1240
Trichuris trichiura (whipworm), 290
Triclabendazole, 297 b
Tricuspid regurgitation, 526, 526b
Tricuspid stenosis, 525-526
Tricuspid valve, disease of, 525-526
Tricyclic antidepressants, 1199, 1199b
poisoning from, 138-139, 139b, 1 39f
Trientine dihydrochloride, Wilson’s
disease, 897
Trigeminal (5th cranial) nerve, tests of,
1063b
Trigeminal neuralgia, 1080, 1096-1097
Trigger finger, 1060
Triglycerides
measurement, 373
reference range of, venous blood,
1360b
Trihexyphenidyl, for Parkinson’s disease,
1114
Triiodothyronine (T3), 633f, 635 f
reference range of, 1 359b
Trimethoprim
acne vulgaris, 1243
brucellosis, 255 b
listeriosis, 260
mechanism of action, 116b
melioidosis, 261
in pregnancy, 120b
urinary tract infection, 428
Triple X syndrome, 44b
Triptans, 17, 1096
Trismus, 1126
Trisomy 13 (Patau’s syndrome), 44b
Trisomy 18 (Edwards’ syndrome), 44b
Trisomy 21 (Down’s syndrome),
genetics, 44b
Trochanteric bursitis, 999b
Trochlear (4th cranial) nerve, tests of,
1063b
Troisier’s sign, 804
Tropheryma whipplei, 100, 106, 809
Tropical diseases
diarrhoea, 232-233
eosinophilia, 233-234
fever, 230-232
skin, 234
Tropical fever, 230-232
causes of, 231b
clinical assessment of, 230-232,
232 b
history taking in, 231b
investigations of, 232, 232 b
management of, 231 f, 232
Tropical pulmonary eosinophilia, 612
Tropical sprue, 233, 807-808
Tropical ulcer, 254, 254b
Tropomyosin, 446
Troponins
cardiac, 450
reference range of, venous blood,
1360b
Trousseau’s sign, 367
‘True’ polycythaemia, 925
Truncus arteriosus, 531-532
Trunk, examination of, in
musculoskeletal system, 982 f
Trypanosoma brucei gambiense
infection, incubation period of,
111b
Trypanosoma cruzi, 794-795
Trypanosomiasis
African (sleeping sickness), 278-279,
278 f
American (Chagas’ disease), 279-280
drugs for, 1 28
Trypsin, 768
Trypsinogen, 770b
Tryptamines, misuse of, 143
Tryptase, 1360b
Tryptophan, 697b
Tube drainage, intercostal, 626-627
Tube feeding, nasogastric, 707, 707b
Tuberculin skin test, 594, 594f
Tuberculoma, 320-321
Tuberculosis (TB), 267, 430, 588-595,
1021
abdominal, 812-813
bone and joint disease in, 591
central nervous system disease in,
591
chronic pulmonary, complications of,
590b
control and prevention of, 594-595
cryptic, 589b
diagnosis of, 592b
epidemiology of, 588, 588f
gastrointestinal, 590, 591 f
genitourinary disease in, 591
granulomas in, 71
HIV-related
prevention of, 323
therapy for, 324, 324b
investigations of, 591-592, 592 f
lymphadenitis and, 590
management of, 592-594, 593b
miliary, 588-589
pathology and pathogenesis of, 588,
588 f
pericardial disease in, 590
pregnancy and, 1277
prognosis for, 595
pulmonary
clinical presentations of, 590b
major manifestations and differential
diagnosis of, 590f
post-primary, 589
primary, 588, 589b, 589f
risk of, factors increasing, 589b
Tuberculous granuloma, 588f
Tuberculous meningitis, 1 1 20-1 121 ,
1121b
HIV-related, 321
Tuberculous pericarditis, 543
Tuberous sclerosis, 1264
Tubular obstruction, drug-induced,
427b
Tubulo-interstitial diseases, 401-403
inherited, 404, 404b
Tularaemia, 261
Tumbu fly, African, 300
Tumour-induced osteomalacia, 1053
Tumour lysis syndrome, 369
cancer and, 1328
Tumour markers, 1322, 1324b
Tumour necrosis factor (TNF), 64-66
Tumour suppressor genes, 51
Tumours, 836-837
adrenal, management of, 669-670
bone, 1056-1057
metastatic, 1329
brain, 1129-1132, 1129b, 1 1 297
clinical features of, 1 1 29
investigations of, 1130, 1 1 30f
management of, 1130-1131
metastatic, 1328, 1328b
prognosis of, 1 1 31
of bronchus, 598-605
of gallbladder and bile duct,
907-908
benign, 908
gastroenteropancreatic neuro¬
endocrine, 678-679, 678 b, 679 f
gastrointestinal stromal cell, 805
head and neck, 1335-1336, 1335b
investigations of, 1 335
management of, 1 335-1 336
pathogenesis of, 1 335
immunology of, 90
of liver, 890-893
benign, 893
primary malignant, 890-892
secondary malignant, 892-893,
893 f
of lungs, 598-605
metastatic, 1328
primary, 599-603
secondary, 603
vascular, 619-622
of mediastinum, 603-605,
603b-604b, 604f
neuro-endocrine, 603b, 678-679,
678 b, 679 f, 813
of oesophagus, 796-797
benign, 796
of pancreas, 842-844
pituitary, 683-684, 1129
of rectum, 827-833
of respiratory system, 598-605
skin, 1229-1235
malignant, 1229-1234
pathogenesis of, 1 229
of small intestine, 813
of stomach, 803-805
of urinary tract, 434-436
urothelial, 435-436
Tunga penetrans, 299-300
Tungiasis, 299-300
Turbidimetry, 348b
Turcot’s syndrome, 829
Turner’s syndrome, 659-660, 660f
genetics of, 44b
Type A (‘augmented’) ADRs, 22
Type B (‘bizarre’) ADRs, 22
Type C (‘chronic/continuous’) ADRs, 22
Type D (‘delayed’) ADRs, 22
Type E (‘end-of-treatment’), 22
Typhoid fever, 260, 260b
Typhus fever
endemic, 271 , 271b
epidemic, 271 , 271b
scrub typhus, 270-271
Tyrosine, 635 f
Tyrosine kinase inhibitors, 959
in chronic myeloid leukaemia, 959b
TZD drugs see Thiazolidinediones
U
UDCA see Ursodeoxycholic acid
UIP see Usual interstitial pneumonia
UK Faculty of Public Health, 92
UK NHS Pregnancy and Newborn
Screening Programmes, 96f
UK Prospective Diabetes Study, 746
Ulceration
aphthous, 790, 790 b
of small intestine, 811, 811b
Ulcerative colitis
active left-sided or extensive, 820
cancer, 1320b
childhood, 823
clinical features of, 81 6, 81 7b
comparison with Crohn’s disease,
814b
complications, 818
differential diagnosis, 81 7b
histology of, 81 6 f
investigations, 818-820
management of, 820, 1 299-1 300
medical, 822 b
surgical, 823, 823b
pathophysiology of, 815-816
pregnancy, 823-824
primary sclerosing cholangitis and,
888
pseudopolyposis in, 81 5f
severe, 820
treatment of, medical, 820
Ulcers
amoebic, 287
Buruli, 254
Chiclero, 285
dendritic, 248
digital, 1038
foot, 761-762
genital
in men, 333-334, 334f
in women, 336
legs, 1223-1224
causes of, 1 223 b, 1 223 f
clinical assessment of, 1223-1224
due to arterial disease, 1 223-1 224
due to neuropathy, 1 224
due to vasculitis, 1 224
due to venous disease, 1223, 1223f
investigations in, 1224
management of, 1 224
leishmaniasis, 285f
leprosy, 268
Marjolin’s, 1021
mouth, 1036
neuropathic, 759 f, 1224
oesophageal, 794
oral, 1043-1044, 1043f
peptic
complications of, 801-802
indications for, 800b
in old age, 801b
perforation, 789, 801
prophylaxis for, in intensive care,
211
rodent, 1229
skin, definition, 1216
small intestine, 811, 811b
solitary rectal ulcer syndrome, 836
tropical, 254
Ulnar nerve
entrapment, 1002b
palsy, 760
Ultrafiltration, 349-350, 384
failure, 425b
Ultrasound
for ascites, 863
for cancer, 1 323
Doppler see Doppler ultrasound
echocardiography see
Echocardiography
endocrine disease
polycystic ovary, 659f
thyroid, 643
endoscopic, 774
for choledocholithiasis, 906f
for hepatobiliary disease, 855
of gastrointestinal tract, 774
oesophageal cancer, 797 f
pancreatitis, 839
for hepatobiliary disease, 853-854
gallstones and, 853-854, 854f
for hepatocellular carcinoma, 891
for musculoskeletal disease, 989
rheumatoid arthritis, 1025
synovitis, 989f
for nervous system, 1073b
for non-alcoholic fatty liver disease,
884
for portal hypertension, 869
renal, 389, 389 f
for renal artery stenosis, 407
for respiratory disease, 553
for splenomegaly, 927
for tachypnoea, 1 90, 1 91 f
of thyroid gland, 643
Ultraviolet radiation, 1229
photosensitivity, 1 220-1 223
psoriasis, 1250f
skin cancer, 1 320b
ultraviolet A, 1 227
ultraviolet B, 1227
Wood’s light, 1214
Under-nutrition, 704-711
causes of, 704b
classification of, 704b
clinical assessment for, 693
clinical features of, 704, 704b
in hospital, 705-708, 706 b
responses to, 694-695
Under water, 1 69-1 7 1
Undifferentiated autoimmune connective
tissue disease, 1 040
Unfractionated heparin (UFH), 938-939
Unilateral leg swelling, 186-187, 186b
clinical assessment of, 186-187
investigations of, 187, 187b-188b,
187 f
presentation of, 186, 187b
United Kingdom End-stage Liver
Disease (UKELD) score, for liver
transplantation, 900-901
Upper airway
defences, 550
disease of, 622-625
Upper respiratory tract infection,
581-587
Uracil, 39
Uraemia
haemolytic uraemic syndrome, 388
see also Renal failure
INDEX • 1415
Urate, reference range of
urine, 13616
venous blood, 13606
Urate-lowering drugs, indications for,
10156
Urea, 3496
acute kidney injury and, 4166
reference range of
urine, 13616
venous blood, 13586
Urea breath test, 7786
Ureidopenicillins, 121
Ureterocele, 434
Ureteropyelogram, retrograde, 436
Ureterovaginal fistula, 437
Ureters, 386
colic, 431-432
diseases of, 433-434
ectopic, 434
megaureter, 434
obstruction, 434
Urethral discharge, 333
Urethral syndrome, 427-428
Urethritis
chlamydial, 333
gonococcal, 333, 3337
non-specific, 333
subclinical, 3346
Urge incontinence, 436-437, 1093
in older people, 1309
Uric acid
crystals, 4316
in gout, 1013-1014
lowering, 1015
metabolism of, 1 01 3f
pool, 1 01 3f
reference values, urine, 13616
Uricosuric drugs, for gout, 1016
Urinalysis
acute kidney injury, 4126
reference range, 13616
Urinary diversion, 436
Urinary incontinence, 397, 436-437
older people, 4366, 1309-1310,
1310 7
Urinary tract, 383 7
calculi, 431
clinical examination of, 382-384,
3827-3837
collecting system
diseases of, 433-434
imaging, 3897
congenital abnormalities of, 433-434,
4347
stones, removal of, 4336, 4337
tumours of, 434-436
Urinary tract disease
investigation of, 386-391
presenting problems in, 391-397
Urinary tract infection, 426-431
antibiotic regimens for, 4296
clinical features, 427-428
investigation of, 4286
management, 428-429
in old age, 4286
pathophysiology, 427
persistent or recurrent, 429, 4296
prophylaxis, 4296
risk factors for, 4286
in stroke patients, 1 1 59 7
vesico-ureteric reflux, 4286
Urine
alkalinisation, 136
black, 947
investigation of, 387-388
microscopy, 387, 3887
retention
acute, 437-438
benign prostatic hyperplasia,
437-438
chronic, 438
volume, 391
see also Anuria; Oliguria
Urine output, decreased, 195
assessment of, 1 95
diagnosis and management of, 1 95
Urine testing
diabetes, 725
glycaemic control, 742
Urobilin, 851
Urobilinogen, 851
Urography, intravenous see Intravenous
urography
Urokinase, 1 31 9f
Urolithiasis, 431-433
Urology, 381-440
Urothelial tumours, 435-436
Ursodeoxycholic acid (UDCA)
gallstones, 9056
for primary biliary cholangitis, 888
Urticaria, 1252-1254
causes of, 1 2536
clinical features of, 1252-1253, 12537
drug-induced, 12666
investigations of, 1253-1254
management of, 1 254
papular, 292
pathogenesis of, 1 253 7
solar, 12216
Ustekinumab
for Crohn’s disease, 822
for inflammatory rheumatic disease,
1007, 10076
for psoriatic arthritis, 1 033-1 034
Usual interstitial pneumonia, 6087
Uterine tumours, 1 31 6f
UTI see Urinary tract infection
Uveal tract, of eye, 1 1 67
Uveitis, 1031, 1172-1173
acute anterior, ankylosing spondylitis,
1030
aetiology of, 11726
brucellosis, 255 7
HTLV-1 , 250
immune recovery, 321
treatment, 258-259
Weil’s disease, 258
UVR see Ultraviolet radiation
V
Vaccines/vaccination, 1 1 4-1 15, 1156
anthrax, 1 1 56
BCG, 595
chickenpox, 239
cholera, 1156
diphtheria, 266
guidelines for, 1156
Haemophilus influenzae type B, 1156
for hepatitis B, 8766
HIV, 327
for human papillomavirus, 343
influenza, 241
Japanese B encephalitis, 250
leprosy, 270
malaria, 277
meningococcal infection, 1120
MMR, 240
mumps, 240
plague, 259
pneumococcal pneumonia, 266
for poliomyelitis, 1123
primary antibody deficiencies and, 79
for rabies, 1 1 22
rotavirus, 249
rubella, 236-237
tetanus, 1126
tick-borne encephalitis, 2306
for tuberculosis, 595
types of, 114-115
typhoid, 261
use of, 115, 1156
varicella zoster virus (VZV), 1156,
239, 2406
whooping cough, 1156
yellow fever, 245
see also Immunisation
Vaccinia virus, 249
Vacuolating cytotoxin (vacA), 798 f
VAD see Ventricular assist devices
Vagina, discharge, 335, 3356, 3357
Vaginosis, bacterial, 335, 3356, 3357
Vagotomy, complication of, in peptic
ulcer, 801
Vagus (1 0th cranial) nerve, tests of,
10636
Valaciclovir
as anti-herpesvirus agent, 126, 1276
for herpes virus infection, genital, 342
Valganciclovir
for CMV infection, 224
herpesvirus infection, 1276
Valine, 6976
Valproate see Sodium valproate
Valsartan
heart failure, 4666
hypertension, 513
myocardial infarction, 500-501
Valves of Heister, 850
Valvular heart disease
causes of, 5156
infective endocarditis, 527-531
prevention, 531
pregnancy and, 1282
rheumatic, 515-517
risks of non-cardiac surgery, 5016,
502
valve replacement, 526-527
Valvuloplasty
aortic, 524
mitral, 519
Van Buchem’s disease, 1 056
Vancomycin, 1176, 123
acute leukaemia, 957
adverse effects, 1 23
Clostridium difficile infection, 264
drug eruptions, 1 2666
for infective endocarditis, 223
meningitis, 11206
pharmacokinetics, 123
respiratory disease, 586
for septic arthritis, 1 020
therapeutic monitoring, 366
toxic shock syndrome, 252
Vancomycin-resistant Staphylococcus
aureus (VRSA), 252
Vandetanib, for medullary carcinoma,
650
Vanishing bile duct syndrome, 889, 902
Variant Creutzfeldt-Jakob disease
(vCJD), 933, 1127, 1 1 277
Variceal band ligation, 8696
Variceal bleeding, 865-866, 8657
cirrhosis, 866-867
management of, 869-871, 8696,
870f-871 f
portal hypertension and, 869
prevention of
primary, 869
secondary, 871
Variceal ligation, 775 f
for variceal bleeding, 870
Varicella, pneumonia, 5826
Varicella zoster virus (VZV), 2386
after HSCT, 9376
HIV infection, 321
immunisation, 1156, 2406
infection from, pregnancy and, 1277
management and prevention of, 239,
2396
in pneumonia, 5826
in pregnancy, 2356, 1277
stem cell transplantation, 9376
Varicella zoster virus immunoglobulin
(VZIG), 239, 2406
Varices
gastric, 865-866, 865 f
oesophageal, 865-866, 8657
rectal, portal hypertension and, 868
Varicose veins, 1 223
Variegate porphyria, 3796
Variola, 248
Vascular dementia, 1 1916
Vascular disease
atherosclerotic see Atherosclerosis
diabetes, 5036, 756
diffuse, 1191
liver, 898-899
peripheral, 502-505
pulmonary, 619-622
pulmonary embolism, 619-621
pulmonary hypertension, 621-622,
6216, 6227
renal, 406-409
Vascular endothelial growth factor, 1318
Vascular imaging, 1151, 11527, 1158
Vascular malformations, jejunal bleeding,
7757
Vascular resistance
portal hypertension, 869
pulmonary, 461 , 467, 5327
systemic, 447
Vasculitides, 611-612
Vasculitis, 1040-1044, 10407, 1261
antineutrophil cytoplasmic antibody,
1041, 10417
cerebral, 10936, 1108
cryoglobulinaemic, 1043
cutaneous, 5816
drug-induced, 12666
leg ulcers due to, 1224
renal artery stenosis, 407
in rheumatoid arthritis, 1024
small-vessel, 409
systemic, 410, 10416, 10427
urticarial, 12536
Vaso-occlusive crisis, 952
Vasoactive agents, actions of, 2066
Vasoactive intestinal peptide (VIP),
7726
Vasodilatation, 2066
splanchnic, for ascites, 862-863
Vasodilators
angina, 487
for heart failure, 467
for hypertension, 513
myocardial infarction, 1996
valvular heart disease, 521
Vasomotor rhinitis, 622
Vasopressin
for refractory hypotension, 198
see also Antidiuretic hormone
Vasopressin receptor agonist
desmopressin, in haemophilia A,
973
Vasopressinase, pregnancy and, 1280
Vasopressors, 206
for variceal bleeding, 8696
VDRL see Venereal Diseases Research
Laboratory (VDRL) test
VDRR see Vitamin D-resistant rickets
Vedolizumab, for inflammatory bowel
disease, 8216
Vegan, 697
vitamin B12 deficiency, 944
Velocardiofacial syndrome, 446
Venae cavae, 444, 4447
see also Inferior vena cava; Superior
vena cava
Venereal Diseases Research Laboratory
(VDRL) test, 338-339
Venesection
haemochromatosis, 895-896
for polycythaemia rubra vera, 970
Venlafaxine, 11996
Veno-occlusive disease, 899
Venography
cerebral, 1162
hepatic portal, 854, 899
venous thrombosis, 1162
Venom, 154, 1546
of animals, 1 566-1 586
clinical effects of, 155-156
insect, allergy to, 85
local effects of, 155, 1556
scorpions, 1566-1576
snakes, 1546, 1566-1576
spiders, 1576
Venomous animals, 154-155
Venomous hymenopterans,
envenomation of, 161-162
Venomous insects, envenomation of,
161-162
Venomous lepidopterans, envenomation
of, 161
Venomous snakes
envenomation of, 160-161
geographical distribution of, 1 53,
1537
Venous disease
cerebral, 1162
causes of, 1 1 626
clinical features of, 1162, 11626
investigations and management of,
1162
leg ulcers due to, 1223, 12237
Venous hypertension, 1223
1416 • INDEX
Venous pulse
distinguishing arterial and, 443d
jugular, 443d
Venous thromboembolism/thrombosis,
169, 975-977
air travellers, 1 69
causes and consequences of, 975,
976 f
clinical features, 619, 61 9d
factors predisposing to, 975d
at high altitude, 1 69
investigations of, 619-620, 619f-620f
management of, 975-976
anticoagulants, 621
caval filters, 621
thrombolytic therapy, 621
pregnancy and, 620d, 1285
prognosis, 621
prophylaxis of, 976-977, 977b
retinal vein, 509 f
stroke, 11517
Wells score, 187d
Ventilation
airway pressure release, 204
continuous positive pressure, 202
intermittent positive pressure,
203-204
mechanical
ARDS, 198
asthma, 573d
COPD, 578
critically ill patients, 202
envenomation, 160
setting, 203, 203 f
non-invasive, 202, 578
‘open lung’, 204
pressure support, progressive
reduction in, 210
respiratory failure, 567
in respiratory system, 549-550
Ventilation-perfusion matching, 549-550
hypoxaemia and, 192
in old age, 550d
Ventricles, of heart, 449f
Ventricular aneurysm, in acute coronary
syndrome, 496, 496f
Ventricular assist devices, 468
Ventricular contractility, reduced, 462d
Ventricular ectopic beats, 474, 475f
Ventricular fibrillation, 456f
cardiac arrest, 456
myocardial infarction, 495
Ventricular inflow obstruction, 462d
Ventricular outflow obstruction, 462d
Ventricular premature beats, 474-475,
475 f
Ventricular remodelling, in acute
coronary syndrome, 496, 496f
Ventricular rupture, in acute coronary
syndrome, 496
Ventricular septal defect, 535-536, 536 f
heart murmur, 460d
incidence, 531 d
tetralogy of Fallot, 536-537
Ventricular septum rupture, in acute
coronary syndrome, 496
Ventricular tachyarrhythmias, 480d, 483
Ventricular tachycardia, 475-476, 475d,
475f-476f
poisoning, 137d
pulseless, 457
Ventricular volume overload, 462d
Ventriculitis, 1122
Ventriculography, left, 453-454
Verapamil
angina, 490-491, 491d, 500
aortic dissection, 508
arrhythmias, 471-472, 480d, 481
for cluster headache, 1 096
hypertension, 513
tachyarrhythmias
atrial fibrillation, 471-472
atrial flutter, 470
Verocytotoxigenic Escherichia coli, 263,
263 f
Verotoxin, 408-409
Verrucae, 1238
Verruga peruana, 272, 272d
Vertebral fracture, 995d
Vertebroplasty, 1002b
for osteoporosis, 1 049
Vertical gaze palsy, 1072b
Vertigo, 1086
benign paroxysmal positional, 1104,
11047
in older people, 1309
Very low-density lipoproteins, 371-372
Vesicle, definition of, 121 If
Vesico-ureteric reflux, 430-431, 431 f
Vesicovaginal fistula, 437
Vessel wall abnormalities, 970
Vestibular disorders, 1 1 04-1105
Vestibular failure, acute, 1104
Vestibular neuronitis, 780 f, 1104
Vestibulitis, 336b
Vestibulocochlear (8th cranial) nerve,
tests of, 1 063d
Vibration-controlled transient
elastography (Fibroscan), 855
Vibrio cholerae, 104b, 264-265
Vibrio parahaemolyticus, 265
Vibrio vulnificus, 227
Vildagliptin, 747
Villous atrophy, 806
Vinblastine, Flodgkin lymphoma, 963
Vinca alkaloids, 936b
Vincristine
bronchial carcinoma, 602
leukaemia, 957b
non-Flodgkin lymphoma, 966
polyneuropathy, 1139b
VIP see Vasoactive intestinal peptide
VIPoma, 678 b
Viral arthritis, 1020-1021
Viral encephalitis, 1121-1123
Viral haemorrhagic fevers, 231 f,
245-247, 245b
Viral hepatitis, 871-878
acute
clinical features of, 871-872
complications of, 872 b
causes of, 87 1 b
chronic, HIV-related, 317-318
features of, 872 b
icteric, 878
immunisation, 876 b
investigations for, 872
management of, 872
non-A, non-B, 877
non-A, non-B, non-C (NANBNC), 878
pregnancy and, 1284
sexual, 343-344
transmission, 873 b
blood donation, 930-931
sexual, 343-344
treatment, 126-127, 127b
see also under individual hepatitis
viruses
Viral infections, 236-250
antiviral agents, 1 26-1 28, 1 27 b,
1238
arthritis, 1020-1021
cancer and, 1320b
diabetes type 1 , 729
gastrointestinal, 249
haemorrhagic fevers, 245-247, 245b
immune deficiencies and, 73 b
nervous system
encephalitis, 1121-1123
meningitis, 1118
with neurological involvement,
249-250
respiratory tract, 249
pneumonia, 241 , 605 b
upper, 581-587
with rheumatological involvement, 250
sexually transmitted, 341-344
of skin, 247-249, 1238-1239
HIV/AIDS, 1238-1239
systemic
with exanthem, 236-240
without exanthem, 240-247
TSEs, 250, 1126-1127
see also specific infections/infectious
diseases
Viral load
hepatitis B, 875, 875 f
HIV, 875
Viral meningitis, 1118
Viral warts, 1238-1239, 1239f
Virchow’s gland, 764f
Virilisation, 657, 1242
Virions, HIV, 309-310
Virology
of hepatitis C, 877
skin, 1215
Viruses, 100
bioterrorism, 1 1 1
incubation period, 232b
life cycle, 1 01 f
oncogenic HPV, 343
Visceral leishmaniasis, 282-284, 282 f
clinical features of, 282
differential diagnosis of, 283
HIV co-infection, 283-284
investigations of, 282-283, 282 f
management of, 283
Vision, 1069, 1 070f
double (diplopia), 1088-1090, 1090f
loss
diabetes, 757
leprosy, 268
older people, 1302f
Vision distortion, of ophthalmic disease,
1171
Visual analogue scale, 1 343b
Visual deficit, 1152
Visual disorders, 1088-1093
antineutrophil cytoplasmic
antibody-associated vasculitis,
1041 f
giant cell arteritis, 1 042
Graves’ disease, 631b, 645-646,
645f
investigation of, 1 1 68-1 1 69
electrophysiology, 1 1 69
imaging, 1168-1169
perimetry, 1 1 68
positive visual phenomena, 1 088
pregnancy and, 1175b
stroke, 1152
Visual disturbance, 1 088-1 093
Visual electrophysiology, 1 1 69
Visual evoked potential (VEP) recording,
1077 f
Visual fields
confrontation for, 631b
loss, 1089b
Visual Infusion Phlebitis (VIP) score,
251b
Visual loss, 1088
Visual pathways, 1 069, 1 069f
Visual phenomena, 1088
Visuo-spatial dysfunction, 1152
Vital capacity (VC), 554f
forced, 550 b, 554f, 555
Vitamin A (retinol), 712-713
biochemical assessment of, 712b
deficiency, 713, 71 3f
dietary sources of, 711b
excess, 713
reference nutrient intake of, 711b
supplements, 713
toxicity, 713
Vitamin B1 see Thiamin
Vitamin B2 see Riboflavin
Vitamin B3 see Niacin
Vitamin B6 see Pyridoxine
Vitamin B1Z, 715, 943-944
absorption, 943-944
biochemical assessment of, 712 b
deficiency, 943, 1 1 38b
causes of, 944
management of, 945
neurological consequences of, 715,
944b, 1139b
neurological findings in, 944b
older people, 712b
pregnancy, 941b
small bowel disease, 944
dietary sources of, 711b
reference nutrient intake of, 711b
reference range of, 1 362b
Vitamin C (ascorbic acid), 715-716
biochemical assessment of, 712b
deficiency, 715-716, 716b, 716 f,
970
dietary sources of, 711b
reference nutrient intake of, 711b
Vitamin D, 713
biochemical assessment of, 712b
concentrations, seasonal changes in,
1050f
deficiency, 713, 1049-1051
older people, 712b, 1049-1051
reference range of, venous blood,
1360b
rickets/osteomalacia management,
1052
dietary sources of, 711b
excess, 713
metabolism of, 1 051 f
for osteoporosis, 1048, 1048b
reference nutrient intake of, 711b
reference range of, venous blood,
1360b
Vitamin D analogues,
hypoparathyroidism, 665
Vitamin D and calcium supplements,
osteoporosis prophylaxis, 1 049b
Vitamin D-deficient osteomalacia,
biochemical abnormalities in,
990 b
Vitamin D-resistant rickets (VDRR),
1052
Vitamin E, 713-714
biochemical assessment of, 712b
deficiency, 714
dietary sources of, 711b
for non-alcoholic fatty liver, 885
reference nutrient intake of, 711b
Vitamin K, 714
antagonists, 938b
anticoagulant poisoning, 714
biochemical assessment of, 712b
blood coagulation, 714
deficiency, 714
dietary sources of, 711b
reference nutrient intake of, 711b
supplements, epilepsy in pregnancy,
1103b
Vitamins, 711-716, 711b
absorption of, 769
biochemical assessment of, 712b
deficiency, 712
in old age, 712b
dietary sources, 711b
excess, 712
fat-soluble, 711b, 712-714
malabsorption of, gastrointestinal
disorders associated with, 712b
reference nutrient intake, 711b
storage of, liver and, 851
water-soluble, 711b, 714-716
see also specific vitamins
Vitiligo, 1257-1258, 1257 f, 1326
Vitrectomy, 1 1 74
Vitreous gel, in eye, 1 1 68
VLDL see Very low-density lipoproteins
Voiding see Micturition
Volatile substance, poisoning from, 144
Volume of distribution (Vd), 18, 18f
Vomiting, 227-230, 780
causes of, 777 b, 780 f
cyclical vomiting syndrome, 803
functional causes of, 803
palliative care, 1353-1354, 1353f
peptic ulcer, 801-802
psychogenic, 803
Von Gierke disease, 370 b
von Hippel-Lindau disease, 1132,
1321b
von Willebrand disease (vWD), 974,
974b
von Willebrand factor, 974
Voriconazole, 125b, 126
acute leukemia and, 957
aspergillosis, 598
candidiasis, 302
fusariosis, 302-303
mycetoma, 301
paracoccidioidomycosis, 304
VT see Ventricular tachycardia
Vulva
chronic pain of, 336, 336b
herpetic ulceration of, 342f
INDEX • 1417
pruritus, 336, 336 5
schistosomal papilloma, 295-296
Vulvodynia, 3365
VUR see Vesico-ureteric reflux
W
Waddling gait, 10635
Waist circumference, 6935
Waldenstrom macroglobulinaemia, 966
Wallenberg syndrome, 10725
Warfarin, 939
adverse reactions of, 225
for antiphospholipid syndrome, 978
for atrial fibrillation, 472
bleeding in, 940
drug interaction of, 245
indications for, 9385
monitoring, 922
for older people, 325, 4725
pharmacodynamic, 245
pharmacokinetic, 245
poisoning, 1485
in pregnancy, 6205, 1282
problems with, 939
pulmonary embolism, 6205
for stroke prevention, 11617
for systemic lupus erythematosus,
1037
venous thromboembolism, 6205
Warfarin-like rodenticides, 1485
Warm antibodies, 949
Warm autoimmune haemolysis, 949
Warts
anogenital, 342-343
seborrhoeic, 1234
viral, 1238-1239, 1239f
Water
absorption and secretion of, 769,
769 f
basic daily requirements of, 3535
depletion, 353
see also Dehydration
distribution of, 349, 349f
excess, 3545
homeostasis, 349, 355-360
inhalation, 169-170
investigations, 357-358
presenting problems in, 352-355
reabsorption, 350
renal handling, 356 f
restriction of, for ascites, 863
safe, for HIV-related exposure, 323
total body (TBW), 349
Water deprivation test, for diabetes
insipidus, 6885
‘Waterbrash’, 791-792
Waterhouse-Friderichsen syndrome,
6715
Watermelon stomach, 1037-1038
Watery/dry eye, of ophthalmic disease,
1170
Wax baths, 1001
Weakness, 1081-1083, 10825, 1082/
facial, 1082-1083
ICU-acquired, 211-212
muscle, 1000, 10005
stroke and, 1152
Weal, definition of, 1252-1253
Weaning, from respiratory support,
209-210
Weber syndrome, 1072, 10725
Wegener’s granulomatosis, 1171
Weight, and endocrine disease, 630/
Weight control, for musculoskeletal
disease, 1001-1002
osteoarthritis, 1012
Weight gain
history of, 700
reversible causes of, 700, 7005
see also Obesity
Weight loss, 785-786
after gastric resection, 801
anorexia nervosa and, 1203
cancer patients, 1 323
causes of, 786 f
diabetes and, 729-730, 732
diets, 701-702, 7015
HIV-related, 313, 3137
investigations, 786
musculoskeletal disease, 1001-1002
obesity, 701
in palliative care, 1354
pancreatitis and, 840
physiological causes of, 785
rheumatoid arthritis, 1 023
Weight management, for diabetes,
744
Weil-Felix test, 1 08
Weil’s disease, 258
Wells score, 1 875
Wenckebach phenomenon, 477f
Werner’s syndrome, 41 , 6895
Wernicke-Korsakoff syndrome, 1 1 95
prevention of, 1 1 95
Wernicke’s aphasia, 1 088f
Wernicke’s area, 1066
Wernicke’s encephalopathy, 714
West Nile encephalitis, 250,
1121-1122
West Nile virus, 250
Western blot, 107
WG see Wegener’s granulomatosis
Wheezing, asthma, 568
Whipple’s disease, 809, 8095
Whipple’s operation, under-nutrition
and, 706
Whipple’s triad, 676-677, 677 f
Whipworm (Trichuris trichiura), 290
White blood cells, 917
appearance of, 926f
count
acute fever without localising signs,
2325
differential, 13625
high, 926-927
low, 925-926
viral hepatitis and, 872
formation, 917
polymorphonuclear see Neutrophils
reference values, 13625
results of, interpreting, 9265
White eye, 1 1 70
White spirit, poisoning, 1485
Whiteheads, 1242
Whitlow, herpetic, 247f
WHO see World Health Organization
Whole bowel irrigation, 136
Whole-exome sequencing, 545
Whole-genome sequencing, 545
Whooping cough, 582
antimicrobial prophylaxis, 1195
immunisation, 1155
incubation period, 1115
periods of infectivity, 1115
Wickham’s striae, 1252
Williams’ syndrome, 445
Wills, living, 1307
Wilm’s tumour, 13215
Wilson’s disease, 718, 896-897
investigations, 897
Kayser-fleischer rings and, 896-897
liver disease and, 896
liver function test (LFT) abnormality in,
8545
neurological aspects of, 1115
Windkessel effect, 447
Winterbottom’s sign, 279
Withdrawal effects, 16, 165
Wnt, in bone remodelling, 9865
Wolbachia spp., 291
Wolff-Parkinson-White (WPW)
syndrome, 473-474, 474/
Wood’s light, 1214
World Health Organization (WHO)
analgesic ladder, 1350, 1 351 f
classification of psychiatric disorders,
1180, 11805
ICD-10, 1180
macronutrient recommendations,
6985
refeeding diet, 7055
Wound dressing, 1226-1227, 12275
Wound infections
staphylococcal, 251, 251 f
tetanus, 1126
WPW syndrome see Wolff-Parkinson-
White (WPW) syndrome
Wrist
fracture, 1045/
pain, 998
Writer’s cramp, 1086
Wuchereria bancrofti infection, 2335,
290, 291 f
X
X chromosome, 38
abnormalities see individual conditions
inactivation, 48-49
see also X-linked
X-linked agammaglobulinaemia, 78
X-linked hypophosphataemic rickets
(XLH), 1052
X-linked inheritance, 475, 48-49
X-rays, 164, 164f
for acute respiratory distress
syndrome, 198, 199f
for ankylosing spondylitis, 1 030f
of body packers, 144/
cardiovascular system see Chest
radiography/X-ray
for Charcot foot, 759 f
chest see Chest radiography/X-ray
for chest pain, 178
for gastrointestinal disease, 772,
7735, 773 f
achalasia, 795 f
contrast studies, 773
inflammatory bowel disease, 818 f,
819-820
hepatobiliary disease, 1 64
hyperparathyroidism, 663
for musculoskeletal disease, 988,
9885
bone fractures, 994-995, 1045/
bony metastases, 662
Charcot joint, 1058 f
chondrocalcinosis, 1 01 6f
complex regional pain syndrome
(CRPS) type 1, 1055f
CPPD crystal deposition disease,
1017
fracture, 994-995
osteoarthritis, 1 009/-1 01 1 f
osteomalacia, 1052, 1052f
osteonecrosis, 1055
osteoporosis, 1045f
osteosarcoma, 1 056-1 057
Paget’s disease, 1 054f
reactive arthritis, 1 032
rheumatoid arthritis, 1025
supraspinatus tendon calcification,
1017 f
of nervous system, 10735
properties of, 1 64f
respiratory system see Chest
radiography/X-ray
of skull, 1073
of spine, 1075f
Xa inhibitors, 472-473
Xanthelasma
cholestatic jaundice and, 8615
hyperlipidaemia and, 346f
Xanthomas, 1264
biliary cholangitis, 887
cholestatic jaundice and, 8615
hyperlipidaemia and, 346 f
tendon, 375
Xanthomatosis, cerebrotendinous, 3755
Xeroderma pigmentosum, 12215,
13215
Xerophthalmia, 713
Xerostomia, 1038
XLH see X-linked hypophosphataemic
rickets
Y
Y chromosome, 38
microdeletions of, 656
Yaws, 253-254, 2545
Yellow Card scheme, 23
Yellow fever, 243 f, 244-245, 2455
incubation period of, 2455
vaccination, 245
Yersinia enterocolitica, 264
in Graves’ thyrotoxicosis, 644
Yersinia pestis, 259
Young adults, diabetes mellitus in,
753-754
Young’s syndrome, 550
Z
Zanamivir, 127, 1275, 241
Zero-order kinetics, 1 9
Zidovudine (ZVD), 3245
adverse reactions of
anaemia, 322
lipodystrophy, 326f
neutropenia, 322, 9265
for HIV/AIDS, 324-325, 3245
muscle pain/weakness from, 10005
for onychomycosis, 316
Zika virus infection, 247
in pregnancy, 2355
Zinc, 717
deficiency, 717
dietary sources of, 7175
refeeding diet, 7055
reference nutrient intake of, 7175
reference range of
urine, 13615
venous blood, 13605
supplements, 717
for Wilson’s disease, 897
Zinc phosphide poisoning, 148
Zinc therapy, for Wilson’s disease, 897
Zoledronic acid
bone metastases, 1329
for osteoporosis, 1 0485
for Paget’s disease, 1 054, 1 0545
Zollinger-Ellison syndrome, 802
Zoonoses
transmission of, 110
viral haemorrhagic fevers, 245-246
Zoster sine herpete, 239
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